Total synthesis of the cyclopeptide alkaloid abyssenine A. Application of inter- and intramolecular copper-mediated coupling reactions in organic synthesis

Article abstract of DOI:10.1021/jo070517u

(Chemical Equation Presented) The first total synthesis of the 15-membered ring cyclopeptide alkaloid abyssenine A 1 has been achieved with a longest linear sequence of 15 steps. Central to the synthetic approach was an efficient copper-mediated Ullmann c

Full text of DOI:10.1021/jo070517u

VOLUME 72, NUMBER 24
NOVEMBER 23, 2007
© Copyright 2007 by the American Chemical Society
Total Synthesis of the Cyclopeptide Alkaloid Abyssenine A.
Application of Inter- and Intramolecular Copper-Mediated Coupling
Reactions in Organic Synthesis
Mathieu Toumi, Franc¸ois Couty, and Gwilherm Evano*
Institut LaVoisier de Versailles, UMR CNRS 8180, UniVersite´ de Versailles Saint Quentin en YVelines,
45 aVenue des Etats-Unis, 78035 Versailles Cedex, France
eVano@chimie.uVsq.fr
ReceiVed March 19, 2007
The first total synthesis of the 15-membered ring cyclopeptide alkaloid abyssenine A 1 has been achieved
with a longest linear sequence of 15 steps. Central to the synthetic approach was an efficient copper-
mediated Ullmann coupling/Claisen rearrangement sequence allowing for both ipso and ortho function-
alization of aromatic iodide 4. This sequence was used for the synthesis of the aromatic core. The synthetic
utility of copper-catalyzed coupling reactions was further demonstrated to install the enamide with a
concomitant straightforward macrocyclization starting from acyclic R-amido-ω-vinyl iodide 13.
Introduction
and mild reaction conditions2,3 together with the extension of
these coupling reactions to the use of vinyl halides for the
synthesis of enamides4 and enol ethers.5 However, whereas the
development of new catalytic systems has received considerable
attention over the past decade, applications of these procedures
for the synthesis of complex molecules remain relatively
undeveloped even if they clearly allow for new and efficient
bond disconnections, as demonstrated by their use for the
installation of key-structural elements of complex natural
products.6,7
Copper-catalyzed C-N and C-O bond formation has long
been a practical and efficient method for the construction of
aromatic amides and ethers. Recently, improved versions of
these Ullmann and Goldberg coupling reactions relying on the
use of new ligands for the stabilization of the active copper
species led to considerable improvements of the original
procedures,1 allowing for the use of a wide range of substrates
(1) For reviews, see: (a) Ley, S. V.; Thomas, A. W. Angew. Chem., Int.
Ed. 2003, 42, 5400-5449. (b) Kunz, K.; Scholz, U.; Ganzer, D. Synlett
2003, 2428-2439. (c) Beletskaya, I. P.; Cheprakov, A. V. Coord. Chem.
ReV. 2004, 248, 2337-2364.
(2) C-O bond formation: (a) Gujadhur, R. K.; Bates, C. G.; Venkat-
araman, D. Org. Lett. 2001, 3, 4315-4317. (b) Wolter, M.; Nordmann, G.;
Job, G. E.; Buchwald, S. L. Org. Lett. 2002, 4, 973-976. (c) Buck, E.;
Song, Z. J.; Tschaen, D.; Dormer, P. G.; Volante, R. P.; Reider, P. J. Org.
Lett. 2002, 4, 1623-1626. (d) Ma, D.; Cai, Q. Org. Lett. 2003, 5, 3799-
3802. (e) Cristau, H.-J.; Cellier, P. P.; Hamada, S.; Spindler, J.-F.; Taillefer,
M. Org. Lett. 2004, 6, 913-916. (f) Chen, Y.-J.; Chen, H.-H. Org. Lett.
2006, 8, 5609-5612.
(3) C-N bond formation: (a) Klapars, A.; Huang, X.; Buchwald, S. L.
J. Am. Chem. Soc. 2002, 124, 7421-7428. (b) Cristau, H.-J.; Cellier, P. P.;
Spindler, J.-F.; Taillefer, M. Chem. Eur. J. 2004, 10, 5607-5622. Also see
ref. 2f.
(4) (a) Shen, R.; Porco, J. A., Jr. Org. Lett. 2000, 2, 1333-1336. (b)
Jiang, L.; Job, G. E.; Klapars, A.; Buchwald, S. L. Org. Lett. 2003, 5, 3667-
3669. (c) Han, C.; Shen, R.; Su, S.; Porco, J. A., Jr. Org. Lett. 2004, 6,
27-30. (d) Pan, X.; Cai, Q.; Ma, D. Org. Lett. 2004, 6, 1809-1812. (e)
Trost, B. M.; Stiles, D. T. Org. Lett. 2005, 7, 2117-2120.
(5) (a) Nordmann, G.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125,
4978-4979. (b) Ma, D.; Cai, Q.; Xie, X. Synlett 2005, 1767-1770.
10.1021/jo070517u CCC: $37.00 © 2007 American Chemical Society
Published on Web 05/18/2007
J. Org. Chem. 2007, 72, 9003-9009
9003

Toumi et al.
More recently, intramolecular versions of these copper-
catalyzed coupling reactions have been reported by Panek,8 Li,9
Ma,10 and us11 and used as challenging but efficient macrocy-
clization procedures.12 In this contribution, we report on the
use of an intramolecular copper-mediated macroamidation
reaction, culminating in the first total synthesis of abyssenine
A 1 (Figure 1).
enamide, has been reported to date.16 We therefore report in
this paper the total synthesis of abyssenine A 1 using copper-
mediated coupling reactions for the installation of key-structural
elements.
Results and Discussion
Retrosynthetic Analysis. Our strategy for the synthesis of
abyssenine A 1 is outlined in Figure 1. Facile generation of the
fully elaborated macrocyclic core relies on a challenging copper-
mediated intramolecular amidation reaction using amido-vinyl
iodide 2 as the enamide precursor. The synthesis of this acyclic
intermediate 2 would then just require an efficient preparation
of the highly functionalized, suitably protected, amino acid 3.
Synthesis of the Amino Acid Fragment 3. The amino acid
fragment 3 was constructed as shown in Scheme 1. Exposure
of a mixture of aromatic iodide 4 and allyl alcohol to catalytic
amounts of copper iodide and 1,10-phenanthroline followed by
simply heating the intermediate allyl ether to 240 °C allowed
for a clean and efficient intermolecular Ullmann coupling-
Claisen rearrangement sequence giving trisubstituted phenol 5
in excellent yield. Subsequent isomerization of the double bond
with catalytic amounts of RuClH(CO)(PPh3)3 cleanly gave
conjugated alkene 6 which was next methylated before being
subjected to oxidative cleavage to give aldehyde 7, a compound
that could hardly be obtained using standard aromatic chemistry
techniques.17 Horner-Emmons reaction of 7 with phosphonate
818 gave the (Z)-dehydrophenylalanine derivative 9 and set the
stage for the enantioselective installation of the amino acid
moiety. Catalytic asymmetric hydrogenation of 9 proceeded
smoothly in the presence of [Rh(COD){(S,S)-Et-DuPHOS}]+-
TfO-19 to afford the corresponding amino ester 10 with good
yield and enantioselectivity (89%, 98% ee), the latter being
finally methylated under racemization-free conditions.20 To
install the Z-vinyl iodide required for the final macroamidation
step, the TBS ether was deprotected using TBAF in THF, and
the resulting primary alcohol was oxidized to 11 with Dess-
Martin periodinane in good overall yield. Finally, Wittig
olefination using the Stork/Zhao protocol21 followed by careful
saponification of the methyl ester led to the desired amino acid
fragment 3 as (Z)-diastereoisomer exclusively.
FIGURE 1. Retrosynthetic analysis of abyssenine A (1).
This 15-membered ring macrocycle, isolated from the roots
and stem bark of several Zizyphus-type Rhamnaceae,13 is part
of the cyclopeptide alkaloids class of natural products, a family
that encompasses over two hundred compounds and has been
shown to display numerous biological activities including
sedative, antibacterial, antifungal, and antiplasmodial.14 While
much work has been devoted to the synthesis of the 13- or 14-
membered ring cyclopeptide alkaloids,11,15 a single synthesis
of a 15-membered ring compound, mucronine B, featuring a
macrolactamization reaction and a stepwise installation of the
(6) For examples featuring C-N bond formation, see: (a) Shen, R.; Lin,
C. T.; Porco, J. A., Jr. J. Am. Chem. Soc. 2002, 124, 5650-5651. (b) Xang,
X.; Porco, J. A., Jr. J. Am. Chem. Soc. 2003, 125, 6040-6041. (c) Nicolaou,
K. C.; Kim, D. W.; Baati, R.; O’Brate, A.; Giannakakou, P. Chem. Eur. J.
2003, 9, 6177-6191. (d) Nakamura, R.; Tanino, K.; Miyashita, M. Org.
Lett. 2003, 5, 3583-3586. (e) Evano, G.; Schaus, J.; Panek, J. S. Org. Lett.
2004, 6, 525-528. (f) Nakamura, R.; Tanino, K.; Miyashita, M. Org. Lett.
2003, 5, 3583-3586. (g) Su, Q.; Panek, J. S. J. Am. Chem. Soc. 2004, 126,
2425-2430. (h) Dias, L. C.; De Oliveira, L. G.; Vilcachagua, J. D.; Nigsch,
F. J. Org. Chem. 2005, 70, 2225-2234. (i) Shen, R.; Inoue, T.; Forgac,
M.; Porco, J. A., Jr. J. Org. Chem. 2005, 70, 3686-3692.
(7) For examples featuring C-O bond formation, see: (a) Xing, X.;
Padmanaban, D.; Yeh, L.-A.; Cuny, G. D. Tetrahedron 2002, 7903-7910.
(b) Cai, Q.; He, G.; Ma, D. J. Org. Chem. 2006, 71, 5268-5273.
(8) Wrona, I.; Gabarda, A. E.; Evano, G.; Panek, J. S. J. Am. Chem.
Soc. 2005, 127, 15026-15027.
Assembly of the Acyclic Skeleton. Having in hand useful
quantities of the amino acid fragment 3, the assembly of the
acyclic skeleton of abyssenine A was next undertaken. To avoid
a stepwise installation of the amide group required for the
macrocyclization step after introduction of the other two
constitutive amino acids of the macrocycle, a direct peptide bond
formation between 3 and isoleucine-leucinamide 1222 was
envisioned. This quite simple fragment coupling proved to be
especially challenging, but after screening a variety of coupling
(9) Hu, T.; Li, C. Org. Lett. 2005, 7, 2035-2038.
(10) Cai, Q.; Zou, B.; Ma, D. Angew. Chem., Int. Ed. 2006, 45, 1276-
1279.
(11) Toumi, M.; Couty, F.; Evano, G. Angew. Chem., Int. Ed. 2007, 46,
572-575.
(12) For the use of stoechiometric intramolecular Ullmann Condensation,
see: (a) Boger, D. L.; Yohannes, D. J. Org. Chem. 1991, 56, 1763-1767.
(b) Nicolaou, K. C.; Boddy, C. N. C.; Natarajan, S.; Yue, T.-Y.; Li, H.;
Bra¨se, S.; Ramanjulu, J. M. J. Am. Chem. Soc. 1997, 119, 3421-3422.
(13) (a) Tschesche, R.; David, S. T.; Zerbes, R.; von Radloff, M.;
Kaussmann, E. U.; Eckhardt, G. Liebigs Ann. Chem. 1974, 1915-1928.
(b) Cassels, B. K.; Eckhardt, G.; Kaussmann, E.-U.; Tschesche, R.
Tetrahedron 1974, 30, 2461-2466. (c) Auvin, C.; Lezenven, F.; Blond,
A.; Augeven-Bour, I.; Pousset, J.-L.; Bodo, B. J. Nat. Prod. 1996, 59, 676-
678.
(14) For reviews, see: (R) Gournelif, D. C.; Laskaris, G. G.; Verpoorte,
R. Nat. Prod. Rep. 1997, 14, 75-82. (b) Joullie´, M. M.; Richard, D. J.
Chem. Commun. 2004, 2011-2015. (c) Tan, N. H.; Zhou, J. Chem. ReV.
2006, 106, 840-895.
(15) (a) Schmidt, U.; Lieberknecht, A.; Bo¨kens, H.; Griesser, H. J. Org.
Chem. 1983, 48, 2680-2685. (b) Heffner, R. J.; Jiang, J.; Joullie´, M. M. J.
Am. Chem. Soc. 1992, 114, 10181-10189. (c) Han, B. H.; Kim, Y. C.;
Park, M. K.; Park, J. H.; Go, H. J.; Yang, H. O.; Suh, D. Y.; Kang, Y. H.
Heterocycles 1995, 41, 1909-1914. (d) Temal-La¨ıb, T.; Chastanet, J.; Zhu,
J. J. Am. Chem. Soc. 2002, 124, 583-590. (e) He, G.; Wang, J.; Ma, D.
Org. Lett. 2007, 9, 1367-1369.
(16) (a) Schmidt, U.; Schanbacher, U. Angew. Chem. Int., Ed. Engl. 1983,
22, 152-153. (b) Schmidt, U.; Schanbacher, U. Liebigs Ann. Chem. 1984,
1205-1215.
(17) Attempts at formylation of 4-hydroxy-benzyl alcohol, 4-methoxy-
benzyl alcohol or their TBS-protected derivatives using standard methods
(lithiation, Vilsmeier, Reimer-Tiemann) failed to give compound 7 (or
unprotected derivatives) in decent yields.
(18) Schmidt, U.; Lieberknecht, A.; Wild, J. Synthesis 1984, 53-60.
(19) Burk, M. J. Acc. Chem. Res. 2000, 33, 363-372.
(20) Coggins, J. R.; Benoiton, N. L. Can. J. Chem. 1971, 49, 1968-
1971.
(21) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 2173-2174.
(22) Prepared in two steps (EDC/HOAt-mediated coupling, hydrogenoly-
sis) from Cbz-isoleucine and leucinamide hydrochloride. See Experimental
Section for details.
9004 J. Org. Chem., Vol. 72, No. 24, 2007

Total Synthesis of Abyssenine A
SCHEME 1. Enantioselective Synthesis of the Amino Acid Fragment
SCHEME 2. Macrocyclization and Completion of the Synthesis
agents and conditions, we eventually found that activation of 3
with BOP and further reaction with 12 gave the fully elaborated
acyclic skeleton 13 in excellent yield and without any noticeable
epimerization (Scheme 2).
Macrocyclization and Completion of the Synthesis. This
set the stage for the crucial macrocyclization step:11 subjection
of the iodo-amide 13 to catalytic copper(I) iodide and N,N′-
dimethylethylenediamine4b in THF under high dilution condi-
J. Org. Chem, Vol. 72, No. 24, 2007 9005

Toumi et al.
washed with brine, dried over MgSO4, filtered, and concentrated
under vacuum. The crude residue was purified by flash chroma-
tography over silica gel (petroleum ether/AcOEt: 9/1) to yield the
desired silyl ether 4 as a white solid (6.4 g, 18.4 mmol, 94%). Mp:
tions at 63 °C smoothly provided the 15-membered ring 14 in
83% yield. The most striking feature of this approach is that
this mild intramolecular amidation protocol proceeds with
complete regioselectivity for the terminal amide, without any
epimerization at the three amino acid stereocenters or isomer-
ization of the Z vinyl iodide and without dimerization or
formation of higher oligomers. Finally, careful removal of the
Boc group using TMSOTf and 2,6-lutidine provided synthetic
abyssenine A 1 which was identical in all respects (1H NMR,
13C NMR, [R]D20, IR, UV, and MS) to the natural product,
therefore establishing both its relative and absolute configura-
tions.
In summary, the first total synthesis of abyssenine A has been
achieved in 15 steps (longest linear sequence) and excellent
overall yield (35%). Notable features of our synthetic approach
include an original and efficient copper(I)-catalyzed Ullmann
coupling/Claisen rearrangement sequence which allows for both
ipso and ortho functionalization of an aromatic iodide. This
effort also documents an efficient intramolecular copper(I)-
mediated vinylation protocol to install the 15-membered mac-
rocyclic enamide. This should contribute to further expand the
scope of those underdeveloped useful reactions which clearly
allow for new bond disconnections in total synthesis and should
permit for the preparation of other natural products featuring a
macrocyclic enamide skeleton.
1
41 °C; H NMR (300 MHz, CDCl3): δ 7.65 (d, J ) 8.3 Hz, 2H),
7.08 (d, J ) 8.3 Hz, 2H), 4.68 (s, 2H), 0.94 (s, 9H), 0.09 (s, 9H);
13C NMR (75 MHz, CDCl3): δ 141.3, 137.6, 128.1, 92.2, 64.5,
26.0, 18.5, -5.1; IR (KBr): νmax 2950, 2853, 1649, 1470, 1399,
1091, 845 cm-1; EIMS: 348, 291, 261, 217.
4-Allyloxy-1-(tert-butyl-dimethyl-silyloxymethyl)-benzene. A
pressure tube was charged with 1-(tert-butyl-dimethyl-silyloxy-
methyl)-4-iodo-benzene 4 (6.0 g, 17.2 mmol), cesium carbonate
(8.4 g, 25.8 mmol), 1,10-phenanthroline (620 mg, 3.4 mmol), and
copper(I) iodide (328 mg, 1.7 mmol). Toluene (17 mL) and allyl
alcohol (3.5 mL, 51.7 mmol) were successively added, the pressure
tube was closed, and the brownish suspension was heated to 110
°C for 12 h and cooled to rt. The crude reaction mixture was finally
filtered over a plug of silica gel (washed with AcOEt) and
concentrated to yield the desired aryl ether as a pale yellow liquid
1
(4.8 g, 17.2 mmol, quant). H NMR (300 MHz, CDCl3): δ 7.14
(d, J ) 8.6 Hz, 2H), 6.79 (d, J ) 8.6 Hz, 2H), 5.89-6.02 (m, 1H),
5.31 (dq, J ) 17.2, 1.5 Hz, 1H), 5.17 (dq, J ) 10.5, 1.4 Hz, 1H),
4.58 (s, 2H), 4.42 (dt, J ) 5.3, 1.4 Hz, 2H), 0.85 (s, 9H), 0.00 (s,
6H); 13C NMR (75 MHz, CDCl3): δ 157.8, 133.9, 133.5, 127.6,
117.6, 114.6, 68.9, 64.8, 26.1, 18.5, -5.1; IR (neat): νmax 2945,
2924, 2852, 1608, 1506, 1250, 1086, 840 cm-1; EIMS: 278, 221,
147; ESIHRMS m/z calcd for C16H27O2Si [M + H]+ 279.1780,
found 279.1787.
2-Allyl-4-(tert-butyl-dimethyl-silyloxymethyl)-phenol 5. A 15
mL pressure tube was charged with 4-allyloxy-1-(tert-butyl-
dimethyl-silyloxymethyl)-benzene (4.2 g, 15.1 mmol), evacuated,
and backfilled with argon. The pressure tube was closed, heated to
230-240 °C for 2 h, and cooled to rt. The crude residue was
purified by flash chromatography over silica gel (petroleum ether/
AcOEt: 8/2) to yield the desired phenol 5 as a pale yellow oil (3.9
g, 14.0 mmol, 93%). 1H NMR (300 MHz, CDCl3): δ 7.08 (d, J )
8.8 Hz, 1H), 7.07 (s, 1H), 6.76 (d, J ) 8.8 Hz, 1H), 5.95-6.09 (m,
1H), 5.13-5.20 (m, 2H), 5.14 (s, 1H), 4.67 (s, 2H), 3.41 (d, J )
6.4 Hz, 2H), 0.95 (s, 9H), 0.11 (s, 6H); 13C NMR (75 MHz,
CDCl3): δ 153.2, 136.6, 133.8, 128.8, 126.1, 125.3, 116.5, 115.7,
65.0, 35.2, 26.1, 18.6, -5.0; IR (neat): νmax 3324, 2929, 2848,
2755, 1496, 1255, 1091, 835 cm-1; EIMS: 221, 147, 75; ESIHRMS
(CI, NH3) m/z calcd for C16H26NaO2Si [M + Na]+ 301.1600, found
301.1621.
Experimental Section
General Information. All reactions were carried out in oven-
or flame-dried glassware under an argon atmosphere employing
standard techniques in handling air-sensitive materials. All solvents
were reagent grade. Tetrahydrofuran (THF) and toluene were freshly
distilled from sodium/benzophenone under argon immediately prior
to use. Dichloromethane, HMPA, and DMF were freshly distilled
from calcium hydride. Methanol was distilled from magnesium
turnings and iodine. Diisopropylethylamine, N,N′-dimethylethyl-
enediamine and 2,6-lutidine were distilled over calcium hydride.
Acetone was synthesis grade and used as supplied, and 99.999%
purity copper(I) iodide was used. All other reagents were used as
supplied. Flash chromatography was performed with silica gel 60
(particle size 35-70 µm). Yields refer to chromatographically and
spectroscopically pure compounds, unless otherwise noted. Proton
NMR spectra were recorded using an internal deuterium lock at
ambient temperature on a 300 MHz spectrometer. Internal references
of δH 7.26 and δH 2.50 were respectively used for CDCl3 and
DMSO-d6. Data are presented as follows: chemical shift (in ppm
on the δ scale relative to δTMS ) 0), multiplicity (s ) singlet, d )
doublet, t ) triplet, q ) quartet, quint. ) quintuplet, m ) multiplet,
br ) broad), coupling constant (J/Hz), and integration. Carbon-13
NMR spectra were recorded at 75 MHz. Internal references of δC
77.16 and δC 39.52 were respectively used for CDCl3 and DMSO-
d6. Optical rotations are reported as follows: [R]D20, concentration
(c in g/ 100 mL) and solvent.
Because of the presence of the tertiary N-Boc group, it was
necessary to record 1H and 13C NMR spectra of most intermediates
in DMSO-d6 at temperatures ranging from 333 to 355K (see details
below; the use of higher temperatures resulted in degradation of
intermediates). Even at those temperatures, some 13C peaks were
poorly resolved and are denoted “broad” (br).
1-(tert-Butyl-dimethyl-silyloxymethyl)-4-iodo-benzene 4. To
a solution of 4-iodo-benzyl alcohol (4.6 g, 19.6 mmol) in THF (50
mL) were added at 0 °C imidazole (1.75 g, 25.5 mmol) and TBSCl
(3.1 g, 20.6 mmol). The resulting mixture was slowly warmed to
rt over 2 h and poured into a mixture of 1 M HCl (50 mL) and
ether (50 mL). The organic layer was separated, and the aqueous
layer was extracted with ether. The combined organic layers were
(E)-4-(tert-Butyl-dimethyl-silyloxymethyl)-2-propenyl-phe-
nol 6. To a solution of 5 (2.8 g, 10.0 mmol) in toluene (25 mL)
was added RuClH(CO)(PPh3)3 (440 mg, 0.46 mmol). The resulting
solution was heated to 80 °C overnight and concentrated. The crude
residue was purified by flash chromatography over silica gel
(petroleum ether/AcOEt: 9/1) to yield the desired isomerized alkene
1
(E isomer) as a pale yellow oil (2.5 g, 9.0 mmol, 90%). H NMR
(300 MHz, CDCl3): δ 7.15 (s, 1H), 6.94 (d, J ) 8.2 Hz, 1H), 6.61
(d, J ) 8.2 Hz, 1H), 6.48 (dq, J ) 15.9, 1.3 Hz, 1H), 6.09 (dq, J
) 15.9, 6.6 Hz, 1H), 5.11 (s, 1H), 4.55 (s, 2H), 1.80 (dd, J ) 6.6,
1.3 Hz, 3H), 0.84 (s, 9H), 0.00 (s, 6H); 13C NMR (75 MHz,
CDCl3): δ 151.6, 133.6, 128.1, 126.3, 125.6, 125.5, 124.9, 115.7,
65.0, 26.1, 19.0, 18.6, -5.0; IR (neat): νmax 3288, 2745, 1660,
1424, 1086, 835 cm-1; EIMS: 278, 221, 147, 91, 75; ESIHRMS
m/z calcd for C16H26NaO2Si [M + Na]+ 301.1600, found 301.1609.
(E)-4-(tert-Butyl-dimethyl-silyloxymethyl)-1-methoxy-(2-pro-
penyl)-benzene. To a solution of 6 (2.3 g, 8.2 mmol) in dry acetone
(60 mL) were added potassium carbonate (1.5 g, 10.8 mmol) and
dimethyl sulfate (0.9 mL, 9.5 mmol). The resulting greenish mixture
was refluxed for 3 h, stirred overnight at rt, concentrated in vacuo,
and diluted with water and CH2Cl2. The aqueous layer was extracted
with CH2Cl2, and combined organic layers were washed with brine,
dried over MgSO4, filtered, and concentrated. The crude residue
was purified by flash chromatography over silica gel (petroleum
ether/AcOEt: 95/5) to yield the desired methyl ether as a colorless
9006 J. Org. Chem., Vol. 72, No. 24, 2007

Total Synthesis of Abyssenine A
oil (2.35 g, 8.0 mmol, 98%). 1H NMR (300 MHz, CDCl3): δ 7.37
(d, J ) 2.0 Hz, 1H), 7.16 (dd, J ) 8.4, 2.0 Hz, 1H), 6.83 (d, J )
8.4 Hz, 1H), 6.75 (dq, J ) 15.9, 1.7 Hz, 1H), 6.25 (dq, J ) 15.9,
6.6 Hz, 1H), 4.70 (s, 2H), 3.85 (s, 3H), 1.93 (dd, J ) 6.6, 1.7 Hz,
3H), 0.97 (s, 9H), 0.12 (s, 6H); 13C NMR (75 MHz, CDCl3): δ
155.4, 133.5, 126.9, 126.5, 125.9, 125.8, 124.7, 110.7, 64.9, 55.7,
26.1, 19.1, 18.6, -5.0; IR (neat): νmax 2950, 2853, 1491, 1255,
1091, 840, 779 cm-1; EIMS: 293, 279, 265, 237, 207, 193, 179,
163, 149, 135, 105, 75.
(d, J ) 7.4 Hz, 1H), 4.63 (s, 2H), 4.48 (app. q, J ) 7.2 Hz, 1H),
3.81 (s, 3H), 3.69 (s, 3H), 3.04 (d, J ) 7.0 Hz, 1H), 1.38 (s, 9H),
0.92 (s, 9H), 0.08 (s, 6H); 13C NMR (75 MHz, CDCl3): δ 173.0,
156.8, 155.4, 133.6, 129.5, 126.5, 124.5, 110.3, 79.6, 64.7, 55.5,
54.2, 52.1, 32.9, 28.4, 26.1, 18.5, -5.1; IR (neat): νmax 3365, 2945,
2853, 1742, 1711, 1501, 1255, 1173, 1066, 830, 768 cm-1; ESIMS
(positive mode): 476.3, 420.2; ESIHRMS m/z calcd for C23H39-
NNaO6Si [M + Na]+ 476.2444, found 476.2458.
(S)-Methyl 2-(tert-butoxycarbonyl-methyl-amino)-3-[5-(tert-
butyl-dimethyl-silyloxymethyl )-2-methoxy-phenyl]-propionate.
To a suspension of sodium hydride (60 wt % in mineral oil, 120
mg, 2.9 mmol) in DMF (10 mL) was slowly added a solution of
10 (1.10 g, 2.42 mmol) and iodomethane (600 µL, 9.7 mmol) in
DMF (18 mL). The resulting mixture was stirred for 1 h and
quenched by slow addition of a saturated aqueous solution of NH4-
Cl. The aqueous layer was extracted with ether, and combined
organic layers were washed with brine, dried over MgSO4, filtered,
and concentrated to yield the desired methylated amino acid as a
colorless oil (1.11 g, 2.35 mmol, 97%). [R]D20 -67 (c 1.5, CHCl3);
1H NMR (300 MHz, DMSO-d6, 345 K): δ 7.14 (dd, J ) 8.3, 2.1
Hz, 1H), 7.04 (d, J ) 2.1 Hz, 1H), 6.92 (d, J ) 8.3 Hz, 1H), 4.71-
4.75 (br s, 1H), 4.63 (s, 2H), 3.80 (s, 3H), 3.68 (s, 3H), 3.20 (A of
ABX syst, J ) 13.9, 4.9 Hz, 1H), 2.96 (B of ABX syst, J ) 13.9,
10.4 Hz, 1H), 2.64 (s, 3H), 1.28 (s, 9H), 0.91 (s, 9H), 0.07 (s, 6H);
13C NMR (75 MHz, DMSO-d6, 345 K): δ 170.8, 156.2, 154.1,
132.5, 128.4, 125.4, 125.0, 110.1, 78.5, 63.8, 58.5, 55.1, 51.2, 31.8,
29.5, 27.4, 25.4, 17.5, -5.7; IR (neat): νmax 2947, 2853, 1739,
1735, 1510, 1255, 1063, 830 cm-1; ESIMS (positive mode): 490.2,
434.2; ESIHRMS m/z calcd for C24H41NNaO6Si [M + Na]+
490.2601, found 490.2574.
5-(tert-Butyl-dimethyl-silyloxymethyl)-2-methoxy-benzalde-
hyde 7. To a solution of (E)-4-(tert-butyl-dimethyl-silyloxymethyl)-
1-methoxy-(2-propenyl)-benzene (2.2 g, 7.5 mmol) in a mixture
of CCl4 (100 mL), tBuOH (40 mL), and water (40 mL) was added
a solution of osmium tetroxide (4 wt % solution in water, 2.4 mL,
0.4 mmol). The resulting gray solution was stirred for 15 min before
adding sodium periodate (4.0 g, 18.8 mmol). The reaction mixture
was vigorously stirred overnight and quenched with a 10% aqueous
sodium thiosulfate solution. The aqueous layer was extracted with
CH2Cl2, combined organic layers were washed with brine, dried
over MgSO4, filtered, and concentrated. The crude residue was
purified by flash chromatography over silica gel (petroleum ether/
AcOEt: 95/5) to yield the desired aldehyde 6 as a gray oil (1.85 g,
1
6.6 mmol, 88%). H NMR (300 MHz, CDCl3): δ 10.46 (s, 1H),
7.74 (d, J ) 2.3 Hz, 1H), 7.56 (dd, J ) 8.6, 2.3 Hz, 1H), 6.98 (d,
J ) 8.6 Hz, 1H), 4.68 (s, 2H), 3.92 (s, 3H), 0.93 (s, 9H), 0.09 (s,
6H); 13C NMR (75 MHz, CDCl3): δ 190.0, 161.1, 134.1, 133.9,
126.4, 124.5, 111.8, 64.3, 55.9, 26.1, 18.5, -5.1; IR (neat): νmax
2950, 2923, 2853, 1685, 1501, 1250, 1112, 840 cm-1; EIMS: 281,
223, 207, 193, 149; ESIHRMS m/z calcd for C15H25O3Si [M +
H]+ 281.1573, found 281.1570.
(Z)-Methyl 2-tert-butoxycarbonylamino-3-[5-(tert-butyl-di-
methyl-silyloxymethyl)-2-methoxy-phenyl]-acrylate 9. To a mix-
ture of 7 (1.6 g, 5.7 mmol) and methyl 2-tert-butoxycarbonylamino-
2-dimethoxyphosphinyl-acetate 818 (2.05 g, 6.85 mmol) in dichlo-
romethane (30 mL) at 0 °C was added N,N,N′,N′-tetramethylguanidine
(3.3 mL, 8.55 mmol). The reaction mixture was then allowed to
warm to room temperature, stirred overnight, and quenched with a
10% aqueous citric acid solution. The aqueous layer was extracted
with CH2Cl2, combined organic layers were washed with brine,
dried over MgSO4, filtered, and concentrated. The crude residue
was purified by flash chromatography over silica gel (petroleum
ether/AcOEt: 7/3) to yield the desired dehydro amino acid 9 (Z
isomer only as demonstrated by NOE experiments) as a colorless
(S)-Methyl 2-(tert-butoxycarbonyl-methyl-amino)-3-(5-hy-
droxymethyl-2-methoxy-phenyl)-propionate. A solution of (S)-
methyl 2-(tert-butoxycarbonyl-methyl-amino)-3-[5-(tert-butyl-di-
methyl-silyloxymethyl)-2-methoxy-phenyl]-propionate (1.0 g, 2.14
mmol) in THF (26 mL) was treated with a solution of TBAF (1 M
solution in THF, 3.2 mL, 3.2 mmol) at -15 °C. The resulting light
yellow mixture was warmed to rt over 3 h and quenched with water.
The aqueous layer was extracted with Et2O, and the combined
organic layers were washed with brine, dried over MgSO4, filtered,
and concentrated. The crude residue was purified by flash chro-
matography over silica gel (petroleum ether/AcOEt: 2/8) to yield
the desired alcohol as a colorless oil (756 mg, 2.14 mmol, quant).
[R]D -64 (c 1.0, CHCl3); H NMR (300 MHz, DMSO-d6, 345
K): δ 7.16 (dd, J ) 8.3, 2.1 Hz, 1H), 7.06 (d, J ) 2.1 Hz, 1H),
6.90 (d, J ) 8.3 Hz, 1H), 4.68-4.75 (m, 2H), 4.41 (d, J ) 4.7 Hz,
2H), 3.80 (s, 3H), 3.68 (s, 3H), 3.18 (A of ABX syst, J ) 13.9, 5.1
Hz, 1H), 2.98 (B of ABX syst, J ) 13.9, 10.8 Hz, 1H), 2.65 (s,
3H), 1.30 (s, 9H); 13C NMR (75 MHz, DMSO-d6, 345 K): δ 170.9,
156.1, 154.1, 133.9, 128.7, 125.7, 124.9, 110.1, 78.6, 62.3, 58.6,
55.1, 51.2, 31.8, 29.5, 27.5; IR (neat): νmax 3447, 2945, 1745, 1696,
1506, 1255, 1168, 1035, 815 cm-1; ESIMS (positive mode): 376.3,
320.2, 276.2; ESIHRMS m/z calcd for C18H27NNaO6 [M + Na]+
376.1736, found 376.1753.
20
1
1
oil (2.5 g, 5.5 mmol, 96%). H NMR (300 MHz, CDCl3): δ 7.43
(d, J ) 2.0 Hz, 1H), 7.30 (s, 1H), 7.28 (dd, J ) 8.6, 2.1 Hz, 1H),
6.89 (d, J ) 8.6 Hz, 1H), 6.41 (br s, 1H), 4.64 (s, 2H), 3.86 (s,
3H), 3.84 (s, 3H), 1.38 (s, 9H), 0.93 (s, 9H), 0.09 (s, 6H); 13C
NMR (75 MHz, CDCl3): δ 166.3, 156.2, 152.9, 133.6, 128.5, 127.8,
125.9, 123.7, 122.9, 111.2, 80.7, 64.6, 56.0, 52.6, 28.2, 26.1, 18.5,
-5.1; IR (neat): νmax 3329, 2950, 2735, 1726, 1716, 1496, 1250,
1168, 835, 779 cm-1; ESIMS (positive mode): 474.2, 418.2, 374.3;
ESIHRMS m/z calcd for C23H37NNaO6Si [M + Na]+ 474.2288,
found 474.2320.
(S)-Methyl 2-tert-butoxycarbonylamino-3-[5-(tert-butyl-di-
methyl-silyloxymethyl)-2-methoxy-phenyl]-propionate 10. A mix-
ture of 9 (1.60 g, 3.54 mmol) and (+)-1,2-bis[(2S,5S)-2,5-diethyl-
phospholano]benzene(cyclooctadiene)-rhodium(I) trifluoromethane-
sulfonate ([Rh(COD){(S,S)-Et-DuPHOS}]+TfO-, 25 mg, 0.017
mmol) in dry and degassed methanol (20 mL) was placed under 5
atm of hydrogen and stirred for 18 h at 25 °C. The solution was
concentrated under reduced pressure, and the residue was purified
by flash column chromatography over silica gel (petroleum ether/
AcOEt: 8/2) to yield the desired aromatic amino acid as a colorless
oil (1.43 g, 3.15 mmol, 89%). Enantiomeric excess was determined
by chiral HPLC analysis (Chiracel OD column, n-heptane/propan-
(S)-Methyl 2-(tert-butoxycarbonyl-methyl-amino)-3-(5-formyl-
2-methoxy-phenyl)-propionate 11. To a solution of (S)-methyl
2-(tert-butoxycarbonyl-methyl-amino)-3-(5-hydroxymethyl-2-meth-
oxy-phenyl)-propionate (732 mg, 2.07 mmol) in CH2Cl2 (40 mL)
were successively added 2,6-lutidine (260 µL, 2.23 mmol) and
Dess-Martin periodinane (15 wt % solution in CH2Cl2, 7.6 mL,
3.7 mmol) at 0 °C. The resulting mixture was stirred for 40 min at
0 °C (a white slurry was obtained) and quenched with a mixture of
10 wt % aqueous sodium thiosulfate solution (50 mL) and saturated
aqueous sodium bicarbonate solution (50 mL). The aqueous layer
was extracted with CH2Cl2, and the combined organic layers were
washed with brine, dried over MgSO4, filtered, and concentrated.
The crude residue was purified by flash chromatography over silica
gel (petroleum ether/AcOEt: 1/1) to yield the desired aldehyde 9
2-ol: 97/3, flow rate 1.00 mL/min, λ ) 254 nm), 98% ee, tR
)
6.15 min (major), 7.64 min (minor). [R]D20 -9 (c 0.9, CHCl3); 1H
NMR (300 MHz, CDCl3): δ 7.18 (dd, J ) 8.4, 1.8 Hz, 1H), 7.02
(d, J ) 1.8 Hz, 1H), 6.81 (d, J ) 8.4 Hz, 1H), 5.28 (s, 1H), 5.21
20
as a colorless oil (667 mg, 1.90 mmol, 92%). [R]D -56 (c 1.3,
1
CHCl3); H NMR (300 MHz, DMSO-d6, 355 K): δ 9.86 (s, 1H),
J. Org. Chem, Vol. 72, No. 24, 2007 9007

Toumi et al.
7.80 (dd, J ) 8.5, 2.1 Hz, 1H), 7.67 (d, J ) 2.1 Hz, 1H), 7.17 (d,
J ) 8.5 Hz, 1H), 4.77-4.83 (m, 1H), 3.94 (s, 3H), 3.70 (s, 3H),
3.26 (A of ABX syst, J ) 14.0, 5.0 Hz, 1H), 3.09 (B of ABX syst,
J ) 14.0, 10.3 Hz, 1H), 2.67 (s, 3H), 1.29 (s, 9H); 13C NMR (75
MHz, DMSO-d6, 355 K): δ 190.3 and 190.2 (rotamers), 170.5,
162.1, 154.0 (br), 130.8, 130.6, 129.1, 126.4, 110.5, 78.7, 58.2 (br),
55.6, 51.3 and 51.2 (rotamers), 31.7, 29.1, 27.3; IR (neat): νmax
2970, 2837, 2735, 1737, 1685, 1603, 1501, 1439, 1260, 1173, 1030
cm-1; ESIMS (positive mode): 374.3, 318.2, 274.2; ESIHRMS m/z
calcd for C18H26NO6 [M + H]+ 352.1760, found 352.1789.
(S,Z)-Methyl 2-(tert-butoxycarbonyl-methyl-amino)-3-[5-(2-
iodo-vinyl)-2-methoxy-phenyl]-propionate. To a suspension of
iodomethyltriphenyl-phosphonium iodide (1.12 g, 2.11 mmol) in
THF (11 mL) was added dropwise at rt a solution of NaHMDS
(2.0 M solution in THF, 1.0 mL, 2.0 mmol). The resulting red-
orange solution was stirred at rt for 20 min and cooled to -78 °C
before adding HMPA (1.3 mL) and a solution of 11 (550 mg, 1.56
mmol) in THF (7 mL). The reaction mixture was stirred at -78
°C for 1 h and 40 min and quenched at -78 °C by addition of a
saturated aqueous solution of NaHCO3. The mixture was warmed
to rt, diluted with Et2O, and filtered through a plug of Celite which
was thoroughly washed with ether. The biphasic filtrate was
separated, and the organic layer was dried over MgSO4, filtered,
and concentrated. The crude residue was purified by flash chro-
matography over silica gel (AcOEt/petroleum ether: 25/75) to give
the desired vinyl iodide as a pale yellow oil (676 mg, 1.42 mmol,
91%). Diastereoisomeric excess was determined by analysis of crude
1H NMR spectra and was found to be higher than 95%. [R]D20 -66
and N-methylmorpholine (2.1 mL, 18.7 mmol) were successively
added at 0 °C, and the solution was stirred for 16 h while
progressively warmed to rt. The yellow slurry was finally concen-
trated and diluted with 1 M HCl aqueous solution. The aqueous
layer was extracted with CH2Cl2, and the combined organic layers
were dried over MgSO4, filtered, and concentrated to give the
desired dipeptide (2.3 g, 6.1 mmol, 81%) as a white solid. Mp:
212 °C; [R]D20 -20 (c 0.3, DMSO); 1H NMR (300 MHz, DMSO-
d6): δ 7.87 (d, J ) 8.3 Hz, 1H), 7.31-7.43 (m, 7H), 7.01 (s, 1H),
5.07 (s, 2H), 4.26-4.33 (m, 1H), 3.92 (t, J ) 8.0 Hz, 1H), 1.70-
1.77 (m, 1H), 1.54-1.67 (m, 1H), 1.41-1.51 (m, 3H), 1.07-1.23
(m, 1H), 0.91 (d, J ) 6.5 Hz, 3H), 0.81-0.87 (m, 9H); 13C NMR
(75 MHz, DMSO-d6): δ 173.9, 170.9, 156.1, 137.1, 128.3, 127.8,
127.6, 65.4, 59.3, 50.7, 41.0, 36.3, 24.4, 24.2, 23.0, 21.6, 15.4, 10.9;
IR (KBr): νmax 3385, 3314, 2945, 1670, 1639, 1537, 1235, 702
cm-1; ESIHRMS m/z calcd for C20H32N3O4 [M + H]+ 378.2393,
found 378.2401.
Isoleucine-leucinamide 12. A slurry of Cbz-isoleucine-leuci-
namide (600 mg, 1.59 mmol) in 95% ethanol (25 mL) was treated
with palladium on carbon (10 wt % on activated carbon, 100 mg)
and stirred under an atmosphere of hydrogen for 1 h. The mixture
was filtered over a plug of Celite and concentrated. The crude
residue was purified by flash chromatography over silica gel
(AcOEt/EtOH/30% aq NH3: 90/9/1) to give the desired peptide as
a white solid (364 mg, 1.50 mmol, 94%). Mp: 121 °C; [R]D20 -25
1
(c 2.0, MeOH); H NMR (300 MHz, MeOH-d4): δ 4.43 (dd, J )
9.1, 5.8 Hz, 1H), 3.21 (d, J ) 5.4 Hz, 1H), 1.44-1.77 (m, 5H),
1.09-1.26 (m, 1H), 0.88-0.98 (m, 12H); 13C NMR (75 MHz,
MeOH-d4): δ 177.4, 177.0, 60.9, 52.5, 42.3, 40.2, 25.9, 25.3, 23.4,
21.9, 16.1, 11.9; IR (KBr): νmax 3411, 3350, 2966, 1706, 1680,
1634, 1506, 1414, 850, 595 cm-1; ESIMS (positive mode): 266.3;
ESIHRMS m/z calcd for C12H26N3O2 [M + H]+ 244.2025, found
244.2035.
1
(c 1.0, CHCl3); H NMR (300 MHz, DMSO-d6, 355 K): δ 7.56
(dd, J ) 8.5, 2.2 Hz, 1H), 7.46 (d, J ) 2.2 Hz, 1H), 7.32 (d, J )
8.5 Hz, 1H), 7.01 (d, J ) 8.5 Hz, 1H), 6.55 (d, J ) 8.5 Hz, 1H),
4.77 (X of ABX syst, J ) 10.0, 4.8 Hz, 1H), 3.85 (s, 3H), 3.69 (s,
3H), 3.24 (A of ABX syst, J ) 14.0, 4.8 Hz, 1H), 3.00 (B of ABX
syst, J ) 14.0, 10.0 Hz, 1H), 2.68 (s, 3H), 1.29 (s, 9H); 13C NMR
(75 MHz, DMSO-d6, 355 K): δ 170.6, 157.2, 154.0, 137.3 and
137.2 (rotamers), 130.2 and 130.1 (rotamers), 128.2, 127.7 and
127.6 (rotamers), 125.1, 110.1, 78.6, 77.1, 58.4 (br), 55.2, 51.2 and
51.1 (rotamers), 31.8, 29.3, 27.4; IR (neat): νmax 2976, 2837, 2356,
1742, 1685, 1603, 1511, 1255, 1178, 1035, 825 cm-1; ESIMS
(positive mode): 498.1, 442.0, 398.1; ESIHRMS m/z calcd for
C19H27INO5 [M + H]+ 476.0934, found 476.0924.
(Z)-[N-Boc-N-Methyl-5-(2-iodo-vinyl)-2-methoxy-phenylala-
nyl]-isoleucine-leucinamide 13. To a solution of 3 (199 mg, 0.43
mmol) in DMF (1 mL) were successively added at 0 °C diisopro-
pylethylamine (83 µL, 0.47 mmol) and (benzotriazol-1-yloxy)-tris-
(dimethylamino)phosphonium hexafluorophosphate (BOP, 200 mg,
0.45 mmol). After stirring for 30 min at 0 °C, 12 (127 mg, 0.52
mmol) was added. The resulting mixture was slowly warmed to rt,
stirred overnight and quenched with a 10% aqueous citric acid
solution. The aqueous layer was extracted with ether, combined
organic layers were successively washed with a saturated aqueous
solution of NaHCO3 and brine, dried over MgSO4, filtered, and
concentrated. The crude residue was purified by flash chromatog-
raphy over silica gel (AcOEt/30% aq NH3: 99/1) to yield the desired
tripeptide 13 as a white solid (272 mg, 0.40 mmol, 92%). Mp: 89
(S,Z)-2-(tert-Butoxycarbonyl-methyl-amino)-3-[5-(2-iodo-vinyl)-
2-methoxy-phenyl]-propionic Acid 3. A solution of (S,Z)-methyl
2-(tert-butoxycarbonyl-methyl-amino)-3-[5-(2-iodo-vinyl)-2-meth-
oxy-phenyl]-propionate (310 mg, 0.65 mmol) in a mixture of MeOH
(2.6 mL), THF (0.7 mL), and water (0.7 mL) was treated with
lithium hydroxide monohydrate (55 mg, 1.30 mmol). The resulting
mixture was stirred at rt for 4 h, quenched by careful addition of
10 wt % aqueous citric acid solution, and extracted with ether.
Combined organic layer were dried over MgSO4, filtered, and
concentrated to give the desired amino acid fragment 3 as a white
sticky foam (291 mg, 0.63 mmol, 97%). [R]D20 -38 (c 1.3, CHCl3);
1H NMR (300 MHz, DMSO-d6, 345 K): δ 7.55 (dd, J ) 8.5, 1.9
Hz, 1H), 7.45 (d, J ) 1.9 Hz, 1H), 7.31 (d, J ) 8.5 Hz, 1H), 6.99
(d, J ) 8.5 Hz, 1H), 6.53 (d, J ) 8.5 Hz, 1H), 4.73 (br s, 1H), 3.84
(s, 3H), 3.22 (A of ABX syst, J ) 14.1, 4.5 Hz, 1H), 2.95 (B of
20
1
°C; [R]D -36 (c 0.7, CHCl3); H NMR (300 MHz, DMSO-d6,
345 K): δ 7.70 (d, J ) 8.0 Hz, 1H), 7.57 (dd, J ) 8.5, 2.2 Hz,
1H), 7.44 (d, J ) 2.2 Hz, 1H), 7.31 (d, J ) 8.5 Hz, 1H), 7.14 (d,
J ) 8.7 Hz, 1H), 6.81 (br s, 2H), 6.55 (d, J ) 8.5 Hz, 1H), 4.87 (X
of ABX syst, J ) 10.2, 4.8 Hz, 1H), 4.21-4.32 (m, 2H), 3.84 (s,
3H), 3.12 (A of ABX syst, J ) 14.5, 4.7 Hz, 1H), 2.95 (B of ABX
syst, J ) 14.5, 10.2 Hz, 1H), 2.71 (s, 3H), 1.76-1.87 (m, 1H),
1.55-1.70 (m, 1H), 1.39-1.53 (m, 3H), 1.30 (s, 9H), 1.03-1.11
(m, 1H), 0.91 (d, J ) 6.5 Hz, 3H), 0.81-0.88 (m, 9H); 13C NMR
(75 MHz, DMSO-d6, 345 K): δ 173.2, 170.0, 169.5, 157.2, 154.5
(br), 137.4, 129.9, 128.2, 127.3, 125.5, 110.0, 78.7, 77.3, 57.9 (br),
56.7, 55.2, 50.8 and 50.7 (rotamers), 40.7, 36.3, 30.2 (br), 28.1,
27.5, 23.9, 22.4, 21.3, 15.0, 10.3; IR (KBr): νmax 3288, 2955, 1675,
1644, 1506, 1260, 1153, 1020, 820 cm-1; ESIMS (positive mode):
709.3, 581.4; ESIHRMS m/z calcd for C30H48IN4O6 [M + H]+
687.2619, found 687.2577.
ABX syst, J ) 14.1, 10.8 Hz, 1H), 2.69 (s, 3H), 1.27 (s, 9H); 13
C
NMR (75 MHz, DMSO-d6, 345 K): δ 174.0, 157.4, 154.3 (br),
137.4, 130.2, 128.3, 127.7, 125.6, 110.1, 78.4, 77.1, 72.2, 55.2,
42.4, 31.5, 27.6; IR (neat): νmax 3293, 1736, 1708, 1450, 1127,
1035, 774 cm-1; ESIMS (positive mode): 484.0, 428.0, 384.1;
ESIHRMS m/z calcd for C18H25INO5 [M + H]+ 462.0777, found
462.0766.
Cbz-Isoleucine-leucinamide. Benzyloxycarbonyl-protected iso-
leucine (Z-Ile-OH, 2.0 g, 7.5 mmol), leucinamide hydrochloride
(H-Leu-NH2,HCl, 1.26 g, 7.5 mmol), and 1-hydroxy-7-azabenzo-
triazole (HOAt, 1.02 g, 7.5 mmol) were dissolved in DMF (50 mL).
The reaction mixture was cooled to 0 °C, 1-(3-dimethylaminopro-
pyl)-3-ethyl-carbodiimide hydrochloride (EDC, 1.44 g, 7.5 mmol)
N-Boc-Abyssenine A 14. A 50 mL flask was charged with iodo-
amide 13 (200 mg, 0.29 mmol), copper(I) iodide (11.1 mg, 0.06
mmol), and cesium carbonate (142 mg, 0.43 mmol). The flask was
evacuated under high vacuum, backfilled with argon, and closed
with a rubber septa. Dry and degassed THF (36 mL) and N,N′-
dimethylethylene-1,2-diamine (13 µL, 0.12 mmol) were next added,
9008 J. Org. Chem., Vol. 72, No. 24, 2007

Total Synthesis of Abyssenine A
20
20
the rubber septa was replaced by a glass stopper, and the light blue
suspension was sonicated for 2 min before being heated to 63 °C
for 3 days. The reaction mixture was cooled to rt and filtered over
a plug of silica gel (washed with AcOEt) and concentrated. The
crude residue was purified by flash chromatography over silica gel
(AcOEt/petroleum ether: 35/65) to give the desired cyclized product
[R]D +163 (c 0.40, CHCl3) {lit.: natural abyssenine A: [R]D :
+160 (c 0.22, CHCl3)};13a [R]D20 -60 (c 0.15, MeOH) {lit.: natural
abyssenine A: [R]D20: -58 (c 0.1, MeOH)};13a 1H NMR (300 MHz,
CDCl3): δ 9.43 (d, J ) 7.5 Hz, 1H), 8.47 (d, J ) 11.3 Hz, 1H),
8.16 (d, J ) 7.2 Hz, 1H), 7.14 (d, J ) 2.1 Hz, 1H), 7.01 (dd, J )
8.5, 2.2 Hz, 1H), 6.88 (d, J ) 8.6 Hz, 1H), 6.83 (dd, J ) 11.3, 9.6
Hz, 1H), 5.60 (d, J ) 9.6 Hz, 1H), 4.47 (ddd, J ) 11.1, 7.7, 3.6
Hz, 1H), 3.86 (s, 3H), 3.46 (dd, J ) 13.6, 6.1 Hz, 1H), 3.25-3.32
(m, 2H), 3.04 (dd, J ) 13.6, 2.3 Hz, 1H), 2.47-2.60 (m, 1H), 2.48
(s, 3H), 2.18 (br s, 1H), 1.92-2.00 (m, 1H), 1.71-1.84 (m, 2H),
1.52 (dqd, J ) 10.6, 7.5, 3.2 Hz, 1H), 1.14 (dqd, J ) 10.6, 7.5, 7.5
Hz, 1H), 1.02 (d, J ) 6.3 Hz, 3H), 0.96 (d, J ) 6.3 Hz, 3H), 0.90
(d, J ) 6.8 Hz, 3H), 0.86 (t, J ) 7.5 Hz, 3H); 13C NMR (75 MHz,
CDCl3): δ 176.2, 172.3, 170.1, 156.3, 129.9, 129.04, 128.99, 125.2,
120.5, 111.7, 109.8, 66.3, 65.8, 55.8, 52.5, 41.2, 36.6, 33.4, 31.3,
25.9, 25.2, 23.5, 21.1, 15.4, 9.7; UV λmax (log ꢀ): 278 (4.25); IR
(KBr): νmax 3407, 3278, 2960, 2858, 1685, 1640, 1465, 1255, 1122,
1030 cm-1; EIMS: 458, 431, 415, 400, 386, 356, 345, 302, 296,
259, 231, 205, 183, 163, 155, 86; ESIHRMS m/z calcd for
C25H39N4O4 [M + H]+ 459.2971, found: 459.2953.
20
14 (134 mg, 0.24 mmol, 83%) as a white solid. Mp: 100 °C; [R]D
1
-144 (c 0.3, CHCl3); H NMR (300 MHz, DMSO-d6, 345 K): δ
8.41 (d, J ) 10.7 Hz, 1H), 8.05 (d, J ) 8.4 Hz, 1H), 7.26 (d, J )
7.7 Hz, 1H), 7.01-7.05 (m, 3H), 6.72 (app. t, J ) 9.8 Hz, 1H),
5.69 (d, J ) 9.8 Hz, 1H), 4.74 (d, J ) 8.4 Hz, 1H), 4.34 (app. q,
J ) 7.5 Hz, 1H), 4.02 (t, J ) 7.5 Hz, 1H), 3.82 (s, 3H), 3.26 (dd,
J ) 13.8, 10.9 Hz, 1H), 2.83 (dd, J ) 13.8, 1.3 Hz, 1H), 2.81 (s,
3H), 1.68-1.83 (m, 1H), 1.41-1.61 (m, 3H), 1.47 (s, 9H), 1.03-
1.21 (m, 1H), 0.90 (d, J ) 6.1 Hz, 3H), 0.86 (d, J ) 6.7 Hz, 6H),
0.83 (t, J ) 7.4 Hz, 3H); 13C NMR (75 MHz, DMSO-d6, 345 K):
δ 170.9, 170.0, 169.7, 155.5, 154.8 (br), 127.8, 127.5, 127.1, 126.9,
120.3, 111.4, 109.8, 79.3, 58.7, 57.6 (br), 55.4, 51.8, 40.3, 35.2,
29.8 (br), 27.7, 26.3 (br), 24.3, 23.9, 22.3, 20.6, 15.0, 9.9; IR
(KBr): νmax 3409, 2963, 1692, 1640, 1459 cm-1; ESIMS (positive
mode): 581.3, 481.3; ESIHRMS m/z calcd for C30H46N4NaO6 [M
+ Na]+ 581.3315, found 581.3283.
Acknowledgment. The authors thank the CNRS for financial
support. M.T. acknowledges the Ministe`re de la Recherche for
a graduate fellowship. We are indebted to Prof. B. Bodo
(Muse´um National d’Histoire Naturelle, Paris) for kindly
providing unpublished spectra of natural abyssenine A. We
gratefully acknowledge Mr. Vincent Steinmetz for mass spec-
trometry analysis.
Abyssenine A 1. To a solution of 14 (50 mg, 0.089 mmol) in
dichloromethane (4.0 mL) were added at -20 °C 2,6-lutidine (10.5
µL, 0.089 mmol) and a solution of trimethylsilyl trifluoromethane-
sulfonate (1.4 M solution in dichloromethane, 255 µL, 0.356 mmol).
The resulting light pink solution was stirred for 2 h while
progressively warmed to 0 °C. The mixture was next hydrolyzed
at 0 °C by addition of a saturated aqueous solution of NaHCO3
and diluted with dichloromethane. The aqueous layer was extracted
with dichloromethane, and the combined organic layers were
washed with brine, dried over MgSO4, filtered, and concentrated.
The crude residue was purified by flash chromatography over silica
gel (CH2Cl2/MeOH/30% aq NH3: 94/5/1) to give the desired
synthetic abyssenine A 1 (39 mg, 0.085 mmol, 95%) as a white
solid. Rf: 0.32 (Merck-Kiesegel 60F254 TLC plates, CH2Cl2/ MeOH/
30% aq NH3: 94/5/1); Mp: 241 °C {lit.: Mp: 237-239 °C};13a
Supporting Information Available: Copies of 1H and 13C NMR
spectra for all intermediates and abyssenine A. 1H-1H COSY and
1H-13C HSQC NMR spectra of synthetic abyssenine A. Abyssenine
A spectral data compared to reported data. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO070517U
J. Org. Chem, Vol. 72, No. 24, 2007 9009