Total synthesis and correct absolute configuration of malyngamide U

Article abstract of DOI:10.1021/jo061456n

The enantioselective synthesis of the previously proposed structure of malyngamide U (1) was accomplished in 18 steps from (S)-(+)-carvone. The key steps involved a hydroxymethylation of (S)-(+)-carvone and an asymmetric Henry reaction of aldehyde (+)-5,

Full text of DOI:10.1021/jo061456n

Total Synthesis and Correct Absolute Configuration of
Malyngamide U
Yang Li, Jian-Peng Feng, Wen-Hua Wang, Jie Chen, 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 July 13, 2006
The enantioselective synthesis of the previously proposed structure of malyngamide U (1) was
accomplished in 18 steps from (S)-(+)-carvone. The key steps involved a hydroxymethylation of (S)-
(+)-carvone and an asymmetric Henry reaction of aldehyde (+)-5, as well as condensation with the acid
1
3. The H and 13C NMR data of the synthetic compound 1 were not consistent with the data of the
reported malyngamide U. The C-2′ epimer of compound 1 was therefore synthesized by a similar reaction
sequence. While the NMR data of C-2′ epimer 23 were in full agreement with those of the reported
product, the discrepancy in the specific rotation data suggested the correct structure of malyngamide U
should be structure 2, in which the absolute configuration of the amine part was enantiomeric with that
in compound 23. Then the correct absolute configuration of revised malyngamide U (2) was confirmed
by the similar synthesis from (R)-(-)-carvone.
Introduction
survey of the literature revealed several reports on the synthesis
of the fatty acid portions but a few on their total synthesis.3 To
provide materials for more extensive biological evaluations, we
focused our interest on the synthesis of these malyngamides
and therefore developed a feasible synthetic strategy for them.
Herein we reported the asymmetric synthesis of malyngamide
U (1) from (S)-(+)-carvone (6) and showed that two of the
stereogenic centers on the cyclohexenone ring were incorrectly
assigned in the original literature,1q as well as confirming the
correct absolute configuration of revised malyngamide U (2)
by the similar synthetic route from (R)-(-)-carvone (6).
Although the configuration of the fatty acid portion was
proposed to have a (4E,7S) configuration on the basis of
spectroscopic evidence and biosynthetic considerations,1 the
absolute configurations of the stereogenic centers on the amine
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.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 or a heterocycle and/or with a functional unit
of a vinylic chloride. These natural products were found to
possess a wide range of biological properties such as antifeedant
activity,2 ichthyotoxicity,1g,1l cytotoxicity to marine animals,1h-j
and anti-HIV,1k anti-leukemic, and anti-tumor activity.1p
A
10.1021/jo061456n CCC: $37.00 © 2007 American Chemical Society
Published on Web 03/09/2007
2344 J. Org. Chem. 2007, 72, 2344-2350

Total Synthesis and Configuration of Malyngamide U
FIGURE 1. Structures of malyngamides: reported (1), revised (2), and V, W, H, I, J, and N.
moiety were not secured.1q Hence, the asymmetric synthesis of
malyngamide U (1) and the confirmation of its absolute
configuration should offer a reference point for the synthesis
of other structurally related malyngamides, such as malynga-
mides V, W, H, I, J and N (Figure 1).
SCHEME 1. Retrosynthetic Analysis
Results and Discussion
The structure of malyngamide U (1) consists of two structural
features: a chiral fatty acid portion containing a 4E double bond
and a 7S chiral center and an oxygenated R,â-unsaturated
cyclohexenone moiety, and the two of them are connected by
an amide linkage. A retrosynthetic analysis of 1 suggested the
preparation of a carboxylic acid component 3 and a cyclohexene
component 4 (Scheme 1). The chiral fatty acid 3, (-)-(4E,7S)-
7-methoxydodec-4-enoic acid had been synthesized earlier by
us in eight steps starting from hexanal in 24% overall yield.4
For the other key intermediate 4, the chiral center at C-1′ could
be prepared from an aldehyde (+)-5 by an asymmetric Henry
reaction.5 The sense of chirality at C-1′ and C-6′ in (+)-5 could
be introduced into the cyclohexene ring via the hydroxymethy-
lation of (S)-(+)-carvone 6 and subsequent stereoselective
functional transformations.
The preparation of aldehyde (+)-5 began with (S)-(+)-
carvone (6) (Scheme 2). Thus, (S)-(+)-carvone was hydroxym-
ethylated with LDA and CH2O at -84 °C to afford cyclohex-
enone (+)-7 as the sole isomer in 59% yield (based on 69%
conversion).6 Protection of the hydroxy group of (+)-7 as its
tert-butyldimethylsilyl (TBS) ether gave the corresponding silyl
ether (-)-8 (94%). Direct protection of the ketone function of
(-)-8 proved to be difficult. Hence it was reduced with NaBH4
in the presence of CeCl3‚7H2O to produce a cyclohexenyl
alcohol (+)-9 (89%).7 Stereoselective epoxidation of (+)-9 with
(1) (a) Cardellina, J. H., II; Dalietos, D.; Marner, F. J.; Mynderse, J. S.;
Moore, R. E. Phytochemistry 1978, 17, 2091. (b) Mynderse, J. S.; Moore,
R. E. J. Org. Chem. 1978, 43, 4359. (c) Cardellina, J. H., II; Marner, F. J.;
Moore, R. E. J. Am. Chem. Soc. 1979, 101, 240. (d) Ainslie, R. D.; Barchi,
J. J.; Kuniyoshi, M.; Moore, R. E.; Mynderse, J. S. J. Org. Chem. 1985,
50, 2859. (e) Gerwick, W. H.; Reyes, S.; Alvarado, B. Phytochemistry 1987,
26, 1701. (f) Praud, A.; Valls, R.; Piovetti, L. Banaigs, B. Tetrahedron
Lett. 1993, 34, 5437. (g) Orjala, J.; Nagle, D.; Gerwick, W. H. J. Nat. Prod.
1995, 58, 764. (h) Todd, J. S.; Gerwick, W. H. Tetrahedron Lett. 1995, 36,
7837. (i) Wu, M.; Milligan, K. E.; Gerwick, W. H. Tetrahedron 1997, 53,
15983. (j) Kan, Y.; Fujita, T.; Nagai, H.; Sakamoto, B.; Hokama, Y. J.
Nat. Prod. 1998, 61, 152. (k) Wan, F.; Erickson, K. L. J. Nat. Prod. 1999,
62, 1696. (l) Tan, L. T.; Okino, T.; Gerwick, W. H. J. Nat. Prod. 2000, 63,
952. (m) Milligan, K. E.; Ma´rquez, B.; Williamson, R. T.; Davies-Coleman,
M.; Gerwick, W. H. J. Nat. Prod. 2000, 63, 965. (n) Gallimore, W. A.;
Scheuer, P. J. J. Nat. Prod. 2000, 63, 1422. (o) Kan, Y.; Sakamoto, B.;
Fujita, T.; Nagai, H. J. Nat. Prod. 2000, 63, 1599. (p) Appleton, D. R.;
Sewell, M. A.; Berridge, M. V.; Copp, B. R. J. Nat. Prod. 2002, 65, 630.
(q) McPhail, K. L.; Gerwick, W. H. J. Nat. Prod. 2003, 66, 132. (r) Nogle,
L. M.; Gerwick, W. H. J. Nat. Prod. 2003, 66, 217. (s) Suntornchaswej,
S.; Suwanborirux, K.; Koga, K.; Isobe, M. Chem. Asian J. 2007, 2, 114.
(2) Wylie, C. R.; Paul, V. J. Mar. Ecol. Prog. Ser. 1988, 45, 23.
(3) (a) Fryhle, C. B.; Williard, P. G.; Rybak, C. M. Tetrahedron Lett.
1992, 33, 2327. (b) Mu¨ller, C.; Voss, G.; Gerlach, H. Liebigs Ann. Chem.
1995, 673. (c) Sankaranarayanan, S.; Sharma, A.; Chattopadhyay, S.
Tetrahedron: Asymmetry 1996, 7, 2639. (d) Mesguiche, V.; Valls, R.;
Piovetti, L.; Peiffer, G. Tetrahedron Lett. 1999, 40, 7473. (e) Braddock, D.
C.; Matsuno, A. Synlett 2004, 2521. (f) Suntornchaswej, S.; Suwanborirux,
K.; Isobe, M. Tetrahedron published on the web, doi: 10.1016/
j.tet.2007.01.035.
(4) (a) Li, Y.; Chen, J.; Cao, X.-P. Synthesis 2006, 320. (b) Chen, J.; Li,
Y.; Cao, X.-P. Tetrahedron: Asymmetry 2006, 17, 933.
(5) Evans, D. A.; Seidel, D.; Rueping, M.; Lam, H. W.; Shaw, J. T.;
Downey, C. W. J. Am. Chem. Soc. 2003, 125, 12692.
(6) (a) Trost, B. M.; Krische, M. J. J. Am. Chem. Soc. 1996, 118, 233.
(b) Trost, B. M.; Haffner, C. D.; Jebaratnam, D. J.; Krische, M. J.; Thomas,
A. P. J. Am. Chem. Soc. 1999, 121, 6183.
(7) Luche, J. L. J. Am. Chem. Soc. 1978, 100, 2226.
(8) Prange´, T.; Rodr´ıguez, M. S.; Sua´rez, E. J. Org. Chem. 2003, 68,
4422.
J. Org. Chem, Vol. 72, No. 7, 2007 2345

Li et al.
SCHEME 2. Preparation of Aldehyde (+)-5
in two steps. First, removal of acetyl group in the presence of
K2CO3 in methanol generated the secondary alcohol (+)-15 in
97% yield. Subsequently the alcohol (+)-15 was protected by
use of TBSCl to furnish the bis(TBS) ether (+)-16 in 88% yield.
After several experimentations, selective deprotection of the
primary TBS ether could be realized with n-Bu4NHSO4 and
p-TsOH‚H2O at -20 °C, giving the primary alcohol (+)-17 in
71% yield on the basis of 50% conversion.11 Finally, Swern
oxidation of alcohol (+)-17 generated aldehyde (+)-5 in 95%
yield.12 Hence, compound (+)-5 could be conveniently prepared
in 12% yield in 12 steps from (S)-(+)-carvone in 2.4 g scale.
With the key (+)-aldehyde 5 in hand, the third chiral center
was then introduced by an asymmetric Henry reaction (Scheme
3). For the choice of the chiral catalyst, Evans’ copper acetate-
5
bis(oxazoline) catalyst {Cu[(-)-18]}(OAc)2 was reported to
give high diastereoselectivities and high yields for aliphatic
aldehydes.13 Indeed, compound (+)-5 gave the desired nitroal-
cohol 19a with high diastereoselectivity (60:1) in 68% yield
on the basis of 37% conversion. 19a and (+)-19b could be
separated by careful flash chromatography over silica gel. The
structure of compound 19a was confirmed by NOE experiment
of its derivative 20. Hence, selective irradiation of H-4R of 20
resulted in signal enhancements of H-4 and H-8R, while
selective irradiation of H-4 resulted in signal enhancements of
H-4R and H-8R. Hence the chiral center in compound 19a has
an S absolute configuration at C-1 position.14
In Scheme 4, treatment of compound 19a with MeOTf in
the presence of 2,6-di-tert-butyl-4-methylpyridine (DTBMP)
afforded the methyl ether 4 in 67% yield. Then reduction of
compound 4 with NaBH4 and NiCl2‚6H2O gave the correspond-
ing amine,15 which was not stable and directly condensed with
acid 3 in the presence of DCC, 1-hydroxybenzotriazole (HOBt),
and 4-methylmorpholine (NMM) to afford amide 21 in 83%
yield. Deprotection of the PMB group from 21 followed by
oxidation of the generated allylic alcohol with DDQ furnished
compound 22 in 85% yield. Finally, compound 22 was treated
with TFA to remove the TBS group to give the target compound
tert-butyl hydroperoxide (TBHP) in the presence of VO(acac)2
generated the desired epoxide (+)-10 in 80% yield with benzene
as the solvent.8 As expected, the stereochemistry of the
epoxidation was directed by the free hydroxyl group. Interest-
ingly, the same epoxidation gave a complex mixture of products
when it was conducted in CH2Cl2. The stereochemistry of (+)-
10 was unambiguously established by its X-ray crystal structure
(CCDC no. 603438; see Supporting Information Figure 1).
Subsequent protection of the hydroxyl function of epoxide (+)-
10 as its p-methoxybenzyl (PMB) ether produced compound
(+)-11. In order to transform the isopropylene group in (+)-11
to a hydroxyl functionality with retention of configuration,
compound (+)-11 was treated with OsO4, with 4-methylmor-
pholine N-oxide (NMO) as a cooxidant, followed by cleavage
of the generated diol with NaIO4 to afford ketone (+)-12 in
83% yield for two steps [from (+)-10 to (+)-12]. It should be
noted that the reaction time for the cleavage reaction of the diol
should not be prolonged (<15 min); otherwise many byproducts
were formed. Baeyer-Villiger rearrangement of ketone (+)-
12 with m-CPBA in a cosolvent of hexane and EtOAc (3/1)
afforded acetate (+)-13 in 76% yield.9 After that, the epoxide
functionality in compound (+)-13 was removed by use of Zn
powder and NaI to reinstall the CdC bond to give compound
(+)-14 in 86% yield.10 The acetyl group in compound (+)-14
was then converted into the corresponding TBS ether (+)-16
1
1 in 75% yield. However, both the H and 13C NMR data of
synthetic 1, especially the 13C NMR chemical shift value of
the C-2′ atom, disagreed with the reported data for isolated
malyngamide U.16 As the absolute configuration of compound
1 had been confirmed by the crystal structure of compound (+)-
10 and the NOE experiments of compound 20, our initial
speculation was that the structure of malyngamide U should be
23, with the absolute configuration at the C-2′ chiral center being
opposite to that of compound 1 (i.e., R instead of S). To prove
the correct structure of malyngamide U, the synthesis of
compound 23 was thus pursued.
On the basis of the synthesis of compound 4, compound 23
was prepared by similar procedures (Scheme 4). By use of the
enantiomeric copper acetate-bis(oxazoline) catalyst {Cu[(+)-
18]}(OAc)2, (+)-19b was obtained in 66% yield on the basis
of 58% conversion [ratio of (+)-19b/19a ) 26/1]. Methylation
of (+)-19b gave compound (+)-24, which was then condensed
(10) Cane, D. E.; Yang, G.; Coates, R. M.; Pyun, H. J.; Hohn, T. M. J.
Org. Chem. 1992, 57, 3454.
(11) Evans, D. A.; Starr, J. T. J. Am. Chem. Soc. 2003, 125, 13531.
(12) Huang, S. L.; Omura, K.; Swern, D. J. Org. Chem. 1976, 41, 3329.
(13) Paintner, F. F.; Allmendinger, L.; Bauschke, G.; Klemann, P. Org.
Lett. 2005, 7, 1423.
(14) Paquette, L. A.; Chang, J.; Liu, Z. J. Org. Chem. 2004, 69, 6441.
(15) Corey, E. J.; Zhang, F. Y. Angew. Chem., Int. Ed. 1999, 38, 1931.
(16) See the Supporting Information.
(9) 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.
2346 J. Org. Chem., Vol. 72, No. 7, 2007

Total Synthesis and Configuration of Malyngamide U
SCHEME 3. Preparation of Nitroalcohols 19a and (+)-19b and Compound 20
SCHEME 4. Preparation of Compounds 1 and 23
SCHEME 5. Preparation of Compound 2
with the acid 3 to furnish 25. Removal of the PMB protective
group followed by oxidation gave the TBS-protected compound
26, and subsequent deprotection of the TBS moiety afforded
compound 23.
CHCl3). As the acid portion of malyngamide U had been
determined to be (-)-(4E,7S)-7-methoxydodec-4-enoic acid
from biosynthetic considerations,1 the only possible explanation
was that the opposite configuration of the amine portion of the
isolated malyngamide U was enantiomeric with the amine part
of compound 23. Hence the correct structure of malyngamide
U should be structure 2 (Figure 1 and Scheme 5). The chiral
centers between the fatty acid part and the amine part were too
remote from each other, and hence one would expect compounds
23 and 2 would have identical 1H and 13C NMR spectral
features. This deduction was further confirmed by our similar
observations of the spectral data of serinol-derived malynga-
mides and their 1′-epi isomers4 and the total synthesis of
compound 2. Thus, the key intermediate (-)-24 was obtained
from (R)-(-)-carvone (6) and {Cu[(-)-18]}(OAc)2 was used
as catalyst for asymmetric Henry reaction in 13 steps in 0.4%
yield (Scheme 5). After amidation and deprotection, compound
2 was accomplished in 10% yield from (-)-24. The NMR data
of synthetic 2 were identical with the data reported for the
isolated malyngamide U. The specific rotation of 2 was found
to be [R]D20 -12 (c 0.20, CHCl3), which is consistent with the
In the synthetic procedure for 23, it was very interesting to
find that 25 was treated with DDQ to give only the product of
deprotected PMB group by TLC monitoring in 10 min under
the same conditions as described for preparation of 22. However,
compound 26 was accomplished by adding 6 equiv of DDQ in
24 h in 80% yield. This result should be explained by the
different steric factors17 of the generated allylic alcohols from
21 and 25. Thus we can imagine that if an enantiomeric catalyst
{Cu[(-)-18]}(OAc)2 or {Cu[(+)-18]}(OAc)2 is not used, com-
pounds 1 and 23 may be synthesized, respectively, because 22
and the allylic alcohol generated from 25 can be separated easily.
The 1H and 13C NMR data of synthetic malyngamide U (23)
were in complete agreement with the data reported for the
isolated malyngamide U (1). However, the specific rotation of
compound 23 was found to be [R]D14 +6 (c 0.35, CHCl3), which
was different from the reported value of [R]D18 -15.8 (c 0.12,
18
(17) Wang, W.; Li, T.; Attardo, G. J. Org. Chem. 1997, 62, 6598.
reported value of [R]D -15.8 (c 0.12, CHCl3). These results
J. Org. Chem, Vol. 72, No. 7, 2007 2347

Li et al.
(+)-9 (18.86 g, 63.60 mmol) in dry PhH (100 mL) was added TBHP
(36.34 mL, 2.63 M in toluene), followed by addition of VO(acac)2
(337 mg, 1.27 mmol) at 0 °C. The stirring was continued for 2 h
at rt, and then the reaction mixture was poured into 2% NaHSO3
solution (50 mL) and extracted with EtOAc (3 × 80 mL). The
organic extracts were dried (MgSO4), filtered, and concentrated in
vacuo. Flash chromatography of the residue over silica gel
(petroleum ether/EtOAc ) 15:1) afforded epoxide (+)-10 as a white
solid (15.90 g, 80% yield): [R]25D ) +50 (c 1.0, CHCl3); mp 65-
showed that the correct absolute configuration of malyngamide
U should be 2.
Conclusion
The enantioselective total synthesis of the previously proposed
structure of malyngamide U (1) was accomplished in 18 steps
in 3% yield. The synthetic transformation utilized relatively
inexpensive (S)-(+)-carvone as the starting material. The
stereochemistry of the amine part were secured by a hydroxym-
ethylation of (S)-(-)-carvone and an asymmetric Henry reaction
of aldehyde (+)-5. It was found that the 1H and 13C NMR data
of the synthesized product 1 were different from those reported
in the literature. Synthesis of the C-2′ epimer of compound 1
(i.e., compound 23) was then carried out, and although the NMR
spectroscopic data of compound 23 agreed well with those of
the isolated compound, specific rotation measurement suggested
that malyngamide U should have a structure of compound 2
and then its correct absolute configuration was confirmed by
further synthesis from (R)-(+)-carvone (6). The synthesis of
the structurally related malyngamides V and W, as well as the
malyngamides containing a heterocycle and/or with a vinylic
chloride functionality, such as A, B, M, O, P, Q, and R, is also
underway.
1
68 °C; IR (neat) 3504, 2929, 1251, 1092, 838 cm-1; H NMR
(CDCl3, 300 MHz) δ 0.01 (s, 6H, 2 × CH3), 0.85 (s, 9H, 3 ×
CH3), 1.36-1.46 (m, 1H), 1.41 (s, 3H, CH3), 1.59 (s, 3H, CH3),
1.71-1.81 (m, 1H), 1.96-2.14 (m, 2H), 2.31 (d, J ) 8.7 Hz, 1H,
OH), 3.18-3.20 (m, 1H, H-2), 3.39 (dd, J ) 9.6 and 3.9 Hz, 1H,
H-3′a), 3.55 (t, J ) 9.6 Hz, 1H, H-6), 4.09 (dd, J ) 9.6 and 3.9
Hz, 1H, H-3′b), 4.69 (s, 2H, H-2′); 13C NMR (CDCl3, 75 MHz) δ
-5.6 (CH3), -5.5 (CH3), 18.2 (CH3 and C), 22.2 (CH3), 25.9 (3 ×
CH3), 31.0 (CH2, C-5), 34.3 (CH), 43.4 (CH), 60.1 (C, C-1), 61.4
(CH2, C-3′), 62.1 (CH), 67.6 (CH), 112.9 (CH2, C-2′), 144.9 (C,
C-1′); HRMS (ESI) m/z [M + Na]+ calcd for C17H32NaO3Si
335.2013, found 335.2018.
According to the preceding procedure, (-)-9 (19.81 g, 66.88
20
mmol) afforded (-)-10 as a waxy solid (16.33 g, 78%). [R]D
)
-48 (c 1.0, CHCl3); 1H and 13C NMR data for (-)-10 are identical
with those for (+)-10; LRMS (ESI) m/z [M + H]+ found 313.0.
(1S,3S,4R,5R,6S)/(1R,3R,4S,5S,6R)-4-[(1,1-Dimethylethyl)dim-
ethylsilyoxymethyl]-5-(4-methoxybenzyloxy)-6-methyl-7-
oxabicyclo[4.1.0]heptan-3-yl Acetate [(+)-13 and (-)-13]. To a
stirred solution of (+)-12 (14.81 g, 34.07 mmol) in hexane and
EtOAc (120 mL, hexane/EtOAc ) 3:1) was added m-CPBA (50%)
(23.55 g, 68.23 mmol) in three portions carefully. The stirring was
continued at rt for 3 days. Then the mixture was diluted with EtOAc
and washed with saturated Na2SO3 solution (3 × 100 mL). The
organic layers were dried (MgSO4), filtered, and concentrated in
vacuo. Flash chromatography of the residue over silica gel
(petroleum ether/EtOAc ) 10:1) afforded acetate (+)-13 as a pale
yellow oil (11.67 g, 76%): [R]D22 ) +5 (c 1.0, CHCl3); IR (neat)
Experimental Section
(5S,6S)/(5R,6R)-6-(Hydroxymethyl)-2-methyl-5-(1-methylethe-
nyl)-2-cyclohexen-1-one [(+)-7 and (-)-7]. To a 1 L, three-necked
round-bottomed flask equipped with an argon inlet and outlet was
added a solution of (S)-(+)-carvone (6) (29.24 g, 194.65 mmol) in
THF (500 mL). LDA (107.21 mL, 2 M in THF) was added to the
stirred solution via syringe over a period of 2 h at -84 °C [N2
(l)/EtOAc] and the stirring was continued for another 1 h. Then a
paraformaldehyde depolymerization apparatus was attached to the
reaction vessel. The argon inlet was placed on the flask containing
paraformaldehyde (61.50 g, 2.05 mol) and a brisk flow of argon
was maintained. It was noticed that the temperature of the oil bath
for depolymerization should be below 190 °C and the incoming
argon should bubble well below the surface of the solution in the
reaction vessel. Once all the paraformaldehyde had cracked, the
depolymerization apparatus was removed and the reaction was
allowed to warm to rt, followed by quenching with saturated NH4-
Cl solution. The reaction mixture was extracted with EtOAc (3 ×
300 mL) and the organic extracts were washed with H2SO4 solution
(0.5 M, 500 mL) and brine (500 mL), dried (MgSO4), filtered, and
concentrated in vacuo. Flash chromatography of the residue over
silica gel (petroleum ether/EtOAc ) 20:1) afforded cyclohexenone
(+)-7 as a pale yellow oil (14.28 g, 59% yield on the basis of 69%
1
2930, 1737, 1513, 1249, 1085, 839 cm-1; H NMR (CDCl3, 300
MHz) δ 0.04 (s, 6H, 2 × CH3), 0.89 (s, 9H, 3 × CH3), 1.34 (s,
3H, CH3), 1.91 (dt, J ) 15.9 and 3.6 Hz, 1H, H-2a), 2.01 (s, 3H,
COCH3), 2.27-2.37 (m, 2H, H-2b and H-4), 3.01 (d, J ) 4.2 Hz,
1H, H-5), 3.70-3.83 (m, 2H, H-1 and H-1′a), 3.81 (s, 3H, OCH3)
3.99 (d, J ) 6.0 Hz, 1H, H-1′b), 4.51 (d, J ) 11.1 Hz, 1H, ArCH-
a), 4.65 (d, J ) 11.1 Hz, 1H, ArCH-b), 5.14-5.19 (m, 1H, H-3),
6.89 (d, J ) 8.7 Hz, 2H, 2 × ArH), 7.31 (d, J ) 8.7 Hz, 2H, 2 ×
ArH); 13C NMR (CDCl3, 75 MHz) δ -5.4 (2 × CH3), 18.2 (C),
20.8 (CH3), 21.3 (CH3), 25.9 (3 × CH3), 27.5 (CH2, C-2), 43.2
(CH, C-4), 55.2 (OCH3), 58.6 (CH), 58.6 (C, C-1), 59.1 (CH2, C-1′),
69.7 (CH), 71.5 (ArCH2), 74.9 (CH), 113.7 (2 × CH), 129.6 (2 ×
CH), 130.1 (C), 159.2 (C), 170.0 (CO); HRMS (ESI) m/z [M +
Na]+ calcd for C24H38NaO6Si 473.2330, found 473.2327.
25
conversion): [R]D ) +17 (c 1.0, CHCl3); IR (neat) 3469, 2923,
According to the preceding procedure, (-)-12 (17.96 g, 41.36
1662, 1373, 1047, 897 cm-1; 1H NMR (CDCl3, 300 MHz) δ 1.74
(s, 3H, CH3), 1.78 (t, J ) 1.2 Hz, 3H, CH3), 2.30 (dt, J ) 18.6 and
4.8 Hz, 1H, H-4a), 2.44-2.54 (m, 2H, H-4b and H-5), 2.66-2.76
(m, 1H, H-6), 3.18 (br s, 1H, OH), 3.64-3.77 (m, 2H, H-3′), 4.86
(s, 2H, H-2′), 6.77-6.79 (m, 1H, H-3); 13C NMR (CDCl3, 75 MHz)
δ 15.6 (CH3), 18.0 (CH3), 31.1 (CH2, C-4), 45.6 (CH, C-5), 50.2
(CH, C-6), 61.0 (CH2, C-3′), 113.8 (CH2, C-2′), 135.0 (C, C-2),
144.4 (C, C-1′), 145.2 (CH, C-3), 203.1 (C, C-1); HRMS (ESI)
m/z [M + Na]+ calcd for C11H16NaO2 203.1043, found 203.1037.
According to the preceding procedure, (R)-(-)-carvone (6) (30.00
g, 199.84 mmol) afforded (-)-7 as a pale yellow oil (16.85 g, 47%).
[R]D20 ) -17 (c 1.0, CHCl3); 1H and 13C NMR data for (-)-7 are
identical with those for (+)-7; LRMS (ESI) m/z [M + H]+ found
181.0.
20
mmol) afforded (-)-13 as a pale yellow oil (13.59 g, 73%). [R]D
) -13 (c 1.0, CHCl3); 1H and 13C NMR data for (-)-13 are
identical with those for (+)-13; LRMS (ESI) m/z [M + H]+ found
451.0.
[(1S,2R,6S)/(1R,2S,6R)-6-(1,1-Dimethylethyl)dimethylsilyoxy-
2-(4-methoxybenzyloxy)-3-methylcyclohex-3-en-1-yl]carbalde-
hyde [(+)-5 and (-)-5]. To a stirred solution of (COCl)2
(0.83 mL, 9.68 mmol) in CH2Cl2 (5 mL) was added a solution of
DMSO (1.39 mL, 19.42 mmol) at -84 °C [N2 (l)/EtOAc] in CH2-
Cl2 (5 mL). After 5 min of stirring, a solution of (+)-17 (2.53 g,
6.44 mmol) in CH2Cl2 (10 mL) was added and the stirring was
continued at this temperature for 15 min. Then Et3N (4.51 mL,
32.42 mmol) was added and the reaction was allowed to warm to
rt in 1 h, followed by quenching with saturated NH4Cl solution.
The reaction mixture was extracted with CH2Cl2 (3 × 30 mL), and
the organic extracts were dried (MgSO4), filtered, and concentrated
in vacuo. Flash chromatography of the residue over silica gel
(1R,2R,3S,4S,6S)/(1S,2S,3R,4R,6R)-3-(1,1-Dimethylethyl)dim-
ethylsilyoxymethyl-1-methyl-4-(1-methylethenyl)-7-oxa-bicyclo-
[4.1.0]heptan-2-ol [(+)-10 and (-)-10]. To a stirred solution of
2348 J. Org. Chem., Vol. 72, No. 7, 2007

Total Synthesis and Configuration of Malyngamide U
(petroleum ether/EtOAc ) 30:1) afforded aldehyde (+)-5 as a pale
yellow oil (2.40 g, 95% yield): [R]D13 ) +140 (c 1.0, CHCl3); IR
HRMS (ESI) m/z [M + NH4]+ calcd for C23H41N2O6Si 469.2728,
found 469.2723.
(neat) 2928, 1724, 1251, 1077, 836 cm-1 1H NMR (CDCl3,
;
{(2S,4S,4RR,5S,8RR)-2-(4-Methoxyphenyl)-8-methyl-4-(ni-
tromethyl)-4R,5,6,8R-tetrahydro-4H-benzo[d]1,3dioxin-5yloxy}(1,1-
dimethylethyl)-dimethylsilane (20). To a stirred solution of 19a
(40 mg, 0.09 mmol) in CH2Cl2 (2 mL) was added DDQ (41 mg,
0.18 mmol) at rt, and the stirring was continued for 12 h. The
reaction mixture was concentrated in vacuo, and flash chromatog-
raphy of the residue over silica gel (petroleum ether/EtOAc ) 15:
1) afforded compound 20 (26 mg, 65% yield) as a pale yellow oil:
300 MHz) δ 0.07 (s, 6H, 2 × CH3), 0.85 (s, 9H, 3 × CH3), 1.73
(s, 3H, CH3), 1.93-2.01 (m, 1H, H-5′a), 2.37-2.48 (m, 1H, H-5′b),
2.48-2.54 (m, 1H, H-1′), 3.80 (s, 3H, OCH3), 4.17 (d, J ) 5.2,
1H, H-2′), 4.44-4.57 (m, 3H, ArCH2 and H-6′), 5.39-5.41 (m,
1H, H-4′), 6.86 (dd, J ) 6.9 and 2.1 Hz, 2H, 2 × ArH), 7.23 (dd,
J ) 6.9 and 2.1 Hz, 2H, 2 × ArH), 9.85 (d, J ) 3.3 Hz, 1H, H-1);
13C NMR (CDCl3, 75 MHz) δ -4.9 (CH3), -4.1 (CH3), 17.9 (C),
20.6 (CH3), 25.7 (3 × CH3), 34.4 (CH2, C-5′), 55.2 (OCH3), 58.2
(CH, C-1′), 65.3 (CH), 74.0 (ArCH2), 77.6 (CH), 113.7 (2 × CH),
122.9 (CH, C-4′), 129.7 (2 × CH), 130.0 (C), 133.6 (C), 159.3
(C), 205.4 (C, C-1); HRMS (ESI) m/z [M + Na]+ calcd for C22H34-
NaO4Si 413.2119, found 413.2120.
14
[R]D ) + 35 (c 1.0, CHCl3); IR (neat) 2927, 1557, 1251, 1082,
834 cm-1; 1H NMR (CDCl3, 400 MHz) δ 0.12 (s, 3H, CH3), 0.19
(s, 3H, CH3), 0.94 (s, 9H, 3 × CH3), 1.75 (s, 3H, CH3), 1.74-1.79
(m, 1H, H-4R), 1.99-2.06 (m, 1H, H-6a), 2.45 (dt, J ) 17.2 and
5.2 Hz, 1H, H-6b), 3.80 (s, 3H, OCH3), 4.24 (d, J ) 2.4 Hz, 1H,
H-8R), 4.46-4.53 (m, 1H, H-5), 4.58 (dd, J ) 14 and 1.6 Hz, 1H,
CHNO2), 4.83-4.86 (m, 1H, H-4), 5.04 (dd, J ) 14 and 10 Hz,
1H, CHNO2), 5.51 (dd, J ) 4.6 and 1.6 Hz, 1H, H-7), 5.62 (s, 1H,
H-2), 6.88 (d, J ) 8.8 Hz, 2H, 2 × ArH), 7.38 (d, J ) 8.8 Hz, 2H,
2 × ArH); 13C NMR (CDCl3, 75 MHz) δ -4.0 (CH3), -3.7 (CH3),
18.0 (C), 20.2 (CH3), 26.0 (3 × CH3), 36.6 (CH2, C-6), 43.8
(CH, C-4R), 55.3 (OCH3), 65.3 (CH), 76.7 (CH), 79.2 (CH2NO2),
79.4 (CH), 101.9 (CH, C-2), 113.5 (2 × CH), 124.9 (CH,
C-7), 127.4 (2 × CH), 130.3 (C), 132.0 (C), 160.0 (C); HRMS
(ESI) m/z [M + H]+ calcd for C23H36NO6Si 450.2306, found
450.2303.
According to the preceding procedure, (-)-17 (2.07 g,
5.28 mmol) afforded (-)-5 as a pale yellow oil (1.92 g, 93%):
20
1
[R]D ) -137 (c 1.0, CHCl3); H and 13C NMR data for (-)-5
are identical with those for (+)-5; LRMS (ESI) m/z [M + H]+
found 391.0.
(1S)-[(1S,2R,6S)-6-(1,1-Dimethylethyl)dimethylsilyoxy-2-(4-
methoxybenzyloxy)-3-methylcyclohex-3-en-1-yl]-2-nitroethan-
1-ol and (1R)-[(1S,2R,6S)/(1S)-[(1R,2S,6R)-6-(1,1-dimethylethyl)-
dimethylsilyoxy-2-(4-methoxybenzyloxy)-3-methylcyclohex-3-en-
1-yl]-2-nitroethan-1-ol [19a, (+)-19b, and (-)-19b]. To a stirred
solution of Cu(OAc)2‚H2O (42 mg, 0.21 mmol) in EtOH (2 mL)
was added chiral catalyst (-)-18 (82 mg, 0.23 mmol). After the
mixture was stirred for 1 h at rt, CH3NO2 (2.25 mL, 41.65 mmol)
was added, followed by a solution of (+)-5 (1.63 g, 4.17 mmol) in
EtOH (6 mL). The stirring was continued at rt for 7 days. Then
the reaction mixture was concentrated in vacuo and flash chroma-
tography of the residue over silica gel (petroleum ether/EtOAc )
20:1) afforded nitroethanol 19a (473 mg, 68% yield) and nitroet-
hanol (+)-19b (12 mg, 1% yield) as pale yellow oils (on the basis
of 37% conversion). 19a: [R]D13 ) +138 (c 1.0, CHCl3); IR (neat)
(4E,7S)-N-{(2S)-[(1S,6S)-6-Hydroxy-3-methyl-2-oxocyclohex-
3-en-1-yl]-2-methoxyethyl}-7-methoxydodec-4-enamide, (4E,7S)-
N-{(2R)-[(1S,6S)-6-hydroxy-3-methyl-2-oxocyclohex-3-en-1-yl]-
2-methoxyethyl}-7-methoxydodec-4-enamide, and (4E,7S)-N-
{(2S)-[(1R,6R)-6-hydroxy-3-methyl-2-oxocyclohex-3-en-1-yl]-2-
methoxyethyl}-7-methoxydodec-4-enamide [1, 23, and 2]. To a
stirred solution of 22 (15 mg, 0.03 mmol) in CH2Cl2 (7.5 mL) were
added TFA (0.6 mL) and H2O (0.15 mL) at 0 °C, and the stirring
was continued at this temperature for 10 h. Then the reaction
mixture was poured into brine (8 mL) and extracted with CH2Cl2
(3 × 10 mL). The organic extracts were washed with saturated
NH4Cl solution, dried (MgSO4), filtered, and concentrated in vacuo.
Flash chromatography of the residue over silica gel (petroleum
ether/EtOAc ) 2:1) afforded amide 1 as a pale yellow oil (9 mg,
3436, 2927, 1554, 1251, 1034, 837 cm-1 1H NMR (CDCl3,
;
300 MHz) δ 0.10 (s, 3H, CH3), 0.12 (s, 3H, CH3), 0.90 (s, 9H, 3
× CH3), 1.88 (s, 3H, CH3), 1.85-2.05 (m, 2H, H-1′ and H-5′a),
2.43 (dt, J ) 17.7 and 4.8 Hz, 1H, H-5′b), 3.74 (br s, 1H, OH),
3.81 (s, 3H, OCH3), 4.04 (d, J ) 3.3 Hz, 1H, H-2′), 4.22-4.31
(m, 1H, H-6′), 4.46-4.80 (m, 5H, ArCH2, H-1 and 2), 5.47-5.49
(m, 1H, H-4′), 6.88-6.92 (m, 2H, 2 × ArH), 7.25-7.29 (m, 2H,
2 × ArH); 13C NMR (CDCl3, 75 MHz) δ -4.6 (CH3), -4.1 (CH3),
17.8 (C), 22.4 (CH3), 25.8 (3 × CH3), 36.4 (CH2, C-5′), 48.9 (CH,
C-1′), 55.2 (OCH3), 66.8 (CH), 70.1 (CH), 73.7 (CH2), 79.4 (CH2),
79.6 (CH), 114.0 (2 × CH), 124.6 (CH, C-4′), 129.6 (C), 129.6 (2
× CH), 133.1 (C), 159.5 (C); HRMS (ESI) m/z [M + Na]+ calcd
for C23H37NNaO6Si 474.2282, found 474.2284.
14
75% yield): [R]D ) +4 (c 0.8, CHCl3); IR (neat) 3352, 2924,
1651, 1438, 1369, 1096 cm-1; 1H NMR (CDCl3, 300 MHz) δ 0.89
(t, J ) 6.0 Hz, 3H, H-12), 1.27-1.42 (m, 8H, H-8, H-9, H-10, and
H-11), 1.78 (s, 3H, CH3), 2.18-2.49 (m, 8H, H-2, H-3, H-6, H-1′′,
and H-5′′a), 2.69-2.76 (m, 1H, H-5′′b), 3.01-3.06 (m, 1H), 3.14-
3.18 (m, 1H), 3.31-3.33 (m, 1H), 3.35 (s, 3H, OCH3), 3.40 (s,
3H, OCH3), 3.83-3.87 (m, 1H), 4.09-4.11 (m, 1H), 4.20-4.28
(m, 1H), 5.47-5.49 (m, 2H, H-4 and H-5), 6.20 (br s, 1H, NH),
6.67-6.69 (m, 1H, H-4′′); 13C NMR (CDCl3, 100 MHz) δ 14.4
(CH3, C-12), 16.3 (2′′-CH3), 23.0 (CH2, C-11), 25.4 (CH2, C-9),
29.0 (CH2, C-3), 32.4 (CH2, C-10), 33.7 (CH2, C-8), 35.1 (CH2,
C-5′′), 36.8 (CH2, C-6), 37.0 (CH2, C-2), 41.8 (CH2, C-1′), 54.0
(CH, C-1′′), 56.9 (7-OCH3), 58.9 (2′-OCH3), 68.5 (CH, C-6′′), 78.4
(CH, C-2′), 81.1 (CH, C-7), 128.2 (CH, C-5), 131.1 (CH, C-4),
136.1 (C, C-3′′), 142.4 (CH, C-4′′), 173.7 (C, C-1), 199.0 (C, C-2′′);
HRMS (ESI) m/z [M + H]+ calcd for C23H40NO5 410.2901. found
410.2896.
According to the preceding procedure, with (+)-18 as chiral
catalyst, (+)-5 (909 mg, 2.33 mmol) afforded 19a (10 mg, 3% yield)
and (+)-19b (402 mg, 66%) as pale yellow oils (on the basis of
53% conversion). (+)-19b: [R]D13 ) +94 (c 1.0, CHCl3); IR (neat)
3464, 2929, 1555, 1252, 1035, 837 cm-1 1H NMR (CDCl3,
;
300 MHz) δ 0.10 (s, 3H, CH3), 0.12 (s, 3H, CH3), 0.90 (s, 9H, 3
× CH3), 1.89 (s, 3H, CH3), 1.91-2.05 (m, 2H, H-1′ and H-5′a),
2.38-2.47 (m, 1H, H-5′b), 3.81 (s, 3H, OCH3), 3.91 (d, J ) 8.4
Hz, 1H, OH), 4.11-4.19 (m, 2H, H-2′ and H-6′), 4.46-4.77 (m,
5H, ArCH2, H-1 and H-2), 5.47-5.49 (m, 1H, H-4′), 6.89 (d, J )
8.4 Hz, 2H, 2 × ArH), 7.27 (d, J ) 8.4 Hz, 2H, 2 × ArH); 13C
NMR (CDCl3, 75 MHz) δ -5.0 (CH3), -4.0 (CH3), 17.8 (C), 22.3
(CH3), 25.7 (3 × CH3), 36.0 (CH2, C-5′), 48.4 (CH, C-1′), 55.1
(OCH3), 65.9 (CH), 69.5 (CH), 73.7 (CH2), 78.6 (CH), 80.2 (CH2),
114.0 (2 × CH), 124.3 (CH, C-4′), 129.2 (C), 129.8 (2 × CH),
132.9 (C), 159.5 (C); HRMS (ESI): m/z [M + NH4]+ calcd for
C23H41N2O6Si 469.2728, found 469.2726.
According to a previous procedure, 26 (9 mg, 0.02 mmol)
afforded amide 23 (5 mg, 71% yield) as a pale yellow oil: [R]14
D
) +6 (c 0.35, CHCl3); IR (neat) 3372, 2922, 1654, 1459, 1368,
1
1070 cm-1; H NMR (CDCl3, 400 MHz) δ 0.89 (t, J ) 6.4 Hz,
3H, H-12), 1.28-1.43 (m, 8H, H-8, H-9, H-10, and H-11), 1.76
(s, 3H, CH3), 2.20-2.27 (m, 4H, H-2 and H-6), 2.35-2.41 (m,
3H, H-3 and H-5′′a), 2.73 (dt, J ) 18.0 and 5.2 Hz, 1H, H-5′′b),
2.82 (dd, J ) 10.8 and 3.2 Hz, 1H, H-1′′), 3.15-3.18 (m, 1H, H-7),
3.33 (s, 3H, 7-OCH3), 3.46 (s, 3H, 2′-OCH3), 3.48-3.57 (m, 2H,
H-1′), 4.21-4.29 (m, 2H, H-2′ and 6′′), 5.45-5.48 (m, 2H, H-4
and H-5), 5.91 (br s, 1H, NH), 6.67-6.69 (m, 1H, H-4′′); 13C NMR
(CDCl3, 100 MHz) δ 14.4 (CH3, C-12), 16.1 (2′′-CH3), 23.0 (CH2,
According to the preceding procedure, with (-)-18 as chiral
catalyst, (-)-5 (1.82 g, 4.66 mmol) afforded (-)-19b (483 mg, 23%
yield) as a pale yellow oil. [R]D20 ) -104 (c 1.0, CHCl3); 1H and
13C NMR data for (-)-19b are identical with those for (+)-19b;
J. Org. Chem, Vol. 72, No. 7, 2007 2349

Li et al.
C-11), 25.4 (CH2, C-9), 28.9 (CH2, C-3), 32.4 (CH2, C-10), 33.7
(CH2, C-8), 34.7 (CH2, C-5′′), 36.8 (CH2, C-6), 36.9 (CH2, C-2),
40.0 (CH2, C-1′), 54.8 (CH, C-1′′), 56.9 (7-OCH3), 58.6 (2′-
OCH3),68.9 (CH, C-6′′), 80.3 (CH, C-2′), 81.2 (CH, C-7), 127.9
(CH, C-5), 131.2 (CH, C-4), 136.5 (C, C-3′′), 142.6 (CH, C-4′′),
172.8 (C, C-1), 198.0 (C, C-2′′); HRMS (ESI) m/z [M + H]+ calcd
for C23H40NO5 410.2901, found 410.2908.
68.9 (CH, C-6′′), 80.3 (CH, C-2′), 81.2 (CH, C-7), 127.9 (CH, C-5),
131.2 (CH, C-4), 136.5 (C, C-3′′), 142.6 (CH, C-4′′), 172.8 (C,
C-1), 198.0 (C, C-2′′); HRMS (ESI) m/z [M + H]+ calcd for C23H40-
NO5 410.2901, found 410.2906.
Acknowledgment. This project (20472025 and QT 20621091)
was supported by the National Natural Science Foundation of
China. We gratefully acknowledge Professor Hak-Fun Chow,
The Chinese University of Hong Kong, for his helpful guidance
in the preparation of the manuscript and Professor Da-Qi Wang,
Laocheng University, for X-ray crystallographic analyses.
According to the preceding procedure, 28 (25 mg, 0.05 mmol)
20
afforded amide 2 (4 mg, 20% yield) as a pale yellow oil. [R]D
)
1
-12 (c 0.20, CHCl3); H NMR (CDCl3, 400 MHz) δ 0.89 (t, J )
6.4 Hz, 3H, H-12), 1.27-1.43 (m, 8H, H-8, H-9, H-10, and H-11),
1.76 (s, 3H, CH3), 2.19-2.26 (m, 4H, H-2 and H-6), 2.33-2.41
(m, 3H, H-3 and H-5′′a), 2.73 (dt, J ) 18.0 and 5.2 Hz, 1H, H-5′′b),
2.81 (dd, J ) 10.8 and 3.2 Hz, 1H, H-1′′), 3.14-3.17 (m, 1H, H-7),
3.33 (s, 3H, 7-OCH3), 3.47 (s, 3H, 2′-OCH3), 3.48-3.56 (m, 2H,
H-1′), 4.21-4.28 (m, 2H, H-2′ and H-6′′), 5.47-5.50 (m, 2H, H-4
and H-5), 5.91 (br s, 1H, NH), 6.67-6.68 (m, 1H, H-4′′); 13C NMR
(CDCl3, 100 MHz) δ 14.4 (CH3, C-12), 16.1 (2′′-CH3), 23.0 (CH2,
C-11), 25.4 (CH2, C-9), 28.9 (CH2, C-3), 32.4 (CH2, C-10), 33.7
(CH2, C-8), 34.7 (CH2, C-5′′), 36.8 (CH2, C-6), 36.9 (CH2, C-2),
40.0 (CH2, C-1′), 54.8 (CH, C-1′′), 56.9 (7-OCH3), 58.6 (2′-OCH3),
Supporting Information Available: Experimental procedures;
1
list of spectral data for other compounds; H and 13C NMR and
DEPT 135 spectra of compounds (+)-7, (+)-10, (+)-13, (+)-5,
19a, (+)-19b, 20 (NOE), (-)-24, 1, 23, and 2; X-ray structure of
epoxide (+)-10; and crystallographic file (CIF, CCDC no. 603438).
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO061456N
2350 J. Org. Chem., Vol. 72, No. 7, 2007