An improved asymmetric synthesis of malyngamide U and its 2′-epimer

Article abstract of DOI:10.1021/jo800876u

(Chemical Equation Presented) An accelerated and improved asymmetric synthesis of malyngamide U (1) and its 2′-epimer (2′-epi-1) was accomplished from readily available n-hexanal, ethanolamine and (R)-(-)-carvone. The key steps involveda Johnson-Claisen rearrangement in the synthesis of an unsaturated carboxylic acid 4 and an aldol reaction in the construction of the skeleton of 1 and 2′-epi-1. There are 13 steps in the synthesis, with a 2.7% overall yield for 1 and a 0.4% yield for 2′-epi-1.

Full text of DOI:10.1021/jo800876u

natural products were scarcely reported. Recently, our group
reported the first total synthesis and revised the correct absolute
configuration of malyngamide U (1),3 which was isolated in
2003 by Gerwick.1b The scarcity of malyngamides from natural
sources has hampered a thorough biological evaluation of these
fascinating molecules. To provide materials for more extensive
biological evaluations, herein we reported an improved and
efficient asymmetric synthesis of malyngamide U (1) and its
2′-epimer from (R)-(-)-carvone using minimal protecting-
group manipulations. This new method greatly shortened the
number of synthetic steps and improved the overall yield of
the target molecule.
An Improved Asymmetric Synthesis of
Malyngamide U and Its 2′-Epimer
Jian-Peng Feng, Zi-Fa Shi, Yang Li, Jun-Tao Zhang,
Xian-Liang Qi, Jie Chen, and Xiao-Ping Cao*
State Key Laboratory of Applied Organic Chemistry and
College of Chemistry and Chemical Engineering, Lanzhou
UniVersity, Lanzhou, 730000, P. R. China
caoxplzu@163.com
ReceiVed April 28, 2008
SCHEME 1. Retrosynthetic Analysis
An accelerated and improved asymmetric synthesis of
malyngamide U (1) and its 2′-epimer (2′-epi-1) was ac-
complished from readily available n-hexanal, ethanolamine
and(R)-(-)-carvone.ThekeystepsinvolvedaJohnson-Claisen
rearrangement in the synthesis of an unsaturated carboxylic
acid 4 and an aldol reaction in the construction of the skeleton
of 1 and 2′-epi-1. There are 13 steps in the synthesis, with
a 2.7% overall yield for 1 and a 0.4% yield for 2′-epi-1.
As showed in retrosynthesis analysis (Scheme 1), the structure
of malyngamide U (1) can be divided into an aldehyde moiety
2 and a cyclohexane part 3. The aldehyde part 2 can be prepared
from ethanolamine and a chiral fatty acid 4. Compound 4 could
be formed stereoselectivity by performing a Johnson-Claisen
rearrangement reaction4 of 5, which in turn could be prepared
by an asymmetric allylation of hexanal.5 The cyclohexane
portion 3 could be derived from (R)-(-)-carvone via functional
transformations. The chirality at C-2′ and C-1′′ positions in the
target molecule could be controlled by conducting an aldol
reaction between components 2 and 3.
The malyngamides are a class of secondary metabolites
isolated from the marine cyanophyte Lyngbya majuscula. Up
to now, 30 different malyngamides have been isolated including
malyngamides A-X, serinol-derived malyngamides, toxic-type
malyngamides (Hermitamides A and B), and isomalyngamides.
These natural products were found to possess a wide range of
biological properties such as antifeedant activity, ichthyotoxicity
and cytotoxicity to marine animals, as well as anti-HIV,
antileukemic, antitumor, antitubercular, and antimalarial activ-
ity.1 Structurally, the malyngamides consist of a fatty acid side
chain containing a 4E double bond and a 7S stereogenic center
connected via an amide linkage to a heavily oxygenated six-
membered ring. In some cases, such as malyngamide X, the
fatty acid moiety is linked via a tripeptide backbone to a
heterocycle.2 A survey on the literature revealed that, apart from
a recent synthesis of malyngamide X, synthetic studies on these
There are a few works reporting the synthesis of acid 4 and
its homologues.2,6 However, the relatively long reaction se-
quence and/or stringent reaction operations,6c and the problem-
(2) (a) Suntornchashwej, S.; Suwanborirux, K.; Koga, K.; Isobe, M. Chem.
Asian J. 2007, 2, 114. (b) Suntornchashwej, S.; Suwanborirux, K.; Isobe, M.
Tetrahedron 2007, 63, 3217.
(3) Li, Y.; Feng, J. P.; Wang, W. H.; Chen, J.; Cao, X. P. J. Org. Chem.
2007, 72, 2344.
(1) (a) Tan, L. T.; Okino, T.; Gerwick, W. H. J. Nat. Prod. 2000, 63, 952.
(b) McPhail, K. L.; Gerwick, W. H. J. Nat. Prod. 2003, 66, 132. Brief overview
of the family of the related malyngamides. For the most recent and, see ref and
references cited therein.
(4) Johnson, W. S.; Werthemann, L.; Bartlett, W. R.; Brocksom, T. J.; Li,
T. T.; Faulkner, D. J.; Petersen, M. R. J. Am. Chem. Soc. 1970, 92, 741.
(5) Hanawa, H.; Hashimoto, T.; Maruoka, K. J. Am. Chem. Soc. 2003, 125,
1708.
10.1021/jo800876u CCC: $40.75
Published on Web 07/26/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 6873–6876 6873

SCHEME 2. Preparation of Fatty Acids
SCHEME 3. Preparation of Ketone 3
atic cis/trans olefin isomerization6a,e are drawbacks for a large-
scale synthesis of the optical pure fatty acid 4. Hence, an
efficient asymmetric synthesis of compound 4 was first sought.
As shown in Scheme 2, the homoallylic alcohol 7a could be
obtained by asymmetric allylation of hexanal 6a (n ) 4) with
allyltributyltin in the presence of a catalytic amount of the
bis{[(R)-binaphthoxy](isopropoxy)titanium} oxide [bis-(R)-
Ti(IV) oxide] in 79% yield (99% ee).5 Alcohol 7a was then
converted to the corresponding methyl ether 8a in 90% yield
by treatment with MeI in the presence of NaH.7 Oxidative
cleavage of the terminal double bond of 8a with ozone followed
by PPh3 workup afforded the corresponding aldehyde,8 which
was immediately treated with vinylmagnesium bromide to yield
a 1:1 diastereomeric mixture (determined by 1H NMR analysis)
of allylic alcohols 9a in 73% yield.9 The alcohols 9a were
subjected to the Johnson-Claisen rearrangement to provide the
γ,δ-unsaturated ethyl ester 10a in 89% yield in exclusive (E)-
stereoselectivity.4 Saponification of the ester 10a with KOH gave
the fatty acid (S)-4 in 93% yield.10 Based on the synthetic route
of 4, the higher homologues, (S)-11 and 12 were also prepared
in 50% and 51% overall yield from 6b and 6c, respectively.
Incidentally, the enantiomeric (R)-11 was also synthesized from
6b using the enantiomeric catalyst bis-(S)-Ti(IV) oxide in 49%
overall yield. The spectral data of the unsaturated acids 4,
(R)-11, (S)-11, and 12 are in good agreement with those reported
in the literature.6g,2,6h
The preparation of the R,ꢀ-unsaturated cyclohexenone 3
began with (R)-(–)-carvone 13 (Scheme 3). Base-catalyzed
epoxidation of (R)-(-)-carvone using hydrogen peroxide led
to the epoxide ketone 14 in 98% yield.11 Reduction of ketone
moiety in compound 14 under Luche’s conditions generated an
epoxy alcohol 15 in 90% yield.12 The hydroxyl group was then
protected as its p-methoxybenzyl (PMB) ether by alkylation of
p-methoxybenzyl bromide13 in the presence of NaH to give
compound 16 in 86% yield.14 In order to transform the
isopropylene group of 16 to a hydroxyl group with retention of
configuration, compound 16 was treated with OsO4 using
4-methylmorpholine N-oxide (NMO) as a cooxidant, followed
by cleavage of the generated diol with NaIO4 to afford ketone
17 in 85% yield. Baeyer-Villiger rearrangement of ketone 17
with m-CPBA in a cosolvent of hexane and EtOAc (hexane/
EtOAc ) 3:1) afforded an acetate 18 in 75% yield based on
recovered starting material (BRSM).15 Removal of acetyl group
in the presence of K2CO3 in methanol generated the secondary
alcohol 19 in 95% yield. Subsequently the alcohol 19 was
protected using allylbromide in the presence of NaH to furnish
(6) (a) Virolleaud, M. A.; Menant, C.; Fenet, B.; Piva, O. Tetrahedron Lett.
2006, 47, 5127. (b) Fryhle, C. B.; Williard, P. G.; Rybak, C. M. Tetrahedron
Lett. 1992, 33, 2327. (c) Mu¨ller, C.; Voss, G.; Gerlach, H. Liebigs Ann. Chem.
1995, 673. (d) Sankaranarayanan, S.; Sharma, A.; Chattopadhyay, S. Tetrahedron:
Asymmetry 1996, 7, 2639. (e) Mesguiche, V.; Valls, R.; Piovetti, L.; Peiffer, G.
Tetrahedron Lett. 1999, 40, 7473. (f) Braddock, D. C.; Matsuno, A. Synlett 2004,
2521. (g) Li, Y.; Chen, J.; Cao, X. P. Synthesis 2006, 320. (h) Chen, J.; Li, Y.;
Cao, X. P. Tetrahedron: Asymmetry 2006, 17, 933.
(11) Hatakeyama, S.; Numata, H.; Osanai, K.; Takano, S. J. Org. Chem.
1989, 54, 3515.
(12) Kirsch, S.; Bach, T. Synthesis 2003, 1827.
(7) Liu, B.; Zhou, W. S. Org. Lett. 2004, 6, 71.
(8) Felzmann, W.; Arion, V. B.; Mieusset, J. L.; Mulzer, J. Org. Lett. 2006,
8, 3849.
(9) Crimmins, M. T.; McDougall, P. J.; Emmitte, K. A. Org. Lett. 2005, 7,
4033.
(13) Burke, S. D.; Hong, J.; Lennox, J. R.; Mongin, A. P. J. Org. Chem.
1998, 63, 6952.
(14) Paquette, L. A.; Chang, J.; Liu, Z. J. Org. Chem. 2004, 69, 6441.
(15) Kabat, M. M.; Garofalo, L. M.; Daniewski, A. R.; Hutchings, S. D.;
Liu, W.; Okabe, M.; Radinov, R.; Zhou, Y. J. Org. Chem. 2001, 66, 6141.
(10) Sonnet, P. E. J. Org. Chem. 1969, 34, 1147.
6874 J. Org. Chem. Vol. 73, No. 17, 2008

SCHEME 4. Completion the Synthesis of 1 and Its 2′-Epimer by Aldol Reaction
the allyl ether 20 in 81% yield.16 The PMB protecting group
was then removed in the presence of DDQ,17 followed by IBX
oxidation18 of the resulting alcohol to provide the corresponding
ketone 22 in 74% yield in two steps. Attempts to reduce the
epoxide 22 by using Zn powder and NaI was unsuccessful.19
After several experimentations, a practical method of reducing
the epoxide based on the work of Adams20 was realized by using
NaI/TFA as the reductant. Thus, the preparation of the optically
pure R,ꢀ-unsaturated cyclohexenone 3 was accomplished in 10
steps and 24% overall yield from (R)-(-)-carvone.
With the acid 4 and R,ꢀ-unsaturated cyclohexenone 3 in hand,
we focused our efforts on the formation of the malyngamide U
skeleton by an aldol reaction (Scheme 4.) Thus, amidation of
acid 4 with ethanolamine in the presence of N-(3-dimethylami-
nopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI) and 1-hy-
droxybenzotriazole (HOBt) produced 23 in 78% yield.21 Oxi-
dation of the primary alcohol 23 with IBX provided the key
intermediate amido-aldehyde 2.18 Aldol condensation of 2 with
the enolate of R,ꢀ-unsaturated cyclohexenone 3 generated in
the presence of LDA in THF at -78 °C afforded the desired
product 24a and its 2′-epimer 24b in a diastereomeric ratio of
4:1. The desired major product 24a could be readily separated
from the minor epimer 24b by column chromatography. The
absolute configuration of C-2′ in compound 24a was confirmed
by a modified method described by Mosher.22 Hence, compound
24a was converted to its (S)- and (R)-MTPA esters. The
chemical shift values of H-1′ and H-1′′ protons were ascertained
for both esters from COSY experiments. The ∆δ () δS - δR)
values (+0.05 ppm for H-1′, +0.68 ppm for NH, and -0.04
ppm for H-1′′) revealed that the absolute configuration of C-2′
was (S) for 24a. At this stage, we were faced with the task of
methylating the ꢀ-hydroxy ketone 24 without promoting epimer-
ization of the C-1′′ stereocenter, retro-aldol cleavage, or
dehydration reactions. Several procedures, including MeI/Ag2O,
various catalyzed diazomethane variants, Meerwein’s salt in the
presence of excess Proton Pronge, methyl triflate and 2,6-di-
tert-butyl-4-methylpyridine were met with limited success.23 It
was ultimately found that treatment 24a and 24b with Ag2O in
neat MeI in the presence of dry CaSO4 smoothly promoted
methylation to give 25a and 25b in 66% yield and 71% yield,
respectively.24 Compound 25a could also be obtained by
Mitsunobu reaction of 24b in 70% yield.25 Finally, removal of
the allyl protecting group with PdCl2 in MeOH/CH2Cl2 ) 3:2
completed the synthesis of malyngamide U (1) and 2′-epi-1.26
The spectral data of 1 were in good agreement with those
reported in literature.3
In summary, an efficient synthesis of malyngamide U (1) and
2′-epi-1 was accomplished in 13 steps in 2.7% and 0.4% overall
yield, respectively. This compared favorably with our previous
reported method in which 18 steps were involved and the target
compound was obtained in only 0.04% overall yield.3 The
preparation of the chiral γ,δ-unsaturated acid 4 was achieved
in 6 steps and 43% overall yield from n-hexanal. The efficient
asymmetric synthesis of malyngamide U (1) and its 2′-epimer
should offer a convenient entry to other structurally related
malyngamides (Figure 1). Further studies on the total synthesis
of these malyngamides are currently underway in our laboratory.
Experimental Section
(4E,7S)-N-{(2S)-[(1R,6R)-6-Allyloxy-3-methyl-2-oxocyclohex-3-
en-1-yl]-2-hydroxyethyl}-7-methoxydodec-4-enamide (24a) and
(4E,7S)-N-{(2R)-[(1R,6R)-6-allyloxy-3-methyl-2-oxocyclohex-3-en-
1-yl]-2-hydroxyethyl}-7-methoxydodec-4-enamide (24b). To a solu-
tion of amide alcohol 23 (180 mg, 0.66 mmol) in dry EtOAc (7
mL) was added IBX (557 mg, 1.99 mmol). The resulting suspension
was immersed in an oil bath set to 80 °C and stirred vigorously
under atmosphere for 7 h. The reaction was cooled to room
temperature and filtered through a medium glass frit. The filter cake
was washed with EtOAc (3 mL), and the filtrate was concentrated
in vacuo. Flash chromatography of the residue over silica gel using
¨
(16) Sezer, S.; Ozdemirhan, D.; S¸ahin, E.; Tanyeli, C. Tetrahedron: Asym-
metry 2006, 17, 2981.
(17) Schmidt, J. P.; Beltra´n-Rodil, S.; Cox, R. J.; McAllister, G. D.; Reid,
M.; Taylor, R. J. K. Org. Lett. 2007, 9, 4041.
(18) More, J. D.; Finney, N. S. Org. Lett. 2002, 4, 3001.
(19) Cane, D. E.; Yang, G.; Coates, R. M.; Pyun, H. J.; Hohn, T. M. J. Org.
Chem. 1992, 57, 3454.
(20) Adams, J.; Lepine-Frenette, C.; Spero, D. M. J. Org. Chem. 1991, 56,
4494.
(21) Nicolaou, K. C.; Chen, D. Y. K.; Huang, X.; Ling, T.; Bella, M.; Snyder,
S. A. J. Am. Chem. Soc. 2004, 126, 12888.
(22) Ohtanoi, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc.
1991, 113, 4092.
(23) Evans, D. A.; Ratz, A. M.; Huff, B. E.; Sheppard, G. S. J. Am. Chem.
Soc. 1995, 117, 3448.
(24) Brummond, K. M.; Hong, S. J. Org. Chem. 2005, 70, 907.
(25) Mitsunonu, O. Synthesis 1981, 1.
(26) Ko¨nig, C. M.; Harms, K.; Koert, U. Org. Lett. 2007, 9, 4777.
J. Org. Chem. Vol. 73, No. 17, 2008 6875

which has the same Rf value as 24a. Fortunately, they could be
separated from each other after methylation. Spectral data for 24b:
[R]20 ) -63 (c 1.0, CHCl3); IR (KBr): 3373, 2922, 2853, 1726,
D
1459, 1379, 1092, 879 cm-1; 1H NMR (CDCl3, 300 MHz) δ 0.89
(t, J ) 6.6 Hz, 3H, CH3, H-12), 1.28-1.36 (m, 6H), 1.40-1.42
(m, 2H), 1.76 (s, 3H, CH3), 2.18-2.21 (m, 2H), 2.27-2.48 (m,
5H), 2.75-2.83 (m, 2H), 3.09-3.18 (m, 2H), 3.32 (s, 3H, OCH3),
3.61-3.68 (m, 1H), 3.97-4.10 (m, 4H, H-7′′, Η-6′′ and H-2′),
5.17 (d, J ) 10.8 Hz, 1H, H-9′′a), 5.26 (d, J ) 16.8 Hz, 1H, H-9′′b),
5.49 (s, 2H, H-4 and H-5), 5.85-5.94 (m, 1H, H-8′′), 6.27 (brs,
1H, NH), 6.65 (s, 1H, H-4′′); 13C NMR (CDCl3, 75 MHz) δ 14.0
(CH3, C-12), 15.7 (CH3), 22.6 (CH2), 24.9 (CH2), 28.5 (CH2), 30.2
(CH2), 31.9 (CH2), 33.2 (CH2), 36.2 (2 × CH2), 43.7 (CH, C-1′),
55.9 (CH, C-1′′), 56.4 (OCH3), 69.9 (CH), 69.9 (CH2, C-7′′), 74.7
(CH), 80.6 (CH, C-7), 117.3 (CH2, C-9′′), 127.7 (CH), 130.5 (CH),
134.5 (CH, C-8′′), 135.7 (C, C-3′′), 142.1 (CH, C-4′′), 174.3 (C,
C-1), 200.4(CO); HRMS (ESI) m/z C25H41NO5Na [M + Na]+ calcd
for 458.2877, found 458.2877.
Acknowledgment. We are grateful to the National Basic
Research Program (973 Program) of China (Grant No.
2007CB108903), and the National Natural Science Foundation
of China (Grant No. 20621091 and 20472025) for the financial
support. We also gratefully acknowledge Professor Hak-Fun
Chow, The Chinese University of Hong Kong, for his helpful
guidance in revising the manuscript.
FIGURE 1. Structures of malyngamide U, V, W, and X.
EtOAc as an eluent yield the crude aldehyde 2. To a solution of
LDA (0.32 mL, 2 M in THF, 0.64 mmol) in THF (5 mL) was
added a solution of the ketone 3 (100 mg, 0.60 mmol) in THF (3
mL) dropwise over 5 min at -78 °C. The mixture was maintained
at this temperature for 45 min, the freshly prepared crude aldehyde
2 in THF (2 mL) was then added. The resulting solution was stirred
for 30 min at -78 °C, then saturated NH4Cl solution was added at
this temperature. The mixture was extracted with EtOAc (4 × 15
mL). The combined organic layers were washed with brine, dried
over MgSO4, filtered, and concentrated in vacuo. Flash chroma-
tography of the residue over silica gel (petroleum/EtOAc ) 3:2)
afforded 24a (84 mg, 32%) and its 2′-epimer 24b (20 mg, 8%).
Pure 24a cannot be obtained due to contamination of aldehyde 2,
Supporting Information Available: Experimental proce-
dures, list of spectral data for other compounds, 1H, 13C NMR,
and DEPT 135 spectra of compounds 3, 4, 9a-c, 10a-c, (R)-
11, (S)-11, 12, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24b, 25a,
25b, 1, 2′-epi-1, (S)- and (R)-Mosher ester of 24a. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO800876U
6876 J. Org. Chem. Vol. 73, No. 17, 2008