Total synthesis of malyngamides K, L, and 5″-epi-C and absolute configuration of malyngamide L

Article abstract of DOI:10.1021/jo2003852

An accelerated, enantioselective, and general synthetic route to a class of malyngamides, K (1), L (3), and 5″-epi-C (4), bearing a cyclohexenone ring or a heavily oxygenated six-membered ring and a vinyl chloride structural motif was developed. The key s

Full text of DOI:10.1021/jo2003852

ARTICLE
pubs.acs.org/joc
Total Synthesis of Malyngamides K, L, and 500-epi-C and Absolute
Configuration of Malyngamide L
Jun-Tao Zhang, Xian-Liang Qi, Jie Chen, Bao-Sheng Li, You-Bai Zhou, 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
S Supporting Information
b
ABSTRACT: An accelerated, enantioselective, and general
synthetic route to a class of malyngamides, K (1), L (3), and
500-epi-C (4), bearing a cyclohexenone ring or a heavily oxyge-
nated six-membered ring and a vinyl chloride structural motif
was developed. The key step was the Suzuki cross-coupling
reaction of boronic acids 6ꢀ8 with unsaturated carboxylic
amides 5a,b possessing the chlorovinyl iodide functionality
for the construction of the skeletons of 1ꢀ4. The key inter-
mediates 10a,b were prepared using Ogilvie’s method for the
construction of the chlorovinyl iodide functionality. The NMR
data of the synthetic compound 2 were in full agreement with those of the reported product, and the discrepancy in the specific
rotation data suggested that the correct structure of malyngamide L should be 3, in which the absolute configuration of the amine
part was enantiomeric to that in compound 2. Then the absolute configuration of the stereogenic center at C(300) and C(400) in
malyngamide L was confirmed by synthesis of compound 3.
’ INTRODUCTION
acetate,3 C acetate,4 D,5 G,6 I acetate,7 iso-K,8 M, N,7 and 29
(Figure 1), which along with another 24 malyngamides were
found to possess a wide range of biological properties.10
Malyngamide K (1), malyngamide L (3),1 and 500-epi-mal-
yngamide C (4)2,3 are members of a class of marine natural
products isolated from the marine cyanophyte Lyngbya majuscu-
la. Malyngamides K and L were isolated from a sample of L.
majuscula collected from Curacao in the Southern Caribbean by
Gerwick’s group in 1997.1 These compounds displayed cyto-
The scarcity of malyngamides from natural sources has
hampered biological evaluation of these fascinating molecules.
To provide materials for more extensive biological evaluation
and to confirm the absolute configuration of unsecured
stereogenic centers, we were interested in establishing a
generally applicable protocol for the preparation of malyng-
amides. To date, the synthesis of malyngamides U11,12 and W,13
bearing a heavily oxygenated six-membered ring or a cyclo-
hexenone ring functionality, and malyngamides M,14 O, P, Q,
and R,15 bearing a vinyl chloride motif, have been realized by
us. However, the synthesis of malyngamides bearing both a
heavily oxygenated six-membered ring or cyclohexenone ring
and a vinyl chloride functionality (i.e., malyngamides K and L)
is still challenging. Although our previous method for the
construction of the vinyl chloride motif used the Wittig
reaction,14,15 this approach would not be so efficient in the
synthesis of such molecules possessing a cyclohexenone motif.
Analysis of the structure of malyngamides K, L, and 500-epi-C
in detail revealed that a coupling reaction between the
cyclohexenone and chlorovinyl iodide would be the best
approach. Herein, we report the synthesis of malyngamides
K (1), L (3), and 500-epi-C (4) and the confirmation of the
absolute configuration of malyngamide L.
toxicity to brine shrimp (the former: IC50 6 μM; the latter: IC50
8
μM) and goldfish (the former: IC50 7 μM; the latter: IC50 15
μM). However, the absolute configurations of C(300) and C(400)
chiral centers on the amine moiety of malyngamide L were not
determined because of the unresolved multiplet nature of proton
resonances for the C(300) and C(400) positions. 500-epi-Malynga-
mide C was isolated from a sample of L. majuscula collected near
Bush Key, Dry Tortugas, Florida, by Luesch’s group in 2010.2 It
was found to be cytotoxic to HT29 colon cancer cells (IC50 15.4
μM) and to inhibit bacterial quorum sensing in a reporter gene
assay. Malyngamide K and 500-epi-malyngamide C were also
isolated from a sample of the marine cyanobacterium L. majus-
cula collected from shallow water in True Blue Bay, Grenada, by
Gerwick’s group in 20103 and found to be moderately cytotoxic
to NCI-H460 human lung tumor (the former: IC50 1.1 μM; the
latter: IC50 4.5 μM) and neuro-2a cancer cell lines (the former:
IC50 0.49 μM; the latter: IC50 10.9 μM). Structurally, these
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 cyclohexenone ring or a heavily oxygenated six-mem-
bered ring with a functional unit of vinylic chloride. This group
also includes malyngamides C, deoxy-C,4 500-O-acetyl-500-epi-C
Received: February 21, 2011
Published: April 15, 2011
r
2011 American Chemical Society
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Figure 1. Structure of malyngamides K, L, 500-epi-C, deoxy-C, 500-O-acetyl-500-epi-C acetate, C, C acetate, D, G, I acetate, iso-K, M, N, and 2, which could
be prepared with Suzuki cross-coupling reaction, and malyngamide W.
Scheme 1. Retrosynthetic Analysis
’ RESULTS AND DISCUSSION
As outlined in Scheme 1, malyngamides K, L, and 500-epi-
malyngamide C are retrosynthetically divided into unsaturated
carboxylic amide components 5a,b that bear the chlorovinyl
iodide part, and boronic acids 6ꢀ8. Suzuki cross-coupling
reaction between two of them would furnish the skeleton of
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Scheme 2. Preparation of Key Intermediates 5a and 5b
Scheme 3. Preparation of Malyngamide K
5a in 61% yield in two steps.11 The synthesis of amide 5b was also
achieved by treatment of tosylate 17 with an excess of aqueous
methylamine in chloroform,22 followed by amidation with acid 9
in 73% yield in two steps.11
With the key intermediate 5a in place, we sought to construct
the C(20)ꢀC(100) framework of malyngamide K via transition
metal-catalyzed cross-coupling reaction initially (Scheme 3), so
the synthesis of stannane 20 and boronic acid 6 was pursued. The
preparation of stannane 20 and boronic acid 6 both began with
2-cyclohexen-1-one (11). Thus, bromination of enone 11 with
bromine in the presence of triethylamine generated the
bromoenone,23 followed by protection of the carbonyl group
with ethylene glycol (HOCH2CH2OH) in the presence of p-
toluenesulfonic acid (p-TsOH) in refluxing benzene to afford the
ketal 19 in 54% yield in two steps.24 Ketal 19 was easily
transformed to viable intermediates stannane 20 and boronic
acid 6 by treatment with tri-n-butyltin chloride (n-Bu3SnCl) in
the presence of tert-butyllithium (t-BuLi),25 or trimethyl borate
[B(OMe)3] in the presence of n-butyllithium (n-BuLi), and then
treatment with hydrogen chloride,18 in 81% and 61% yield,
respectively. On the basis of the preparation of the key inter-
mediates 20 and 6, we focused our efforts on the synthesis of
malyngamide K by the Stille coupling reaction;26 several con-
ditions were examined (Supporting Information, Table S1).
No desired product resulted when stannane 20 was reacted with
the amide 5a using tetrakis(triphenylphosphine)palladium(0)
[Pd(PPh3)4] as catalyst in the presence of copper(I) chloride27
in THF, cesium fluoride28 in THF at 50 °C, or copper(I) iodide
in DMF at rt to 50 °C29 (entries 1ꢀ3). The same result
was obtained using bis(acetonitrile)dichloropalladium [PdCl2-
(MeCN)2] as catalyst under various conditions (entries
4ꢀ6).26,30,25 A survey of the literature prompted us to turn our
attention to the Suzuki coupling reaction,31 which is very
sensitive to the palladium source and ligand. However, no
favorable results were obtained when using Pd(PPh3)4 or Pd-
(PhCN)2Cl2 as catalyst in ethanol,32 DME/H2O,33 or THF/
H2O34 (entries 7ꢀ9). No reaction occurred when using palla-
dium diacetate [Pd(OAc)2] as catalyst without ligand or using
triphenylphosphine as ligand (entries 10 and 11).35 Fortunately,
malyngamide K was achieved in 89% yield when Pd(OAc)2 and
the target malyngamides. 5a,b could be formed by an amide
linkage between acid 9 and amines 10a,b. In turn, the chlorovinyl
iodide functionality of amines 10a,b could be generated from
ethyl propiolate (14) using Ogilvie’s method,16,17 and the chiral
fatty acid 9, (ꢀ)-(4E,7S)-7-methoxytetradec-4-enoic acid, had
been synthesized earlier by us in six steps using a Johnsonꢀ
Claisen rearrangement as a key step, starting from octanal, in 50%
overall yield.12 6ꢀ8 could be prepared from cyclohexenone ring
derivatives via functional transformations.18
The preparation of amides 5a,b began with ethyl propiolate
(14) (Scheme 2).16 Thus, compound 14 was converted to ester
15 by exposure to n-tetrabutylammonium iodide (n-Bu4NI) in
refluxing 1,2-dichloroethane. Subsequent reduction of the ester
15 with diisobutylaluminum hydride (DIBALH) in DCM at 0 °C
gave the intermediate alcohol 16 in 84% yield as a mixture of E-
and Z-isomers (E:Z = 1.1:1). This mixture could be separated
carefully by flash chromatography over silica gel, and the E-
isomer could be converted to the desired Z-isomer in 80% yield
(based on 60% conversion) by irradiation with UV light
(>350 nm) in DCM.16 The Z-configuration of the vinyl chloride
was consistent with that in natural malyngamides K, L, and 500-
epi-C, which provided a foundation for the preparation of these
malyngamides. Then activation of the hydroxyl group in alcohol
(Z)-16 with p-toluenesulfonyl chloride (p-TsCl) in the presence
of triethylamine and 4-(N,N-dimethylamino)pyridine (DMAP)
in DCM at 0 °C afforded the tosylate 17 in 88% yield,19 which
was followed by azidation with sodium azide in acetone/water
(3:1) to give the azide 18 in 87% yield.20 Reduction of azide 18
with lithium aluminum hydride (LAH) in diethyl ether at 0 °C
generated the corresponding amine,21 which was directly con-
densed with the acid 9 in the presence of N,N0-dicyclohexylcar-
bodiimide (DCC), 1-hydroxybenzotriazole (HOBt), and N-
methylmorpholine (NMM) in DCM at 0 °C to afford amide
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Scheme 4. Preparation of 2
the enone (ꢀ)-12, which was prepared in three steps from
(R)-(ꢀ)-carvone [(ꢀ)-21] as follows:13 Stereoselective epox-
idation of enone (ꢀ)-21 with hydrogen peroxide in the presence
of sodium hydroxide in methanol at ꢀ20 °C generated the
desired R,β-epoxide ketone;37 subsequently, reductive ring-
opening of the resulting epoxide ketone by a catalytic amount
of diphenyl diselenide (PhSeSePh) in the presence of N-acetyl-L-
cysteine and sodium hydroxide in methanol38 followed by
ozonization in methanol/DCM (2:1) at ꢀ78 °C followed by
treatment with copper(II) acetate monohydrate [Cu(OAc)2
3
H2O] and iron sulfate heptahydrate (FeSO4 7H2O) at ꢀ20 °C
3
resulted in the desired enone (ꢀ)-1239 in 44% yield in three
steps. Then protection of the hydroxyl group in enone (ꢀ)-12
with methoxymethyl chloride (MOMCl) in the presence of N,N-
diisopropylethylamine in DCM at 0 °C gave the corresponding
ether (ꢀ)-22 in 64% yield,40 which underwent bromination to
afford the bromoenone (ꢀ)-23 in 93% yield.23 In order to
protect the carbonyl group of bromoenone (ꢀ)-23, several
conditions were tested. Initially, aromatization of the R,β-un-
saturated cyclohexenone moiety in bromoenone (ꢀ)-23 oc-
curred when treated with HOCH2CH2OH and p-TsOH in
benzene at reflux,24 and the starting material was recovered when
using 1,2-bis(trimethylsilyloxy)ethane (TMSOCH2CH2OTMS)
and trimethylsilyl trifluoromethanesulfonate (TMSOTf) even
if HOCH2CH2OH was added at ꢀ78 °C.41 Fortunately, when
the reaction temperature was maintained at ꢀ78 °C for 4 h and
then raised to rt for 20 h, ketal (ꢀ)-24a and (ꢀ)-24b were
achieved in 31% and 50% yields, respectively. Then deprotection of
the TMS group of ketal (ꢀ)-24a with potassium carbonate in
methanol afforded ketal (ꢀ)-24b in 71% yield,42 and this was a
spontaneous reaction when exposed to the air. The stereochemistry
of ketal (ꢀ)-24b was unambiguously established to be 9R and 10R
by X-ray crystallographic analysis (Supporting Information,
Figure S1). Subsequently, protection of the hydroxyl group of
ketal (ꢀ)-24b using allyl bromide in the presence of sodium
hydride in DMF at 0 °C furnished the allyl ether (ꢀ)-25 in 65%
yield.43 Finally, boronic acid (ꢀ)-7 was prepared by a procedure
similar to that for the preparation of boronic acid 6; treatment of
allyl ether (ꢀ)-25 with B(OMe)3 in the presence of n-BuLi
followed by hydrogen chloride produced desired intermediate
(ꢀ)-7 in 93% yield in two steps.18 The allyl ether was the most
suitable protecting group among those tested. At this stage, we were
faced with the task of the construction of the skeleton of compound
2 via Suzuki coupling reaction of boronic acid (ꢀ)-7 and amide 5b.
Surprisely, compound 26a was achieved using SPhos as ligand in
tri-tert-butylphosphonium tetrafluoroborate (t-Bu3P HBF4)
3
were used in the presence of cesium carbonate (entry 13), while
the use of the biphenyl ligand 2-dicyclohexylphosphino-20,60-
dimethoxybiphenyl (SPhos) resulted in a lower yield (entry
12).35 The spectral data of synthetic malyngamide K (1) were
in good agreement with that reported in the literature.1 As
expected, the preparation of the relatively simple malyngamide
K was accomplished smoothly in seven steps in 23% yield.
Encouraged by the synthesis of malyngamide K, we continued
to synthesize malyngamide L, possessing a more challenging
structure, in which the absolute configurations of C(300) and
C(400) have not been confirmed. At the onset of this project, our
initial speculation was that the structure of malyngamide L
should be that of compound 2, with the absolute configuration
at the C(300) and C(400) center being syn, bearing R stereochem-
istry for both centers, on the basis of biogenesis analysis and
other ‘‘normal’’ malyngamides such as malyngamides I acetate
and W (see Figure 1).7,36 Hence, target compound 2 was pursued
first (Scheme 4). Thus, boronic acid (ꢀ)-7 was first prepared,
using a reaction sequence similar to that used previously, from
42% yield,35 but no desired product resulted when t-Bu3P HBF4
3
was used. Perhaps the coupling reaction of boronic acid (ꢀ)-7 and
amide 5b failed with t-Bu3P as ligand because of competing π-allyl
complex formation between Pd catalyst and allyl group in com-
pound (ꢀ)-7.44,45 SPhos was used as ligand, because the L2Pd
complex is too large to allow for the PdꢀC interaction and is most
likely much too hindered to participate in an oxidative addition
process. One of the ligands must dissociate to arrive at a complex
similar to L Pd prior to oxidative addition, and the Pd possibly
3
coordinated to the aromatic ring.46 The LPd cannot form the
competing π-allyl complex, so compound 26a was achieved.
Finally, removal of the allyl group with palladium(II) chloride in
methanol/DCM (3:2) completed the synthesis of 300,400-epi-mal-
yngamide L (2) in 70% yield.47 Thus, the preparation of the 300,400-
epi-malyngamide L (2) was finished in ten steps in 3.4% yield.
The 1H and 13C NMR data of synthetic malyngamide L (2)
were in complete agreement with the data reported for the
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Scheme 5. Preparation of Malyngamide L
Scheme 6. Preparation of Key Intermediate 8
isolated malyngamide L. However, the specific rotation of
compound 2 was found to be [R]20D ꢀ16 (c 0.3, EtOH), which
was opposite to the reported value of [R]20 þ17.3 (c 0.1,
D
EtOH).1 The acid portion of malyngamide L was determined to
be (ꢀ)-(4E,7S)-7-methoxytetradec-4-enoic acid from biosyn-
thetic considerations. The only possible explanation was that the
opposite configuration of the amine portion of the isolated
malyngamide L was enantiomeric with the amine part of
compound 2 (i.e., S instead of R). Hence, the structure and
absolute configuration of malyngamide L should be that in
compound 3. The chiral centers between the fatty acid part
and the amine part were too remote from each other, and hence
cleavage of the NꢀO bond in the presence of palladium on
activated carbon (Pd/C) in methanol under H2 atmosphere
(1 atm) to give diol 2850 in 42% yield in three steps. Subsequently,
deketalization and elimination of diol 28 with hydrogen chloride
in THF/water (1:1) afforded enone 13 in 65% yield.49 Protec-
tion of the hydroxyl group in enone 13 with tert-butyldimethyl-
silyl chloride (TBSCl)50 in the presence of imidazole in DMF
followed by bromination of the corresponding silyl ether gave
bromoenone 2923 in 90% yield in two steps. Then treatment of
ketone 29 with TMSOCH2CH2OTMS, HOCH2CH2OH, and
TMSOTf at 20 °C for 5 h gave 30a and 30b in 39% and 46%
yields, respectively.41 Note that the control of reaction tem-
perature was very important; aromatization of the substrate
occurred when the reaction temperature was raised to 30 °C,
and the reaction was very slow below 10 °C. Deprotection of
ketal 30a also afforded ketal 30b in 81% yield. The hydroxyl
group in alcohol 30b was protected again as the allyl ether 31
by allyl bromide in 64% yield.43 Then the boronic acid 8 was
prepared by a procedure similar to that for the preparation of
boronic acid 6 in 70% yield in two steps. Again, the allyl ether
gave a satisfactory result in the preparation of desired boronic
acid 8.
1
compounds 2 and 3 would have identical H and 13C NMR
spectral features. This deduction was further confirmed by our
similar observations of the spectral data of serinol-derived
malyngamides,48 malyngamides U,11,12 Q, and R, derived by
total synthesis.15 Thus, the key intermediate (þ)-7 was prepared
from (S)-(þ)-carvone [(þ)-21] in nine steps in 13% overall
yield. After Suzuki cross-coupling reaction and deprotection,
compound 3 was accomplished in 29% yield from boronic acid
(þ)-7 (Scheme 5). In the synthesis of the compound 3, the
stereochemistry of ketal (þ)-24b was also established as 9S and
10S by X-ray crystallographic analysis (Supporting Information,
Figure S2). The NMR data of synthetic compound 3 were
identical with those reported for the isolated malyngamide L
and compound 2. The specific rotation of compound 3 was
found to be [R]20D þ20 (c 0.3, EtOH), which is consistent with
the reported value [R]20D þ17.3 (c 0.1, EtOH).1 These results
revealed that the absolute configuration of malyngamide L
should be that observed in compound 3.
On the basis of the successful access to malyngamides K and L,
the Suzuki cross-coupling could also be applied to the synthesis
of 500-epi-malyngamide C in our project (Schemes 6 and 7). First,
the synthesis of key intermediate 8 could begin with the known
ketone 13, which was prepared from monoketal 27 in four steps.
Thus, oxidation of the monoketal 27 using nitrosobenzene in the
presence of L-proline in DMF gave the corresponding hydro-
xylamine. The resultant hydroxylamine was reduced to afford a
single alcohol using Luche conditions,49 followed by reductive
With the key intermediates 5a and 8 in hand, the skeleton of
the 500-epi-malyngamide C could be constructed via Suzuki cross-
coupling reaction. Thus, using the same conditions as those used
for the preparation of 26a and 26b, compound 32 was obtained
in 56% yield.35 The remaining task was to complete stereoselec-
tive epoxidation to finish the preparation of 500-epi-malyngamide
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Scheme 7. Preparation of 500-epi-Malyngamide C (4) and
Malyngamide C
stereocenter in the cyclohexenone. Then completely stereose-
lective Sharpless epoxidation of the allylic alcohol finished the
preparation of malyngamide C.
’ CONCLUSION
The enantioselective total synthesis of malyngamide K,
malyngamide L, and 500-epi-malyngamide C have been accom-
plished via a highly convergent strategy in seven steps in 23% yield,
in ten steps in 3.7% yield, and in fourteen steps in 2.7% yield,
respectively. The key step was the Suzuki cross-coupling reaction
for the construction of the skeletons of 1ꢀ4. The determination
of the absolute configuration of C(300) and C(400) in the amine
portion of malyngamide L was accomplished by the synthesis of
compounds 2 and 3. Further application of this strategy toward
the synthesis of the structurally related malyngamides containing
a cyclohexenone ring or a heavily oxygenated six-membered ring
and with a vinylic chloride functionality, such as C, C acetate,
deoxy-C, D, G, I acetate, N, and 2, is currently underway and will
be presented in due course.
’ EXPERIMENTAL SECTION
Ethyl 3-Chloro-2-iodoprop-2-enoate (15).16
To a stirred solution of ethyl propiolate (14) (2.00 g, 20.41 mmol) in
DCM (80 mL) was added n-Bu4NI (22.59 g, 61.23 mmol). The reaction
mixture was heated at reflux for 18 h. Then the reaction mixture was
cooled to rt, diluted with EtOAc, and washed with NaHSO3 (20 wt %
solution), saturated NaHCO3 solution, and brine. The organic layer was
then dried over MgSO4, filtered, and concentrated in vacuo. Flash
chromatography of the residue over silica gel (petroleum ether/EtOAc
10:1) afforded ester 15 (3.82 g, 72% yield) as a colorless oil. 1H NMR
(CDCl3, 400 MHz) δ 7.01 (s, 1H, H-3), 4.31 (dd, J = 14.0, 7.2 Hz, 2H,
H-10), 1.35 (t, J = 7.2 Hz, 3H, H-20); 13C NMR (CDCl3, 100 MHz) δ
162.4 (C, C-1), 128.7 (CH, C-3), 85.0 (C, C-2), 62.6 (CH2, C-10), 13.9
(CH3, C-20); MS (EI) m/z (%) 260 (Mþ, 23), 225 (32), 215 (78), 133
(6), 53 (100).
C. A survey of the literature revealed that stereoselectivity in
favor of C(100)ꢀC(600) double bond epoxidation seemed plau-
sible, because the epoxidation was certain to be impeded by the
presence of the adjacent steric hindrance from the protective
group of the C-500 hydroxyl group. Thus, the allyl ether was
converted to silyl ether 33, bearing more steric bias, by treatment
(E)-3-Chloro-2-iodoprop-2-en-1-ol and (Z)-3-Chloro-2-io-
doprop-2-en-1-ol [(E)-16 and (Z)-16].16
with PdCl2 and then TBSCl and imidazole50 in 69% yield in
47
To a stirred solution of ester 15 (4.50 g, 17.31 mmol) in DCM
(100 mL) was added DIBALH (52 mL, 1 M in hexanes, 52 mmol) at
0 °C. The reaction mixture was allowed to warm to rt and then
maintained for 2 h. Then MeOH (5 mL) was carefully added dropwise
to quench the reaction. A saturated solution of Rochelle’s salt (100 mL)
was introduced, and the resulting mixture was stirred until both layers
became clear. The organic layer was dried over MgSO4, filtered, and
concentrated in vacuo. Flash chromatography of the residue over silica
gel (petroleum ether/EtOAc 5:1) afforded alcohol (E)-16 (1.66 g, 44%
yield) and alcohol (Z)-16 (1.51 g, 40% yield) as a colorless oil. For (E)-
16: 1H NMR (CDCl3, 400 MHz) δ 6.60 (d, J = 0.4 Hz, 1H, H-3), 4.38 (s,
2H, H-1), 2.80 (br, 1H, OH); 13C NMR (CDCl3, 100 MHz) δ 120.2
(CH, C-3), 102.6 (C, C-2), 63.6 (CH2, C-1); MS (EI) m/z (%) 218
(Mþ, 23), 127 (56), 91 (100), 55 (31), 39 (28). For (Z)-16: 1H NMR
(CDCl3, 400 MHz) δ 6.75 (s, 1H, H-3), 4.32 (s, 2H, H-1), 2.85 (br, 1H,
two steps. Then stereoselective epoxidation of 33 with hydrogen
peroxide and benzyltrimethylammonium hydroxide (triton B)50
in THF at 0 °C smoothly provided the corresponding epoxide 34
as a single stereoisomer in 93% yield (only one stereoisomer was
1
observed by H NMR analysis of the crude product). Finally,
removal of the TBS protecting group with tetrabutylammonium
fluoride (TBAF)51 in THF at 0 °C in 87% yield finished the
synthesis of 500-epi-malyngamide C. The spectral data of syn-
thetic 500-epi-malyngamide C (4) were in good agreement with
the reported data for the isolated 500-epi-malyngamide C.2 500-epi-
Malyngamide C could be converted to malyngamide C via the
Mitsunobu reaction.2 Malyngamide C could also be achieved by
the same route as that used for the synthesis of 500-epi-malyng-
amide C, using D-proline-mediated oxygenation to introduce the
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OH); 13C NMR (CDCl3, 100 MHz) δ 125.4 (CH, C-3), 109.4 (C, C-2),
69.7 (CH2, C-1); MS spectra data of (Z)-16 is identical to that of (E)-16.
A stirred solution of alcohol (E)-16 (300 mg, 1.38 mmol) in DCM
(50 mL) was irradiated with UV light (>350 nm) for 3 h, then the solvent
was evaporated in vacuo. Flash chromatography of the residue over silica
gel (petroleum ether/EtOAc 5:1) afforded alcohol (Z)-16 (144 mg, 80%
yield on the basis of 60% conversion).
(611 mg, 61% yield in two steps) as a colorless oil. [R]20D ꢀ5 (c 1.0,
CHCl3); IR (KBr) 3286, 3049, 2927, 1653, 1543, 1460, 1097, 970 cmꢀ1
;
1H NMR (CDCl3, 400 MHz) δ 6.66 (s, 1H, H-30), 5.98 (s, 1H, NH),
5.52ꢀ5.49 (m, 2H, H-4 and H-5), 4.21 (d, J = 6.0 Hz, 2H, H-10), 3.32 (s,
3H, H-15), 3.19ꢀ3.14 (m, 1H, H-7), 2.36 (t, J = 5.6 Hz, 2H, H-2), 2.29
(dd, J = 12.8, 6.0 Hz, 2H, H-6), 2.21 (t, J = 5.2 Hz, 2H, H-3), 1.44ꢀ1.43
(m, 2H, H-8), 1.27 (s, 10H, H-9, H-10, H-11, H-12, and H-13), 0.88 (t,
J = 7.2 Hz, 3H, H-14); 13C NMR (CDCl3, 100 MHz) δ 172.2 (C, C-1),
130.7 (CH, C-4), 128.0 (CH, C-5), 126.5 (CH, C-30), 106.2 (C, C-20),
80.6 (CH, C-7), 56.4 (CH3, C-15), 49.1 (CH2, C-10), 36.3 (CH2, C-2),
36.2 (CH2, C-6), 33.3 (CH2, C-8) 31.8 (CH2, C-9), 29.7 (CH2, C-12),
29.3 (CH2, C-11), 28.5 (CH2, C-3), 25.3 (CH2, C-10), 22.6 (CH2,
C-13), 14.1 (CH3, C-14); HRMS (ESI) m/z C18H32ClINO2 [M þ H]þ
calcd 456.1161, found 456.1155.
(Z)-3-Chloro-2-iodoallyl 4-Methylbenzenesulfonate (17).
To a stirred solution of alcohol (Z)-16 (2.10 g, 9.63 mmol) in Et3N
(30 mL) and DCM (60 mL) were added p-TsCl (7.34 g, 38.52 mmol)
and DMAP (117 mg, 0.96 mmol) at 0 °C, The reaction mixture was
allowed to warm to rt and then maintained for 20 h. The reaction
mixture was washed with H2O (100 mL ꢁ 3). The organic layer was
dried over Mg2SO4, filtered, and concentrated in vacuo. Flash chroma-
tography of the residue over silica gel (petroleum ether/EtOAc 10:1)
afforded compound 17 (3.15 g, 88% yield) as a white solid. Mp
76ꢀ77 °C; IR (KBr) 3051, 1594, 1364, 1175, 950, 843, 666,
(ꢀ)-(4E,7S)-N-[(Z)-3-Chloro-2-iodoprop-2-ene]-7-meth-
oxy-N0-methyltetradec-4-enamide (5b).
1
533 cmꢀ1; H NMR (CDCl3, 400 MHz) δ 7.80 (d, J = 8.4 Hz, 2H,
To a stirred solution of compound 17 (1.2 g, 3.23 mmol) in CHCl3
(12 mL) was added MeNH2 (12 mL, 40% in H2O), and the reaction
mixture was maintained at rt for 2 d. The CHCl3 layer was separated,
and the H2O layer was extracted with CHCl3 (10 mL ꢁ 2). The
combined organic layer was dried over MgSO4, filtered, and concen-
trated in vacuo to afford the amine 10b as a yellow oil. Then according to
the procedure for the preparation of amide 5a, acid 9 (691 mg, 2.70
mmol) afforded amide 5b (1.11 g, 73% yield in two steps) as a colorless
oil. [R]20D ꢀ10 (c 1.0, CHCl3); IR (KBr) 3734, 3396, 2926, 1651, 1460,
1099, 971, 827, 670 cmꢀ1; 1H NMR (CDCl3, 400 MHz) δ 6.58/6.55 (s,
1H, H-30), 5.52ꢀ5.48 (m, 2H, H-4 and H-5), 4.38 (4.22) (s, 2H, H-10),
3.32 (s, 3H, H-15), 3.15 (t, J = 5.6 Hz, 1H, H-7), 2.98/2.88 (s, 3H,
NCH3), 2.41ꢀ2.37 (m, 4H, H-2 and H-6), 2.19 (t, J = 5.6 Hz, 2H, H-3),
1.43 (s, 2H, H-8), 1.27 (s, 10H, H-9, H-10, H-11, H-12, and H-13), 0.87
(t, J = 6.8 Hz, 3H, H-14); 13C NMR (CDCl3, 100 MHz) δ 172.6/172.5
(C, C-10), 131.0/130.9 (CH, C-4), 127.3/127.5 (CH, C-5), 126.3/125.7
(CH, C-30), 105.2/105.6 (C, C-20), 80.7 (CH, C-7), 56.47/56.50 (CH3,
C-15), 56.3/59.3 (CH2, C-1), 36.3/32.9 (CH2, C-2), 35.0/33.1 (CH3,
NCH3), 33.4 (CH2, C-6), 33.3 (CH2, C-8) 31.8 (CH2, C-9), 29.7 (CH2,
C-12), 29.3 (CH2, C-11), 28.0 (28.2) (CH2, C-3), 25.3 (CH2, C-10),
22.6 (CH2, C-13), 14.1 (CH3, C-14); HRMS (ESI) m/z C19H34ClINO2
[M þ H]þ calcd 470.1317, found 470.1305.
2ArH), 7.37 (d, J = 8.4 Hz, 2H, 2ArH), 6.76 (s, 1H, H-3), 4.77 (s, 2H,
H-1), 2.46 (s, 3H, CH3); 13C NMR (CDCl3, 100 MHz) δ 145.3 (C,
ArC), 132.8 (C, ArC), 130.1 (CH, C-3), 129.9 (CH, ArCH), 128.0 (CH,
ArCH), 99.0 (C, C-2), 74.7 (CH2, C-1), 21.6 (CH3); HRMS (ESI) m/z
C10H14ClINO3S [M þ NH4]þ calcd 389.9422, found 389.9419.
(Z)-3-Chloro-2-iodoprop-2-en-1-azide (18).
To a stirred solution of compound 17 (1.60 g, 4.30 mmol) in acetone
and H2O (48 mL, acetone/H2O 3:1) was added NaN3 (1.12 g, 17.20
mmol), and the reaction mixture was maintained at this temperature for
5 h. After removal of acetone, the reaction mixture was extracted with
EtOAc (50 mL ꢁ 3). The organic layer was dried over MgSO4, filtered,
and concentrated in vacuo. Flash chromatography of the residue over
silica gel (petroleum ether/EtOAc 5:1) afforded azide 18 (909 mg, 87%
yield) as a colorless oil. IR (KBr) 3044, 2102, 1589, 1279, 825,
1
588 cmꢀ1; H NMR (CDCl3, 400 MHz) δ 6.72 (d, J = 0.8 Hz, 1H,
H-3), 4.17 (s, 2H, H-1); 13C NMR (CDCl3, 100 MHz) δ 127.7 (CH,
C-3), 102.0 (C, C-2), 60.1 (CH2, C-1); HRMS (ESI) m/z C3H7ClIN4
[M þ NH4]þ calcd 260.9398, found 260.9400.
6-Bromo-1,4-dioxaspiro[4.5]dec-6-ene (19).22,23
(ꢀ)-(4E,7S)-N-[(Z)-3-Chloro-2-iodoprop-2-ene]-7-meth-
oxytetradec-4-enamide (5a).
To a stirred solution of 2-cyclohexenone 11 (1.40 g, 14.58 mmol) in
DCM (40 mL) was added a solution of Br2 (0.8 mL, 16.10 mmol) in
DCM (10 mL) in a dropwise fashion at 0 °C, followed by Et3N (2.2 mL,
16.10 mmol). After stirring for 5 min, the reaction mixture was washed
with H2O (50 mL ꢁ 3). The organic layer was dried over MgSO4,
filtered, and concentrated in vacuo. Flash chromatography of the residue
over silica gel (petroleum ether/EtOAc 3:1) afforded 2-bromo-2-
cyclohexen-1-one as a colorless oil. To a solution of this ketone (1.90
g, 10.86 mmol) in benzene (60 mL) were added HOCH2CH2OH (1.35
g, 21.72 mmol) and p-TsOH (93 mg, 0.54 mmol). The reaction mixture
was refluxed for 12 h under a DeanꢀStark setup. The mixture was
concentrated in vacuo. Flash chromatography of the residue over silica
gel (petroleum ether/EtOAc 5:1) afforded compound 19 (1.72 g,
To a suspension of LAH (125 mg, 3.30 mmol) in Et2O (20 mL) was
added a solution of azide 18 (534 mg, 2.20 mmol) in Et2O (10 mL)
dropwise at 0 °C, and the reaction mixture was maintained at this
temperature for 2 h. NaOH (1 mL, 3% in water) was added, and the
mixture was stirred for an additional 1 h. The resulting mixture was
filtered through Celite, dried over MgSO4, filtered, and concentrated in
vacuo to afford the amine 10a as a colorless oil. To a stirred solution of
this amine in DCM (5 mL) was added acid 9 (353 mg, 1.38 mmol) in
DCM (5 mL), followed by DCC (314 mg, 1.50 mmol), HOBt (224 mg,
1.7 mmol), and NMM (154 mg, 1.50 mmol) at 0 °C. The mixture was
allowed to warm to rt over 3 h, stirring was continued for 10 h, and then
the mixture was concentrated in vacuo. Flash chromatography of the
residue over silica gel (petroleum ether/EtOAc 2:1) afforded amide 5a
1
54% in two steps) as a colorless oil. H NMR (400 MHz, CDCl3) δ
3952
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The Journal of Organic Chemistry
ARTICLE
6.34 (t, J = 4.0 Hz, 1H, H-7), 4.21ꢀ4.18 (m, 2H, H-3), 4.01ꢀ3.97 (m,
2H, H-2), 2.12ꢀ2.08 (m, 2H, H-8), 1.94ꢀ1.91 (m, 2H, H-10),
1.82ꢀ1.76 (m, 2H, H-9); 13C NMR (400 MHz, CDCl3) δ 135.9
(CH, C-7), 124.5 (C, C-6), 105.7 (C, C-5), 65.7 (CH2, C-3), 65.7
(CH2, C-2), 35.5 (CH2, C-10), 27.4 (CH2, C-8), 20.2 (CH2, C-9); MS
(EI) m/z (%) 218 (Mþ, 1), 190 (100), 139 (8), 109 (3) 79 (5).
2-Tri-n-butylstannyl-2-cyclohexen-1-one (20).24
vessel was purged for 10 min with argon, Pd(OAc)2 (5 mg, 0.02 mmol)
was added, and the reaction mixture was maintained at rt for 30 h
under argon. The mixture was concentrated in vacuo. Flash chroma-
tography of the residue over silica gel (petroleum ether/EtOAc 2:1)
afforded malyngamide K (1) (83 mg, 89%) as a colorless oil. [R]20
D
ꢀ5.7 (c 0.4, CHCl3); IR (KBr) 3370, 2926, 1673, 1543, 1457, 1364,
1256, 1095, 972, 809 cmꢀ1; 1H NMR (CDCl3, 400 MHz) δ 6.94 (t, J =
4.0 Hz, 1H, H-600), 6.28 (s, 1H, H-30), 6.12 (s, 1H, NH), 5.48ꢀ5.45 (m,
2H, H-4 and H-5), 3.93 (dd, J = 5.2, 0.8 Hz, 2H, H-10), 3.32 (s, 3H,
H-15), 3.17ꢀ3.11 (m, 1H, H-7), 2.54ꢀ2.47 (m, 4H, H-300 and H-500),
2.33ꢀ2.29 (m, 2H, H-3), 2.23ꢀ2.17 (m, 4H, H-2 and H-6), 2.10ꢀ2.04
(m, 2H, H-400), 1.44ꢀ1.42 (m, 2H, H-8), 1.30ꢀ1.27 (m, 10H, H-9,
H-10, H-11, H-12, and H-13), 0.88 (t, J = 7.2 Hz, 3H, H-14); 13C NMR
(CDCl3, 100 MHz) δ 198.7 (C, C-200), 172.5 (C, C-1), 151.5 (CH,
C-600), 136.7 (C, C-20), 136.5 (C, C-100), 130.9 (CH, C-4), 127.9 (CH,
C-5), 119.7 (CH, C-30), 81.0 (CH, C-7), 56.7 (CH3, C-15), 44.0 (CH2,
C-10) 38.6 (CH2, C-300), 36.7 (CH2, C-2), 36.6 (CH2, C-6), 33.6 (CH2,
C-8), 32.1 (CH2, C-9), 30.0 (CH2, C-12), 29.5 (CH2, C-11), 28.8 (CH2,
C-3), 26.3 (CH2, C-500), 25.5 (CH2, C-10), 22.9 (CH2, C-13), 22.9
(CH2, C-400), 14.3 (CH3, C-14); HRMS (ESI) m/z C24H39ClNO3
[M þ H]þ calcd 424.2613, found 424.2607.
To a stirred solution of compound 19 (168 mg, 0.77 mmol) in Et2O
(5 mL) was added t-BuLi (1.9 mL, 0.8 M in hexane, 1.54 mmol) via
syringe under argon at ꢀ78 °C, and the reaction mixture was maintained
at this temperature for 30 min. Then a cooled solution of n-Bu3SnCl
(277 mg, 0.85 mmol) was added, and the reaction mixture was
maintained at this temperature for 1 h. To the reaction mixture was
added HCl (5 mL, 2 M), and the mixture was stirred for 3 h. The reaction
mixture was extracted with EtOAc (8 mL ꢁ 4). The organic layer was
dried over MgSO4, filtered, and concentrated in vacuo. Flash chroma-
tography of the residue over silica gel (petroleum ether/EtOAc 1:1)
afforded stannane 20 (241 mg, 81% yield) as a colorless oil. 1H NMR
(CDCl3, 400 MHz) δ 7.12 (t, J = 3.6 Hz, 1H, H-3), 2.43 (t, J = 6.4 Hz,
2H, H-6), 2.35 (dd, J = 10.0, 5.6 Hz, 2H, H-4), 2.02ꢀ1.95 (m, 2H, H-5),
1.51ꢀ1.43 (m, 6H, 3 ꢁ CH2), 1.34ꢀ1.25 (m, 6H, 3 ꢁ CH2), 0.95ꢀ0.86
(m, 15H, 3 ꢁ CH2 and 3 ꢁ CH3); 13C NMR (CDCl3, 100 MHz) δ
202.5 (C, C-1), 159.4 (CH, C-3), 145.3 (CH, C-2), 38.1 (CH2, C-6),
29.0 (CH2), 27.9 (CH2, C-4), 27.3 (CH2), 23.0 (CH2, C-5), 13.6
(CH3), 9.6 (CH2); MS (ESI) m/z 387.1 ([M þ H]þ)
(ꢀ)-(5R,6R)-5-Hydroxy-6-methylcyclohex-2-enone and
(þ)-(5S,6S)-5-Hydroxy-6-methylcyclohex-2-enone [(ꢀ)-12
and (þ)-12].13
To a stirred solution of (R)-(ꢀ)-carvone [(ꢀ)-21] (5.00 g, 33.33
mmol) in MeOH (80 mL) was added NaOH (2.5 mL, 4 M) at ꢀ20 °C,
followed by the dropwise addition of H2O2 (45.3 mL, 30% purity,
40 mmol) over 50 min. The reaction mixture was quenched by saturated
Na2SO3 solution. The mixture was then extracted with DCM (100 mL
ꢁ 4). The organic layer was dried over MgSO4, filtered, and concen-
trated in vacuo. Flash chromatography of the residue over silica gel
(petroleum ether/EtOAc 50:1) afforded the corresponding epoxy
ketone as a colorless oil. To a stirred and degassed solution of this
epoxy ketone (5.15 g, 31.00 mmol), N-acethyl-L-cysteine (15.16 g, 93.00
mmol), and PhSeSePh (967 mg, 3.10 mmol) in MeOH (300 mL)
was added NaOH (15.5 mL, 6 M) under argon, and the reaction mixture
was maintained at rt for 1.5 h. The reaction mixture was then diluted
with H2O (200 mL), saturated with NaCl, and extracted with DCM
(200 mL ꢁ 4). The organic layer was dried over MgSO4, filtered, and
concentrated in vacuo. Flash chromatography of the residue over silica
gel (petroleum ether/EtOAc 5:1) afforded corresponding β-alcohol
ketone as a white solid. A stirred solution of this β-alcohol ketone (3.59
g, 21.39 mmol) in MeOH and DCM (90 mL, MeOH/DCM 2:1) was
bubbled with O3 at ꢀ78 °C. After consumption of the β-alcohol ketone
(monitored by TLC), argon was purged and the reaction mixture
2-Dihydroxyboryl-2-cyclohexen-1-one (6).
To a stirred solution of compound 19 (805 mg, 3.69 mmol) in THF
(10 mL) was added n-BuLi (1.5 mL, 2.5 M in hexane, 3.7 mmol) via
syringe under argon at ꢀ78 °C, and the reaction mixture was maintained
at this temperature for 1 h. Then a cooled solution of B(OMe)3 (426 mg,
4.10 mmol) in THF (10 mL) was added, and the reaction mixture was
maintained at this temperature for 2 h and then diluted with HCl (9 mL,
2 M) and extracted with EtOAc (20 mL ꢁ 4). The organic layer was
dried over MgSO4, filtered, and concentrated in vacuo. Flash chroma-
tography of the residue over silica gel (petroleum ether/EtOAc 1:1)
afforded boronic acid 6 (315 mg, 61% yield) as a white solid. Mp
52ꢀ54 °C; IR (KBr) 3362, 2955, 1629, 1411, 1334, 1100, 552 cmꢀ1; 1H
NMR (CDCl3, 400 MHz) δ 7.92 (t, J = 4 Hz, 1H, H-3), 7.45 (s, 2H, 2 ꢁ
OH), 2.49ꢀ2.46 (m, 4H, H-4 and H-6), 2.07ꢀ2.00 (m, 2H, H-5); 13C
NMR (CDCl3, 100 MHz) δ 207.0 (C, C-1), 165.5 (CH, C-3), 37.9
(CH2, C-6), 27.1 (CH2, C-4), 22.4 (CH2, C-5); HRMS (ESI) m/z
C6H10BO3 [M þ H]þ calcd 141.0717, found 141.0715.
was allowed to warm to ꢀ20 °C. Then Cu(OAc)2 H2O (8.51 g,
3
42.78 mmol) was added, the reaction mixture was maintained at this
temperature for 20 min, and FeSO4 7H2O (7.14 g, 25.67 mmol) was
3
(ꢀ)-(4E,7S)-N-[(2Z)-2-Chloromethyleneethyl-(2-oxocy-
added in small portions. The suspension was stirred at ꢀ20 °C for 7 h
and then allowed to warm to rt, this temperature was maintained for 3 h,
H2O (30 mL) was added, and the mixture was extracted with DCM
(80 mL ꢁ 3). The combined organic layer was washed with saturated
NaHCO3 solution and brine, dried over MgSO4, filtered, and concen-
trated in vacuo. Flash chromatography of the residue over silica gel
(petroleum ether/EtOAc 1:1) afforded R,β-unsaturated cyclohexenone
(ꢀ)-12 (1.85 g, 44% yield in three steps) as a colorless oil. [R]20D ꢀ48
(c 1.0, CHCl3); IR (KBr) 3426, 2935, 1670, 1394, 1209, 1054,
clohex-1-enyl)]-7-methoxytetradec-4-enamide
[malyngamide K (1)].
To a stirred solution of boronic acid 6 (54 mg, 0.44 mmol) and amide
1
5a (101 mg, 0.22 mmol) in toluene (3 mL) were added t-Bu3P HBF4
897 cmꢀ1; H NMR (CDCl3, 400 MHz) δ 6.85ꢀ6.81 (m, 1H, H-3),
3
(13 mg, 0.04 mmol) and Cs2CO3 (143 mg, 0.44 mmol), the reaction
6.04 (dt, J = 10.0, 2.0 Hz, 1H, H-2), 4.29 (s, 1H, H-5), 2.71ꢀ2.53
3953
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ARTICLE
(m, 4H, H-4, H-6, and OH), 1.20 (d, J = 7.2 Hz, 3H, H-7); 13C NMR
(CDCl3, 100 MHz) δ 201.2 (C, C-1), 145.4 (CH, C-3), 129.2 (CH,
C-2), 70.6 (CH, C-5), 47.6 (CH, C-6), 33.3 (CH2, C-4), 10.5 (CH3,
C-7); HRMS (ESI) m/z calcd for C7H14NO2 [M þ NH4]þ 144.1019,
found 144.1023.
(ꢀ)-(9R,10R)-6-Bromo-10-methyl-9-trimethylsilyloxyspiro-
[4.5]dec-6-ene, (ꢀ)-(9R,10R)-6-Bromo-9-hydroxy-10-meth-
ylspiro[4.5]dec-6-ene, (þ)-(9S,10S)-6-Bromo-10-methyl-9-
trimethylsilyloxyspiro[4.5]dec-6-ene, and (þ)-(9S,10S)-6-
Bromo-9-hydroxy-10-methylspiro[4.5]dec-6-ene [(ꢀ)-24a,
(ꢀ)-24b, (þ)-24a, and (þ)-24b].
According to the above procedure, (þ)-21 (1.60 g, 10.67 mmol)
afforded (þ)-12 (605 mg, 45% yield in three steps) as a colorless oil.
[R]20D þ42 (c 1.0, CHCl3); 1H NMR (CDCl3, 400 MHz), 13C NMR
(CDCl3, 100 MHz), and MS spectra data of (þ)-12 are identical with
those of (ꢀ)-12.
(ꢀ)-(5R,6R)-5-Methoxymethoxy-6-methylcyclohex-2-en-
one and (þ)-(5S,6S)-5-Methoxymethoxy-6-methylcyclohex-
2-enone [(ꢀ)-22] and (þ)-22].
To a stirred solution of ketone (ꢀ)-23 (504 mg, 2.03 mmol) in DCM
(20 mL) were added TMSOCH2CH2OTMS (1.3 mL, 5.30 mmol),
HOCH2CH2OH (0.2 mL, 3.20 mmol), and TMSOTf (0.02 mL,
0.06 mmol) at ꢀ78 °C, and the reaction mixture was maintained at this
temperature for 4 h. Then the reaction mixture was allowed to warm to
rt, and it was maintained at this temperature for 12 h. The reaction
mixture was diluted with Et3N (2 mL) and extracted with DCM (30 mL ꢁ
3). The organic layer was dried with MgSO4, filtered, and concentrated
in vacuo. Flash chromatography of the residue over silica gel (petroleum
ether/EtOAc 5:1) afforded compounds (ꢀ)-24a (202 mg, 31% yield) as
a pale yellow oil and (ꢀ)-24b (252 mg, 50% yield) as a white solid. To a
stirred solution of compound (ꢀ)-24a (646 mg, 2.01 mmol) in MeOH
(20 mL) was added K2CO3 (277 mg, 2.01 mmol) at 0 °C, and the
reaction mixture was maintained at this temperature for 2 h. Then the
solvent was concentrated in vacuo. Flash chromatography of the residue
over silica gel (petroleum ether/EtOAc 2:1) also afforded compound
To a stirred solution of ketone (ꢀ)-12 (1.50 g, 11.90 mmol) in DCM
(50 mL) were added MOMCl (2.6 mL, 35.70 mmol) and i-Pr2NEt
(6.2 mL, 35.70 mmol) at 0 °C. The reaction mixture was allowed to
warm to rt, and this temperature was maintained for 4 h. Then the
reaction mixture was diluted with H2O (40 mL) and extracted with
DCM (50 mL ꢁ 3). The organic layer was dried with MgSO4, filtered,
and concentrated in vacuo. Flash chromatography of the residue over
silica gel (petroleum ether/EtOAc 5:1) afforded the MOM ether (ꢀ)-
22 (1.30 g, 64%) as a colorless oil. [R]20D ꢀ18 (c 1.0, CHCl3); IR (KBr)
3347, 2937, 1681, 1389, 1208, 1149, 1104, 1046, 917 cmꢀ1; 1H NMR
(CDCl3, 400 MHz) δ 6.75 (dd, J = 9.2, 3.6 Hz, 1H, H-3), 6.00 (t, J = 5.6
Hz, 1H, H-2), 4.65ꢀ4.55 (m, 2H, OCH2), 4.08 (s, 1H, H-5), 3.31 (t, J =
2.4 Hz, 3H, OCH3), 2.64ꢀ2.52 (m, 3H, H-4 and H-6), 1.16ꢀ1.13 (m,
3H, H-7); 13C NMR (CDCl3, 100 MHz) δ 200.5 (C, C-1), 144.9 (CH,
C-3), 129.3 (CH, C-2), 95.5 (OCH2), 76.1 (CH, C-5), 55.5 (OCH3),
46.6 (CH, C-6), 30.5 (CH2, C-4), 10.7 (CH3, C-7); HRMS (ESI) m/z
calcd for C9H18NO3 [M þ NH4]þ 188.1281, found 188.1285.
(ꢀ)-24b (354 mg, 71% yield). For (ꢀ)-24a: [R]20 ꢀ32 (c 1.0,
D
CHCl3); IR (KBr) 3520, 2956, 1336, 1253, 1151, 1085, 1020, 899,
842, 749 cmꢀ1; 1H NMR (CDCl3, 400 MHz) δ 6.17 (dd, J = 5.6, 3.2 Hz,
1H, H-7), 4.25ꢀ3.88 (m, 5H, H-2, H-3, and H-9), 2.17ꢀ2.02 (m, 3H,
H-8 and H-10), 0.97 (d, J = 7.2 Hz, 3H, H-11), 0.11 (s, 9H, 3 ꢁ CH3);
13C NMR (CDCl3, 100 MHz) δ 132.1 (CH, C-7), 123.9 (C, C-6), 109.0
(C, C-5), 67.3 (CH, C-9), 66.3 (CH2, C-2), 65.2 (CH2, C-3), 45.2 (CH,
C-10), 32.6 (CH2, C-8), 7.1 (CH3, C-11), 0.0 (CH3). For (ꢀ)-24b: Mp
79ꢀ81 °C; [R]20 ꢀ11 (c 1.0, CHCl3); IR (KBr) 3413, 2897, 1638,
According to the above procedure, (þ)-12 (259 mg, 2.05 mmol)
afforded (þ)-22 (310 mg, 89%) as a colorless oil. [R]20D þ26 (c 1.0,
CHCl3); 1H NMR (CDCl3, 400 MHz), 13C NMR (CDCl3, 100 MHz),
and MS spectra data of (þ)-22 are identical with those of (ꢀ)-22.
(ꢀ)-(5R,6R)-2-Bromo-5-methoxymethoxy-6-methylcyclo-
hex-2-enone and (þ)-(5S,6S)-2-Bromo-5-methoxymethoxy-
6-methylcyclohex-2-enone [(ꢀ)-23 and (þ)-23].
D
1337, 1148, 1067, 867, 589 cmꢀ1; 1H NMR (CDCl3, 400 MHz) δ 6.18
(t, J = 4.0 Hz, 1H, H-7), 4.30ꢀ4.28 (m, 2H, H-2), 4.05ꢀ4.01 (m, 3H,
H-3 and H-9), 2.57 (br, 1H, OH), 2.32ꢀ2.24 (m, 3H, H-8 and H-10),
1.08 (d, J = 7.2 Hz, 3H, H-11); 13C NMR (CDCl3, 100 MHz) δ 131.3
(CH, C-7), 124.6 (C, C-6), 107.9 (C, C-5), 69.0 (CH, C-9), 67.3 (CH2,
C-2), 66.3 (CH2, C-3), 44.0 (CH, C-10), 35.2 (CH2, C-8), 10.2 (CH3,
C-11); HRMS (ESI) m/z calcd for C9H14BrO3 [M þ H]þ 249.0121,
found 249.0123.
According to the above procedure, (þ)-23 (309 mg, 1.25 mmol)
afforded (þ)-24a (132 mg, 33% yield) as a pale yellow oil {[R]20D þ25
(c 1.0, CHCl3)} and (þ)-24b (143 mg, 46% yield) as a white solid {Mp
79ꢀ81 °C; [R]20D þ16 (c 1.0, CHCl3)}. (þ)-24a (332 mg, 1 mmol)
afforded (þ)-24b (201 mg, 81% yield). 1H NMR (CDCl3, 400 MHz),
13C NMR (CDCl3, 100 MHz), and MS spectra data of (þ)-24a and
(þ)-24b are identical with those of (ꢀ)-24a and (ꢀ)-24b.
According to the bromination procedure for the preparation of 19,
(ꢀ)-22 (531 mg, 3.12 mmol) afforded (ꢀ)-23 (720 mg, 93% yield) as a
colorless oil. [R]20D ꢀ20 (c 0.2, CHCl3); IR (KBr) 3373, 2936, 1694,
1148, 1095, 1033, 916 cmꢀ1; 1H NMR (CDCl3, 400 MHz) δ 7.21 (t, J =
4.4 Hz, 1H, H-3), 4.64 (dd, J = 26.8, 6.8 Hz, 2H, OCH2), 4.13 (dd, J =
7.6, 3.6 Hz, 1H, H-5), 3.35 (s, 3H, OCH3), 2.86ꢀ2.80 (m, 1H, H-6),
2.78ꢀ2.61 (m, 2H, H-4), 1.26 (d, J = 6.8 Hz, 3H, H-7); 13C NMR
(CDCl3, 100 MHz) δ 192.3 (C, C-1), 145.0 (CH, C-3), 123.4 (CH,
C-2), 95.7 (OCH2), 75.9 (CH, C-5), 55.7 (OCH3), 47.5 (CH, C-6),
33.0 (CH2, C-4), 11.3 (CH3, C-7); HRMS (ESI) m/z calcd for
C9H17BrNO3 [M þ NH4]þ 266.0386, found 266.0389.
(ꢀ)-(9R,10R)-9-Allyloxy-6-bromo-10-methylspiro[4.5]dec-
6-ene and (þ)-(9S,10S)-9-Allyloxy-6-bromo-10-methylspiro-
[4.5]dec-6-ene [(ꢀ)-25 and (þ)-25].
According to the above procedure, (þ)-22 (291 mg, 1.71 mmol)
afforded (þ)-23 (411 mg, 97%) as a colorless oil. [R]20 þ2 (c 1.0,
To a stirred solution of ketone (ꢀ)-24b (411 mg, 1.66 mmol) in
DMF (6 mL) was added NaH (74 mg, 55% purity, 1.70 mmol) at 0 °C,
the reaction mixture was maintained at this temperature for 1 h, and allyl
D
CHCl3); 1H NMR (CDCl3, 400 MHz), 13C NMR (CDCl3, 100 MHz),
and MS spectra data of (þ)-23 are identical with those of (ꢀ)-23.
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bromide (0.2 mL, 1.70 mmol) was then added. The reaction mixture was
allowed to warm to rt, and this temperature was maintained for 8 h. Then
the reaction mixture was diluted with H2O (6 mL) and extracted with
EtOAc (20 mL ꢁ 3). The organic layer was dried with MgSO4, filtered,
and concentrated in vacuo. Flash chromatography of the residue over
silica gel (petroleum ether/EtOAc 10:1) afforded compound (ꢀ)-25
(337 mg, 65% yield) as a colorless oil. [R]20D ꢀ23 (c 2.0, CHCl3); IR
(KBr) 3431, 2896, 1727, 1336, 1147, 1075, 865, 588 cmꢀ1; 1H NMR
(CDCl3, 400 MHz) δ 6.21ꢀ6.19 (m, 1H, H-7), 5.96ꢀ5.87 (m, 1H,
CH), 5.30ꢀ5.16 (m, 2H, dCH2), 4.28ꢀ3.88 (m, 7H, H-2, H-3, H-9,
and CH2), 2.39ꢀ2.10 (m, 3H, H-8 and H-10), 0.99 (d, J = 6.8 Hz, 3H,
H-11); 13C NMR (CDCl3, 100 MHz) δ 134.9 (CH), 131.7 (CH, C-7),
124.0 (C, C-6), 116.8 (CH2, dCH2), 108.8 (C, C-5), 73.8 (CH, C-9),
69.4 (CH2), 66.4 (CH2, C-2), 65.3 (CH2, C-3), 41.8 (CH, C-10), 29.9
(CH2, C-8), 7.7 (CH3, C-11); HRMS (ESI) m/z calcd for C12H18BrO3
[M þ H]þ 289.0434, found 289.0441.
0.27 mmol) afforded 26a (58 mg, 42% yield) as a colorless oil. [R]20D ꢀ5.0
(c 1.0, CHCl3); IR (KBr) 3464, 2985, 2256, 1741, 1375, 1242, 1408, 919,
735, 608 cmꢀ1; 1H NMR (CDCl3, 400 MHz) δ 6.66/6.61 (t, J = 4.4 Hz,
1H, H-600), 6.13/6.12 (s, 1H, H-30), 5.88ꢀ5.83 (m, 1H, CH), 5.50ꢀ5.45
(m, 2H, H-4 and H-5), 5.28ꢀ5.14 (m, 2H, dCH2), 4.25ꢀ3.91 (m, 5H,
H-10, H-400, and CH2), 3.32 (s, 3H, H-15), 3.16ꢀ3.13 (m, 1H, H-7),
2.94/2.87 (s, 3H, NCH3), 2.83ꢀ2.77 (m, 1H, H-300), 2.69ꢀ2.62 (m,
2H, H-500), 2.31ꢀ2.27 (m, 4H, H-3 and H-2), 2.20ꢀ2.16 (m, 2H, H-6),
1.44ꢀ1.41 (m, 2H, H-8), 1.27ꢀ1.25 (m, 10H, H-9, H-10, H-11, H-12,
and H-13), 1.19 (t, J = 6.8 Hz, 3H, H-700), 0.88 (t, J = 6.8 Hz, 3H, H-14);
13C NMR (CDCl3, 100 MHz) δ 198.4/198.7 (C, C-200), 172.4/172.9
(C, C-1), 144.7/145.7 (CH, C-600), 135.4/136.0 (C, C-20), 135.1/134.3
(C, C-100), 134.6/134.5 (CH), 131.1 (CH, C-4), 127.1/127.2 (CH,
C-5), 118.0/118.2 (CH, C-30), 116.8/117.0 (dCH2), 80.7/80.8 (CH,
C-7), 76.47/76.49 (CH, C-400), 69.8/70.0 (CH2), 56.45/56.48 (CH3,
C-15), 51.1/53.5 (CH2, C-10), 46.4/46.6 (CH, C-300), 36.3/36.4 (CH2,
C-6), 35.2/33.4 (CH3, NCH3), 33.31/33.36 (CH2, C-2), 33.28/32.7
(CH2, C-500), 31.8 (CH2, C-8), 29.6/29.8 (CH2, C-12), 29.7 (CH2,
C-10), 29.24/29.27 (CH2, C-11), 28.1/28.3 (CH2, C-3), 25.2/25.3
(CH2, C-9), 22.6 (CH2, C-13), 14.1 (CH3, C-14), 10.4/10.5 (CH3,
C-700); HRMS (ESI) m/z C29H47ClNO4 [M þ H]þ calcd 508.3188,
found 508.3183.
According to the above procedure, (þ)-24b (159 mg, 0.64 mmol)
afforded (þ)-25 (120 mg, 65% yield) as a colorless oil. [R]20D þ35 (c
1
1.0, CHCl3); H NMR (CDCl3, 400 MHz), 13C NMR (CDCl3, 100
MHz), and MS spectra data of (þ)-25 are identical with those of (ꢀ)-25.
(ꢀ)-(5R,6R)-5-Allyloxy-2-dihydroxyboryl-6-methyl-2-cy-
clohexen-1-one and (þ)-(5S,6S)-5-Allyloxy-2-dihydroxybor-
yl-6-methyl-2-cyclohexen-1-one [(ꢀ)-7 and (þ)-7].
According to the procedure for the preparation of 1, except using
Sphos as the ligand, (þ)-7 (80 mg, 0.38 mmol) and 5b (89 mg, 0.19
mmol) afforded 26b (37 mg, 38% yield) as a colorless oil. [R]20D ꢀ5 (c
1
1.0, CHCl3); H NMR (CDCl3, 400 MHz), 13C NMR (CDCl3, 100
MHz), and MS spectra data of 26b are identical with those of 26a.
(ꢀ)-(4E,7S)-N-{(2Z)-[(3R,4R)-4-Hydroxy-3-methyl-2-oxo-
cyclohex-1-enyl]-2-chloromethyleneethyl}-N-methyl-7-met-
hoxytetradec-4-enamide and (þ)-(4E,7S)-N-{(2Z)-[(3S,4S)-4-
Hydroxy-3-methyl-2-oxocyclohex-1-enyl]-2-chloromethyle-
neethyl}-N-methyl-7-methoxytetradec-4-enamide [300,400-epi-
malyngamide L (2) and malyngamide L (3)].
According to the procedure for the preparation of 6, (ꢀ)-25 (263 mg,
0.91 mmol) afforded (ꢀ)-7 (178 mg, 93% yield) as a colorless oil.
[R]20 ꢀ6 (c 1.0, CHCl3); IR (KBr) 3385, 2926, 2026, 1652, 1342,
D
1072, 926, 783 cmꢀ1; 1H NMR (CDCl3, 400 MHz) δ 7.69 (t, J = 3.6 Hz,
1H, H-3), 7.12 (s, 2H, 2 ꢁ OH), 5.91ꢀ5.82 (m, 1H, CH), 5.29ꢀ5.12
(m, 2H, dCH2), 4.04ꢀ3.89 (m, 3H, H-5 and CH2), 2.78ꢀ2.63 (m, 3H,
H-6 and H-4), 1.18 (d, J = 6.8 Hz, 3H, H-7); 13C NMR (CDCl3, 100
MHz) δ 208.1 (C, C-1), 159.8 (CH, C-3), 134.5 (CH), 117.1
(CH2, dCH2), 76.7 (CH, C-5), 70.1 (CH2), 46.1 (CH, C-6), 31.0
(CH2, C-4), 10.5 (CH3, C-7); HRMS (ESI) m/z calcd for C10H16BO4
[M þ H]þ 211.1136, found 211.1138.
According to the procedure for the preparation of 6, (þ)-25 (166 mg,
0.58 mmol) afforded (þ)-7(87 mg, 71% yield) as a colorless oil. [R]20D þ10
1
(c 0.2, CHCl3); H NMR (CDCl3, 400 MHz), 13C NMR (CDCl3, 100
MHz), and MS spectra data of (þ)-7 are identical with those of (ꢀ)-7.
(ꢀ)-(4E,7S)-N-{(2Z)-[(3R,4R)-4-Allyloxy-3-methyl-2-oxocy-
clohex-1-enyl]-2-chloromethyleneethyl}-N-methyl-7-meth-
oxytetradec-4-enamide and (ꢀ)-(4E,7S)-N-{(2Z)-[(3S,4S)-4-
allyloxy-3-methyl-2-oxocyclohex-1-enyl]-2-chloromethylen-
eethyl}-N-methyl-7-methoxytetradec-4-enamide (26a and
26b).
To a stirred solution of allyl ether 26a (22 mg, 0.04 mmol) in MeOH
and DCM (2 mL, MeOH/DCM 3:2) was added PdCl2 (50 mg, 0.28
mmol). The dark brown suspension was stirred at rt for 7 h, and then
toluene (2 mL) was added. The reaction mixture was concentrated in
vacuo. Flash chromatography of the residue over silica gel (petroleum
ether/EtOAc 1:2) afforded 300,400-epi-malyngamide L (2) (13 mg, 70%
yield) as a colorless oil. [R]20D ꢀ17 (c 0.3, EtOH); IR (KBr) 3414, 2928,
1678, 1634, 1460, 1358, 1097, 970, 812, 601 cmꢀ1; 1H NMR (CDCl3,
400 MHz) δ 6.59/6.63 (s, 1H, H-600), 6.21/6.15 (s, 1H, H-30),
5.47ꢀ5.43 (m, 2H, H-4 and H-5), 4.28ꢀ4.15 (m, 2H, H-10),
4.15ꢀ3.98 (m, 1H, H-400), 3.317/3.324 (s, 1H, H-15), 3.19ꢀ3.11 (m,
1H, H-7), 2.97/2.87 (s, 3H, NCH3), 2.75/2.80 (t, J = 3.2 Hz, 1H, H-300),
2.72ꢀ2.63 (m, 2H, H-500), 2.35ꢀ2.22 (m, 4H, H-2 and H-3), 2.18ꢀ2.14
(m, 2H, H-6), 1.43ꢀ1.42 (m, 2H, H-8), 1.30ꢀ1.22 (m, 13H, H-9, H-10,
H-11, H-12, H-13, and H-700), 0.88 (t, J = 6.4 Hz, 3H, H-14); 13C NMR
(CDCl3, 100 MHz) δ 197.53 (C, C-200), 173.72/172.98 (C, C-1),
143.70/145.39 (CH, C-600), 136.32 (C, C-20), 135.66 (C, C-100),
131.03/129.74 (CH, C-4), 127.15/126.77 (CH, C-5), 118.66 (CH,
C-30), 80.74 (CH, C-7), 71.57 (70.55) (CH, C-400), 56.48/56.25 (CH3,
C-15), 52.39/53.47 (CH2, C-10), 48.12/47.84 (CH, C-300), 36.36/36.18
According to the procedure for the preparation of 1, except using
Sphos as the ligand, (ꢀ)-7 (113 mg, 0.54 mmol) and 5b (125 mg,
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(CH2, C-6), 34.91/33.20 (CH3, NCH3), 34.63/33.92 (CH2, C-500),
33.43/33.58 (CH2, C-2), 33.30/32.51 (CH2, C-8), 31.80/31.04 (CH2,
C-12), 29.72 (CH2, C-10), 29.27 (CH2, C-11), 27.79/28.20 (CH2,
C-3), 25.24/25.38 (CH2, C-9), 22.63/22.77 (CH2, C-13), 14.08 (CH3,
C-14), 11.22/10.71 (CH3, C-700); HRMS (ESI) m/z C26H43ClNO4
[M þ H]þ calcd 468.2875, found 468.2872.
(CH, C-2), 66.0 (CH, C-4), 35.3 (CH2, C-5), 32.2 (CH2, C-6); MS
(ESI) m/z 135.1 ([M þ Na]þ).
(þ)-(R)-2-Bromo-4-tert-butyldimethylsilyloxycyclohex-2-
enone (29).
According to the above procedure, 26b (12 mg, 0.02 mmol) afforded
malyngamide L (3) (7 mg, 76% yield) as a colorless oil. [R]20D þ20 (c
1
0.25, EtOH); H NMR (CDCl3, 400 MHz), 13C NMR (CDCl3, 100
MHz), and MS spectra data of 3 are identical with 2.
(7R,8R)-1,4-Dioxaspiro[4.5]decane-7,8-diol (28).45,46
To a stirred solution of ketone 13 (110 mg, 0.98 mmol) in DMF
(2 mL) were added TBSCl (369 mg, 2.45 mmol) and imidazole (180
mg, 2.65 mmol) at 0 °C, and the reaction mixture was maintained at this
temperature for 4 h. Then the reaction mixture was diluted with H2O
(4 mL) and extracted with EtOAc (5 mL ꢁ 3). The organic layer was
dried with MgSO4, filtered, and concentrated in vacuo. Flash chroma-
tography of the residue over silica gel (petroleum ether/EtOAc 5:1)
afforded silyl ether as a colorless oil. According to the bromination
procedure for the preparation of 19, the silyl ether afforded 29 (268 mg,
90% yield in two steps) as a colorless oil. [R]20D þ12 (c 1.0, CHCl3); IR
(KBr) 3379, 2955, 1700, 1601, 1468, 1360, 1256, 1105, 972, 873, 837,
779, 669, 490 cmꢀ1; 1H NMR (CDCl3, 400 MHz) δ 7.25 (dd, J = 2.8, 1.2
Hz, 1H, H-3), 4.55ꢀ4.51 (m, 1H, H-4), 2.81ꢀ2.74 (m, 1H, H-6a),
2.50ꢀ2.42 (m, 1H, H-6b), 2.26ꢀ2.19 (m, 1H, H-5a), 2.07ꢀ1.98 (m,
1H, H-5b), 0.89 (s, 9H, 3 ꢁ CH3), 0.11 (3H, CH3), 0.10 (3H, CH3);
13C NMR (CDCl3, 100 MHz) δ 190.4 (C, C-1), 153.7 (CH, C-3), 123.8
(C, C-2), 68.3 (CH, C-4), 34.7 (CH2, C-5), 32.7 (CH2, C-6), 25.6
(CH3), ꢀ4.8 (CH3), ꢀ4.9 (CH3); HRMS (ESI) m/z calcd for
C12H25BrNO2Si [M þ NH4]þ 322.0832, found 322.0824.
To a stirred solution of 1,4-cyclohexanedione monoethyleneketal
(27) (1.00 g, 6.41 mmol) and L-proline (110 mg, 0.96 mmol) in DMF
(15 mL) was added a solution of nitrosobenzene (343 mg, 3.21 mmol)
in DMF (4 mL) over 15 h by syringe pump at 0 °C, and the reac-
tion mixture was maintained at this temperature for 2 h. Then MeOH
(8 mL) and CeCl3 7H2O (2.61 g, 7.00 mmol) were added to the
3
mixture, followed by NaBH4 (266 mg, 7.00 mmol). The reaction
mixture was stirred for 30 min at 0 °C, diluted with H2O (10 mL),
and extracted with EtOAc (30 mL ꢁ 3). The organic layer was dried with
MgSO4, filtered, and concentrated in vacuo. Flash chromatography of
the residue over silica gel (petroleum ether/EtOAc 2:1) afforded the
alcohol. To a solution of this alcohol in MeOH (10 mL) was added Pd/
C (30 mg, 10% purity), and the mixture was stirred under H2 atmo-
sphere at rt for 5 h. The reaction mixture was filtered and concentrated in
vacuo. Flash chromatography of the residue over silica gel (petroleum
ether/EtOAc 1:1) afforded diol 28 (469 mg, 42% yield in three steps) as
a light brown oil. [R]20D 0 (c 0.3, CHCl3); IR (KBr) 3393, 2924, 1456,
(þ)-(R)-6-Bromo-8-trimethylsilyloxy-spiro[4.5]dec-6-ene
and (ꢀ)-(R)-8ꢀ6-Bromo-hydroxyspiro[4.5]dec-6-ene (30a
and 30b).
1359, 1053, 923, 808, 599 cmꢀ1 1H NMR (CDCl3, 400 MHz) δ
;
3.99ꢀ3.91 (m, 4H, H-3 and H-2), 3.75 (br, 2H, OH), 3.64ꢀ3.58 (m,
1H, H-7), 3.48ꢀ3.42 (m, 1H, H-8), 2.08ꢀ2.03 (m, 1H, H-6a),
1.92ꢀ1.87 (m, 1H, H-6b), 1.84ꢀ1.73 (m, 1H, H-9a), 1.73ꢀ1.61 (m,
3H, H-9b and H-10); 13C NMR (CDCl3, 100 MHz) δ 108.7 (C, C-5),
74.0 (CH, C-8), 72.6 (CH, C-7), 64.32 (CH2, C-3), 64.28 (CH2, C-2),
40.3 (CH2, C-6), 32.4 (CH2, C-10), 28.0 (CH2, C-9); MS (ESI) m/z
197.1 ([M þ Na]þ).
To a stirred solution of ketone 29 (297 mg, 0.98 mmol) in DCM
(10 mL) were added TMSOCH2CH2OTMS (0.8 mL, 3.30 mmol),
HOCH2CH2OH (0.1 mL, 2.00 mmol), and TMSOTf (9 mg, 0.04
mmol) at 0 °C, and the reaction mixture was maintained at this
temperature for 1 h. Then the reaction mixture was allowed to warm
to 20 °C, and this temperature was maintained for 5 h. The reaction
mixture was diluted with Et3N (1 mL) and extracted with DCM (20 mL
ꢁ 3). The organic layer was dried with MgSO4, filtered, and concen-
trated in vacuo. Flash chromatography of the residue over silica gel
(petroleum ether/EtOAc 2:1) afforded compounds 30a (117 mg, 39%
yield) and 30b (105 mg, 46% yield) as a colorless oil. According to the
procedure for the preparation of (ꢀ)-24b, 30a (156 mg, 0.51 mmol)
also afforded compound 30b (97 mg, 81% yield). For 30a: [R]20D þ2 (c
1.0, CHCl3); IR (KBr) 3396, 2957, 1638, 1463, 1364, 1257, 1090, 1019,
946, 882, 839, 800, 540 cmꢀ1; 1H NMR (CDCl3, 400 MHz) δ 6.24 (d,
J = 2.8 Hz, 1H, H-7), 4.23ꢀ4.16 (m, 3H, H-3 and H-8), 4.04ꢀ3.91 (m,
2H, H-2), 2.12ꢀ1.91 (m, 2H, H-10), 1.85ꢀ1.76 (m, 2H, H-9), 0.13 (s,
9H, 3 ꢁ CH3); 13C NMR (CDCl3, 100 MHz) δ 139.0 (CH, C-7), 126.7
(C, C-6), 105.5 (C, C-5), 67.9 (CH, C-8), 66.1 (CH2, C-3), 65.8 (CH2,
(þ)-(R)-4-Hydroxycyclohex-2-enone (13).45
To a stirred solution of diol 28 (456 mg, 2.62 mmol) in THF and
H2O (50 mL, THF/H2O 1:1) was added HCl (3.3 mL, 2 M), and the
mixture was stirred at rt for 24 h. A saturated aqueous solution of
(NH4)2SO4 (25 mL) was added to quench the reaction. Then the
mixture was extracted with EtOAc (80 mL ꢁ 3). The organic layer was
dried with MgSO4, filtered, and concentrated in vacuo. Flash chroma-
tography of the residue over silica gel (petroleum ether/EtOAc 1:1)
afforded ketone 13 (189 mg, 65% yield) as a colorless oil. [R]20D þ89 (c
0.7, CHCl3); IR (KBr) 3392, 2924, 2140, 1672, 1456, 1378, 1254, 1205,
1065, 943, 862, 760, 547 cmꢀ1; 1H NMR (CDCl3, 400 MHz) δ 6.98 (d,
J = 10.0 Hz, 1H, H-3), 5.96 (d, J = 10.0 Hz, 1H, H-2), 4.58 (dd, J = 4.4,
2.4 Hz, 1H, H-4), 3.50 (br, 1H, OH), 2.61ꢀ2.55 (m, 1H, H-6a),
2.43ꢀ2.32 (m, 2H, H-6b and H-5a), 2.05ꢀ1.95 (m, 1H, H-5b); 13C
NMR (CDCl3, 100 MHz) δ 199.4 (C, C-1), 153.6 (CH, C-3), 128.8
C-2), 32.4 (CH2, C-10), 30.5 (CH2, C-9), 0.1 (CH3). For 30b: [R]20
D
ꢀ10 (c 1.0, CHCl3); IR (KBr) 3392, 2923, 1634, 1460, 1345, 1155,
1085, 940, 747, 523 cmꢀ1; 1H NMR (CDCl3, 400 MHz) δ 6.38 (d, J =
2.8 Hz, 1H, H-7), 4.24ꢀ4.18 (m, 3H, H-3 and H-8), 4.06ꢀ3.93 (m, 2H,
H-2), 2.19 (br, 1H, OH), 2.15ꢀ2.05 (m, 2H, H-10), 1.87ꢀ1.73 (m, 2H,
H-9); 13C NMR (CDCl3, 100 MHz) δ 138.3 (CH, C-7), 127.6 (C, C-6),
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105.4 (C, C-5), 67.5 (CH, C-8), 66.2 (CH2, C-3), 65.8 (CH2, C-2), 32.2
(CH2, C-10), 30.1 (CH2, C-9); MS (EI) m/z (%) 234 (Mþ, 1), 208 (9)/
206 (10), 192 (12)/190 (39), 155 (89), 127 (28), 99 (100)/97 (22).
Elemental Anal. Calcd for C8H11BrO3: C, 40.87; H, 4.72. Found: C,
41.23; H, 4.52.
(CH, C-600), 135.9 (C, C-20), 135.7 (C, C-100), 134.3 (CH), 130.7 (CH,
C-4), 127.7 (CH, C-5), 119.8 (CH, C-30), 117.6 (dCH2), 80.7 (CH,
C-7), 72.5 (CH, C-500), 70.0 (CH2), 56.4 (CH3, C-15), 43.4 (CH2,
C-10), 36.4 (CH2, C-6), 36.3 (CH2, C-2), 35.6 (CH2, C-8), 33.3 (CH2,
C-300), 31.8 (CH2, C-12), 29.7 (CH2, C-10), 29.3 (CH2, C-11), 29.2
(CH2, C-3), 28.5 (CH2, C-400), 25.3 (CH2, C-9), 22.6 (CH2, C-13), 14.1
(CH3, C-14); HRMS (ESI) m/z calcd for C27H43ClNO4 [M þ H]þ
480.2875, found 480.2887.
(þ)-(R)-8-Allyloxy-6-bromospiro[4.5]dec-6-ene (31).
(þ)-(4E,7S)-N-[(2Z)-(R-5-tert-Butyldimethylsilyloxy-2-oxo-
cyclohex-1-enyl)-2-chloromethyleneethyl]-7-methoxyte-
tradec-4-enamide (33).
According to the procedure for the preparation of (ꢀ)-25, 30b (263
mg, 1.12 mmol) afforded 31 (196 mg, 64% yield) as a colorless oil.
[R]20 þ37 (c 0.3, CHCl3); IR (KBr) 3393, 2923, 1740, 1643, 1459,
D
1358, 1161, 1088, 1024, 946, 791 cmꢀ1; 1H NMR (CDCl3, 400 MHz) δ
6.40 (d, J = 2.8 Hz, 1H, H-7), 5.95ꢀ5.85 (m, 1H, CH), 5.31ꢀ5.16 (m,
2H, dCH2), 4.23ꢀ4.16 (m, 2H, CH2), 4.03ꢀ3.90 (m, 5H, H-2, H-3,
and H-8), 2.14ꢀ1.91 (m, 2H, H-10), 1.89ꢀ1.77 (m, 2H, H-9); 13C
NMR (CDCl3, 100 MHz) δ 135.9 (CH, C-7), 134.5 (CH), 128.1 (C,
C-6), 117.0 (dCH2), 105.5 (C, C-5), 73.6 (CH, C-8), 69.3 (CH2), 66.0
(CH2, C-3), 65.8 (CH2, C-2), 32.1 (CH2, C-10), 26.7 (CH2, C-9);
HRMS (ESI) m/z calcd for C11H15BrO3Na [M þ Na]þ 297.0097,
found 297.0093.
According to the procedure for the preparation of 2, 32 (19 mg, 0.04
mmol) afforded corresponding alcohol (17 mg, 75% yield) as a colorless
oil. To a stirred solution of this alcohol (13 mg, 0.03 mmol) in DMF
(1 mL) were added TBSCl (12 mg, 0.09 mmol) and imidazole (6 mg,
0.09 mmol) at 0 °C, and the reaction mixture was maintained at this
temperature for 4 h. Then the reaction mixture was diluted with H2O
(4 mL) and extracted with EtOAc (5 mL ꢁ 3). The organic layer was
dried with MgSO4, filtered, and concentrated in vacuo. Flash chroma-
tography of the residue over silica gel (petroleum ether/EtOAc 5:1)
afforded silyl ether 33 (15 mg, 69% yield in two steps) as a colorless oil.
(þ)-(R)-6-Allyloxy-2-dihydroxyboryl-2-cyclohexen-1-one
(8).
[R]20 þ5 (c 0.1, CHCl3); IR (KBr) 3369, 2923, 2854, 1660, 1460,
D
1378, 1097, 1025, 723 cmꢀ1; 1H NMR (CDCl3, 400 MHz) δ 6.77 (s,
1H, H-600), 6.31 (s, 1H, H-30), 6.05 (br, 1H, NH), 5.49ꢀ5.46 (m, 2H,
H-4 and H-5), 4.63ꢀ4.59 (m, 1H, H-500), 4.03ꢀ3.98 (m, 1H, H-10a),
3.91ꢀ3.86 (m, 1H, H-10b), 3.33 (s, 3H, H-15), 3.18ꢀ3.12 (m, 1H, H-7),
2.72ꢀ2.40 (m, 2H, H-300), 2.35ꢀ2.31 (m, 2H, H-3), 2.27ꢀ2.01 (m, 6H,
H-6, H-2, and H-400), 1.43 (s, 2H, H-8), 1.28ꢀ1.27 (m, 10H, H-9, H-10,
H-11, H-12, and H-13), 0.93ꢀ0.88 (m, 12H, 3 ꢁ CH3 and H-14), 0.14
(s, 3H, CH3), 0.15(s, 3H, CH3); 13C NMR (CDCl3, 100 MHz) δ 197.6
(C, C-200), 172.3 (C, C-1), 154.0 (CH, C-600), 135.8 (C, C-20), 135.0 (C,
C-100), 130.7 (CH, C-4), 127.7 (CH, C-5), 120.0 (CH, C-30), 80.7 (CH,
C-7), 67.0 (CH, C-500), 56.5 (CH3, C-15), 43.5 (CH2, C-10), 36.5 (CH2,
C-6), 36.4 (CH2, C-2), 35.8 (CH2, C-8), 33.4 (CH2, C-300), 32.8 (CH2,
C-12), 31.8 (CH2, C-10), 29.8 (CH2, C-11), 29.3 (CH2, C-3), 28.6
(CH2, C-400), 25.7 (CH3), 25.3 (CH2, C-9), 22.7 (CH2, C-13), 14.1
(CH3, C-14), ꢀ4.6 (CH3), ꢀ4.7 (CH3); HRMS (ESI) m/z calcd for
C30H53ClNO4Si [M þ H]þ 554.3427, found 554.3416.
According to the procedure for the preparation of 6, 31 (200 mg, 0.73
mmol) afforded 8 (100 mg, 70% yield) as a yellow oil. [R]20D þ41 (c 0.3,
CHCl3); IR (KBr) 3302, 2926, 1655, 1536, 1417, 1094, 925 cmꢀ1; 1H
NMR (CDCl3, 400 MHz) δ 7.81 (s, 1H, H-3), 6.33 (s, 2H, 2 ꢁ OH),
5.99ꢀ5.90 (m, 1H, CH), 5.36ꢀ5.23 (m, 2H, dCH2), 4.28ꢀ4.24 (m,
1H, H-4), 4.16ꢀ4.10 (m, 2H, CH2), 2.72ꢀ2.03 (m, 4H, H-5 and H-6);
13C NMR (CDCl3, 100 MHz) δ 205.7 (C, C-1), 164.3 (CH, C-3), 134.3
(CH), 117.7 (CH2, dCH2), 73.2 (CH, C-4), 70.1 (CH2), 36.0 (CH2,
C-6), 29.3 (CH2, C-5); MS (EI) m/z (%) 196 (Mþ, 1), 195 (5), 151
(14), 111 (100), 96 (33), 94 (9). Elemental Anal. Calcd for C9H13BO4:
C, 55.15; H, 6.69. Found: C, 55.23; H, 7.02.
(þ)-(4E,7S)-N-[(2Z)-(R-5-Allyloxy-2-oxocyclohex-1-enyl)-
(ꢀ)-(4E,7S)-N-[(2Z)-2-(1S,5R,6S-5-tert-Butyldimethylsily-
loxy-2-oxo-7-oxabicyclo[4.1.0]heptan-1-yl)-2-chloromethy-
leneethyl]methoxytetradec-4-enamide (34).
2-chloromethyleneethyl]-7-methoxytetradec-4-enamide (32).
According to the procedure for the preparation of 1, except using
Sphos as the ligand, 5a (64 mg, 0.14 mmol) afforded 32 (38 mg, 56%
yield) as a colorless oil. [R]20D þ8 (c 0.5, CHCl3); IR (KBr) 3372, 2923,
2854, 1661, 1460, 1378, 1096, 1027, 402 cmꢀ1; 1H NMR (CDCl3, 400
MHz) δ 6.91(d, J = 1.2 Hz, 1H, H-600), 6.31 (s, 1H, H-30), 6.05 (br, 1H,
NH), 5.97ꢀ5.90 (m, 1H, CH), 5.48ꢀ5.45 (m, 2H, H-4 and H-5),
5.35ꢀ5.22 (m, 2H, dCH2), 4.33ꢀ4.29 (m, 1H, H-500), 4.14ꢀ4.12 (m,
2H, CH2), 4.02ꢀ3.97 (m, 1H, H-10a), 3.91ꢀ3.86 (m, 1H, H-10b), 3.32
(s, 3H, H-15), 3.16ꢀ3.13 (m, 1H, H-7), 2.73ꢀ2.42 (m, 2H, H-300),
2.40ꢀ2.04 (m, 8H, H-3, H-6, H-2, and H-400), 1.42 (s, 2H, H-8), 1.27 (s,
10H, H-9, H-10, H-11, H-12, and H-13), 0.88 (t, J = 6.8 Hz, 3H, H-14);
13C NMR (CDCl3, 100 MHz) δ 197.3 (C, C-200), 172.3 (C, C-1), 150.8
To a stirred solution of silyl ether 33 (3 mg, 5.42 μmol) in THF
(1 mL) at 0 °C were added H2O2 (0.5 mL) and triton B (0.1 mg, 1.00
μmol). The reaction mixture was stirred for 30 min at 0 °C, and then
NH4Cl (2.0 mg) was added. The mixture was concentrated in vacuo.
Flash chromatography of the residue over silica gel (petroleum ether/
EtOAc 2:1) afforded the corresponding epoxide 34 (3 mg, 93% yield) as
a colorless oil. [R]20D ꢀ8 (c 0.2, MeOH); IR (KBr) 3394, 2923, 2854,
1740, 1650, 1541, 1460, 1377, 1094, 722 cmꢀ1; 1H NMR (CDCl3, 400
MHz) δ 6.37 (s, 1H, H-30), 6.11 (br, 1H, NH), 5.48ꢀ5.46 (m, 2H, H-4
and H-5), 4.87ꢀ4.46 (m, 1H, H-500), 4.00ꢀ3.95 (m, 1H, H-10a),
3.85ꢀ3.80 (m, 1H, H-10b), 3.42 (d, J = 2.4 Hz, 1H, H-600), 3.32
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ARTICLE
(s, 3H, H-15), 3.17ꢀ3.11 (m, 1H, H-7), 2.40ꢀ2.31 (m, 3H, H-300 and
H-3a), 2.26ꢀ2.22 (m, 2H, H-3b and H-6a), 2.19ꢀ2.17 (m, 2H, H-6b
and H-2a), 2.07ꢀ1.99 (2H, H-2b and H-400a), 1.82ꢀ1.75 (m, 1H,
H-400b), 1.44ꢀ1.42 (m, 2H, H-8), 1.27 (br, 10H, H-9, H-10, H-11, H-12,
and H-13), 0.93ꢀ0.86 (m, 12H, 3 ꢁ CH3 and H-14), 0.132 (s, 3H,
CH3), 0.126 (s, 3H, CH3); 13C NMR (CDCl3, 100 MHz) δ 203.2 (C,
C-200), 172.2 (C, C-1), 133.2 (C, C-20), 130.7 (CH, C-4), 127.6 (CH,
C-5), 122.5 (CH, C-30), 80.8 (CH, C-7), 64.9 (CH, C-600), 64.3 (CH,
C-500), 60.5 (CH3, C-100), 56.5 (CH3, C-15), 40.8 (CH2, C-10), 36.5
(CH2, C-6), 36.4 (CH2, C-2), 33.4 (CH2, C-8), 32.2 (CH2, C-300), 31.8
(CH2, C-12), 29.8 (CH2, C-10), 29.3 (CH2, C-11), 28.5 (CH2, C-3),
25.8 (CH2, C-400), 25.7 (CH3), 25.3 (CH2, C-9), 22.7 (CH2, C-13), 14.1
(CH3, C-14), ꢀ4.7 (CH3), ꢀ5.0 (CH3); HRMS (ESI) m/z calcd for
C30H53ClNO5Si [M þ H]þ 570.3376, found 570.3366.
malyngamide L (3) and 300,400-epi-malyngamide L. Comparison
1
13
of H and C NMR spectra of 500-epi-malyngamide C (4)
(isolated 4 and synthetic 4). This material is available free of
charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: caoxplzu@163.com
’ ACKNOWLEDGMENT
The authors are grateful to the National Basic Research
Program (973 Program) of China (Grant No. 2010CB833203),
the National Natural Science Foundation of China (Grant Nos.
20872055 and 20972060), Specialized Research Fund for
the Doctoral Program of Higher Education (Grant No.
20090211110007), and the 111 Project for continuing financial
support. We also gratefully acknowledge Dr. Ling Zhou, National
University of Singapore, for his helpful guidance in preparing the
manuscript.
(ꢀ)-(4E,7S)-N-[(2Z)-2-(1S,5R,6S-5-Hydroxy-2-oxo-7-oxabi-
cyclo[4.1.0]heptan-1-yl)-2-chloromethyleneethyl]methoxy-
tetradec-4-enamide [500-epi-malyngamide C (4)].
To a stirred solution of epoxide 34 (3 mg, 5.26 μmol) in THF (1 mL)
at 0 °C was added TBAF (5 mg, 0.02 mmol). The reaction mixture was
stirred for 30 min at 0 °C, and then the reaction mixture was
concentrated in vacuo. Flash chromatography of the residue over silica
gel (petroleum ether/EtOAc 1:1) afforded 4 (2 mg, 87% yield) as a
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b
ure S2. Comparison of H and 13C NMR spectral data for
1
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