Studies towards the synthesis of crotogoudin

Article abstract of DOI:10.1055/s-0032-1318366

An effective synthesis of the tricyclic core structure of the new diterpene crotogoudin was achieved. The synthesis features an intermolecular domino Michael reaction to construct a bicyclo[2.2.2]octane motif and an aldol condensation to close ring B. Stork reductive alkylation with allyl bromide proceeded from the β side, resulting in the wrong stereochemistry at C-10. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0032-1318366

LETTER
▌705
lSettteur dies Towards the Synthesis of Crotogoudin
Crotogoudin Core Structure
Dmitry B. Ushakov, Martin E. Maier*
Institut für Organische Chemie, Universität Tübingen, Auf der Morgenstelle 18, 72076 Tübingen, Germany
Fax +49(7071)295137; E-mail: martin.e.maier@uni-tuebingen.de
Received: 07.01.2013; Accepted after revision: 12.02.2013
ed for the latter strategy where the synthesis will begin
with a bicyclo[2.2.2]octane derivative. The A ring in ke-
tone 4 could be introduced via a Stork reductive alkylation
strategy.5 The closure of the B ring would rely on an intra-
Abstract: An effective synthesis of the tricyclic core structure of
the new diterpene crotogoudin was achieved. The synthesis features
an intermolecular domino Michael reaction to construct a bicyc-
lo[2.2.2]octane motif and an aldol condensation to close ring B.
Stork reductive alkylation with allyl bromide proceeded from the β molecular aldol condensation of bicyclo[2.2.2]octane de-
side, resulting in the wrong stereochemistry at C-10.
rivative 6, which would arise from enone 7 and methyl
acrylate via a domino Michael reaction.6 Construction of
Key words: crotogoudin, atisane, diterpene, domino Michael reac-
tion, Stork reductive alkylation
this bicylic motif by intermolecular domino Michael reac-
tion has been broadly described in the literature.7 Howev-
er, application of this strategy for the synthesis of atisane-
related compounds was unknown.8,9 On the other hand in-
tramolecular double Michael reactions were used in the
synthesis of atisirene10 and atisine.11 Vinylogous ester 8
appeared as an appropriate starting material for our plan.
Two closely related 3,4-seco-atisane diterpenes croto-
goudin (1) and crotobarin (2) were recently discovered
during the screening of plant extracts from Madagascan
plants Croton goudotii and C. barorum in 2010 (Figure
1).1 Initial cell-cycle analysis led to the conclusion that
these two compounds arrest the cells at the G2/M stage.
The enone functionality present in 1 and 2 might prohibit
their development as drugs, however, this functional
group might help to elucidate the cellular target by affini-
ty-based methods.2 Due to the interesting biological pro-
file and the challenging structural features these new
natural products appear as interesting targets for total syn-
thesis. We focused our research on the simpler of the two
compounds, namely crotogoudin (1). This novel diterpene
contains a polycyclic ring system with a six-membered
ring fused to a bicyclo[2.2.2]octane subunit. The absolute
stereochemistry of 1 has not been established yet.
aldol
Stork reductive
condensation
alkylation
O
X
CO2Me
B
B
A
1
O
O
H
4
5
Baeyer–Villiger
oxidation
domino Michael with
O
OR
O
O
acrylate
CO2Me
Oi-Bu
O
6
7
8
12
H
R
11
H
13
14
16
15
11
1
4
10
H
16
Scheme 1 Retrosynthetic analysis of crotogoudin (1)
1
9
8
10
5
8
O
O
The synthesis commenced with addition of the Grignard
reagent derived from 1-chlorobutanol to vinylogous ester
8, which is easily available from 1,3-cyclohexanedione12
(Scheme 2). After the 1,2-addition to vinylogous ester 8
and acid-mediated hydrolysis of the addition product,
enone 7a was obtained in good yield. Next, the hydroxyl
group of enone 7a was protected as tert-butyldimethyl-
silyl ether before it was introduced in the double Michael
reaction with methyl acrylate (2 equiv) to afford bicyclic
keto ester 9a as a single diastereomer. Best results were
obtained with LiN(SiMe3)2 (1.3 equiv) as base in a mix-
ture of THF and hexane. The orientation of the ester group
could be inferred from the NOESY spectrum which shows
a cross peak between 15-H and 14-H (atisane numbering).
This assignment was confirmed by X-ray analysis on a
similar compound in the synthesis of the core structure of
palhinine A.13 Fluoride-mediated cleavage of the silyl
ether converted keto ester 9a into primary alcohol 9b.
H
O
crotogoudin (1) R = H
crotobarin (2) R = OAc
atisane (3)
Figure 1 Structures of crotogoudin (1), crotobarin (2), and atisane
(3)
Our retrosynthetic plan for (±)-crotogoudin (1) features a
Baeyer–Villiger oxidation3 and intramolecular translac-
tonization leading to ketone 4 (Scheme 1). This step most
likely corresponds to the biosynthetic pathway.4 With an
advanced target molecule like 4, a late- or early-stage for-
mation of the bicyclic ring system can be chosen. We opt-
SYNLETT 2013, 24, 0705–0708
Advanced online publication: 05.03.2013
DOI: 10.1055/s-0032-1318366; Art ID: ST-2013-B0022-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

706
D. B. Ushakov, M. E. Maier
LETTER
Since the yields for the formation of hydroxyenone 7a The next challenge involved allylic oxidation of enone 10
were moderate, we investigated a slightly modified route to diketone 14. Being disappointed by inefficiency of dif-
to 9b which utilizes readily available THP-protected 4- ferent selenium (SeO2, dioxane, reflux; SeO2, TBHP,
chlorobutanol for the Grignard addition to vinylogous es- CH2Cl2, r.t.) and chromium-based methods (3,5-dimeth-
ter 8.14 Acid-mediated hydrolysis of the vinylogous hemi- ylpyrazole, CrO3, CH2Cl2, –20 °C to r.t.)15 to introduce a
acetal obtained from the Grignard reaction led to enone 7c carbonyl moiety in the allylic position, we were success-
in 86% yield. Treatment of the lithium enolate, generated ful with a four-step sequence starting with allylic bromi-
from 7c using LiN(SiMe3)2 (2.5 equiv) as base with meth- nation (Scheme 3). Thus, Ziegler–Wohl bromination of
yl acrylate (2.5 equiv) resulted in formation of bicyclic enone 10 furnished bromide 11 (dr = 1:1). This was fol-
compound 9c also in high yield and as a single isomer (di- lowed by substitution of the bromide to the corresponding
astereomers on the acetal carbon of the THP group). Acid- acetate 12. Only one diastereomer of 12 was observed.
induced cleavage of the THP protecting group provided We attribute this to a SN1-type mechanism. Without addi-
alcohol 9b as well. Although the use of THP as a protect- tion of acetic acid, a 1:1 mixture of diastereomers was ob-
ing group made workup and NMR analysis inconvenient tained. A subsequent base-mediated hydrolysis of acetate
(diastereomeric mixture on the acetal carbon), the yields 12 furnished allylic alcohol 13. Under these conditions no
were higher in comparison to the use of the previous epimerization next to the ester function (C-15) took place.
method. Subsequent Dess–Martin oxidation of primary Also during the aldol condensation (6 to 10) this stereo-
alcohol 9b gave keto aldehyde 6 in good overall yield. center remained untouched. A Dess–Martin oxidation of
Base-mediated intramolecular aldol condensation provid- alcohol 13 resulted in diketone 14 (66% yield for four
ed enone 10. The olefinic H of enone 10 resonates at δ = steps). After further experimentation we found even a sin-
6.93 ppm.
gle-step procedure for the desired transformation of enone
10 to 1,4-enedione 14, namely a Pd-catalyzed oxidation
using tert-butylhydroperoxide.16,17
OMgCl
a)
MgCl
We next faced the challenge of introducing substituents at
C-10. This was achieved by [3+2] cycloaddition of freshly
prepared diazomethane18 to the electron-poor double bond
of enedione 14 at room temperature. This resulted in for-
mation of a pyrazoline derivative, which underwent nitro-
gen elimination even under ambient temperature to give
diketone 5 (Scheme 3).19 The presence of the 10-CH3
group is evident from an additional peak in the 1H NMR
spectrum of 5 at δ = 2.17 ppm. The regiochemistry can be
explained by attack of the negatively charged carbon cen-
ter at the less hindered position of the enedione.20,21 Next,
a Stork reductive alkylation was called for construction of
the quaternary center at C-10. Accordingly, dienolate A,
prepared by treatment of diketone 5 with lithium in liquid
ammonia, was quenched with allyl bromide. After work-
up only one regio- and stereoisomer was detected and its
structure was assigned to 15.22 As can be seen, C-al-
lylation took place on the less hindered carbon atom (C-
10), while the other enolate underwent O-allylation. Un-
fortunately, the stereochemistry of the newly formed ste-
reocenter was opposite with respect to the one required for
C-10 of crotogoudin (1). This can be explained by shield-
ing of the enolate face syn to the ester group at C-15. The
stereochemistry in the allylation step followed from a rel-
atively strong NOESY cross peak between the allyl CH to
14-H (methylene group). In addition, the other 14-H
showed a NOESY correlation with 15-H (α proton next to
the ester group).
LiHMDS, THF–hexane
then methyl acrylate
–78 °C to r.t.
O
OR
THF, –78 to 0 °C
b) HCl, H2O, r.t.
(50%, 2 steps)
8
(100%)
TBSCl, imidazole
CH2Cl2, 0 °C to r.t.
(89%)
7a R = H
7b R = TBS
O
15
14
RO
CO2Me
TBAF⋅3H2O
THF, r.t.
(64%)
9a R = TBS
9b R = H
OTHP
O
OTHP LiHMDS, THF–hexane
then methyl acrylate
–78 °C to r.t.
MgCl
THF, reflux
8
(86%)
14
(91%)
7c
O
15
RO
CO2Me
9c R = THP
9b R = H
HCl, THF–H2O
r.t. (96%)
Dess–Martin
CH2Cl2, r.t.
K2CO3
O
MeOH, r.t.
O
9b
(82%)
(74%)
CO2Me
CO2Me
In summary, an efficient synthesis of the carbocyclic core
structure of crotogoudin (1) has been achieved by exploit-
ing an intermolecular domino Michael reaction to access
bicyclo[2.2.2]octane derivative 9b, followed by intramo-
lecular aldol condensation resulting in enone 10. Its Pd-
catalyzed allylic oxidation, followed by 1,3-dipolar cyclo-
addition with diazomethane gave diketone 5. The shorter
O
6
10
H
Scheme 2 Synthesis of enone 10 via intermolecular domino Michael
reaction, followed by aldol condensation
Synlett 2013, 24, 705–708
© Georg Thieme Verlag Stuttgart · New York

LETTER
Crotogoudin Core Structure
707
(3) For a recent example of Baeyer–Villiger oxidation on a
polycyclic ketone, see: (a) Yokoe, H.; Mitsuhashi, C.;
NBS, AIBN, CCl4
O
AgOAc, AcOH
r.t.
reflux
10
Matsuoka, Y.; Yoshimura, T.; Yoshida, M.; Shishido, K.
J. Am. Chem. Soc. 2011, 133, 8854. (b) Ushakov, D. B.;
Raja, A.; Franke, R.; Sasse, F.; Maier, M. E. Synlett 2012,
23, 1358.
(92%)
(84%)
(dr = 1:1)
CO2Me
Br
11
O
O
Dess–Martin
CH2Cl2, r.t.
(4) (a) Pradhan, B. P.; Chakraborty, S.; Weyerstahl, P.
Tetrahedron Lett. 1989, 30, 5463. (b) Fried, J.; Thoma, R.
W.; Klinsberg, A. J. Am. Chem. Soc. 1953, 75, 5764.
(c) Laskin, A. I.; Grabowich, P.; Meryers, C. de L.; Fried, J.
J. Med. Chem. 1964, 406.
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1218. (b) Stork, G.; Logusch, E. W. J. Am. Chem. Soc. 1980,
102, 1219. (c) Nemoto, H.; Matsuhashi, N.; Imaizumi, M.;
Nagai, M.; Fukumoto, K. J. Org. Chem. 1990, 55, 5625.
(d) Jung, M. E.; Yoo, D. Org. Lett. 2011, 13, 2698.
(6) Michael, A. J. Prakt. Chem. 1887, 35, 349.
CO2Me
CO2Me
(93%)
RO
O
K2CO3
12 R = Ac
13 R = H
14
MeOH–H2O, r.t.
(92%)
O
Pd(OH)2/C, TBHP
K2CO3, CH2Cl2, r.t.
14
CO2Me
(78%)
(7) (a) Ihara, M.; Fukumoto, K. Angew. Chem., Int. Ed. Engl.
1993, 32, 1010; Angew. Chem. 1993, 105, 1059 . (b) Lee, R.
A. Tetrahedron Lett. 1973, 14, 3333. (c) White, K. B.;
Reusch, W. Tetrahedron 1978, 34, 2439. (d) Roberts, M. R.;
Schlessinger, R. H. J. Am. Chem. Soc. 1981, 103, 724.
(e) Gibbons, E. G. J. Am. Chem. Soc. 1982, 104, 1767.
(f) Nagdoka, H.; Kobayashi, K.; Matsui, T.; Yamada, Y.
Tetrahedron Lett. 1987, 28, 2021. (g) Iwashima, M.;
Nagaoka, H.; Kobayashi, K.; Yamada, Y. Tetrahedron Lett.
1992, 33, 81. (h) Stork, G. Pure Appl. Chem. 1989, 61, 439.
(i) Fukushima, M.; Morii, A.; Hoshi, T.; Suzuki, T.;
Hagiwara, H. Tetrahedron 2007, 63, 7154. (j) Srikrishna,
A.; Ravi, G.; Satyanarayana, G. Tetrahedron Lett. 2007, 48,
73. (k) Srikrishna, A.; Ravi, G. Tetrahedron 2008, 64, 2565.
(l) Hagiwara, H.; Yamada, Y.; Sakai, H.; Suzuki, T.; Ando,
M. Tetrahedron 1998, 54, 10999. (m) Hagiwara, H.; Endou,
S.; Fukushima, M.; Hoshi, T.; Suzuki, T. Org. Lett. 2004, 6,
1115. (n) Yang, J.; Huang, H.; Jin, Z.; Wu, W.; Ye, J.
Synthesis 2011, 1984. (o) Spitzner, K.; Oesterreich, K. Eur.
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Synth. 1987, 66, 37; Org. Synth., Coll. Vol. VIII 1993, 219.
(8) For the synthesis of atisane-type natural products, see ref. 8
and 9. See also: (a) Toyota, M.; Wada, T.; Fukumoto, K.;
Ihara, M. J. Am. Chem. Soc. 1998, 120, 4916. (b) Toyota,
M.; Wada, T.; Ihara, M. J. Org. Chem. 2000, 65, 4565.
(c) Abad, A.; Agullo, C.; Cunat, A. C.; Navarro, I.; de
Arellano, M. C. R. Synlett 2001, 349. (d) Toyota, M.; Asano,
T.; Ihara, M. Org. Lett. 2005, 7, 3929. (e) Abad, A.; Agullo,
C.; Cunat, A. C.; Marzal, I. de A.; Navarro, I.; Gris, A.
Tetrahedron 2006, 62, 3266. (f) Abad, A.; Agullo, C.;
Cunat, A. C.; Marzal, I. de A.; Gris, A.; Navarro, I.; de
Arellano, C. R. Tetrahedron 2007, 63, 1664.
10
O
Li, NH3, THF
–78 °C
CH2N2, Et2O
CHCl3, r.t.
14
15
10
CO2Me
14
(78%)
O
5
NOE
allyl bromide
–78 °C to r.t.
LiO
O
(63%)
CO2Me
LiO
CO2Me
15
O
A
Scheme 3 Allylic oxidation of enone 10 to enedione 14, introduction
of a methyl group at C-10, followed by allylation of dienolate A with
allyl bromide to give 15
route to 5 via enone 7c proceeded in 30% overall yield
starting from vinylogous ester 8 with a longest linear se-
quence of seven steps. Further studies on the facial selec-
tivity of the Stork reductive alkylation and application of
the present strategy toward the total synthesis of croto-
goudin (1) and its analogues are in progress in our labora-
tory.
Acknowledgment
Financial support by the Deutsche Forschungsgemeinschaft and the
Fonds der Chemischen Industrie is gratefully acknowledged. This
work was carried out within the framework of COST action
CM0804 – Chemical Biology with Natural products. We thank Dr.
A. Khartulyari, D. Gaugele, for helpful discussions and Dr. D.
Wistuba (all University of Tübingen) for assistance in obtaining
high-resolution mass spectra.
(9) A similar polycyclic motif can be also found in platencin.
For a review, see: Palanichami, K.; Kaliappan, K. P. Chem.
Asian J. 2010, 5, 668.
(10) (a) Ihara, M.; Toyota, M.; Fukumoto, K. J. Chem. Soc.,
Perkin Trans. 1 1986, 2151. (b) Ihara, M.; Toyota, M.;
Fukumoto, K.; Kametani, T. Tetrahedron Lett. 1985, 26,
1537.
(11) Ihara, M.; Suzuki, M.; Fukumoto, K.; Kametani, T.; Kabuto,
C. J. Am. Chem. Soc. 1988, 110, 1963.
Supporting Information for this article is available online at
(12) (a) Hara, R.; Furukawa, T.; Kashima, H.; Kusama, H.;
Horiguchi, Y.; Kuwajima, I. J. Am. Chem. Soc. 1999, 121,
3072. (b) Yamada, S.; Suemune, H. Chem. Pharm. Bull.
2000, 48, 1171. (c) Gulias, M.; Rodriguez, R.; Castedo, L.;
Mascarenas, J. L. Org. Lett. 2003, 5, 1975.
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
r
t
References and Notes
(13) Gaugele, D.; Maier, M. E. unpublished results.
(14) (a) Conia, J.-M.; Rouessac, F. Tetrahedron 1961, 16, 45.
(b) Becker, D.; Harel, Z.; Nagler, M.; Gillon, A. J. Org.
(1) Rakotonandrasana, O. L.; Raharinjato, F. H.; Rajaonarivelo,
M.; Dumontet, V.; Martin, M.-T.; Bignon, J.; Rasoanaivo, P.
J. Nat. Prod. 2010, 73, 1730.
(2) Evans, M. J.; Cravatt, B. F. Chem. Rev. 2006, 106, 3279.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 705–708

708
D. B. Ushakov, M. E. Maier
LETTER
ppm. ESI-HRMS: m/z [M + Na]+ calcd for C15H18O4Na:
Chem. 1982, 47, 3297. (c) Schinzer, D. Angew. Chem., Int.
Ed. Engl. 1984, 23, 308; Angew. Chem. 1984, 96, 292.
285.109730; found: 285.109658.
(15) Salmond, W. G.; Rarta, M. A.; Havens, J. L. J. Org. Chem.
1978, 43, 2057.
(16) Yu, J.-Q.; Corey, E. J. J. Am. Chem. Soc. 2003, 125, 3232.
(17) Enedione 14
(20) For a review, see: (a) Ess, D. H.; Jones, G. O.; Houk, K. N.
Adv. Synth. Catal. 2006, 348, 2337. (b) 1,3-Dipolar
Cycloaddition Chemistry; Regitz Heydt, H.; Padwa, A.,
Eds.; Wiley: New York, NY, 1984, 393–558.
Pd(OH)2/C (Pearlman’s catalyst, 20%, 1.1 g, 2.0 mmol) was
added to a stirred suspension of enone 10 (10.0 g, 43.0
mmol), K2CO3 (1.5 g. 10.0 mmol) in CH2Cl2 (200 mL),
followed by addition of TBHP (5.0–6.0 M in decaline, 43
mL, 215.0 mmol) at r.t. The resulting mixture was stirred
overnight at r.t. The reaction mixture was then filtered
through a short pad of silica gel, washed with CH2Cl2, and
concentrated in vacuo at r.t. The residue was purified by
flash chromatography (PE–EtOAc, 1:1) to give 1,4-diketone
12 (8.3 g, 78%) as a colorless oil. Rf = 0.40 (PE–EtOAc,
1:1). 1H NMR (400 MHz, CDCl3, atoms numbered
according to the naphthalene system): δ = 1.74–1.79 (m, 1 H,
10-H), 1.84–1.99 (m, 4 H, 5-H, 10-H, 2 × 9-H), 2.11–2.21
(m, 3 H, 2 × 3-H, 5-H), 2.30 (ddd, J = 16.8, 7.3, 5.3 Hz, 1 H,
6-H), 2.45 (ddd, J = 16.7, 9.9, 5.8 Hz, 1 H, 6-H), 2.60 (ddd,
J = 5.8, 3.0, 3.0 Hz, 1 H, 2-H), 2.79 (dd, J = 9.6, 6.1 Hz, 1 H,
4-H), 3.63 (s, 3 H, OCH3), 6.50 (s, 1 H, 8-H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 22.7 (C-9), 28.0 (C-3), 29.8 (C-5),
31.1 (C-10), 34.4 (C-6), 38.6 (C-4a), 40.4 (C-2), 46.7 (C-4),
52.2 (OCH3), 125.4 (C-8), 152.4 (C-8a), 174.3 (ester), 198.8
(C-7), 201.8 (C-1) ppm. ESI-HRMS: m/z [M + Na]+ calcd
for C14H16O4Na: 271.094080; found: 271.094073.
(21) (a) For related examples, see: 5c and 5d. See also: Cermola,
F.; Iesce, M. R. Tetrahedron 2006, 62, 10694. (b) Nemoto,
H.; Nagai, M.; Moizumi, M.; Kohzuki, K.; Fukumoto, K.;
Kametani, T. Tetrahedron Lett. 1988, 29, 4959.
(22) Allylation of Dienolate of Enedione 5 to 15: Methyl
(2S,4S,4aS,8S)-8-Allyl-1-(allyloxy)-8-methyl-7-oxo-
3,4,5,6,7,8-hexahydro-2H-2,4a-ethanonaphthalene-4-
carboxylate (15)
Lithium (60 mg, 8.82 mmol) was added in small portions to
stirred liquid NH3 (10 mL) at –78 °C. The resulting blue
solution was stirred for 1 h before it was treated with a
solution of diketone 5 (50 mg, 0.19 mmol) in THF (4 mL).
After complete addition stirring was continued for 2 h at the
same temperature. Then, allyl bromide (1.6 mL, 18.90
mmol) was added dropwise at –78 °C and the mixture stirred
for 30 min before the cooling bath was removed and the NH3
was allowed to evaporate. The resulting white suspension
was diluted with H2O (20 mL) and extracted with Et2O
(3 × 10 mL). The combined organic layers were washed
with sat. NaCl solution (20 mL), dried over MgSO4, filtered,
and concentrated in vacuo. The residue was purified by flash
chromatography (PE–EtOAc, 4:1) to give ketone 15 (41 mg,
63%) as a colorless oil. Rf = 0.64 (PE–EtOAc = 1:1). 1H
NMR (400 MHz, CDCl3): δ = 1.29–1.76 (m, 7 H, 2 × 3-H, 5-
H, 2 × 9-H, 2 × 10-H), 1.33 (s, 3 H, 8-CH3), 1.85 (ddd,
J = 12.6, 9.7, 2.8 Hz, 1 H, 3-H), 2.01–2.08 (m, 1 H, 5-H),
2.25 (ddd, J = 8.5, 5.1, 2.9 Hz, 2 H, 2 × 6-H), 2.45 (dd,
J = 9.8, 5.8 Hz, 1 H, 4-H), 2.51 [dd, J = 13.1, 7.6 Hz, 1 H, 8-
(CH2CH=CH2)], 2.80–2.86 [m, 2 H, 2-H, 8-(CH2CH=CH2)],
3.60 (s, 3 H, OCH3), 4.30–4.39 [m, 2 H, 1-(OCH2CH=CH2)],
4.87–4.89 [m, 2 H, 8-(CH2CH=CH2)], 5.22 [ddd, J = 12.1,
1.5, 1.5 Hz, 1 H, 1-(OCH2CH=CH2)], 3.56 [ddd, J = 17.2,
3.3, 1.6 Hz, 1 H, 1-(OCH2CH=CH2)], 5.55 [dddd, J = 17.2,
10.0, 7.4, 7.4 Hz, 1H, 8-(CH2CH=CH2)], 5.99 [dddd,
J = 17.2, 10.4, 5.2, 5.0 Hz, 1 H, 1-(OCH2CH=CH2)] ppm.
13C NMR (100 MHz, CDCl3): δ = 24.8 (8-CH3), 26.1 (C-9),
30.4 (C-2), 30.8 (C-5), 32.4 (C-3), 34.7 (C-10), 37.3 (C-6),
41.0 (C-4a), 42.9 [8-(CH2CH=CH2)], 49.2 (C-4), 51.6
(OCH3, C-8), 68.8 [1-(OCH2CH=CH2)], 116.8 [8-
(18) (a) Arndt, F. Org. Synth. 1935, 15, 3; Org. Synth., Coll. Vol.
II 1943, 165. (b) de Boer, T. J.; Backer, H. J. Org. Synth.
1956, 36, 16; Org. Synth., Coll. Vol. IV 1963, 250.
(19) Enedione 5
A solution of diazomethane in Et2O (200 mL) was added to
a stirred solution of enedione 14 (4.7 g, 0.019 mol) in CHCl3
(150 mL) at 0 °C. The mixture was allowed to warm to r.t.
and stirred for 6 h before the solvents were removed with a
flow of nitrogen. The residue was purified by flash
chromatography (PE–EtOAc, 4:1 to 1:1) to give enedione 5
(3.9 g, 78%) as white crystals (mp 97–98.5 °C). Rf = 0.45
(PE–EtOAc, 1:1). 1H NMR (400 MHz, CDCl3): δ = 1.61–
1.68 (m, 1 H, 10-H), 1.78–2.00 (m, 4 H, 5-H, 10-H, 2 × 9-H),
2.06–2.14 (m, 3 H, 2 × 3-H, 5-H), 2.17 (s, 3 H, 8-CH3) 2.34
(ddd, J = 16.4, 6.8, 5.0 Hz, 1 H, 6-H), 2.49 (ddd, J = 16.4,
10.9, 5.8 Hz, 1 H, 6-H), 2.55 (ddd, J = 6.1, 3.0, 3.0 Hz, 1 H,
2-H), 2.69 (dd, J = 8.6, 7.3 Hz, 1 H, 4-H), 3.60 (s, 3 H,
OCH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 12.0 (CCH3),
22.6 (C-9), 28.1 (C-3), 29.8 (C-5), 31.1 (C-10), 34.0 (C-6),
39.8 (C-4a), 42.2 (C-2), 47.2 (C-4), 52.0 (OCH3), 138.2 (C-
8), 144.6 (C-8a), 174.6 (ester), 199.6 (C-7), 204.7 (C-1)
(CH2CH=CH2), 1-(OCH2CH=CH2)], 118.5 (C-8a), 134.2 [1-
(OCH2CH=CH2)], 136.1 [(8-(CH2CH=CH2)], 154.5 (C-1),
175.9 (ester), 215.2 (C-7) ppm. ESI-HRMS: m/z [M + Na]+
calcd for C23H30O4Na: 393.203631; found: 393.203799.
Synlett 2013, 24, 705–708
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