Total Synthesis of Dendroamide A: Oxazole and Thiazole Construction Using an Oxodiphosphonium Salt

Article abstract of DOI:10.1021/jo0302657

The total synthesis of dendroamide A (1), a multidrug-resistance reversing bistratamide-type peptide-derived macrocycle, has been accomplished in 19% yield. Fmoc-protected amino acids were condensed into appropriately protected dipeptides which were treated with bis-(triphenyl)oxodiphosphonium trifluoromethanesulfonate to afford oxazoles and thiazolines (oxidized to thiazoles) with high chemo- and stereoselectivity. The convergent condensation of three heterocyclic amino acids followed by macrocyclization afforded the natural product.

Full text of DOI:10.1021/jo0302657

Tota l Syn th esis of Den d r oa m id e A:
Oxa zole a n d Th ia zole Con str u ction Usin g
a n Oxod ip h osp h on iu m Sa lt
Shu-Li You and J effery W. Kelly*
Department of Chemistry and The Skaggs Institute for
Chemical Biology, The Scripps Research Institute,
La J olla, California 92037
jkelly@scripps.edu
F IGURE 1. Retrosynthetic analysis of dendroamide A (1).
Received August 18, 2003
of the oxazole substructure from a â-ketodipeptide and
the thiazolines from fully protected cysteine-containing
dipeptides, in all cases utilizing bis(triphenyl)oxodiphos-
phonium trifluoromethanesulfonate.7
Our retrosynthetic analysis of dendroamide A (1),
outlined in Figure 1, features disconnection at three
amide bonds. The resulting appropriately protected
heterocyclic amino acid fragments 2-4 are derived from
dipeptides, which were synthesized from ordinary Fmoc-
protected amino acids. The ketone side chain used to
produce 4 results from the Dess-Martin oxidation of a
threonine-containing dipeptide.
As shown in Scheme 1, compound 5 was synthesized
by coupling N-Fmoc-L-S-tritylcysteine with allyl alcohol
utilizing HBTU (2-(1H-benzotriazole-1-yl)-1,1,3,3-tetra-
methyluronium hexafluorophosphate) and HOBt (N-
hydroxybenzotriazole) in the presence of DIEA (N, N-
diisopropylethylamine). Diethylamine removal of the
Fmoc protecting group afforded an amine that was
coupled with N-Fmoc-D-alanine or N-Fmoc-D-valine em-
ploying HBTU and HOBt in the presence of DIEA,
yielding dipeptides 6 and 7, respectively. Transformation
of the fully protected cysteine-containing dipeptides to
thiazolines 8 and 9 was accomplished in high yield
utilizing bis(triphenyl)oxodiphosphonium trifluoro-
methanesulfonate,7,8 generated from triphenyl phosphine
oxide and triflic anhydride. The thiazolines in 8 and 9
were oxidized to thiazoles using activated manganese
oxide. The stereochemical purity of 2 and 3 exceeded
96% ee as ascertained by chiral HPLC.
Abstr a ct: The total synthesis of dendroamide A (1), a
multidrug-resistance reversing bistratamide-type peptide-
derived macrocycle, has been accomplished in 19% yield.
Fmoc-protected amino acids were condensed into appropri-
ately protected dipeptides which were treated with bis-
(triphenyl)oxodiphosphonium trifluoromethanesulfonate to
afford oxazoles and thiazolines (oxidized to thiazoles) with
high chemo- and stereoselectivity. The convergent condensa-
tion of three heterocyclic amino acids followed by macro-
cyclization afforded the natural product.
Dendroamide A (1) was first isolated from the ter-
restrial blue-green alga (cyanobacterium) Stigonema
dendroideum fremy in 1996.1 This natural product re-
verses multiple drug resistance (MDR)2 by acting as a
P-glycoprotein and MRP1 antagonist at noncytotoxic
doses. Dendroamide A could be useful against cancers
exhibiting MDR and therefore has attracted the attention
of synthetic and natural product chemists. Its total
synthesis has been reported by two groups.3 The thiazole
substructure was prepared either by Hantzsch’s proce-
dure using a thioamide as an intermediate4 or by
employing a condensation reaction between cysteine
esters and N-protected imino esters, followed by the
oxidation of the resulting thiazolines.5 Synthesis of the
oxazole substucture was achieved by oxidation of the
oxazoline, made from a â-hydroxy amide utilizing the
Burgess reagent.6
In this paper, we report the synthesis of dendroamide
A in 19% overall yield. Highlights include the preparation
The synthesis of oxazole fragment 4 is outlined in
Scheme 2. Dipeptide 10 was synthesized by coupling
Fmoc-D-alanine and L-threonine benzyl ester. A Dess-
Martin oxidization of the hydroxy group in dipeptide 10
led to ketone 11 in 80% yield.9 Bis(triphenyl)oxodiphos-
phonium trifluoromethanesulfonate was utilized to con-
vert the â-ketodipeptide 11 to the protected oxazole
amino acid 4 in 84% yield without compromising the Ala-
derived stereocenter (98% ee). Unlike the oxobisphos-
phonium salt utilized here, the PPh3/I2 reagent utilized
* To whom correspondence should be addressed. Fax: 858-784-9899.
(1) Ogino, J .; Moore, R. E.; Patterson, G. M. L.; Smith, C. D. J . Nat.
Prod. 1996, 59, 581.
(2) (a) Borst, P. Ann. Oncol. 1999, 10, Suppl. 4, 162-164. (b) Kaye,
S. B. Curr. Opin. Oncol. 1998, 10, Suppl. 1, S15. (c) Leith, C. Curr.
Opin. Oncol. Hematol. 1998, 5, 287. (d) Lawrence, D. S.; Copper, J .
E.; Smith, C. D. J . Med. Chem. 2001, 44, 594.
(3) (a) Xia, Z.; Smith, C. D. J . Org. Chem. 2001, 66, 3459. (b)
Bertram, A.; Pattenden, G. Synlett 2000, 1519. (c) Bertram, A.;
Pattenden, G. Heterocycles 2002, 58, 521.
(4) (a) Schmidt, U.; Utz, R. Angew. Chem., Int. Ed. Engl. 1984, 23,
725. (b) Schmidt, U.; Gleich, P. Angew. Chem., Int. Ed. Engl. 1985,
24, 569. (c) Schmidt, U.; Utz, R.; Lieberknecht, A.; Griesser, H.; Potzolli,
B.; Bahr, J .; Wagner, K.; Fischer, P. Synthesis 1987, 233. (d) Breden-
kamp, M. W.; Holzapfel, C. W.; Zyl, W. J . V. Synth. Commun. 1990,
20, 2235. (e) Deng, S.; Taunton, J . J . Am. Chem. Soc. 2002, 124, 916.
(f) Downing, S. V.; Aguilar, E.; Meyers, A. I. J . Org. Chem. 1999, 64,
826. (g) Wang, W.; Nan, F. J . Org. Chem. 2003, 68, 1636.
(5) (a) North, M.; Pattenden, G. Tetrahedron 1990, 46, 8267. (b)
Boden, C. D. J .; Pattenden, G.; Ye, T. Synlett 1995, 417. (c) Boden, C.
D. J .; Pattenden, G. J . Chem. Soc., Perkin Trans. 1 2001, 875.
(6) Wipf, P.; Fritch, P. C. J . Am. Chem. Soc. 1996, 118, 12358.
(7) You, S.-L.; Razavi, H.; Kelly, J . W. Angew. Chem., Int. Ed. 2003,
42, 83.
(8) (a) Hendrickson, J . B.; Schwartzman, S. M. Tetrahedron Lett.
1975, 277. (b) Hendrickson, J . B.; Hussoin, M. S. Synthesis 1989, 217.
(c) Hendrickson, J . B.; Hussoin, M. S. Synlett 1990, 423. (d) Hendrick-
son, J . B.; Walker, M. A.; Varvak, A.; Hussoin, M. S. Synlett 1996,
661. (e) Yokokawa, F.; Hamada, Y.; Shioiri, T. Synlett 1992, 153.
(9) Dess, D. B.; Martin, J . C. J . Am. Chem. Soc. 1991, 113, 7277.
10.1021/jo0302657 CCC: $25.00 © 2003 American Chemical Society
Published on Web 11/07/2003
9506
J . Org. Chem. 2003, 68, 9506-9509

SCHEME 1. Syn th esis of Th ia zole-Con ta in in g Am in o Acid s 2 a n d 3
SCHEME 2. Syn th esis of Oxa zole-Con ta in in g
Am in o Acid 4 fr om a Th r -Ba sed Dip ep tid e
In summary, dendroamide A (1) has been synthesized
in a highly convergent fashion from three appropriately
protected heterocyclic amino acids. The oxazole amino
acid results from cyclodehydration of a â-ketodipeptide.
The thiazole amino acids are obtained from oxidation of
their corresponding thiazoline amino acids, which are
synthesized by the cyclodehydration of fully protected
cysteine-based dipeptides. In each case bis(triphenyl)-
oxodiphosphonium trifluoromethanesulfonate was em-
ployed to make the heterocyclic amino acids from the
dipeptide by amide carbonyl activation/dehydration. The
oxophosphonium salt accomplished these reactions with
notable chemo- and stereoselectivity. The final macrocy-
clization proceeds in high yield (81%) affording 1 in an
overall yield of 19%.
previously for this transformation requires the use of a
base increasing the risk of racemization.10
The allyl group in compound 3 was removed utilizing
a palladium catalyst, generated from Pd(OAc)2 and
polymer-supported triphenylphosphine, in the presence
of phenylsilane.11 The use of this solid-phase catalyst
greatly simplified workup of the reaction, as the carboxy-
lic acid could be separated from the catalyst by filtration
through a short silica gel column. The Fmoc group in
compound 2 was removed by diethylamine, allowing its
amino terminus to be coupled with the carboxylic acid
derived from 3, utilizing HBTU and HOBt in the presence
of DIEA, affording the peptidic bis-heterocycle 12 (92%).
The benzyl group in 4 was removed by a Pd/C-mediated
hydrogenation. The resulting carboxylic acid was coupled
with the free amine resulting from the diethylamine
deprotection of compound 12, yielding compound 13 in
94% yield. The macrolide precursor 14 can be obtained
from peptide 13 by removing the Fmoc and allyl groups
as described above. The final cyclization promoted by
PyBOP (benzotriazole-1-yl-oxy-tris-pyrrolidino-phospho-
nium hexafluorophosphate) and DMAP can be achieved
by slowly adding 14 to a solution of PyBOP and DMAP
in CH2Cl2/DMF (2/1) with a syringe pump affording 1 in
Exp er im en ta l Section
Com p ou n d 5. A solution of NR-Fmoc-L-Cys(S-trityl)-OH (5.86
g, 10 mmol) in DMF (50 mL) was treated with HOBt‚H2O (1.68
g, 11 mmol) and HBTU (4.17 g, 11 mmol) at 25 °C. After 10
min, allyl alcohol (1.36 mL, 20 mmol) and DIEA (3.65 mL, 21
mmol) were added separately, and the resulting mixture was
stirred at 25 °C overnight. After regular workup, the resulting
crude product was purified by flash chromatography (EtOAc/
hexanes ) 1/3) to afford compound 5 (5.63 g, 90%) as a white
foam: [R]24D ) +18.1 (c 1.0, CHCl3); 1H NMR (600 MHz, CDCl3,
25 °C, TMS) δ 2.63-2.70 (m, 2H), 4.22 (dd, J ) 7.0, 6.6 Hz, 1H),
4.33-4.39 (m, 3H), 4.58 (m, 2H), 5.23 (d, J ) 10.5 Hz, 1H), 5.28-
5.30 (m, 2H), 5.86 (m, 1H), 7.18-7.29 (m, 11H), 7.37-7.40 (m,
8H), 7.60 (dd, J ) 6.1, 5.7 Hz, 2H), 7.75 (dd, J ) 6.6, 6.1 Hz,
2H); 13C NMR (150 MHz, CDCl3) δ 34.0, 47.0, 52.9, 66.2, 67.0,
67.1, 118.7, 119.9, 125.1 (2 C), 126.8, 126.9, 127.0, 127.7, 127.9,
128.0 (3 C), 129.4 (3 C), 129.5, 131.3, 141.2 (2 C), 143.7, 143.8,
144.2, 155.5, 170.2; HRMS (MALDI-FTMS) calcd for C40H35NO4S
(M + Na+) 648.2179, found 648.2176.
Com p ou n d 6 (Gen er a l P r oced u r e for Dieth yla m in e-
Med ia ted Dep r otection of F m oc Gr ou p a n d HOBt, HBTU-
Med ia ted P ep tid e Cou p lin g). Diethylamine (30 mL) was
added to a solution of 5 (5.63 g, 9 mmol) in CH3CN (30 mL),
and the resulting mixture was stirred at 25 °C for 30 min to
ensure complete removal of the Fmoc protecting group. After
concentration in vacuo, the reaction mixture was azeotroped to
dryness with CH3CN (2 × 30 mL), and the residue was dissolved
in DMF (40 mL). In another flask, a solution of NR-Fmoc-D-
alanine (3.11 g, 10 mmol) in DMF (40 mL) was treated with
HOBt‚H2O (1.53 g, 10 mmol) and HBTU (3.79 g, 10 mmol). After
10 min, this mixture and DIEA (3.65 mL, 21 mmol) were
sequentially added to the above free amino ester. The reaction
1
81% yield as a white solid (Scheme 3). The H and 13C
NMR spectra of 1 are identical to those reported in the
literature.1, 3
(10) Wipf, P.; Miller, P. C. J . Org. Chem. 1993, 58, 3604. Also see
PPh3/C2Cl6-mediated synthesis of oxazole: Morwick, T.; Hrapchak, M.;
Deturi, M.; Campbell, S. Org. Lett. 2002, 4, 2665.
(11) Dessolin, M.; Guillerez, M.-G.; Thieriet, N.; Guibe´, F.; Loffet,
A. Tetrahedron Lett. 1995, 36, 5741.
J . Org. Chem, Vol. 68, No. 24, 2003 9507

SCHEME 3. Syn th esis of Den d r oa m id e A (1) fr om 3 Heter ocyclic Am in o Acid s Der ived fr om Dip ep tid es
was stirred at 25 °C for 8 h. After regular workup, the resulting
crude product was purified by flash chromatography (EtOAc/
hexanes ) 1/3) to afford compound 6 (5.83 g, 93%) as a pale oil:
[R]24D ) +42.7 (c 1.0, CHCl3); 1H NMR (600 MHz, CDCl3, 25 °C,
TMS) δ 1.40 (d, J ) 6.6 Hz, 3H), 2.61-2.63 (m, 2H), 4.18 (t, J )
7.0 Hz, 1H), 4.30-4.38 (m, 3H), 4.52 (m, 1H), 4.56 (d, J ) 5.7
Hz, 2H), 5.20 (d, J ) 10.5 Hz, 1H), 5.25 (dd, J ) 17.1, 1.3 Hz,
1H), 5.48 (d, J ) 7.0 Hz, 1H), 5.85-5.79 (m, 1H), 6.67 (d, J )
6.6 Hz, 1H), 7.18-7.29 (m, 11H), 7.35-7.39 (m, 8H), 7.54 (d, J
) 7.5 Hz, 1H), 7.56 (d, J ) 7.0 Hz, 1H), 7.74 (d, J ) 7.0 Hz, 2H);
13C NMR (150 MHz, CDCl3) δ 18.8, 33.7, 47.0, 50.3, 51.2, 66.2,
66.7, 67.1, 118.8, 119.9, 125.0, 125.1, 126.8, 127.0 (2 C), 127.6,
127.8, 128.0, 129.4, 131.3, 141.2, 143.6, 143.9, 144.1, 155.8, 169.8,
171.9; HRMS (MALDI-FTMS) calcd for C43H40N2O5S (M + Na+)
719.2550, found 719.2551.
(d, J ) 7.5 Hz, 1H), 5.91 (m, 1H), 7.26-7.30 (m, 2H), 7.38 (t, J
) 7.5 Hz, 2H), 7.58 (d, J ) 7.5 Hz, 1H), 7.60 (d, J ) 7.5 Hz, 1H),
7.74 (d, J ) 7.5 Hz, 2H); 13C NMR (150 MHz, CDCl3) δ 20.2,
35.3, 47.0, 49.7, 66.1, 66.7, 77.7, 118.8, 119.8, 124.9, 125.0, 126.9,
127.0, 127.6, 127.7, 127.8, 131.3, 141.1 (2 C), 143.6, 143.8, 146.8,
155.4, 170.0, 176.9; HRMS (MALDI-FTMS) calcd for C24H24N2O4S
(M + H+) 437.1529, found 437.1525.
Com p ou n d 9. Compound 9 was synthesized from 7 in 90%
yield as a white solid by following the procedure used for the
synthesis of 8: mp 73-75 °C; [R]24D ) +47.3 (c 1.02, CHCl3); 1H
NMR (600 MHz, CDCl3, 25 °C, TMS) δ 0.94 (d, J ) 7.0 Hz, 3H),
1.01 (d, J ) 6.6 Hz, 3H), 2.19 (m, 1H), 3.54 (dd, J ) 10.0, 9.6
Hz, 1H), 3.62 (m, 1H), 4.25 (dd, J ) 7.5, 7.0 Hz, 1H), 4.38 (m,
1H), 4.44 (m, 1H), 4.56 (dd, J ) 8.8, 5.3 Hz, 1H), 4.68 (d, J )
6.1 Hz, 2H), 5.17 (dd, J ) 9.2, 8.3 Hz, 1H), 5.24 (d, J ) 9.2 Hz,
1H), 5.32-5.35 (m, 1H), 5.42 (d, J ) 8.8 Hz, 1H), 5.91 (m, 1H),
7.27-7.33 (m, 2H), 7.40 (dd, J ) 7.5, 7.0 Hz, 2H), 7.60 (d, J )
7.5 Hz, 1H), 7.61 (d, J ) 7.5 Hz, 1H), 7.76 (d, J ) 7.9 Hz, 2H);
13C NMR (150 MHz, CDCl3) δ 17.0, 19.3, 32.2, 35.3, 47.1, 58.8,
66.2, 66.9, 77.8, 118.9, 119.9, 125.0, 125.1, 127.0, 127.1, 127.6,
127.8, 127.9, 131.4, 141.2, 143.7, 143.9, 146.8, 156.1, 170.1, 175.9;
HRMS (MALDI-FTMS) calcd for C26H28N2O4S (M + H+) 465.1842,
found 465.1846.
Com p ou n d 7. Compound 7 was synthesized from 5 and NR-
Fmoc-D-valine in 93% yield as a white foam by following the
procedure used for the synthesis of 6: [R]24 ) +33.5 (c 0.68,
D
1
CHCl3); H NMR (600 MHz, CDCl3, 25 °C, TMS) δ 0.93 (d, J )
6.6 Hz, 3H), 0.97 (d, J ) 5.7 Hz, 3H), 2.14 (m, 1H), 2.61 (m,
2H), 4.07 (m, 1H), 4.19 (m, 1H), 4.36 (m, 2H), 4.56 (m, 1H), 4.60
(m, 2H), 5.23 (d, J ) 10.5 Hz, 1H), 5.28 (d, J ) 17.1 Hz, 1H),
5.37 (d, J ) 8.8 Hz, 1H), 5.85 (m, 1H), 6.42 (d, J ) 7.9 Hz, 1H),
7.19-7.30 (m, 11H), 7.36-7.39 (m, 8H), 7.57 (m, 2H), 7.76 (d, J
) 6.6 Hz, 2H); 13C NMR (150 MHz, CDCl3) δ 17.6, 19.2, 31.2,
33.8, 47.1, 51.2, 59.9, 66.3, 66.7, 67.0, 118.8, 119.9, 125.1, 126.8,
126.9, 127.0, 127.6, 127.9, 128.0, 129.3, 129.4, 131.3, 141.2, 143.6,
143.9, 144.1, 156.3, 169.8, 170.8; HRMS (MALDI-FTMS) calcd
for C45H44N2O5S (M + Na+) 747.2863, found 747.2854.
Com p ou n d 2. To a solution of 8 (436 mg, 1 mmol) in CH2Cl2
(5 mL), activated MnO2 (<5 µm, 85%, 1.02 g, 10 mmol) was
added. The reaction mixture was stirred overnight at 25 °C, then
filtered through a short silica gel and Celite column and washed
with EtOAc. The organic solution was concentrated. The result-
ing crude product was purified by flash chromatography (EtOAc/
hexanes ) 1/3) to afford compound 2 (387 mg, 89%) as a white
Com p ou n d 8. To a solution of triphenylphosphine oxide (8.35
g, 30 mmol) in dry CH2Cl2 (100 mL) was added trifluoro-
methanesulfonic anhydride (2.35 mL, 15 mmol) slowly at 0 °C.
The reaction mixture was stirred for 10 min at 0 °C and then
adjusted to -20 °C using a brine-ice bath. Then, a solution of
6 (6.97 g, 10 mmol) in 10 mL CH2Cl2 was added. The reaction
progress was monitored by TLC and was completed in 2 h. After
regular workup, the resulting crude product was purified by
flash chromatography (EtOAc/hexanes ) 1/3) to afford compound
8 (3.97 g, 91%) as an oil: [R]24D ) +37.8 (c 2.67, CHCl3); 1H NMR
(600 MHz, CDCl3, 25 °C, TMS) δ 1.46 (d, J ) 7.0 Hz, 3H), 3.51
(t, J ) 11.0 Hz, 1H), 3.59 (dd, J ) 11.0, 8.0 Hz, 1H), 4.21 (t, J
) 7.0 Hz, 1H), 4.34 (dd, J ) 10.1, 7.5 Hz, 1H), 4.42 (dd, J )
10.5, 7.0 Hz, 1H), 4.67-4.69 (m, 3H), 5.12 (dd, J ) 9.2, 8.8 Hz,
1H), 5.23 (d, J ) 10.5 Hz, 1H), 5.33 (d, J ) 17.1 Hz, 1H), 5.66
solid: mp 154-157 °C; [R]24 ) +19.8 (c 0.61, CHCl3); 1H NMR
D
(600 MHz, CDCl3, 25 °C, TMS) δ 1.63 (d, J ) 5.7 Hz, 3H), 4.20
(m, 1H), 4.40 (m, 1H), 4.47 (dd, J ) 10.5, 6.6 Hz, 1H), 4.84 (d, J
) 4.8 Hz, 2H), 5.17 (m, 1H), 5.29 (d, J ) 10.5 Hz, 1H), 5.40 (d,
J ) 17.1 Hz, 1H), 5.67 (br, 1H), 6.02 (m, 1H), 7.25-7.27 (m, 4H),
7.56 (br, 2H), 7.74 (br, 2H), 8.11 (s, 1H); 13C NMR (150 MHz,
CDCl3) δ 21.6, 47.0, 49.2, 65.9, 66.8, 118.9, 119.9, 124.9, 125.0,
127.0, 127.5, 127.6, 131.7, 141.2, 143.6, 146.7, 155.5, 160.8, 173.9;
HRMS (MALDI-FTMS) calcd for C24H22N2O4S (M + H+) 435.1373,
found 435.1371; HPLC (Chiralcel OD-H column, 254 nm, 90/10
hexane/2-propanol to 70/30 hexane/2-propanol gradient over 60
min, flow ) 1.0 mL/min) tR ) 50.8 (S), 57.6 (R) min.
Com p ou n d 3. Compound 3 was synthesized from 9 in 91%
yield as a white solid by following the procedure used for the
9508 J . Org. Chem., Vol. 68, No. 24, 2003

synthesis of 2: mp 104-106 °C; [R]24 ) +42.7 (c 1.0, CHCl3);
NMR (600 MHz, CDCl3, 25 °C, TMS) δ 0.93 (d, J ) 6.6 Hz, 3H),
0.95 (d, J ) 6.6 Hz, 3H), 1.79 (d, J ) 6.5 Hz, 3H), 2.28 (m, 1H),
4.22 (m, 1H), 4.47 (d, J ) 6.6 Hz, 2H), 4.81 (d, J ) 5.7 Hz, 2H),
4.87 (dd, J ) 8.3, 6.6 Hz, 1H), 5.27 (d, J ) 10.5 Hz, 1H), 5.38 (d,
J ) 17.1 Hz, 1H), 5.60 (m, 1H), 5.73 (d, J ) 8.8 Hz, 1H), 6.01
(m, 1H), 7.25-7.29 (m, 2H), 7.38 (dd, J ) 7.5, 7.0 Hz, 2H), 7.59
(t, J ) 8.4 Hz, 2H), 7.75 (d, J ) 7.5 Hz, 2H), 8.02 (s, 1H), 8.04
(d, J ) 8.3 Hz, 1H), 8.10 (s, 1H); 13C NMR (150 MHz, CDCl3) δ
17.6, 19.4, 20.9, 33.0, 47.1 (2 C), 58.4, 65.8, 66.7, 118.8, 119.9,
123.6, 124.9, 126.9, 127.6 (2 C), 131.7, 141.2, 143.6, 146.6, 149.2,
156.0, 160.4, 160.7, 171.9, 173.0; HRMS (MALDI-FTMS) calcd
for C32H32N4O5S2 (M + H+) 617.1887, found 617.1902.
D
1H NMR (600 MHz, CDCl3, 25 °C, TMS) δ 0.94 (d, J ) 7.0 Hz,
3H), 0.96 (d, J ) 7.0 Hz, 3H), 2.43 (m, 1H), 4.22 (dd, J ) 6.6,
6.1 Hz, 1H), 4.44 (m, 2H), 4.85 (d, J ) 5.7 Hz, 2H), 4.94 (dd, J
) 8.8, 6.6 Hz, 1H), 5.30 (d, J ) 10.5 Hz, 1H), 5.41 (d, J ) 15.1
Hz, 1H), 5.59 (d, J ) 8.3 Hz, 1H), 6.04 (m, 1H), 7.31 (m, 2H),
7.40 (t, J ) 7.5 Hz, 2H), 7.60 (dd, J ) 6.1, 5.3 Hz, 2H), 7.76 (d,
J ) 7.5 Hz, 2H), 8.10 (s, 1H); 13C NMR (150 MHz, CDCl3) δ 17.5,
19.4, 33.3, 47.1, 58.5, 65.9, 66.8, 118.8, 119.9, 124.9, 125.0, 127.0,
127.2, 127.6, 131.8, 141.2, 143.6, 143.7, 146.9, 156.0, 160.8, 172.2;
HRMS (MALDIFTMS) calcd for C26H26N2O4S (M + H+) 463.1686,
found 463.1684; HPLC (Chiralcel OD-H column, 254 nm, 90/10
hexane/2-propanol to 70/30 hexane/2-propanol gradient over 60
min, flow ) 1.0 mL/min) tR ) 26.5 (S), 30.9 (R) min.
Com p ou n d 13. Pd on activated carbon (15 mg) was added
to a flask containing 4 (154 mg, 0.32 mmol) in MeOH (3 mL)
and THF (3 mL). The reaction flask was filled with a H2 balloon,
evacuated, and purged with H2 three times. The reaction
progress was monitored by TLC and was complete in 1 h. After
removal of the solvent, the residue was passed through a short
silica gel column eluted with MeOH. The carboxylic acid was
used in the next step without further purification. By following
the procedure for the synthesis of 6, the carboxylic acid was
coupled with 12 (185 mg, 0.3 mmol) affording 13 as a white foam
Com p ou n d 10. Compound 10 was synthesized from NR-
Fmoc-D-valine and L-threonine benzyl ester oxalate in 85% yield
as a white foam by following the procedure used for the synthesis
of 6: [R]24D ) -25.7 (c 0.77, DMSO); 1H NMR (600 MHz, DMSO-
d6, 25 °C) δ 1.04 (d, J ) 6.1 Hz, 3H), 1.26 (d, J ) 7.0 Hz, 3H),
4.18-4.27 (m, 5H), 4.37 (d, J ) 8.8 Hz, 1H), 5.08-5.11 (m, 1H),
5.13-5.16 (m, 2H), 7.30-7.37 (m, 7H), 7.41 (t, J ) 7.5 Hz, 2H),
7.62 (d, J ) 7.5 Hz, 1H), 7.73 (m, 2H), 7.89-7.91 (m, 3H); 13C
NMR (150 MHz, DMSO-d6) δ 18.5, 20.1, 46.6, 57.6, 65.7, 65.9,
66.4, 120.1, 125.3 (2 C), 127.1, 127.6, 127.9, 128.3, 135.9, 140.7,
143.8, 143.9, 155.7, 170.4, 173.2; HRMS (MALDI-FTMS) calcd
for C29H30N2O6 (M + Na+) 525.1996, found 525.1996.
(217 mg, 94%): [R]24 ) +30.7 (c 1.46, CHCl3); 1H NMR (600
D
MHz, CDCl3, 25 °C, TMS) δ 1.01 (d, J ) 6.1 Hz, 3H), 1.02 (d, J
) 6.1 Hz, 3H), 1.59 (d, J ) 6.6 Hz, 3H), 1.79 (d, J ) 7.0 Hz, 3H),
2.45 (m, 1H), 2.61 (s, 3H), 4.22 (dd, J ) 7.0, 6.6 Hz, 1H), 4.42-
4.44 (m, 2H), 4.82 (d, J ) 5.7 Hz, 2H), 5.02 (m, 1H), 5.25-5.85
(m, 2H), 5.38 (d, J ) 17.1 Hz, 1H), 5.56-5.61 (m, 2H), 6.00 (m,
1H), 7.27-7.29 (m, 2H), 7.38 (t, J ) 7.5 Hz, 2H), 7.47 (d, J )
9.2 Hz, 1H), 7.58 (dd, J ) 8.7, 8.3 Hz, 2H), 7.75 (d, J ) 7.5 Hz,
2H), 7.91 (d, J ) 7.9 Hz, 1H), 8.01 (s, 1H), 8.08 (s, 1H); 13C NMR
(150 MHz, CDCl3) δ 11.7, 17.9, 19.5, 19.6, 20.9, 33.0, 45.0, 47.0
(2 C), 55.9, 65.9, 66.9, 118.8, 119.9, 123.6, 124.9, 126.9, 127.7,
128.4, 131.7, 141.2, 143.5, 143.7, 146.6, 149.1, 154.0, 155.5, 160.4,
160.8, 161.3, 161.5, 171.8, 173.1; HRMS (MALDI-FTMS) calcd
for C39H40N6O7S2 (M + H+) 769.2473, found 769.2479.
Com p ou n d 11. Dess-Martin periodinane (306 mg, 97%
purity, 0.7 mmol) was added to a flask containing 10 (251 mg,
0.5 mmol) in 30 mL of CH2Cl2. The resulting reaction mixture
was stirred at 25 °C for 1 h. After regular workup, the resulting
crude product was purified by flash chromatography (EtOAc/
hexanes ) 1/2) to afford compound 11 (200 mg, 80%) as a gel:
[R]24 ) +28.7 (c 0.90, CHCl3); 1H NMR (600 MHz, CDCl3, 25
D
°C, TMS) δ 1.38 (m, 3H), 2.27 (s, 3H), 4.19 (t, J ) 5.7 Hz, 1H),
4.36-4.42 (m, 3H), 5.13 (m, 1H), 5.22 (dd, J ) 12.3, 7.9 Hz, 1H),
5.28 (d, J ) 5.7 Hz, 1H), 5.59 (dd, J ) 17.7, 7.5 Hz, 1H), 7.26-
7.30 (m, 8H), 7.36 (t, J ) 7.0 Hz, 2H), 7.56 (m, 2H), 7.73 (d, J )
7.5 Hz, 2H); 13C NMR (150 MHz, CDCl3) δ 18.6, 27.9, 47.0, 50.1,
63.1, 67.0, 68.2, 119.9, 125.0, 127.0, 127.6, 128.3, 128.4 (2 C),
128.6 (2 C), 128.7, 128.8, 134.4, 141.2, 143.6, 143.8, 155.9, 165.6,
172.3, 197.9; HRMS (MALDI-FTMS) calcd for C29H28N2O6 (M
+ Na+) 523.1839, found 523.1836.
Den d r a m id e A (1). Deprotecting the Fmoc group in 13 (76.9
mg, 0.1 mmol) used the procedure described for the synthesis of
6. The allyl group was removed by a palladium catalyst as
described in the synthesis of 12. The resulting amino acid 14
was dissovled in CH2Cl2/DMF (10 mL, v/v: 2/1) as a 0.01 M
solution. This solution was added to a flask containing PyBOP
(104 mg, 0.2 mmol) and DMAP (24.4 mg, 0.2 mmol) in CH2Cl2/
DMF (20 mL, v/v 2/1) over 8 h using a syringe pump. After the
addition was complete, the mixture was stirred for 2 h. Regular
workup and purification by flash chromatography gave 1 as a
colorless semisolid (39.6 mg, 81%): [R]25D ) +83.8 (c 0.76, CHCl3)
Com p ou n d 4. Compound 4 was synthesized from 11 in 84%
yield as a colorless gel following the procedure used for the
synthesis of 8: [R]24 ) +26.2 (c 0.81, CHCl3); 1H NMR (600
D
MHz, CDCl3, 25 °C, TMS) δ 1.54 (d, J ) 6.6 Hz, 3H), 2.53 (s,
3H), 4.20 (t, J ) 7.0 Hz, 1H), 4.40 (d, J ) 6.6 Hz, 2H), 5.00 (m,
1H), 5.35 (s, 2H), 5.59 (d, J ) 7.4 Hz, 1H), 7.28-7.39 (m, 7H),
7.42 (d, J ) 7.0 Hz, 2H), 7.58 (t, J ) 7.9 Hz, 2H), 7.75 (d, J )
7.5 Hz, 2H); 13C NMR (150 MHz, CDCl3) δ 12.1, 20.2, 45.1, 47.1,
66.6, 67.0, 119.9, 125.0, 127.0, 127.4, 127.6, 128.3, 128.4, 128.5,
135.6, 141.2, 143.7, 143.8, 155.5, 156.6, 162.5, 168.9; HRMS
(MALDI-FTMS) calcd for C29H26N2O5 (M + Na+) 483.1914, found
483.1916; HPLC (chiralcel OD-H column, 254 nm, 90/10 hexane/
2-propanol to 70/30 hexane/2-propanol gradient over 60 min, flow
) 1.0 mL/min) tR ) 30.9 (R), 39.8 (S) min.
1
[lit.3b [R]D ) +53.9 (c 0.2, CHCl3)]; H NMR (600 MHz, CDCl3,
25 °C, TMS) δ 0.98 (d, J ) 7.0 Hz, 3H), 1.08 (d, J ) 7.0 Hz, 3H),
1.71 (d, J ) 7.0 Hz, 3H), 1.73 (d, J ) 7.0 Hz, 3H), 2.33 (m, 1H),
2.68 (s, 3H), 5.21 (q, J ) 6.6 Hz, 1H), 5.31 (dd, J ) 7.9, 4.8 Hz,
1H), 5.72 (dq, J ) 8.3, 6.6 Hz, 1H), 8.14 (s, 1H), 8.15 (s, 1H),
8.49 (d, J ) 8.3 Hz, 1H), 8.55 (d, J ) 8.3 Hz, 1H), 8.65 (d, J )
6.1 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 11.6, 18.3, 18.4, 20.9,
24.9, 35.1, 44.3, 47.0, 55.9, 123.7,123.8, 128.4, 148.8 (2 C), 153.8,
159.6, 159.8, 160.5, 161.7, 168.2, 171.1; HRMS (MALDI-FTMS)
calcd for C21H24N6O4S2 (M + H+) 489.1373, found 489.1373.
Com p ou n d 12. Pd(OAc)2 (4.5 mg, 0.02 mmol) and styrene
polymer-bound triphenylphosphine (101 mg, 1.59 mol/g, 0.16
mmol) were added to a flask containing CH2Cl2 (10 mL). After
the mixture was stirred for 10 min, 3 (462 mg, 1 mmol) and
PhSiH3 (0.24 mL, 2 mmol) were added separately. The reaction
progress was monitored by TLC, and the reaction was complete
in 15 min. After removal of the solvent, the residue was passed
through a short silica gel column eluted with CHCl3/EtOH
(1/1). The carboxylic acid was used in the next step without
Ack n ow led gm en t. We gratefully acknowledge NIH
support (grant GM63212) and support from the Skaggs
Institute for Chemical Biology. We thank Professor
Evan T. Powers for helpful discussions.
Su p p or tin g In for m a tion Ava ila ble: General procedures
and NMR spectra for 1-13. This material is available free of
charge via the Internet at http://pubs.acs.org.
further purification. Coupling with
2 (391 mg, 0.9 mmol)
following the procedure used for the synthesis of 6 gave 12 as a
white foam (511 mg, 92%): [R]24 ) +23.6 (c 0.74, CHCl3); 1H
J O0302657
D
J . Org. Chem, Vol. 68, No. 24, 2003 9509