Facile asymmetric synthesis of spongianone analogue through biomimetic cyclization

Article abstract of DOI:10.1016/j.tetlet.2009.08.066

Facile synthesis of (+)-tetracyclic-homoditerpene lactone has been achieved from sclareol through [2,3] sigmatropic rearrangement followed by biomimetic cyclization.

Full text of DOI:10.1016/j.tetlet.2009.08.066

Tetrahedron Letters 50 (2009) 6402–6403
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Tetrahedron Letters
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Facile asymmetric synthesis of spongianone analogue through
biomimetic cyclization
*
Sanjay J. Mishra, Kiran B. Upar, Sujata V. Bhat
Laboratory for Advanced Research in Natural and Synthetic Chemistry, V. G. Vaze College, Mithagar Road, Mulund (East), Mumbai 400 081, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Facile synthesis of (+)-tetracyclic-homoditerpene lactone has been achieved from sclareol through [2,3]
sigmatropic rearrangement followed by biomimetic cyclization.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 23 July 2009
Revised 18 August 2009
Accepted 21 August 2009
Available online 24 August 2009
Keywords:
Chiral LBA
BINOL
Biomimetic cyclization
Tetracyclic (+)-c-lactone
Spongianone
21
Me
Cascade reactions are some of the most powerful tools for the
total synthesis of complex natural products, since complicated
structures can be constructed directly in one-pot sequences. The
benefits of cascade reactions include atom economy, as well as sav-
ings in labor, resource management, and waste generation.1 The
construction of polycyclic molecules from acyclic precursors is a
general theme in biosynthesis. During the last two decades, the
biomimetic cyclization of polyene molecules has been developed
to a high degree of sophistication and practical utility.2 The Lewis
acid-assisted chiral Brønsted acids (chiral LBAs) prepared in situ
from chiral alcohols and tin(IV) chloride were found to be highly
effective as artificial cyclases for the enantioselective biomimetic
cyclization of polyprenoids.3
Continuing our efforts in this field, we report herein facile
asymmetric synthesis of tetracyclic homoditerpene (+)-c-lactone
1, an analogue of spongianone (2), which is a metabolite of marine
sponge Dictyodendrilla cavernosa.4 The synthesis of tetracyclic lac-
tone 3 has been reported through chlorosulfonic acid cyclization of
homoterpenic acid 4.5 Similarly murrayanolide (5), a metabolite of
marine sponge Dendrobeania murrayana,6 is a diacetoxy-tetracy-
O
20
17
Me
13
H
Me
O
O
O
SnCl4
1
15
H
H
4
Bn
H
Me
18
Me
19
(R)-BINOL-Bn
Chiral LBA
1
The present synthetic approach to the tetracyclic (+)-c-lactone
1 from (ꢀ)-sclareol (6) involves the [2,3] sigmatropic rearrange-
ment of an allylic alcohol to the homologous amide followed by
the hydrolysis of the amide to acid and biomimetic enatioselective
cyclization of the resulting acid promoted by (R)-2-benzyloxy-20-
hydroxy-1,10-binaphthyl [(R)-benzyl-BINOL] and SnCl4 (chiral
LBA).
7
The commercial sample of (+)-sclareol (6) was heated with
N,N-dimethylformamide dimethyl acetal (DMFDMA) to obtain
one carbon homologation to the corresponding starting materials
with incorporation of terminal amide functionality. Thus, the
refluxing of a mixture of (ꢀ)-sclareol and DMFDMA in xylene for
clic-c-lactone.
14 h yielded an E/Z-mixture of the b,c-unsaturated amides 7a
and 7b (2.2:1) in 80% yield (Scheme 1), which were easily sepa-
rated by silica gel column chromatography.8 The alkaline hydroly-
sis of amide 7a afforded the acid 8, which was subjected to
cyclization in the presence of (R)-benzyl-BINOL and SnCl4 at
ꢀ78 °C for 3 h and subsequently at ꢀ20 °C for 3 days to give tetra-
cyclic (+)-lactone (1),9 yield 58.6%, ee = 96%.
* Corresponding author. Tel.: +91 022 21631421x113; fax: +91 022 21634262.
E-mail address: sujata8b@gmail.com (S.V. Bhat).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.08.066

S. J. Mishra et al. / Tetrahedron Letters 50 (2009) 6402–6403
6403
In conclusion, we have achieved efficient enantioselective syn-
thesis of spongianone analogue starting from sclareol through
[2,3] sigmatropic rearrangement and chiral LBA-induced biomi-
metic cyclization as key steps.
Me
H
O
H
O
20
O
17
Me
H
Me
13
Me
Me
O
1
15
H
H
H
Acknowledgments
4
H
Me
Me
Me
19
We are grateful to Kelkar Education Trust, Mumbai, for encour-
agement and support. We are also thankful to the Department of
Chemistry and Sophisticated Analytical Instrumentation Facility,
Indian Institute of Technology, Mumbai, for NMR spectral data.
Me
2
18
3
Me
H
AcO
O
O
COOH
Me
Me
Me
Supplementary data
H
H
H
CH2OAc
Supplementary data (1H NMR, 13C NMR spectra and Chiral HPLC
graph of tetracyclic-c-lactone 1) associated with this article can be
H
H
Me
Me
Me
Me
found, in the online version, at doi:10.1016/j.tetlet.2009.08.066.
5
4
References and notes
The cis-stereochemistry of C/D rings of (+)-homo-diterpene-c-
lactone 1 could be assigned by the comparison of 13C NMR chem-
ical shifts of lactone 1 with that of lactone 3. The C-21 angular
methyl group in lactone 1 appears at d 29.7 as in lactone 3, which
appears at 29.8 ppm. The stereochemistry of the C-17 b-methyl
group was obtained by the comparison of 13C NMR chemical shifts
of lactone 1 with that of lactone 2. In lactone 1 C-17 b-methyl
group appears at d 15.7 ppm as in lactone 2, which appears at
15.7 ppm.
1. Nicolaou, K. C.; Edmons, D. J.; Bulger, P. G. Angew. Chem., Int. Ed. 2006, 45, 7134–
7186.
2. Yamamoto, H.; Futatsugi, K. Angew. Chem., Int. Ed. 2005, 44, 1924–1942.
3. Ishihara, K.; Ishibashi, H.; Yamamoto, H. J. Am. Chem. Soc. 2002, 124, 3647–3655.
4. Kernan, M. R.; Cambie, R. C. J. Nat. Prod. 1990, 53, 724–727.
5. Imamara, P. M.; Santiago, M. P. Synth. Commun. 1997, 27, 2479–2485.
6. Yu, C.-M.; Wright, J. L. C. J. Nat. Prod., 1995, 58, 1978–1982.
7. Basabe, P.; Bodero, O.; Marcos, I. S.; Diez, D.; de Roman, M.; Blanco, A.; Urones, J.
G. Tetrahedron 2007, 63, 11838–11843.
8. Barrero, A. F.; Altarejos, J.; Alvarez-Manzaneda, E. J.; Ramos, J. M.; Salido, S. J. Org.
Chem. 1996, 61, 2215–2218.
9. Synthesis of tetradecahydro-[3b,6,6,9a,11a-pentamethyl-(3aR,3bR,5aS,9aS,9bR,
11aS)]phenanthro[2,1-b]furan-2(3H)-one (1): To a solution of (R)-2-benzyloxy-
20-hydroxy-1,10-binaphthyl (260 mg, 0.69 mmol) in toluene (3 mL) was added
tin(IV) chloride (0.4 mL, 3.37 mmol) at -20 °C and the solution was stirred for
30 min. This complex of 2-benzyloxy-20-hydroxy-1,10-binapthyl–SnCl4 prepared
in situ was cooled to ꢀ78 °C and acid 8 (210 mg, 0.66 mmol) in toluene (6 mL)
was added dropwise over a period of 5 min. The reaction mixture was stirred at
ꢀ78 °C for 3 h and kept at ꢀ20 °C for 3 days, quenched with saturated aqueous
NaHCO3, and extracted with ethyl acetate. The combined organic extracts were
dried over anhydrous Na2SO4 and concentrated. The crude product was purified
by column chromatography on silica gel to yield lactone (1) (150 mg, 71.4%,
Me
Me
CH2
R
OH
Me
H
Me
Me
H
O
i
H
OH
H
Me Me
6
Me
hexane–ethyl acetate 95:5); mp 166–168 °C (hexane); ½a D25
ꢁ
+70.0 (c 0.64 CHCl3),
chiral HPLC (MeCN:H2O—65:35, kmax 216 nm, flow rate—0.5 mL/min) tR = 5.1
Me
R= NMe2
ii
7a
(major isomer), 4.5 (minor isomer) min, ee = 96%, IR (KBr) 2936, 1772
(c
lactone), 1458, 1235, 946 cmꢀ1 1H NMR (400 MHz, CDCl3) d 0.81 (s, 3H), 0.86 (s,
;
iii
3H), 0.87 (s, 3H), 0.92 (s, 3H), 1.31 (s, 3H), 1–1.66 (m, 14H), 1.68–1.80 (m, 2H),
2.24–2.33 (m, 1H), 2.39 (d, J = 18 Hz,1H), 2.72 (dd, J = 7.9, 18 Hz, 1H); 13C NMR
(100 MHz, CDCl3) d 175.7 (C-16), 85.8 (C-13), 56.8 (C-9), 56.5 (C-5), 55.4 (C-14),
42.5 (C-7), 42.0 (C-3), 40.1 (C-1), 37.4 (C-10), 36.5 (C-8), 35.1 (C-12), 33.4 (C-18),
33.3 (C-4), 32.9 (C-15), 29.7 (C-21), 21.5 (C-19), 18.5 (C-2), 18.1 (C-6), 17.9
(C-11), 16.3 (C-20), 15.7 (C-17), Anal. Calcd for C21H34O2 (318.49): C, 79.19; H,
10.76. Found: C, 78.79; H, 10.77.
1
R= OH
8
Scheme 1. Synthesis of (+)-homo-diterpene-c-lactone 1. Reagents and conditions:
(i) DMFDMA, xylene, reflux, 12 h; (ii) KOH, MeOH–water, reflux, 8h; (iii) 2-
benzyloxy-20-hydroxy-1,10-binaphthyl, SnCl4, toluene, ꢀ78 °C, 3 h and at ꢀ20 °C,
3 days.