A convergent route for the total synthesis of malyngamides O, P, Q, and R

Article abstract of DOI:10.1021/jo9003103

(Chemical Equation Presented) A convergent, enantioselective and general synthetic route to a class of marine natural products - malyngamides O (1), P (2), Q (3), R (4), 5″-epi-3 and 5″-epi-4 - bearing a novel vinyl chloride structural motif was developed. The key steps involved construction of the vinyl chloride functionality by Wittig reaction, a DCC/HOBt-promoted amidation, an aldol reaction in the construction of the basic backbone of 1, 2, 3, 4, 5″-epi-3, and 5″-epi-4, and methylation of an enol moiety via either base/acid conditions or a Mitsunobu reaction. Moreover, the absolute configuration of the stereogenic center at C-5″ in 3 was further confirmed by synthesis of the natural product and its C-5″ epimer.

Full text of DOI:10.1021/jo9003103

A Convergent Route for the Total Synthesis of Malyngamides O, P,
Q, and R
Jie Chen, Xiao-Gang Fu, Ling Zhou, Jun-Tao Zhang, Xian-Liang Qi, and Xiao-Ping Cao*
State Key Laboratory of Applied Organic Chemistry and College of Chemistry and Chemical Engineering,
Lanzhou UniVersity, Lanzhou, 730000, People’s Republic of China
caoxplzu@163.com
ReceiVed February 11, 2009
A convergent, enantioselective and general synthetic route to a class of marine natural productss
malyngamides O (1), P (2), Q (3), R (4), 5′′-epi-3 and 5′′-epi-4sbearing a novel vinyl chloride structural
motif was developed. The key steps involved construction of the vinyl chloride functionality by Wittig
reaction, a DCC/HOBt-promoted amidation, an aldol reaction in the construction of the basic backbone
of 1, 2, 3, 4, 5′′-epi-3, and 5′′-epi-4, and methylation of an enol moiety via either base/acid conditions
or a Mitsunobu reaction. Moreover, the absolute configuration of the stereogenic center at C-5′′ in 3 was
further confirmed by synthesis of the natural product and its C-5′′ epimer.
Introduction
Malyngamides O and P were isolated from the sea hare
Stylocheilus longicauda, which was known to feed on L.
majuscula by Scheuer’s group in 2000.1c Bioassay assessment
with mouse lymphoma (P-388), human lung carcinoma (A-549),
and human colon carcinoma (HT-29) cell lines indicated that
malyngamide O possessed moderate activity (IC50 2 µg/mL),
but the biological activity of malyngamide P was still unknown
due to an inadequate quantity of the sample. Malyngamides Q
and R were isolated from a shallow-water Madagascan L.
majuscula by Gerwick’s group in 2000.1d While the biological
properties of the former compound could not be evaluated due
to its instability, and its absolute configuration of the C-5′′ center
was not secured, the latter compound displayed brine-shrimp
toxicity (LD50 18 ppm). The total synthesis of malyngamide X
was first reported by Isobe’s group,2 while the first total
synthesis and the structural revision of the correct absolute
The malyngamides are a class of secondary metabolites
isolated from the marine cyanophyte Lyngbya majuscule. To
date, 30 different malyngamides have been isolated including
malyngamides A-X, serinol-derived malyngamides, toxic-type
malyngamides (hermitamides A and B), and isomalyngamides.1
Interestingly, 18 of the malyngamide family members are a class
of amide compounds containing a fatty acid chain bonded to
an amine moiety carrying a communal, but an interesting
terminal vinylic chloride functionality. These natural products
have been found to possess a wide range of biological properties.
(1) (a) Cardellina, J. H., II; Dalietos, D.; Marner, F. J.; Mynderse, J. S.; Moore,
R. E. PhytoVhemistry 1978, 17, 2091. (b) Suntornchaswej, S.; Suwanborirux,
K.; Koga, K.; Isobe, M. Chem. Asian J. 2007, 2, 114. (c) Gallimore, W. A.;
Scheuer, P. J. J. Nat. Prod. 2000, 63, 1422. (d) Milligan, K. E.; Ma´rquez, B.;
Williamson, R. T.; Davies-Coleman, M.; Gerwick, W. H. J. Nat. Prod. 2000,
63, 965. (e) Li, Y.; Feng, J. P.; Wang, W. H.; Chen, J.; Cao, X. P. J. Org.
Chem. 2007, 72, 2344 Brief overview of the family of the related malyngamides.
See ref 1e and references cited therein.
(2) Suntornchashwej, S.; Suwanborirux, K.; Isobe, M. Tetrahedron 2007,
63, 3217.
10.1021/jo9003103 CCC: $40.75
Published on Web 04/24/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 4149–4157 4149

Chen et al.
FIGURE 1. Structure of malyngamides O, P, Q, R, A, B, iso-A, iso-B, M, T, 5′′-epi-3, and 5′′-epi-4.
configuration of malyngamide U,1e,3 and its 2′-epimer,3 as well
as several serinol-derived malyngamides were accomplished by
us.4However, there are no reports on the total synthesis of
malyngamides containing the terminal vinylic chloride moiety.
The scarcity of malyngamides in natural sources has hampered
biological evaluation of these fascinating molecules. To provide
materials for more extensive biological evaluation and confirm
the absolute configuration of their stereogenic centers, we are
interested in the synthesis of these malyngamides with such a
structurally interesting vinyl chloride functionality.
A survey of the literature revealed several methods for
the construction of terminal vinyl chlorides such as Wittig
reaction,5a-c Takai-type reaction,5d,e transition metal-cata-
lyzed cross-coupling reactions of deliberately functionalized
precursors,5f,g Mg/TiCl4/CHCl3,5h Julia olefination,5i and other
methods.5j-n The Wittig reaction, Takai-type reaction, and
metal-mediated coupling reaction have been used widely in
the synthesis of natural products. In the present study, we
chose the Wittig reaction to construct the vinyl chloride motif
in this work, and a highly general synthetic route to these
malyngamides O (1), P (2), Q (3), R (4), 5′′-epi-3, and 5′′-
epi-4 was reported. This newly developed procedure should
allow the synthesis of other structurally related malyngamides
containing the same vinyl chloride structure, such as ma-
lyngamides A, B, iso-A, iso-B, M, and T (Figure 1).
Results and Discussion
As outlined in Scheme 1, malyngamides O (1), P (2), Q (3),
R (4), 5′′-epi-3, and 5′′-epi-4 could be retrosynthetically divided
into three parts: a carboxylic acid component 5, a Boc-protected
amine component 6 that bears the vinyl chloride part, and an
acetate 7 or an acetamide 8 that contains a pyrrolidone moiety.
Amidation of 5 and 6 and aldol reaction of 6 and 7 (or 8) would
furnish the skeleton of the target malyngamides. The chiral fatty
acid 5, E,(7S)-7-methoxytetradec-4-enoic acid, had been syn-
thesized earlier by us in six steps using a Johnson-Claisen
rearrangement as a key step starting from octanal in 50% overall
yield.3 Other key intermediates, such as the vinyl chloride in 6,
could be introduced via Wittig reaction of the oxidized derivative
of 9, and alcohol 9 in turn could be derived from 10 via
functional transformations. Pyrrolidone derivative 8 could be
generated from L- or D-serine 11, and hence the sense of chirality
at C-5′′ in malyngamides Q and R could be derived from the
chirality of the serine.
(3) Feng, J. P.; Shi, Z. F.; Li, Y.; Zhang, J. T.; Qi, X. L.; Chen, J.; Cao,
X. P. J. Org. Chem. 2008, 73, 6873.
(4) Chen, J.; Li, Y.; Cao, X. P. Tetrahedron: Asymmetry 2006, 17, 933.
(5) (a) Mu¨nstedt, R.; Wannagat, U.; Wrobel, D. J. Organomet. Chem. 1984,
264, 135. (b) Esmieu, W. R.; Worden, S. M.; Catterick, D.; Wilson, C.; Hayes,
C. J. Org. Lett. 2008, 10, 3045. (c) MacCoss, R. N.; Balskus, E. P.; Ley, S. V.
Tetrahedron Lett. 2003, 44, 7779. (d) Takai, K.; Nitta, K.; Utimoto, K. J. Am.
Chem. Soc. 1986, 108, 7408. (e) Smith, A. B., III; Razler, T. M.; Meis, R. M.;
Pettit, G. R. J. Org. Chem. 2008, 73, 1201. (f) Lemay, A. B.; Vulic, K. S.;
Ogilvie, W. W. J. Org. Chem. 2006, 71, 3615. (g) Me´tay, E.; Hu, Q.; Negishi,
E. I. Org. Lett. 2006, 8, 5773. (h) Tsai, C. C.; Chien, C. T.; Chang, Y. C.; Lin,
H. C.; Yan, T. H. J. Org. Chem. 2005, 70, 5745. (i) Lebrun, M. E.; Marquand,
P. L.; Berthelette, C. J. Org. Chem. 2006, 71, 2009. (j) Barluenga, J.; Baragan˜a,
B.; Concello´n, J. M. J. Org. Chem. 1999, 64, 2843. (k) Takeda, T.; Endo, Y.;
Reddy, C. S.; Sasaki, R.; Fujiwara, T. Tetrahedron 1999, 55, 2475. (l) Nader,
B. S.; Cordova, J. A.; Reese, K. E.; Powell, C. L. J. Org. Chem. 1994, 59,
2898. (m) Wei, H. X.; Gao, J. J.; Li, G. Tetrahedron Lett. 2001, 42, 9119. (n)
Hoffmann, R. W.; Haeberlin, E.; Rohde, T. Synthesis 2002, 207.
The preparation of compound 6 began with ethyl 4-chloro-
3-oxobutanoate (10) (Scheme 2). Thus, reaction of 10 with
sodium azide provided a 78% yield of the azide 12 in acetone/
4150 J. Org. Chem. Vol. 74, No. 11, 2009

Total Synthesis of Malyngamides O, P, Q, and R
SCHEME 1. Retrosynthetic Analysis
SCHEME 2. Preparation of Key Intermediates 6 and 14
chloride (TBDPSCl) to give the corresponding silyl ether 9 in
68% yield for two steps. As expected, oxidation of secondary
alcohol 9 with 2-iodoxybenzoic acid (IBX) in EtOAc provided
the corresponding ketone, which was subjected directly to Wittig
olefination with chloromethyltriphenylphosphonium iodide
(Ph3P+CH2ClI-) in the presence of n-BuLi in THF to give the
vinyl chloride 6 in a 72% yield as a mixture of Z- and E-isomers
(Z:E, 3:1).9 The mixture could be separated by careful flash
chromatography over silica gel. Fortunately, the major product
6 with the Z-configuration was the desired one which was
obtained in 54% yield. The Z-configuration of the vinyl chloride
was consistent with that in natural malyngamides O and P, which
provided a foundation for the preparation of these malynga-
mides. Finally, N-methylation of (Z)-6 provided the key vinyl
chloride 14 in 99% yield.
With fatty acid 5 and vinyl chloride 14 in hand, we focused
our efforts on the formation of the skeleton of malyngamides
O and P via aldol and amidation reactions (Scheme 3). Thus,
deprotection of the TBDPS group of compound 14 with TBAF
in THF generated alcohol 15 in 94% yield, followed by
oxidation of alcohol 15 with IBX to afford aldehyde 16, which
was used directly in the next step without further purification.
Subsequently, the aldehyde 16 underwent successfully low-
temperature condensation with the enolate derived from methyl
acetate in THF to give alcohol 17 in 57% (brsm 87%) yield.10
Racemic 17 was immediately submitted to deprotection of
the Boc group with trifluoroacetic acid (TFA) to generate the
corresponding amine, which was directly condensed with the
carboxylic acid 5 in the presence of N,N′-dicyclohexylcarbo-
diimide (DCC), 1-hydroxybenzotriazole (HOBt), and N-meth-
ylmorpholine (NMM) in CH2Cl2 to afford amide 18 in 85%
yield.1e Finally, oxidation of 18 with Dess-Martin periodinane
water (3:1) under reflux.6 Subsequent hydrogenation of 12 under
H2 atmosphere with 10% Pd/C in the presence of di-tert-butyl
dicarbonate (Boc2O) in EtOAc gave the Boc-protected amine
13 in 71% yield.7 Reduction of both keto and ester carbonyl
groups in ester 13 with diisobutylaluminum hydride (DIBAL-
H) afforded the intermediate diol,8 followed by monoprotection
of the primary hydroxy group with tert-butyldiphenylsilyl
(6) Yasohara, Y.; Kizaki, N.; Hasegawa, J.; Wada, M.; Kataoka, M.; Shimizu,
S. Tetrahedron: Asymmetry 2001, 12, 1713.
(7) McCall, W. S.; Grillo, T. A.; Comins, D. L. Org. Lett. 2008, 10, 3255.
(8) Nicolaou, K. C.; Jennings, M. P.; Dagneau, P. Chem. Commun. 2002,
2480.
(9) (a) Kahnberg, P.; Lee, C. W.; Grubbs, R. H.; Sterner, O. Tetrahedron
2002, 58, 5203. (b) Kahnberg, P.; Sterner, O. Tetrahedron 2001, 57, 7181.
(10) Williams, D. R.; Patnaik, S.; Clark, M. P. J. Org. Chem. 2001, 66, 8463.
J. Org. Chem. Vol. 74, No. 11, 2009 4151

Chen et al.
SCHEME 3. Preparation of Malyngamides O and P
SCHEME 4. Preparation of Pyrrolidone 8
with TFA provided pure amine 21 in 42% yield from 19 via
flash chromatography over silica gel. Several other procedures
were attempted to synthesize the enol ether 20, including NaH/
Me2SO4/HMPA (no product),10 K2CO3/Me2SO4/acetone (19%
yield),13 and K2CO3/Me2SO4/DMSO (11% yield),14 but the
product yields were all unsatisfactory in this case. Finally,
N-acetylation of 21 with n-BuLi and acetyl chloride provided
N-acetyl pyrrolidone (S)-8 in 81% yield.15 Using DMAP/
MeMgBr/AcCl conditions developed by Isobe’s group met with
limited success in our hands,2 and with Et3N/AcCl, 21 was
obtained only in 16% yield.16 In a similar manner, (R)-8 was
also prepared from D-serine in 29% total yield.
With the key intermediates 8 and 16 in hand, we sought to
construct the C(1)-C(6) framework of 22 via aldol reaction of
aldehyde 16 and ketone (S)-8 (Scheme 5). Thus, various
conditions were tried as shown in Table 1. No desired product
resulted when aldehyde 16 was subjected to the enolate of (S)-8
in the presence of LDA at -78 or -40 °C; however, as the
reaction temperature was raised to 0 °C, (S)-8 was found to
decompose. Aldol reaction of oxazolidinone (S)-8 with aldehyde
16 under Evans condition (Bu2BOTf) provided a complex
mixture.17 Fortunately, compound 22 was achieved by the aldol
reaction of the chlorotitanium enolate of ketone (S)-8 (enoliza-
tion with 1.1 equiv of TiCl4 and excess i-Pr2NEt) and aldehyde
16 in 53% yield.18 Subsequent deprotection of the Boc group
of 22 followed by amidation with acid 5 resulted in little of the
desired compound 23 after several experiments. Therefore we
in CH2Cl2 gave malyngamide P (2) in 71% yield.10 As expected,
malyngamide O (1) could be prepared from 2 via deprotionation
with NaH in hexamethylphosphoramide (HMPA) followed by
methylation with freshly distilled dimethyl sulfate in 53%
yield.10 The spectral data of synthetic malyngamides O (1) and
P (2) were in good agreement with those reported in the
literature.1c
On the basis of the preparation of malyngamides O and P,
we continued to synthesize malyngamides Q and R bearing the
more challenging structure. Hence, using a similar reaction
sequence, construction of the amine portion via aldol reaction
and then amidation with acid 5 would form the carbon
framework of malyngamides Q and R. The acetamide 8 bearing
the pyrrolidone ring was prepared as described in Scheme 4.
Thus, protection of the amino group in L-serine (11) with Boc2O
followed by silylation of the hydroxy group provided acid 19
in 90% yield.11 Then the reaction of 19 with Meldrum’s acid
using DCC and 4-dimethylaminopyridine (DMAP) in CH2Cl2,
followed by removal of the solvent and then heating in MeOH
furnished the pyrrodidone intermediate,12 which was subjected
to a Mitsunobu reaction by treatment with PPh3 and diisopropyl
azodicarboxylate (DIAD) in MeOH to give O-methyl pyrroli-
done derivative 20.2 Compound 20 happened to have a similar
Rf value as the reduced byproduct of DIAD, and separation was
carried out in the next step. Hence, removal of the Boc group
(13) Ahmad, N. M.; Rodeschini, V.; Simpkins, N. S.; Ward, S. E.; Blake,
A. J. J. Org. Chem. 2007, 72, 4803.
(14) Hanquet, G.; Salom-Roig, X. J.; Gressot-Kempf, L.; Lanners, S.;
Solladie´, G. Tetrahedron: Asymmetry 2003, 14, 1291.
(15) Guerlavais, V.; Carroll, P. J.; Joullie´, M. M. Tetrahedron: Asymmetry
2002, 13, 675.
(16) Sasaki, H.; Mori, Y.; Nakamura, J.; Shibasaki, J. J. Med. Chem. 1991,
34, 628.
(17) (a) Kim, H.; Lee, H.; Kim, J.; Kim, S.; Kim, D. J. Am. Chem. Soc.
2006, 128, 15851. (b) Sawamura, K.; Yoshida, K.; Suzuki, A.; Motozaki, T.;
Kozawa, I.; Hayamizu, T.; Munakata, R.; Takao, K. I.; Tadano, K. I. J. Org.
Chem. 2007, 72, 6143. (c) Yokoe, H.; Sasaki, H.; Yoshimura, T.; Shindo, M.;
Yoshida, M.; Shishido, K. Org. Lett. 2007, 9, 969.
(11) (a) Garner, P.; Park, J. M. J. Org. Chem. 1987, 52, 2361. (b) Nicolaou,
K. C.; Bunnage, M. E.; Koide, K. J. Am. Chem. Soc. 1994, 116, 8402.
(12) He, G.; Wang, J.; Ma, D. W. Org. Lett. 2007, 9, 1367.
(18) Crimmins, M. T.; Tabet, E. A. J. Am. Chem. Soc. 2000, 122, 5473.
4152 J. Org. Chem. Vol. 74, No. 11, 2009

Total Synthesis of Malyngamides O, P, Q, and R
SCHEME 5. Aldol Reaction
SCHEME 6. Preparation of Primary Alcohols 27 and 30
TABLE 1. Optimization for the Aldol Reaction of 16 and (S)-8
entry
1
condition
% yield of 23
LDA, THF, -78 °C, 1 h,
no reaction
then 16, -78 °C (2 h)a
2
3
4
5
LDA, THF, -78 °C, 1 h,
no reaction
complex
complex
53
then 16, -78 to -40 °C (2 h)b
LDA, THF, -78 °C, 1 h,
then 16, -78 to 0 °C (1 h)c
Bu2BOTf, Et3N, CH2Cl2, 0 °C, 1 h,
then -78 °C, 16, -78 to 0 °C (1 h)c
TiCl4, i-Pr2NEt, CH2Cl2, -78 °C, 2.5 h,
then 16, -78 to 0 °C (2 h)c
a Reaction was performed at -78 °C and maintained at this
temperature throughout the procedure. b After the addition of 16, the
reaction was allowed to warm to -40 °C, and kept there for 2 h. c After
the addition of 16, the reaction was allowed to warm to 0 °C, and kept
there for 1 or 2 h.
TABLE 2. Deprotection of Silyl Ether 28
decided to carry out the amidation of 5 and (Z)-6 first, and then
conduct the aldol reaction with (S)-8 in the second step.
Thus, starting from the key intermediates (Z)-6 and 14, removal
of the Boc groups in both compounds was carried out first (Scheme
6), followed by amidation with acid 5 in the presence of DCC,
HOBt, and NMM in CH2Cl2 to produce amides 24 and 25 in 86%
and 87% yields, respectively. Subsequent deprotection of the
TBDPS groups in 24 and 25 with TBAF in THF gave the
corresponding alcohols 26 and 27 (97% and 98% yields, respec-
tively). Oxidation of alcohol 26 with IBX followed by aldol reaction
with (S)-8 gave no desired product, presumably due to the
interference of the amide NH bond.19 So the acidic hydrogen of
amide 24 was protected as the Boc protected silyl ether 28 in 93%
yield.19b,c However, deprotection of the TBDPS group by TBAF
gave only the Boc transferred side-product 29 in 95% yield.20
Several other conditions were tried (Table 2). Finally we found
that conducting the desilylation in the presence of TBAF/AcOH
1:1 resulted in good selectivity for 30 (30:29, 20:1) with satisfactory
yield. Thus, the primary alcohol 30 was obtained in 85% yield.
With alcohols 27 and 30 in hand, the remaining task was to
complete the aldol reaction to construct the skeleton of malynga-
mides Q and R. As shown in Scheme 7, oxidation of alcohol 27
with IBX provided condensation precursor amido aldehyde 31,
entry
condition
product
% conversion
1
2
TBAF
TBAF:AcOH
(3:1)
TBAF:AcOH
(1:1)
only 29
30:29
(1:1)
30:29
(20:1)
95
92
3
89
which was used in the next step without purification. Condensation
of 31 with the enolate of pyrrolidone (S)-8 in the presence of TiCl4/
i-Pr2NEt afforded a diastereomeric mixture of alcohols 23 in 56%
(brsm 91%) yield for two steps. The diastereomeric mixture of
alcohols 33 was also prepared by using the similar procedure
described above in 57% (brsm 92%) yield for two steps. Both
alcohols 23 and 33 were immediately submitted for oxidation to
give the ꢀ-keto esters 34 and 35 with Dess-Martin periodinane
in CH2Cl2 in 75% and 73% yields, respectively. At this stage, we
are faced with the task of forming the methyl enol ethers of ꢀ-keto
esters 34 and 35. Several conditions including NaH/Me2SO4/
HMPA, K2CO3/Me2SO4/DMSO, and K2CO3/Me2SO4/acetone tested
on compound 34 were all unsuccessful due to decomposition under
basic conditions. So acidic conditions were attempted, and the
desired methyl enol ether was achieved as expected. Thus, treatment
of 34 with trimethyl orthoformate in the presence of a catalytic
amount of sulfuric acid in MeOH gave the desired malyngamide
R (4) in 52% yield with the TBS group removed simultaneously.21
On the other hand, intermediate 36 with only the TBS group
(19) (a) Toumi, M.; Couty, F.; Evano, G. Tetrahedron Lett. 2008, 49, 1175.
(b) Haug, B. E.; Rich, D. H. Org. Lett. 2004, 6, 4783. (c) Burk, M. J.; Allen,
J. G. J. Org. Chem. 1997, 62, 7054.
(20) Bunch, L.; Norrby, P. O.; Frydenvang, K.; Krogsgaard-Larsen, P.;
Madsen, U. Org. Lett. 2001, 3, 433.
(21) Shao, J.; Panek, J. S. Org. Lett. 2004, 6, 3083.
J. Org. Chem. Vol. 74, No. 11, 2009 4153

Chen et al.
SCHEME 7. Preparation of Malyngamides Q and R
removed was also obtained in 36% yield, which could be
transformed to 4 in 50% yield when repeated under the same
conditions. The 4′E- and 2′Z-configuration double bonds in the
amine moiety of 4 were confirmed by NOE experiments. Hence,
selective irradiation of H-5′ of 4 resulted in signal enhancement
of H-8′, while selective irradiation of H-7′ resulted in enhancement
of H-3′a (see the Supporting Information). The spectral data and
optical rotation value of synthetic 4 were in good agreement with
isolated 4.1d Using the similar route for the preparation of
malyngamide R, enol methylation of 35 gave N-Boc protected 37
in 52% yield. Removal of the Boc group by various concentrations
of TFA gave either starting material or decomposed mixture.22
Finally, according to the literature,23 the preparation of malynga-
mide Q (3) was accomplished under the mild Lewis acid Mg-
(ClO4)2 in CH3CN in 78% (brsm 87%) yield. The NMR spectral
data and optical rotation value of synthetic 3 were all consistent
with those reported in the literature.1d In the accumulation of 13
C
NMR spectrum, compound 3 was found to decompose in CDCl3
for 1.5 h, but was stable in the pretreated CDCl3 bypass through a
short column of neutral Al2O3.
The chirality of the stereocenter C-5′′ in the amine portion was
determinated as the S configuration by chiral GCMS analysis of
the amino acid fragment produced from the isolated malyngamide
R (4) by degradative methods. However, the chirality of the
stereocenter C-5′′ in the amine portion of malyngamide Q (3) was
not determined directly, and it was assigned with the same absolute
configuration as that of C-5′′ in malyngamide R (the structures of
isolated malyngamides Q and R were drawn incorrectly as having
the R configuration at the C-5′′ position in the literature).1d To
further confirm the structures of malyngamides Q and R, the other
two diastereoisomers were then synthesized (Scheme 8). Thus,
(22) (a) Connell, R. D.; Rein, T.; Åkermark, B.; Helquist, P. J. Org. Chem.
1988, 53, 3845. (b) Papageorgiou, G.; Ogden, D.; Corrie, J. E. T. J. Org. Chem.
2004, 69, 7228. (c) Farran, D.; Toupet, L.; Martinez, J.; Dewynter, G. Org. Lett.
2007, 9, 4833. (d) Ferreira, P. M. T.; Monteiro, L. S.; Pereira, G.; Ribeiro, L.;
Sacramento, J.; Silva, L. Eur. J. Org. Chem. 2007, 5934.
(23) (a) Stafford, J. A.; Brackeen, M. F.; Karanewsky, D. S.; Valvano, N. L.
Tetrahedron Lett. 1993, 34, 7873. (b) Padwa, A.; Zhang, H. J. J. Org. Chem.
2007, 72, 2570. (c) Burkhart, F.; Hoffmann, M.; Kessler, H. Angew. Chem., Int.
Ed. 1997, 36, 1191.
4154 J. Org. Chem. Vol. 74, No. 11, 2009

Total Synthesis of Malyngamides O, P, Q, and R
SCHEME 8. Preparation of 5′′-epi-3 and 5′′-epi-4
alcohol 9 (840 mg, 1.89 mmol) in dry EtOAc (15 mL) was added
IBX (1.59 g, 5.67 mmol) under an argon atmosphere. The resulting
suspension was refluxed for 8 h. The reaction was cooled to rt and
filtered through a short column with EtOAc as an eluent to give
the crude ketone. To a suspension of Ph3P+CH2ClI- (2.90 g, 6.62
mmol) in dry THF (50 mL) was added n-BuLi (1.89 mL, 2.5 M in
hexane, 4.73 mmol) at -78 °C. The mixture was stirred at this
temperature for 1 h and allowed to warm to -30 °C slowly. The
resulting red solution was recooled to -78 °C, and the above ketone
was added in dry THF (5 mL) dropwise. After an additional 2 h,
the reaction mixture was warmed to -30 °C and stirred for 1 h,
and then quenched by the addition of saturated NH4Cl solution (40
mL) and extracted with Et2O (4 × 35 mL). The organic extracts
were dried over Na2SO4, filtered, and concentrated in vacuo. Flash
chromatography of the residue over silica gel (petroleum ether/
EtOAc ) 30:1) afforded compound (Z)-6 (483 mg, 54% yield) as
a colorless oil. IR (KBr) 2933, 1714, 1504, 1169, 1109, 739, 704
cm-1; 1H NMR (CDCl3, 300 MHz) δ 1.11 (s, 9H, 3 × CH3), 1.48
(s, 9H, 3 × CH3), 2.38 (t, J ) 6.2 Hz, 2H, H-3), 3.80 (t, J ) 6.2
Hz, 2H, H-4), 3.93 (d, J ) 5.7 Hz, 2H, H-1), 4.95 (br, 1H, NH),
5.98 (s, 1H, H-5), 7.39-7.48 (m, 6H, 6 × ArH), 7.69-7.72 (m,
4H, 4 × ArH); 13C NMR (CDCl3, 75 MHz) δ 19.0 (C), 26.7 (CH3),
28.2 (CH3), 36.1 (CH2, C-3), 39.5 (CH2, C-1), 62.1 (CH2, C-4),
79.1 (C), 116.2 (CH, C-5), 127.6 (CH), 129.6 (CH), 133.2 (C),
135.4 (CH), 136.9 (C, C-2), 155.8 (C); HRMS (ESI) m/z
C26H37ClNO3Si [M + H]+ calcd 474.2226, found 474.2224.
(5Z)-Methyl 6-(tert-Butoxycarbonylmethylamino)-5-(chloro-
methylene)-3-hydroxyhexanoate (17). To a solution of alcohol 15
(230 mg, 0.92 mmol) in dry EtOAc (8 mL) was added IBX (773
mg, 2.76 mmol) under an argon atmosphere. The resulting
suspension was refluxed for 6 h. The reaction was then cooled to
rt and filtered through a short column with EtOAc as an eluent to
give the crude aldehyde 16. To a solution of LDA (0.46 mL, 2 M
in THF/pentane, 0.92 mmol) in dry THF (1.5 mL) was added a
solution of methyl acetate (7) (68 mg, 0.92 mmol) in THF (1 mL)
dropwise over 6 min under an argon atmosphere at -78 °C. The
mixture was stirred for 40 min at this temperature, followed by the
addition of the crude aldehyde 16 in THF (1 mL) via syringe. After
being stirred for 1 h at -78 °C, the reaction mixture was quenched
by the addition of saturated NH4Cl solution (10 mL) and extracted
with EtOAc (3 × 15 mL). The organic extracts were dried over
Na2SO4, filtered, and concentrated in vacuo. Flash chromatography
of the residue over silica gel (petroleum ether/EtOAc ) 2:1)
afforded ester 17 (169 mg, 57% yield) as a colorless oil. IR (KBr)
3429, 2976, 1737, 1694, 1394, 1252, 1158, 874, 771 cm-1; 1H NMR
(CDCl3, 300 MHz) δ 1.47 (s, 9H, 3 × CH3), 2.19-2.21 (m, 2H,
H-4), 2.44-2.46 (m, 2H, H-2), 2.78 (s, 3H, NCH3), 3.71 (s, 3H,
OCH3), 4.11-4.26 (m, 3H, H-3 and H-6), 6.13 (s, 1H, H-7); 13C
NMR (CDCl3, 75 MHz) δ 28.1 (CH3), 33.5 (NCH3), 39.0 (CH2,
C-4), 41.1 (CH2, C-2), 46.4 (CH2, C-6), 51.6 (OCH3), 65.4/66.4
(CH, C-3), 79.9 (C), 117.7 (CH, C-7), 135.0 (C, C-5), 156.3 (C),
172.3 (C, C-1); HRMS (ESI) m/z C14H24ClNO5Na [M + Na]+ calcd
344.1235, found 344.1241.
beginning with (R)-8, after aldol reaction with compound 31 or
32, followed by Dess-Martin oxidation, enol methylation, and
deprotection of the Boc group, 5′′-epi-4 and 5′′-epi-3 were
accomplished in 21% and 17% yields, respectively, from (R)-8.
The NMR data of 5′′-epi-3 and 5′′-epi-4 were identical to the data
reported for isolated 3 and 4, presumably because the chiral centers
between the fatty acid and amine moieties were too remote from
each other. This deduction was also confirmed by our similar
observations of the spectral data from the total synthesis and correct
absolute configuration of malyngamide U, and the synthesis of
serinol-derived malyngamides and their 1′-epi isomers.1e,4 The
specific rotation values of 5′′-epi-3 and 5′′-epi-4 were found to be
[R]20D -37 (c 0.4, MeOH) and [R]20D -46 (c 1.0, MeOH), which
were different from the reported values of [R]20 +2.1 (c 0.8,
D
MeOH) and [R]20D +2 (c 0.9, MeOH) for isolated 3 and 4.1d The
specific rotation values of the synthetic 3 and 4 were found to be
[R]20D +4.5 (c 1.0, MeOH) and [R]20D +4 (c 1.0, MeOH), which
were consistent with those in isolated 3 and 4. These results further
prove that the absolute configuration of the 5′′ position is S in
malyngamide R, and also confirm the same configuration of
malyngamide Q at the C-5′′ position. It is very interesting to note
that 5′′-epi-3 was more stable than synthetic 3 in CDCl3, as it was
not changed in CDCl3 over a period of 2 h.
Conclusion
In summary, we have achieved the first total synthesis of novel
chlorinated malyngamides O, P, Q, and R via a highly convergent
strategy. The determination of the absolute configuration of C-5′′
in the amine portion of malyngamides Q and R was accomplished
by total synthesis and the synthesis of their diastereomers 5′′-epi-3
and 5′′-epi-4. The key steps involved a Wittig reaction employed
in the preparation of terminal vinyl chlorides with a Z-configuration,
an amidation, and an aldol reaction. 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, F, G, I, K, M, and T is currently in progress and will be
presented in due course.
E,(7S)-N-[(2Z)-(Chloromethylene)-4-oxo-5-(methoxycarbonyl)-
pentanyl]-7-methoxy-N′-methyltetradec-4-enamide [Malyngamide
P (2)].1c To a stirred solution of compound 18 (57 mg, 0.12 mmol)
in CH2Cl2 (4 mL) was added Dess-Martin periodinane (140 mg,
0.30 mmol) at 0 °C. The reaction mixture was stirred for 2.5 h at
this temperature, and the solution was then concentrated in vacuo.
Flash chromatography of the residue over silica gel (petroleum
ether/EtOAc ) 3:1 to 2:1) afforded malyngamide P (2) (39 mg,
71% yield) as a colorless oil. [R]20 -72 (c 0.05, MeOH) [lit.1c
D
[R]20 -75 (c 0.02, MeOH)]; IR (KBr) 2928, 2855, 1742, 1723,
D
1
1644, 1406, 1098, 972, 771 cm-1; H NMR (CDCl3, 300 MHz) δ
0.88 (t, J ) 6.6 Hz, 3H, H-14), 1.27-1.36 (m, 10H, 5 × CH2,
H-9, H-10, H-11, H-12, and H-13), 1.42-1.45 (m, 2H, H-8), 2.19
(t, J ) 5.4 Hz, 2H, H-6), 2.34-2.36 (m, 4H, H-2 and H-3), 2.90/
2.92 (s, 3H, NCH3), 3.15 (t, J ) 6.0 Hz, 1H, H-7), 3.29 (s, 2H,
H-3′), 3.33 (s, 3H, OCH3, H-15), 3.46/3.50 (s, 2H, H-5′), 3.73/
Experimental Section
(2Z)-N-(tert-Butoxycarbonyl)-4-(tert-butyldiphenylsilyloxy)-2-
(chloromethylene)-1-butylamine [(Z)-6]. To a solution of amide
J. Org. Chem. Vol. 74, No. 11, 2009 4155

Chen et al.
3.74 (s, 3H, OCH3), 4.22/4.25 (s, 2H, H-1′), 5.46-5.55 (m, 2H,
H-4 and H-5), 6.10/6.17 (s, 1H, H-7′); 13C NMR (CDCl3, 75 MHz)
δ 14.0 (CH3, C-14), 22.5 (CH2, C-13), 25.2 (CH2, C-9), 27.9 (CH2,
C-3), 29.2 (CH2, C-11), 29.6 (CH2, C-10), 31.7 (CH2, C-12), 33.0
(CH2, C-2), 33.2 (CH2, C-8), 35.1 (NCH3), 36.2 (CH2, C-6), 46.1
(CH2, C-3′), 46.2 (CH2, C-1′), 48.8 (CH2, C-5′), 52.2 (OCH3), 56.4
(OCH3, C-15), 80.6 (CH, C-7), 120.3 (CH, C-7′), 127.0 (CH, C-4),
131.1 (CH, C-5), 131.4 (C, C-2′), 167.4 (C, C-6′), 173.2 (C, C-1),
199.3 (C, C-4′); MS (ESI) m/z 458.4 ([M + H]+).
temperature. Diisopropylethylamine (0.35 mL, 2.13 mmol) was then
added dropwise slowly, and the mixture was stirred at the same
temperature for 2.5 h. Subsequently, a solution of aldehyde 31 in
CH2Cl2 (2 mL) was added dropwise, and the reaction was stirred
at -78 °C for 30 min. The reaction mixture was allowed to warm
to 0 °C slowly and stirred at 0 °C for another 2 h, followed by the
addition of saturated NH4Cl solution (10 mL) at 0 °C. The solution
was then warmed to rt and extracted with CH2Cl2 (3 × 20 mL).
The organic extracts were dried over Na2SO4, filtered, and
concentrated in vacuo. Flash chromatography of the residue over
silica gel (petroleum ether/EtOAc ) 3:1 to 1:1) afforded the
E,(7S)-N-[(2Z,4E)-2-(Chloromethylene)-4-methoxy-5-(methoxy-
carbonyl)-4-pentenyl]-7-methoxy-N′-methyltetradec-4-enamide [Ma-
lyngamide O (1)].1c To a suspension of NaH (3 mg, 55% in mineral
oil, 0.08 mmol) in HMPA (1.2 mL) was added a solution of
compound 2 (19 mg, 0.04 mmol) in HMPA (0.2 mL) via syringe
at 0 °C, then the mixture was stirred until gas evolution ceased.
Dimethyl sulfate (11 mg, 0.09 mmol) was then added. The reaction
was stirred for 30 h at rt, followed by the addition of saturated
NH4Cl solution (8 mL), and extracted with Et2O (3 × 10 mL).
The organic extracts were dried over Na2SO4, filtered, and
concentrated in vacuo. Flash chromatography of the residue over
silica gel (petroleum ether/EtOAc ) 4:1 to 3:1) afforded malyn-
gamide O (1) (10 mg, 53% yield) as a colorless oil. [R]20D -53 (c
0.05, MeOH) [lit.1c [R]20D -55.6 (c 0.018, MeOH)]; IR (KBr) 2927,
2854, 1711, 1649, 1627, 1282, 1141, 824 cm-1; 1H NMR (CDCl3,
300 MHz) δ 0.88 (t, J ) 6.9 Hz, 3H, H-14), 1.21-1.31 (m, 10H,
5 × CH2, H-9, H-10, H-11, H-12, and H-13), 1.38-1.44 (m, 2H,
H-8), 2.19 (t, J ) 5.6 Hz, 2H, H-6), 2.35-2.42 (m, 4H, H-2 and
H-3), 2.85/2.90 (s, 3H, NCH3), 3.15 (t, J ) 5.6 Hz, 1H, H-7), 3.33
(s, 3H, OCH3, H-15), 3.51/3.54 (s, 2H, H-3′), 3.64 (s, 3H, OCH3,
H-8′), 3.66/3.68 (s, 3H, OCH3), 4.18/4.33 (s, 2H, H-1′), 5.10 (s,
1H, H-5′), 5.47-5.53 (m, 2H, H-4 and H-5), 6.07/6.19 (s, 1H, H-7′);
13C NMR (CDCl3, 75 MHz) δ 14.1 (CH3, C-14), 22.7 (CH2, C-13),
25.3 (CH2, C-9), 28.1/28.3 (CH2, C-3), 29.3 (CH2, C-11), 29.7 (CH2,
C-10), 31.8 (CH2, C-12), 33.0/33.9 (NCH3), 33.3 (CH2, C-2), 33.3
(CH2, C-8), 33.9/34.3 (CH2, C-3′), 36.3 (CH2, C-6), 45.2/48.8 (CH2,
C-1′), 50.9/51.1 (OCH3), 55.7 (OCH3, C-8′), 56.5 (OCH3, C-15),
80.8 (CH, C-7), 92.1 (CH, C-5′), 117.7/118.8 (CH, C-7′), 127.0
(CH, C-4), 131.3/131.4 (CH, C-5), 133.6/134.5 (C, C-2′), 167.6
(C, C-6′), 171.5/171.6 (C, C-4′), 172.8 (C, C-1); MS (ESI) m/z
472.4 ([M + H]+).
secondary alcohol 23 (325 mg, 56% yield) as a colorless oil. [R]20
D
+34 (c 1.0, CHCl3); IR (KBr) 3405, 2929, 1729, 1632, 1321, 1114
1
cm-1; H NMR (CDCl3, 400 MHz) δ -0.09 (s, 3H, CH3), -0.07
(s, 3H, CH3), 0.76 (s, 9H, 3 × CH3), 0.83 (t, J ) 6.4 Hz, 3H,
H-14), 1.21-1.25 (m, 10H, 5 × CH2, H-9, H-10, H-11, H-12, and
H-13), 1.38-1.40 (m, 2H, H-8), 2.13-2.16 (m, 4H, 2 × CH2),
2.30-2.36 (m, 4H, 2 × CH2), 2.81-2.88 (m, 4H, NCH3 and H-5′a),
3.11 (t, J ) 5.6 Hz, 1H, H-7), 3.18 (dd, J ) 17.6 and 3.2 Hz, 1H,
H-5′b), 3.28 (s, 3H, OCH3, H-15), 3.81-3.87 (m, 4H, H-4′ and
H-7′′), 4.19-4.29 (m, 3H, H-1′ and H-6′′a), 4.39 (d, J ) 14.4 Hz,
1H, H-6′′b), 4.50-4.53 (m, 1H, H-5′′), 5.07/5.05 (s, 1H, H-3′′),
5.41-5.52 (m, 2H, H-4 and H-5), 6.16 (s, 1H, H-7′); 13C NMR
(CDCl3, 100 MHz) δ -5.8 (CH3), -5.7 (CH3), 14.0 (CH3, C-14),
17.9 (C), 22.5 (CH2), 25.2 (CH2), 25.5 (CH3), 28.1 (CH2), 29.2
(CH2), 29.7 (CH2), 31.7 (CH2), 33.2 (CH2), 33.3 (CH2), 34.4
(NCH3), 36.3 (CH2), 39.1 (CH2, C-3′), 43.7 (CH2, C-5′), 45.1 (CH2,
C-1′), 56.4 (OCH3, C-15), 58.6 (CH and CH2, C-5′′ and C-6′′),
61.1 (OCH3, C-7′′), 65.9 (CH, C-4′), 80.7 (CH, C-7), 94.8 (CH,
C-3′′), 118.0 (CH, C-7′), 127.1 (CH, C-5), 131.1 (CH, C-4), 135.0
(C, C-2′), 170.4 (C, C-4′′), 171.7 (C, C-2′′), 172.9 (C, C-1), 177.2
(C, C-6′); HRMS (ESI) m/z C35H62ClN2O7Si [M + H]+ calcd
685.4009, found 685.4020. (A mixture of diastereomeric alcohol
23, which could be used in the next step for oxidation directly,
could be separated by flash chromatography. The large amount of
isomers was used for spectral determination. Though absolute
configuration of compound 23 was not comfirmed. The same
phenomenon was found in compound 5′′-epi-23.)
According to the preceding procedure (the second method), 27
(407 mg, 1.05 mmol) and (R)-8 (285 mg, 0.95 mmol) afforded
alcohols 5′′-epi-23 (364 mg, 56% yield) as a colorless oil. [R]20
E,(7S)-N-{(2Z)-(Chloromethylene)-4-hydroxy-6-oxo-[(5S)-(tert-
butyldimethylsilyloxymethyl)-4-methoxy-2-oxo-1H-pyrrol-1(5H)-
yl]hexyl}-7-methoxy-N′-methyltetradec-4-enamide and E,(7S)-
N-{(2Z)-(Chloromethylene)-4-hydroxy-6-oxo-[(5R)-(tert-
butyldimethylsilyloxymethyl)-4-methoxy-2-oxo-1H-pyrrol-1(5H)-
yl]hexyl}-7-methoxy-N′-methyltetradec-4-enamide (23 and 5′′-
epi-23). To a stirred solution of compound 22 (35 mg, 0.07 mmol)
in CH2Cl2 (3 mL) was added TFA (1 mL) at 0 °C, and the mixture
was stirred at this temperature for 1 h, followed by the addition of
saturated NaHCO3 solution (6 mL), and extracted with CH2Cl2 (3
× 6 mL). The organic extracts were dried over Na2SO4, filtered,
and concentrated to afford the crude methylamine as a pale yellow
oil. To a stirred solution of the methylamine in CH2Cl2 (2 mL)
was added acid 5 (18 mg, 0.07 mmol) in CH2Cl2 (1 mL), DCC (17
mg, 0.08 mmol), HOBt (11 mg, 0.08 mmol), and NMM (8 mg,
0.08 mmol) at 0 °C. The reaction mixture was allowed to warm to
rt over 1 h, and the stirring was continued for 8 h, followed by
concentration in vacuo. Flash chromatography of the residue over
silica gel (petroleum ether/EtOAc ) 1:1) afforded alcohol 23 (3
mg, 6% yield) as a colorless oil. Compound 23 had also been
prepared by the below method. Then, to a solution of compound
27 (364 mg, 0.94 mmol) in dry EtOAc (15 mL) was added IBX
(790 mg, 2.82 mmol) under argon atmosphere. The resulting
suspension was reflux for 8 h. The reaction was then cooled to rt
and filtered through a short column with EtOAc as an eluent to
give the crude aldehyde 31. To a stirred solution of (S)-8 (255 mg,
0.85 mmol) in dry CH2Cl2 (4.5 mL) was added TiCl4 (0.10 mL,
0.94 mmol) dropwise in CH2Cl2 (1 mL) under argon atmosphere
at -78 °C, and the mixture was stirred for 10 min at this
D
-38 (c 1.0, CHCl3); IR (KBr) 3404, 2928, 2855, 1631, 1321, 1114,
835, 778 cm-1; 1H NMR (CDCl3, 300 MHz) δ -0.09 (s, 3H, CH3),
-0.08 (s, 3H, CH3), 0.76 (s, 9H, 3 × CH3), 0.83 (t, J ) 6.3 Hz,
3H, H-14), 1.20-1.24 (m, 10H, 5 × CH2, H-9, H-10, H-11, H-12,
and H-13), 1.36-1.40 (m, 2H, H-8), 2.12-2.14 (m, 4H, 2 × CH2),
2.31-2.34 (m, 4H, 2 × CH2), 2.83-2.87 (m, 4H, NCH3 and H-5′a),
3.11 (t, J ) 6.0 Hz, 1H, H-7), 3.18 (dd, J ) 17.7 and 3.6 Hz, 1H,
H-5′b), 3.28 (s, 3H, OCH3, H-15), 3.81-3.85 (m, 4H, H-4′ and
H-7′′), 4.19-4.24 (m, 3H, H-1′ and H-6′′a), 4.36-4.41 (m, 1H,
H-6′′b), 4.50-4.53 (m, 1H, H-5′′), 5.05/5.10 (s, 1H, H-3′′),
5.44-5.46 (m, 2H, H-4 and H-5), 6.16 (s, 1H, H-7′); 13C NMR
(CDCl3, 75 MHz) δ -5.8 (CH3), -5.7 (CH3), 14.0 (CH3, C-14),
17.9 (C), 22.5 (CH2), 25.2 (CH2), 25.5 (CH3), 28.0 (CH2), 29.2
(CH2), 29.6 (CH2), 31.7 (CH2), 33.3 (2 × CH2), 34.4 (NCH3), 36.3
(CH2), 39.1 (CH2), 43.6 (CH2, C-5′), 45.1 (CH2, C-1′), 56.4 (OCH3,
C-15), 58.5 (CH, C-5′′), 58.6 (CH2, C-6′′), 61.1 (OCH3, C-7′′), 65.8
(CH, C-4′), 80.6 (CH, C-7), 94.8 (CH, C-3′′), 118.0 (CH, C-7′),
127.1 (CH, C-5), 131.1 (CH, C-4), 135.0 (C, C-2′), 170.4 (C, C-4′′),
171.6 (C, C-2′′), 173.0 (C, C-1), 177.2 (C, C-6′); HRMS (ESI) m/z
C35H62ClN2O7Si [M + H]+ calcd 685.4009, found 685.4015.
E,(7S)-N-{(2Z,4E)-2-(Chloromethylene)-4-methoxy-6-oxo-[(5S)-
hydroxymethyl-4-methoxy-2-oxo-1H-pyrrol-1(5H)-yl]-4-hexenyl}-
7-methoxy-N′-methyltetradec-4-enamide and E,(7S)-N-{(2Z,4E)-
2-(Chloromethylene)-4-methoxy-6-oxo-[(5R)-hydroxymethyl-4-
methoxy-2-oxo-1H-pyrrol-1(5H)-yl]-4-hexenyl}-7-methoxy-N′-
methyltetradec-4-enamide [Malyngamide R (4)1d and 5′′-epi-4]. To
a stirred solution of ꢀ-keto ester 34 (35 mg, 0.05 mmol) in MeOH
(1.1 mL) was added trimethylorthoformate (0.22 mL, 2.02 mmol)
4156 J. Org. Chem. Vol. 74, No. 11, 2009

Total Synthesis of Malyngamides O, P, Q, and R
and sulfuric acid (2 mg, 0.02 mmol). The reaction mixture was
stirred for 30 h at rt, followed by the addition of saturated NaHCO3
solution (1 mL), and extracted with EtOAc (3 × 5 mL). The organic
extracts were dried over Na2SO4, filtered, and concentrated in vacuo.
Flash chromatography of the residue over silica gel (petroleum
ether/EtOAc ) 1:2) afforded pure malyngamide R (4) (15 mg, 52%
yield) and ꢀ-keto ester 36 (10 mg, 36% yield) as a colorless oil.
[R]20D +4 (c 1.0, MeOH) [lit.1d [R]20D +2 (c 0.9, MeOH)]; IR (KBr)
3397, 2929, 1718, 1629, 1460, 1389, 1316, 1164, 1075, 976, 776
and H-13), 1.38-1.39 (m, 2H, H-8), 2.13-2.27 (m, 6H, H-2, H-3
and H-6), 3.07-3.12 (m, 2H, H-3′a and H-7), 3.28 (s, 3H, OCH3,
H-15), 3.68 (s, 3H, OCH3, H-8′), 3.80 (dd, J ) 12.0 and 2.4 Hz,
1H, H-6′′a), 3.87 (s, 3H, OCH3, H-7′′), 3.96 (dd, J ) 14.0 and 5.2
Hz, 1H, H-1′a), 4.12 (dd, J ) 14.0 and 6.8 Hz, 1H, H-1′b), 4.18
(d, J ) 13.6 Hz, 1H, H-3′b), 4.36 (dd, J ) 12.0 and 2.4 Hz, 1H,
H-6′′b), 4.59-4.61 (m, 1H, H-5′′), 5.11 (s, 1H, H-3′′), 5.40-5.44
(m, 2H, H-4 and H-5), 5.95 (br, 1H, NH), 6.04 (s, 1H, H-7′), 6.90
(s, 1H, H-5′); 13C NMR (CDCl3, 100 MHz) δ 14.1 (CH3, C-14),
22.6 (CH2, C-12), 25.3 (CH2, C-9), 28.4 (CH2, C-3), 29.3 (CH2,
C-11), 29.7 (CH2, C-10), 31.8 (CH2, C-13), 33.3 (CH2, C-8), 36.2
(CH2, C-2), 36.3 (CH2, C-6), 36.6 (CH2, C-3′), 37.8 (CH2, C-1′),
56.0 (OCH3, C-8′), 56.4 (OCH3, C-15), 58.7 (OCH3, C-7′′), 59.6
(CH2, C-6′′), 62.4 (CH, C-5′′), 80.7 (CH, C-7), 95.1 (CH, C-3′′),
95.4 (CH, C-5′), 118.3 (CH, C-7′), 127.6 (CH, C-5), 130.6 (CH,
C-4), 135.3 (C, C-2′), 165.7 (C, C-6′), 170.8 (C, C-2′′), 171.6 (C,
C-4′), 172.7 (C, C-1), 176.7 (C, C-4′′); HRMS (ESI) m/z
C29H45ClN2O7Na [M + Na]+ calcd 591.2808, found 591.2804.
1
cm-1; H NMR (CDCl3, 400 MHz) δ 0.85 (t, J ) 6.0 Hz, 3H,
H-14), 1.23-1.32 (m, 10H, 5 × CH2, H-9, H-10, H-11, H-12, and
H-13), 1.37-1.40 (m, 2H, H-8), 2.14-2.31 (m, 6H, H-2, H-3 and
H-6), 2.78/2.82 (s, 3H, NCH3), 2.92 (d, J ) 14.8 Hz, 1H, H-3′a),
3.09-3.11 (m, 1H, H-7), 3.29 (s, 3H, OCH3, H-15), 3.65/3.70 (s,
3H, OCH3, H-8′), 3.79 (d, J ) 14.7 Hz, 1H, H-6′′a), 3.86 (s, 3H,
OCH3, H-7′′), 3.97 (d, J ) 13.6 Hz, 1H, H-1′a), 4.31-4.55 (m,
4H, H-3′b, H-1′b, H-5′′, H-6′′b), 5.08/5.10 (s, 1H, H-3′′), 5.41-5.43
(m, 2H, H-4 and H-5), 6.14/6.16 (s, 1H, H-7′), 6.82/6.96 (s, 1H,
H-5′); 13C NMR (CDCl3, 100 MHz) δ 14.1 (CH3, C-14), 22.6 (CH2,
C-12), 25.3 (CH2, C-9), 28.0 (CH2, C-3), 29.3 (CH2, C-10), 29.8
(CH2, C-13), 31.8 (CH2, C-11), 33.4 (CH2, C-2), 33.4 (CH2, C-8),
33.8 (NCH3), 36.4 (CH2, C-3′), 36.7 (CH2, C-6), 44.7 (CH2, C-1′),
55.7 (OCH3, C-8′), 56.5 (OCH3, C-15), 58.6 (OCH3, C-7′′), 59.2
(CH2, C-6′′), 62.5 (CH, C-5′′), 80.8 (CH, C-7), 95.1 (2 × CH, C-5′
and C-3′′), 119.9 (CH, C-7′), 127.4 (CH, C-5), 130.8 (CH, C-4),
133.5 (C, C-2′), 165.3 (C, C-6′), 170.9 (C, C-4′), 170.9 (C, C-2′′),
173.5 (C, C-1), 176.9 (C, C-4′′); HRMS (ESI) m/z C30H48ClN2O7
[M + H]+ calcd 583.3145, found 583.3150. (The data of 13C NMR
spectrum were identified via following ref 1d, as for 5′′-epi-4.)
According to the preceding procedure, 5′′-epi-34 (21 mg, 0.03
mmol) afforded amide 5′′-epi-4 (9 mg, 53% yield) as a pale yellow
oil. [R]20D -46 (c 1.0, MeOH); IR (KBr) 3398, 2929, 1717, 1630,
According to the preceding procedure, 5′′-epi-37 (20 mg, 0.03
mmol) afforded 5′′-epi-3 (13 mg, 76% yield) as a pale yellow oil.
[R]20D -37 (c 0.4, MeOH); IR (KBr) 3315, 2929, 1718, 1631, 1606,
1
1317, 1215, 1162, 1076, 974, 843 cm-1; H NMR (CDCl3, 400
MHz) 0.85 (t, J ) 6.8 Hz, 3H, H-14), 1.22-1.24 (m, 10H, 5 ×
CH2, H-9, H-10, H-11, H-12, and H-13), 1.39-1.40 (m, 2H, H-8),
2.13-2.26 (m, 6H, H-2, H-3, and H-6), 3.08-3.13 (m, 2H, H-3′a
and H-7), 3.28 (s, 3H, OCH3, H-15), 3.69 (s, 3H, OCH3, H-8′),
3.80 (dd, J ) 12.0 and 2.4 Hz, 1H, H-6′′a), 3.87 (s, 3H, OCH3,
H-7′′), 3.97 (dd, J ) 14.0 and 5.2 Hz, 1H, H-1′a), 4.09-4.34 (m,
2H, H-1′b and H-3′b), 4.36 (dd, J ) 12.0 and 2.4 Hz, 1H, H-6′′b),
4.58-4.60 (m, 1H, H-5′′), 5.11 (s, 1H, H-3′′), 5.40-5.44 (m, 2H,
H-4 and H-5), 5.97 (br, 1H, NH), 6.05 (s, 1H, H-7′), 6.89 (s, 1H,
H-5′); 13C NMR (CDCl3, 100 MHz) δ 14.1 (CH3, C-14), 22.6 (CH2,
C-12), 25.3 (CH2, C-9), 28.4 (CH2, C-3), 29.3 (CH2, C-11), 29.7
(CH2, C-10), 31.8 (CH2, C-13), 33.3 (CH2, C-8), 36.3 (CH2, C-2),
36.4 (CH2, C-6), 36.7 (CH2, C-3′), 37.9 (CH2, C-1′), 56.0 (OCH3,
C-8′), 56.4 (OCH3, C-15), 58.7 (OCH3, C-7′′), 59.8 (CH2, C-6′′),
62.5 (CH, C-5′′), 80.7 (CH, C-7), 95.2 (CH, C-3′′), 95.5 (CH, C-5′),
118.4 (CH, C-7′), 127.8 (CH, C-5), 130.6 (CH, C-4), 135.2 (C,
C-2′), 165.7 (C, C-6′), 170.8 (C, C-2′′), 171.6 (C, C-4′), 172.9 (C,
C-1), 176.7 (C, C-4′′); HRMS (ESI) m/z C29H45ClN2O7Na [M +
Na]+ calcd 591.2808, found 591.2801.
1
1389, 1316, 1248, 1212, 1163, 1097, 975, 844 cm-1; H NMR
(CDCl3, 400 MHz) δ 0.86 (t, J ) 6.0 Hz, 3H, H-14), 1.23-1.30
(m, 10H, 5 × CH2, H-9, H-10, H-11, H-12, and H-13), 1.38-1.40
(m, 2H, H-8), 2.14-2.32 (m, 6H, H-2, H-3, and H-6), 2.78/2.83
(s, 3H, NCH3), 2.94 (d, J ) 14.8 Hz, 1H, H-3′a), 3.09-3.12 (m,
1H, H-7), 3.29 (s, 3H, OCH3, H-15), 3.65/3.70 (s, 3H, OCH3, H-8′),
3.79 (d, J ) 12.0 Hz, 1H, H-6′′a), 3.86 (s, 3H, OCH3, H-7′′), 3.98
(d, J ) 13.6 Hz, 1H, H-1′a), 4.30-4.55 (m, 4H, H-3′b, H-1′b, H-5′′,
H-6′′b), 5.09/5.10 (s, 1H, H-3′′), 5.40-5.45 (m, 2H, H-4 and H-5),
6.14/6.16 (s, 1H, H-7′), 6.82/6.96 (s, 1H, H-5′); 13C NMR (CDCl3,
100 MHz) δ 14.1 (CH3, C-14), 22.6 (CH2, C-12), 25.3 (CH2, C-9),
28.1 (CH2, C-3), 29.3 (CH2, C-10), 29.8 (CH2, C-13), 31.8 (CH2,
C-11), 33.4 (CH2, C-2), 33.5 (CH2, C-8), 33.9 (NCH3), 36.4 (CH2,
C-3′), 36.7 (CH2, C-6), 44.7 (CH2, C-1′), 55.7 (OCH3, C-8′), 56.5
(OCH3, C-15), 58.6 (OCH3, C-7′′), 59.3 (CH2, C-6′′), 62.5 (CH,
C-5′′), 80.8 (CH, C-7), 95.1 (CH, C-3′′), 95.2 (CH, C-5′), 119.8
(CH, C-7′), 127.5 (CH, C-5), 130.8 (CH, C-4), 133.6 (C, C-2′),
165.3 (C, C-6′), 170.9 (C, C-4′), 170.9 (C, C-2′′), 173.5 (C, C-1),
176.9 (C, C-4′′); HRMS (ESI) m/z C30H48ClN2O7 [M + H]+ calcd
583.3145, found 583.3148.
Acknowledgment. The authors are grateful to the National
Basic Research Program (973 Program) of China (Grant No.
2007CB108903) and the National Natural Science Foundation of
China (Grant Nos. 20621091 and 20872055) 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.
Supporting Information Available: Experimental procedures;
1
E,(7S)-N-{(2Z,4E)-2-(Chloromethylene)-4-methoxy-6-oxo-[(5S)-
hydroxymethyl-4-methoxy-2-oxo-1H-pyrrol-1(5H)-yl]-4-hexenyl}-
7-methoxytetradec-4-enamide and E,(7S)-N-{(2Z,4E)-2-(Chloro-
methylene)-4-methoxy-6-oxo-[(5R)-hydroxymethyl-4-methoxy-2-
oxo-1H-pyrrol-1(5H)-yl]-4-hexenyl}-7-methoxytetradec-4-enam-
ide [Malyngamide Q (3)1d and 5′′-epi-3]. To a stirred solution of
enol methyl ether 37 (27 mg, 0.04 mmol) in CH3CN (1 mL) was
added Mg(ClO4)2 (4 mg, 0.02 mmol). The reaction mixture was
heated to 50 °C for 10 h, then cooled to rt and diluted with NaHCO3
(5 drops), then the solvent was concentrated in vavuo. Flash
chromatography of the residue over silica gel (petroleum ether/
EtOAc ) 1:4) afforded malyngamide Q (3) (18 mg, 78% yield) as
a colorless oil. [R]20 +4.5 (c 1.0, MeOH) [lit.1d [R]20 +2.1 (c
list of spectral data for other compound; comparison of H and
13C NMR spectral data for malyngamides O and P (isolated 1 and
2, synthetic 1 and 2); 1H NMR spectral data for malyngamides Q
and R (isolated 3 and 4, synthetic 3 and 4) and 5′′-epi-3 and 5′′-
epi-4; 13C NMR spectral data for malyngamides Q and R (isolated
1
3 and 4, synthetic 3 and 4) and 5′′-epi-3 and 5′′-epi-4; H, 13C
NMR, and DEPT 135 spectra of compounds 12, 13, 9, 6, 14, 15,
17, 18, 2, 1, (S)-21, (R)-21, (S)-8, (R)-8, 22, 23, 5′′-epi-23, 24, 26,
27, 28, 29, 30, 33, 5′′-epi-33, 34, 5′′-epi-34, 35, 5′′-epi-35, 4, 4
(NOE), 5′′-epi-4, 37, 5′′-epi-37, 3, and 5′′-epi-3; comparison of
1H and 13C NMR spectra for malyngamides Q and R (isolated 3
and 4, synthetic 3 and 4) and 5′′-epi-3 and 5′′-epi-4. This material
is available free of charge via the Internet at http://pubs.acs.org.
D
D
0.8, MeOH)]; IR (KBr) 3314, 2928, 1718, 1632, 1318, 1214, 1163,
975, 776 cm-1; 1H NMR (CDCl3, 400 MHz) δ 0.85 (t, J ) 6.8 Hz,
3H, H-14), 1.23-1.25 (m, 10H, 5 × CH2, H-9, H-10, H-11, H-12,
JO9003103
J. Org. Chem. Vol. 74, No. 11, 2009 4157