Total synthesis of malyngamide M and isomalyngamide M

Article abstract of DOI:10.1016/j.tet.2010.03.004

The stereoselective synthesis of malyngamide M (1) was accomplished in nine steps from o-cresol in 12% overall yield. The key steps involved the Wittig reaction of an α-NHBoc aryl ketone 4 for the introduction of vinyl chloride functionality, an amidation

Full text of DOI:10.1016/j.tet.2010.03.004

Tetrahedron 66 (2010) 3499–3507
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Total synthesis of malyngamide M and isomalyngamide M
*
Jie Chen, Zi-Fa Shi, Ling Zhou, An-Le Xie, Xiao-Ping Cao
State Key Laboratory of Applied Organic Chemistry and College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
The stereoselective synthesis of malyngamide M (1) was accomplished in nine steps from o-cresol in 12%
Received 17 September 2009
Received in revised form 26 February 2010
Accepted 2 March 2010
overall yield. The key steps involved the Wittig reaction of an a-NHBoc aryl ketone 4 for the introduction
of vinyl chloride functionality, an amidation of lyngbic acid 3 with a secondary amine 2 for the frame-
work of target molecule, and an isomerization of a (Z)-vinyl chloride to the (E)-configuration using
benzophenone as a photosensitizer. The isomalyngamide M (Z-1) was also synthesized.
Crown Copyright Ó 2010 Published by Elsevier Ltd. All rights reserved.
Available online 12 March 2010
Keywords:
Malyngamide
Lyngbic acid
Amine
Amidation
Isomerization
Total synthesis
1. Introduction
containing a vinylic chloride moiety. Since 1978, 30 different malyng-
amides have been isolated. These natural products were found to
Cyanobacteria of the genus Lyngbya majuscula are a rich source of
a wide variety of biologically active secondary metabolites. The
malyngamides, common metabolites of L. majuscula, are N-substituted
amides of long chain fatty acids. The amine portion of them often
possesses a wide structural variety. It can be a heavily oxygenated six-
membered ring, a heterocycle, an aromatic ring, a tripeptide, or a unit
possess a wide range of biological activities.1
ThetotalsynthesesofmalyngamideX,2 malyngamideU,1b,3 20-epi-
malyngamide U,3 and serinol-derived malyngamides4 have been
reported. A convergent route for the total syntheses of malyngamides
O, P, Q, and R has been accomplished by us recently.5 We are also
interested in a subclass of malyngamides that bears a communal and
HO
HO
O
OCH3
O
OCH3
N
N
6
6
Cl
Cl
Isomalyngamide M
Malyngamide M
OCH3
OCH3
O
OH
OH
O
N
O
N
O
N
O
N
O
N
O
O
N
N
N
OCH3
OCH3
OCH3
OCH3
Cl
Malyngamide A
Cl
Cl
Malyngamide B
Cl
Isomalyngamide A
Isomalyngamide B
Figure 1. Structure of malyngamides M, iso-M, A, iso-A, B and iso-B.
* Corresponding author. Tel.: þ86 931 3911268; fax: þ86 931 8912582; e-mail
address: caoxplzu@163.com.
0040-4020/$ – see front matter Crown Copyright Ó 2010 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.03.004

3500
J. Chen et al. / Tetrahedron 66 (2010) 3499–3507
interesting terminal vinyl chloride functionality, such as malynga-
mides A, B, M, and isomalyngamides A, B, M (Fig. 1). Malyngamide M
(1) was isolated from the Hawaiian red alga Gracilaria coronopifolia by
Nagai’s group.6 It was the first example of a natural aromatized
malyngamide, which possesses a special terminal vinyl chloride sub-
structure. The compound also shows weak cytotoxicity to NB cells
Claisen rearrangement as the key step.3 The vinyl chloride func-
tionality of the other key intermediate 2 could be introduced via
a Wittig reaction of the ketone 4, which in turn could be obtained
from o-cresol (5) by a Friedel–Crafts acetylation reaction followed
by a series of functional group transformations.
The preparation of amine segment 2 began with o-cresol (5)
(Scheme 2). Thus, Friedel–Crafts acetylation of 5 with chloro-
acetonitrile in the presence of boron trichloride and aluminum tri-
chloride gave phenol 6 in 78% yield (based on recovered starting
material 95%).8 Thenreactionof6 withsodiumazideprovidedphenol
7 in 85% yield.9 Protection of phenol 7 with methoxymethyl chloride
(MOMCl) was conducted in the presence of i-Pr2NEt to provide MOM
ether 8 in 84% yield.10 Subsequent hydrogenation of 8 by 10% Pd/C in
EtOAc and in situ protection with di-tert-butyl dicarbonate (Boc2O)
afforded the Boc-protected amine 4 in 97% yield.11 Compound 4 was
then subjected directly to a Wittig olefination with chloromethyl-
triphenylphosphonium iodide (Ph3PþCH2ClIꢀ) in the presence of
n-BuLi in THF (ꢀ78 to ꢀ30 ꢁC) to afford (Z)-vinyl chloride 9 in 48%
yield (vide infra). The predominant formation of the Z-isomer with
(IC50>20 mM). However, only 0.6 mg of malyngamide M (1) was
obtained from 4.8 kg of sample, and the synthesis of 1 had not been
reported so far. Herein we wish to disclose efficient stereoselective
synthesis of malyngamide M (1) and its geometrical isomer, iso-
malyngamide M (Z-1), which provide us with enough samples for
a thorough examination of their biological activities.
2. Results and discussion
Malyngamide M (1) can be retrosynthetically divided into two
parts: a lyngbic acid 31,2,3 containing a 4E double bond and a 7S
chiral center, and an amino phenol moiety (Scheme 1). According to
our earlier works, the preparation of the lyngbic acid 3 could be
achieved by two routes. One was based on a reduction strategy by
using Na/l-NH3,7 while the other strategy employed a Johnson–
a
-amino ketone 4 was similar to reported precedents12 involved
structurally similar -alkoxy substituted ketones. In order to improve
a
the yield of 9, other reaction conditions were tested by varying the
bases used (KHMDS, LiHMDS, n-BuLi) and the reaction temperature.
In cases where KHMDS or LiHMDS was used as the base, no product
was obtained. Using Mg/TiCl4/CHCl3 to prepare vinyl chloride 9 from
ketone 4 also met with limited success.5 No product could be
obtained when the Wittig reaction was operated in the presence of
n-BuLi at ꢀ78 ꢁC, while a complex mixture was formed when the
temperature was raised to 0 ꢁC. Finally, it was found that the optimal
temperature was between ꢀ78 and ꢀ30 ꢁC. Subsequently, N-meth-
ylation of compound 9 gave the corresponding methyl derivative 10
in98%yield.13 The(Z)-configurationof thevinylchloridefunctionality
in 10 was confirmed by NOE experiment. Hence selective irradiation
of H-3 of 10 resulted in signal enhancement of H-60. Finally, simul-
taneous removal of both the MOM and Boc groups in 10 by tri-
fluoroacetic acid (TFA) afforded the amine portion 2 in 86% yield.
Preparation of the lyngbic acid segment 3 was achieved accord-
ing to our earlier work for the syntheses of other Malyngamide
homologs.7 As shown in Scheme 3, octanal (11) was reacted with
allyltributyltin in the presence of a catalytic amount of bis{[(R)-
binaphthoxy](isopropoxy)titanium} oxide [bis(R)-Ti(IV) oxide]
afforded chiral alcohol 12 in 88% yield.14 Alcohol 12 was treated with
CH3I in the presence of NaH to give the corresponding methyl ether
13 in 96% yield. The double bond of 13 was then cleaved with OsO4/
3''
15
OCH3
7
HO
2''
O
1'
4
2'
1 N
1''
Cl
3'
Malyngamide M (1)
HO
OCH3
O
+
6
OH
HN
Cl
3
2
HO
MOMO
BocHN
O
5
4
Scheme 1. Retrosynthetic analysis.
HO
HO
HO
O
MOMO
N3
BCl3, ClCH2CN
AlCl3
MOMCl
NaN3
85%
(i-Pr)2NEt
Cl
N3
78%
84%
5
O
6
7
O
8
MOMO
MOMO
MOMO
BocHN
Pd/C, H2
Ph3P CH2ClI
NaH, MeI
98%
(Boc)2O
n-BuLi, THF
BocHN
BocN
97%
48%
O
4
9
10
Cl
Cl
HO
10% TFA
86%
HN
2
Cl
Scheme 2. Preparation of methyl amine 2.

J. Chen et al. / Tetrahedron 66 (2010) 3499–3507
3501
NaIO4 using 4-methylmorpholine N-oxide (NMO) as a co-oxidant,
2, DCC
HOBt
HO
HO
and followed by reaction with PPh3/CBr4 to produce unstable vi-
nylic dibromide 14.15 Compound 14 was then immediately reacted
with 3-bromo-1-tetrahydropyranyloxypropane in the presence of
n-BuLi to furnish alkyne 15 in 42% yield.7 Subsequent stereo-
controlled reduction of 15 with sodium in liquid ammonia in the
presence of t-BuOH produced alkene 16 in 98% yield with E-con-
figuration.16 Then removal of tetrahydro-2H-pyran (THP) group in
compound 16 by a catalytic amount of pyridinium p-toluenesulfo-
nate (PPTS) in EtOH afforded primary alcohol 17 in 92% yield, and
subsequent oxidation of 17 with pyridinium dichromate (PDC) gave
lyngbic acid 3 in 85% yield. The configuration and diastereomeric
purityof lyngbic acid segment 3 wereidentical tothose described for
the natural lyngbic acid.1a On the other hand, lyngbic acid 3 could
been also synthesized in six steps using a Johnson–Claisen rear-
rangement as a key step in 50% overall yield using the intermediate
13.3 The second strategy gave more satisfactory overall yield in large
scale preparation and is more convenient to handle.
OCH3
O
NMM
3
6
N
83%
Cl
Z-1
300 nm, benzophenone
67%
OCH3
O
6
N
1
Cl
Scheme 4. Preparation of malyngamide M (1) and isomalyngamide M (Z-1).
1) OsO4, NaIO4
2) Ph3P, CBr4
OH
OCH3
Bu3Sn
MeI, NaH
96%
6
6
6
O
bis-(R)-Ti(IV) oxide
11
12
13
88%
OCH3
OCH3
Na, NH3(l)
OTHP
n-BuLi, HMPA
98%
Br
6
6
Br
OTHP
Br
14
15
42%
O
Ti
O
Oi-Pr
OCH3
OCH3
O
PDC
85%
O
O
Ti
O
OR
OH
6
6
i-PrO
3
16, R = THP
17, R = H
PPTS, 92%
bis-(R)-Ti(IV) oxide
Scheme 3. Preparation of lyngbic acid 3.
With the secondary amine 2 and lyngbic acid 3 in hand, their
coupling was run in the presence of N,N0-dicyclohexylcarbodiimide
(DCC), 1-hydroxybenzotriazole (HOBt), and 4-methylmorpholine
Table 1
Optimization for transforming Z-isomers to E-isomers
(NMM) to afford isomalyngamide (Z-1) in 83% yield (Scheme 4).1b As
20
expected, the 1H NMR, 13C NMR data, and specific rotation [
a
]
D
ꢀ9 (c
Substrate
Wavelength of Photosensitizer Results
UV light (nm)
0.2, MeOH) of synthetic isomalyngamide disagreed with the data of
reported for the natural malyngamide M due to the difference in the
double bond geometry. These results further confirmed the Z-con-
figuration of vinyl chloride of the intermediate 9. Hence, at this stage,
wewere faced withthe taskof transforming Z-vinyl chloride toE-vinyl
chloride in order to complete the synthesis of the natural product.
According to the literature,12 Z-vinyl chloride could be converted to E-
vinyl chloride by irradiation with UV light in the presence of catalytic
amounts of I2, but no expected product was obtained in ourcase. When
Z-1 was exposed to visible light in the presence of the same catalyst,
the reaction was very messy. Then we tried to conduct the isomeri-
zation of the intermediates 9 and 10 (Table 1). Compound 9 was found
to decompose under light of different wavelengths (254 nm–780 nm)
in the presence of I2, while compound 10 remained unaltered under
the same conditions. All the experiments tested on 9,10, and Z-1 inthe
presence of I2 were unsuccessful.Finally, itwas found thatZ-1 could be
converted to a mixture of 1/Z-1 (2.5:1) when exposed to UV-light
9
9
9
9
254
I2
I2
I2
Complex
Complex
Complex
ꢂ300
380–780
ꢂ300
254
Benzophenone Complex
d
9
No reaction
No reaction
No reaction
10
10
10
10
Z-1
Z-1
Z-1
254
I2
I2
ꢂ300
ꢂ300
ꢂ300
254–380
ꢂ300
ꢂ300
Benzophenone Complex
d
No reaction
Complex
I2
Benzophenone 67% yield E-1
d
20% yield E-1
44% yield E-18
I2
Benzophenone 45% yield E-18
ꢂ300
NHBoc
Z-18
Cl
Cl
I2
Complex
Benzophenone 43% yield E-19
(
l
ꢂ300 nm) in the presence of benzophenone in CH2Cl2 for 8 h at
ꢂ300
rt.17 Fortunately, the two isomers could be separated by flash chro-
matography over silica gel easily, and pure 1 was obtained in 67% yield.
While under the same condition in the absence of benzophenone,
NHBoc
Z-19
Cl

3502
J. Chen et al. / Tetrahedron 66 (2010) 3499–3507
T1
S1
HO
HO
HO
Ar2C O
R
R
R
O
N
N
N
O
hv
+
−
+
−
Cl
CAr2
CAr2
Cl
Cl
21
Z-1
20
HO
HO
HO
R
R
R
Ar2C O +
Ar2C O +
N
N
N
Cl
Cl
Cl
Z-1
1
22
Scheme 5. The possible mechanism of photochemical isomerization of Z-1 to 1.
compound 1 was obtained only in 20% yield. The spectral data (1H
available reagents were used as received. The solvents were dried
by distillation over the appropriate drying reagents. Petroleum
ether used had a bp range of 60–90 ꢁC. Reactions were monitored
by TLC on silica gel GF 254 plates. Column chromatography was
generally performed through silica gel (200–300 mesh). IR spectra
were recorded on a Nicolet NEXUS 670 FT-IR spectrophotometer
and reported in wavenumbers (cmꢀ1). Melting points were de-
termined by use of a Reichert Microscope apparatus and are un-
corrected. 1H and 13C NMR spectra, DEPT 135, and NOE experiments
were recorded on a Mercury Plus-400 spectrometer or a Mercury
20
NMR, 13C NMR, IR, MS) and specific rotation [
a]
D
ꢀ31 (c 0.1, MeOH) of
synthetic malyngamide M (1) were identical with those of the natural
product.6 While comparing the NMR data of Z-1 with those of isolated
malyngamide M, the obvious differences of chemical shift were ob-
served in the vicinity of the vinyl chloride functionality, such as H-10,
H-30, H-NCH3, C-10, C-30 and C-100 position. The maximum discrepancy
1
of chemical shift was 0.23 ppm for H NMR at H-10 position, and
2.9 ppm for 13CNMRatC-10 andC-100 positions.Itshouldbenotedthat,
some of the 1H NMR signals of synthetic 1 and Z-1 appeared as pairs of
peaks due to the presence of two tert-amide isomers, but 13C NMR
signals did not appear as pairs of peaks, but this is a fairly common
phenomenon observed among the malyngamides.1a,6,18
Plus-300 spectrometer. Chemical shifts (
relative to TMS ( 0.00) or chloroform ( 7.26) or acetone (
the 1H NMR, and to chloroform (
77.0) or acetone ( 30.6) for the
d) are reported in ppm
d
d
d
2.05) for
d
d
The benzophenone-sensitized photochemical Z-E isomerization
reaction of vinyl chloride was also applied to other substrates. In the
above conditions, compound 9 and 10 were both decomposed maybe
due to the existence of the MOM group in their skeletons. E-18 and E-
19 were obtained from Z-18 and Z-19 in 45% and 43% yields, re-
spectively. The possible mechanism (Scheme 5) of photochemical Z-E
isomerization of vinyl chloride (Z-1 to 1), sensitized by benzophe-
13C NMR measurements. High resolution mass spectra (HRMS) and
mass spectra (MS) were obtained on a Bruker Daltonics APEX II 47e
and a Finnegan LCQ mass spectrometer, respectively. The photo-
chemical reaction was irradiated at
mercury lamp (500 W).
lꢂ300 nm with a high-pressure
4.2. 2-Chloro-1-(2-hydroxy-3-methylphenyl)ethanone (6)8
none, involves electron transfer pathway19 from the vinyl chloride
p-
bond to the excited singlet acceptors-benzophenone, generating
a radical cation as part of a singlet pair 20. The triplet radical ion pair
21 formed by intersystem crossing, on the other hand, undergoes
electron transfer to produce the triplet vinyl chloride of orthogonal
geometry, capable therefore of partitioning to either the Z-1 or 1.
3'
HO
2'
Cl
6'
1
O
6
3. Conclusion
To a stirred solution of BCl3 (15 mL, 30 mmol) in CH2Cl2
(15 mL) was added o-cresol (2.70 g, 25 mmol) in CH2Cl2 (25 mL),
ClCH2CN (1.9 mL, 30 mmol), and AlCl3 (1.67 g, 12.5 mmol) at 0 ꢁC.
The reaction mixture was stirred at rt for 40 h, then, ice and 2 N
HCl (20 mL) were added and the reaction mixture was stirred for
2 h to hydrolyze the corresponding ketimine. The mixture was
extracted with CH2Cl2 (3ꢃ20 mL) and the combined organic
layers were washed with brine (60 mL), dried (MgSO4), filtered,
and concentrated in vacuo. Flash chromatography of the residue
over silica gel (petroleum ether/EtOAc, 40:1) afforded ketone 6
(3.60 g, 78% yield) as a white solid. Mp 65.5–66.5 ꢁC; IR (KBr):
In summary, the first concise and efficient stereoselective total
syntheses of malyngamide M and isomalyngamide M has been ach-
ieved using the Wittig reaction, amidation, and isomerization re-
action as key steps. Both the stereo- and geometric-isomerisms were
established in a facile manner with high selectivity. The synthesis of
malyngamide M consisted of nine steps starting from commercially
available o-cresol in 12% overall yield. Further application of this
strategy toward the synthesis of the structurally related malynga-
mides with a vinylic chloride functionality, such as A, B, iso-A, iso-B, I,
K, F, and G iscurrently inprogress and willbepresented in due course.
3418, 1653, 1428, 1263, 1244, 1072, 767, 708 cmꢀ1
;
1H NMR
4. Experimental section
4.1. General
(CDCl3, 400 MHz) 2.27 (s, 3H, CH3), 4.73 (s, 2H, CH2, H-2), 6.83
d
(t, 1H, J¼8.0 Hz, ArH), 7.38 (d, 1H, J¼8.0 Hz, ArH), 7.53 (d, 1H,
J¼8.0 Hz, ArH), 11.98 (br, 1H, OH); 13C NMR (CDCl3, 100 MHz)
d
15.5 (CH3), 45.4 (CH2, C-2), 116.4 (C, C-10), 118.7 (ArCH), 127.0
All reactions that required anhydrous condition were carried by
standard procedures under argon atmosphere. Commercially
(ArCH), 128.0 (ArC, C-30), 138.0 (ArCH), 161.2 (ArC, C-20), 196.6 (C,
C-1); MS (ESI) m/z: 185.1 ([MþH]þ).

J. Chen et al. / Tetrahedron 66 (2010) 3499–3507
3503
4.3. 2-Azido-1-(2-hydroxy-3-methylphenyl)ethanone (7)
Flash chromatography of the residue over silica gel (petroleum
ether/EtOAc, 10:1) afforded ketone 4 (510 mg, 97% yield) as a pale
yellowoil. IR (KBr): 3373, 2977,1699,1502,1245,1160,1073, 957, 783,
3'
HO
2'
598 cmꢀ1; 1H NMR (CDCl3, 300 MHz)
d
1.45 (s, 9H, 3ꢃCH3), 2.34 (s,
3H, CH3), 3.48 (s, 3H, OCH3), 4.53 (d, 2H, J¼4.8 Hz, NCH2, H-2), 4.97 (s,
2H, OCH2), 5.49 (br, 1H, NH), 7.10 (t, 1H, J¼7.6 Hz, ArH), 7.36 (d, 1H,
J¼7.6 Hz, ArH), 7.42 (d,1H, J¼7.6 Hz, ArH); 13C NMR (CDCl3, 75 MHz)
N3
6'
1
O
7
d
16.6 (CH3), 28.2 (CH3), 50.4 (NCH2), 57.6 (OCH3), 79.5 (C), 100.5
To a stirred solution of compound 6 (590 mg, 3.20 mmol) in ac-
etone and H2O (40 mL, acetone/H2O, 1:1) was added NaN3 (2.08 g,
32.00 mmol). The reaction mixture was stirred at rt for 6 h. After
removal of acetone, the reaction mixture was diluted with H2O
(20 mL) and extracted with EtOAc (3ꢃ35 mL). The organic layers
were dried (MgSO4), filtered, and concentrated in vacuo. Flash
chromatography of the residue over silica gel (petroleum ether/
EtOAc, 35:1) afforded phenol 7 (520 mg, 85% yield) as a white solid.
(OCH2), 124.3 (ArCH), 126.9 (ArCH), 131.6 (ArC), 132.4 (ArC), 135.1
(ArCH), 154.3 (ArC, C-20), 155.6 (C), 198.1 (C, C-1); HRMS (ESI) m/z
C16H23NO5Na [MþNa]þ calcd for 332.1468, found 332.1462.
4.6. (Z)-N-(tert-Butoxycarbonyl)-3-chloro-2-[2-(methoxy-
methoxy)-3-methylphenyl]-prop-2-en-amine (9)
3'
MOMO
2'
Mp 67–68 ꢁC; IR (KBr): 3391, 2119, 1645, 1423, 1270, 761, 742 cmꢀ1
;
1H NMR (CDCl3, 300 MHz)
d
2.25 (s, 3H, CH3), 4.56 (d, 2H, J¼1.8 Hz,
NCH2, H-2), 6.79–6.85 (m, 1H, ArH), 7.36–7.39 (m, 2H, 2ꢃArH); 13
C
BocHN 1
Cl
2
3
NMR (CDCl3, 75 MHz) d
15.4 (CH3), 54.1 (NCH2, C-2), 116.4 (C, C-10),
118.7 (ArCH),126.0 (ArCH),128.0 (ArC, C-30),137.9(ArCH),160.8 (ArC,
C-20), 198.6 (C, C-1); MS (EI) m/z (%): 191 (Mþ, 20), 135 (83), 77 (91),
51 (82), 39 (100). Various attempts to further characterize 7 by high
resolution mass spectrometry, including RSI and FAB as ionization
techniques were unsuccessful.
9
To a stirred suspension of (choromethyl)triphenylphosphonium
iodide (999 mg, 2.28 mmol) in dry THF (15 mL) under Ar atmosphere
was added n-BuLi (0.68 mL, 1.71 mmol, 2.5 M in hexane) slowly at
ꢀ78 ꢁC. The stirring was continued at this temperature for 1 h and
allowed to warm to ꢀ10 ꢁC over 50 min. The resulting red solution
was cooled again to ꢀ78 ꢁC, and the ketone 4 (176 mg, 0.57 mmol)
was added in THF dropwise (2 mL). The mixture was stirred for
20 min at ꢀ78 ꢁC and allowed to warm to ꢀ30 ꢁC over 30 min, and
then quenched with saturated NH4Cl solution (25 mL), and extracted
with EtOAc (3ꢃ25 mL). The organic extracts were dried (MgSO4), fil-
tered, and concentrated in vacuo. Flash chromatography of the resi-
due over silica gel (petroleum ether/EtOAc, 20:1) afforded vinyl
chloride 9 (93 mg, 48% yield) as a pale yellow oil. IR (KBr): 3367, 2976,
4.4. 2-Azido-1-[2-(methoxymethoxy)-3-methylphenyl]-
ethanone (8)
3'
MOMO
2'
N3
6'
1
O
8
;
1714, 1506, 1249, 1162, 1071, 969, 773 cmꢀ1 1H NMR (CDCl3,
To a stirred solution of compound 7 (501 mg, 2.62 mmol) in
CH2Cl2 (18 mL) was added MOMCl (2.00 mL, 26.2 mmol) and
i-Pr2NEt (1.36 mL, 7.86 mmol) at 0 ꢁC. The reaction mixture was
allowed to warm to rt and continued for 4 h. Then the reaction
mixture was diluted with H2O (20 mL) and extracted with CH2Cl2
(3ꢃ20 mL). The organic layers were dried (MgSO4), filtered, and
concentrated in vacuo. Flash chromatography of the residue over
silica gel (petroleum ether/EtOAc, 30:1) afforded MOM ether 8
(517 mg, 84% yield) as a pale yellow oil. IR (KBr): 2830, 2050, 1719,
300 MHz)
d
1.30 (s, 9H, 3ꢃCH3), 2.31 (s, 3H, CH3), 3.53 (s, 3H, OCH3),
4.31 (d, 2H, J¼5.7 Hz, NCH2), 4.90 (s, 2H, OCH2), 4.97 (br,1H, NH), 6.21
(s,1H, H-3), 6.99–7.10 (m, 2H, 2ꢃArH), 7.14–7.17(m,1H, ArH);13C NMR
(CDCl3, 75 MHz)
d 16.7 (CH3), 28.2 (CH3), 40.7 (NCH2), 57.5 (OCH3),
79.0 (C), 99.2 (OCH2),118.4 (CH, C-3),124.5 (ArCH),128.2 (ArCH),131.4
(2ꢃArC),131.6(ArCH),138.9(C, C-2),153.4(ArC),155.8(C);HRMS(ESI)
m/z C17H24ClNO4Na [MþNa]þ calcd for 364.1286, found 364.1286.
;
1603, 1511, 1249, 1177, 832, 790, 666 cmꢀ1 1H NMR (CDCl3,
4.7. (Z)-N-(tert-Butoxycarbonyl)-3-chloro-2-[2-(methoxy-
methoxy)-3-methylphenyl]-N0-methyl-prop-2-en-amine (10)
300 MHz) 2.34 (s, 3H, CH3), 3.46 (s, 3H, OCH3), 4.51 (s, 2H, NCH2, H-
d
2), 4.97 (s, 2H, OCH2), 7.14 (t,1H, J¼7.8 Hz, ArH), 7.40 (t, 2H, J¼8.0 Hz,
2ꢃArH); 13C NMR (CDCl3, 75 MHz)
d 16.6 (CH3), 57.9 (OCH3 and
3'
MOMO
2'
NCH2), 100.4 (OCH2), 124.7 (ArH), 127.1 (ArH), 131.8 (ArC), 132.3
(ArC), 135.5 (ArCH), 154.3 (ArC, C-20), 196.9 (C, C-1); HRMS (ESI) m/z
C11H13N3O3Na [MþNa]þ calcd for 258.0849, found 258.0855.
N 1
Boc
2
3
10
4.5. 2-[(tert-Butoxycarbonyl)amino]-1-[2-(methoxymethoxy)-
3-methylpheny]-ethanone (4)
Cl
To a stirred solution of compound 9 (89 mg, 0.26 mmol) in THF
(3 mL) was added NaH (23 mg, 0.52 mmol, 55% in oil) at 0 ꢁC. The
reaction mixture was stirred for 10 min and CH3I (0.05 mL,
0.78 mmol) was then added. The reaction mixture was allowed to
warm to rt and stirred for 10 h, then quenched with saturated
NH4Cl solution (10 mL), and extracted with EtOAc (3ꢃ15 mL). The
combined organic layers were washed with saturated brine
(40 mL), dried (MgSO4), filtered and concentrated in vacuo. Flash
chromatography of the residue over silica gel (petroleum ether/
EtOAc, 30:1) afforded Boc-protected amine 10 (91 mg, 98% yield) as
a pale yellow oil. IR (KBr): 2974, 1698, 1394, 1247, 1152, 970,
3'
6'
MOMO
2'
BocHN
1
O
4
To a stirred mixture of azide 8 (400 mg, 1.70 mmol) and (Boc)2O
(742 mg, 3.40 mmol) in EtOAc (15 mL) was added 10% Pd/C (40 mg).
The reaction mixture was stirred for 1.5 h under H2 (1 atm) atmo-
sphere at rt, then filtered, and the filtrate was concentrated in vacuo.

3504
J. Chen et al. / Tetrahedron 66 (2010) 3499–3507
771 cmꢀ1
;
1H NMR (CDCl3, 300 MHz)
d
1.23/1.30 (s, 9H, 3ꢃCH3),
1H, H-4), 5.09–5.14 (m, 2H, H-1), 5.75–5.87 (m, 1H, H-2); 13C NMR
(CDCl3, 75 MHz): 14.0 (CH3), 22.6 (CH2), 25.6 (CH2), 29.2 (CH2),
29.6 (CH2), 31.8 (CH2), 36.8 (CH2), 41.9 (CH2), 70.7 (CH, C-4), 117.9
(CH2, C-1), 134.9 (CH, C-2); MS (EI) m/z (%): 152 ([MꢀH2O]þ, 1), 69
(100), 55 (60), 41 (84).
2.30 (s, 3H, CH3), 2.65/2.75 (s, 3H, NCH3), 3.52 (s, 3H, OCH3), 4. 48 (s,
2H, NCH2, H-1), 4.91 (s, 2H, OCH2), 6.22/6.27 (s, 1H, CH, H-3), 6.87–
6.99 (m, 2H, 2ꢃArH), 7.13–7.16 (m, 1H, ArH); 13C NMR (CDCl3,
d
75 MHz) d 16.6 (CH3), 27.9 (CH3), 33.5 (NCH3), 47.4 (NCH2, C-1), 57.3
(OCH3), 79.1 (C), 99.1 (OCH2), 118.7 (CH, C-3), 124.2 (ArCH), 128.6
(ArCH), 131.2 (ArC), 131.4 (ArC), 131.7 (ArCH), 138.6 (C, C-2), 153.5
(ArC), 155.3 (ArC); HRMS (ESI) m/z C18H26ClNO4Na [MþNa]þ calcd
for 378.1443, found 378.1442. The 1H NMR signals of compound 10
appeared as pairs of peaks due to the presence of two inter-
converting tert-amide isomers.
4.10. (S)-4-Methoxy-1-undecene (13)3
OCH3
13
4.8. (Z)-3-Chloro-2-[2-hydroxy-3-methylphenyl]-N-methyl-
prop-2-en-amine (2)
To a stirred solution of compound 12 (952 mg, 5.59 mmol) in THF
(15 mL) was added NaH (488 mg, 11.18 mmol, 55% in oil) at 0 ꢁC. The
reaction mixture was stirred for 10 min and CH3I (1.04 mL,
16.77 mmol) was then added. The reaction mixture was allowed to
warm to rt and stirred for 12 h, then quenched with saturated NH4Cl
solution(20 mL), and extractedwithEtOAc (3ꢃ20 mL). The combined
organic layers were washed with brine (55 mL), dried (MgSO4), fil-
tered and concentrated invacuo. Flashchromatographyof theresidue
over silica gel (petroleum ether/EtOAc, 50:1) afforded 13 (988 mg,
3'
HO
2
2'
N
H
1
3
Cl
2
To a stirred solution of compound 10 (64 mg, 0.18 mmol) in
CH2Cl2 (2 mL) was added TFA (0.2 mL) at 0 ꢁC. The reaction mixture
was stirred at this temperature for 1 h, followed by the addition of
saturated NaHCO3 solution (5 mL), and extracted with EtOAc
(3ꢃ15 mL). The combined organic layers were dried (Na2SO4), fil-
tered and concentrated in vacuo. Flash chromatography of the
residue over silica gel (petroleum ether/EtOAc/triethylamine,
96:12:1) afforded the secondary amine 2 (33 mg, 86% yield) as
a pale yellow oil. IR (KBr): 3312, 2920, 1462, 1422, 1253, 1097, 769,
20
20
96% yield) as a pale yellow oil. [
(c 1.0, CHCl3)]; IR (KBr): 2928, 2856, 1641, 1100, 912 cmꢀ1; H NMR
(CDCl3, 300 MHz):
a]
D
ꢀ12 (c 1.0, CHCl3) [Ref. 3 [
a
]
ꢀ11
D
1
d
0.88 (t, 3H, J¼6.6 Hz, CH3), 1.22–1.48 (m, 12H,
6ꢃCH2, H-5, H-6, H-7, H-8, H-9, and H-10), 2.24–2.28 (m, 2H, H-3),
3.18–3.22 (m, 1H, H-4), 3.34 (s, 3H, OCH3), 5.03–5.10 (m, 2H, H-1),
5.77–5.86 (m, 1H, H-2); 13C NMR (CDCl3, 75 MHz):
d 14.1 (CH3), 22.6
(CH2), 25.2 (CH2), 29.3 (CH2), 29.7 (CH2), 31.8 (CH2), 33.3 (CH2), 37.7
(CH2), 56.5(OCH3), 80.5(CH, C-4),116.7 (CH2, C-1),135.0 (CH, C-2); MS
(EI) m/z (%): 183 ([MꢀH]þ, 1), 143 (31), 111 (15), 69 (100).
744 cmꢀ1; 1H NMR (CDCl3, 300 MHz)
d 2.24 (s, 3H, CH3), 2.59 (s, 3H,
NCH3), 3.62 (s, 2H, NCH2), 6.35 (s, 1H, CH, H-3), 6.67 (t, 1H, J¼5.5 Hz,
4.11. (7S)-7-Methoxy-1-tetrahydropyranyloxy-4-
ArH), 6.88 (d, 1H, J¼5.5 Hz, ArH), 7.09 (d, 1H, J¼5.5 Hz, ArH); 13C
tetradecyne (15)2,20b,d
NMR (CDCl3, 75 MHz)
d 16.7 (CH3), 35.2 (NCH3), 49.8 (NCH2, H-1),
118.3 (CH, C-3), 120.8 (ArCH), 125.4 (ArC), 126.2 (ArC), 127.1 (ArCH),
131.1 (ArCH), 139.4 (C, C-2), 154.5 (ArC); HRMS (ESI) m/z [MþH]þ
C11H15ClNO calcd for 212.0837, found 212.0843.
O
4
OCH3
7
O
1'
4.9. (S)-Undec-1-en-4-ol (12)3,14
15
OH
To a stirred solution of compound 13 (400 mg, 2.17 mmol) in
THF and H2O (16 mL, THF/H2O, 3:1) was added NMO (305 mg,
2.60 mmol) and OsO4 (20 mg). The reaction mixture was stirred at
rt for two days. The reaction mixture was quenched with saturated
Na2SO3 solution (20 mL) and extracted with EtOAc (3ꢃ30 mL). The
combined organic extracts were concentrated in vacuo to give the
diol. The crude diol was dissolved in THF and H2O (18 mL, THF/H2O,
1.25:1), then NaIO4 (650 mg, 3.04 mmol) was added. The reaction
mixture was stirred at rt for 2 h, then quenched with saturated
Na2S2O3 solution (20 mL) and extracted with ether (3ꢃ25 mL). The
organic layers were washed with water (70 mL), dried (MgSO4),
filtered and concentrated in vacuo. The residue was passed through
a short silica gel column to afford the aldehyde. This aldehyde in
CH2Cl2 (2 mL) was added to a stirred solution of CBr4 (1307 mg,
3.94 mmol), and PPh3 (2067 mg, 7.88 mmol) in CH2Cl2 (5 mL) at
0 ꢁC, the reaction mixture was stirred for 1 h, then the solvent was
concentrated in vacuo. Flash chromatography of the residue over
silica gel (petroleum ether/EtOAc, 80:1) afforded dibromide 14
(624 mg, 84% yield) as a pale yellow oil. To a stirred solution of 14
(526 mg, 1.54 mmol) in THF (10 mL) was added n-BuLi (2.5 M in
hexane, 1.23 mL, 3.08 mmol) at ꢀ78 ꢁC under an argon atmosphere.
Stirring was continued at this temperature for 1 h and then the
reaction mixture was allowed to warm to ꢀ10 ꢁC over 1 h. Then the
solution was cooled to ꢀ78 ꢁC, HMPA (2 mL) followed by bromide
12
On the similar method of the Reference,3,14 to a stirred solution
of TiCl4 (66 mL, 0.60 mmol) in CH2Cl2 (6 mL) was added Ti(i-PrO)4
(0.53 mL, 1.80 mmol) at 0 ꢁC under argon atmosphere. The solution
was allowed to warm to rt. After 3 h, Ag2O (278 mg, 1.20 mmol) was
added, and the reaction mixture was stirred for 5 h under exclusion
of direct light. The mixture was diluted with CH2Cl2 (16 mL), and
treated with (R)-binaphthol (687 mg, 2.40 mmol) at rt for 2 h to
furnish chiral bis-Ti(IV) oxide. The in situ generated chiral bis-Ti(IV)
oxide in CH2Cl2 (6 mL) was cooled to ꢀ15 ꢁC and treated sequen-
tially with aldehyde 11 (1.54 g, 12.00 mmol) in CH2Cl2 (4 mL) and
allyltributyltin (4.05 mL, 13.20 mmol) in this temperature. The re-
action was allowed to 0 ꢁC and stirred for 20 h, then quenched with
saturated NaHCO3 solution (10 mL), and extracted with ether
(3ꢃ40 mL). The organic extracts were dried (Na2SO4), filtered and
concentrated in vacuo. Flash chromatography of the residue over
silica gel (petroleum ether/EtOAc, 40:1) afforded alcohol 12
(1798 mg, 88% yield, 98% ee) as a pale yellow oil. [
20
a
]
ꢀ9 (c 1.0,
D
20
CHCl3) [Ref. 3 [
a]
ꢀ9 (c 1.0, CHCl3)]; IR (KBr): 3350, 2927, 2856,
D
1641, 1463, 995, 913 cmꢀ1; 1H NMR (CDCl3, 300 MHz):
d
0.87 (t, 3H,
J¼6.6 Hz, CH3), 1.21–1.49 (m, 12H, 6ꢃCH2, H-5, H-6, H-7, H-8, H-9,
and H-10), 1.71 (br, 1H, OH), 2.07–2.31 (m, 2H, H-3), 3.60–3.64 (m,

J. Chen et al. / Tetrahedron 66 (2010) 3499–3507
3505
(344 mg, 1.54 mmol) in THF (2 mL) was added. The reaction mix-
ture was allowed to warm to rt for 5 h. Work-up as above prepa-
chromatography of the residue over silica gel (CH2Cl2/MeOH, 20:1)
20
afforded acid 3 as a colorless oil (172 mg, 85% yield). [
a
]
ꢀ13.8 (c
D
20
20
ration of 13 afforded 15 (210 mg, 42% yield) as a colorless oil. [
a
]
0.2, CHCl3) [Ref. 1a [
a
]
ꢀ8.3 (c 0.18, CHCl3)]; IR (KBr): 3126, 2928,
D
D
22
ꢀ22 (c 1.0, CHCl3) [Ref. 20d [
2929, 2857, 2214,1736,1461,1169,1100,1035 cmꢀ1; 1H NMR (CDCl3,
300 MHz):
a
]
ꢀ3.7 (c 1.47, CHCl3)]; IR (KBr):
2856, 1737, 1712, 1440, 1098, 971 cmꢀ1; 1H NMR (CDCl3, 300 MHz):
D
d
0.88 (t, 3H, J¼6.8 Hz, CH3, H-14), 1.27–1.45 (m, 12H, 6ꢃCH2, H-8,
d
0.88 (t, 3H, J¼6.6 Hz, CH3), 1.22–1.50 (m, 12H, 6ꢃCH2),
H-9, H-10, H-11, H-12, and H-13), 2.19–2.45 (m, 6H, H-2, H-3, and H-
6), 3.12–3.20 (m,1H, H-7), 3.33 (s, 3H, OCH3), 5.43–5.56 (m, 2H, H-4,
1.52–1.62 (m, 4H, 2ꢃCH2), 1.67–1.84 (m, 4H, 2ꢃCH2), 2.26–2.43 (m,
4H, 2ꢃCH2), 3.20–3.26 (m, 1H, H-7), 3.37 (s, 3H, OCH3), 3.43–3.54
(m, 2H, OCH2), 3.78–3.90 (m, 2H, OCH2), 4.59 (t, 1H, J¼3.2 Hz, H-10);
and H-5), 11.25 (br, 1H, CO2H); 13C NMR (CDCl3, 75 MHz):
d 14.1
(CH3), 22.6 (CH2), 25.2 (CH2), 27.6 (CH2), 29.3 (CH2), 29.7 (CH2), 31.8
(CH2), 33.3 (CH2), 33.9 (CH2), 36.3 (CH2), 56.5 (OCH3), 80.8 (CH, C-
7), 127.7 (CH), 130.1 (CH), 179.2 (C, C-1); HRMS (ESI) m/z C15H32NO3
[MþNH4]þ calcd for 274.2377, found 274.2373.
13C NMR (CDCl3, 75 MHz):
d 14.1 (CH3), 15.7 (CH2), 19.5 (CH2), 22.6
(CH2), 23.4 (CH2), 25.2 (CH2), 25.4 (CH2), 29.2 (CH2), 29.2 (CH2), 29.6
(CH2), 30.6 (CH2), 31.8 (CH2), 33.6 (CH2), 56.9 (OCH3), 62.1 (OCH2),
66.0 (OCH2), 76.9 (C), 79.8 (CH, C-7), 81.0 (C), 98.7 (CH, C-10); MS
(EI) m/z (%): 187 (59), 181 (36), 167 (45), 157 (47), 143 (26), 137 (1),
88 (1), 69 (67), 43 (100).
4.14. E,(7S)-N-[(Z)-3-Chloro-2-(2-hydroxy-3-methylphenyl)-
allyl]-7-methoxy-N-methyl-tetradec-4-enamide
[isomalyngamide (Z-1)]
4.12. E,(7S)-7-Methoxy-1-tetrahydropyranyloxy-4-
7''
tetradecene (16)2,20b,d
3''
HO
2''
OCH3
7
O
1'
OCH3
7
O
1
1'
2'
4
O
N
1''
3'
Z-1
16
Cl
To a dry liquid ammonia (approximate 24 mL) was added sodium
metal (190 mg, 8.26 mmol), followed by THF (4 mL) and t-BuOH
(2 mL). Then a solution of 15 (354 mg,1.09 mmol) in THF (4 mL) was
added immediately. The reaction mixture was held under ammonia
reflux for 1.5 h, quenched by NH4Cl (200 mg), after the ammonia
evaporation, water (20 mL) was added. The mixture was extracted
with EtOAc (3ꢃ15 mL). The organic layers were washed with brine
(40 mL), dried (MgSO4), filtered, and concentrated in vacuo. Flash
chromatography of the residue over silica gel (petroleum ether/
EtOAc, 30:1) afforded alkene 16 (348 mg, 98% yield) as a colorless
To a stirred solution of amine 2 (27 mg, 0.13 mmol) in CH2Cl2
(2 mL) was added a solution of acid 3 (33 mg, 0.13 mmol) in CH2Cl2
(2 mL), DCC (27 mg, 0.13 mmol), HOBt (22 mg, 0.16 mmol), and
a solution of NMM (13 mg, 0.13 mmol) in CH2Cl2 (1 mL) at 0 ꢁC. The
stirring was allowed to warm to rt and continued for 10 h, and then
solvent was concentrated in vacuo. Flash chromatography of the
residue over silica gel (petroleum ether/EtOAc, 10:1) afforded am-
ide isomalyngamide M (Z-1) (49 mg, 83% yield) as a pale yellow oil.
20
[a
]
ꢀ9 (c 0.2, MeOH); IR (KBr): 3293, 2927, 2855, 1628, 1462, 1213,
D
20
28
oil. [
(KBr): 2928, 1735, 1461, 1357, 1120, 1079, 1032, 976 cmꢀ1
(CDCl3, 300 MHz):
a
]
ꢀ14 (c 1.0, CHCl3) [Ref. 2 [
a
]
ꢀ10.34 (c 0.5, CHCl3)]; IR
1096, 972, 767 cmꢀ1 1H NMR (Me2CO-d6, 400 MHz)
; d 0.88 (t, 3H,
D
D
;
1H NMR
J¼6.4 Hz, H-14), 1.23–1.36 (m, 10H, 5ꢃCH2, H-9, H-10, H-11, H-12,
and H-13), 1.37–1.43 (m, 2H, CH2, H-8), 2.12–2.40 (m, 7H, H-3, H-6,
and H-700), 2.38 (t, 2H, J¼7.2 Hz, H-2), 3.07–3.18 (m, 4H, NCH3, and
H-7), 3.27 (s, 3H, OCH3, H-15), 4.33 (s, 2H, H-10), 5.40–5.52 (m, 2H,
H-4, and H-5), 6.23 (s, 1H, H-30), 6.69 (t, 1H, J¼7.6 Hz, H-500), 6.85 (d,
1H, J¼7.6 Hz, H-600), 7.08 (d, 1H, J¼7.6 Hz, H-400), 9.33 (br, 1H, ArOH);
d
0.88 (t, 3H, J¼6.6 Hz, CH3), 1.27–1.88 (m, 20H,
10ꢃCH2), 2.06–2.21 (m, 4H, H-6, and H-3), 3.10–3.16 (m, 1H, H-7),
3.33 (s, 3H, OCH3), 3.34–3.51 (m, 2H, OCH2), 3.70–3.89 (m, 2H,
OCH2), 4.58 (t,1H, J¼3.9 Hz, H-10), 5.37 (dt,1H, J¼15.9, 6.0 Hz, H-4 or
H-5), 5.54 (dt, 1H, J¼15.9, 6.0 Hz, H-5 or H-4); 13C NMR (CDCl3,
75 MHz): d 14.0 (CH3), 19.6 (CH2), 22.6 (CH2), 25.2 (CH2), 25.5 (CH2),
13C NMR (Me2CO-d6, 100 MHz)
d
14.4 (CH3, C-14), 16.6 (CH3, C-700),
29.2 (2ꢃCH2), 29.5 (CH2), 29.7 (CH2), 30.7 (CH2), 31.8 (CH2), 33.3
(CH2), 36.3 (CH2), 56.4 (OCH3), 62.2 (OCH2), 66.9 (OCH2), 80.8 (CH, C-
7), 98.8 (CH, C-10), 126.5 (CH), 132.0 (CH); MS (EI) m/z (%): 326 (Mþ,
2), 281 (11), 239 (21), 69 (86), 45 (63), 41 (100).
23.3 (CH2, C-13), 26.0 (CH2, C-9), 28.7 (CH2, C-3), 30.0 (2ꢃCH2, C-10,
and C-11), 32.8 (CH2, C-12), 33.5 (CH2, C-2), 34.2 (CH2, C-8), 37.2
(CH2, C-6), 38.0 (NCH3), 51.0 (CH2, C-10), 56.5 (OCH3, C-15), 81.4 (CH,
C-7), 118.2 (CH, C-30), 119.9 (CH, C-500), 126.0 (C, C-100), 126.6 (C, C-
300), 128.1 (CH, C-5), 129.0 (CH, C-600), 131.8 (CH, C-400), 132.0 (CH, C-
4), 138.9 (C, C-20), 154.1 (C, C-200), 174.1 (C, C-1); HRMS (ESI) m/z
C26H41ClNO3 [MþH]þ calcd for 450.2769, found 450.2763.
4.13. E,(7S)-7-Methoxytetradec-4-enoic acid [lyngbic
acid (3)]1–3,20
OCH3
7
O
4.15. E,(7S)-N-[(E)-3-Chloro-2-(2-hydroxy-3-methylphenyl)-
allyl]-7-methoxy-N-methyl-tetradec-4-enamide
[malyngamide M (1)]6
4
OH
3
7''
To a stirred solution of compound 16 (320 mg, 0.98 mmol) in
ethanol (5 mL) was added PPTS (cat.), then the reaction was stirred
at 65 ꢁC for 5 h. The solvent was then concentrated in vacuo. Flash
chromatography of the residue over silica gel (petroleum ether/
EtOAc, 5:1) afforded the primary alcohol 17 (219 mg, 92% yield) as
a colorless oil. To a stirred solution of 17 (191 mg, 0.79 mmol) in
DMF (6 mL) was added PDC (2.08 g, 5.53 mmol). After 12 h, the
mixture was quenched with cold water (10 mL), and extracted with
EtOAc (3ꢃ15 mL). The combined organic layers were washed with
KHSO4 (40 mL, 1 mol/L), water (40 mL), and brine (40 mL), re-
spectively, dried (MgSO4), filtered, and concentrated in vacuo. Flash
3''
15
OCH3
7
HO
2''
O
1'
4
2'
1 N
1''
Cl
3'
Malyngamide M (1)
To a solution of isomalyngamide M (27 mg, 0.06 mmol) in CH2Cl2
(20 mL) was added benzophenone (4 mg, 0.02 mmol). The reaction
mixture was irradiated with UV-light (
l
ꢂ300 nm) for 8 h, then the

3506
J. Chen et al. / Tetrahedron 66 (2010) 3499–3507
solvent was concentrated in vacuo. Flash chromatography of the
53% yield) as a white solid. Mp 142.0–143.0 ꢁC; IR (KBr): 3413, 3005,
2925, 1715, 1422, 1363, 1221, 1093, 902, 786 cmꢀ1; 1H NMR (CDCl3,
residue over silica gel (petroleum ether/EtOAc, 2:1) afforded amide
20
malyngamide M (1) (18 mg, 67% yield) as a pale yellow oil. [
a]
ꢀ31
400 MHz)
d
1.40 (s, 9H, 3ꢃCH3), 4.37 (d, J¼5.2 Hz, 2H, NCH2), 4.64
D
20
(c 0.1, MeOH) [Ref. 6 [
2855, 1629, 1463, 1209, 1095, 972, 746 cmꢀ1
400 MHz)
0.88 (t, 3H, J¼6.2 Hz, H-14),1.20–1.39 (m,10H, 5ꢃCH2, H-
a]
ꢀ35 (c 0.06, MeOH)]; IR (KBr): 3275, 2927,
(br, 1H, NH), 6.38 (s, 1H, H-3), 7.27–7.31 (m, 4H, 4ꢃArH); 13C NMR
D
;
1H NMR (Me2CO-d6,
(CDCl3, 100 MHz) d 28.3 (CH3), 39.5 (NCH2), 79.7 (C), 118.8 (CH, C-3),
d
128.0 (ArCH), 128.8 (ArCH), 134.2 (ArC), 135.7 (ArC), 139.4 (C-2),
155.6 (ArC); HRMS (ESI) m/z C14H21Cl2N2O2 [MþNH4]þ calcd for
319.0975, found 317.0983. The Z-configuration of Z-19 was con-
firmed by its NOE experiment. Selective irradiation of H-3 of 19
resulted in signal enhancement of H-60. However, there is no signal
enhancement of H-3 when irradiated H-1.
9, H-10, H-11, H-12, and H-13),1.40–1.45 (m, 2H, CH2, H-8), 2.12–2.20
(m, 2H, H-6), 2.21 (s, 3H, H-700), 2.28–2.33 (q, 2H, J¼7.4 Hz, H-3), 2.52
(t, 2H, J¼7.4 Hz, H-2), 3.12–3.16 (m,1H, H-7), 3.27 (s, 3H, OCH3, H-15),
3.29 (s, 3H, NCH3), 4.10 (s, 2H, H-10), 5.50–5.54 (m, 2H, H-4 and H-5),
6.39 (s,1H, H-30), 6.73 (t,1H, J¼7.4 Hz, H-500), 6.85 (d,1H, J¼7.4 Hz, H-
600), 7.07 (d, 1H, J¼7.4 Hz, H-400), 8.95 (br, 1H, ArOH); 13C NMR
According to the preceding procedure for the preparation of
malyngamide M (1), Z-19 (50 mg, 0.16 mmol) afforded E-19 (26 mg,
43% yield) as a white solid. Mp 62.0–63.0 ꢁC; IR (KBr): 3369, 2919,
(Me2CO-d6, 100 MHz) d
14.3 (CH3, C-14), 16.4 (CH3, C-700), 23.3 (CH2,
C-13), 25.9 (CH2, C-9), 28.6 (CH2, C-3), 29.9 (CH2, C-10), 30.1 (CH2, C-
11), 32.5 (CH2, C-12), 33.6 (CH2, C-2), 34.1 (CH2, C-8), 37.2 (CH2, C-6),
38.0 (NCH3), 53.8 (CH2, C-10), 56.5 (OCH3, C-15), 81.3 (CH, C-7),116.8
(CH, C-30), 119.6 (CH, C-500), 123.1 (C, C-100), 126.1 (C, C-300), 128.1 (CH,
C-5),128.2 (CH, C-600),131.5 (CH, C-400),131.9 (CH, C-4),138.6 (C, C-20),
153.5 (C, C-200), 174.2 (C, C-1); HRMS (ESI) m/z C26H41ClNO3 [MþH]þ
calcd for 450.2769, found 450.2763.
1716, 1366, 1217, 1168, 1026, 786 cmꢀ1 1H NMR (CDCl3, 400 MHz)
;
d
1.40 (s, 9H, 3ꢃCH3), 4.04 (d, J¼4.8 Hz, 2H, NCH2), 4.63 (br, 1H, NH),
6.33 (s, 1H, H-3), 7.26–7.28 (m, 2H, 2ꢃArH), 7.35–7.38 (m, 2H,
2ꢃArH); 13C NMR (CDCl3, 100 MHz)
d 28.3 (CH3), 45.5 (NCH2), 79.9
(C), 116.7 (CH, C-3), 128.6 (ArCH), 129.8 (ArCH), 133.9 (ArC), 134.0
(ArC), 138.7 (C-2), 155.4 (ArC); HRMS (ESI) m/z C14H21Cl2N2O2
[MþNH4]þ calcd for 319.0975, found 317.0983.
4.16. (Z)/(E)-N-(tert-Butoxycarbonyl)-3-chloro-2-phenyl-
prop-2-en-amine (Z-18 and E-18)
Acknowledgements
The authors are grateful to the National Basic Research Program
of China (973 Program) (Grant No. 2010CB833203), the National
Natural Science Foundation of China (Grant Nos. 20872055 and
20972060), Specialized Research Fund for the Doctoral Program of
Higher Education, and the 111 Project for continuing financial
support. We also gratefully acknowledge Professor Hak-Fun Chow,
The Chinese University of Hong Kong, for his helpful guidance in
revising the manuscript.
As above described procedure for the preparation of 9, 2-N-(tert-
butoxycarbonyl)amino-1-phenylethanone21 (235 mg, 1.00 mmol)
afforded vinyl chloride Z-18 (Z-18/E-18¼1:1) (116 mg, 43% yield) as
a white solid. Mp 157–158 ꢁC; IR (KBr): 3422, 3005, 2970, 1715,
References and notes
1421, 1363, 1221, 1092, 902, 786 cmꢀ1 1H NMR (CDCl3, 400 MHz)
;
d
1.39 (s, 9H, 3ꢃCH3), 4.40 (d, J¼5.6 Hz, 2H, NCH2), 4.64 (br, 1H, NH),
1. (a) Cardellina, J. H., II; Dalietos, D.; Marner, F. J.; Mynderse, J. S.; Moore, R. E.
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6.38 (s, 1H, H-3), 7.26–7.36 (m, 5H, 5ꢃArH); 13C NMR (CDCl3,
100 MHz)
d 28.3 (CH3), 39.6 (NCH2), 79.5 (C), 118.3 (CH, C-3), 126.5
(ArCH), 128.2 (ArCH), 128.6 (ArCH), 137.2 (C, C-2), 140.1 (ArC), 155.6
(ArC); HRMS (ESI) m/z C14H18ClNO2Na [MþNa]þ calcd for 290.0918,
found 290.0921. The Z-configuration of Z-18 was confirmed by its
NOE experiment. Selective irradiation of H-3 of 18 resulted in signal
enhancement of H-60. However, there is no signal enhancement of
H-3 when irradiated H-1.
According to the preceding procedure for the preparation of
malyngamide M (1), Z-18 (20 mg, 0.07 mmol) afforded E-18 (9 mg,
45%yield)asawhitesolid. Mp74.0–75.0 ꢁC;IR(KBr):3390,2979,1702,
1490, 1367, 1250, 1166, 1092, 838 cmꢀ1 1H NMR (CDCl3, 400 MHz)
;
d
1.42 (s, 9H, 3ꢃCH3), 4.08 (d, J¼5.2 Hz, 2H, NCH2), 4.61 (br, 1H, NH),
6.34 (s,1H, H-3), 7.27–7.43 (m, 5H, 5ꢃArH); 13C NMR (CDCl3,100 MHz)
d
28.3 (CH3), 45.7 (NCH2), 79.7 (C),116.2 (CH, C-3),128.1 (ArCH), 128.3
(ArCH), 128.4 (ArCH), 135.6 (C, C-2), 139.7 (ArC), 155.5 (ArC); HRMS
(ESI) m/zC14H18ClNO2Na [MþNa]þ calcdfor290.0918,found290.0921.
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J. Chen et al. / Tetrahedron 66 (2010) 3499–3507
3507
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