First total synthesis of cyrmenin

Article abstract of DOI:10.1021/jo802209m

A short and efficient synthesis of cyrmenin B₁ an antifungal metabolite of myxobacteria Cystobacter armeniaca and Archangium gephyra, is described. The crucial steps of the synthesis included the formation of the dehydroalanine moiety from the corresponding serine acetate and the formation of the β-methoxyacrylate system via trimethylsilyldiazomethane methylation of the corresponding β-hydroxy enamide.

Full text of DOI:10.1021/jo802209m

First Total Synthesis of Cyrmenin B1
Narayan S. Chakor, Loana Musso, and Sabrina Dallavalle*
Dipartimento di Scienze Molecolari Agroalimentari, UniVersita‘ di Milano, Via Celoria 2, 20133 Milano, Italy
sabrina.dallaValle@unimi.it
ReceiVed October 07, 2008
A short and efficient synthesis of cyrmenin B1, an antifungal metabolite of myxobacteria Cystobacter armeniaca
and Archangium gephyra, is described. The crucial steps of the synthesis included the formation of the
dehydroalanine moiety from the corresponding serine acetate and the formation of the ꢀ-methoxyacrylate
system via trimethylsilyldiazomethane methylation of the corresponding ꢀ-hydroxy enamide.
Introduction
(2E,4Z)-undecadienoic or dodecadienoic acid residue. With their
two adjacent dehydro-amino acids, the cyrmenins represent a
unique series of natural products. Although the substituted
2-amino-3-methoxyacrylate unit is not known to exist in other
natural products, the ꢀ-methoxyacrylate system can be found
in related families of natural fungicides such as strobilurins,2
oudemansins,4 and myxothiazol.5
The agrochemical industry is continuously searching for new
active pesticide compounds. The main goal of this research is
to develop substances with lower application doses, increased
selectivity, and reduced resistance, and without undesired
ecological impact.1
Natural products have been and still are a large reservoir of new
biologically active substances, and many pesticides have been
developed from naturally occurring lead compounds. An outstand-
ing example is the class of fungicides that has been generated from
strobilurins, antifungal metabolites of myxobacteria.2
Recently, Sasse et al.3 isolated novel antifungal metabolites,
named cyrmenin A, B1, and B2, from the culture broth of strains
of myxobacteria Cystobacter armeniaca and Archangium gephyra.
Like the compounds belonging to the aforementioned groups
of fungicides, cyrmenins inhibit mitochondrial respiration by
blocking electron transfer between cytochrome b and cyto-
chrome c1.3b They exhibit high activity against Botrytis cinerea,
Pythium debaryanum, Hansenula anomala, and Metschnikowia
pulcherrima, showing at the same time an exceptionally low
toxicity for animal cell cultures.3b
Although cyrmenins have attracted considerable attention, no
total syntheses of these novel compounds have been reported
The cyrmenins are modified N-acyldipeptide esters containing
a dehydroalanine, a 2-amino-3-methoxyacrylate moiety, and a
(3) (a) Leibold, T.; Sasse, F.; Reichenbach, H.; Ho¨fle, G. Eur. J. Org. Chem.
2004, 431–435. (b) Sasse, F.; Leibold, T.; Kunze, B.; Ho¨fle, G.; Reichenbach,
H. J. Antibiot. 2003, 56, 827–831.
(1) Kra¨mer, W., Schirmer, U., Eds. Modern Crop Protection; Wiley-VCH:
Weinheim, Germany, 2007.
(2) Sauter, H.; Steglich, W.; Anke, T. Angew. Chem., Int. Ed. Engl. 1999,
38, 1328–1349.
(4) Anke, T.; Hecht, H. J.; Schramm, G.; Steglich, W. J. Antibiot. 1979, 32,
1112–1117.
(5) Steinmetz, H.; Forche, E.; Reichenbach, H.; Ho¨fle, G. Tetrahedron 2000,
56, 1681–1684.
844 J. Org. Chem. 2009, 74, 844–849
10.1021/jo802209m CCC: $40.75 2009 American Chemical Society
Published on Web 11/26/2008

First Total Synthesis of Cyrmenin B1
SCHEME 1. Retrosynthetic Analysis
isobutyl chloroformate and 4-methylmorpholine as a base to
afford compound 13 in 83% yield. Deprotection of the O-(tert-
butyldimethylsilyl) group afforded alcohol 14 in 52% yield.
However, many attempts to oxidize the alcohol with a variety
of oxidizing reagents to the corresponding aldehyde for further
functionalization failed, giving decomposition products (Scheme
3).
Reasoning that this instability was due to the dehydroalanine
moiety, we postponed the introduction of the double bond until
a later stage in the synthetic pathway. Therefore, amide alcohol
10 was protected with TBDPSCl to give ester 15 that was
hydrolyzed to afford the acid 16. This acid was coupled with
serine methyl ester using BOP and iPr2NEt to give 17 in 53%
yield, thus assembling the complete carbon skeleton. Several
trials for oxidation using PCC, PDC, and TEMPO gave
decomposition of starting material, while with Dess-Martin
periodinane and Swern oxidation no reaction occurred. Finally,
the use of IBX for 7 h at reflux in ethyl acetate afforded aldehyde
18 in quantitative yield.
SCHEME 2
One of the critical structural features of cyrmenin is the
ꢀ-methoxyacrylate group. On the basis of the existing literature
for related substructures,8 we reasoned that a useful method for
constructing this key unit could involve the formation of the
dimethylacetal of aldehyde 18 that, via elimination of methanol,
could give the required ꢀ-methoxyacrylate. Accordingly, we
prepared the dimethylacetal of 18, but the elimination of
methanol under either acidic or basic conditions was unsuc-
cessful, even after several attempts. However, taking into
account the possible enolization of 18, we treated it with
TMSCHN2 in MeOH/toluene9 to obtain a crude product that
was purified by flash chromatography. The desired methyl
ꢀ-methoxyacrylate derivative 19 was isolated as a single isomer
(Z, 63% yield) together with decomposition products (Scheme
4).
The Z-configuration of the newly introduced ꢀ-methoxyacry-
late moiety in 19 was elucidated by inspection of the 1H NMR
chemical shift of the proton at the ꢀ-position. In fact, the
chemical shift of the H-2′ proton (7.35 ppm) is in agreement
with the reported value for the Z-isomer of 2-benzoylamino-3-
methoxyacrylic acid methyl ester (7.31 ppm), which is used as
a model compound.3b The chemical shifts of the corresponding
proton in the E isomer of 2-benzoylamino-3-methoxyacrylic acid
methyl ester, strongly deshielded by the carbonyl group, was
shifted to 8.08 ppm. Moreover, in natural cyrmenins, this signal
is located at 7.32-7.33 ppm.3b
so far. As part of a research program aimed at studying new
antifungal compounds, we have developed a synthetic pathway
which may, in principle, have value in the preparation of
cyrmenins themselves as well as in synthesizing different
analogues.
In this paper, we detail the efforts aimed at the preparation
of cyrmenin B1 (2a). The methodology developed could support
future structure-activity relationship studies.
Results and Discussion
In order to check the feasibility of the synthesis, we decided
to use as a model compound the unknown (8E,10E) isomer of
cyrmenin B1 (2b). The retrosynthetic analysis (Scheme 1)
identified compound 4, deriving from dienoic acid 5 and two
units of serine, as possible precursors.
For the synthesis of the acid moiety of 2b (Scheme 2) we
started from commercially available methyl tiglate 6 and
converted it into bromide 7 by NBS bromination. The Arbuzov
reaction afforded phosphonate 8,6 which was subsequently
condensed with octanal, to furnish all-E ester 9 in 72% yield.
Hydrolysis with LiOH in THF/H2O afforded acid 5.
With diene acid 5 now prepared, we began to construct the
complete carbon skeleton of cyrmenin by installing the two
amino acid fragments. A first coupling with serine methyl ester
hydrochloride, using BOP as a condensing agent, provided
amide alcohol 10 in 96% yield. Mesylation, followed by
eliminating the mesyl group with TEA (10 equiv), gave ester
11 that was hydrolyzed to give acid 12 in 20% yield. Even
though this acid proved to be unstable (partial polymerization),
it was coupled with O-(tert-butyldimethylsilyl)serine7 using
Deprotection of the silyl ether by treatment with TBAF gave
the free dipeptide alcohol 20 in 75% yield. A crucial step in
this synthesis was the formation of the dehydroalanine moiety.
There is ample literature10 to prepare dehydro-amino acids from
the corresponding alcohols via mesyl formation followed by
use of a base-like TEA or DBU. However, with alcohol 20 we
observed the predominant formation of oxazoline 21, most
probably because of the proximity of the amido carbonyl that
made formation of an intramolecular five-membered ring a
favorable process.11 Other methods reported in the literature
(8) Beautement, K.; Clough, J. M. Tetrahedron Lett. 1987, 28, 475–478.
(9) Coleman, R. S.; Tierney, M. T.; Cortright, S. B.; Carper, D. J. J. Org.
Chem. 2007, 72, 7726–7733.
(10) Bonauer, C.; Walenzyk, T.; Ko¨nig, B. Synthesis 2006, (1), 1–20.
(11) (a) Misner, J. W.; Fisher, J. W.; Gardner, J. P.; Pedersen, S. W.; Trinkle,
K. L.; Jackson, B. G.; Zhang, T. Y. Tetrahedron Lett. 2003, 44, 5991–5993. (b)
Avenoza, A.; Busto, J. H.; Canal, N.; Peregrina, J. M. J. Org. Chem. 2005, 70,
330–333.
(6) (a) Ishii, H.; Ishige, M.; Matsushima, Y.; Tohojoh, T.; Ishikawa, T.;
Kawanabe, E. J. Chem. Soc., Perkin Trans. 1 1985, 2353–2359. (b) Kitahara,
T.; Horiguchi, A.; Mori, K. Tetrahedron 1988, 44, 4713–4720.
(7) Novachek, K. A.; Meyers, A. I. Tetrahedron Lett. 1996, 37, 1743–1746.
J. Org. Chem. Vol. 74, No. 2, 2009 845

Chakor et al.
SCHEME 3
SCHEME 4
such as the use of oxalyl chloride and TEA12 or SOCl2/DBU13
gave decomposition products, while the starting material
remained unreacted with Martin sulfurane.14 Finally, it was
found that treatment of the acetyl derivative 22 with DBU at
-15 °C in the presence of LiClO415 afforded (8E,10E)-cyrmenin
B1 (2b) in 54% yield.
Having developed a flexible methodology for the synthesis
of the geometrical isomer of cyrmenin B1, we focused on the
synthesis of the natural compound. We decided to follow the
(12) Ranganathan, D.; Shah, K.; Vaish, N. Chem. Commun. (Cambridge,
U.K.) 1992, (16), 1145–1147.
(13) Stohlmeyer, M. M.; Tanaka, H.; Wandless, T. J. J. Am. Chem. Soc.
1999, 121, 6100–6101.
(14) Yokokawa, F.; Shioiri, T. Tetrahedron Lett. 2002, 43, 8679–8682.
(15) Sommerfeld, T. L.; Seebach, D. HelV. Chim. Acta 1993, 76, 1702–1714.
846 J. Org. Chem. Vol. 74, No. 2, 2009

First Total Synthesis of Cyrmenin B1
SCHEME 5
chromatography (20% EtOAc/ hexane) to afford 25 (3.96 g, 98%)
as a yellow oil. Rf ) 0.53 (30% EtOAc in hexane). 1H NMR
(CDCl3) δ: 5.45-5.65 (m, 2H), 4.16 (d, J ) 6.1 Hz, 2H), 2.35
(brs, 1H), 2.05 (dt, J ) 6.7, 7.0 Hz, 2H), 1.12-1.45 (m, 10H),
0.87 (t, J ) 7.0 Hz, 3H). 13C NMR (CDCl3) δ: 133.0, 128.5, 58.5,
31.9, 29.7, 29.3, 29.2, 27.5, 22.7, 14.1. HRMS (ESI+) calcd for
C10H20ONa [M + Na]+ 179.1406; found 179.1403.
(Z)-Dec-2-enal (26). Alcohol 25 (2.5 g, 15.9 mmol) was
dissolved in DMSO (41 mL), and IBX (6.71 g, 23.9 mmol) was
added. The resulting mixture was stirred for 2 h at rt. Water was
added (30 mL), and the mixture was stirred for 5 min. The
precipitate was filtered through a Celite pad, and the filtrate was
extracted with Et2O (3 × 75 mL). The combined organic layer was
dried over Na2SO4, filtered, and concentrated to afford 26 (2.43 g,
98%) as a yellow liquid, which was used for the next reaction
1
without purification. Rf ) 0.7 (10% EtOAc in hexane). H NMR
showed the presence of about 10% E isomer. 1H NMR (CDCl3) δ:
10.08 (d, J ) 8.2 Hz, 1H), 6.62 (dt, J ) 8.9, 7.2 Hz, 1H), 5.92 (dd,
J ) 8.2, 8.9 Hz, 1H), 2.58 (dt, J ) 7.2, 7.1 Hz, 2H), 1.40-1.50
(m, 2H), 1.20-1.40 (m, 8H), 0.87 (t, J ) 7.0 Hz, 3H). 13C NMR
(CDCl3) δ: 191.1, 153.7, 130.3, 31.8, 29.3, 29.1, 28.1, 22.7, 14.2.
HRMS (ESI+) calcd for C10H18ONa [M + Na]+ 177.1250; found
177.1255.
(2E,4Z)-3-Hydroxy-2-(2-methyldodeca-2,4-dienoylamino)-
propionic Acid Methyl Ester (29). Compound 28 (Supporting
Information, 1.70 g, 8.09 mmol) was dissolved in THF (150 mL),
BOP (3.94 g, 8.90 mmol), and serine methyl ester hydrochloride
(1.25 g, 8.09 mmol), and the resulting suspension was treated with
iPr2NEt (3.05 mL, 17.82 mmol) and stirred for 3.5 h at rt. The
organic solvent was removed under reduced pressure. The residue
was dissolved in EtOAc (200 mL) and washed with 1 N HCl, water,
saturated aqueous NaHCO3, water, and saturated aqueous NaCl.
The organic layer was dried over anhydrous Na2SO4, filtered, and
concentrated, and then the residue was purified by flash chroma-
tography to afford 29 (2.39 g, 95%) as a pale yellow solid. Mp: 38
same pathway starting from acid 28, with the 2E,4Z-configu-
ration. A stereocontrolled approach was developed to prepare
this intermediate (Scheme 5).
Alkylation of the dianion of propargyl alcohol with 1-bro-
moheptane gave dec-2-yn-1-ol 24,16 which was hydrogenated
in the presence of the Lindlar catalyst to afford quantitatively
(2Z)-dec-2-en-1-ol 25 as a single product. Oxidation with IBX
to aldehyde 26 (ratio E/Z, 1:10) followed by stereoselective
Horner-Wadsworth-Emmons olefination gave (2E,4Z) ester
27 in 82% yield, after column purification. The ester then was
hydrolyzed to the expected acid 28. The remaining steps of the
synthesis followed the pathway already described for the
8E,10E-isomer of cyrmenin B1 (Scheme 6).
No stereomutation of the olefinic bond of the original dienoate
28 had occurred at any stage of the synthesis, as confirmed by
1H spectroscopy. The final compound, obtained in 14 steps with
an overall yield of about 5%, completely matched natural
cyrmenin B1 in all spectroscopical properties and in the
antifungal activity against some selected fungal strains. Evalu-
ation of the antifungal activity of cyrmenin isomer 2b is in
progress.
In summary, the first total synthesis of cyrmenin B1 was
designed and carried out. Crucial steps for our strategy included
the formation of the dehydroalanine moiety from the corre-
sponding serine acetate and the formation of the ꢀ-methoxy-
acrylate moiety via trimethylsilyldiazomethane methylation of
the corresponding ꢀ-hydroxy enamide. Because of the modular
nature of our synthetic strategy, ready access to partial structures
and preparation of congeners and analogues is available.
1
°C. Rf ) 0.55 (75% EtOAc in hexane). H NMR (CDCl3) δ: 7.29
(d, J ) 10.9 Hz, 1H), 6.82 (d, J ) 5.91 Hz, 1H), 6.25 (dd, J )
10.9, 10.4 Hz), 5.78 (dt, J ) 10.4, 8.9 Hz, 1H), 4.62-4.70 (m,
1H), 3.90-4.10 (m, 2H), 3.76 (s, 3H), 2.25 (dt, J ) 8.77, 7.44 Hz,
2H), 1.95 (s, 3H), 1.30-1.50 (m, 10H), 0.90 (t, J ) 7.4 Hz, 3H).
13C NMR (CDCl3) δ: 171.3, 169.6, 139.8, 130.1, 128.4, 123.3, 63.2,
55.2, 52.7, 31.8, 29.5, 29.2, 28.2, 22.7, 14.1, 12.6. HRMS (ESI+)
calcd for C17H29NO4Na [M + Na]+ 334.1989; found 334.1985.
2-[3-(tert-Butyl-diphenyl-silanyloxy)-2-((2E,4Z)-2-methyl-
dodeca-2,4-dienoylamino)-propionylamino]-3-hydroxy-propi-
onic Acid Methyl Ester (32). Ice-cooled aqueous LiOH ·H2O
(0.426 g, 10.1 mmol) in water (24 mL) was added dropwise to the
rapidly stirred solution of ester 30 (Supporting Information, 2.80 g,
5.09 mmol) in THF (73 mL) at 0 °C. The reaction mixture was
stirred at 0 °C for 5 min, then warmed to rt and stirred for 1 h. The
reaction mixture was cooled to 0 °C, and ice-cooled 1 M HCl was
added dropwise to the rapidly stirred solution causing the solution
to become cloudy. The reaction mixture was partitioned between
aqueous NaCl (30 mL) and EtOAc (40 mL), and the layers were
separated. The aqueous layer was extracted with EtOAc (3 × 40
mL). The combined organic layer was dried over Na2SO4, filtered,
and concentrated to afford 31 as white crude solid (2.69 g, 99%),
which was used for the next reaction without purification. Rf )
0.59 (50% EtOAc in hexane). A mixture of 31 (1.74 g, 3.25 mmol)
and serine methyl ester hydrochloride (0.60 g, 3.91 mmol) in THF
(90 mL) was treated with BOP (1.73 g, 3.91 mmol) and iPr2NEt
(1.22 mL, 7.17 mmol) at 0 °C. The resulting reaction mixture was
stirred for 3 h at rt. The organic solvent was removed under reduced
pressure, and the residue was dissolved in EtOAc (250 mL) and
washed with aqueous HCl (pH ≈ 5), water, saturated aqueous
NaHCO3, water, and brine. The organic layer was dried over
anhydrous Na2SO4, filtered, and concentrated, and the residue was
purified by flash chromatography (43% EtOAc in hexane) to give
32 (1.10 g, 53%) as a white solid. Mp: 126 °C. Rf ) 0.67 (70%
Experimental Section
(Z)-Dec-2-en-1-ol (25). A mixture of dec-2-yn-1-ol (24) (4 g,
1.0 mmol), EtOH (78 mL), pyridine (13 mL), and Lindlar catalyst
(444 mg) was stirred at rt under a hydrogen gas atmosphere for
1 h. The mixture was filtered through a Celite pad. The filtrate was
concentrated to obtain crude product which was purified by column
(16) Yoshida, T.; Murai, M.; Abe, M.; Ichimaru, N.; Harada, T.; Nishioka,
T.; Miyoshi, H. Biochemistry 2007, 46, 10365–10372.
J. Org. Chem. Vol. 74, No. 2, 2009 847

Chakor et al.
SCHEME 6
EtOAc in hexane). 1H NMR (CDCl3) δ: 7.56-7.67 (m, 4H),
7.37-7.47 (m, 7H), 7.18 (d, J ) 7.4 Hz, 1H), 6.75 (d, J ) 6.5 Hz,
1H), 6.23 (dd, J ) 10.7, 7.4 Hz, 1H), 5.80 (dt, J ) 10.7, 7.6 Hz,
1H), 4.55-4.65 (m, 2H), 3.75-4.20 (m, 4H), 3.76 (s, 3H), 2.25
(dt, J ) 7.6, 6.7 Hz, 2H), 2.12 (brs, 1H), 1.94 (s, 3H), 1.20-1.50
(m, 10H), 1.10 (s, 9H), 0.86 (t, J ) 7.4 Hz, 3H). 13C NMR (CDCl3)
δ: 170.1, 169.6, 169.2, 139.5, 135.0, 134.9, 134.3, 132.2, 131.8,
129.6, 127.7, 127.4, 122.7, 63.1, 62.2, 54.8, 54.6, 52.3, 31.3, 29.0,
28.8, 28.7, 27.7, 26.3, 22.1, 18.7, 13.6, 12.0. HRMS (ESI+) calcd
for C36H52N2O6SiNa [M + Na]+ 659.3487; found 659.3490.
2-[3-(tert-Butyl-diphenyl-silanyloxy)-2-((2E,4Z)-2-methyl-
dodeca-2,4-dienoylamino)-propionylamino]-3-methoxyacrylic Acid
Methyl Ester (34). A solution of 32 (1.20 g, 1.88 mmol) in EtOAc
(130 mL) was treated with IBX (1.056 g, 3.77 mmol), and the
reaction mixture was warmed at reflux for 8 h. The reaction mixture
was cooled to rt and filtered. The filtrate was poured into 10%
aqueous Na2S2O4 (10 mL), and the mixture was stirred for 1 h.
The mixture was extracted with EtOAc (4 × 50 mL). The combined
organic layer was washed with saturated aqueous NaHCO3 and
brine, dried over anhydrous Na2SO4, filtered, and concentrated to
afford 33 as a crude unstable product (1.18 g, 99%), which was
immediately used for the next reaction without purification. Rf )
0.42 (20% EtOAc in hexane). Compound 33 (1.10 g, 1.73 mmol)
in MeOH/toluene (1:1, 200 mL) at rt was treated with trimethyl-
silyldiazomethane (2 M in hexane, 2.15 mL, 4.33 mmol), and the
reaction mixture was stirred for 2 h at rt. The organic solvents were
removed under reduced pressure, and the residue was purified by
flash chromatography (38% EtOAc/hexane) to afford 34 (0.67 g,
59%) as a yellow oil. Rf ) 0.53 (60% EtOAc in hexane).1H NMR
(CDCl3) δ: 7.60-7.78 (m, 5H), 7.30-7.49 (m, 8H), 6.90 (d, J )
11.2 Hz, 1H), 6.82 (d, J ) 6.1 Hz, 1H), 6.25 (dd, J ) 10.9, 11.1
Hz, 1H), 5.80 (dt, J ) 10.9, 7.4 Hz, 1H), 4.75-4.85 (m, 1H),
4.15-4.25 (m, 1H), 3.85 (s, 3H), 3.80-3.90 (m, 1H), 3.72 (s, 3H),
2.29 (m, 1H), 1.93 (s, 3H), 1.20-1.50 (m, 10H), 1.10 (s, 9H), 0.95
(t, J ) 7.4 Hz, 3H). 13C NMR (CDCl3) δ: 171.2, 169.1, 165.3,
155.4, 135.6, 133.0, 132.4, 130.1, 129.6, 129.0, 128.0, 107.0, 63.7,
60.5, 54.2, 52.0, 31.9, 29.6, 29.3, 28.3, 26.9, 22.7, 21.3, 20.9, 14.4.
HRMS (ESI+) calcd for C37H52N2O6SiNa [M + Na]+ 671.3487;
found 671.3497.
2-[3-Hydroxy-2-((2E,4Z)-2-methyl-dodeca-2,4-dienoylamino)-
propionylamino]-3-methoxy-acrylic Acid Methyl Ester (35). To
a solution of 34 (0.460 g, 0.709 mmol) in THF (40 mL) was added
TBAF (1.0 M in THF, 0.85 mL, 0.851 mmol) at 0 °C, and then the
mixture was stirred for 1 h at rt. The reaction was quenched with
saturated aqueous NH4Cl. The organic layer was separated, and
the aqueous layer was extracted with EtOAc (3 × 30 mL). The
combined organic layer was dried over anhydrous Na2SO4, filtered,
and concentrated. The crude product was purified by flash chro-
matography (70% EtOAc/hexane) to afford 35 (0.159 g, 54% yield)
1
as a yellow liquid. Rf ) 0.32 (EtOAc). H NMR (CDCl3) δ: 7.87
(s, 1H), 7.30 (s, 1H), 7.26 (m, 1H), 6.93 (d, J ) 6.3 Hz, 1H), 6.23
(dd, J ) 11.2, 10.8 Hz, 1H), 5.79 (dt, J ) 10.8, 8.6 Hz, 1H),
4.62-4.69 (m, 1H), 4.16-4.20 (m, 1H), 3.87 (s, 3H), 3.50-3.75
(m, 5H), 2.26 (dt, J ) 8.6, 7.1 Hz, 2H), 1.96 (s, 3H), 1.30-1.50
(m, 10H), 0.87 (t, J ) 7.4 Hz, 3H). 13C NMR (CDCl3) δ: 170.3,
170.0, 165.4, 156.2, 140.0, 130.2, 128.5, 123.4, 106.8, 63.2, 62.4,
54.3, 52.1, 31.9, 29.8, 29.6, 29.3, 20.3, 22.8, 14.2, 12.7. HRMS
(ESI+) calcd for C21H34N2O6Na [M + Na]+ 433.2309; found
433.2307.
2-[3-Acetoxy-2-((2E,4Z)-2-methyldodeca-2,4-dienoylamino)-
propionylamino]-3-methoxy-acrylic Acid Methyl Ester (36). To
a solution of 35 (0.112 g, 0.272 mmol) in CH2Cl2 (12 mL), was
added pyridine (0.039 mL, 0.487 mmol) dropwise at 0 °C followed
by AcCl (0.028 mL, 0.40 mmol). The resulting solution was stirred
for 2 h at rt, and then it was cooled to 0 °C and quenched with 1
M HCl (2 mL). The organic layer was separated, and the aqueous
layer was extracted with CH2Cl2 (3 × 3 mL). The combined organic
layer was dried over Na2SO4, filtered, and concentrated. The crude
product was purified by flash chromatography (47% EtOAc/hexane)
to afford 36 (113 mg, 92%). Rf ) 0.48 (80% EtOAc in hexane).
848 J. Org. Chem. Vol. 74, No. 2, 2009

First Total Synthesis of Cyrmenin B1
1
1H NMR (CDCl3) δ: 7.50 (s, 1H), 7.20-7.30 (m, 2H), 6.78 (d, J
) 7.1 Hz, 1H), 6.23 (dd, J ) 11.6, 10.9 Hz, 1H), 5.79 (dt, J )
10.9, 7.8 Hz, 1H, 1H), 4.92-4.96 (m, 1H, 1H), 4.54 (dd, J ) 11.6,
6.5 Hz, 1H), 4.34 (dd, J ) 11.6, 5.15 Hz, 1H), 3.86 (s, 3H), 3.70
(s, 3H), 2.27 (dt, J ) 7.8, 7.1 Hz, 2H), 2.07 (s, 3H), 1.95 (s, 3H),
1.15-1.50 (m, 10H), 0.86 (t, J ) 7.4 Hz, 3H). 13C NMR (CDCl3)
δ: 171.4, 169.5, 167.7, 165.2, 155.7, 139.9, 130.1, 128.5, 123.4,
106.7, 63.9, 62.4, 52.8, 52.0, 31.9, 29.8, 29.6, 29.4, 29.3, 28.3, 22.8,
21.0, 14.2, 12.7. HRMS (ESI+) calcd for C23H36N2O7Na [M + Na]+
475.2415; found 475.2418.
0.41 (15% Et2O in CH2Cl2). H NMR (CDCl3) δ: 8.50 (brs, 1H),
7.33 (s, 1H), 7.29 (d, J ) 11.1 Hz, 1H), 7.08 (brs, 1H), 6.67 (d, J
) 1.7 Hz, 1H), 6.24 (dd, J ) 11.1, 11.4 Hz, 1H), 5.80 (dt, J )
11.4, 7.4 Hz, 1H), 5.39 (d, J ) 1.7 Hz, 1H), 3.91 (s, 3H), 3.76 (s,
3H), 2.28 (dt, J ) 7.4, 6.1 Hz, 2H), 1.99 (s, 3H), 1.25-1.40 (m,
2H), 1.10-1.30 (m, 8H), 0.86 (t, J ) 7.1 Hz, 3H). 13C NMR
(CDCl3) δ: 167.9, 165.2, 162.8, 155.3, 140.1, 134.3, 130.1, 129.6,
123.5, 106.8, 102.4, 62.6, 52.2, 31.9, 29.8, 29.6, 29.3, 28.3, 22.8,
14.2, 12.6. HRMS (ESI+) calcd for C21H32N2O5Na: [M + Na]+
415.2203; found 415.2200.
Cyrmenin B1 (2a). Compound 36 (90 mg, 0.199 mmol) and
LiClO4 (0.211 g, 1.98 mmol) were dissolved in THF (7 mL) and
cooled to -15 °C, and then DBU (0.033 mL, 0.218 mmol) was
added dropwise. The resulting reaction mixture was stirred for 3.5 h
in the same cooling bath. After dilution with EtOAc (20 mL), the
organic layer was washed with 10% citric acid. The aqueous layer
was extracted with EtOAc (3 × 10 mL). The combined organic
layer was dried over Na2SO4, filtered, and concentrated. The residue
was purified by flash column chromatography (7% Et2O in CH2Cl2)
to afford cyrmenin B1 (2a) (45 mg, 58%) as a colorless oil. Rf )
Acknowledgment. We are indebted to the University of
Milano (FIRST Funds) for financial support.
Supporting Information Available: Experimental proce-
dures and spectroscopic data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO802209M
J. Org. Chem. Vol. 74, No. 2, 2009 849