Total synthesis of malyngamide X and its 7′S-epi isomer

Article abstract of DOI:10.1016/j.tet.2007.01.035

Stereoselective syntheses of malyngamide X (1) and its 7′(S)-epimer are described. A Lewis acid (Et₂AlCl) mediated anti-aldol reaction was employed to generate the stereocenters C-7 and C-8. The route is convergent and provides a convenient acc

Full text of DOI:10.1016/j.tet.2007.01.035

Tetrahedron 63 (2007) 3217–3226
Total synthesis of malyngamide X and its 70S-epi isomer
Suchada Suntornchashwej,a Khanit Suwanboriruxb and Minoru Isobea,
*
aLaboratory of Organic Chemistry, Graduate School of Bioagricultural Sciences and Institute of Advanced Research,
Nagoya University, Chikusa, Nagoya 464-8601, Japan
bCenter for Bioactive Natural Products from Marine Organisms and Endophytic Fungi (BNPME), Faculty of Pharmaceutical Sciences,
Chulalongkorn University, Bangkok 10330, Thailand
Received 16 January 2007; accepted 18 January 2007
Available online 21 January 2007
Abstract—Stereoselective syntheses of malyngamide X (1) and its 70(S)-epimer are described. A Lewis acid (Et2AlCl) mediated anti-aldol
reaction was employed to generate the stereocenters C-7 and C-8. The route is convergent and provides a convenient access to the synthesis of
structural variants of malyngamide X. Stereochemistry at C-70 in the molecules of natural and synthetic 1, and 70(S)-epi 1 was confirmed by
NMR chiral solvation experiments.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
confirm its stereostructure and to perform further biological
studies. Herein, we report a convenient and stereocontrolled
total synthesis of both 1 and its 70(S)-epi isomer.
As part of our research program for biologically active com-
pounds from Thai marine organisms, we have found a new
malyngamide, which we named as malyngamide X (1) and
isolated from EtOAc extract of sea hare Bursatella leachii.1
Compound 1 possesses a new skeleton of malyngamide fam-
ily, thus it includes an unusual tripeptide portion connecting
to a methoxylated fatty acyl chain. It is active against mal-
arial parasite Plasmodium falciparum (multidrug resistant
strain) and tuberculous bacterium Mycobacterium tubercu-
losis. Absolute configurations of the four stereogenic centers
in the tripeptide portion of 1 determined as 2S,5S,7S,8R,
14S were solved with various NMR spectral analyses and
combined method with molecular mechanic calculations.
For the remaining remote stereogenic center located in the
fatty acyl chain, we have also reported that the diastereo-
meric solvates between 1 and the NMR chiral solvating
agent (2,2,2-trifluoro-1-(9-anthryl)ethanol, TFAE, or Pirkle’s
alcohol)2 showed unequivocal shifts of the 70-OCH3 proton
signals (DdRS<0). Further, we have assigned 70R to 1 by em-
ploying the same TFAE experiments with a known 70S-iso-
malyngamide A and a series of two enantiomers at C-70 of
the synthetic fatty acyl fragments of 1 (DdRS<0 for 70R-con-
figuration and DdRS>0 for 70S-configuration).1 Continuation
of our recent works on malyngamide X has prompted us to
synthesize this unique malyngamide, which is available only
in limited amount from nature. The synthesis allowed us to
2. Results and discussion
When we initiated the synthetic studies of malyngamide X,
the C-70 configuration was presumed to be S as it is the
homolog of other malyngamides, which led us to adopt the
synthetic route to malyngamide X having 70S-configuration.
Although the malyngamide 70(S)-epi 1 exhibited completely
identical H and 13C NMR data to that of natural malyng-
1
amide X, the specific rotation showed a little difference
between each other. Fortunately, the 70-OCH3 signal in each
compounds shifted to opposite direction (positive and nega-
tive) in the presence of the same NMR chiral solvent, thus,
indicating opposite absolute configuration to each other. So
that, the configuration at 70 position in natural malyngamide
X was concluded to be R.
2.1. Synthetic plan
AsoutlinedinScheme1, thewholemoleculeofmalyngamide
X was retrosynthetically divided into four building blocks
2–5; thus, the fatty acids (4E,7R)-(+)-7-methoxytetradec-
4-enonic acid (2a) and (4E,7S)-(ꢀ)-7-methoxytetradec-4-
enonic acid or lyngbic acid (2b)3 could be synthesized from
commercially available materials 6–8. The two amino acid
derivatives 3 and 4 would be generated from N-methyl-L-al-
anine and Boc-L-alanine methyl ester, respectively. The right
segment, pyrrolidone derivative 5 would be derived from
* Corresponding author. Tel.: +81 52 789 4109; fax: +81 52 789 4111;
e-mail: isobem@agr.nagoya-u.ac.jp
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.01.035

3218
S. Suntornchashwej et al. / Tetrahedron 63 (2007) 3217–3226
peptide
coupling
aldol
coupling
15'
OCH3
15
O
OH
O
H
N
5
8
18
N
2
N
10
14
1'
OCH3
7
14'
7'
4'
O
9
6
11
O
malyngamide X (1)
O
15
O
OCH3
N
OCH3
H13C6
COOH
1
BocHN
BocN
COOH
H
O
7
4
2a
3
4
5
O
O
O
O
O
O
C6H13MgBr
OTs
OTHP
Cl
BocHN
COOH
7
8
10
9
11
6a
OCH3
O
C6H13MgBr
OTs
OTHP
H13C6
COOH
7'(S)-epi 1
7
8
6b
lyngbic acid (2b)
3
4
5
Scheme 1. Retrosynthetic analysis of malyngamide X (1) and its 70(S)-epimer.
Boc-L-valine 9, Meldrum’s acid 10, and propionyl chloride
11.4 Introduction of a stereogenic center at C7 of lyngbic
acid and homologous fatty acids has been reported in various
synthetic approaches, including the racemic total synthesis5
and asymmetric total synthesis.6 Recently, the stereogenic
center of homologous fatty acid was constructed by catalytic
asymmetric allylation reaction.7 In our synthetic plan mak-
ing both of the two enantiomers of fatty acid 2, the stereo-
genic center at C7 in 2a and 2b would directly fix by
employing commercially available enantiopure R and S-gly-
cidyl tosylates (6a and 6b) to couple with hexylmagnesium
bromide 7 and acetylide 8. The fragments would be con-
nected by stepwise peptide couplings and aldol addition of
aldehyde 4 with the enolate of an imide pyrrolidone 5.
Coupling of the pyrrolidone moiety at C8 of 5 is the
key step as an integral part of the aldol reaction with the
C7 of 4 in this synthetic route to introduce 7S,8R stereogenic
centers.
THF¼4/1) at ꢀ78 ꢁC gave homopropargylic alcohol 14a in
98% yield. Alcohol 14a was converted into the correspond-
ing methyl ether by treatment with CH3I in the presence of
dimsyl anion in THF at room temperature for 3 h to furnish
the homopropargylic methyl ether 15 in 71% yield. The
trans reduction of acetylene was achieved with Li metal
in liq. NH3–tBuOH at temperatures between ꢀ40 and
ꢀ35 ꢁC to provide the trans olefinic methyl ether 16a in
81%. The THP-protecting group was removed by treatment
of 16a with PPTS in MeOH at 40 ꢁC for 3 h. Oxidation of
the corresponding secondary alcohol 17a proceeded under
Jone’s reagent in acetone at 0 ꢁC gave fatty acid 2a in 93%
yield.
The enantiomeric synthesis of fatty acid 2b could also be
achieved in the same manner as 2a except the use of S-gly-
cidyl tosylate as starting material instead of R-glycidyl tosy-
late. The use of alternative hydride reduction of 14b with
NaOMe–LAH in refluxing THF for 24–48 h provided homo-
allylic alcohol 18 in 76%. The O-methylation of alcohol 18,
by refluxing its THF mixture with CH3I and NaH–DMSO for
12 h, afforded homoallylic methyl ether 16b in 82% yield.
Subsequently, the THP was cleaved and the corresponding
alcohol 17b was oxidized to free acid 2b in quantitative yield
under the same condition for 17a. It was noted that the reac-
tivity toward O-methylation of homoallylic alcohol was
much less than that of homopropargylic alcohol. The reason
was not studied. Spectroscopic and analytical data of both 2a
and 2b are in agreement with those reported for lyngbic acid
{2a: [a]2D6 +11.2 (c 1.3, CHCl3); 2b: [a]2D6 ꢀ13.3 (c 2.5,
CHCl3); natural lyngbic acid in Ref. 8 [a]2D6 ꢀ9.0 (c 7.3,
CHCl3)}.
2.2. Synthesis of fatty acid portion
In order to set a stereogenic center at the C-7 and the 14 car-
bon atoms’ chain length of 2a, the homopropargylic alcohol
14a was generated by consecutive alkylation and alkynyl-
ation of R-glycidyl tosylate (6a) (Scheme 2). Thus, alkylation
of 6a with hexyl organocuprate generated from C6H13MgBr
and 0.1 mol % Li2CuCl4 in THF at ꢀ78 to ꢀ50 ꢁC for 1.5 h
gave only the desired alcohol 12a (determined by 1H NMR).
The conversion of alcohol 12a to epoxynonane 13a was
achieved by stirring with solid K2CO3 in MeOH at room tem-
perature for 2 h. A mixture of 13a, acetylide 8, and n-BuLi in
the presence of BF3$Et2O in a mixed solvents (Et2O–

S. Suntornchashwej et al. / Tetrahedron 63 (2007) 3217–3226
3219
OH
OH
O
a
O
b
90%
in two steps
OTHP
d
71%
c
H13C6
OTs
H13C6
H13C6
OTs
98%
12a
13a
14a
6a
OCH3
OCH3
O
OCH3
e
81%
g
OTHP
H13C6
H13C6
H13C6
OR 93%
OH
16a (R = THP)
17a (R = H)
15
2a
f
quant.
OH
OH
O
OTHP
i
a-c
77%
h
76%
H13C6
H13C6
OTs
OTHP
82%
6b
14b
18
OCH3
OCH3
O
g
H13C6
H13C6
OR
OH
quant.
16b (R = THP)
17b (R = H)
2b
f
Scheme 2. Synthesis of 2a and 2b. (a) C6H13MgBr (7), Li2CuCl4, THF, ꢀ78 to ꢀ50 ꢁC, 1.5 h; (b) K2CO3, MeOH, rt, 2 h; (c) CH^C(CH2)3OTHP (8), n-BuLi,
BF3$Et2O, Et2O–THF, ꢀ78 ꢁC, 1.5 h; (d) CH3I, NaH–DMSO, THF, rt, 3 h; (e) Li wire/liq. NH3–tBuOH, ꢀ40 to ꢀ35 ꢁC, 2 h; (f) PTS, MeOH, 40 ꢁC, 3 h; (g)
CrO3, H2SO4, acetone, 0 ꢁC, 30 min; (h) LAH–NaOMe, THF, reflux, 24 h; (i) CH3I, NaH–DMSO, THF, reflux, 24 h.
2.3. Synthesis of the tripeptide portion
Removal of the Boc-protecting group performed with 50%
TFA in CH2Cl2 at 0 ꢁC for 0.5 h provided amine 21. Treat-
ment of 21 with CH3MgBr in THF at 0 ꢁC, followed by ad-
dition of propionyl chloride, and warming of the reaction
mixture to room temperature for 2 h gave N-propionyl pyr-
rolidone 5 in 68% yield from 9. Next step was the coupling
of the pyrrolidone derivative 5 with N-Boc-L-alaninal (4). In
order to generate the two stereogenic centers at the C-2 and
C-3 positions of the pyrrolidone derivative 23, the Lewis
acid (Et2AlCl) mediated anti-aldol reaction9 was employed
in the coupling reaction (Scheme 3). The starting material,
imide pyrrolidone 5 containing a chiral isopropyl group,
was converted into the (Z)-imide enolate 22 by treatment
After the synthesis of both enantiomers of fatty acid segment
in 1, the remaining tripeptide segment had to be prepared and
successively connected. First, commercially available N-
Boc-L-valine (9) was coupled with Meldrum’s acid (10) us-
ing DCC and DMAP in CH2Cl2 at room temperature for 3 h,
followed by removal of the solvent and subsequent reaction
in refluxing MeOH for 1 h to furnish pyrrolidone derivative
19. Mitsunobu condition of 19 with PPh3 and DEAD in THF
at 0 ꢁC, addition of MeOH, and warming of the reaction mix-
ture to room temperature afforded O-methyl pyrrolidone de-
rivative 20 as the only isomer (determined by H NMR).9
1
O
a
b
OH
d
68%
in four steps
OH
OCH3
R
OCH3
BocHN
O
BocHN
N
N
O
OH
O
O
O
O
O
9
19
5
20 (R = Boc)
21 (R = H)
c
10
OH
O
44%
3%
BocHN
BocHN
Bu
O
Bu
OCH3
OCH3
N
B
N
O
f
e
O
23
OH
O
OCH3
N
22
O
24
Scheme 3. Synthesis of 5 and aldol coupling to C5–C18 segment of malyngamide X (23). (a) DCC, Meldrum’s acid (10), DMAP, CH2Cl2, rt, 3 h, then MeOH,
reflux, 1 h; (b) PPh3, DEAD, CH3OH, THF, rt, 2 h; (c) 50% TFA in CH2Cl2, 0 ꢁC, 0.5 h; (d) CH3MgBr, C2H5COCl, THF, 0 ꢁC to rt, 2 h; (e) n-Bu2BOTf,
i-Pr2NEt, CH2Cl2, 0 ꢁC, 1 h; (f) Et2AlCl, Boc-L-alaninal (4), ꢀ78 ꢁC.

3220
S. Suntornchashwej et al. / Tetrahedron 63 (2007) 3217–3226
MTPA plane
group anti to the aldehyde substituent, but was instead syn
−0.006
H
−0.022
H3C
C
O
to the chelated aldehyde. The antiperiplanar model 26
was disfavored due to steric, gauche interactions between
the pyrrolidone group of the imide enolate and a chiral
bulky alkyl group of the chelated aldehyde. The sterically
demanding methyl group shielded the re-face of the alde-
hyde. This would favor the nucleophilic attack from the
si-face.
CF3
−0.028H
(OCH3)
(Ph)
Ph
O
H
CH3
+0.044
OCH3
+0.085
NHBoc
+0.024
S-MTPA of 23
or
R-MTPA of 23
3
J
α,β= 7.8
Δδ = δ
− δ
S-23
R-23
2.5. Total synthesis of malyngamide X and its epimer
−0.042
NHBoc
−0.006 MTPA plane
−0.067
With all essential pieces in hand, the linear lipopeptide of
malyngamide 1 and 70(S)-epi 1 isomer was constructed,
respectively, by ligating the segments 2a and 2b with N-
methyl-L-alanine and amine derivative 29. As summarized
in Scheme 5, treatment of 23 with a solution of 50% TFA
in CH2Cl2 at 0 ꢁC for 10 min afforded the amine 27. Peptide
formation of amine 27 and Boc-N-Me-L-alanine with
EDC$HCl–HOAt in CH2Cl2 at room temperature for 3 h
gave the desired tripeptide segment 28 in quantitative yield.
The Boc group was cleaved with 50% TFA in CH2Cl2 at 0 ꢁC
for 10 min providing amine 29. The coupling of amine
29 and R-lyngbic acid segment 2a was accomplished by
stirring EDC$HCl–HOAt and i-Pr2NEt at room temperature
for 18 h to give 1 in 44% yield. The coupling of lyngbic
acid segment 2b with amine 29 under the same reaction
condition as that of 1 gave 70(S)-epi 1 in the same yield
(Scheme 6).12
H
H
8
O
CF3
−0.215CH3
C
(OCH3)
(Ph)
Ph
O
CH3
5
+0.044
OCH3
+0.092
H
+0.014
S-MTPA of 24
or
R-MTPA of 24
3
J
α,β = 2.4
Δδ = δ
− δ
S-24
R-24
Figure 1. The Dd values for the MTPA ester of 23 and 24.
with n-Bu2BOTf and i-Pr2NEt at 0 ꢁC in CH2Cl2 for 1 h.
Exposure of 22 to alaninal derivative 4 and Et2AlCl at
ꢀ78 ꢁC for 5 h allowed to give anti-aldol product 23 in
44% yield with >90% de. The use of alternative Lewis
acids, such as EtAlCl2, Et3Al, BF3$Et2O, and SnCl4, low-
ered anti (23):syn (24) selectivity. The stereochemistry of
23 (2S,3S,4R) and 24 (2S,3R,4R) was confirmed by analysis
of its MTPA esters and vicinal coupling constants of Ca/Cb
protons (Fig. 1).10
1
The H and 13C NMR data measured on the synthetic ma-
lyngamides 1 and 70(S)-epi 1 were in good agreement with
the data of natural malyngamide X (see Supplementary
data). This must be due to the large distance between C-70
and the other five stereogenic centers in the tripeptide por-
tion. We found that only the specific rotation values and
the signs of chemical shift non-equivalence (DdRS) in the
NMR chiral solvation experiments were different. The spe-
cific rotation value of natural malyngamide X, [a]D ꢀ6.2
(c 0.8, MeOH) only matched with that of malyngamide 1
having 70R-configuration {1: [a]D ꢀ5.9 (c 0.8, MeOH)}
but differed from 70(S)-epi 1, [a]D ꢀ15.4 (c 0.8, MeOH).
When natural 1, synthetic 70(S)-epi 1, and a known 70S-iso-
malyngamide A were analyzed by 1H NMR in CDCl3
solution at 283 K in the presence of 20 equiv of 2,2,2-tri-
fluoro-1-(9-anthryl)ethanol (TFAE or Pirkle’s alcohol), the
DdRS observed for 70-OCH3 protons was ꢀ0.032, +0.016,
and +0.023 ppm, respectively.1 TFAE experiments with the
synthetic malyngamide 1 were carried out under the same
condition. Spectral analysis of the solvated complex be-
tween 1 and R-TFAE gave the methoxyl protons’ signal at
2.4. Aldol reaction and stereochemistry
From the literature, it is known that the five- or six-mem-
bered chelation proceeds with Lewis acids and aldehydes
having two or more coordinating groups.11 Thus, two models
of transition state are proposed to explain the outcome of
the reaction, the synclinal model 25 and the antiperiplanar
model 26 (Scheme 4). The vinyl hydrogen was placed in
the stereochemically most demanding position. Five-mem-
bered chelation between aldehyde 4 and Et2AlCl seems to
be crucial for facial selectivity of the attack on the (Z)-imide
enolate 22 (chelation control). Based upon the results that
indicate si-face attack to the aldehyde, the reaction was pro-
posed to proceed via synclinal model 25. In this chelation
model, the participating p bonds were arranged at approx.
30ꢁ to each other. The destabilizing interactions were
decreased because Lewis acid was no longer on the carbonyl
Bu
O
Bu
O
Bu
O
Bu
O
B
N
B
N
H
H
H
H
si-face
attack
re-face
attack
Me
H
Me
23, anti-aldol
24, syn-aldol
Me
Me
O
O
H
OCH3
OCH3
i-Pr
Et
i-Pr
HN Al
Al NH
Et
Boc
Boc
Et
Et
25 (favored)
26 (unfavored)
Scheme 4. Two model transition states of Lewis acid (Et2AlCl) mediated anti-aldol reaction.

S. Suntornchashwej et al. / Tetrahedron 63 (2007) 3217–3226
3221
15
15
OH
7
O
OH
7
O
H
N
5
6
8
9
5
8
RN
18
OCH3
18
b
N
14
10
RN
N
10
2
14
OCH3
quant.
O
11
O
11
O
28 (R = Boc)
29 (R = H as TFA salt)
c
23 (R = Boc)
a
82%
quant.
27 (R = H as TFA salt)
OCH3
O
1
4
C6H13
OH
OH
7
2a
1
Malyngamide X
d
44%
OCH3
7
O
1
C6H13
4
2b
7'(S) epi-Malyngamide X
d
44%
Scheme 5. Synthesis of 1a and 70(S)-epi 1. (a) 50% TFA in CH2Cl2, 0 ꢁC, 10 min; (b) Boc-N-Me-L-alanine (3), EDC$HCl, HOAt, CH2Cl2, rt, 3 h; (c) 50% TFA
in CH2Cl2, 0 ꢁC, 0.5 h; (d) EDC$HCl, HOAt, i-Pr2NEt, CH2Cl2, rt, 18 h.
dH 3.243, while in the solvated complex with S-TFAE at dH
a
96%
3.255 corresponding to 70R-OCH3 DdRS ꢀ0.025 (Fig. 2).
These results not only confirmed the structure of 1, but
also indicated the reliability of this NMR method for deter-
mining absolute configuration at C-70 of the malyngamide
family.
OBn
-Cl+H2N
+
2a
O
OCH3
7'
O
CH3
H13C6
OR
N
2
O
30 (R = Bn)
31 (R = H)
b
68%
3. Conclusion
29%
We have achieved the first stereoselective total synthesis of
malyngamide X, a new skeleton of the malyngamides con-
taining a tripeptide backbone and the first 70R-lyngbic acid
substructure, and its 70(S)-epi isomer. Optically active 6a
and 6b were used to incorporate into the above synthesis
to produce the optically active (4E,7R)-(+)-7-methoxytetra-
dec-4-enonic acid, and its enantiomer (lyngbic acid). In our
synthesis, the two stereogenic centers at C7(R) and C8(S) of
1 were successfully generated by Lewis acid (Et2AlCl)
1
27, c
21%
2(R)-epi 1
Scheme 6. (a) N-Me-L-alanine-OBn, 2-chloro-1,3-dimethyl-2-imidazol-
inium PF6 (CIP), i-Pr2NEt, CH2Cl2, 0 ꢁC to rt, 14 h; (b) 1 N KOH,
MeOH, rt, 1 h, 68%; (c) CIP, i-Pr2NEt, CH2Cl2, 0 ꢁC to rt, 20 h.
Figure 2. DdRS for 70-OCH3 protons signal of natural and synthetic 1, 70(S)-epi 1, and isomalyngamide A in the presence of 20 equiv R-TFAE (—) and S-TFAE
(- - -) (CDCl3, 283 K, 600 MHz). Arrows were used to indicate the unequivocal shifts of 70-OCH3 protons signal from R-TFAE to S-TFAE solvated complexes.

3222
S. Suntornchashwej et al. / Tetrahedron 63 (2007) 3217–3226
mediated stereoselective anti-aldol coupling reaction be-
tween alaninal derivative 4 and imide pyrrolidone 5. The
segments’ coupling of fatty acids 2a and 2b with a tripeptide
segment 29 using EDC$HCl–HOAt under careful control of
reaction acidity was employed to avoid formation of ester
bond. The synthetic sample of malyngamide X having 70R
configuration (1) had the same spectroscopic data, particu-
larly the results of the TFAE experiments, and physical prop-
erties as those of natural compound. These results allowed
the confirmation of the structure and stereochemistry of
the natural malyngamide X to be as 1.
Compound 13a: colorless oil; Rf 0.57, EtOAc–Hex (1:4);
1
[a]2D7 +8.67 (c 1.1, CHCl3); H NMR (CDCl3, 400 MHz)
d 0.88 (dist. t, 7.2), 1.20–1.40 (8H, br s), 1.45 (m), 1.52
(m), 2.47 (dd, 5.2, 2.4), 2.75 (dd, 5.2, 4), 2.91 (m); IR
(KBr): n 2925, 2855, 1747, 1457, 1374, 1265, 1178, 1096,
814 cmꢀ1; HRMS (EI) C9H18O [M]+ calcd: 142.1358,
found: 142.1354.
4.1.2. 1-(Tetrahydro-pyran-2-yloxy)-tetradec-4-yn-7(R)-
ol, 14a. To a solution of 2-pent-4-ynyloxy-tetrahydro-pyran
(8) in a mixture of 80 ml Et2O and 20 ml THF at ꢀ78 ꢁC was
added 1.59 M n-BuLi in hexane, 8.4 ml (13.39 mmol), via
a dropping funnel over a 10–15 min period. The slightly
cloudy solution was stirred at ꢀ78 ꢁC for 1 h. Then
2.07 ml of 13a, 1.73 g (12.17 mmol), was added via syringe.
4. Experimental
4.1. General
Then
a
solution of redistilled BF3$Et2O, 1.54 ml
(12.17 mmol), in dry Et2O (1:1, v/v), was added dropwise
over a 15 min period. The resulting clear solution was stirred
for 1.5 h at ꢀ78 ꢁC. The reaction was quenched by the addi-
tion of 60 ml aq saturated ammonium chloride and the re-
sulting mixture was left to stir at room temperature for 1 h.
The organic layer was separated. The aqueous layer was
partitioned with cold Et2O (ꢂ2). The combined organic
extracts were washed with saturated NaHCO3, brine, dried
(Na2SO4), and concentrated. The residual oil was purified
by column chromatography on SiO2 (0–10% EtOAc–Hex)
yielding 3.69 g of 14a (98% yield).
All moisture-sensitive reactions were carried out under ni-
trogen or argon atmosphere. Optical rotations were mea-
sured on a Perkin–Elmer 341 polarimeter using a sodium
lamp operating at 589 nm. IR spectrum was obtained on
a Perkin–Elmer 2000 FT-IR spectrometer. All NMR data
were obtained from a Bruker AV-400 or a Bruker AMX-
1
600 spectrometer. Chemical shifts (d) for H NMR spectra
are given in parts per million relative to tetramethylsilane
(d 0.00) as internal standard and coupling constants (J) in
hertz. Chemical shifts (d) for 13C NMR spectra are given
in parts per million relative to CDCl3 (d 77.0) as internal
standard. The ESI/Q/TOF/MS spectra were recorded on
a Micromass LC-Q-TOF mass spectrometer. The FABMS
and EIMS spectra were obtained with a JEOL JMS-700
mass spectrometer. All experiments were performed in the
positive ion mode. Elemental analyses were done in the
combustion analytical laboratories in Nagoya U.
Compound 14a: colorless oil; Rf 0.23, EtOAc–Hex (1:4);
1
[a]2D7 ꢀ3.78 (c 1.73, CHCl3); H NMR (CDCl3, 400 MHz)
dH 0.87 (3H, dist. t, 7.2), 1.10–1.40 (10H, br s), 1.35–1.85
(10H, m), 2.15–2.45 (4H, m), 3.40–3.54 (2H, m), 3.66
(1H, m), 3.76–3.90 (2H, m), 4.58 (dd, 4.4, 2.4); IR (KBr):
n 3436, 2937, 2866, 1461, 1362, 1127, 1033, 899 cmꢀ1
;
elemental analysis calcd for C19H34O3: C 73.50, H 11.04;
found: C 73.50, H 11.62.
4.1.1. 2R-Epoxynonane, 13a. To a solution of 0.10 M
Li2CuCl4 dissolved in THF, 10.8 ml (0.001 mol) were
added at ꢀ78 ꢁC, dry THF, 140 ml, and a solution of 2.0 M
hexylmagnesium bromide in ether, 12.5 ml (0.025 mol),
over a 30–60 min period via dropping funnel. The yellow so-
lution was stirred at ꢀ78 ꢁC for 2 h. A pre-cooled solution of
2R-glycidyl tosylate, 5.0 g (0.02 mol), in 60 ml dry THF was
added via cannula (5 ml washed). The resulting yellow-red
clear solution was stirred for 0.5 h at ꢀ78 ꢁC, then for 1 h
at ꢀ50 ꢁC. Excess hexylmagnesium bromide was quenched
by the addition of 60 ml saturated ammonium chloride at
ꢀ50 ꢁC. The mixture was left to stir at room temperature
for 30–60 min. The precipitate of magnesium salt was fil-
tered and washed with cold Et2O. The filtrate was partitioned
with cold Et2O. The combined organic extracts were washed
with saturated NH4Cl, brine, dried (Na2SO4), and concen-
trated. The residual white solid, 6.0 g, of 12a (determined
by 1H NMR) was used in next step without further purifica-
tion. To a solution of 12a in 100 ml MeOH was added 3.3 g
(0.024 mol) of K2CO3. The slurry was stirred at room tem-
perature for 2 h. Excess K2CO3 was filtered and washed
with cold Et2O. The filtrate was combined and partitioned
with hexane/cold 70% aq MeOH. The aqueous layer was re-
peatedly extracted with hexane (2–3 times). The combined
hexane extracts were washed with brine, dried (Na2SO4),
and concentrated. The residual yellow oil was purified by
column chromatography on SiO2 (0–10% Et2O–Hex) giving
2.6 g of 13a (90% yield in two steps).
4.1.3. 2-((R)-7-Methoxytetradec-4-ynyloxy)-tetrahydro-
2H-pyran, 15. A suspension of 50–70% sodium hydride
suspension in oil, 600 mg (8.02 mmol), in 5.4 ml DMSO
was transferred to a solution of 14a (1.67 g, 5.35 mmol) in
60 ml dry THF at room temperature. Methyl iodide, 1.0 ml
(16.05 mmol), was introduced into the resulting white sus-
pension. The mixture was left to stir at room temperature
for 3 h. Pre-cooled Et2O, 10 ml, was cautiously added into
the flask and the mixture was poured into crushed ice. The
aqueous layer was extracted with cold Et2O (ꢂ2). The com-
bined organic extracts, pale yellow, were washed with satd
NH4Cl, brine, dried (Na2SO4), and concentrated. The resid-
ual oil was subjected to SiO2 column (10% EtOAc–Hex)
yielding 1.20 g of 15 (71% yield).
Compound 15: Pale yellow oil; Rf 0.37, EtOAc–hexane
(1:4); [a]2D8 +19.5 (c 2.39, CHCl3); 1H NMR (CDCl3,
400 MHz) dH 0.88 (3H, dist. t, 7.2), 1.20–1.36 (10H, br s),
1.48–1.90 (10H, m), 2.30–2.44 (4H, m), 3.24 (1H, m),
3.37 (3H, s), 3.43–3.57 (2H, m), 3.60–3.95 (2H, m), 4.59
(1H, t, 4.4); IR (KBr): n 2934, 2846, 1456, 1356, 1198,
1038 cmꢀ1; elemental analysis calcd for C20H36O3: C
74.03, H 11.18; found: C 73.95, H 11.35.
4.1.4. 2-((R,E)-7-Methoxytetradec-4-enyloxy)-tetrahy-
dro-2H-pyran, 16a. Gaseous NH3 was introduced to a flame

S. Suntornchashwej et al. / Tetrahedron 63 (2007) 3217–3226
3223
dry two-neck flask at ꢀ78 ꢁC condensing approximately
80 ml of liq. NH3. Acetone–dry ice bath was, then, replaced
with acetonitrile–dry ice (temp ꢀ35 to ꢀ40 ꢁC). A solution
of 15 (2.0 g, 6.4 mmol) in 3 ml of tBuOH and 10 ml of THF
was added via syringe. Small piece of Li wire was added to
the stirred solution until deep blue solution persists for more
than 1 h. Solid NH4Cl of 1 g was then added to neutralize
tBuOLi; ammonia was allowed to evaporate overnight. The
mixture was diluted with ice-water and extracted with
Et2O. Combined organic extracts were washed with aq
NH4Cl, brine, dried (Na2SO4), and concentrated. The pale
yellow oily residue, 1.8 g, was subjected to SiO2 column
(0–10% EtOAc–Hex) yielding 1.64 g of 16a (81% yield).
(CH2-2), 36.4 (CH2-6), 56.5 (7-OCH3), 83.8 (CH-7), 127.9
(CH-5), 130.1 (CH-4), 177.5 (C-1); IR (KBr): n 2927,
2856, 1713, 1457, 1183, 970 cmꢀ1; HRMS (EI) C15H28O3
[M]+ calcd: 256.2038, found: 256.2032.
4.1.7. (S,E)-1-(Tetrahydro-2H-pyran-2-yloxy)tetradec-4-
en-7-ol, 18. Using the same procedure as described for 14a,
compound 14b (2.16 g, 77% in three steps) was obtained
from 6b. To a solution of 14b, 2.16 g (7.0 mmol), in 60 ml
THF was added 1.5 g (27.8 mmol) of NaOMe powder. The
resulting slurry was heated at 40 ꢁC for 1 h and LiAlH4 pow-
der, 580 mg (14.0 mmol), in 20 ml dry THF was then added
at this temperature in several portion via syringe. The flask
was heated to reflux at 80 ꢁC under N2 atmosphere for
24 h. The excess LiAlH4 was quenched by slowly dropping
80 ml of wet Et2O at room temperature. The mixture was
poured into 40 ml cold Na–K tartrate and stirred for 1 h.
The precipitate was filtered through a pad of Celite and
washed with Et2O. The filtrate was partitioned with cold
Et2O. The combined organic extracts were washed with
brine, dried (Na2SO4), and concentrated. The residual oil,
2.5 g, was subjected to SiO2 column (20% EtOAc–Hex)
yielding 1.66 g of 18 (76% yield).
Compound 16a: pale yellow oil; Rf 0.34, EtOAc–hexane
(1:4); [a]2D8 +10.4 (c 2.28, CHCl3); 1H NMR (CDCl3,
400 MHz) dH 0.88 (3H, dist. t, 7.2), 1.20–1.34 (10H, br s),
1.40–1.95 (10H, m), 2.05–2.40 (4H, m), 3.16 (1H, m),
3.35 (3H, s), 3.40–4.00 (4H, m), 4.60 (1H, t, 4.4), 5.38–
5.54 (2H, dd, 15.2, 6.4); IR (KBr): n 2923, 2858, 1456,
1353, 1101, 1036 cmꢀ1; elemental analysis calcd for
C20H38O3: C 73.57, H 11.73; found: C 73.57, H 11.94.
4.1.5. (R,E)-7-Methoxytetradec-4-en-1-ol, 17a. p-Toluene
sulfonic acid (PTS) monohydrate, 4.3 g, was added in
several portions to a solution of 16a, 1.5 g (4.59 mmol), in
25 ml of MeOH (pH 3). The reaction mixture was stirred
at 40 ꢁC for 3 h. The reaction was neutralized with 90 ml
of satd NaHCO3. The aqueous phase was partitioned with
cold Et2O (ꢂ2). The combined organic extracts were washed
with brine and dried (Na2SO4). After removal of solvent by
rotary evaporation and purification by SiO2 column (10–
20% EtOAc–hexane), 17a was obtained (1.31 g, quant.
yield).
Compound 14b: colorless oil; Rf 0.23, EtOAc–Hex (1:4);
1
[a]2D7 ꢀ2.25 (c 0.5, CHCl3); H NMR (CDCl3, 400 MHz)
and 13C NMR (CDCl3, 100 MHz) spectra were identical to
14a; MS (EI) C19H33O3 [MꢀH]ꢀ calcd: 309.24, found:
309.24.
Compound 18: pale yellow oil; Rf 0.23, EtOAc–Hex (1:4);
1
[a]2D8 +1.75 (c 0.5, CHCl3); H NMR (CDCl3, 400 MHz)
dH 0.79 (3H, dist. t, 6.4), 1.30–1.90 (20H, br s), 1.95–2.30
(4H, m), 3.30.3.90 (5H, m), 4.55 (1H, m), 5.35–5.60 (2H,
m); IR (KBr): n 3452, 2943, 2857, 1456, 1353, 1120,
1035, 812 cmꢀ1; HRMS (EI) C19H36O3 [M]+ calcd:
312.2664, found: 312.2694.
Compound 17a: pale yellow oil; Rf 0.17, EtOAc–hexane
(1:4); [a]2D8 +11.3 (c 1.28, CHCl3); 1H NMR (CDCl3,
400 MHz) dH 0.89 (3H, dist. t, 7.2), 1.20–1.40 (10H, br s),
1.45 (2H, m), 1.65 (2H, m), 2.12 (2H, q, 6.8), 2.20 (2H, t,
5.6), 3.17 (1H, pent, 6.0), 3.33 (3H, s), 3.66 (2H, t, 8.8),
5.35–5.541 (2H, dd, 15.2, 6.4); IR (KBr): n 3364, 2928,
2858, 1457, 1366, 1097, 969 cmꢀ1; elemental analysis calcd
for C15H30O2: C 74.32, H 12.47; found: C 74.33, H 12.43.
4.1.8. 2-((S,E)-7-Methoxytetradec-4-enyloxy)-tetra-
hydro-2H-pyran, 16b. A suspension of 50–70% sodium
hydride suspension in oil, 1.0 g (18.3 mmol), in 10 ml
DMSO was transferred to a solution of 18 (1.60 g,
6.1 mmol) in 40 ml dry THF at room temperature. Methyl
iodide, 1.25 ml (18.3 mmol), was introduced into the result-
ing white suspension. The mixture was heated to reflux for
overnight. Pre-cooled Et2O, 10 ml, was cautiously added
in flask and the mixture was poured into crushed ice. The
aqueous layer was extracted with cold Et2O (ꢂ2). The com-
bined organic extracts were washed with satd NH4Cl, brine,
dried (Na2SO4), and concentrated. The residual oil was sub-
jected to SiO2 column (10% EtOAc–Hex) yielding 1.62 g of
16b (82% yield).
4.1.6. (R,E)-7-Methoxytetradec-4-enoic acid, 2a. To a so-
lution of 17a, 850 mg (3.50 mmol), in 50 ml acetone was
added Jone’s reagent at 0 ꢁC until reaction color remain.
Excess Jone’s reagent was destroyed by slowly adding iso-
propanol. Top layer was decanted, and the lower layer was
extracted with cold Et2O. Combined organic extracts were
washed with brine, dried (Na2SO4), and concentrated. The
crude product was purified by SiO2 column using 1% acetic
acid in EtOAc as eluting solvent giving 830 mg of 2a (93%
yield).
Compound 16b: pale yellow oil; Rf 0.34, EtOAc–hexane
(1:4); [a]2D8 ꢀ10.34 (c 0.5, CHCl3); 1H NMR (CDCl3,
400 MHz) and 13C NMR (CDCl3, 100 MHz) spectra were
identical to 16a; HRMS (EI) C20H38O3 [M]+ calcd:
326.2821, found: 326.2802.
Compound 2a: pale yellow oil; Rf 0.43, EtOAc–hexane
(1:1); [a]2D8 +11.2 (c 1.30, CHCl3); 1H NMR (CDCl3,
400 MHz) dH 0.89 (3H, dist. t, 7.2), 1.20–1.40 (10H, br s),
1.45 (2H, m), 2.21 (2H, t, 6.0), 2.36 (2H, m), 2.39 (2H,
m), 3.17 (1H, pent, 6.0), 3.33 (3H, s), 5.35–5.541 (2H, dd,
15.2, 6.4); 13C NMR (CDCl3, 100 MHz) dC 14.1 (CH3-14),
22.6 (CH2-13), 25.3 (CH2-9), 27.7 (CH2-3), 29.3 (CH2-
10), 29.7 (CH2-11), 31.8 (CH2-12), 33.4 (CH2-8), 33.7
4.1.9. (R,E)-7-Methoxytetradec-4-en-1-ol, 17b. Using the
same procedure as described for 17a, compound 17b
(1.0 g, 89% yield) was obtained from 16b (1.5 g,
4.60 mmol).

3224
S. Suntornchashwej et al. / Tetrahedron 63 (2007) 3217–3226
Compound 17b: pale yellow oil; Rf 0.17, EtOAc–hexane
(1:4); [a]2D8 ꢀ15.79 (c 1.90, CHCl3); 1H NMR (CDCl3,
400 MHz) and 13C NMR (CDCl3, 100 MHz) spectra were
identical to 17a; MS (EI) C15H29O2 [MꢀH]ꢀ calcd:
241.2168, found: 241.22.
were added 0.3 ml (0.31 mmol) of 1 M Bu2BOTf in
CH2Cl2 and 0.060 ml (0.34 mmol) of freshly distilled
i-Pr2NEt. After 1 h at 0 ꢁC, it was cooled to ꢀ78 ꢁC and
0.340 ml (0.31 mmol) of 0.92 M Et2AlCl in hexane was
added. The solution of 60 mg (0.31 mmol) of N-Boc-L-alani-
nal in 1.0 ml CH2Cl2 was then added. After 5 h, the reaction
was quenched with 1 ml of pH 7 phosphate buffer and 3 ml
of ether. The mixture was allowed to warm to temperature,
the organic layer was separated, and the aqueous layer was
extracted with ether. The combined organic layers were
washed with brine and the solvent was removed in vacuo.
The residue was dissolved in 4 ml of MeOH and cooled to
0 ꢁC, and a 1 ml of 30% H2O2 was added dropwise. After
1 h, 4 ml of H2O was added and then MeOH was removed
under vacuo. The aqueous layer was extracted with EtOAc.
The combined organic layers were washed with cold satu-
rated aq NH4Cl, saturated aq NaHCO3, brine, and dried
(Na2SO4). After evaporation of the solvent, the residue
was purified by preparative TLC (lower phase of CH2Cl2–
MeOH–H2O, 90:10:5) to give 47 mg (44% yield) of 23
and 3.1 mg of 24 (2.9%).
4.1.10. (S,E)-7-Methoxytetradec-4-enoic acid, 2b. Using
the same procedure as described for 2a, compound 2b
(0.59 g, quant.) was obtained from 16b (0.5 g, 2.06 mmol).
Compound 2b: pale yellow oil; Rf 0.43, EtOAc–hexane
1
(1:1); [a]2D8 ꢀ13.3 (c 2.50, CHCl3); H (CDCl3, 400 MHz)
and 13C NMR (CDCl3, 100 MHz) spectra were identical to
the reported data of 2a; HRMS (EI) C15H28O3 [M]+ calcd:
256.2038, found: 256.1990.
4.1.11. (S)-5-Isopropyl-4-methoxy-1-propionyl-1H-pyr-
rol-2(5H)-one, 5. To the stirred solution of N-Boc-L-valine
(9), 2.0 g (9 mmol), in 20 ml CH2Cl2 were added Meldrum’s
acid (10), 1.33 g (9 mmol), DCC, 2.23 g (11 mmol), and
DMAP, 2.2 g (18 mmol). The mixture was stirred at room
temperature for 3 h, and then filtered. The filtrate was diluted
with 30 ml CH2Cl2, and washed with 0.5 N HCl, H2O, brine,
dried (Na2SO4), and concentrated. The residual oil was then
refluxed in 150 ml MeOH for 1 h. The solvent was concen-
trated in vacuo, and the residue of 19 was then dissolved in
50 ml THF. To this solution in an ice bath were added Ph3P,
3 g (11.69 mmol), and 40% diethyl diazocarboxylate in tol-
uene, 4.5 ml (9.9 mmol), and MeOH, 2.0 ml (49.5 mmol).
The mixture was stirred for 0.5 h in an ice bath and 2 h at
room temperature, and the solvent was removed in vacuo.
The product was roughly purified by column chromato-
graphy on SiO2 plug (Et2O) to afford crude product of pyr-
Compound 23: yellow oil; Rf 0.28, lower phase of CH2Cl2–
1
MeOH–H2O (90:10:5); [a]2D9 +8.15 (c 0.10, CHCl3); H
NMR (CDCl3, 400 MHz) d 0.76 (d, 6.8), 1.10 (d, 6.8),
1.19 (d, 6.8), 1.21 (d, 6.8), 1.46 (s, Boc), 2.61 (m), 3.59
(dd, 8.0, 2.4), 3.82 (m), 3.85 (s), 3.98 (dq, 8.0, 6.8), 4.54
(d, 2.8), 4.80 (br s), 5.09 (s); IR (KBr): n 3365, 2977,
2938, 1695, 1622, 1507, 1456, 1319, 1173, 955 cmꢀ1
;
HRMS (TOF) C19H32N2O6Na [M+Na]+ calcd: 385.2339,
found: 407.2167.
Compound 24: yellow oil; Rf 0.16, lower phase of CH2Cl2–
MeOH–H2O (90:10:5); [a]2D9 +8.15 (c 0.15, CHCl3); H
1
1
rolidone 20 (determined by H NMR). To the solution of
19 in CH2Cl2 (100 ml) in an ice bath was added TFA
(30 ml), and the mixture was left to stir for 0.5 h. The TFA
was removed by azeotroping with hexane (three times) to
yield 21 as TFA salt.
NMR (CDCl3, 400 MHz) d 0.75 (d, 6.8), 1.10 (d, 6.8),
1.19 (d, 6.8), 1.21 (d, 6.8), 1.46 (s, Boc), 2.52 (m), 3.79
(m), 3.84 (m), 3.84 (s), 4.05 (m), 4.59 (d, 2.8), 4.80 (br s),
5.08 (s); HRMS (TOF) C19H33N2O6 [M+H]+ calcd:
385.2339, found: 385.2368.
To the stirred solution of 21 in 50 ml THF in an ice bath were
added DMAP, 2.75 g (22.5 mmol), and 0.93 M MeMgBr in
THF, 10.6 ml (9.9 mmol). After 0.5 h, 1.18 ml (13.5 mmol)
of propionyl chloride was added. The mixture was stirred at
room temperature for 2 h, and poured into 20 ml NaHCO3/
crushed ice. The precipitate was filtered through a pad of
Celite and washed with Et2O. The filtrate was partitioned
with EtOAc. The combined organic extracts were washed
with brine, dried (Na2SO4), and concentrated. The residual
oil was subjected to SiO2 column (Et2O–hexane, 1:1) yield-
ing 1.30 g of 5 (68% overall yield).
4.1.13. tert-Butyl (S)-1-((2S,3S,4R)-3-hydroxy-5-((S)-2-
isopropyl-3-methoxy-1H-pyrrol-2(5H)-one)-4-methyl-5-
oxopentan-2-ylcarbamoyl)ethylmethylcarbamate, 28. To
the solution of 23, 240 mg (0.62 mmol), in CH2Cl2 (20 ml)
in an ice bath was added TFA (5 ml), and the mixture was
left to stir for 10 min. The TFAwas removed by azeotroping
with hexane (three times) to yield 27 as a light yellow oil.
To the stirred solution of Boc-N-methyl-L-alanine (144 mg,
0.71 mmol), HOAt (102 mg, 0.75 mmol), and EDC$HCl
(136 mg, 0.71 mmol) in CH2Cl2 (20 ml) at room tempera-
ture was added a solution of 27, 200 mg (0.50 mmol), and
i-Pr2NEt (60 ml, 0.35 mmol) in 15 ml CH2Cl2 at 0 ꢁC. The
mixture was stirred at 0 ꢁC to room temperature over 3 h pe-
riod, and the solvent was removed in vacuo. The residue was
extracted with CH2Cl2, and the organic layer was washed
with 0.5 N HCl, H2O, brine, dried (Na2SO4), and concen-
trated. The residual oil was subjected to SiO2 column
(2.5% MeOH–EtOAc) yielding 237 mg of 28 (quant.).
Compound 5: pale yellow solid; Rf 0.20, EtOAc–hexane
(1:3); [a]2D8 +75.3 (c 0.60, CH2Cl2); 1H NMR (CDCl3,
400 MHz) d 0.74 (d, 7.2), 1.11 (d, 7.2), 1.15 (t, 7.2), 2.55
(m, H-6), 2.94 (q, 7.2), 3.83 (s, H3-9), 4.37 (d, 2.4), 5.06
(s); IR (KBr): n 3113, 2965, 2882, 1685, 1624, 1458,
1241, 997 cmꢀ1
; HRMS (ESI/Q/TOF) C11H17NO3Na
[M+Na]+ calcd: 234.1106, found: 234.1108.
4.1.12. tert-Butyl (2S,3S,4R)-3-hydroxy-5-((S)-2-isopro-
pyl-3-methoxy-1H-pyrrol-2(5H)-one)-4-methyl-5-oxo-
pentan-2-ylcarbamate, 23. To a solution of 60 mg
(0.28 mmol) of imide 5 in 1.0 ml of dry CH2Cl2 at 0 ꢁC
Compound 28: pale yellow oil; Rf 0.57, 2.5% MeOH in
1
EtOAc; [a]2D9 +8.15 (c 0.10, CHCl3); H NMR (CDCl3,
400 MHz) d 0.76 (d, 7.2), 1.10 (d, 6.4), 1.11 (d, 10.0), 1.20

S. Suntornchashwej et al. / Tetrahedron 63 (2007) 3217–3226
3225
Figure 3. NMR spectra of malyngamide X: Upper, natural; Middle, synthetic; and Bottom, 70S-epimer.
(d, 6.8), 1.53 (d, 7.2), 2.62 (m), 2.99 (s), 3.63 (br d, 8.0), 3.85
(s), 3.89 (m), 4.16 (m), 4.19 (q, 6.8), 4.52 (d, 2.8), 5.07
(s), 6.40 (br); IR (KBr): n 3395, 2979, 2932, 1702, 1624,
1508, 1458, 1319, 1173, 988 cmꢀ1; HRMS (TOF) m/z
C23H40N3O7 [M+H]+ calcd: 470.2866, found: 470.2871.
concentrated. The residual oil was purified by preparative
TLC (EtOAc) to give 20 mg of 1 (44%).
Compound 1: pale yellow oil; Rf 0.34, EtOAc; [a]2D7 ꢀ5.9
(c 0.8, MeOH); 1H (600 MHz) d 0.77 (d, 7.2), 0.88 (t, 6.6),
1.10 (d, 6.6), 1.14 (d, 6.6), 1.21 (d, 6.6), 1.23–1.33 (m),
1.35 (d, 7.2), 1.44 (m), 2.19 (t), 2.37 (m), 2.43 (m), 2.63
(m), 2.95 (s), 3.15 (pentet, 6.0), 3.32 (s), 3.63 (dd, 9.0,
2.4), 3.85 (s), 3.88 (dq, 9.0, 6.6), 4.07 (m), 4.53 (d, 2.4),
5.08 (s), 5.23 (q, 7.2), 5.48 (dt, 15.6, 6.0), 5.53 (dt, 15.6,
6.0), 6.48 (d, 9.0); 13C (150 MHz); d 13.7 (C-3), 14.2
(C-9), 14.1 (C-140), 15.4 (C-16), 18.1 (C-6), 18.7 (C-17),
22.6 (C-130), 25.3 (C-90), 28.1 (C-30), 29.0 (C-15), 29.3
(C-100), 29.7 (C-110), 30.6 (C-1), 31.8 (C-120), 33.4 (C-80),
33.8 (C-20), 36.4 (C-60), 42.4 (C-8), 46.7 (C-5), 51.9 (C-2),
56.5 (C-150), 58.5 (C-18), 64.5 (C-14), 77.4 (C-7), 80.8
(C-70), 94.6 (C-12), 127.3 (C-40), 131.1 (C-50), 171.0
(C-11), 171.4 (C-4), 173.5 (C-10), 175.7 (C-10), 179.9
(C-13); IR (KBr): n 3336, 2929, 2855, 1719, 1680, 1624,
1457, 1379, 1319, 1247, 1101, 953 cmꢀ1; HRMS (FAB)
C33H58N3O7 [M+H]+ calcd: 608.4275, found: 608.4294.
4.1.14. Malyngamide X, 113 (Fig. 3). To the solution of 28,
70 mg (0.15 mmol), in CH2Cl2 (3 ml) in an ice bath was
added TFA (0.5 ml), and the mixture was left to stir for
10 min. The TFA was removed by azeotroping with hexane
(three times) to yield 29 as a light yellow oil.
To the stirred solution of fatty acid 2a (20.0 mg,
0.078 mmol), HOAt (9.0 mg, 0.082 mmol), and EDC$HCl
(12.0 mg, 0.078 mmol) in CH2Cl2 (1 ml) at room tempera-
ture was added a solution of 29, 38 mg (0.078 mmol), and
i-Pr2NEt (20 ml, 0.12 mmol) in CH2Cl2 1 ml at 0 ꢁC. The
mixture was stirred at 0 ꢁC to room temperature over 18 h
period, and the solvent was removed in vacuo. The residue
was extracted with CH2Cl2, and the organic layer was
washed with 0.5 N HCl, H2O, brine, dried (Na2SO4), and

3226
S. Suntornchashwej et al. / Tetrahedron 63 (2007) 3217–3226
4.1.15. 70(S)-Malyngamide X, 70(S)-epi 1. Using the same
procedure as described for 1, compound 70(S)-epi 1 (20 mg,
44% yield) was obtained from 2b (20 mg, 0.078 mmol).
3. Lyngbic acid is the major fatty acid substructure in the malyng-
amides. See: (a) Tan, L. T.; Okino, T.; Gerwick, W. H. J. Nat.
Prod. 2000, 63, 952–955; (b) Nogle, L. M.; Gerwick, W. H.
ꢀ
J. Nat. Prod. 2003, 66, 217–220; (c) Milligan, K. E.; Marquez,
Compound 70(S)-epi 1: pale yellow oil; Rf 0.34, EtOAc;
B.; Williamson, T.; Davies-Coleman, M.; Gerwick, W. H.
J. Nat. Prod. 2000, 63, 965–968; (d) Kan, Y.; Sakamoto, B.;
Fujita, T.; Nagai, H. J. Nat. Prod. 2000, 63, 1599–1602.
4. (a) Akaji, K.; Hayashi, Y.; Kiso, Y.; Kuriyama, N. J. Org. Chem.
1999, 64, 405–411; (b) Ma, D.; Ma, J.; Ding, W.; Dai, L.
Tetrahedron: Asymmetry 1996, 7, 2365–2370.
1
[a]2D7ꢀ15.4 (c 0.8, MeOH); H NMR (600 MHz) and 13C
NMR (150 MHz) spectra were identical to that of 1; IR
(KBr): n 3336, 2931, 2856, 1719, 1684, 1624, 1457, 1379,
1319, 1248, 1097, 953 cmꢀ1; HRMS (FAB) C33H58N3O7
[M+H]+ calcd: 608.4275, found: 608.4305.
5. (a) Fryhle, C. B.; Williard, P. G.; Rybak, C. M. Tetrahedron
Lett. 1992, 33, 2327–2330; (b) Sankaranarayanan, S.;
Sharma, A.; Chattopadhyay, S. Tetrahedron: Asymmetry
1996, 7, 2639–2643; (c) Mesguiche, V.; Valls, R.; Piovetti,
L.; Peiffer, G. Tetrahedron Lett. 1999, 40, 7473–7476.
6. Voss, M. G.; Gerlach, H. Liebigs Ann. 1995, 673–676.
7. (a) Li, Y.; Chen, J.; Cao, X.-P. Synthesis 2006, 320–324; (b)
Chen, J.; Li, Y.; Cao, X.-P. Tetrahedron: Asymmetry 2006,
933–941.
8. Mynderse, J. S.; Moore, R. E. Phytochemistry 1978, 17, 2091–
2095.
9. (a) Walker, M. A.; Heathcock, C. H. J. Org. Chem. 1991, 56,
5747–5750; (b) Danda, H.; Hansen, M. M.; Heathcock, C. H.
J. Org. Chem. 1990, 55, 173–181.
10. For a-methyl-b-hydroxycarbonyl compounds, the observed
vicinal coupling constants for anti Ca/Cb protons is large
(3JH,H¼7–12 Hz) whereas that of the gauche Ca/Cb protons
is small (3JH,H¼0–4 Hz); see: (a) Heathcock, C. H.; Pirrung,
M. C.; Sohn, J. E. J. Org. Chem. 1979, 44, 4294–4299; (b)
Paik, S.; Carmeli, S.; Cullingham, J.; Moore, R. E.; Patterson,
G. M. L.; Tius, M. A. J. Am. Chem. Soc. 1994, 116, 8116–
8125 (see Fig. 1).
Acknowledgements
The authors are grateful for financial support from MEXT
Grant-in-Aid for Specially Promoted Research (16002007),
Japan. BNPME is supported by a grant for centers of excel-
lence, Chulalongkorn University, and Commission of Higher
Education and Strategic Consortia for Human Resource
Development, Thailand. We thank Prof. H. Nagai at Tokai
Univ. for authentic sample of isomalyngamide A, M. Kuse
for MS measurements, K. Koga for special NMR spectros-
copy, and S. Kitamura for elemental analyses. Authors are
indebted to Prof. T. Nishikawa for helpful discussion during
this work.
Supplementary data
1H NMR spectra for compounds 2a, 23, 24, 28, 1 (natural
and synthetic), and 70(S)-epi 1. Supplementary data associ-
ated with this article can be found in the online version, at
doi:10.1016/j.tet.2007.01.035.
11. (a) Panek, J. S.; Cirillo, P. F. J. Org. Chem. 1993, 58, 999–1002;
(b) Nelson, S. G. Tetrahedron: Asymmetry 1998, 9, 357–389;
(c) Arya, P.; Qin, H. Tetrahedron 2000, 56, 917–947.
12. The different segments’ coupling method was applied to 1.
Sequentially, lyngbic acid 2a was coupled to N-Me-L-ala-
nine-OBn using 2-chloro-1,3-dimethyl-2-imidazolinium PF6
(CIP) and i-Pr2NEt, debenzylation of the corresponding
lipopeptide 30 by basic hydrolysis provided free acid 31,
final coupling of 31 with amine derivative 27 by reaction
with CIP and i-Pr2NEt accomplishing in 50% yield as a 1:1
mixture of diastereomers (determined by 1H NMR). Fortu-
nately, the isomers could be isolated by preparative TLC
(EtOAc–Hex–Et3N, 4:5:0.1). Thus, the malyngamide 1 was
isolated in 29% yield. Another isomer would be its C-2(R) epi-
mer because of the propensity for racemization of the N-Me-L-
alanine residue after activation with CIP (see Scheme 6).
13. The tripeptide moiety was numbered with respect to janolus-
imide, a very similar tripeptide. See: Sodano, G.; Spinella, A.
Tetrahedron Lett. 1986, 27, 2505–2508.
References and notes
1. Suntornchashwej, S.; Suwanborirux, K.; Koga, K.; Isobe, M.
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CSA and a pair of enantiomers are diastereomers, which
1
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