Total synthesis of lathyranoic acid A

Article abstract of DOI:10.1021/jo102033h

The first total synthesis of lathyranoic acid A (1) was accomplished stereoselectively in a linear sequence of 20 steps and an overall yield of 1.4%. This modular synthesis featured a cyclic, stereocontrolled Cu-catalyzed intramolecular cyclopropanation t

Full text of DOI:10.1021/jo102033h

pubs.acs.org/joc
activity5 as well as P-glycoprotein inhibition.6 Among these
Total Synthesis of Lathyranoic Acid A
diterpenoids, lathyranoic acid A is a secolathyrane diterpe-
noid with an unprecedented skeleton, originally proposed
as an oxidation product of Euphorbia factor L11 isolated
from the seeds of E. lathyris.1 Lathyranoic acid A possesses a
unique stereochemical distribution, including a stereode-
fined cis-vinylcyclopropane and a 2-methylene-1,3-alkoxide.
These interesting moieties combined with the potential bio-
logical activity drew our attention; we elected to synthesize
and generate its analogues for further biological examina-
tions.
Li-Fang Yu, Hai-Ning Hu, and Fa-Jun Nan*
Chinese National Center for Drug Screening, State Key
Laboratory of Drug Research, Shanghai Institute of
Materia Medica, Chinese Academy of Sciences,
189 Guoshoujing Road, Zhangjiang Hi-Tech Park, Shanghai,
201203, People’s Republic of China
fjnan@mail.shcnc.ac.cn
Our retrosynthetic analysis of lathyranoic acid A was
outlined in Figure 1.7 The skeleton could presumably be
accomplished by an appropriate addition of alkenyllithium
fragment 2 to the highly functionalized aldehyde 3. The
cyclopentenone moiety was constructed using an intramole-
cular ring-closing metathesis reaction of 4, while the well-
defined stereochemistry was generated via a methyllithium
syn conjugate addition of enoate 6. The framework of the
aldehyde 3 could be constructed from lactone 5, which could
be formed in turn from a Cu-catalyzed intramolecular
cyclopropanation of diazoacetate 7.
Received October 20, 2010
Propargyl alcohol was advanced to the chiral 1,2-diol 8
following the reported procedure in four steps.8 The primary
hydroxy group was selectively protected with TBS to give 9,
which was then transformed to 10 by using glyoxylic acid
chloride p-toluenesulfonyl hydrazone.9 Copper-catalyzed
intramolecular cyclopropanation of diazoacetate 10 afforded
the exo intermediate bicyclic lactone 11 in 42% yield as
a single product.10 Unfortunately, the configuration of the
cis-cyclopropane unit in 11 was found to be opposite to that
of the natural product as seen from the single-crystal X-ray
analysis of 4-bromobenzoate 12, which was obtained through a
two-step functional transformation of 11.
The first total synthesis of lathyranoic acid A (1) was
accomplished stereoselectively in a linear sequence of 20
steps and an overall yield of 1.4%. This modular synthesis
featured a cyclic, stereocontrolled Cu-catalyzed intra-
molecular cyclopropanation to construct the cis-cyclo-
propane unit, a Grubbs metathesis to construct the γ-sub-
stituted cyclopentenone moiety, and an anion-mediated
conjugate addition.
The exo product was expected to be favored thermodyna-
mically more than the endo isomer.10 To get the correct exo
product we turned our attention to the inverted secondary
hydroxy 13, which was obtained through a configuration
inversion of 9 in two steps. Under similar conditions as used
for 11, compound 13 was converted into the exo bicyclic
lactone 5 as a main product (5:14=2.6:1). It is worth men-
tioning that the cis-cyclopropane was constructed in a cyclic
stereocontrolled manner without the use of chiral catalyst.
The absolute configuration of 5 was confirmed by the crystal
structure of the deprotected derivative 15 (Scheme 1).
Lathyranoic acid A (1) was first isolated in 20051 from the
seeds of Euphorbia lathyris, a common traditional Chinese
medicine used for the treatment of hydropsy, ascites, scabies,
and snakebites.2 To date, a series of diterpenoids from
species in the Euphorbiaceae family have been reported to
show many important biological effects, including the acti-
vation of protein kinase C,3 anticancer,4 and anti-HIV
(1) Liao, S. G.; Zhan, Z. J.; Yang, S. P.; Yue, J. M. Org. Lett. 2005, 7,
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Fei, B. Y. Science 1976, 191, 571–572. (b) Majekodunmi, O. F.; Lu, Z.;
Joseph, E. O.; Guoen, S.; Jerry, L. M. J. Med. Chem. 1996, 39, 1005–1008. (c)
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Dumontet, C.; Pietro, A. D. J. Nat. Prod. 2003, 66, 140–142. (b) Ana, M. M.;
Nora, G.; Jose, R. A.; Pedro, M. A.; Joseph, M.; Maria-Jose, U. F. J. Nat.
Prod. 2006, 69, 950–953.
(7) For the cis-cyclopropane unit, most of the known synthetic ap-
proaches required the enantiomerically pure natural product 3-carene as
the starting material: (a) Kim, S.; Winkler, J. D. Chem. Soc. Rev. 1997, 26,
387–399. (b) Winkler, J. D.; Kim, S.; Harrison, S.; Lewin, N. E.; Blumberg,
P. M. J. Am. Chem. Soc. 1999, 121, 296–300. (c) Tomoo, M.; Shosuke, Y.;
Yukimasa, T. Tetrahedron Lett. 2000, 41, 2189–2192. (d) Tang, N.; Yusuff,
N.; Wood, J. L. Org. Lett. 2001, 3, 1563–1566.
(8) Kong, L. L.; Zhuang, Z. Y.; Chen, Q. S.; Deng, H. B.; Tang, Z. Y.; Jia,
X. S.; Li, Y. L.; Zhai, H. B. Tetrahedron: Asymmetry 2007, 18, 451–454.
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1448 J. Org. Chem. 2011, 76, 1448–1451
Published on Web 01/28/2011
DOI: 10.1021/jo102033h
r
2011 American Chemical Society

Yu et al.
JOCNote
SCHEME 2. Preparation of Fragment 3
(>95:5 E/Z ratio). DMP (Dess-Martin periodinane) oxidation
of the alcohol 18 (93%) followed by a Wittig methylenation
yielded ene 19 in 70% yield. Removal of the TBS group under
acidic condition in the presence of water, followed by DMP
oxidation provided the fragment aldehyde 3 in a good yield
(88%) (Scheme 2).
FIGURE 1. Retrosynthetic analysis of lathyranoic acid A.
SCHEME 1. Preparation of Intermediate 5
It was reported that the chiral cyclopentenone system
could be constructed via intermolecular Pauson-Khand
reaction.12 Here we described a more robust approach, using
Grubbs metathesis as a key step. The stereoselective pre-
paration of (S)-(-)-4-methyl-2-cyclopentenone (23) began
with the commercially available compound, L-ascorbic acid.
Following a known method,13 aldehyde 21 was obtained in a
good yield. Wittig methylenation of 21 followed by Grignard
vinylation via the Weinreb amide afforded diene 4, which was
treated by Grubbs II catalyst to provide the RCM product 23 in
an acceptable isolated yield. Cyclopentenone 23 was converted
to its protected bromide 24 by monobromination and acetal
formation (Scheme 3).
With the desired precursors 24 and 3 in hand, we then
turned our attention to the assembly of the skeleton of
lathyranoic acid A. The acetal bromide 24 underwent lithium-
halogen exchange, and the resulting lithio intermediate was
treated with aldehyde 3 in THF containing 2 equiv of HMPA
at -78 °C to give alcohols 25 and 26 in 75% yield (25:26=2:3).
After acetylation, deprotection of the acetal and tert-butyl pro-
tecting groups the final product 1 was obtained (Scheme 4). The
1H and 13C NMR spectra as well as the [R]D value of the
synthetic lathyranoic acid A were consistent with that of the
natural product.1
In summary, the total synthesis of lathyranoic acid A was
accomplished selectively in a linear sequence of 20 steps and
an overall yield of 1.4% from easily accessible starting
materials. Herein, we have reported a flexible and conver-
gent synthetic route that could generate further natural
product analogues of 1. To date, we have prepared some
analogues of lathyranoic acid A using this reported metho-
dology and we expect to report this in the near future.
With the desired lactone 5 in hand, we intended to
selectively transform it to the corresponding aldehyde 17.
A wide variety of reaction conditions were screened but were
invariably plagued by the simultaneous reduction of the
benzoyl group. A selection of the methods tried included
DIBAL-H/THF, DIBAL-H/PhMe, NaBH4/MeOH, NaBH4/
EtOH/CH2Cl2, and red-Al/THF at different temperatures.
Only treatment with red-Al at a lower temperature realized
the selective reduction of 5. The highest yield (92%) was
obtained in the temperature range of -78 to -40 °C. Subse-
quently, selective oxidation of primary alcohol to an aldehyde
using BAIB ((diacetoxyiodo)benzene) in the presence of a
catalytic amount of TEMPO (2,2,6,6-tetramethyl-1-piperidi-
nyloxyl free radical) converted 16 into 17 (98%). Aldehyde 17
was reacted with Wittig reagent11 to afford the E-ester 18
Experimental Section
(2S,3R)-1-(tert-Butyldimethylsilyloxy)-2-(2-diazoacetoxy)-6-
methylhept-5-en-3-yl Benzoate (10). A suspension of glyoxylic acid
p-toluenesulfonyl hydrazone (510 mg, 1.98 mmol) in a solution of
(12) Verdaguer, X.; Vazquez, J.; Fuster, G.; Bernard-Genisson, V.;
Greene, A. E.; Moyano, A.; Pericas, M. A.; Riera, A. J. Org. Chem. 1998,
63, 7037–7052.
(13) Al Dulayymi, J. R.; Baird, M. S.; Roberts, E.; Deysel, M.; Verschoor,
J. Tetrahedron 2007, 63, 2571–2592.
(11) Shing, T. K. M.; Yang, J. J. Org. Chem. 1995, 60, 5785–5789.
J. Org. Chem. Vol. 76, No. 5, 2011 1449

Yu et al.
JOCNote
SCHEME 3. Synthesis of Cyclopropenane Moiety
yield. 1H NMR (300 MHz, CDCl3) δ8.05 (d, 2H, J = 7.8 Hz), 7.61
(t, 1H, J = 7.2 Hz), 7.47 (t, 2H, J = 7.5 Hz), 5.35 (d, 1H, J = 7.2
Hz), 4.87-4.82 (m, 1H), 3.85 (d, 2H, J = 4.2), 2.38 (dd, 1H, J =
15.6, 3.3 Hz), 1.79 (d, 1H, J = 8.4 Hz), 1.51-1.41 (m, 1H),
1.26-1.22 (m, 1H), 1.19 (s, 3H), 1.14 (s, 3H), 0.86 (s, 9H), -0.04 (s,
6H); 13C NMR (75 MHz, CDCl3) δ 170.2, 165.3, 133.4, 129.7,
129.6, 128.5, 78.1, 70.0, 62.9, 29.2, 27.6, 26.8, 25.8, 21.3, 19.9, 18.3,
16.7, -5.3, -5.4; [R]20D -40.4 (c 1.4, CHCl3); HR-FABMS (m/z)
calcd for C23H34O5NaSi [M þ Na]þ 441.2068, found 441.2083; IR
(KBr) ν 3431, 2956, 2928, 2856, 1724, 1452, 1271, 839, 714 cm-1
.
(1R,4R,5R,7S)-4-((tert-Butyldimethylsilyloxy)methyl)-8,8-di-
methyl-2-oxo-3-oxabicyclo[5.1.0]octan-5-yl Benzoate (5) and
(1S,4R,5R,7R)-4-((tert-butyldimethylsilyloxy)methyl)-8,8-di-
methyl-2-oxo-3-oxabicyclo[5.1.0]octan-5-yl Benzoate (14). Accord-
ing to the procedure for the synthesis of 11, compound 13 was
SCHEME 4. Completion of the Synthesis of Lathyranoic
Acid A
1
transformed to the intermediate diazoacetate in 75% yield. H
NMR (300 MHz, CDCl3) δ 8.02 (d, 2H, J = 8.1 Hz), 7.54 (t, 1H,
J=7.2 Hz), 7.42 (t, 2H, J = 7.2 Hz), 5.41-5.35 (m, 1H), 5.24-
5.13 (m, 2H), 4.75 (s, 1H), 3.75 (d, 1H, J = 5.4 Hz), 3.80 (dd, 1H,
J=12.6, 6.6 Hz), 1.65 (s, 3H), 1.59 (s, 3H), 0.86 (s, 9H), 0.01 (d, 6H,
J=1.2 Hz); 13C NMR (75 MHz, CDCl3) δ165.8, 135.5, 133.0, 130.3,
129.7, 128.5, 118.0, 74.3, 72.2, 61.7, 46.3, 29.5, 25.9, 25.8, 18.2,
17.9, -5.4, -5.5; [R]20D þ19.8 (c 0.45, CHCl3); HR-FABMS (m/z)
calcd for C23H34N2O5NaSi [M þ Na]þ 469.2129, found 469.2130.
According to the procedure for the conversion of 10 into 11, 5
and 14 were obtained (2.6:1, 58%). 5: 1H NMR (300 MHz,
CDCl3) δ 8.00 (d, 2H, J = 7.8 Hz), 7.53 (t, 1H, J = 7.2 Hz), 7.40
(t, 2H, J = 7.6 Hz), 5.48-5.46 (m, 1H), 5.01-4.98 (m, 1H), 3.84
(d, 1H, J = 6.6 Hz), 1.66 (d, 1H, J = 8.4 Hz), 1.21-1.10 (m, 7H),
1.06-0.97 (m, 1H), 0.77 (s, 9H), -0.05 (s, 3H), -0.13 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 170.0, 165.4, 133.3, 129.8, 129.7,
128.5, 78.3, 70.3, 60.9, 29.3, 27.7, 27.0, 25.7, 22.8, 21.2, 18.1,
16.7, -5.5, -5.6; HR-FABMS (m/z) calcd for C24H34O5NaSi
[M þ Na]þ 441.2073, found 441.2075; IR (KBr) ν 3475, 2927,
2856, 1716, 1454, 1269, 1027, 835, 711 cm-1. 14: 1H NMR (300
MHz, CDCl3) δ 8.03 (d, 2H, J = 7.8 Hz), 7.55 (t, 1H, J = 7.2
Hz), 7.41 (t, 2H, J = 7.6 Hz), 5.18-5.13 (m, 1H), 4.67-4.61 (m,
1H), 3.94 (dd, 1H, J = 10.2, 6.3 Hz), 3.85 (dd, 1H, J = 10.2, 5.4
Hz), 2.08-2.00 (m, 1H), 1.76-1.66 (m, 1H), 1.58-1.49 (m, 1H),
1.28-1.92 (m, 1H), 1.16 (s, 3H), 1.06 (s, 3H), 0.84 (s, 9H), 0.02
(d, 6H, J = 5.4 Hz); 13C NMR (75 MHz, CDCl3) δ 170.8, 166.0,
133.4, 129.9, 129.7, 128.6, 78.1, 74.0, 60.7, 27.4, 25.9, 25.6, 24.1,
24.0, 21.0, 18.3, 16.3, -5.3; [R]17D -28.9 (c 1.25, CHCl3); HR-
FABMS (m/z) calcd for C23H34O5NaSi [M þ Na]þ 441.2068,
found 441.2085; IR (KBr) ν 2954, 2929, 2856, 1730, 1471, 1269,
10 mL of anhydrous benzene and 1 mL of thionyl chloride was
refluxed with stirring for 1.5 h under an argon atmosphere. The
solvent was placed on a high-vacuum line for 1 h to remove residual
thionyl chloride. This material was used immediately without
purification. The crude glyoxylic acid chloride p-toluenesulfonyl
hydrazone in 2 mL of CH2Cl2 was dropped into a solution of 9
(500 mg, 1.32 mmol) in 30 mL of anhydrous CH2Cl2 in an ice bath
under an argon atmosphere. Dimethylaniline (235 μL, 1.85 mmol)
was added with stirring for 15 min prior to addition of Et3N
(235 μL, 1.98 mmol). The resulting dark orange solution was
stirred for 10 min at 0 °C and then 20 min at room temperature.
The CH2Cl2 solution was evaporated. Flash column chromatog-
raphy (PE:EtOAc = 40:1) provided 10 (500 mg) as a yellow oil in
85% yield. 1H NMR (300 MHz, CDCl3) δ 8.01 (d, 2H, J = 8.1
Hz), 7.56 (t, 1H, J = 7.2 Hz), 7.44 (t, 2H, J = 7.2 Hz), 5.41-5.36
(m, 1H), 5.28-5.23 (m, 1H), 5.15 (t, 1H, J = 6.6 Hz), 4.77 (s, 1H),
3.88 (dd, 1H, J = 11.1, 4.5 Hz), 3.80 (dd, 1H, J = 10.8, 6.0 Hz),
2.47 (t, 2H, J = 6.6 Hz), 1.65 (s, 3H), 1.59 (s, 3H), 0.87 (s, 9H), 0.02
(d, 6H, J = 4.2 Hz); 13C NMR (75 MHz, CDCl3) δ 165.8, 135.2,
133.1, 130.4, 129.8, 128.6, 118.5, 74.9, 72.8, 61.7, 46.5, 29.3, 26.0,
1111, 1059, 837, 779, 714 cm-1
.
(R)-1-((1S,3R)-3-((E)-3-tert-Butoxy-2-methyl-3-oxoprop-1-enyl)-
2,2-dimethylcyclopropyl)-3-((S)-hydroxy((S)-8-methyl-1,4-di-
oxaspiro[4.4]non-6-en-6-yl)methyl)but-3-en-2-yl Benzoate (25).
To a solution of acetal bromide 24 (60 mg, 0.27 mmol) in
THF (2 mL) was added n-butyllithium (1.6 M in hexane, 156 μL,
0.25 mmol) at -78 °C under an argon atmosphere and the mixture
was stirred for 30 min at the same temperature. HMPA (7 μL, 0.04
mmol) was added and subsequently aldehyde 3(18 mg, 0.04 mmol).
After 1 h of stirring at -78 °C, the reaction was quenched by a
saturated ammonium chloride solution. The aqueous layer was
extracted with EtOAc. The combined organic phases were washed
with brine and dried (Na2SO4). The crude was purified by flash
chromatography on silica gel (PE:EtOAc = 6:1) to afford the
desired compounds 25 (8 mg) and 26 (10 mg) (75% yield). 25: 1H
NMR (300 MHz, CDCl3) δ 8.07 (d, 2H, J = 7.8 Hz), 7.57 (t, 1H,
J=7.5 Hz), 7.45 (t, 2H, J =7.8 Hz), 6.45 (d, 1H, J = 10.2 Hz), 6.00
(s, 1H), 5.95 (s, 1H), 5.52 (dd, 1H, J = 3.9, 10.2 Hz), 5.44 (s, 1H),
5.40 (s, 1H), 4.80 (s, 1H), 4.01-3.87 (m, 4H), 3.20 (d, 1H, J = 3.0
Hz), 2.72 (m, 1H), 2.28 (dd, 1H, J = 7.5, 13.5 Hz), 1.95-1.83 (m,
5H), 1.62-1.55 (m, 1H), 1.48-1.35 (m, 10H), 1.18-1.04 (m, 9H);
HR-FABMS (m/z) calcd for C33H44O7Na [M þ Na]þ 575.2985,
found 575.2996. 26: 1H NMR (300 MHz, CDCl3) δ 8.04 (d, 2H,
26.0, 25.9, 18.4, 18.1; [R]17 þ22.3 (c 0.7, CHCl3); HR-FABMS
D
(m/z) calcd for C23H34N2O5NaSi [M þ Na]þ 469.2129, found
469.2130; IR (KBr) ν 2956, 2929, 2858, 2114, 1718, 1380, 1271,
1109, 839, 779, 712 cm-1
.
(1S,4S,5R,7R)-4-((tert-Butyldimethylsilyloxy)methyl)-8,8-di-
methyl-2-oxo-3-oxabicyclo[5.1.0]octan-5-yl Benzoate (11). To a re-
fluxing solution of bis(tert-butylsalicylaldiminato)copper(II)10
(7 mg, 0.0168 mmol) in anhydrous, deoxygenated toluene (10 mL)
was added a solution of 10 (150 mg, 0.336 mmol) in deoxy-
genated toluene (10 mL) over 30 min under an argon atmosphere.
The resulting mixture was refluxed for a further 30 min and then
allowed to cool to room temperature. It was concentrated under
reduced pressure and then purified by flash chromatography (PE:
EtOAc = 50:1 to 30:1) to give 60 mg of 11 as a yellow oil in 42%
1450 J. Org. Chem. Vol. 76, No. 5, 2011

Yu et al.
JOCNote
J = 7.2 Hz), 7.54 (t, 1H, J = 7.5 Hz), 7.42 (t, 2H, J = 7.5 Hz), 6.47
(d, 1H), 5.85 (s, 1H), 5.66 (t, 1H), 5.47 (s, 1H), 5.40 (s, 1H), 4.96 (s,
1H), 4.01-3.86 (m, 4H), 2.72-2.58 (m, 1H), 2.24-2.18 (m, 1H),
1.96 (t, 1H, J = 6.9 Hz), 1.84 (s, 3H), 1.47-1.36 (m, 10H), 1.07 (s,
3H), 1.05 (s, 3H), 0.73 (d, 3H, J = 6.6 Hz); HR-FABMS (m/z)
calcd for C33H44O7Na [M þ Na]þ 575.2979, found 575.2996.
(R)-3-((S)-Acetoxy-((S)-8-methyl-1,4-dioxaspiro[4.4]non-6-en-
6-yl)methyl)-1-((1S,3R)-3-((E)-3-tert-butoxy-2-methyl-3-oxoprop-
1-enyl)-2,2-dimethylcyclopropyl)but-3-en-2-yl Benzoate (27). Ac2O
(80 μL, 0.85 mmol), pyridine (200 μL, 2.5 mmol), and DMAP
(1 mg, 0.008 mmol) were added to a solution of 25 (10 mg, 0.019
mmol) in 1 mL of CH2Cl2 at 0 °C. After 4 h of stirring at room
temperature, the crude was purified by flash chromatography on
silica gel (PE:EtOAc = 10:1) to afford 7 mg of the desired
1.14-1.09 (m, 1H), 1.07 (s, 6H); 13C NMR (75 MHz, CDCl3) δ
206.3, 169.6, 167.5, 165.7, 167.7, 144.3, 142.4, 138.5, 133.3,
130.5, 129.9, 128.6, 115.9, 80.0, 74.2, 68.1, 43.9, 33.9, 30.3, 29.9,
29.0, 29.0, 28.4, 27.4, 24.0, 21.0, 20.0, 16.1, 13.0. To a solution
of the ketone product above (4 mg, 0.007 mmol) in anhydrous
CH2Cl2 was added TFA (0.2 mL, 3.2 mmol) dropwise at 0 °C.
After 30 min of stirring at room temperature the reaction
mixture was concentrated and the residue was purified by flash
chromatography on silica gel (PE:EtOAc:acetone = 7:1:3) to
1
give the desired product (3 mg) in 72% yield in two steps. H
NMR (300 MHz, CDCl3) δ 8.05 (d, 2H, J=7.8 Hz), 7.57 (t, 1H,
J=6.9 Hz), 7.47-7.43 (m, 3H), 6.67 (d, 1H, J = 10.2 Hz), 6.03
(s, 1H), 5.42-5.38 (m, 2H), 5.33 (s, 1H), 3.03-2.92 (m, 1H),
2.68 (dd, 1H, J = 6.0, 18.6 Hz), 2.06-1.99 (m, 2H), 1.93-1.89
(m, 5H), 1.49-1.42 (m, 1H), 1.21-1.14 (m, 4H), 1.11 (s, 3H),
1.09 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 206.5, 171.4, 169.4,
166.0, 165.4, 144.2, 142.4, 142.0, 133.1, 130.1, 129.6, 128.4,
127.5, 115.1, 73.8, 67.6, 43.6, 33.7, 30.2, 29.7, 28.8, 27.6, 24.9,
20.8, 19.8, 16.0, 12.3; [R]25D -25 (c 0.15, CHCl3); HR-ESIMS
(m/z) calcd for C29H34O7Na [M þ Na]þ 517.2197, found
517.2197; IR (KBr) ν 3492, 2958, 2929, 1701, 1633, 1452,
1
compound 27 (69%). H NMR (300 MHz, CDCl3) δ 8.06 (d,
2H, J = 8.1 Hz), 7.56 (t, 1H, J = 7.2 Hz), 7.44 (t, 2H, J = 7.8 Hz),
6.45 (d, 1H, J = 9.9 Hz), 6.04 (s, 1H), 5.95 (s, 1H), 5.60 (t, 1H, J =
6.0Hz), 5.40(s, 1H), 5.36(s, 1H), 3.94-3.78(m, 4H), 2.65-2.79(m,
1H), 2.28 (dd, 1H, J = 7.2, 13.5 Hz), 1.97-1.83 (m, 8H), 1.68-1.60
(m, 1H), 1.48-1.38 (m, 10H), 1.10-0.96 (m, 10H); 13C NMR (75
MHz, CDCl3) δ169.9, 167.5, 165.6, 145.4, 143.6, 138.8, 133.1, 130.1,
129.9, 128.6, 119.0, 114.6, 79.9, 74.3, 68.1, 65.4, 64.9, 45.1, 35.4, 30.1,
29.1, 29.0, 28.3, 27.3, 24.0, 21.3, 20.6, 16.1, 13.0; HR-FABMS (m/z)
calcd for C35H46O8Na [M þ Na]þ 617.3085, found 617.3077.
(E)-3-((1R,3S)-3-((R)-3-((S)-Acetoxy-((S)-3-methyl-5-oxocy-
clopent-1-enyl)methyl)-2-(benzoyloxy)but-3-enyl)-2,2-dimethyl-
cyclopropyl)-2-methylacrylic Acid (Lathyranoic Acid A, 1). To a
solution of 27 (5 mg, 0.08 mmol) in a mixture of acetone (1 mL)
and water (40 μL) was added p-TsOH (cat.). After 10 min of
stirring at room temperature the reaction solution was con-
centrated and dissolved in CH2Cl2 (2 mL), dried (Na2SO4),
filtered, and concentrated. The residue was purified by flash
chromatography on silica gel (PE:EtOAc = 8:1) to give inter-
mediate ketone (4 mg). 1H NMR (300 MHz, CDCl3) δ 8.04 (d,
2H, J=7.2 Hz), 7.56 (t, 1H, J=7.2 Hz), 7.47-7.42 (m, 3H), 6.46
(d, 1H, J = 6.9 Hz), 6.06 (s, 1H), 5.46 (t, 1H, J = 6.6 Hz), 5.41
(s, 1H), 5.34 (s, 1H), 2.95 (m, 1H), 2.66 (dd, 1H, J=6.3, 18.6
Hz), 2.02 (dd, 1H, J = 2.1, 18.9 Hz), 1.97-1.92 (m, 1H), 1.89 (s,
3H), 1.85 (s, 3H), 1.47-1.37 (m, 10H), 1.17 (d, 3H, J =7.2 Hz),
1367, 1270, 1117, 1026, 714 cm-1
.
These spectroscopic data matched those reported for natural
product 1 (see the Supporting Information).
Acknowledgment. This work was supported by The Na-
tional Natural Science Foundation of China (Grants 30725049
and 81021062) and National Science & Technology Major
Project “Key New Drug Creation and Manufacturing Pro-
gram”, China (No. 2009ZX09301-001, No. 2009ZX09302-
001). We thank Professor Jian-Min Yue for kindly providing
us natural lathyranoic acid A.
Supporting Information Available: Experimental details,
characterization data including the crystallographic data, and
1
copies of the H and 13C NMR spectra of the synthetic inter-
mediates. This material is available free of charge via the
Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 76, No. 5, 2011 1451