Total synthesis and revision of stereochemistry of the marine metabolite trunkamide A

Article abstract of DOI:10.1021/jo9914566

The isolation of the cytotoxic Lissoclinum sp. metabolite trunkamide A was reported in 1996. After completion of a total synthesis in 1999, it became clear that the structure of this marine natural product had to be revised. We now report the first preparation of actual trunkamide A in a total synthesis that serves as an unambiguous structural and stereochemical proof. Highlights of our synthetic strategy are a Lewis acid assisted aziridine opening that was used for the preparation of the novel reverse- prenylated serine and threonine side chains as well as an efficient oxazoline-thiazoline interconversion on the macrocyclic skeleton. In addition, several stereoisomers prepared by complementary synthetic protocols serve to illustrate the general scope of our methodology and confirm the configurational assignment.

Full text of DOI:10.1021/jo9914566

J . Org. Chem. 2000, 65, 1037-1049
1037
Tota l Syn th esis a n d Revision of Ster eoch em istr y of th e Ma r in e
Meta bolite Tr u n k a m id e A
Peter Wipf* and Yoshikazu Uto
Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260
Received September 14, 1999
The isolation of the cytotoxic Lissoclinum sp. metabolite trunkamide A was reported in 1996. After
completion of a total synthesis in 1999, it became clear that the structure of this marine natural
product had to be revised. We now report the first preparation of actual trunkamide A in a total
synthesis that serves as an unambiguous structural and stereochemical proof. Highlights of our
synthetic strategy are a Lewis acid assisted aziridine opening that was used for the preparation of
the novel reverse-prenylated serine and threonine side chains as well as an efficient oxazoline-
thiazoline interconversion on the macrocyclic skeleton. In addition, several stereoisomers prepared
by complementary synthetic protocols serve to illustrate the general scope of our methodology and
confirm the configurational assignment.
Among the azole-containing cyclopeptide alkaloids
found in marine organisms,1 in particular ascidians from
the genus Lissoclinum,2 patellin 1 (1),3 patellin 2 (2),3,4
patellin 3 (3),3 patellin 4 (4),3 patellin 5 (5),3 patellin 6
(6),3 and mollamide (7),5 as well as comoramides A (8)6
and B (9),6 are structurally uniquely characterized by the
presence of a single thiazoline heterocycle in the peptide
backbone as well as threonine and serine residues whose
side chains have been modified as dimethylallyl (reverse
prenylated) ethers (Figure 1).7 While all of these mod-
erately cytotoxic natural products have been isolated
from ascidians, albeit from many different geographic
locations, it is quite likely that they are actually produced
by symbiotic prochlorophytes, prokaryotic algal sym-
bionts such as Prochloron sp., that are associated with
most Lissoclinum and Didemnum ascidians.6,8 In support
of this hypothesis, the structurally closely related keena-
mide A (10) has been isolated from the marine mollusk
Pleurobranchus forskalii.9
Recent synthetic activity toward other azole-containing
cyclopeptide alkaloids has been intense,,2,11,12 but no
synthesis of a reverse-prenylated member of this class
has yet been reported.13 As part of our program toward
the total synthesis,14 stereochemical and conformational
analysis,15 and bioinorganic chemistry16 of these struc-
turally unique marine metabolites, we were interested
in a synthetic approach toward trunkamide A. Total
synthesis of trunkamide A represents the only realistic
supply of natural product necessary for further biological
evaluation,17 and allows the preparation of analogues for
SAR studies.15
Our retrosynthetic analysis of trunkamide A is shown
in Scheme 1. A key feature of our approach was the use
of oxazoline 12 as a precursor to the thiazoline ring in
trunkamide A.18 We have previously demonstrated the
advantages of using oxazolines as masked thiazolines,14a
i.e., a much lower risk of racemization at chiral centers
attached to the heterocycle as well as a simplified
protective group scheme since thiol-containing building
blocks are avoided.19 Disconnection of the macrocycle at
the L-alanine/L-isoleucine amide bond leads to the N-
Fmoc-protected heptapeptide derivative 13. While other
disconnections (e.g., at the proline/phenylalanine amide
The cycloheptapeptide alkaloid trunkamide A (11)3 was
isolated in 1996 from a small green and colorless colonial
ascidian, Lissoclinum sp., collected at the Great Barrier
Reef, Australia, and its structure was reported as shown
in Figure 2. While details of trunkamide A’s biological
effects are not available, this compound appears to have
quite promising antitumor activity.10
(11) For recent total syntheses, see: (a) Downing, S. V.; Aguilar,
E.; Meyers, A. I. J . Org. Chem. 1999, 64, 826. (b) Freeman, D. J .;
Pattenden, G. Tetrahedron Lett. 1998, 39, 3251. (c) Norley, M. C.;
Pattenden, G. Tetrahedron Lett. 1998, 39, 3087. (d) Moody, C. J .;
Bagley, M. C. J . Chem. Soc., Perkin Trans. 1 1998, 601. (e) Kigoshi,
H.; Yamada, S. Tetrahedron 1999, 55, 12301.
(1) Faulkner, D. J . Nat. Prod. Rep. 1999, 16, 155.
(2) (a) Wipf, P. In Alkaloids: Chemical and biological perspectives;
Pelletier, S. W., Ed.; Pergamon: New York, 1998; pp 187-228. (b)
Davidson, B. S. Chem. Rev. 1993, 93, 1771.
(12) Wipf, P. Chem. Rev. 1995, 95, 2115.
(3) Carroll, A. R.; Coll, J . C.; Bourne, D. J .; MacLeod, J . K.; Zabriskie,
T. M.; Ireland, C. M.; Bowden, B. F. Aust. J . Chem. 1996, 49, 659.
(4) Zabriskie, T. M.; Foster, M. P.; Stout, T. J .; Clardy, J .; Ireland,
C. M. J . Am. Chem. Soc. 1990, 112, 8080.
(5) . Carroll, A. R.; Bowden, B. F.; Coll, J . C.; Hockless, D. C. R.;
Skelton, B. W.; Colorless, A. H. Aust. J . Chem. 1994, 47, 61.
(6) Rudi, A.; Aknin, M.; Gaydou, E. M.; Kashman, Y. Tetrahedron
1998, 54, 13203.
(13) For a preliminary account of our work, see: Wipf, P.; Uto, Y.
Tetrahedron Lett. 1999, 40, 5165. Note added in proof: For a synthesis
of mollamide, see: McKeever, B.; Pattenden, G. Tetrahedron Lett. 1999,
40, 9317.
(14) (a) Wipf, P.; Fritch, P. C. J . Am. Chem. Soc. 1996, 118, 12358.
(b) Wipf, P.; Miller, C. P. J . Am. Chem. Soc. 1992, 114, 10975.
(15) Wipf, P.; Fritch, P. C.; Geib, S. J .; Sefler, A. M. J . Am. Chem.
Soc. 1998, 120, 4105.
(7) For other reverse-prenylated peptide derivatives from the marine
environment, see: (a) Nagatsu, A.; Kajitani, H.; Sakakibara, J .
Tetrahedron Lett. 1995, 36, 4097. (b) Carroll, A. R.; Feng, Y.; Bowden,
B. F.; Coll, J . C. J . Org. Chem. 1996, 61, 4059.
(8) Prinsep, M. R.; Moore, R. E.; Levine, I. A.; Patterson, G. M. L.
J . Nat. Prod. 1992, 55, 140.
(9) Wesson, K. J .; Hamann, M. T. J . Nat. Prod. 1996, 59, 629.
(10) Bowden, B. F.; Garcia, G. D. WO9739025A1, Oct. 23, 1997;
Chem. Abstr. 1997, 127, 290919m.
(16) Wipf, P.; Venkatraman, S.; Miller, C. P.; Geib, S. J . Angew.
Chem., Int. Ed. Engl. 1994, 33, 1516.
(17) The yield of isolated trunkamide A from freeze-dried ascidian
is 0.016%, and samples of Lissoclinum sp. have to be collected using
SCUBA.3
(18) Wipf, P.; Miller, C. P.; Venkatraman, S.; Fritch, P. C. Tetra-
hedron Lett. 1995, 36, 6395.
(19) (a) Wipf, P.; Fritch, P. C. Tetrahedron Lett. 1994, 35, 5397. (b)
Wipf, P.; Venkatraman, S. Synlett 1997, 1.
10.1021/jo9914566 CCC: $19.00 © 2000 American Chemical Society
Published on Web 12/31/1999

1038 J . Org. Chem., Vol. 65, No. 4, 2000
Wipf and Uto
Sch em e 1
15 containing the novel reverse-prenylated threonine and
serine side chains. Simple O-allylation of serine and
threonine is straightforward;20 however, a direct install-
ment of the reverse prenyl ether moiety onto these amino
acids was low-yielding under basic and acidic protocols
due to the ease of â-elimination to the dehydroamino
acids and regioisomeric ether formation. Therefore, we
employed a Lewis-acid assisted ring-opening of activated
aziridine derivatives 16 and 17,21 which were obtained
in 52-61% overall yield according to literature proto-
cols.22 The modular approach of this retrosynthetic
strategy, as well as the use of the oxazoline intermediate,
allowed a ready access to stereoisomers and analogues
of trunkamide A. In particular, the ability to prepare a
series of stereoisomeric sequences would become a crucial
advantage at a later stage in this work.
F igu r e 1. Structures of reverse-prenylated cyclopeptide
alkaloids.
Resu lts a n d Discu ssion
Esterification of L-serine, N-tritylation, mesylation of
the side chain hydroxy group, intramolecular displace-
ment of the mesylate to give the aziridine, and N-
deprotection followed by carbamoylation with Cbz-Cl
provided a convenient route for the synthesis of aziridine
F igu r e 2. Structure originally assigned to the reverse-
prenylated cyclopeptide alkaloid trunkamide A.
(20) Stanley, M. S. J . Org. Chem. 1992, 57, 6421.
(21) (a) Nakajima, K.; Neya, M.; Yamada, S.; Okawa, K. Bull. Chem.
Soc. J pn. 1982, 55, 3049. (b) Wipf, P.; Venkatraman, S.; Miller, C. P.
Tetrahedron Lett. 1995, 36, 3639.
(22) (a) Tanaka, T.; Nakajima, K.; Okawa, K. Bull. Chem. Soc. J pn.
1980, 53, 1352. (b) Larsson, U.; Carlson, R. Acta Chem. Scand. 1994,
48, 511.
bond) and protective group strategies were explored as
well, we were unable to identify a viable alternative. To
ensure a highly convergent approach to the natural
product target, a tetrapeptide sequence 14 of all standard
amino acid residues was to be combined with a tripeptide

Synthesis and Stereochemistry of Trunkamide A
J . Org. Chem., Vol. 65, No. 4, 2000 1039
Sch em e 2
Sch em e 4
Sch em e 3
Sch em e 5
16 (Scheme 2).22 In analogous sequence, L-threonine was
converted to the corresponding aziridine 17 in 61% yield.
Treatment of 16 and 17 with an excess of 1,1-dimethyl-
allyl alcohol (21) in the presence of 2 equiv of BF3‚OEt2
opened the aziridine ring selectively to give the desired
ethers 18 and 19 in 72% and 88% yield, respectively.
Chemoselective deprotection of the Cbz group in the
presence of the alkene was readily accomplished by
exposure of 18 to Et3SiH and catalytic Pd(OAc)2 in 97%
yield.23
The diastereomeric purity of 19 was ascertained by
cleavage of the reverse prenyl group with TFA and
comparison with authentic Cbz-protected amino acid
(Scheme 3). Diprotected threonine derivative 22 was
identical in all regards to a literature sample.24
After saponification of 18 and coupling of the resulting
acid with L-isoleucine methyl ester in the presence of
diethyl phosphorcyanidate (DEPC),25 the N-terminus of
dipeptide 23 was deprotected selectively under catalytic
hydrogen transfer conditions and acylated with the acid
derived from reverse-prenylated threonine 19 (Scheme
4). The tripeptide segment 15 was thus obtained in an
overall yield of 59% based on 18. Increased palladium
catalyst loadings were necessary for the subsequent Cbz-
group deprotection to amine 25, which was used in the
segment condensation with tetrapeptide 14.
terminal Cbz-group in extended chains without partial
hydrogenation of prenyl groups. Boc-technology was also
incompatible with the acid-sensitive reverse prenyl func-
tions. The use of C-terminal benzyl esters was superior
to methyl esters because considerable cleavage of the
Fmoc-group was observed during slow saponification
processes. With both peptide strands 14 and 25 in hand,
segment condensation was initiated by catalytic hydro-
genation of the benzyl ester and addition of PyBOP27 to
a solution of acid and amine 25 in CH2Cl2. While
successful use of this coupling method was somewhat
sequence-dependent and not without potential stereo-
chemical pitfalls (vide infra), PyBOP-mediated condensa-
tion provided heptapeptide 13 in 78% yield.
The assembly of 14 employed iterative DEPC-mediated
couplings of Fmoc-L-alanine, L-proline, L-phenylalanine,
and O-TBS-protected L-serine (Scheme 5).26 Fmoc-protec-
tion of the N-terminus of 14 was crucial since in our
preliminary studies we were unable to cleave an N-
After successful segment coupling, the Fmoc group in
13 was removed by tris(2-aminoethyl)amine (TAEA)28
(26) An N- to C-terminal chain extension sequence was chosen for
the preparation of segment 14 rather than the commonly used C- to
N-terminus strategy, since removal of the N-Fmoc protective group
from dipeptide Fmoc-Phe-Ser(OTBS)-OBn led to diketopiperazine
formation.
(27) . Frerot, E.; Coste, J .; Pantaloni, A.; Dufour, M.-N.; J ouin, P.
Tetrahedron 1991, 47, 259.
(23) (a) Sakatani, M.; Kurokawa, N.; Ohfune, Y. Tetrahedron Lett.
1986, 27, 3753. (b) Coleman, R. S.; Shah, J . A. Synthesis 1999, 1399.
(24) Lit. [R]D -18.7 (c 1.0, MeOH); Yamada, T.; Isono, N.; Inui, A.;
Miyazawa, T.; Kuwata, S.; Watanabe, H. Bull. Chem. Soc. J pn. 1978,
51, 1897.
(25) Hamada, Y.; Rishi, S.; Shioiri, T.; Yamada, S.-I. Chem. Pharm.
Bull. 1977, 25, 224.
(28) Carpino, L. A.; Sadat-Aalaee, D.; Beyermann, M. J . Org. Chem.
1990, 55, 1673.

1040 J . Org. Chem., Vol. 65, No. 4, 2000
Wipf and Uto
Sch em e 6
Sch em e 7
treatment, and the methyl ester was cleaved with tet-
rabutylammonium hydroxide (TBAH)29 in preparation for
the macrocyclization step (Scheme 6). The 21-membered
ring was closed with HATU,30 and after desilylation of
the serine residue with TBAF, cycloheptapeptide 27 was
isolated in 26% yield. HPLC analysis of the constituent
amino acids after hydrolysis of 27 and derivatization
according to Marfey’s procedure31 confirmed the presence
of L-Ile and the absence of any detectable amounts of
epimeric D-allo-Ile. Accordingly, macrolactamization pro-
ceeded without racemization at the peptide C-terminus.
After cyclodehydration of the serine residue in 27 with
DAST to the oxazoline 12,32 we applied our oxazoline f
thiazoline interconversion protocol for the conversion of
12 to the target heterocycle 11.14a,18 Thiolysis of the
oxazoline with hydrogen sulfide in a solution of methanol/
triethylamine (2:1) provided the thioamide intermediate
in 88% yield. Finally, a second cyclodehydration with 2
equiv of DAST33 proceeded to the desired thiazoline-
containing 11. To our considerable surprise, while all
spectroscopic data for synthetic 11 were consistent with
our structural assignment, there were significant differ-
A thorough analysis of the absolute configuration of
all amino acid building blocks in synthetic 11 was
complicated by thiazoline-related side reactions during
the acid hydrolysis step of the Marfey analysis. Since the
assignment of the configuration of the natural product
had originally also been based on HPLC assays of Marfey
fragments,3 we immediately suspected that natural
trunkamide A was in fact a stereoisomer of 11, most
likely at the readily epimerizable C(40) or C(45) centers.13
Another potential source of errors was the assignment
of the configuration at the reverse-prenylated threonine
C(30), since it was highly questionable that L-threonine
and L-allo-threonine were clearly distinguishable after
Marfey derivatization. Since natural product was un-
available for further examination or derivatization,35 only
total synthesis of trunkamide A stereoisomers was able
to solve the structural puzzle.
1
ences in H and 13C NMR spectra and a major difference
in the [R]D measured for 11 and the corresponding data
reported for the natural product.34
(29) Abdel-Magid, A.; Cohen, J . H.; Maryanoff, C. A.; Shah, R. D.;
Villani, F. J .; Zhang, F. Tetrahedron Lett. 1998, 39, 3391.
(30) Ehrlich, A.; Heyne, H.-U.; Winter, R.; Beryermann, M.; Haber,
H.; Carpino, L. A.; Bienert, M. J . Org. Chem. 1996, 61, 8831.
(31) Adamson, J . G.; Hong, T.; Crivici, A.; Lajoie, G. Anal. Biochem.
1992, 202, 210.
(32) (a) Lafargue, P.; Guenot, P.; Lellouche, J .-P. Heterocycles 1995,
41, 947. (b) Harm, A. M.; Knight, J . G.; Stemp, G. Synlett 1996, 677.
(c) Muir, J . C.; Pattenden, G.; Thomas, R. M. Synthesis 1998, 613.
(33) . Lafargue, P.; Guenot, P.; Lellouche, J .-P. Synlett 1995, 171.
(34) The [R]D originally reported3 for natural trunkamide A needs
to be corrected to -23.1 (c 0.06, CHCl3); there were also minor
adjustments necessary for NMR spectral data (see Table 1). Prof. B.
F. Bowden, personal communication.
Among the new synthetic targets that we considered
essential as reference materials for an unambiguous
structural correlation were the (40R,45R)-, (40S,45S)-,
(35) Prof. B. F. Bowden, J ames Cook Unversity, Australia, personal
communication.

Synthesis and Stereochemistry of Trunkamide A
J . Org. Chem., Vol. 65, No. 4, 2000 1041
Sch em e 8
Sch em e 9
fication, however, was necessary for the segment coupling
with 25. The use of PyBOP, which had been successful
for preparations of the L-serine containing 13 and 29, led
to a significant amount of epimerization at the D-serine
R-carbon in 34 and 39. With HATU as the coupling agent,
we were able to overcome this problem and prepare the
desired heptapeptide intermediates in high diastereo-
meric purity.
and (40S,45R)-stereoisomers of 11. The total synthesis
of the (40R,45R)-isomer 31 is summarized in Scheme 7.
D-Phenylalanine benzyl ester was now used for the chain
extension of dipeptide 26, but tripeptide 25 could be used
unchanged in the segment condensation reaction. The
macrolactamization of the amino acid derived from
heptapeptide 29 gave only poor yields using the standard
(HATU) conditions. A significantly improved result was
achieved with 3 equiv of TBTU36 in the presence of
HOAt.37 Further cyclodehydration and oxazoline f thia-
zoline conversion proceeded uneventfully to the desired
(40R,45R)-macrocycle 31. In a similar fashion, the
(40S,45S)- and (40S,45R)-stereoisomers 36 and 41, re-
spectively, were prepared from intermediates of the
previous syntheses (Schemes 8 and 9). Ester 32 had been
obtained in the conversion of 26 to 14 (Scheme 5), and
ester 37 was formed in the C-terminal chain extension
from 26 to 28 (Scheme 7). A major experimental modi-
In summary, we were able to extend our original
approach13 toward the cyclopeptide alkaloid 11 with some
tactical modifications toward the total synthesis of three
stereoisomers, 31, 36, and 41, in overall yields of 3-5%
based on Fmoc-L-alanine. A careful comparison of 1H and
13C NMR resonances for all synthetic trunkamide A
analogues with the data available for the natural product
revealed that the (40R,45R)-isomer 31 provided an excel-
lent spectroscopic match (Table 1). Major differences
between the natural compound and isomers 11, 36, and
41 were reflected by a large number of shift disagree-
ments ∆δ > 0.05/0.5 ppm (1H/13C) for methyl groups,
amide bond hydrogens, and even carbonyl groups. Most
significantly, there were no differences ∆δ > 0.5 ppm in
the 13C NMR spectra of natural product and synthetic
(36) (a) Zimmer, S.; Hoffmann, E.; J ung, G.; Kessler, H. Liebigs Ann.
Chem. 1993, 497. (b) Trzeciak, A.; Bannwarth, W. Tetrahedron Lett.
1992, 33, 4557. (c) Ehrlich, A.; Rothemund, S.; Brudel, M.; Beyermann,
M.; Carpino, L. A.; Bienert, M. Tetrahedron Lett. 1993, 34, 4781.
(37) Carpino, L. A.; El-Faham, A. J . Org. Chem. 1995, 60, 3561.

1042 J . Org. Chem., Vol. 65, No. 4, 2000
Wipf and Uto
Ta ble 1. Com p a r ison of 1H a n d 13C NMR Ch em ica l Sh ifts of Na tu r a l Tr u n k a m id e A3,34 w ith Syn th etic 11, 31, 36, a n d 41.
Differ en ces ∆δ > 0.05/0.5 p p m (1H/13C) Ar e Ma r k ed in Bold . Assign m en ts Ar e Su p p or ted by 500 MHz H/C-COSY
trunkamide A
1H 13C
11
31
36
41
Position
1H
13C
1H
13C
1H
13C
1H
13C
C(1)
C(2)H
C(3)H2
C(4)H2
C(5)H2
C(7)
-
171.1
59.8
28.5
25.5
47.1
170.0
47.7
17.8
-
170.5
57.9
36.5
16.1
23.6
11.9
-
170.9
56.5
62.2
77.8
25.6
27.3
142.0
115.7
-
168.6
55.2
67.2
18.5
75.9
25.6
25.6
142.6
114.9
-
-
170.8
59.8
29.9
25.3
47.4
169.9
47.9
18.5
-
170.5
57.7
36.6
16.3
24.0
12.3
-
171.9
56.5
62.1
77.9
25.6
27.5
142.4
115.9
-
169.3
56.2
67.4
19.1
76.2
26.0
25.9
142.4
115.2
-
-
171.0
60.0
28.7
25.7
47.2
170.1
47.8
18.1
-
170.6
58.0
36.6
16.2
23.8
12.1
-
171.0
56.6
62.3
78.0
25.8
27.5
142.2
116.0
-
168.7
55.4
67.4
18.7
76.1
25.8
25.9
142.7
115.1
-
-
170.5
60.5
27.9
25.2
46.9
170.3
47.4
18.4
-
170.5
57.4
35.8
16.4
24.4
12.5
-
170.5
57.2
61.7
78.4
25.8
26.4
142.4
115.9
-
170.3
57.0
66.4
19.5
76.0
25.6
25.5
142.8
115.1
-
-
170.9
59.6
26.9
25.8
47.3
170.0
46.6
20.1
-
170.2
57.8
35.9
16.4
24.4
12.5
-
170.5
57.3
61.7
78.4
25.8
27.9
142.4
115.9
-
170.0
57.3
65.5
18.4
76.0
25.8
25.8
142.9
115.2
-
4.38
1.80
2.30, 1.80
3.52, 3.50
-
4.49
1.20
7.20
-
4.55
2.50
0.95
1.35
0.95
6.32
-
4.55
3.89, 3.44
-
1.50
1.35
5.91
5.27, 5.23
7.55
-
4.55
4.02
1.10
-
1.25
1.25
5.73
4.78
4.40
4.82
4.69
2.01
1.87, 1.54
2.49, 1.87
3.33
-
4.53
1.18
7.22
-
4.59
2.36
0.88
1.34
0.88
6.19
-
4.39
3.83, 3.43
-
1.43
1.34
5.88
5.25, 5.22
7.49
-
4.53
3.91
1.11
-
1.21
1.18
5.68
5.09, 5.06
8.10
1.89
1.95, 1.83
2.66, 2.06
3.34, 3.52
-
4.75
0.96
7.52
-
4.66
2.45
0.96
1.21
0.96
6.11
-
4.56
3.85, 3.58
-
1.52
1.41
5.95
5.30, 5.26
8.03
-
4.35
4.26
1.08
-
1.28
1.26
5.75
5.15, 5.14
7.98
2.22, 1.89
3.51
-
4.50
1.21
7.22
-
4.59
2.35
0.94
1.26
0.94
6.32
-
4.59
3.89, 3.45
-
1.48
1.38
5.91
5.27, 5.24
7.56
-
4.59
4.02
1.06
-
1.24
1.27
5.73
5.15, 5.12
7.95
-
4.92
3.72, 3.62
-
2.36, 1.70
3.54
-
4.90
1.24
7.57
-
4.69
2.45
0.91
0.91
0.91
6.05
-
4.44
3.88, 3.54
-
1.53
1.42
5.95
5.31, 5.25
8.26
-
4.36
4.55
1.07
-
1.30
1.28
5.78
5.17, 5.16
8.13
-
4.81
3.54
-
C(8)H
C(9)H3
N(10)H
C(11)
C(12)H
C(13)H
C(14)H3
C(15)H2
C(16)H3
N(17)H
C(18)
C(19)H
C(20)H2
C(22)
C(23)H3
C(24)H3
C(25)H
C(26)H2
N(27)H
C(28)
C(29)H
C(30)H
C(31)H3
C(33)
C(34)H3
C(35)H3
C(36)H
C(37)H2
N(38)H
C(39)
C(40)H
C(41)H2
C(43)
C(45)H
C(46)H2
N(53)H
5.15, 5.11
7.93
-
4.92
3.71, 3.62
-
5.25
3.20, 2.90
7.30
170.1
78.1
36.4
173.3
52.6
40.0
-
-
4.94
3.59, 3.54
-
4.94
169.9
77.9
36.6
172.8
53.7
40.7
-
170.3
78.3
36.6
173.5
52.8
40.2
-
-
4.66
3.71, 3.34
-
5.03
172.9
79.2
36.5
173.8
53.8
39.0
-
172.5
78.8
35.5
173.3
53.4
41.5
-
5.20
3.15, 2.93
7.25
5.08
3.15, 2.96
8.26
3.15, 2.87
8.38
3.34, 2.96
7.98
31, and the small differences for methylene protons at
positions C(3), C(4), and C(15) could well be due to the
broad character of the multiplets at these positions,
which, in addition, are partially covered by other peaks
even at 500 MHz. Accordingly, we conclude that the
stereochemistry of trunkamide A has to be revised as
shown for synthetic 31, e.g., the D-configuration at the
phenylalanine-derived C(45)-stereocenter. Despite the
differences in [R]D values between synthetic and natural
product, the NMR analysis provides overwhelming sup-
port for this structural assignment.
able to realize a general and efficient synthetic strategy
that provides trunkamide A and a series of unnatural
analogues in sufficient quantities (>10 mg) for further
evaluation of their biological profile. In addition, on the
basis of the total synthesis of the structure originally
proposed for trunkamide A as well as three specific
stereoisomers, we were able to revise the assignment of
the stereochemistry of the natural product to 31. As
observed for many other thiazoline-containing metabo-
lites, the stereocenter exocyclic to the heterocyclic ring
assumes a D-amino acid configuration. This trend is likely
due to conformational preferences in the macrocycle.15
Further analysis of the three-dimensional structure of
trunkamide A and its congeners as well as the results of
structure-activity studies will be reported in due course.
Con clu sion s
The total synthesis of marine natural products poses
considerable challenges for synthetic methodology due to
the frequent combinations of unusual new functionalities,
incomplete structural assignment, and the high degree
of diversity among these targets. While many successful
approaches to cyclopeptides have been realized, every
sequence defines new and unexpected limitations for
protective group manipulations and, in particular, mac-
rocyclization steps. This is especially true for the prepa-
ration of heavily backbone- and side chain-modified
cyclopeptide alkaloids. As an extension of our prior work
in the field of Lissoclinum peptides, we have now been
Exp er im en ta l Section
Gen er a l Meth od s. NMR spectra are reported at 300 MHz
in CDCl3 unless otherwise noted. Optical rotations were
measured on a Perkin-Elmer 241 polarimeter. Anhydrous
solvents were freshly distilled from either sodium benzophe-
none ketyl, P2O5, or CaH2. Flash chromatography was used
to separate and purify the crude reaction mixtures.
Gen er a l P r oced u r e A for Dep r otection a n d Rep r otec-
tion of Azir id in es. (2S)-Azir id in e-1,2-d ica r boxylic a cid
1-Ben zylester 2-Meth yl Ester (16). A solution of 0.755 g

Synthesis and Stereochemistry of Trunkamide A
J . Org. Chem., Vol. 65, No. 4, 2000 1043
(2.20 mmol) of (S)-1-trityl-aziridine-2-carboxylic acid methyl
ester22 in 3 mL of CHCl3 and 3 mL of MeOH was cooled to 0
°C, treated with 3 mL of TFA, and allowed to stir for 2.5 h at
0 °C. Evaporation of the solvent in vacuo gave a solid residue
which was dissolved in ether. The solvent was evaporated, and
the ether treatment was repeated two additional times to
ensure complete removal of TFA. The resulting residue was
dissolved in ether and extracted with water. The combined
aqueous extracts were treated portionwise with 0.93 g (11
mmol) of NaHCO3. After addition of EtOAc, the mixture was
cooled to 0 °C and a solution of benzyl chloroformate (0.35 mL,
2.5 mmol) in 2 mL of EtOAc was added dropwise over 10 min
under vigorous stirring. The reaction mixture was allowed to
warm to room temperature and stirred overnight (13 h). After
addition of water and EtOAc, the organic layer was washed
with brine, dried (Na2SO4), and concentrated in vacuo. Puri-
fication of the residue by chromatography on SiO2 (hexanes/
EtOAc, 8:1) yielded 0.375 g (73%) of 16 as a colorless oil: 1H
NMR δ 7.34 (s, 5 H), 5.15 (s, 2 H), 3.71 (s, 3 H), 3.12 (dd, 1 H,
J ) 3.2, 5.4 Hz), 2.60 (dd, 1 H, J ) 3.2, 1.4 Hz), 2.49 (dd, 1 H,
J ) 1.4, 5.4 Hz); 13C NMR δ 168.8, 160.9, 135.4, 128.7, 128.6,
127.8, 68.8, 52.9, 35.0, 31.6; MS(EI) m/z (rel intensity) 235 (M+,
purified by chromatography on SiO2 (hexanes/EtOAc, 2:1) to
yield 26.4 mg (69%) of 22 as a colorless solid: [R]D -19.4 (c
0.99, MeOH, 23 °C), lit [R]D -18.7 (c 1.0, MeOH, 20 °C);24 1H
NMR δ 7.36-7.26 (m, 5 H), 5.62 (d, 1 H, J ) 8.3 Hz), 5.13 (s,
2 H), 4.34 (d, 2 H, J ) 7.5 Hz), 3.77 (s, 3 H), 2.02 (s, 1 H), 1.25
(d, 3 H, J ) 6.8 Hz).
Cbz-Ser (r p r en yl)-Ile-OMe (23). A solution of Cbz-Ser-
(rprenyl)-OMe 18 (2.15 g, 6.96 mmol) in THF/H2O (3:1, 120
mL) was treated with LiOH‚H2O (0.306 g, 7.29 mmol). The
reaction mixture was stirred at room temperature for 11 h,
H2O (30 mL) was added, and THF was removed in vacuo. The
solution was acidified with 1 M KH2PO4 and extracted with
EtOAc, dried (Na2SO4), and concentrated to afford 2.1 g (100%)
of acid intermediate as a colorless solid. A solution of this acid
(2.06 g, 6.69 mmol) in CH2Cl2 (22 mL) was cooled to -10 °C,
and DEPC (93%, 1.1 mL, 6.7 mmol) was added dropwise.38
After the mixture had been stirred for 15 min and warmed to
-5 °C, a solution of L-Ile-OMe‚HCl (1.22 g, 6.69 mmol) and
(i-Pr)2NEt (2.3 mL, 13 mmol) in CH2Cl2 (14 mL) was added
slowly. The reaction mixture was stirred at -5 °C for 1 h,
quenched with water (100 mL), extracted with chloroform,
dried (Na2SO4), and concentrated. Purification of the residue
by chromatography on SiO2 (hexanes/EtOAc, 4:1) yielded 2.33
g (80%) of 23 as a colorless solid: mp 55.5-57.5 °C; [R]D +30.8
0.3), 129 (23), 107 (52), 91 (100); HRMS m/z calcd for C12H13
-
NO4 235.0845, found 235.0836.
(c 0.39, CHCl3, 22 °C), IR (film) 3331, 1738, 1667, 1501 cm-1
;
Gen er al P r ocedu r e B for Azir idin e Open in g by 2-Meth -
yl-3-bu ten -2-ol. (2S)-2-(Ben zyloxyca r bon yla m in o)-3-(1,1-
d im eth yla llyloxy)p r op ion ic Acid Meth yl Ester (18). To
a solution of 16 (2.47 g, 10.5 mmol) in 2-methyl-3-buten-2-ol
(330 mL) was added dropwise at 0 °C BF3‚Et2O (2.7 mL, 21
mmol). The reaction mixture was allowed to stir overnight (16
h) at room temperature and then washed with water (250 mL)
and brine (250 mL), dried (Na2SO4), and concentrated in vacuo.
Purification of the residue by chromatography on SiO2 (hex-
anes/EtOAc, 6:1) yielded 2.43 g (72%) of 18 as a colorless
solid: mp 46.0-47.7 °C; [R]D +9.9 (c 0.95, CHCl3, 23 °C); IR
1H NMR δ 7.37-7.20 (m, 6 H), 5.83 (dd, 1 H, J ) 17.7, 10.6
Hz), 5.71 (d, 1 H, J ) 4.7 Hz), 5.18-5.02 (m, 4 H), 4.58 (dd, 1
H, J ) 4.9, 8.7 Hz), 4.35-4.25 (m, 1 H), 3.80-3.65 (m, 4 H),
3.35 (t, 1 H, J ) 8.4 Hz), 1.93-1.83 (m, 1 H), 1.50-1.30 (m, 1
H), 1.30 (s, 6 H), 1.25-1.10 (m, 1 H), 0.95-0.85 (m, 6 H); 13C
NMR δ 172.2, 170.3, 156.2, 142.9, 136.3, 128.8, 128.4, 115.0,
67.3, 62.7, 56.8, 54.4, 52.3, 38.2, 25.7, 25.3, 15.7, 11.8; MS (EI)
m/z (rel intensity), 434 (M+, 0.7), 336 (40), 291 (30), 253 (39),
91 (100); HRMS m/z calcd for C23H34N2O6 434.2417, found
434.2399.
(film) 3440, 3089, 3069, 1724, 1509 cm-1 1H NMR δ 7.38-
;
Cbz-Th r (r p r en yl)-Ser (r p r en yl)-Ile-OMe (15). A suspen-
sion of Et3SiH (0.81 mL, 5.1 mmol), Pd(OAc)2 (51.4 mg, 0.229
mmol), and Et3N (64 µL, 0.46 mmol) in CH2Cl2 (10 mL) was
stirred at room temperature for 15 min under a nitrogen
atmosphere. To this mixture was added a solution of Cbz-Ser-
(rprenyl)-Ile-OMe 23 (995 mg, 2.29 mmol) in CH2Cl2 (10 mL).
The resulting mixture was stirred for 16 h and quenched with
saturated aqueous NaHCO3 solution. The product was ex-
tracted with CHCl3, dried (Na2SO4), and then concentrated.
Purification of the residue by chromatography on SiO2 (hex-
anes/EtOAc, 4:1, then 1:1, followed by CHCl3/MeOH, 10:1)
yielded 780 mg of 24 as a dark oil. A solution of Cbz-Thr-
(rprenyl)-OMe (19, 2.53 g, 7.55 mmol) in THF/H2O (3:1, 120
mL) was treated with LiOH‚H2O (0.352 g, 8.39 mmol). The
reaction mixture was stirred at room temperature for 14.5 h,
H2O was added, and THF was removed in vacuo. The solution
was acidified with 1 M KH2PO4, extracted with EtOAc, dried
(Na2SO4), and concentrated to afford 2.41 g (100%) of acid
intermediate as a colorless solid. A solution of this acid (739
mg, 2.29 mmol) in CH2Cl2 (8 mL) was cooled to -10 °C, and
DEPC (93%, 376 µL, 2.29 mmol) was added dropwise.38 After
the mixture had been stirred for 15 min and warmed to -5
°C, a solution of the amine 24 prepared above (780 mg) and
(i-Pr)2NEt (0.40 mL, 2.3 mmol) in CH2Cl2 (5 mL) was added
slowly. The reaction mixture was stirred at -5 °C for 3 h,
diluted with CH2Cl2, washed with water and brine, dried (Na2-
SO4), and concentrated. Purification of the residue by chro-
matography on SiO2 (hexanes/EtOAc, 2:1) yielded 2.33 g (74%)
of 15 as a colorless solid: mp 86.0-88.0 °C; [R]D +40.6 (c 0.83,
7.26 (m, 5 H), 5.70 (dd, 1 H, J ) 10.5, 17.8 Hz), 5.62 (d, 1 H,
J ) 8.7 Hz), 5.13, 5.12 (AB, 2 H, J ) 12.1 Hz), 5.12-5.06 (m,
2 H), 4.45 (ddd, 1 H, J ) 3.0, 3.0, 8.7 Hz), 3.75 (s, 3 H), 3.74
(dd, 1 H, J ) 3.0, 9.2 Hz), 3.53 (dd, 1 H, J ) 3.0, 9.2 Hz), 1.21
(s, 3 H), 1.20 (s, 3 H); 13C NMR δ 171.2, 156.2, 143.1, 136.4,
128.7, 128.3, 114.5, 75.6, 67.2, 62.9, 54.7, 52.5, 25.7, 25.6; MS
(FAB) m/z (rel intensity) 344 ([M + Na]+, 40), 322 ([M + H]+,
26), 91 (100); HRMS m/z calcd for C17H24NO5 (M + H)
322.1654, found 322.1663.
(2S,3S)-3-Meth yla zir id in e-1,2-d ica r boxylic a cid 1-Ben -
zyl Ester 2-Meth yl Ester (17). According to general proce-
dure A, 5.14 g (14.4 mmol) of (2S,3S)-1-trityl-3-methylaziridine-
2-carboxylic acid methyl ester22 provided 3.46 g (96%) of 17
as a colorless oil: 1H NMR δ 7.36-7.27 (m, 5 H), 5.14, 5.12
(AB, 2 H, J ) 12.1 Hz), 3.78 (s, 3 H), 3.19 (d, 1 H, J ) 6.7 Hz),
2.81 (dq, 1 H, J ) 6.7, 5.7 Hz), 1.35 (d, 3 H, J ) 5.7 Hz); 13C
NMR δ 167.8, 161.7, 135.4, 128.7, 128.6, 128.5, 68.7, 52.6, 39.9,
39.0, 13.0; MS(EI) m/z (rel intensity) 249 (M+, 0.6), 232 (1),
207 (2), 190 (1), 114 (52), 91 (100); HRMS m/z calcd for C13H15
-
NO4 249.1001, found 249.1008.
(2S)-(Ben zyloxyca r bon yla m in o)-(3S)-(1,1-d im eth yla l-
lyloxy)bu tyr ic Acid Meth yl Ester (19). According to general
procedure B, aziridine 17 (3.46 g, 13.9 mmol) and BF3‚Et2O
(1.8 mL, 14 mmol) in 2-methyl-3-buten-2-ol (290 mL) provided
4.09 g (88%) of 19 as a pale yellow oil: [R]D +17.2 (c 1.1, CHCl3,
1
23 °C); IR (film) 3444, 3033, 1754, 1728, 1506 cm-1; H NMR
δ 7.41-7.31 (m, 5 H), 5.69 (dd, 1 H, J ) 10.7, 17.7 Hz), 5.58
(d, 1 H, J ) 9.6 Hz), 5.13 (s, 2 H), 5.10 (dd, 1 H, J ) 17.8, 0.8
Hz), 5.08 (dd, 1 H, J ) 10.8, 0.8 Hz), 4.21 (dd, 1 H, J ) 9.6,
1.7 Hz), 4.11 (dq, 1 H, J ) 1.7, 6.9 Hz), 3.73 (s, 3 H), 1.21 (s,
6 H), 1.17 (d, 1 H, J ) 6.9 Hz); 13C NMR δ 171.7, 156.9, 143.7,
136.5, 128.7, 128.3, 128.0, 114.1, 76.0, 68.3, 67.2, 59.9, 52.3,
26.4, 26.2, 21.1; MS (FAB) m/z (rel intensity) 358 ([M + Na]+,
56), 336 ([M + H]+, 10), 91 (100); HRMS (FAB) m/z calcd for
CHCl3, 23 °C); IR (film) 3325, 3086, 1747, 1741, 1666 cm-1
;
1H NMR δ 7.45 (d, 1 H, J ) 7.6 Hz), 7.39-7.26 (m, 5 H), 7.06
(d, 1 H, J ) 8.9 Hz), 5.96-5.89 (m, 2 H), 5.80 (dd, 1 H, J )
10.5, 17.9 Hz), 5.30-5.05 (m, 6 H), 4.62-4.56 (m, 2 H), 4.25-
4.20 (m, 1 H), 4.10-4.00 (m, 1 H), 3.84 (dd, 1 H, J ) 2.7, 8.6
Hz), 3.71 (s, 3 H), 3.33 (dd, 1 H, J ) 6.1, 8.5 Hz), 1.95-1.85
C
18H26NO5 (M + H) 336.1811, found 336.1819.
Cbz-Th r -OMe (22). A solution of 19 (48.4 mg, 0.144 mmol)
(38) According to Shioiri’s original DEPC protocol, a solution of acid
and amine in DMF should be treated with DEPC and then triethyl-
amine.25 We used an alternative sequence of additions following a
protocol by Pettit, G. R.; Taylor, S. R. J . Org. Chem. 1996, 61, 2322.
in CH2Cl2 (1.0 mL) was treated with 40 µL of TFA/H2O (9:1)
for 14 h. The mixture was diluted with EtOAc, washed with
saturated aqueous NaHCO3 and brine, dried (Na2SO4), and

1044 J . Org. Chem., Vol. 65, No. 4, 2000
Wipf and Uto
(m, 1 H), 1.50-1.40 (m, 2 H), 1.43 (s, 3 H), 1.36 (s, 3 H), 1.28
(s, 6 H), 1.09 (d, 3 H, J ) 6.4 Hz), 0.98-0.84 (m, 6 H); 13C
NMR δ 172.1, 170.0, 169.2, 156.1, 142.9, 136.4, 128.7, 128.4,
128.2, 115.2, 114.9, 76.1, 68.0, 67.1, 62.6, 59.0, 56.8, 53.5, 52.1,
37.9, 27.5, 25.9, 25.7, 25.5, 25.1, 17.3, 15.7, 11.7; MS(FAB) m/z
(rel intensity) 626 ([M + Na]+, 42), 604 ([M + H]+, 100); MS
(EI) m/z (rel intensity) 603 (M+, 0.3), 423 (23), 358 (30), 315
(57), 146 (35), 91 (76); HRMS (EI) m/z calcd for C32H49N3O8
603.3520, found 603.3514.
F m oc-Ala -P r o-OBn (26). A solution of Fmoc-Ala-OH (3.45
g, 11.1 mmol) in DMF (18 mL) was cooled to -14 °C and DEPC
(93%, 1.8 mL, 11 mmol) was added dropwise. After the reaction
mixture had been stirred for 25 min at -10 °C, a solution of
L-Pro-OBn‚HCl (2.68 g, 12.1 mmol) and (i-Pr)2NEt (3.8 mL,
21 mmol) in CH2Cl2 (18 mL) was added via syringe pump over
a period of 30 min. The reaction mixture was stirred for 11 h,
diluted with CHCl3, washed with water and brine, dried (Na2-
SO4), and concentrated. Purification of the residue by chro-
matography on SiO2 (hexanes/EtOAc, 2:1) yielded 4.85 g (88%)
of 26 as a colorless foam: [R]D -62.2 (c 0.94, CHCl3, 23 °C);
IR (film) 3415, 3292, 3066, 3015, 1716, 1647 cm-1; 1H NMR δ
7.76 (d, 2 H, J ) 4.7 Hz), 7.59 (d, 2 H, J ) 7.2 Hz), 7.42-7.25
(m, 9 H), 5.75 (d, 1 H, J ) 7.9 Hz), 5.22, 5.12 (AB, 2 H, J )
12.3 Hz), 4.63-4.59 (m, 1 H), 4.53 (p, 1 H, J ) 7.2 Hz), 4.36-
4.30 (m, 2 H), 4.23-4.18 (m, 1 H), 3.7-3.55 (m, 2 H), 2.23-
2.20 (m, 1 H), 2.10-1.90 (m, 3 H), 1.36 (d, 3 H, J ) 6.8 Hz);
13C NMR δ 171.8, 171.5, 155.8, 144.0, 143.9, 141.4, 135.6,
128.7, 128.5, 128.3, 127.8, 127.2, 125.3, 120.1, 67.1, 59.1, 48.4,
47.2, 47.0, 46.6, 29.0, 25.1,18.4; MS (EI) m/z (rel intensity) 498
(M+, 0.2), 302 (39), 258 (36), 178 (100), 167 (36); HRMS m/z
calcd for C30H30N2O5 498.2155, found 498.2179.
Gen er a l P r oced u r e C for th e Syn th esis of Ster eoiso-
m er s of F m oc-Ala -P r o-P h e-OBn (32). A solution of Fmoc-
Ala-Pro-OBn (26, 3.83 g, 7.68 mmol) in EtOAc/EtOH (2:1, 60
mL) was treated with Pd/C (10% Pd, 0.419 g) and H2 gas for
17 h. The reaction mixture was filtered through a plug of Celite
and concentrated. Purification of the residue by chromatog-
raphy on SiO2 (hexanes/EtOAc, 1:1, then CHCl3/MeOH, 5:1)
yielded 3.11 g (99%) of the acid as a colorless solid. A solution
of this acid (3.11 g, 7.61 mmol) in CH2Cl2 (25 mL) was cooled
to -10 °C, and DEPC (93%, 1.2 mL, 7.4 mmol) was added
dropwise. After the mixture had been stirred for 30 min and
warmed to -5 °C, a solution of L-Phe-OBn‚TsOH (3.25 g, 7.61
mmol) and (i-Pr)2NEt (2.6 mL, 15 mmol) in CH2Cl2 (15 mL)
was added via cannula. The reaction mixture was stirred at
-5 °C for 11 h, diluted with chloroform, washed with water
and brine, dried (Na2SO4), and concentrated. Purification of
the residue by chromatography on SiO2 (hexanes/EtOAc, 1:1,
then 1:2) yielded 3.88 g (79%) of 32 as a colorless wax: [R]D
-62.2 (c 0.94, CHCl3, 23 °C); IR (film) 3300, 3064, 1739, 1643
cm-1; 1H NMR (methanol-d4) δ 7.83-7.75 (m, 2 H), 7.70-7.62
(m, 2 H), 7.42-7.10 (m, 14 H), 5.13-5.05 (m, 2 H), 4.70-4.60
(m, 1 H), 4.50-4.35 (m, 4 H), 4.35-4.28 (m, 1 H), 3.78-3.68
(m, 1 H), 3.68-3.45 (m, 1 H), 3.15-3.05 (m, 2 H), 2.22-2.00
(m, 2 H), 2.00-1.80 (m, 2 H), 1.40-1.22 (m, 3 H); 13C NMR δ
172.7, 171.3, 170.7, 155.8, 144.0, 141.4, 137.2, 135.9, 135.2,
129.5, 128.8, 127.9, 127.2, 125.3, 120.1, 67.4, 67.1, 60.1, 53.5,
48.3, 47.3, 37.9, 27.6, 25.1, 18.6, 16.6; MS (EI) m/z (rel
intensity) 645 (M+, 0.1), 380 (31), 352 (10), 178 (95); HRMS
(FAB) m/z calcd for C39H40N3O6 (M + H) 646.2917, found
646.2930.
concentrated. Purification of the residue by chromatography
on SiO2 (hexanes/Et2O, 1:1) gave 5.40 g (64%) of L-Ser(TBS)-
OBn.
A solution of Fmoc-Ala-Pro-Phe-OH (3.01 g, 5.42 mmol) in
CH2Cl2 (18 mL) was cooled to -10 °C, and DEPC (0.89 mL,
5.5 mmol) was added dropwise. After the reaction mixture had
been stirred for 30 min and warmed to -5 °C, a solution of
L-Ser(TBS)-OBn (1.68 g, 5.42 mmol) and (i-Pr)2NEt (0.94 mL,
5.3 mmol) in CH2Cl2 (12 mL) was added via cannula. The
mixture was stirred at -5 °C for 11 h, diluted with CHCl3 (70
mL), washed with water and brine, dried (Na2SO4), and
concentrated. Purification of the residue by chromatography
on SiO2 (hexanes/EtOAc, 1:1, then 1:2) yielded 3.88 g (80% over
two steps) of 14 as a colorless amorphous solid: [R]D -39.0 (c
0.97, CHCl3, 23 °C); IR (film) 3304, 3065, 1716, 1639 cm-1; 1H
NMR (benzene-d6, 343 K) δ 7.58 (d, 2 H, J ) 7.6 Hz), 7.55-
7.45 (m, 2 H), 7.35-6.95 (m, 15 H), 6.72 (bs, 1 H), 5.42 (bs, 1
H), 5.05, 5.00 (AB, 2 H, J ) 12.4 Hz), 4.86-4.68 (m, 2 H), 4.48-
4.30 (m, 4 H), 4.10 (t, 1 H, J ) 6.6 Hz), 3.95 (dd, 1 H, J ) 3.3,
10.0 Hz), 3.79 (dd, 1 H, J ) 3.9, 10.0 Hz), 3.20-2.80 (m, 4 H),
2.13-2.04 (m, 1 H), 1.64-1.48 (m, 1 H), 1.47-1.23 (m, 2 H),
1.09 (d, 3 H, J ) 6.6 Hz), 0.88 (s, 9 H), -0.01 (s, 3 H), -0.03
(s, 3 H); 13C NMR δ 172.8, 170.8, 170.5, 169.9, 155.8, 144.0,
143.9, 141.4, 136.5, 135.4, 129.5, 129.2, 128.8, 128.7, 128.5,
127.9, 127.2, 125.3, 120.2, 67.4, 67.1, 63.4, 60.2, 54.6, 54.3, 48.4,
47.3, 47.2, 38.4, 27.7, 25.9, 25.1, 18.7, 18.3, -5.4, -5.5; MS
(FAB) m/z (rel intensity) 848 ([M + H]+, 10), 391 (8), 310 (11),
179 (100).
Gen er a l P r oced u r e E for Segm en t Con d en sa tion w ith
P yBOP . F m oc-Ala -P r o-P h e-Ser (TBS)-Th r (r p r en yl)-Ser -
(r p r en yl)-Ile-OMe (13). A suspension of Et3SiH (228 µL, 1.43
mmol), Pd(OAc)2 (29.2 mg, 0.130 mmol), and Et3N (36 µL, 0.260
mmol) in CH2Cl2 (4 mL) was stirred at room temperature for
15 min under a nitrogen atmosphere. To this mixture was
added a solution of Cbz-Thr(rprenyl)-Ser(rprenyl)-Ile-OMe (15,
391 mg, 0.648 mmol) in CH2Cl2 (5 mL). The reaction mixture
was stirred for 37 h, quenched with saturated aqueous
NaHCO3 solution, and extracted with CHCl3. The organic layer
was dried (Na2SO4), concentrated, and purified by chromatog-
raphy on SiO2 (hexanes/EtOAc, 4:1, then 1:1, followed by
CHCl3/MeOH, 10:1) to yield 280 mg (92%) of 25 as a dark oil.
A solution of Fmoc-Ala-Pro-Phe-Ser(TBS)-OBn (14, 1.00 g,
1.18 mmol) in EtOAc/EtOH (2:1, 15 mL) was treated with Pd/C
(10% Pd, 64 mg) and H2 gas for 20 h. The reaction mixture
was filtered through
a plug of Celite and concentrated.
Purification of the residue by chromatography on SiO2 (hex-
anes/EtOAc, 1:1, then CHCl3/MeOH, 5:1) yielded 0.805 g (90%)
of the acid as a colorless solid. This acid (79.0 mg, 0.104 mmol)
and the amine 25 (48.9 mg, 0.104 mmol) prepared above and
PyBOP (65.4 mg, 0.125 mmol) were dissolved in CH2Cl2 (2.0
mL), and the coupling reaction was initiated by addition of
(i-Pr)2NEt (37 µL, 0.208 mmol). The reaction mixture was
stirred at room temperature for 16 h and diluted with CHCl3,
and the organic layer was washed with 10% citric acid,
saturated aqueous NaHCO3, and brine and dried (Na2SO4).
Purification by chromatography on SiO2 (hexanes/EtOAc, 1:2)
yielded 102 mg (78% over two steps) of 13 as a colorless foam:
[R]D -6.5 (c 0.95, CHCl3, 23 °C); IR (film) 3303, 1721, 1690
cm-1 1H NMR (benzene-d6, 343 K), δ 7.78 (d, 1 H, J ) 6.7
;
Hz), 7.67 (d, 3 H, J ) 6.9 Hz), 7.61 (d, 2 H, J ) 6.8 Hz), 7.35-
7.05 (11 H, m), 7.00 (bs, 1 H), 6.12 (dd, 1 H, J ) 10.9, 17.6
Hz), 5.94 (dd, 1 H, J ) 10.9, 17.6 Hz), 5.67 (bs, 1 H), 5.29-
5.06 (m, 4 H), 4.93-4.82 (m, 2 H), 4.76-4.66 (m, 2 H), 4.53-
4.39 (m, 5 H), 4.25-4.20 (m, 2 H), 4.06-4.00 (m, 2 H), 3.82
(dd, 1 H, J ) 6.8, 9.7 Hz), 3.48-3.40 (m, 1 H), 3.44 (s, 3 H),
3.32-3.25 (m, 2 H), 3.20-3.05 (m, 2 H), 2.25-2.10 (m, 1 H),
2.05-1.90 (m, 1 H), 1.60-1.40 (m, 3 H), 1.52 (s, 3 H), 1.47 (s,
3 H), 1.40-1.15 (m, 14 H), 1.06 (s, 9 H), 1.05-0.90 (m, 6 H),
0.21 (s, 6 H); 13C NMR (benzene-d6, 343 K) δ 172.9, 172.5,
171.6, 170.4, 169.9, 156.4, 145.1, 144.6, 144.1, 142.3, 138.3,
130.2, 129.1, 127.8, 127.3, 125.8, 120.6, 114.5, 114.4, 77.8, 76.6,
68.3, 67.6, 64.2, 63.5, 61.0, 59.3, 57.5, 56.2, 55.8, 54.6, 51.6,
49.3, 48.5, 47.4, 38.9, 28.1, 26.6, 26.4, 26.3, 26.2, 25.2, 19.0,
18.8, 18.1, 16.4, 16.1, 11.9, -4.8; MS (FAB) m/z (rel intensity)
1230 ([M + Na]+, 9), 179 (100).
Gen er a l P r oced u r e D for th e Syn th esis of Ster eoiso-
m er s of F m oc-Ala -P r o-P h e-Ser (TBS)-OBn (14). A solution
of Fmoc-Ala-Pro-Phe-OBn (32, 3.82 g, 5.92 mmol) in EtOAc/
EtOH (2:1, 60 mL) was treated with Pd/C (10% Pd, 0.32 g)
and H2 gas for 17 h. The reaction mixture was filtered through
a plug of Celite and concentrated. Purification of the residue
by chromatography on SiO2 (hexanes/EtOAc, 1:1, then CHCl3/
MeOH, 5:1) yielded 3.19 g (96%) of Fmoc-Ala-Pro-Phe-OH as
a colorless solid.
To a solution of L-Ser-OBn‚TsOH (10.0 g, 27.2 mmol) and
imidazole (6.48 g, 95.2 mmol) in DMF (20 mL) was added
TBS-Cl (4.64 g, 30.8 mmol) at room temperature. The reaction
mixture was stirred for 24 h and diluted with Et2O. The
organic layer was washed with H2O, dried (Na2SO4), and

Synthesis and Stereochemistry of Trunkamide A
J . Org. Chem., Vol. 65, No. 4, 2000 1045
Gen er a l P r oced u r e F for Ma cr ola cta m iza tion w ith
HATU. Cyclo[Ala-P r o-P h e-Ser -Th r (r pr en yl)-Ser (r pr en yl)-
Ile] (27). A solution of 13 (90.2 mg, 74.7 µmol) in CH2Cl2 (3.0
mL) was treated with tris(2-aminoethyl)amine (TAEA, 185 µL,
1.24 mmol) under a nitrogen atmosphere at room temperature
for 30 min. The reaction mixture was diluted with CHCl3 and
washed with brine and phosphate buffer (pH 5.5). Additional
CHCl3 was used for back extractions. The organic layer was
dried (Na2SO4) and concentrated. The purification of the
residue by chromatography on a short plug of SiO2 (EtOAc,
then CHCl3/MeOH, 5:1) yielded 73.6 mg of amine as a colorless
solid.
H), 1.25 (s, 3 H), 1.15 (d, 3 H, J ) 6.7 Hz), 1.20-1.05 (m, 2 H),
1.00-0.85 (m, 6 H), 0.81-0.74 (m, 3 H); 13C NMR δ 172.8,
170.8, 170.4, 170.2, 169.1, 167.7, 142.7, 142.3, 136.6, 129.7,
128.4, 126.9, 115.9, 115.2, 77.9, 76.1, 70.9, 68.0, 67.1, 62.1, 59.9,
57.7, 56.3, 56.1, 49.4, 47.9, 47.4, 38.0, 36.7, 29.9, 27.5, 25.9,
25.8, 25.6, 25.3, 23.8, 19.1, 18.4, 16.2, 12.3; MS (FAB) m/z (rel
intensity) 844 ([M + Na]+, 80), 822 ([M + H]+, 100); HRMS
(FAB) m/z calcd for (M + Na) C43H63N7O9Na 844.4585, found
844.4605.
Gen er a l P r oced u r e H for Th iolysis of Oxa zolin es.
Cyclo[Ala -P r o-P h eΨ{(CdS)NH }-Ser -Th r (r p r en yl)-Ser -
(r p r en yl)-Ile]. A solution of 12 (13 mg, 16 µmol) in MeOH/
Et3N (2:1, 1.0 mL) was saturated with H2S gas at room
temperature. The reaction mixture was stirred for 2 d and then
concentrated. Purification of the residue by preparative TLC
gave 11.7 mg (88%) of cyclo[Ala-Pro-PheΨ{(CdS)NH}-Ser-Thr-
(rprenyl)-Ser(rprenyl)-Ile] as a colorless solid: mp 181-183
°C; [R]D -68.6 (c 0.64, CHCl3, 22 °C); IR (film) 3296, 1641, 1519
cm-1; 1H NMR δ 9.47 (d, 1 H, J ) 6.7 Hz), 7.40-7.05 (m, 7 H),
6.98 (d, 1 H, J ) 8.5 Hz), 6.72 (d, 1 H, J ) 6.5 Hz), 6.62 (d, 1
H, J ) 5.4 Hz), 5.75 (dd, 1 H, J ) 17.7, 10.7 Hz), 5.73 (dd, 1
H, J ) 17.5, 10.7 Hz), 5.35-5.25 (m, 1 H), 5.17 (d, 1 H, J )
17.5 Hz), 5.18 (d, 1 H, J ) 11.2 Hz), 5.14 (d, 1 H, J ) 17.5 Hz),
5.11 (d, 1 H, J ) 10.6 Hz), 5.05-4.90 (m, 1 H), 4.74 (dd, 1 H,
J ) 1.2, 9.6 Hz), 4.59 (p, 1 H, J ) 6.6 Hz), 4.30-4.20 (m, 2 H),
4.20-4.10 (m, 2 H), 4.05-3.90 (m, 2 H), 3.75 (d, 1 H, J ) 9.1
Hz), 3.68 (dd, 1 H, J ) 3.9, 13.7 Hz), 3.38-3.10 (m, 2 H), 3.00-
2.75 (m, 2 H), 2.30-2.20 (m, 1 H), 1.85-1.68 (m, 2 H), 1.65-
1.45 (m, 3 H), 1.33 (d, 3 H, J ) 7.0 Hz), 1.29 (s, 6 H), 1.23 (s,
3 H), 1.20 (s, 3 H), 1.18-1.02 (m, 2 H), 1.00 (d, 3 H, J ) 6.5
Hz), 0.95-0.75 (m, 6 H); 13C NMR δ 201.5, 172.3, 171.6, 170.8,
170.4, 169.7, 168.9, 143.1, 142.8, 137.1, 129.3, 129.0, 127.6,
115.4, 114.8, 76.3, 75.0, 73.1, 66.9, 64.1, 63.0, 62.5, 60.9, 59.1,
57.9, 53.8, 48.9, 46.8, 41.6, 36.1, 31.7, 27.1, 25.9, 25.0, 22.1,
21.5, 16.6, 15.5, 11.4; MS (FAB) m/z (rel intensity) 878 ([M +
Na]+, 100); HRMS (FAB) m/z calcd for C43H65N7O9NaS (M +
Na) 878.4462, found 878.4478.
A suspension of this amine in THF (3.0 mL) was treated
with tetrabutylammonium hydroxide (TBAH, 40 wt %, 98 µL,
0.15 mmol) at 0 °C for 4 h. The reaction mixture was diluted
with CHCl3, washed with phosphate buffer (pH 5.5), dried
(Na2SO4), and concentrated to yield 60.1 mg (83% over two
steps) of amino acid that was used without further purification.
This amino acid (18.9 mg, 0.0195 mmol) and HATU (8.8 mg,
0.023 mmol) were dissolved in DMF (20 mL), and the coupling
reaction was initiated by addition of (i-Pr)2NEt (10.5 µL, 0.0585
mmol) at room temperature. The reaction mixture was stirred
for 7 d and treated with NaHCO3, and the solvents were
removed at reduced pressure. The residue was dissolved in
CHCl3 and washed with 10% citric acid, saturated aqueous
NaHCO3, and brine. The organic layer was dried (Na2SO4),
concentrated, and purified by preparative TLC (CHCl3/MeOH,
15:1) to give 7.1 mg of colorless solid that was dissolved in
THF (1.0 mL) and treated with NH4F (1.5 mg, 0.040 mmol)
and 1 M TBAF in THF (20 µL, 0.020 mmol). After 30 min, the
reaction mixture was dissolved in CHCl3, washed with 10%
citric acid and brine, dried (Na2SO4), and concentrated. The
purification of the residue by preparative TLC (CHCl3/MeOH,
15:1) yielded 5.2 mg (26% over four steps) of 27 as a colorless
solid: mp 167-169 °C; [R]D -94.0 (c 0.60, CHCl3, 23 °C); IR
(film) 3311, 1637, 1517, cm-1; 1H NMR δ 7.87 (d, 2 H, J ) 6.5
Hz), 7.34-7.16 (m, 5 H), 7.10 (d, 1 H, J ) 8.0 Hz), 7.00 (d, 1
H, J ) 8.6 Hz), 6.65 (d, 1 H, J ) 6.4 Hz), 6.47 (d, 1 H, J ) 4.9
Hz), 5.75 (dd, 1 H, J ) 10.6, 17.2 Hz), 5.73 (dd, 1 H, J ) 10.8
Hz, 17.5 Hz), 5.25-5.10 (m, 4 H), 4.79-4.64 (m, 3 H), 4.47-
4.42 (m, 2 H), 4.34 (d, 1 H, J ) 7.7 Hz), 4.23-4.04 (m, 3 H),
3.98-3.88 (m, 1 H), 3.80-3.70 (m, 1 H), 3.65-3.55 (m, 1 H),
3.43-3.32 (m, 3 H), 3.10-2.98 (m, 1 H), 2.33-2.27 (m, 1 H),
1.92-1.47 (m, 4 H), 1.40-1.10 (m, 20 H), 1.00-0.87 (m, 6 H);
13C NMR δ 172.2, 171.8, 171.0, 170.8, 170.4, 170.1, 169.6,
143.3, 142.9, 136.7, 129.8, 129.2, 129.0, 128.3, 127.5, 115.2,
114.6, 76.2, 75.9, 66.9, 64.2, 62.5, 61.2, 60.9, 57.9, 55.9, 54.4,
53.9, 48.8, 46.9, 38.3, 36.6, 31.7, 29.9, 27.0, 25.9, 25.8, 25.0,
24.8, 21.9, 21.4, 16.4, 15.4, 11.5; MS (EI) m/z (rel intensity)
839 (M+, 0.2), 822 (1), 753 (1), 727 (2); HRMS m/z calcd for
Cyclo[Ala -P r o-P h e-Ser (th ia z)-Th r (r p r en yl)-Ser (r p r e-
n yl)-Ile] (11). According to general procedure G, cyclo[Ala-
Pro-PheΨ{(CdS)NH}-Ser-Thr(rprenyl)-Ser(rprenyl)-Ile] (5.4
mg, 6.3 µmol) provided 4.0 mg (76%) of 11 as a colorless
amorphous solid: [R]D -10.4° (c 0.5, CHCl3, 22 °C); IR (neat)
1
3375, 1671, 1634 cm-1; H NMR (500 MHz) δ 8.38 (d, 1 H, J
) 6.9 Hz), 8.10 (d, 1 H, J ) 7.0 Hz), 7.49 (d, 1 H, J ) 7.0 Hz),
7.22 (d, 1 H, J ) 5.6 Hz), 7.12-7.08 (m, 3 H), 7.02-6.98 (m, 2
H), 6.19 (d, 1 H, J ) 10.0 Hz), 5.88 (dd, 1 H, J ) 10.8, 17.5
Hz), 5.68 (dd, 1 H, J ) 10.9, 17.5 Hz), 5.25 (d, 1 H, J ) 17.5
Hz), 5.22 (d, 1 H, J ) 10.6 Hz), 5.09 (d, 1 H, J ) 11.0 Hz), 5.06
(d, 1 H, J ) 18.4 Hz), 4.97-4.90 (m, 2 H), 4.78 (d, 1 H, J ) 7.8
Hz), 4.59 (dd, 1 H, J ) 2.9, 10.0 Hz), 4.56-4.51 (m, 2 H), 4.40-
4.38 (m, 1 H), 3.91 (p, 1 H, J ) 5.9 Hz), 3.83 (dd, 1 H, J ) 1.5,
9.0 Hz), 3.59 (t, 1 H, J ) 11.2 Hz), 3.54 (t, 1 H, J ) 11.1 Hz),
3.43 (dd, 1 H, J ) 3.2, 9.2 Hz), 3.41-3.24 (m, 2 H), 3.15 (dd,
1 H, J ) 5.5, 14.0 Hz), 2.87 (dd, 1 H, J ) 5.7, 14.1 Hz), 2.51-
2.47 (m, 1 H), 2.37-2.34 (m, 1 H), 1.93-1.80 (m, 2 H), 1.58-
1.50 (m, 1 H), 1.43 (s, 3 H), 1.34 (s, 3 H), 1.24-1.17 (m, 2 H),
1.21 (s, 3 H), 1.18 (s, 6 H), 1.11 (d, 3 H, J ) 6.6 Hz), 0.92-0.84
(m, 6 H); 13C NMR δ 172.8, 171.9, 170.8, 170.5, 169.9, 169.3,
142.8, 142.4, 136.5, 129.7, 128.3, 127.0, 115.9, 115.2, 77.9, 76.2,
67.4, 62.1, 59.8, 57.7, 56.5, 56.2, 53.7, 47.9, 47.4, 40.7, 36.6,
35.9, 29.9, 27.5, 26.0, 25.9, 25.6, 25.3, 24.0, 19.1, 18.5, 16.3,
12.3; MS (FAB) m/z (rel intensity), 838 ([M + H]+, 100), 860
([M + Na]+, 24); HRMS (FAB) m/z calcd for C43H63N7O8NaS
(M + Na) 860.4357, found 860.4314.
C
38H55N7O9 (M-C5H10O) 753.4061, found 753.4026.
Gen er a l P r oced u r e for Cyclod eh yd r a t ion w it h
G
DAST. Cyclo[Ala -P r o-P h e-Ser (oxa z)-Th r (r p r en yl)-Ser -
(r p r en yl)-Ile] (12). A solution of 27 (21.5 mg, 25.6 µmol) in
CH2Cl2 (0.2 mL) was cooled to -20 °C under a N2 atmosphere,
and a 0.28 M solution of DAST in CH2Cl2 (100 µL) was slowly
added. After 30 min, additional DAST solution (100 µL) was
added slowly. After stirring for an additional 30 min, the
reaction mixture was quenched at -20 °C with saturated
aqueous NaHCO3, warmed to room temperature, and treated
with additional saturated aqueous NaHCO3. The mixture was
extracted with CHCl3, dried (Na2SO4), and concentrated. The
purification of the residue by chromatography on SiO2 (CHCl3/
MeOH, 30:1) gave 13.2 mg (63%) of 12 as a colorless solid:
mp 148-150 °C; [R]D +9.8 (c 0.66, CHCl3, 22 °C); IR (film)
3371, 1666 cm-1; 1H NMR δ 8.21 (d, 1 H, J ) 6.7 Hz), 8.06, (d,
1 H, J ) 6.5 Hz), 7.47 (d, 1 H, J ) 6.8 Hz), 7.29-6.98 (m, 6
H), 6.22 (d, 1 H, J ) 9.7 Hz), 5.91 (dd, 1 H, J ) 10.7, 17.6 Hz),
5.73 (dd, 1 H, J ) 10.9, 17.6 Hz), 5.31 (d, 1 H, J ) 17.5 Hz),
5.29 (d, 1 H, J ) 10.6 Hz), 5.15 (d, 1 H, J ) 10.7 Hz), 5.11 (d,
1 H, J ) 17.6 Hz), 4.98-4.86 (m, 2 H), 4.76-4.54 (m, 5 H),
4.51-4.44 (m, 2 H), 3.98-3.86 (m, 2 H), 3.54-3.41 (m, 3 H),
3.17 (dd, 1 H, J ) 5.0, 13.9 Hz), 2.95 (dd, 1 H, J ) 5.2 Hz, 13.9
Hz), 2.61-2.54 (m, 1 H), 2.45-2.39 (m, 1 H), 2.06-1.86 (m, 2
H), 1.76-1.56 (m, 1 H), 1.48 (s, 3 H), 1.39 (s, 3 H), 1.27 (s, 3
F m oc-Ala -P r o-D-P h e-OBn (37). According to general pro-
cedure C, Fmoc-Ala-Pro-OH (1.36 g, 3.33 mmol) and D-Phe-
OBn‚TsOH (1.43 g, 3.33 mmol) provided 1.78 g (83%) of 37 as
a colorless amorphous wax: [R]D -53.0 (c 0.27, CHCl3, 22 °C);
1
IR (film) 3399, 3307, 3059, 3032, 1716, 1680 cm-1; H NMR
(methanol-d4) δ 7.73 (d, 2 H, J ) 7.3 Hz), 7.65-7.50 (m, 2 H),
7.38-7.00 (m, 14 H), 5.08 (s, 2 H), 4.72-4.58 (m, 1 H), 4.40-
4.20 (m, 3 H), 4.14 (t, 1 H, J ) 6.4 Hz), 4.10-3.90 (m, 1 H),
3.70-3.53 (m, 1 H), 3.50-3.40 (m, 1 H), 3.17 (dd, 1 H, J )
5.4, 13.7 Hz), 2.95 (dd, 1 H, J ) 9.0, 13.7 Hz), 2.05-1.83 (m,
1 H), 1.80-1.65 (m, 2 H), 1.63-1.50 (m, 1 H), 1.23 (d, 3 H, J

1046 J . Org. Chem., Vol. 65, No. 4, 2000
Wipf and Uto
) 6.9 Hz); 13C NMR (methanol-d4) δ 174.2, 174.0, 172.5, 158.4,
145.4, 145.3, 142.7, 138.1, 137.2, 130.6, 129.7, 129.5, 128.9,
128.3, 128.0, 126.3, 121.1, 68.2, 68.0, 61.4, 55.2, 38.8, 30.4, 25.9,
17.2; MS (EI) m/z (rel intensity) 645 (M+, 0.4), 449 (3), 167
(68); HRMS m/z calcd for C39H39N3O6 645.2839, found 645.2856.
F m oc-Ala -P r o-D-P h e-Ser (TBS)-OBn (28). According to
general procedure D, Fmoc-Ala-Pro-D-Phe-OBn (37, 1.78 g,
2.75 mmol) and L-Ser-(TBS)-OBn (0.836 g, 2.70 mmol) provided
1.59 g (68% over two steps) of 28 as a colorless foam: [R]D
-37.1 (c 0.35, CHCl3, 22 °C); IR (film) 3329, 3030, 1743, 1704,
1650 cm-1; 1H NMR (methanol-d4) δ 7.79 (d, 2 H, J ) 7.5 Hz),
7.64 (t, 2 H, J ) 6.3 Hz), 7.42-7.17 (m, 14 H), 5.16 (s, 2 H),
4.73 (dd, 1 H, J ) 4.9, 9.7 Hz), 4.56 (t, 1 H, J ) 4.8 Hz), 4.42-
4.30 (m, 4 H), 4.23-4.13 (m, 1 H), 3.98-3.82 (m, 2 H), 3.72-
3.62 (m, 1 H), 3.56-3.48 (m, 1 H), 3.25 (dd, 1 H, J ) 5.1, 14.0
Hz), 2.82 (dd, 1 H, J ) 13.9, 10.0 Hz), 2.01-1.90 (m, 1 H),
1.90-1.78 (m, 2 H), 1.61-1.48 (m, 1 H), 1.28 (d, 3 H, J ) 6.9
Hz), 0.85 (s, 9 H), 0.02 (s, 3 H), 0.00 (s, 3 H); 13C NMR
(methanol-d4) δ 174.3, 173.7, 173.2, 171.5, 158.1, 145.4, 145.3,
142.7, 138.7, 137.1, 130.5, 129.7, 129.5, 128.9, 128.3, 127.9,
126.3, 121.1, 68.2, 68.0, 64.1, 61.7, 56.4, 55.5, 48.5, 38.9, 30.3,
26.5, 26.0, 19.2, 17.5, -5.1, -5.2; MS (EI) m/z (rel intensity)
790 ([M - C4H8]+, 2), 567 (100), 310 (55), 178 (55); HRMS m/z
calcd for C44H50N4O8Si (M - C4H8) 790.3398, found 790.3404.
F m oc-Ala -P r o-D-P h e-Ser (TBS)-Th r (r p r en yl)-Ser (r p r e-
n yl)-Ile-OMe (29). According to general procedure E, Fmoc-
Ala-Pro-D-Phe-Ser(TBDMS)-OBn (28, 0.964 g, 1.14 mmol) and
amine 25 (0.490 g, 1.04 mmol) provided 0.702 g (51% over two
steps) of 29 as a colorless foam: [R]D +8.8 (c 0.43, CHCl3, 22
was diluted with CHCl3, washed with 10% citric acid and
brine, and dried (Na2SO4). Chromatography on SiO2 (CHCl3/
MeOH, 40:1) yielded 57.6 mg (38% over four steps) of 30 as a
colorless solid: mp 162-164 °C; [R]D -12.4 (c 0.33, CHCl3, 22
°C); IR (film) 3319, 1643 cm-1; 1H NMR δ 8.13 (d, 1 H, J ) 8.1
Hz), 7.77 (d, 1 H, J ) 7.5 Hz), 7.32-7.15 (m, 8 H), 6.80 (d, 1
H, J ) 5.4 Hz), 5.82 (dd, 1 H, J ) 10.8 Hz, 17.5 Hz), 5.80 (dd,
1 H, J ) 10.8, 17.8 Hz), 5.21-5.09 (m, 4 H), 4.96 (d, 1 H, J )
7.4 Hz), 4.80-4.65 (m, 3 H), 4.48-4.44 (m, 1 H), 4.34 (d, 1 H,
J ) 7.6 Hz), 4.22-4.15 (m, 2 H), 4.02-3.88 (m, 2 H), 3.72 (d,
1 H, J ) 11.0 Hz), 3.61-3.52 (m, 2 H), 3.48-3.43 (m, 1 H),
3.31 (dd, 1 H, J ) 5.0, 14.4 Hz), 3.04 (dd, 1 H, J ) 9.3, 14.3
Hz), 2.22-2.10 (m, 1 H), 2.10-1.80 (m, 3 H), 1.32 (s, 3 H),
1.29 (s, 3 H), 1.26 (s, 6 H), 1.15 (d, 3 H, J ) 6.3 Hz),1.20-1.00
(m, 6 H), 0.98-0.85 (m, 6 H); 13C NMR δ 172.3, 171.7, 171.4,
171.2, 171.1, 170.0, 169.7, 143.6, 142.4, 137.1, 129.2, 128.8,
127.1, 115.5, 114.4, 77.0, 76.6, 66.9, 65.0, 62.6, 61.5, 59.5, 59.1,
54.7, 54.5, 53.2, 48.0, 46.7, 37.5, 35.9, 29.3, 27.6, 26.0, 25.9,
25.8, 25.5, 24.6, 20.7, 17.0, 16.4, 12.0; HRMS (FAB) m/z calcd
for C43H65N7O10Na (M + Na) 862. 4691, found 862.4763.
Cyclo[Ala -P r o-D-P h e-Ser (oxa z)-Th r (r p r en yl)-Ser (r p r e-
n yl)-Ile]. According to general procedure G, 30 (44.8 mg, 53.4
µmol) provided 40.7 mg (93%) of cyclo[Ala-Pro-D-Phe-Ser(oxaz)-
Thr(rprenyl)-Ser(rprenyl)-Ile] as a colorless solid: mp 147-
149 °C; [R]D +14.6 (c 0.35, CHCl3, 22 °C); IR (film) 3380, 1664
1
cm-1; H NMR δ 7.87 (d, 1 H, J ) 6.5 Hz), 7.48 (d, 1 H, J )
7.9 Hz), 7.30-7.22 (m, 4 H), 7.10-7.07 (m, 2 H), 6.92 (d, 1 H,
J ) 7.5 Hz), 6.32 (d, 1 H, J ) 9.8 Hz), 5.90 (dd, 1 H, J ) 10.7,
17.6 Hz), 5.73 (dd, 1 H, J ) 10.9, 17.6 Hz), 5.27 (d, 1 H, J )
17.5 Hz), 5.24 (d, 1 H, J ) 10.7 Hz), 5.15 (d, 1 H, J ) 10.8 Hz),
5.11 (d, 1 H, J ) 17.6 Hz), 4.99 (dd, 1 H, J ) 6.9, 12.6 Hz),
4.64-4.55 (m, 5 H), 4.53-4.48 (m, 2 H), 4.42-4.37 (m, 1 H),
4.01 (p, 1 H, J ) 5.7 Hz), 3.90 (dd, 1 H, J ) 1.8, 9.0 Hz), 3.55-
3.47 (m, 2 H), 3.43 (dd, 1 H, J ) 3.2, 9.0 Hz), 3.20 (dd, 1 H, J
) 5.0, 13.7 Hz), 2.93 (dd, 1 H, J ) 6.8, 13.7 Hz), 2.42-2.35
(m, 1 H), 2.22-2.13 (m, 1 H), 2.00-1.78 (m, 3 H), 1.47 (s, 3
H), 1.37 (s, 3 H), 1.40-1.30 (m, 2 H), 1.26 (s, 3 H), 1.24 (s, 3
H), 1.21 (d, 3 H, J ) 6.6 Hz), 1.03 (d, 3 H, J ) 6.5 Hz), 0.96-
0.80 (m, 6 H); 13C NMR δ 171.6, 171.0, 170.8, 170.5, 170.2,
169.0, 168.7, 142.8, 142.2, 136.0, 129.6, 128.6, 127.3, 115.9,
115.2, 78.0, 76.1, 71.5, 68.1, 67.3, 62.4, 60.1, 58.0, 56.5, 55.4,
48.2, 48.0, 47.3, 39.1, 36.6, 28.9, 27.4, 26.0, 25.9, 25.8, 25.7,
23.7, 18.6, 18.1, 16.2, 12.2; MS (FAB) m/z (rel intensity) 844
([M + Na]+, 100), 822([M + H]+, 30); HRMS (FAB) m/z calcd
for C43H64N7O9 (M + H) 822.4766, found 822.4811.
1
°C); IR (film) 3301, 1642 cm-1; H NMR (methanol-d4) δ 7.78
(d, 2 H, J ) 6.8 Hz), 7.70-7.52 (m, 2 H), 7.40-7.10 (m, 9 H),
5.92 (dd, 1 H, J ) 10.9, 17.4 Hz), 5.77 (dd, 1 H, J ) 10.6, 17.6
Hz), 5.25-5.05 (m, 4 H), 4.70-4.60 (m, 1 H), 4.54-4.48 (m, 1
H), 4.47-4.36 (m, 4 H), 4.35-4.23 (m, 3 H), 4.42-4.12 (m, 1
H), 4.05-3.97 (m, 1 H), 3.92-3.78 (m, 2 H), 3.67 (s, 3 H), 3.72-
3.60 (m, 2 H), 3.58-3.45 (m, 1 H), 3.43-3.33 (m, 1 H), 3.33-
3.23 (m, 1 H), 2.86 (t, 1 H, J ) 12 Hz), 2.00-1.77 (m, 3 H),
1.60-1.00 (m, 22 H), 0.92-0.75 (m, 6 H), 0.87 (s, 9 H), 0.06 (s,
6 H); 13C NMR (benzene-d6) δ 172.9, 172.4, 172.1, 171.4, 171.0,
170.4, 169.7, 156.4, 145.0, 144.8, 143.9, 143.6, 142.1, 138.3,
130.2, 129.0, 127.2, 126.0, 125.9, 123.3, 120.6, 115.1, 114.9,
77.8, 76.5, 68.3, 67.4, 64.0, 63.3, 60.6, 58.7, 57.2, 55.1, 54.0,
51.8, 49.2, 48.0, 47.0, 38.5, 28.4, 26.6, 26.2, 26.0, 25.8, 25.6,
25.4, 18.8, 17.9, 16.0, 12.0, -4.8; MS (FAB) m/z (rel intensity)
1247 ([M + K], 100).
Cyclo[Ala -P r o-D-P h e-Ser -Th r (r ev)-Ser (r ev)-Ile] (30). A
solution of Fmoc-Ala-Pro-D-Phe-Ser(TBS)-Thr(rprenyl)-Ser-
(rprenyl)-Ile-OMe (29, 218 mg, 0.180 mmol) in CH2Cl2 (5.0 mL)
was treated with tris(2-aminoethyl)amine (TAEA, 0.45 mL, 3.0
mmol) at room temperature for 30 min. The reaction mixture
was diluted with CHCl3 and washed with brine and phosphate
buffer (pH 5.5). Additional CHCl3 was used for back extraction.
The combined organic layers were dried (Na2SO4) and con-
centrated. The purification of the residue by chromatography
on a short plug of SiO2 (EtOAc, then CHCl3/MeOH, 5:1) yielded
210 mg of amine as a colorless solid.
A solution of TBAH (40 wt %) in THF (0.072 M, 5.0 mL)
was added slowly at 0 °C to this amine. The reaction mixture
was stirred for 4 h at 0 °C. The reaction mixture was diluted
with CHCl3, washed with phosphate buffer (pH 5.5), dried
(Na2SO4), and then concentrated to yield 142.3 mg (82% over
two steps) of amino acid that was used without further
purification.
To a solution of this amino acid in CH2Cl2 (98 mL) was
added at 0 °C a solution of TBTU (144 mg, 0.447 mmol) in
acetonitrile (3.0 mL), followed by HOAt (59.7 mg, 0.441 mmol).
After addition of (i-Pr)2NEt (0.98 mL, 1% v/v) over a period of
15 min at 0 °C, the reaction mixture was stirred for 2 h at 0
°C and then for 3 d at room temperature. The solution was
washed with 10% citric acid, saturated aqueous NaHCO3, and
brine, dried (Na2SO4), and concentrated. Chromatography on
a short plug of SiO2 (CHCl3/MeOH, 20:1) yielded 102.1 mg of
a colorless solid, which was mixed with NH4F (11.7 mg, 0.316
mmol), dissolved in THF (15 mL), and treated with 1 M TBAF
in THF (150 µL, 0.150 mmol) for 30 min. The reaction mixture
Cyclo[Ala -P r o-D-P h eΨ{(CdS)NH }-Ser -Th r (r p r en yl)-
Ser (r p r en yl)-Ile]. According to general procedure H, cyclo-
[Ala-Pro-D-Phe-Ser(oxaz)-Thr(rprenyl)-Ser(rprenyl)-Ile] (36 mg,
44 µmol) provided 28 mg (74%) of cyclo[Ala-Pro-D-PheΨ{(Cd
S)NH}-Ser-Thr(rprenyl)-Ser(rprenyl)-Ile] as a colorless solid:
mp 150-152 °C; [R]D +0.5 (c 0.40, CHCl3, 22 °C); IR (film)
1
3304, 1675 cm-1; H NMR δ 9.03 (bs, 1 H), 8.12 (d, 1 H, J )
7.4 Hz), 7.32-7.21 (m, 6 H), 7.08 (bs, 1 H), 6.83 (bs, 1 H), 6.76
(bs, 1 H), 5.81 (dd, 1 H, J ) 10.8, 17.5 Hz), 5.80 (dd, 1 H, J )
10.4, 17.8 Hz), 5.70 (d, 1 H, J ) 6.7 Hz), 5.19 (d, 1 H, J ) 11.4
Hz), 5.18 (d, 1 H, J ) 16.9 Hz), 5.14 (d, 1 H, J ) 17.3 Hz), 5.11
(d, 1 H, J ) 10.8 Hz), 5.12-5.08 (m, 1 H), 4.78-4.60 (m, 2 H),
4.43 (d, 1 H, J ) 6.2 Hz), 4.35 (d, 1 H, J ) 6.9 Hz), 4.19 (d, 2
H, J ) 6.2 Hz), 4.05-3.95 (m, 1 H), 3.90-3.80 (m, 1 H), 3.77-
3.65 (m, 1 H), 3.60-3.44 (m, 4 H), 3.03 (dd, 1 H, J ) 9.6, 14.1
Hz), 2.20-1.70 (m, 6 H), 1.52-1.40 (m, 1 H), 1.32 (s, 6 H),
1.26 (s, 6 H), 1.30-1.10 (m, 4 H), 1.15 (d, 3 H, J ) 6.3 Hz),
0.97-0.85 (m, 6 H); 13C NMR δ 202.8, 172.4, 171.4, 171.2,
169.7, 169.3, 168.5, 143.6, 142.3, 137.0, 129.2, 128.9, 127.2,
115.6, 114.4, 79.2, 67.0, 62.8, 62.0, 61.2, 59.9, 59.1, 52.7, 47.9,
46.7, 35.9, 29.2, 27.6, 26.1, 25.9, 25.6, 24.6, 21.0, 16.9, 16.4,
12.0; MS (FAB) m/z (rel intensity) 878 ([M + Na]+, 100).
Cyclo[Ala -P r o-D -P h e -Se r (t h ia z)-Th r (r p r e n yl)-Se r -
(r p r en yl)-Ile] (31). According to general procedure G, cyclo-
[Ala-Pro-D-PheΨ{(CdS)NH}-Ser-Thr(rprenyl)-Ser(rprenyl)-
Ile] (27.6 mg, 32.6 µmol) provided 23.1 mg (85%) of 31 as a
colorless amorphous solid: [R]D -4.1 (c 0.32 CHCl3, 22 °C); IR
(film) 3375, 3054, 1669 cm-1; 1H NMR (500 MHz) δ 7.95 (d, 1
H, J ) 6.7 Hz), 7.56 (d, 1 H, J ) 7.9 Hz), 7.27-7.22 (m, 4 H),
7.22 (d, 1 H, J ) 7.6 Hz), 7.14-7.10 (m, 2 H), 6.32 (d, 1 H, J

Synthesis and Stereochemistry of Trunkamide A
J . Org. Chem., Vol. 65, No. 4, 2000 1047
) 9.7 Hz), 5.91 (dd, 1 H, J ) 10.7, 17.5 Hz), 5.73 (dd, 1 H, J
) 10.9, 17.4 Hz), 5.27 (d, 1 H, J ) 19.4 Hz), 5.24 (d, 1 H, J )
10.9 Hz), 5.30-5.10 (m, 1 H), 5.15 (d, 1 H, J ) 10.9 Hz), 5.12
(d, 1 H, J ) 17.7 Hz), 4.92 (t, 1 H, J ) 9.6 Hz), 4.62-4.55 (m,
3 H), 4.52-4.47 (m, 1 H), 4.41-4.38 (m, 1 H), 4.02 (p, 1 H, J
) 6.0 Hz), 3.89 (dd, 1 H, J ) 1.5, 9.5 Hz), 3.72 (t, 1 H, J )
10.5 Hz), 3.62 (t, 1 H, J ) 10.5 Hz), 3.55-3.47 (m, 2 H), 3.45
(dd, 1 H, J ) 3.1, 9.2 Hz), 3.15 (dd, 1 H, J ) 5.5, 14.0 Hz),
2.93 (dd, 1 H, J ) 6.0, 13.9 Hz), 2.39-2.31 (m, 1 H), 2.26-
2.18 (m, 1 H), 1.97-1.81 (m, 3 H), 1.48 (s, 3 H), 1.38 (s, 3 H),
1.33-1.20 (m, 2 H), 1.27 (s, 3 H), 1.24 (s, 3 H), 1.21 (d, 3 H, J
) 6.6 Hz), 1.06 (d, 3 H, J ) 6.6 Hz), 0.98-0.90 (m, 6 H); 13C
NMR δ 173.5, 171.3, 171.0, 170.6, 170.3, 170.1, 168.7, 142.7,
142.2, 135.8, 129.8, 128.5, 127.3, 116.0, 115.1, 78.3, 78.0, 76.1,
67.4, 62.3, 60.0, 58.0, 56.6, 55.4, 52.8, 47.8, 47.2, 40.2, 36.6,
36.4, 28.7, 27.5, 25.9, 25.8, 25.7, 23.8, 18.7, 18.1, 16.2, 12.1;
MS (FAB) m/z (rel intensity) 860 ([M + Na]+, 100), 838 ([M +
H]+, 34); HRMS (FAB) m/z calcd for C43H64N7O8S (M + H)
838.4537, found 838.4588.
solid: mp 143-145 °C; [R]D -59.4 (c 0.48, CHCl3, 22 °C); IR
(film) 3319, 1642 cm-1 1H NMR (methanol-d4) δ 7.40-7.10
;
(m, 5 H), 5.86 (dd, 2 H, J ) 10.8, 17.6 Hz), 5.22-5.03 (m, 4
H), 4.63-4.52 (m, 2 H), 4.52-4.47 (m, 2 H), 4.45-4.35 (m, 1
H), 4.29 (d, 1 H, J ) 7.2 Hz), 4.14 (dd, 1 H, J ) 2.6, 6.4 Hz),
3.98 (d, 1 H, J ) 2.4 Hz), 3.87 (dd, 1 H, J ) 4.2, 10.9 Hz), 3.75
(dd, 1 H, J ) 4.7, 9.3 Hz), 3.70 (dd, 1 H, J ) 6.3, 10.7 Hz),
3.61 (dd, 1 H, J ) 4.6, 9.5 Hz), 3.38-3.25 (m, 2 H), 3.09 (t, 1
H, J ) 13 Hz), 2.78 (t, 1 H, J ) 10.3 Hz), 2.39-2.32 (m, 1 H),
2.12-2.00 (m, 1 H), 1.90-1.77 (m, 1 H), 1.67-1.50 (m, 2 H),
1.30 (s, 6 H), 1.28 (s, 3 H), 1.25 (s, 3 H), 1.25 (d, 3 H, J ) 5.9
Hz), 1.20-1.10 (m, 2 H), 1.06 (d, 3 H, J ) 6.7 Hz), 1.0-0.80
(m, 6 H); 13C NMR δ 173.0, 171.8, 170.7, 170.2, 142.5, 142.1,
137.5, 128.8, 128.5, 126.8, 115.8, 115.1, 78.1, 76.7, 66.9, 62.3,
60.8, 57.6, 56.9, 56.2, 47.7, 28.6, 27.2, 25.6, 24.2, 17.9, 16.4;
HRMS (FAB) m/z calcd for C43H66N7O10 (M + H) 840.4871,
found 840.4898.
Cyclo[Ala -P r o-P h e-D-Ser (oxa z)-Th r (r p r en yl)-Ser (r p r e-
n yl)-Ile]. According to general procedure G, 35 (65.7 mg, 78.3
µmol) provided 47.8 mg (74%) of cyclo[Ala-Pro-Phe-D-Ser(oxaz)-
Thr(rprenyl)-Ser(rprenyl)-Ile] as a colorless solid: mp 193-
195 °C; [R]D -37.8 (c 0.55, CHCl3, 22 °C); IR (film) 3349, 1651
F m oc-Ala -P r o-P h e-D-Ser (TBS)-OBn (33). According to
general procedure D, 32 (1.87 g, 3.36 mmol) and D-Ser(TBS)-
OBn (1.04 g, 3.36 mmol) provided 2.61 g (88% over two steps)
of 33 as a colorless amorphous solid: [R]D -52.6 (c 0.43, CHCl3,
1
cm-1; H NMR δ 8.00 (d, 1 H, J ) 4.2 Hz), 7.80 (d, 1 H, J )
1
22 °C); IR (film) 3411, 3301, 3059, 1739, 1719 cm-1; H NMR
7.8 Hz), 7.72 (d, 1 H, J ) 4.4 Hz), 7.25-7.18 (m, 3 H), 6.98-
6.92 (m, 3 H), 5.97 (d, 1 H, J ) 10.2 Hz), 5.92 (dd, 1 H, J )
10.8, 17.6 Hz), 5.74 (dd, 1 H, J ) 10.6, 17.8 Hz), 5.27 (d, 1 H,
J ) 16.2 Hz), 5.22 (d, 1 H, J ) 10.7 Hz), 5.14 (d, 1 H, J ) 10.7
Hz), 5.13 (d, 1 H, J ) 17.5 Hz), 4.89-4.76 (m, 3 H), 4.70-4.60
(m, 2 H), 4.51 (t, 1 H, J ) 10.6 Hz), 4.40-4.23 (m, 4 H), 3.83
(dd, 1 H, J ) 2.8, 9.4 Hz), 3.57 (dd, 1 H, J ) 3.4, 9.4 Hz), 3.54-
3.50 (m, 1 H), 3.40-3.30 (m, 2 H), 3.04 (dd, 1 H, J ) 3.1, 13.7
Hz), 2.48-2.41 (m, 2 H), 2.08-1.90 (m, 3 H), 1.49 (s, 3 H),
1.39 (s, 3 H), 1.27 (s, 3 H), 1.25 (s, 3 H), 1.22-1.18 (m, 2 H),
1.10 (d, 3 H, J ) 6.9 Hz), 1.02 (d, 3 H, J ) 6.4 Hz), 0.98-0.8
(m, 6 H); 13C NMR 172.3, 170.8, 170.7, 170.4, 170.1, 169.8,
168.6, 142.8, 142.3, 136.0, 129.7, 128,1, 127.1, 115.9, 115.1,
78.4, 75.9, 70.4, 69.0, 66.0, 61.6, 60.7, 57.6, 57.3, 57.1, 49.3,
47.3, 46.7, 37.4, 35.5, 28.0, 25.8, 25.6, 25.3, 25.1, 24.5, 20.1,
17.9, 16.5, 12.5; MS (FAB) m/z (rel intensity) 860 ([M + K]+,
13), 844 ([M + Na]+, 39), 822 ([M + H]+, 62), 686 (100); HRMS
(FAB) m/z calcd for C43H63N7O9Na (M + Na) 844.4585, found
844.4612.
(methanol-d4, major rotamer) δ 7.80 (d, 2 H, J ) 7.4 Hz), 7.65
(d, 2 H, J ) 7.5 Hz), 7.45-7.15 (m, 14 H), 5.16 (s, 2 H), 4.72
(t, 1 H, J ) 7 Hz), 4.55-4.44 (m, 1 H), 4.43-4.25 (m, 4 H),
4.25-4.18 (m, 1 H), 3.90 (dd, 1 H, J ) 4.4, 10.3 Hz), 3.75-
3.62 (m, 2 H), 3.60-3.47 (m, 1 H), 3.14 (dd, 1 H, J ) 7, 13.7
Hz), 2.97 (dd, 1 H, J ) 7.5, 13.8 Hz), 2.25-2.00 (m, 1 H), 2.00-
1.75 (m, 3 H), 1.30 (d, 3 H, J ) 6.8 Hz), 0.84 (s, 9 H), -0.00 (s,
3 H), -0.01 (s, 3 H); 13C NMR (benzene-d6) δ 173.1, 171.8,
171.4, 170.9, 156.5, 144.9, 142.1, 138.0, 136.4, 130.3, 130.0,
129.0, 127.8, 127.3, 126.0, 120.6, 67.4, 64.0, 60.9, 55.3, 54.4,
49.1, 48.0, 47.3, 38.0, 28.6, 26.3, 25.3, 18.7, 18.6, -5.1, -5.3;
MS (FAB) m/z (rel intensity) 885 ([M + K]+, 74), 869 ([M +
Na]+, 39), 847 ([M + H]+, 100); HRMS (FAB) m/z calcd for
C
48H58N4O8NaSi (M + Na) 869.3922, found 869.3948.
Gen er a l P r oced u r e I for Segm en t Con d en sa tion w ith
HATU. F m oc-Ala -P r o-P h e-D-Ser (TBS)-Th r (r p r en yl)-Ser -
(r p r en yl)-Ile-OMe (34). A solution of 33 (2.28 g, 2.69 mmol)
in EtOAc/EtOH (2:1, 50 mL) was treated with Pd/C (10% Pd,
146 mg) and H2 gas for 12 h. The reaction mixture was filtered
through a plug of Celite and concentrated. Chromatography
on SiO2 (CHCl3/MeOH, 1:0, 20:1, and 5:1) yielded 1.55 g (76%)
of the acid as a colorless solid. This acid (41.3 mg, 54.5 µmol),
amine 25 (25.5 mg, 54.5 µmol), and HATU (20.7 mg, 54.5 µmol)
were dissolved in DMF (0.5 mL), and the coupling reaction
was initiated by addition of (i-Pr)2NEt (19 µL, 0.11 mmol). The
reaction mixture was stirred at room temperature for 2 h and
diluted with CHCl3, and the organic layer was washed with
10% citric acid, saturated aqueous NaHCO3, and brine and
dried (Na2SO4). Chromatography on SiO2 (hexanes/EtOAc, 1:2,
then 1:4) yielded 55.1 mg (64% over two steps) of 34 as a
colorless foam: [R]D -14.4 (c 0.50, CHCl3, 22 °C); IR (film)
Cyclo[Ala -P r o-P h eΨ{(CdS)NH }-D-Ser -Th r (r p r en yl)-
Ser (r p r en yl)-Ile]. According to general procedure H, cyclo-
[Ala-Pro-Phe-D-Ser(oxaz)-Thr(rprenyl)-Ser(rprenyl)-Ile] (32.7
mg, 39.8 µmol) provided 31.5 mg (93%) of cyclo[Ala-Pro-PheΨ-
{(CdS)NH}-D-Ser-Thr(rprenyl)-Ser(rprenyl)-Ile] as a colorless
solid: mp 145-147 °C; [R]D +22.9 (c 0.58, CHCl3, 22 °C); IR
(film) 3388, 1644 cm-1 1H NMR (methanol-d4) δ 9.35-9.25
;
(bs, 1 H), 8.78-8.68 (bs, 1 H), 8.58-8.48 (bs, 1 H), 8.45-8.35
(bs, 1 H), 7.49 (d, 1 H, J ) 7.5 Hz), 7.32-7.15 (m, 5 H), 6.95-
6.85 (bs, 1 H), 5.81 (dd, 2 H, J ) 11.5, 17.1 Hz), 5.25-5.03 (m,
6 H), 4.59-4.44 (m, 2 H), 4.43-4.30 (m, 2 H), 4.15-4.05 (m, 2
H), 3.97-3.85 (m, 3 H), 3.70 (dd, 1 H, J ) 4.7, 9.4 Hz), 3.63-
3.50 (m, 2 H), 3.24-3.05 (m, 1 H), 2.85-2.75 (m, 1 H), 2.33-
2.21 (m, 1 H), 2.18-2.05 (m, 1 H), 1.92-1.78 (m, 1 H), 1.65-
1.45 (m, 2 H), 1.43-1.35 (m, 1 H), 1.27 (s, 6 H), 1.30-1.00 (m,
7 H), 1.20 (s, 3 H), 1.00 (d, 3 H, J ) 6.7 Hz), 0.95-0.83 (m, 6
H); 13C NMR (methanol-d4) δ 203.4, 174.2, 173.7, 173.3, 173.1,
172.4, 145.1, 144.2, 139.3, 130.3, 129.9, 129.6, 128.1, 115.7,
115.0, 77.5, 68.6, 64.1, 63.4, 63.1, 62.4, 61.8, 59.5, 56.9, 47.6,
40.9, 31.5, 27.3, 26.6, 26.4, 26.1, 22.5, 21.4, 16.9, 16.5, 15.8,
12.2; MS (FAB) m/z (rel intensity) 894 ([M + K]+, 19), 878 ([M
+ Na]+, 100); HRMS (FAB) m/z calcd for C43H65N7O9NaS (M
+ Na) 878.4462, found 878.4479.
1
3310, 1650 cm-1; H NMR (methanol-d4) δ 7.80 (d, 2 H, J )
7.5 Hz), 7.70-7.60 (m, 2 H), 7.45-7.10 (m, 9 H), 5.94 (dd, 1
H, J ) 10.7, 17.6 Hz), 5.83 (dd, 1 H, J ) 10.9, 17.7 Hz), 5.25-
5.05 (m, 4 H), 4.65-4.50 (m, 2 H), 4.45-4.30 (m, 7 H), 4.21 (t,
2 H, J ) 6.5 Hz), 4.05-3.97 (m, 1 H), 3.85-3.60 (m, 3 H), 3.67
(s, 3 H), 3.57-3.48 (m, 2 H), 3.20-3.10 (m, 1 H), 3.04-2.95
(m, 1 H), 2.15-2.00 (m, 1 H), 1.97-1.65 (m, 4 H), 1.55-1.46
(m, 1 H), 1.38 (s, 3 H), 1.33 (s, 3 H), 1.30 (s, 6 H), 1.30-1.22
(m, 3 H), 1.10 (d, 3 H, J ) 6.4 Hz), 1.08-0.99 (m, 1 H), 0.98-
0.87 (m, 6 H), 0.90 (s, 9 H), 0.05 (s, 6 H); 13C NMR δ 172.7,
172.2, 171.1, 170.8, 170.1, 169.6, 168.8, 155.9, 144.1, 142.9,
141.4, 136.8, 129.4, 128.7, 127.9, 127.2, 125.3, 120.1, 115.1,
114.8, 76.0, 67.3, 67.2, 63.0, 62.8, 60.4, 57.8, 56.8, 55.0, 54.4,
53.4, 52.1, 48.5, 47.5, 47.3, 37.9, 28.1, 27.5, 26.0, 25.7, 25.4,
25.2, 25.0, 18.4, 17.3, 15.6, 11.6, -5.3; MS (FAB) m/z (rel
intensity) 1246 ([M + K]+, 27), 1230 ([M + Na]+, 100), 1208
([M + H]+, 39).
Cyclo[Ala -P r o-P h e -D -Se r (t h ia z)-Th r (r p r e n yl)-Se r -
(r p r en yl)-Ile] (36). According to general procedure G, cyclo-
[Ala-Pro-PheΨ{(CdS)NH}-D-Ser-Thr(rprenyl)-Ser(rprenyl)-
Ile] (19.5 mg, 22.8 µmol) provided 12.1 mg (64%) of 36 as a
colorless amorphous solid: [R]D -36.6 (c 0.50, CHCl3, 22 °C);
IR (film) 3354, 1666 cm-1 1H NMR δ 8.03 (d, 1 H, J ) 5.4
;
Hz), 7.98 (d, 2 H, J ) 4.8 Hz), 7.51 (d, 1 H, J ) 7.0 Hz), 7.20-
7.08 (m, 3 H), 7.02-6.90 (m, 2 H), 6.10 (d, 1 H, J ) 10.1 Hz),
5.94 (dd, 1 H, J ) 10.7, 17.5 Hz), 5.75 (dd, 1 H, J ) 11.3, 17.1
Hz), 5.29 (d, 1 H, J ) 16.8 Hz), 5.25 (d, 1 H, J ) 10.2 Hz), 5.15
Cyclo[Ala -P r o-P h e-D-Ser -Th r (r p r en yl)-Ser (r p r en yl)-
Ile] (35). According to general procedure F, 34 (38.8 mg, 32.1
µmol) provided 5.7 mg (21% over four steps) of 35 as a colorless

1048 J . Org. Chem., Vol. 65, No. 4, 2000
Wipf and Uto
(d, 1 H, J ) 10.5 Hz), 5.14 (d, 1 H, J ) 17.8 Hz), 5.05-4.95
(m, 1 H), 4.81 (d, 1 H, J ) 7.4 Hz), 4.77-4.67 (m, 1 H), 4.65-
4.58 (m, 2 H), 4.56 (t, 1 H, J ) 5.0 Hz), 4.38-4.30 (m, 1 H),
4.30-4.20 (m, 1 H), 3.84 (dd, 1 H, J ) 2.2, 9.3 Hz), 3.70 (dd,
1 H, J ) 8.7, 11.0 Hz), 3.53-3.43 (m, 2 H), 3.40-3.20 (m, 3
H), 2.96 (dd, 1 H, J ) 3.3, 13.7 Hz), 2.68-2.55 (m, 1 H), 2.48-
2.38 (m, 1 H), 2.13-1.97 (m, 1 H), 1.97-1.75 (m, 2 H), 1.52 (s,
3 H), 1.41 (s, 3 H), 1.28 (s, 3 H), 1.25 (s, 3 H), 1.21-1.10 (m, 2
H), 1.07 (d, 3 H, J ) 6.5 Hz), 1.00-0.82 (m, 9 H); 1H NMR
(500 MHz) δ 8.03 (d, 1 H, J ) 5.4 Hz), 7.98 (t, 2 H, J ) 4.6
Hz), 7.52 (d, 1 H, J ) 7.1 Hz), 7.22-7.15 (m, 3 H), 7.03-6.98
(m, 2 H), 6.11 (d, 1 H, J ) 10.1 Hz), 5.95 (dd, 1 H, J ) 10.8,
17.6 Hz), 5.75 (dd, 1 H, J ) 11.0, 17.4 Hz), 5.30 (d, 1 H, J )
17.6 Hz), 5.26 (d, 1 H, J ) 10.8 Hz), 5.15 (d, 1 H, J ) 10.7 Hz),
5.14 (d, 1 H, J ) 17.7 Hz), 5.06-5.00 (m, 1 H), 4.82 (d, 1 H, J
) 7.8 Hz), 4.75 (t, 1 H, J ) 6.8 Hz), 4.72-4.60 (m, 2 H), 4.56
(t, 1 H, J ) 5.0 Hz), 4.40-4.30 (m, 1 H), 4.30-4.22 (m, 1 H),
3.85 (dd, 1 H, J ) 2.4, 9.4 Hz), 3.71 (dd, 1 H, J ) 8.7, 11.1
Hz), 3.58 (dd, 1 H, J ) 3.3, 9.4 Hz), 3.52 (dd, 1 H, J ) 9.9,
17.1 Hz), 3.43-3.25 (m, 3 H), 2.96 (dd, 1 H, J ) 3.3, 13.7 Hz),
2.70-2.62 (m, 1 H), 2.50-2.40 (m, 1 H), 2.10-2.02 (m, 1 H),
2.00-1.90 (m, 1 H), 1.88-1.78 (m, 1 H), 1.52 (s, 3 H), 1.41 (s,
3 H), 1.28 (s, 3 H), 1.26 (s, 3 H), 1.26-1.16 (m, 2 H), 1.08 (d,
3 H, J ) 6.4 Hz), 1.02-0.90 (m, 9 H); 13C NMR δ 173.8, 172.9,
170.5, 170.3, 142.8, 142.4, 136.0, 129.9, 128.0, 127.0, 115.9,
115.1, 79.2, 78.4, 76.0, 66.4, 61.7, 60.5, 57.4, 57.2, 57.0, 53.8,
47.4, 46.9, 39.0, 36.5, 35.8, 27.9, 26.4, 25.8, 25.6, 25.5, 25.2,
24.4, 19.5, 18.4, 16.4, 12.5; MS (FAB) m/z (rel intensity) 860
([M + Na]+, 48), 838 ([M + H]+, 55), 770 (35), 702 (100); HRMS
(FAB) m/z calcd for C43H63N7O8NaS (M + Na), 860.4357, found
860.4412.
colorless solid: mp 154-156 °C; [R]D -8.0 (c 0.50, CHCl3, 22
1
°C); IR (film) 3378, 3315, 1668 cm-1; H NMR δ 8.57 (d, 1 H,
J ) 9.0 Hz), 7.75 (d, 1 H, J ) 7.6 Hz), 7.38 (d, 1 H, J ) 5.7
Hz), 7.30-7.20 (m, 5 H), 7.06 (d, 1 H, J ) 8.8 Hz), 6.95 (d, 1
H, J ) 8.6 Hz), 6.57 (d, 1 H, J ) 9.3 Hz), 5.85 (dd, 1 H, J )
10.8, 17.4 Hz), 5.75 (dd, 1 H, J ) 10.9, 17.5 Hz), 5.26 (d, 1 H,
J ) 10.7 Hz), 5.24 (d, 1 H, J ) 17.4 Hz), 5.18 (d, 1 H, J ) 10.8
Hz), 5.15 (d, 1 H, J ) 17.6 Hz), 5.02-4.90 (m, 1 H), 4.87-4.78
(m, 1 H), 4.68 (dd, 1 H, J ) 5.5, 8.5 Hz), 4.55-4.40 (m, 3 H),
4.17-4.05 (m, 2 H), 3.90-3.75 (m, 2 H), 3.70-3.50 (m, 2 H),
3.48-3.37 (m, 3 H), 2.93 (dd, 1 H, J ) 10.3, 14.0 Hz), 2.45-
2.10 (m, 2 H), 1.90-1.78 (m, 2 H), 1.75-1.60 (m, 1 H), 1.60-
1.42 (m, 1 H), 1.39 (s, 3 H), 1.34 (s, 3 H), 1.29 (s, 3 H), 1.27 (s,
3 H), 1.26 (d, 3 H, J ) 5.5 Hz), 1.06 (d, 3 H, J ) 6.3 Hz), 1.00-
0.93 (m, 6 H), 0.90-0.80 (m, 2 H); 13C NMR δ 172.3, 171.8,
171.3, 170.7, 170.1, 142.4, 142.2, 137.3, 129.4, 128.7, 127.1,
116.2, 115.5, 67.5, 63.8, 62.0, 60.8, 58.1, 57.1, 55.9, 55.6, 54.4,
47.9, 47.7, 38.4, 36.3, 29.3, 26.9, 26.5, 26.1, 25.7, 25.5, 23.9,
19.7, 17.3, 16.5, 12.1; HRMS (FAB) m/z calcd for C43H66N7O10
(M + H) 840.4871, found 840.4911.
Cyclo[Ala -P r o-D-P h e -D-Se r (oxa z)-Th r (r p r e n yl)-Se r -
(r p r en yl)-Ile]. According to general procedure G, 40 (34.6 mg,
41.2 µmol) provided 20.8 mg (61%) of cyclo[Ala-Pro-D-Phe-D-
Ser(oxaz)-Thr(rprenyl)-Ser(rprenyl)-Ile] as a colorless glass:
[R]D -27.1 (c 0.93, CHCl3, 22 °C); IR (film) 3338, 1666 cm-1
;
1H NMR δ 8.18 (d, 1 H, J ) 6.1 Hz), 8.03 (d, 1 H, J ) 4.3 Hz),
7.87 (d, 1 H, J ) 3.9 Hz), 7.68 (d, 1 H, J ) 8.1 Hz), 7.20-7.05
(m, 5 H), 6.00 (d, 1 H, J ) 10.6 Hz), 5.93 (dd, 1 H, J ) 17.6,
10.8 Hz), 5.78 (dd,1 H, J ) 17.7, 10.7 Hz), 5.28 (d, 1 H, J )
17.7 Hz), 5.24 (1 H, J ) 10.8 Hz), 5.16 (d, 1 H, J ) 17.0 Hz),
5.16 (d, 1 H, J ) 11.5 Hz), 5.07-4.97 (m, 1 H), 4.95-4.85 (m,
1 H), 4.75-4.60 (m, 2 H), 4.55-4.30 (m, 5 H), 4.25-4.15 (m, 1
H), 3.87 (dd, 1 H, J ) 2.8, 9.4 Hz), 3.62 (dd, 1 H, J ) 3.3, 9.3
Hz), 3.55-3.35 (m, 2 H), 3.12 (dd, 1 H, J ) 4.6, 14.0 Hz), 2.91
(dd, 1 H, J ) 7.6, 13.9 Hz), 2.50-2.35 (m, 2 H), 2.10-1.85 (m,
2 H), 1.77-1.60 (m, 1 H), 1.51 (s, 3 H), 1.39 (s, 3 H), 1.35-
1.10 (m, 11 H), 1.03 (d, 3 H, J ) 6.4 Hz), 0.98-0.82 (m, 6 H);
13C NMR δ 172.4, 171.5, 170.5, 170.2, 170.1, 169.8, 168.8,
142.9, 142.4, 136.6, 129.4, 128.6, 126.7, 115.9, 115.1, 79.1, 78.3,
76.0, 70.4, 68.5, 65.6, 61.7, 59.4, 57.5, 57.3, 48.6, 47.2, 46.7,
39.3, 35.8, 27.9, 25.7, 25.5, 24.3, 20.0, 18.0, 16.4, 12.5; HRMS
(FAB) m/z calcd for C43H63N7O9Na (M + Na) 844.4585, found
844.4594.
F m oc-Ala -P r o-D-P h e-D-Ser (TBS)-OBn (38). According to
general procedure D, 37 (2.15 g, 3.88 mmol) and D-Ser(TBS)-
OBn (1.20 g, 3.88 mmol) provided 1.59 g (81%) of 38 as a
colorless foam: [R]D -43.8 (c 0.26, CHCl3, 22 °C); IR (film)
1
3418, 3300, 1724, 1658 cm-1; H NMR (benzene-d6) δ 7.60-
7.35 (m, 5 H), 7.28-6.95 (m, 15 H), 5.95 (d, 1 H, J ) 8.0 Hz),
5.05-4.78 (m, 4 H), 4.53-4.36 (m, 3 H), 4.30-4.22 (m, 1 H),
4.15-4.10 (m, 1 H), 3.92 (dd, 1 H, J ) 3.2, 10.0 Hz), 3.80 (dd,
1 H, J ) 3.8, 10.0 Hz), 3.23 (dd, 1 H, J ) 5.3, 14.0 Hz), 3.11
(dd, 1 H, J ) 8.1, 13.9 Hz), 3.05-2.92 (m, 1 H), 2.90-2.80 (m,
1 H), 2.05-1.95 (m, 1 H), 1.72-1.55 (m, 1 H), 1.33 (d, 3 H, J
) 6.8 Hz), 1.25-1.10 (m, 2 H), 0.87 (s, 9 H), -0.03 (s, 3 H),
-0.05 (s, 3 H); 13C NMR (benzene-d6) δ 173.2, 171.5, 171.4,
170.8, 156.3, 144.9, 144.8, 142.1, 138.0, 136.3, 130.2, 129.5,
128.9, 127.7, 127.3, 125.9, 120.6, 67.4, 64.1, 60.5, 55.7, 55.5,
49.1, 48.0, 47.2, 38.7, 27.5, 26.4, 25.3, 18.9, -5.0, -5.1; HRMS
(FAB) m/z calcd for C48H59N4O8Si (M + H) 847.4102, found
847.4132.
Cyclo[Ala -P r o-D-P h eΨ{(CdS)NH}-D-Ser -Th r (r p r en yl)-
Ser (r p r en yl)-Ile]. According to general procedure H, cyclo-
[Ala-Pro-D-Phe-D-Ser(oxaz)-Thr(rprenyl)-Ser(rprenyl)-Ile] (19.5
mg, 23.8 µmol) provided 16 mg (79%) of cyclo[Ala-Pro-D-PheΨ-
{(CdS)NH}-D-Ser-Thr(rprenyl)-Ser(rprenyl)-Ile] as a colorless
solid: mp 140-142 °C; [R]D +25.7 (c 0.23, CHCl3, 22 °C); IR
1
F m oc-Ala -P r o-D-P h e -D-Se r (TBS)-Th r (r p r e n yl)-Se r -
(r p r en yl)-Ile-OMe (39). According to general procedure I,
benzyl ester deprotection of 38 (0.768 g, 0.917 mmol) in EtOAc/
EtOH (10:1, 8 mL) and the condensation with the amine 25
(30.8 mg, 65.8 µmol) provided 55.1 mg (54% over two steps) of
39 as a colorless foam: [R]D -4.4 (c 0.18, CHCl3, 22 °C); IR
(film) 3314, 1670 cm-1; H NMR δ 9.79 (d, 1 H, J ) 7.8 Hz),
7.83 (d, 1 H, J ) 7.6 Hz), 7.38 (d, 2 H, J ) 5.9 Hz), 7.35-7.20
(m, 5 H), 6.65 (d, 1 H, J ) 8.9 Hz), 6.52 (d, 1 H, J ) 9.4 Hz),
5.85 (dd, 1 H, J ) 10.9, 17.3 Hz), 5.75 (dd, 1 H, J ) 10.9, 17.5
Hz), 5.45-5.40 (m, 1 H), 5.25 (d, 1 H, J ) 10.6 Hz), 5.23 (d, 1
H, J ) 17.5 Hz), 5.19 (d, 1 H, J ) 10.5 Hz), 5.15 (d, 1 H, J )
17.6 Hz), 4.74 (dd, 1 H, J ) 5.4, 8.6 Hz), 4.65-4.32 (m, 4 H),
4.22-4.10 (m, 2 H), 3.93-3.68 (m, 4 H), 3.59 (dd, 1 H, J )
4.7, 9.3 Hz), 3.40-3.25 (m, 2 H), 2.90 (dd, 1 H, J ) 10.8, 13.9
Hz), 2.47-2.30 (m, 1 H), 1.85-1.70 (m, 2 H), 1.70-1.48 (m, 2
H), 1.39 (s, 3 H), 1.33 (s, 3 H), 1.30 (s, 3 H), 1.27 (s, 3 H), 1.25
(d, 3 H, J ) 6.7 Hz), 1.25-1.00 (m, 3 H), 1.03 (d, 3 H, J ) 6.3
Hz), 1.00-0.83 (m, 6 H); 13C NMR δ 205.2, 171.8, 171.3, 171.0,
170.4, 170.1, 170.0, 142.3, 142.1, 137.5, 129.3, 128.7, 127.1,
116.3, 115.6, 76.5, 67.5, 63.0, 61.9, 60.5, 58.0, 57.2, 55.7, 47.9,
47.7, 41.9, 36.4, 29.1, 26.8, 26.5, 26.0, 25.7, 25.4, 23.7, 19.8,
17.2, 16.5, 12.1; HRMS (FAB) m/z calcd for C43H66N7O9S (M
+ H) 856.4643, found 856.4669.
1
(film) 3315, 1719, 1644 cm-1; H NMR δ 7.77 (d, 2 H, J ) 7.4
Hz), 7.65-7.55 (m, 2 H), 7.41 (t, 4 H, J ) 7.2 Hz), 7.34-7.20
(m, 9 H), 7.06 (d, 2 H, J ) 8.5 Hz), 6.90 (d, 1 H, J ) 6.9 Hz),
5.94 (dd, 1 H, J ) 10.7, 17.6 Hz), 5.87-5.75 (m, 2 H), 5.32-
5.04 (m, 4 H), 4.70-4.45 (m, 4 H), 4.36 (d, 3 H, J ) 7.4 Hz),
4.25-4.18 (m, 1 H), 4.05-3.95 (m, 1 H), 3.90-3.80 (m, 2 H),
3.75-3.55 (m, 2 H), 3.70 (s, 3 H), 3.34 (t, 1 H, J ) 7.4 Hz),
3.20-3.00 (m, 3 H), 2.25-2.18 (m, 1 H), 2.20-1.75 (m, 4 H),
1.45 (s, 3 H), 1.36 (s, 3 H), 1.35-1.10 (m, 5 H), 1.29 (s, 6 H),
1.03 (d, 3 H, J ) 6.4 Hz), 0.98-0.83 (m, 6 H), 0.87 (s, 9 H),
0.06 (2s, 6 H); 13C NMR δ 172.8, 172.1, 171.4, 171.0, 170.3,
169.8, 168.8, 155.9, 144.0, 142.8, 141.4, 136.8, 136.5, 129.5,
128.8, 128.5, 127.9, 127.2, 125.3, 120.1, 115.1, 114.9, 76.2, 67.2,
63.0, 62.5, 60.4, 58.0, 56.9, 55.3, 54.6, 53.4, 52.1, 48.7, 47.3,
37.8, 27.6, 26.0, 25.7, 25.3, 25.2, 18.4, 18.2, 17.5, 15.7, 11.6,
-5.2; MS (FAB) m/z (rel intensity) 1247 ([M + K]+, 100), 1231
([M + Na]+, 75).
Cyclo[Ala -P r o-D-P h e-D-Ser (t h ia z)-Th r (r p r en yl)-Ser -
(r p r en yl)-Ile] (41). According to general procedure G, cyclo-
[Ala-Pro-D-PheΨ{(CdS)NH}-D-Ser-Thr(rprenyl)-Ser(rprenyl)-
Ile] (6.4 mg, 8.1 µmol) provided 4.9 mg (79%) of 41 as a
colorless amorphous solid: [R]D -28.0 (c 0.49, CHCl3, 22 °C);
IR (film) 3345, 1667 cm-1; 1H NMR δ 8.30-8.20 (m, 2 H), 8.13
(d, 1 H, J ) 4.8 Hz), 7.58 (d, 1 H, J ) 7.8 Hz), 7.27-7.10 (m,
5 H), 6.05 (d, 1 H, J ) 10.4 Hz), 5.95 (dd, 1 H, J ) 10.8, 17.6
Cyclo[Ala -P r o-D-P h e-D-Ser -Th r (r p r en yl)-Ser (r p r en yl)-
Ile] (40). According to general procedure F, 39 (119 mg, 92.7
µmol) provided 27.9 mg (36% over four steps) of 40 as a

Synthesis and Stereochemistry of Trunkamide A
J . Org. Chem., Vol. 65, No. 4, 2000 1049
Hz), 5.78 (dd, 1 H, J ) 10.6, 17.8 Hz), 5.31 (d, 1 H, J ) 17.7
Hz), 5.25 (d, 1 H, J ) 10.9 Hz), 5.19-5.13 (m, 2 H), 5.17-5.01
(m, 1 H), 4.92 (t, 1 H, J ) 7.0 Hz), 4.81 (t, 1 H, J ) 11 Hz),
4.69 (d, 2 H, J ) 9.5 Hz), 4.60-4.50 (m, 1 H), 4.48-4.38 (m, 1
H), 4.37-4.33 (m, 1 H), 3.88 (dd, 1 H, J ) 9.3, 2.3 Hz), 3.65-
3.40 (m, 5 H), 3.16 (dd, 1 H, J ) 5.4, 14.0 Hz), 2.96 (dd, 1 H,
J ) 7.6, 13.9 Hz), 2.50-2.30 (m, 2 H), 2.10-1.95 (m, 2 H),
1.80-1.65 (m, 1 H), 1.53 (s, 3 H), 1.42 (s, 3 H), 1.30 (s, 3 H),
1.28 (s, 3 H), 1.23 (d, 3 H, J ) 6.8 Hz), 1.07 (d, 3 H, J ) 6.4
Hz), 1.00-0.85 (m, 8 H); 1H NMR (500 MHz) δ 8.30-8.22 (m,
2 H), 8.13 (d, 1 H, J ) 4.4 Hz), 7.57 (d, 1 H, J ) 7.7 Hz), 7.30-
7.22 (m, 3 H), 7.20-7.13 (m, 2 H), 6.05 (d, 1 H, J ) 10.4 Hz),
5.95 (dd, 1 H, J ) 10.8, 17.5 Hz), 5.78 (dd, 1 H, J ) 10.8, 17.7
Hz), 5.31 (d, 1 H, J ) 17.5 Hz), 5.25 (d, 1 H, J ) 10.8 Hz), 5.17
(d, 1 H, J ) 11.6 Hz), 5.16 (d, 1 H, J ) 16.3 Hz), 5.12-5.04
(m, 1 H), 4.90 (t, 1 H, J ) 7.1 Hz), 4.81 (t, 1 H, J ) 10 Hz),
4.69 (d, 2 H, J ) 8.1 Hz), 4.55 (t, 1 H, J ) 5.5 Hz), 4.47-4.40
(m, 1 H), 4.36 (s, 1 H), 3.88 (d, 1 H, J ) 9.2 Hz), 3.68-3.40 (m,
5 H), 3.15 (dd, 1 H, J ) 5.4, 13.9 Hz), 2.96 (dd, 1 H, J ) 7.7,
13.9 Hz), 2.50-2.40 (m, 1 H), 2.42-2.32 (m, 1 H), 2.10-1.92
(m, 2 H), 1.78-1.62 (m, 1 H), 1.53 (s, 3 H), 1.42 (s, 3 H), 1.30
(s, 3 H), 1.28 (s, 3 H), 1.28-1.20 (m, 3 H), 1.07 (d, 3 H, J ) 6.3
Hz), 1.00-0.82 (m, 8 H); 13C NMR δ 173.3, 172.5, 170.9, 170.5,
170.2, 170.0, 142.9, 142.4, 136.7, 129.6, 128.5, 126.9, 115.9,
115.2, 78.8, 78.4, 76.0, 65.5, 61.7, 59.6, 57.8, 57.3, 53.4, 47.3,
46.6, 41.5, 35.9, 35.5, 27.9, 26.0, 25.8, 25.5, 24.4, 20.1, 18.4,
16.4, 12.5; HRMS (FAB) m/z calcd for C43H64N7O8S (M + H)
838.4537, found 838.4566.
(5 mL) was heated in a sealed tube at 105 °C for 22 h. The
resulting mixture was concentrated, dried in vacuo, dissolved
in distilled water (40 µL), and derivatized with 5-fluoro-2,4-
dinitrophenyl-L-alanine amide (FDAA, 0.5 mg) in acetone (60
µL) and 1 N sodium bicarbonate (20 µL) at 40 °C for 1 h. The
reaction mixture was acidified with 2 N HCl (10 µL) and stored
in the dark until HPLC analysis (Varian C18 MICROSORB-
MV 100 Å; linear gradient elution, aqueous TFA/acetonitrile
(0.1%), from 95:5 to 60:40 in 100 min; 1.2 mL/min; UV
detection at 340 nm). No D-amino acid residues were detected
in comparison to a standard mixture containing the follow-
ing: D/L mixture of serine, threonine, proline, alanine, isoleu-
cine, and phenylalanine.
Ack n ow led gm en t. This work was supported by the
National Institutes of Health (GM55433). We thank
Prof. Bruce Bowden (J ames Cook University, Towns-
ville, Australia) for copies of NMR spectra of natural
trunkamide A.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for all synthetic intermediates and trunkamide A
stereoisomers. 1H and 13C NMR spectra for natural trunk-
amide A. This material is available free of charge via the
Internet at http://pubs.acs.org.
Degr a d a tion of Cyclo[Ala -P r o-P h e-Ser -Th r (r p r en yl)-
Ser (r p r en yl)-Ile] (27). A solution of 27 (0.4 mg) in 6 N HCl
J O9914566