Enantiospecific synthesis of the tricyclic core structure of lippifolianes

Article abstract of DOI:10.1016/j.tetasy.2010.04.001

An enantiospecific synthesis of the [6.6.3]-tricyclic carbon framework, 2,6,6,9-tetra-methyltricyclo[5.4.0.0^2,4]undecane, present in the sesquiterpenes lippifolianes and the diterpenes cyclosclareol, metasequoic acids and parguerols, starting f

Full text of DOI:10.1016/j.tetasy.2010.04.001

Tetrahedron: Asymmetry 21 (2010) 719–724
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Enantiospecific synthesis of the tricyclic core structure of lippifolianes
*
Adusumilli Srikrishna , R. Ramesh Babu, Baire Beeraiah
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An enantiospecific synthesis of the [6.6.3]-tricyclic carbon framework, 2,6,6,9-tetra-methyltricy-
clo[5.4.0.02,4]undecane, present in the sesquiterpenes lippifolianes and the diterpenes cyclosclareol, meta-
sequoic acids and parguerols, starting from the readily available monoterpene (R)-carvone, is described.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 15 March 2010
Accepted 6 April 2010
Available online 11 May 2010
1. Introduction
ularia oryzae.6 The marine tetracyclic diterpenes parguerol 11,
parguerol 16-acetate 12, and deoxyparguerol 13 isolated from
Lippifolianes are a small group of tricyclic sesquiterpenes con-
taining a 6–6–3 ring system, tricyclo[5.4.0.02,4]undecane 1, iso-
lated from Lippia integrifolia (Griseb.) Hieron., a woody aromatic
shrub belonging to central and northern Argentina, which is widely
used in traditional medicine as a diuretic, emmenagogue, sto-
machic, and nervine agent. The first member of this group was iso-
lated by Catalan et al. who proposed the structure 2 and named it
africanone.1 Subsequently, based on the incisive spectral analysis
followed by its formation from integrafolian-1,5-dione 3 (whose
structure was established by X-ray crystallography), revised the
structure as 4 and renamed as lippifoli-1(6)-en-5-one, and coined
the general name ‘lippifoliane’ for the carbon framework.2 Subse-
quently, the research groups of Catalan and Joseph-Nathan re-
ported the isolation of three more derivatives of lippifolianes 5–
7, Chart 1.3 Recently, the absolute configuration of lippifolianes
along with that of the africananes have been assigned by Joseph-
Nathan et al. on the basis of the analysis of circular dichroism data
in combination with density functional theory minimum energy
molecular models.4
the sea hare Aplysia dactylomela by Schmitz et al. also contain the
tricyclic system 1 in its core structure.7
The 6,6,3-ring system, tricyclo[5.4.0.02,4]undecane 1, present in
the lippifolianes 4–7 and in the diterpenes 8–13 is an interesting
tricyclic system. The novel structures and interesting biological
activity have made these terpenes interesting and novel targets
for chemical synthesis. To date, only one total synthesis of the
diterpenes metasequoic acids 9 and 10 has been reported.8 So far
there is no report on either the total synthesis or model studies
of lippifolianes 4–7 and the diterpenes 8, 11–13 either in a racemic
or an enantiospecific manner. In continuation of our interest in the
enantiospecific synthesis of polycyclic sesquiterpenes and diterpe-
noids from the readily and abundantly available monoterpene (R)-
carvone,9 herein we report an efficient enantiospecific approach to
the 6,6,3-tricyclic ring system of lippifolianes 4–7, which is also
present as part structure in the diterpenes 8–13.
2. Results and discussion
The tricyclo[5.4.0.02,4]undecane 1 was also present as an inte-
gral part in a few diterpenoids. Gnapholium pellitum is used as an
ornamental plant, and, in folk medicine, it is applied to reduce
swelling. Gnapholium graoeolens, whose local name is vira-vira
and grows in Colombia at high altitudes, is used to cure skin infec-
tions and as an anti-inflammatory agent; in certain regions it is
also used against cancer. In 1992, Waibel et al. reported the isola-
tion and structure elucidation of the diterpene 13-epi-cyclosclareol
8, containing the tricyclic system 1, from both G. pellitum and G.
graoeolens.5 Similarly, Zinkel and Magee reported6 the isolation of
cycloanticopalic acid 9 from the needle oleoresin of Pinus strobes.
Metasequoic acids A 10 and B 9 (same as cycloanticopalic acid)
are two antifungal diterpenes isolated from Metasequoia glyptostro-
boides, which were found to inhibit the spore germination of Pyric-
It was contemplated that carvone 14 could serve as the A-ring
of lippifolianes, as depicted in Scheme 1. The lippifolianes could
be generated from the suitably substituted tricyclic system 15
(bissecolippifoliane), which could be obtained by intramolecular
cyclopropanation of the isopropenyl group in the acid 16 via the
corresponding diazo ketone 17. The acid 16 could be generated
from the readily available carvone 14.
The synthetic sequence starting from the readily available
monoterpene (R)-carvone 14 is depicted in Schemes 2 and 3. Reg-
ioselective generation of the kinetic enolate of carvone with lith-
ium diisopropylamide, followed by alkylation with methyl
bromoacetate generated the ketoester 18 in a highly stereoselec-
tive manner, anti to the isopropenyl group,10 in 80% yield. To avoid
regiochemical problems at a later stage, the ketone group in 18 was
masked. Thus, chemo- and stereoselective reduction of the keto
ester 18 with sodium borohydride in methanol at ꢀ20 °C
furnished exclusively the hydroxy ester 19 in 83% yield.11 The
* Corresponding author. Tel.: +91 8022 932 215; fax: +91 80 23600529.
E-mail address: ask@orgchem.iisc.ernet.in (A. Srikrishna).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.04.001

720
A. Srikrishna et al. / Tetrahedron: Asymmetry 21 (2010) 719–724
2
HO
H
H
H
10
4
H
H
H
O
8
6
O
2
O
O
O
1
3
4
5
H
H
HO
H
H
H
HO
HO
H
O
O
6
7
8
9
OH
OH
HOOC
H
H
H
H
HO
HO
H
H
HO
RO
Br
OAc
OAc
H
H
Br
HOOC
11 R = H
10
13
12 R = Ac
Chart 1.
C
H
A
B
R
O
O
O
Lippifoliane
16 R = OH
15
14
17 R = CHN2
Scheme 1.
H
H
H
H
H
H
H
O
a
a
91%
X
b
21
COOMe
80%
CHO
H
88%
OH
H
O
O
O
H
OMOM
b
OMOM
15
18
20
83%
28
27
H
H
H
c
81%
c
d
H
H
N2
91%
COOMe
COOH
COOMe
d
H
H
H
COOMe
COOMe
OH
OMOM
OMOM
88%
H
O
23
19
21
H
OMOM
O
e
OMOM
26
H
29
H
H
e
84%
H
H
f
N2
O
+
78%
O
H
H
H
H
O
f
COOMe
COOMe
H
OMOM
OMOM
( 6 : 5 )
OMOM
83%
24
25
22
O
O
H
MOMO
OMOM
Scheme 2. Reagents and conditions: (a) LDA, THF, BrCH2COOMe; (b) NaBH4, MeOH;
(c) MOMCl, EtN(iPr)2, DMAP, CH2Cl2; (d) NaOH, MeOH–H2O; (e) (i) (COCl)2, C6H6;
(ii) CH2N2, Et2O; (f) Rh2(OAc)4, CH2Cl2.
30
31
g
82%
H
H
COOMe
stereochemistry of the hydroxy group in the ester 19 was assigned
as trans to the acetate side chain, by analogy to the reduction of
5-alkylcyclohexenones12 (the lactone 20 would have formed read-
ily if they are cis to each other). The hydroxy group in the hydroxy
ester 19 was protected as its methoxymethyl (MOM) ether by treat-
ment with methoxymethyl chloride, and ethyldiisopropylamine
(DIPEA) in the presence of a catalytic amount of 4-dimethylamino-
pyridine (DMAP) in anhydrous methylene chloride at rt to furnish
the MOM ether 21 in 91% yield, whose structure was established
COOMe
OH
NO2
NO2
h
O
O
75%
H
OMOM
H
OMOM
32
33
Scheme 3. Reagents and conditions: (a) LAH, Et2O; (b) PDC, CH2Cl2; (c) N2CHCO-
OMe, SnCl2ꢁ2H2O, CH2Cl2; (d) TsN3, Et3N, CH3CN; (e) Rh2(OAc)4, CH2Cl2; (f) NaH,
MeI, THF-DMF, TBAI; (g) NaBH4, MeOH; (h) 3,5-dinitrobenzoic acid, DCC, DMAP,
CH2Cl2.

A. Srikrishna et al. / Tetrahedron: Asymmetry 21 (2010) 719–724
721
from its spectral data. Initially, for the construction of the BC rings of
lippifolianes, rhodium acetate catalyzed13 intramolecular insertion
of the diazoketone 22, derived from the ester 21 was explored.
Accordingly, hydrolysis of the ester in 21 generated the acid 23.
Reaction of the acid 23 with oxalyl chloride followed by treatment
of the resultant acid chloride with ethereal diazomethane furnished
the diazoketone 22. However, rhodium acetate catalyzed reaction of
the diazoketone 22 led to the formation of a mixture of products, in
78% yield. Purification of the mixture yielded a 5:1 mixture of the
anti and syn isomers of the tricyclic ketone 24 and the bicyclic enone
25 in 6:5 ratio, whose structures were assigned on the basis of the
spectral data, in particular the 1H and 13C NMR spectra.
(R)-Carvone was employed as the A-ring of lippifolianes, and BC
rings were constructed via rhodium acetate catalyzed intramolec-
ular cyclopropanation of the
a-diazo-b-ketoester 26. The trans–
anti–cis stereostructure was confirmed by single crystal X-ray
diffraction analysis of the dinitrobenzoate 33. The additional car-
bon present in the form of an ester in 31 could be removed, when
required, either by employing Barton’s radical mediated decarbox-
ylation via the corresponding ester derived from N-hydroxypyri-
dine-2-thione or Krapcho dealkoxycarboxylation.
4. Experimental
Consequently, it was decided to construct the BC rings of lippi-
folianes via the intramolecular cyclopropanation of the a-diazo-b-
IR spectra were recorded on a Jasco FTIR 410 spectrophotome-
ter. 1H (400 MHz) and 13C (100 MHz) NMR spectra were recorded
on a Brucker Avance 400 spectrometer. The chemical shifts (d
ppm) and coupling constants (Hz) are reported in the standard
fashion with reference to either internal tetramethylsilane (for
1H) or the central line (77.0 ppm) of CDCl3 (for 13C). A 1:1 mixture
of CDCl3 and CCl4 was used as a solvent for recording the NMR
spectra. In the 13C NMR, the nature of carbons (C, CH, CH2, and
CH3) was determined by recording the DEPT-135 spectra, and is gi-
ven in parentheses. High-resolution mass spectra were recorded
using Micromass Q-TOF micro mass spectrometer using electron
spray ionization mode. Optical rotations were measured using a
ketoester 26, Scheme 3. For the synthesis of the diazo ester 26, the
ester in 21 was transformed into the corresponding aldehyde.
Thus, reduction of the ester 21 with lithium aluminum hydride
(LAH) in ether furnished the primary alcohol 27 in 91% yield, which
on oxidation with pyridinium dichromate (PDC) in methylene
chloride generated the aldehyde 28 in 88% yield. Treatment of
the aldehyde 28 with methyl diazoacetate in the presence of a cat-
alytic amount of stannous chloride generated the b-keto ester 29 in
81% yield.14 Diazo transfer reaction of the b-keto ester 29 with tol-
uenesulfonyl azide and triethylamine in acetonitrile furnished the
a
-diazo-b-keto ester 26 in 88% yield. Treatment of the diazo ester
Jasco DIP-370 digital polarimeter and [
a]D values are given in units
26 at room temperature with a catalytic amount of rhodium ace-
tate in methylene chloride furnished the tricyclic ketoester 30 in
84% yield, in a highly stereo- and regioselective manner.15 The
structure of the tricyclic compound 30 was established from its
spectroscopic data. Finally, introduction of the gem dimethyl group
at C-6 was accomplished by sodium hydride mediated dialkylation
of the tricyclic ketone 30 to furnish the ketoester 31, which con-
tained the complete carbon framework of lippifolianes. For an
unambiguous assignment of the stereochemistry of all the chiral
centers, single crystal X-ray diffraction analysis of a crystalline
derivative was chosen. Thus, regioselective reduction of the ketoes-
ter 30 with sodium borohydride in methanol furnished, in 82% yield,
the hydroxy ester 32 in a highly stereoselective manner via the ap-
proach of the hydride from the exo face of the bicyclo[4.1.0]heptane
moiety in 30. Coupling of the secondary alcohol 32 with 3,5-dinitro-
benzoic acid in the presence of dicyclohexylcarbodiimide (DCC) and
DMAP in methylene chloride furnished the dinitrobenzoate 33, mp
146.5–148.5. Single crystal X-ray diffraction analysis of the dinitro-
benzoate 33, ORTEP diagram is depicted in Figure 1, confirmed the
trans, anti, cis arrangement of the tricyclic ring system.
of 10ꢀ1 deg cm2 gꢀ1
.
4.1. Methyl 2-[(1S,2R,6R)-2-(2-methoxymethoxy)-3-methyl-6-
(1-methylethenyl)cyclohex-3-enyl]acetate 21
To an ice cold solution of the alcohol11 19 (422 mg, 1.88 mmol)
in dry CH2Cl2 (2 mL) were added diisopropylethylamine (0.7 mL,
3.76 mmol), DMAP (20 mg, 10 mol %), and MOMCl (0.3 mL,
3.57 mmol) and stirred for 30 min at the same temperature. The
reaction mixture was stirred at rt for 5 h and then poured in water
(3 mL) and extracted with CH2Cl2 (2 ꢂ 5 mL). Combined CH2Cl2 ex-
tract was washed with brine (4 mL) and dried (Na2SO4). Evapora-
tion of the solvent and purification of the residue on a silica gel
column using ethyl acetate–hexane (1:19) as eluent furnished
the MOM ether 21 (460 mg, 91%) as colorless oil. ½a D23
¼ þ84:4 (c
ꢃ
7.4, CHCl3); IR (neat):
m
max/cmꢀ1 3074, 2951, 2927, 2855, 1739
(OC@O), 1645, 1439, 1377, 1272, 1250, 1198, 1161, 1094, 1029,
1
919, 895; H NMR: d 5.53 (1H, br s, H-40), 4.75 (2H, s, C@CH2),
4.71 and 4.62 (2H, 2 ꢂ d, J 6.7 Hz, OCH2O), 4.06 (1H, d, J 8.6 Hz,
H-20), 3.62 (3H, s, COOCH3), 3.38 (3H, s, OCH3), 2.60–2.30 (3H,
m), 2.20–2.05 (2H, m), 2.00–1.85 (1H, m), 1.70 (3H, s) and 1.66
(3H, s) [2 ꢂ olefinic-CH3]; 13C NMR: d 173.0 (C, OC@O), 146.2 (C,
C@CH2), 134.3 (C, C-30), 124.8 (CH, C-40), 113.3 (CH2, H2C@C),
97.1 (CH2, OCH2O), 82.1 (CH, C-20), 56.0 (CH3) and 51.0 (CH3)
[2 ꢂ OCH3], 45.7 (CH), 39.5 (CH), 34.1 (CH2), 30.3 (CH2), 20.0
(CH3), 18.3 (CH3); HRMS: m/z calcd for C15H24O4Na (M+Na):
291.1572; found: 291.1562.
4.2. (1R,7S,8R)-8-Methoxymethoxy-2,9-dimethyltricyclo-
[5.4.0.02,4]undec-9-en-5-one 24 and (1S,7S,11R)-11-methoxy-
methoxy-6,10-dimethylbicyclo[5.4.0]undec-9-en-3-one 25
To a magnetically stirred solution of the ester 21 (400 mg,
1.49 mmol) in methanol (10 mL) was added 10% aq NaOH (10 mL)
and refluxed for 7 h. It was then cooled, acidified with 3 N HCl
(10 mL), and extracted with CH2Cl2 (3 ꢂ 5 mL). The combined
CH2Cl2 layer was washed with brine (4 mL) and dried (Na2SO4).
Evaporation of the solvent furnished the acid 23 (321 mg, 84%) as
Figure 1. ORTEP diagram of the dinitrobenzoate 33.
3. Conclusion
colorless oil. IR (neat):
1378, 1278, 1213, 1150, 1093, 1071, 1028, 950, 919, 896. To a mag-
m
max/cmꢀ1 3073, 2921, 1707, 1644, 1440,
In conclusion, we have accomplished the first enantiospecific
synthesis of the [6.6.3]-tricyclic structure of the lippifolianes 4–7.

722
A. Srikrishna et al. / Tetrahedron: Asymmetry 21 (2010) 719–724
netically stirred solution of the acid 23 (250 mg, 1.0 mmol) in dry
benzene (2 mL) was added oxalyl chloride (0.2 mL, 3.0 mmol) and
stirred for 2 h at rt. Evaporation of the excess oxalyl chloride and sol-
vent under reduced pressure gave the acid chloride, which was ta-
ken in dry ether (10 mL) and added to a cold ethereal solution of
diazomethane [excess, prepared from N-nitroso-N-methylurea
(412 mg, 4 mmol), 20 mL of 60% aq KOH and 15 mL ether]. The reac-
tion mixture was stirred at 0 °C for 2 h. Careful evaporation of the
solvent and excess diazomethane on a hot water bath and purifica-
tion of the residue on a silica gel column using ethyl acetate–hexane
(1:5) as eluentfurnished the diazoketone 22 (112 mg, 40%) as yellow
38.6 (CH), 33.9 (CH2), 30.3 (CH2), 20.1 (CH3), 18.4 (CH3); HRMS:
m/z calcd for C14H24O3Na (M+Na): 263.1617; found: 263.1611.
4.4. 2-[(1S,2R,6R)-(2-Methoxymethoxy)-3-methyl-6-(1-methyl-
ethenyl)cyclohex-3-enyl]ethanal 28
To a magnetically stirred solution of the primary alcohol 27
(77 mg, 0.32 mmol) in anhydrous CH2Cl2 (1 mL) was added PDC
(240 mg, 0.64 mmol) and stirred at rt for 6 h. The reaction mixture
was then filtered through a small silica gel column using CH2Cl2 as
eluent. Evaporation of the solvent and purification of the residue
on a silica gel column using ethyl acetate–hexane (1:19) as eluent
oil. IR (neat): m
max/cmꢀ1 3079, 2917, 2102, 1645, 1442, 1378, 1330,
1151, 1094, 1047, 1028, 894. To a magnetically stirred solution of
Rh2(OAc)4 (6 mg) in anhydrous CH2Cl2 (2 mL) was added a solution
of the diazoketone 22 (200 mg, 0.72 mmol) in anhydrous CH2Cl2
(20 mL) over a period of 30 min and stirred for 25 min. Evaporation
of the solvent and purification of the residue over a silica gel column
using ethyl acetate–hexane (1:5) as eluent first furnished the bicy-
furnished the aldehyde 28 (67 mg, 88%) as oil. ½a D25
¼ þ79:6 (c 7.6,
ꢃ
CHCl3); IR (neat): m
max/cmꢀ1 3076, 2949, 2848, 2729, 2851, 1716,
1637, 1441, 1381, 1212, 1154, 1093, 1032, 966, 918, 900; 1H
NMR: d 9.67 (1H, s, H-C@O), 5.50 (1H, br s, H-40), 4.75 (2H, s,
C@CH2), 4.61 and 4.55 (2H, 2 ꢂ d, J 6.9 Hz, OCH2O), 3.88 (1H, d, J
8.7 Hz, H-20), 3.33 (3H, s, OCH3), 2.60–1.80 (6H, m), 1.67 (3H, s)
and 1.61 (3H, s) [2 ꢂ olefinic-CH3]; 13C NMR: d 201.1 (CH, HC@O),
146.2 (C, C@CH2), 134.4 (C, C-30), 124.9 (CH, C-40), 113.8 (CH2,
C@CH2), 97.3 (CH2, OCH2O), 83.2 (CH, C-20), 56.1 (CH3, OCH3),
46.7 (CH), 44.9 (CH2, C-2), 39.1 (CH), 30.4 (CH2, C-50), 19.9 (CH3),
18.4 (CH3); HRMS: m/z calcd for C14H22O3Na (M+Na): 261.1467;
found: 261.1467.
clic enone 25 (65 mg, 36%) as colorless oil. ½a D22
¼ þ43:6 (c 2.5,
ꢃ
CHCl3); IR (neat): m
max/cmꢀ1 2928, 2854, 1673, 1453, 1378, 1149,
1101, 1055, 1026, 921; 1H NMR: d 6.25 (1H, dd, J 11.3 and 6.2 Hz,
H-5), 5.93 (1H, d, J 11.3 Hz, H-4), 5.58 (1H, d, J 4.4 Hz, H-10), 4.69
and 4.63 (2H, 2 ꢂ d, J 7.1 Hz, OCH2O), 3.88 (1H, d, J 9.5 Hz), 3.41
(3H, s, OCH3), 2.95 (1H, d, J 16.4 Hz), 2.90–2.70 (1H, m), 2.41 (1H,
dd, J 16.4 and 9.0 Hz), 2.25–1.50 (4H, m), 1.68 (3H, s, olefinic-CH3),
1.18 (3H, d, J 6.9 Hz); 13C NMR: d 203.6 (C, C@O), 148.5 (CH, C-5),
135.6 (C, C-10), 132.2 (CH, C-4), 126.0 (CH, C-9), 96.3 (CH2, OCH2O),
82.0 (CH, C-11), 56.2 (CH3, OCH3), 43.1 (CH2), 42.2 (CH), 41.3 (CH),
35.0 (CH), 28.8 (CH2), 19.7 (CH3), 16.2 (CH3); HRMS: m/z calcd for
C15H22O3Na (M+Na): 273.1467; found: 273.1453.
4.5. Methyl 4-[(1S,2R,6R)-2-methoxymethoxy-3-methyl-6-(1-
methylethenyl)cyclohex-3-enyl]-3-oxobutanoate 29
To a magnetically stirred solution of the aldehyde 28 (340 mg,
1.43 mmol) and methyl diazoacetate (285 mg, 2.85 mmol) in anhy-
drous CH2Cl2 (8 mL) was added SnCl2ꢁ2H2O (100 mg, 30 mol %) in
two portions over a period of 15 min and stirred the reaction mix-
ture for 45 min at rt. Solvent was evaporated under reduced pres-
sure and the residue was purified over a silica gel column using
ethyl acetate–hexane (1:19) as eluent to furnish the b-keto ester
Further elution of the column with ethyl acetate–hexane (1:5)
furnished a 5:1 diastereomeric mixture of the tricyclic ketone 24
(76 mg, 42%) as oil. IR (neat): m
max/cmꢀ1 2960, 2924, 1688, 1454,
1151, 1093, 1062, 1026, 920, 862; 1H NMR (peaks due to the major
isomer): d 5.54 (1H, br s, H-10), 4.60 (2H, s, OCH2O), 3.72 (1H, d, J
8.4 Hz), 3.41 (3H, s, OCH3), 2.54 (1H, d, J 10.1 Hz), 2.50–2.00 (2H,
m), 1.53 (3H, s, olefinic-CH3), 2.00–1.60 (3H, m), 1.54 (1H, dd, J
9.6 and 5.0 Hz), 1.30–1.00 (2H, m), 1.13 (3H, s, tert-CH3); 13C
NMR (peaks due to the major isomer): d 208.1 (C, C@O), 134.8
(C, C-9), 125.3 (CH, C-10), 96.9 (CH2, OCH2O), 83.5 (CH, C-8), 56.2
(CH3, OCH3), 47.2 (CH), 39.5 (CH), 38.8 (CH2), 35.5 (CH), 30.2
(CH2), 28.8 (C), 28.0 (CH2), 22.8 (CH3), 19.6 (CH3); HRMS: m/z calcd
for C15H22O3Na (M+Na): 273.1467; found: 273.1458.
29 (360 mg, 81%) as colorless oil. ½a D27
¼ þ13:0 (c 2.8, CHCl3); IR
ꢃ
(neat):
m
max/cmꢀ1 3072, 2953, 2923, 2853, 1749 (OC@O), 1718
(C@O), 1315, 1150, 1094, 1069, 1028, 897; 1H NMR: d 5.53 (1H,
br s, H-40), 4.78 (1H, s) and 4.76 (1H, s) [C@CH2], 4.65 and 4.59
(2H, 2 ꢂ d, J 6.5 Hz, OCH2O), 4.05–3.90 (1H, m), 3.73 (3H, s,
COOCH3), 3.43 (2H, s, H-2), 3.36 (3H, s, OCH3), 2.74 and 2.61 (2H,
2 ꢂ dd, J 17.8 and 4.7 Hz), 2.43 (1H, dt, J 11.4 and 4.8 Hz), 2.30–
2.05 (2H, m), 1.92 (1H, d, J 17.5 Hz), 1.70 (3H, s) and 1.63 (3H, s)
[2 ꢂ olefinic-CH3]; 13C NMR: d 201.3 (C, C@O), 167.4 (C, OC@O),
146.7 (C, C@CH2), 134.4 (C, C-30), 124.9 (CH, C-40), 113.6 (CH2,
C@CH2), 97.3 (CH2, OCH2O), 82.8 (CH, C-20), 55.9 (CH3, OCH3),
52.0 (CH3, OCH3), 49.6 (CH2, C-2), 46.2 (CH), 43.2 (CH2, C-4), 39.3
(CH), 30.2 (CH2, C-50), 19.9 (CH3), 18.2 (CH3); HRMS: m/z calcd
for C17H26O5Na (M+Na): 333.1678; found: 333.1665.
4.3. 2-[(1S,2R,6R)-(2-Methoxymethoxy)-3-methyl-6-(1-methyl-
ethenyl)cyclohex-3-enyl]ethanol 27
To a magnetically stirred solution of the ester 21 (460 mg,
1.71 mmol) in dry ether (2 mL) was added LAH (130 mg,
3.42 mmol) in portions. The reaction mixture was stirred at rt for
1 h. Ethyl acetate (0.5 mL) was added to consume excess LAH
and the reaction was then quenched with water (4 mL) and ex-
tracted with ether (3 ꢂ 4 mL). The ether extract was washed with
brine (4 mL) and dried (Na2SO4). Evaporation of the solvent and
purification of the residue over a silica gel column using ethyl ace-
tate–hexane (1:9) as eluent furnished the primary alcohol 27
4.6. Methyl (1R,2S,4R,7S,8R)-(8-methoxymethoxy-2,9-dimethyl-
5-oxotricyclo[5.4.0.02,4] undec-9-ene-4-carboxylate 30
To
a magnetically stirred solution of the b-ketoester 29
(315 mg, 1.02 mmol) in acetonitrile (3 mL) were added triethyl-
amine (0.2 mL, 1.51 mmol) and TsN3 (250 mg, 1.51 mmol), and
stirred the reaction mixture for 4 h at rt. Evaporation of the solvent
under reduced pressure at rt and purification of the residue over a
silica gel column using ethyl acetate–hexane (1:19) as eluent fur-
(376 mg, 91%) as oil. ½a D27
¼ þ36:0 (c 19.1, CHCl3); IR (neat):
ꢃ
m
max/cmꢀ1 3415 (OH), 3073, 2926, 2857, 1643, 1446, 1377, 1237,
1
1213, 1151, 1092, 1030, 919, 891; H NMR: d 5.58 (1H, s, H-40),
4.76 (2H, s, C@CH2), 4.73 and 4.65 (2H, 2 ꢂ d, J 6.7 Hz, OCH2O),
4.02 (1H, d, J 8.1 Hz, H-20), 3.90–3.50 (2H, m, CH2OH), 3.43 (3H, s,
OCH3), 3.20–2.95 (1H, br s, CH2OH), 2.23 (1H, td, J 10.4 and
4.4 Hz), 2.20–2.00 (1H, m), 2.00–1.75 (3H, m), 1.67 (6H, s, 2 ꢂ ole-
finic-CH3), 1.65–1.45 (1H, m); 13C NMR: d 146.7 (C, C@CH2), 133.7
(C, C-30), 125.9 (CH, C-40), 112.7 (CH2, C@CH2), 95.7 (CH2, OCH2O),
82.5 (CH, C-20), 60.1 (CH2, CH2OH), 56.1 (CH3, OCH3), 46.7 (CH),
nished the
which was used in the subsequent reaction without further charac-
terization. IR (neat):
max/cmꢀ1 3072, 2955, 2133 (N@N), 1724
a-diazo-b-ketoester 26 (300 mg, 88%) as colorless oil,
m
(OC@O), 1659 (C@O), 1439, 1374, 1309, 1230, 1213, 1094, 1028,
917, 898, 746. To a magnetically stirred solution of Rh2(OAc)4
(2 mg) in anhydrous CH2Cl2 (2 mL) was added a solution of the
a-diazo-b-keto ester 26 (150 mg, 0.44 mmol) in anhydrous CH2Cl2

A. Srikrishna et al. / Tetrahedron: Asymmetry 21 (2010) 719–724
723
(13 mL) over a period of 30 min and stirred for 1 h. Evaporation of
the solvent and purification of the residue on a silica gel column
using ethyl acetate–hexane (1:9) as eluent furnished the tricyclic
s, tert-CH3), 1.19 and 0.84 (2H, 2 ꢂ d, J 4.8 Hz, H-3); 13C NMR: d
173.1 (C, OC@O), 134.8 (C, C-9), 125.6 (CH, C-10), 97.0 (CH2,
OCH2O), 83.4 (CH, C-8), 68.4 (CH, C-5), 56.3 (CH3) and 52.1 (CH3)
[2 ꢂ OCH3], 42.9 (CH), 39.8 (C, C-4), 39.7 (CH), 31.4 (CH2), 30.7
(CH2), 29.2 (C, C-2), 21.6 (CH2), 19.6 (CH3), 17.7 (CH3); HRMS: m/
z calcd for C17H26O5Na (M+Na): 333.1678; found: 333.1670.
b-keto ester 30 (115 mg, 84%) as colorless oil. ½a D27
¼ ꢀ27:6 (c
ꢃ
3.1, CHCl3); IR (neat): m
max/cmꢀ1 2951, 2893, 2850, 1738 (OC@O),
1694 (C@O), 1454, 1436, 1390, 1348, 1238, 1152, 1103, 1062,
1026; 1H NMR: d 5.55 (1H, br s, H-10), 4.62 (2H, s, OCH2O), 3.76
(3H, s, COOCH3), 3.76–3.70 (1H, m, H-8), 3.41 (3H, s, OCH3), 2.70
(1H, d, J 12.4 Hz), 2.30–1.70 (5H, m), 1.70–1.50 (2H, m), 1.67 (3H,
s, olefinic-CH3), 1.12 (3H, s, tert-CH3); 13C NMR: d 202.7 (C, C@O),
168.8 (C, OC@O), 134.9 (C, C-9), 124.9 (CH, C-10), 97.0 (CH2,
OCH2O), 83.3 (CH, C-8), 56.2 (CH3, OCH3), 52.3 (CH3, OCH3), 46.1
(C, C-4), 45.5 (CH), 39.8 (CH), 38.9 (CH2), 33.9 (C), 30.5 (CH2),
30.0 (CH2), 19.6 (CH3), 18.9 (CH3); HRMS: m/z calcd for C17H24O5Na
(M+Na): 331.1521; found: 331.1522.
4.9. Methyl (1R,2S,4R,5R,7S,8R)-8-methoxymethoxy-2,9-
dimethyl-5-(3,5-dinitrobenzoyloxy)tricyclo[5.4.0.02,4]undec-9-
ene-4-carboxylate 33
To a magnetically stirred solution of the secondary alcohol 32
(50 mg, 0.16 mmol) in dry CH2Cl2 (1 mL) were added 3,5-dinitro-
benzoic acid (51 mg, 0.24 mmol), DCC (66 mg, 0.32 mmol), and
DMAP (5 mg) and stirred for 2 h at rt. The reaction mixture was
then filtered through a small pad of silica gel using ethyl acetate
as eluent. Evaporation of the solvent and purification of the residue
over a silica gel column using ethyl acetate–hexane (1:9) as eluent
furnished the 3,5-dinitrobenzoate 33 (61 mg, 75%), which was
4.7. Methyl (1R,2S,4R,7R,8R)-8-methoxymethoxy-2,6,6,9-tetra-
methyl-5-oxotricyclo[5.4.0.02,4]undec-9-ene-4-carboxylate 31
A suspension of sodium hydride (26 mg, 60% dispersion in oil,
0.645 mmol) in hexane (1 mL) under nitrogen atmosphere was
magnetically stirred for 10 min and the solvent was syringed out.
The oil free sodium hydride was suspended in dry THF (1 mL)
and anhydrous DMF (0.5 mL), and the ketoester 30 (40 mg,
0.13 mmol) was added, followed by methyl iodide (0.1 mL,
1.29 mmol). The reaction mixture was magnetically stirred for
15 h at rt. The reaction was then quenched with water (2 mL)
and the reaction mixture was extracted with ether (3 ꢂ 4 mL).
The combined ether extract was washed with brine (3 mL) and
dried (Na2SO4). Evaporation of the solvent and purification of the
residue on a silica gel column using ethyl acetate–hexane (1:19)
as eluent furnished the lippifoliane ketoester 31 (36 mg, 83%) as
recrystallised from propan-2-ol. Mp: 146.5–148.5 °C;
½
a 2D4
ꢃ
¼
ꢀ50:0 (c 1.3, CHCl3); IR (thin film):
m
max/cmꢀ1 3096, 2927, 1731
(OC@O), 1546, 1345, 1277, 1231, 1166, 1112, 1075, 1028, 921,
730, 720; 1H NMR: d 9.19 (1H, t, J 1.5 Hz) and 9.08 (2H, d, J
1.5 Hz) [Ar-H], 6.11 (1H, dd, J 11.2 and 6.0 Hz, H-5) 5.56 (1H, d, J
4.4 Hz, H-10), 4.65 and 4.59 (2H, 2 ꢂ d, J 7.2 Hz, OCH2O), 3.69
(3H, s, COOCH3), 3.80–3.60 (1H, m), 3.43 (3H, s, CH2OCH3), 2.58
(1H, dd, J 11.2 and 4.4 Hz), 2.40–2.00 (2H, m), 1.66 (3H, s, ole-
finic-CH3), 1.80–0.50 (5H, m), 1.14 (3H, s, tert-CH3); 13C NMR: d
171.4 (C, OC@O), 161.6 (C, OC@O), 148.7 (2 C, C), 134.6 (C), 134.3
(C), 129.2 (2 C, CH), 125.6 (CH), 122.1 (CH), 96.3 (CH2, OCH2O),
83.2 (CH, C-8), 75.3 (CH, C-5), 56.2 (CH3) and 52.2 (CH3)
[2 ꢂ OCH3], 42.1 (CH), 39.8 (CH), 36.2 (C, C-4), 30.3 (CH2), 30.1
(C, C-2), 28.3 (CH2), 23.0 (CH2), 19.5 (CH3), 17.6 (CH3); HRMS: m/
z calcd for C24H28N2O10Na (M+Na): 527.1642; found: 527.1647.
Anal. Calcd for C24H28N2O10: C, 57.14; H, 5.59; N, 5.55. Found: C,
56.82; H, 5.58; N, 5.87.
oil. ½a 2D7
ꢃ
¼ þ103 (c 1.4, CHCl3); IR (neat):
m
max/cmꢀ1 2934, 1732
(OC@O), 1704 (C@O), 1457, 1437, 1384, 1312, 1242, 1198, 1168,
1149, 1088, 1044, 1024, 941, 926; 1H NMR: d 5.90 (1H, d, J
7.6 Hz, H-10), 4.64 and 4.61 (2H, 2 ꢂ d, J 7.2 Hz, OCH2O), 3.83
(1H, s, H-8), 3.67 (3H, s, COOCH3), 3.37 (3H, s, OCH3), 2.50–2.00
(2H, m), 1.77 (3H, s, olefinic-CH3), 1.95–1.50 (2H, m), 1.30 (3H, s)
1.17 (3H, s) and 0.83 (3H, s), 1.10–0.60 (2H, m); 13C NMR: d
212.4 (C, C@O), 169.3 (C, OC@O), 136.2 (C, C-9), 128.7 (CH, C-10),
93.6 (CH2, OCH2O), 72.6 (CH, C-8), 55.4 (CH3) and 52.4 (CH3)
[2 ꢂ OCH3], 51.0 (CH), 49.9 (C), 45.8 (CH), 37.8 (C), 32.6 (C), 29.9
(CH2), 26.0 (CH3), 25.3 (CH2), 22.0 (CH3), 19.9 (CH3), 12.3 (CH3);
HRMS: m/z calcd for C19H28O5Na (M+Na): 359.1834; found:
359.1833.
Crystal data for the dinitrobenzoate 33: X-ray data were collected
at 291 K on a SMART CCD-BRUKER diffractometer with graphite-
monochromated MoKa radiation (k = 0.71073 Å). The structure
was solved by direct methods (SIR 92). Refinement was by full-ma-
trix least-squares procedures on F2 using SHELXL-97. The non-hydro-
gen atoms were refined anisotropically whereas hydrogen atoms
were refined isotropically. Mol. for. C24H28N2O10; MW = 505.49; col-
orless; crystal system: monoclinic; space group P 1 21 1; cell param-
eters, a = 12.2773(3) Å, b = 7.6632(10) Å, c = 13.4463(3) Å;
b 98.689(10),
90.00, V = 1250.55(2) Å3, Z = 2, Dc = 1.342 g cmꢀ3
F(0 0 0) = 4533.9,
= 0.105 mmꢀ1. Total number of l.s. parame-
ters = 330, R1 = 0.0613 for 3336 F0 >2 (F0) and 0.0873 for all 4635
a 90.00,
c
,
4.8. Methyl (1R,2S,4R,5R,7S,8R)-8-methoxymethoxy-2,9-
dimethyl-5-hydroxytricyclo[5.4.0.02,4]undec-9-ene-4-
carboxylate 32
l
r
data. wR2 = 0.1712, GOF = 1.060, restrained GOF = 1.060 for all data.
An ORTEP diagram is depicted in Figure 1. Crystallographic data has
been deposited with Cambridge Crystallographic Data Centre (CCDC
768842).
To an ice cold, magnetically stirred solution of the tricyclic
b-keto ester 30 (27 mg, 0.09 mmol) in dry methanol (1 mL) was
added NaBH4 (10 mg, 0.32 mmol) and stirred the reaction mixture
over a period of 45 min at same temperature. Solvent was removed
under reduced pressure and the reaction was quenched with water
(2 mL) and the reaction mixture was extracted with ether
(2 ꢂ 5 mL). The combined ether extract was washed with brine
(4 mL) and dried (Na2SO4). Evaporation of the solvent and purifica-
tion of the residue over a silica gel column using ethyl acetate–hex-
ane (1:4) as eluent furnished the hydroxy ester 32 (23 mg, 82%) as
Acknowledgments
We thank the Indian Institute of Science and University Grants
Commission, New Delhi for the award of research fellowships to
B.B. and R.R.B. We thank CCD facility of Indian Institute of Science
for the single crystal X-ray diffraction analysis. We also thank Drs.
P. Ravi Kumar and U. Desai for the preliminary experiments.
oil. ½a 2D4
ꢃ
¼ ꢀ106:0 (c 2.0, CHCl3); IR (neat):
m
max/cmꢀ1 3444 (OH),
References
2950, 2889, 1725 (OC@O), 1463, 1438, 1281, 1228, 1151, 1117,
1090, 1063, 1032, 922, 885; 1H NMR: d 5.45 (1H, br s, H-10),
4.59 and 4.55 (2H, 2 ꢂ d, J 6.8 Hz, OCH2O), 4.70–4.30 (1H, m,
H-5), 3.66 (3H, s, COOCH3), 3.75–3.50 (1H, m, H-8), 3.35 (3H,
s, OCH3), 2.20–1.20 (7H, m), 1.59 (3H, s, olefinic-CH3), 1.00 (3H,
1. Dartayet, G. H.; Catalan, C. A. N.; Retamar, J. A.; Gros, E. G. Phytochemistry 1984,
23, 688.
2. Catalan, C. A. N.; de Fenik, I. J. S.; Dartayet, G. H.; Gros, E. G. Phytochemistry
1991, 30, 688.

724
A. Srikrishna et al. / Tetrahedron: Asymmetry 21 (2010) 719–724
3. Catalan, C. A. N.; de Lampasona, M. E. P.; de Fenik, I. J. S.; Cerda-Garcia-Rojas, C.
11. Srikrishna, A.; Kumar, P. R. Tetrahedron Lett. 2004, 45, 6867; Srikrishna, A.;
Kumar, P. R. Indian J. Chem. 2008, 47B, 1414.
M.; Mora-Perez, Y.; Joseph-Nathan, P. J. Nat. Prod. 1994, 57, 206.
4. Cerda-Garcia-Rojas, C. M.; Coronel, A. D. C.; de Lampasona, M. E. P.; Catalan, C.
A. N.; Joseph-Nathan, P. J. Nat. Prod. 2005, 68, 659; Cerda-Garcia-Rojas, C. M.;
Catalan, C. A. N.; Muro, A. C.; Joseph-Nathan, P. J. Nat. Prod. 2008, 71, 967.
5. Torrenegra, R.; Pedrozo, J.; Robles, J.; Waibel, R.; Achenbach, H. Phytochemistry
1991, 31, 2415.
12. Garver, L.; van Eikeren, P.; Byrd, J. E. J. Org. Chem. 1976, 41, 2773.
13. Ye, T.; McKervey, M. A. Chem. Rev. 1994, 94, 1091; Doyle, M. P.. In
Comprehensive Organometallic Chemistry II; Hegedus, L. S., Ed.; Pergamon
Press: New York, 1995; Vol. 12,. Chapter 5.2 Doyle, M. P.; McKervey, M. A.; Ye,
T. Modern Catalytic Methods for Organic Synthesis with Diazo Compounds: From
Cyclopropanes to Ylides; John Wiley and Sons: New York, 1998. Chapter 3.
14. Holmquist, C. R.; Roskamp, E. J. J. Org. Chem. 1989, 54, 3258.
6. Zinkel, D. F.; Magee, T. V. Phytochemistry 1987, 26, 769; Sakan, F.; Iwashita, T.;
Hamanaka, N. Chem. Lett. 1988, 123.
7. Schmitz, F. J.; Michaud, D. P.; Schmidt, P. C. J. Am. Chem. Soc. 1982, 104, 6415.
8. Abad, A.; Agulló, C.; Arnó, M.; Cantín, A.; Cuñat, A. C.; Meseguer, B.; Zaragozá, R.
J. J. Chem. Soc., Perkin Trans. 1 1997, 1837.
15. Although the exact origin of the high regioselectivity in the insertion reaction is
not very clear, it is probably due to the presence of all three substituents on the
cyclohexene ring in pseudoequitorial orientation, and for the insertion of the
rhodium carbenoid in the cyclohexene olefin they need to be in high energy
conformation, where all the three substituents need to be in axial orientation.
Similarly, origin of the stereoselectivity is also not very clear, but probably due
to the reaction of the more preferred rotamer i, over iii, of the rhodium
9. For recent examples: Srikrishna, A.; Gharpure, S. J. J. Chem. Soc., Perkin Trans. 1
2000, 3191; Srikrishna, A.; Gharpure, S. J. J. Org. Chem. 2001, 65, 4379;
Srikrishna, A.; Anebouselvy, K. J. Org. Chem. 2001, 65, 7102; Srikrishna, A.;
Kumar, P. R. Tetrahedron Lett. 2002, 43, 1109; Srikrishna, A.; Dethe, D. H.;
Kumar, P. R. Tetrahedron Lett. 2004, 45, 2939; Srikrishna, A.; Dethe, D. H. Org.
Lett. 2004, 6, 165; Srikrishna, A.; Ramasastry, S. S. V. Tetrahedron Lett. 2004, 45,
379; Srikrishna, A.; Ravi Kumar, P.; Ramasastry, S. S. V. Tetrahedron Lett. 2004,
45, 383; Srikrishna, A.; Kumar, P. P.; Reddy, T. J. Indian J. Chem. 2005, 44B, 1430;
Srikrishna, A.; Satyanarayana, G. Tetrahedron: Asymmetry 2005, 16, 3992;
Srikrishna, A.; Pardeshi, V. H.; Satyanarayana, G. Tetrahedron Lett. 2007, 48,
4087; Srikrishna, A.; Ravi, G.; Satyanarayana, G. Tetrahedron Lett. 2007, 48, 73;
Srikrishna, A.; Pardeshi, V. H.; Satyanarayana, G. Tetrahedron: Asymmetry 2008,
19, 1984; Srikrishna, A.; Pardeshi, V. H.; Triveni, P. Tetrahedron: Asymmetry
2008, 19, 1392.
carbenoid derived from the
a
-diazo-b-ketoester 26. The corresponding
rhodium carbenoid ii derived from the
a
-diazoketone 22, being less stable
and more reactive than i, exhibited lower selectivity.
O
O
H
H
OMOM
OMOM
X
X
'Rh'
CH3
'Rh'
H
H
i. X = COOMe
ii. X = H
iii
10. Gesson, J.-P.; Jacquesy, J.-C.; Renoux, B. Tetrahedron Lett. 1986, 27, 4461.