Studies on novel macrocyclization methods of cembrane-type diterpenoids: A Stille cyclization approach to (±)-isocembrene

Article abstract of DOI:10.1016/S0040-4039(03)01408-4

An efficient total synthesis of (±)-isocembrene via an intramolecular Stille cross-coupling reaction is described. A novel strategy towards the 1,3-diene-based cembrane-type macrocyclic diterpenoids has been realized.

Full text of DOI:10.1016/S0040-4039(03)01408-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 5921–5923
Studies on novel macrocyclization methods of cembrane-type
diterpenoids: a Stille cyclization approach to (±)-isocembrene
Lizeng Peng, Fengzhi Zhang, Tiansheng Mei, Tao Zhang and Yulin Li*
National Laboratory of Applied Organic Chemistry, Institute of Organic Chemistry, Lanzhou University, Lanzhou 730000,
PR China
Received 30 August 2002; revised 21 April 2003; accepted 30 May 2003
Abstract—An efficient total synthesis of (±)-isocembrene via an intramolecular Stille cross-coupling reaction is described. A novel
strategy towards the 1,3-diene-based cembrane-type macrocyclic diterpenoids has been realized.
©
2003 Elsevier Ltd. All rights reserved.
Cembranoids, a large family of diterpenoid natural
products characterized by the presence of a 14-mem-
bered ring, have been isolated from various marine
tant methodology for the construction of unsaturated
heterocycles and carbocycles, providing an attractive
3
route for the assembly of a variety of cembrane-type
4
sources as well as some terrestrial organisms since the
compounds.
1
1
960s. These diterpenoids have been of great interest
to synthetic chemists and biologists because of their
unusual structural features and remarkably wide range
of biological activities. Although a number of synthetic
Isocembrene 1, a cembrane diterpenoid, was first iso-
5
lated by Kashtanova and co-workers in 1968 from
1
Pinus sibirica and characterized spectroscopically and
chemically as (1S,2E,7E,11E)-2,4(18),7,11-cembratetra-
ene. Pattenden and Smithies accomplished the first total
strategies for the construction of a 14-membered-ring
system have appeared in the literature over the past
three decades and notable progress has been made in
this field, the lack of general method for the prepara-
tion of 14-membered rings presents an on-going chal-
6
synthesis of (±)-1 in 1996. In continuation of our
on-going project on the total synthesis and novel
macrocyclization methods of cembrane diterpenoids,
we have also completed a total synthesis of 1 using the
2
lenge for total synthesis. In continuation of our
2
2
on-going project on the total synthesis and macrocy-
clization of cembrane-type diterpenoids, we describe
herein an efficient macrocyclization methods which
should be of general applicability in terpene synthesis.
Intramolecular Pd-catalyzed cross coupling between an
alkenylstannane and an alkenyl halide (or triflate) func-
tionalities has now been firmly established as an impor-
Stille sp –sp macrocyclization reaction as a key step to
elaborate the stereodefined 1,3-diene unit in this com-
pound. The synthetic strategy from the readily available
E-geranyl acetone as outlined in Scheme 1 involves (1)
chemoselective synthesis of E-alkenylstannanes from
keto aldehydes 3 using Bu SnCHI2 in DMF, (2)
3
regioselective synthesis of vinyl triflate from a ketonic
Scheme 1. Retrosynthesis of isocembrene 1 based on intramolecular Pd-catalyzed Stille cross-coupling reaction.
Keywords: isocembrene; diterpenoids; cembranoids; Stille reaction.
*
Corresponding author. Fax: +86-9318912283; e-mail: liyl@lzu.edu.cn
0
040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01408-4

5
922
L. Peng et al. / Tetrahedron Letters 44 (2003) 5921–5923
Scheme 2. Reagents and conditions: (a) 1. 5+n-BuLi, THF, −40°C, 1.5 h, then 6, −40°C to rt, 1.5 h, 89%; 2. Na (Hg), Na HPO ,
2
4
MeOH, rt, 16 h, 84%; (b) TBAF, THF, rt, 30 min, 95%; (c) p-TsOH, acetone, rt, 4 h, 95%; (d) DMSO, (COCl) , Et N, CH Cl ,
2
3
2
2
−
78°C to rt, 2 h, 92%; (e) Bu SnCHI , CrCl , DMF, rt, 5 h, 74%; (f) NaHMDS, PhNTf , THF, −78°C, 2 h, 84%; (g) (Ph P) Pd,
3 2 2 2 3 4
LiCl, THF, reflux, 6 h, 76%.
carbonyl and (3) macrocyclization of precursor 2 con-
taining the vinyl tin and vinyl triflate groups by an
intramolecular Stille cross-coupling reaction.
Natural Science Foundation of China (Grant No.
20072012) and the Special Research Grant for Doctoral
Sites in Chinese Universities (Grant No. 20010730001).
Total synthesis of 1 is detailed in Scheme 2. Allylic
7
alcohol 4, readily available from geranyl acetone, was
References
converted into the corresponding iodide 6 by a stan-
8
dard method. Coupling reaction of iodide 6 with the
1. Tursch, B.; Braeckamn, J. C.; Dolaze, D.; Kaisin, M. In
Marine Natural Products: Chemical and Biological Per-
spectives; Scheuer, P. J., Ed.; Academic Press: New York,
9
lithium salt of 5 (formed by treatment with n-BuLi in
THF at −40°C) in THF at −40°C proceeded smoothly
to afford a coupling adduct, which was desulfonated to
1
978; Vol. 2, pp. 286–387.
1
0
7
7
by treatment with Na(Hg) in MeOH. Desilylation of
2
. (a) Tius, M. A. Chem. Rev. 1988, 88, 719–732; (b) Cox,
N. J. G.; Mills, S. D.; Pattenden, G. J. Chem. Soc.,
Perkin Trans. 1 1992, 1313–1321 and references cited
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. For reviews see: (a) Stille, J. K. Angew Chem., Int. Ed.
Engl. 1986, 25, 508–524; (b) Farina, V.; Krishnamurthy,
V.; Scott, W. J. Org. React. 1997, 50, 1–652.
. Duncton, M. A. J.; Pattenden, G. J. Chem. Soc., Perkin
Trans. 1 1999, 1235–1246 and references cited therein.
. Kashtanova, N. K.; Lisina, A. I.; Pentegova, V. A. Khim.
Prir. Soedin. 1968, 4, 52–53.
. Pattenden, G.; Smithies, A. J. J. Chem. Soc., Perkin
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983, 24, 4883–4886.
. (a) Prepared from 2-isopropyl-1,3-propandiol by three
steps. ((1). NaH, THF, TBSCl, rt, 96%; (2). I , Imid.,
Et O/MeCN, rt, 89%; (3). PhSO Na, DMF, rt, 90%); (b)
For the selective protection of one of two chemically
equivalent primary hydroxyl groups in 1,n-diols using
TBSCl, see: Yu, C. Z.; Liu, B.; Hu, L. Q. Tetrahedron
Lett. 2000, 41, 4281–4285 and references cited therein.
with tetra-n-butylammonium fluoride in THF at rt
gave the alcohol 8, which was then treated with a
catalytic amount of p-TsOH in acetone to give the keto
alcohol 9. After Swern oxidation, the keto aldehyde 3
3
1
1
was transformed into E-alkenylstannane 10 by treat-
12
ment with Bu SnCHI in DMF in one step in good
3
2
yield (74%); no methylenated material was observed in
4
5
6
7
1
the crude H NMR. Adding sodium hexamethyldisil-
azide (NaHMDS) rapidly to a diluted solution of vinyl
1
3
tin 10 and N-phenyl triflimide in excess (1.5–1.7
equiv.) at −78°C gave the triflate 2 containing only
1
small amounts (<6% by 400 MHz H NMR) of thermo-
14
dynamic enolate in yield of 84%. Cyclization of 2 was
accomplished with tetrakis(triphenylphosphine) palla-
dium (5 mol%) in the presence of lithium chloride (3
9
−
3
equiv.) under high dilution (10 M) in refluxing THF.
Under these mild reaction conditions, no E to Z iso-
merization and no rearrangement of the exocyclic dou-
ble bond occurred. Synthetic 1 showed identical
spectral data with those of natural product 1 reported
1
9
2
2
2
1
5
previously.
In summary, an efficient and convergent total synthesis
of (±)-isocembrene has been accomplished via an
intramolecular Stille cross-coupling reaction. This pro-
tocol is expected to be applicable to the other cem-
brane-type diterpenoids.
1
0. (a) Hodgson, D. M.; Foley, A. M.; Boulton, L. T.;
Lovell, P. J.; Maw, G. N. J. Chem. Soc., Perkin Trans. 1
1999, 2911–2922; (b) Hodgson, D. M.; Foley, A. M.;
Boulton, L. T.; Lovell, P. J. Synlett 1999, 744–746.
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1
1
Acknowledgements
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This work was financially supported by the National

L. Peng et al. / Tetrahedron Letters 44 (2003) 5921–5923
5923
1
1
1
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5. Selected spectral data. 2, IR (film): 2957, 2927, 1601,
H, 8.36. Found: C, 55.35; H, 8.14.
1, IR (film): 2930, 2855, 1470, 978 cm ; H NMR (400
−
1 1
6
MHz, CDCl ): l 0.84 (d, J=7.0 Hz, 3H, Me), 0.89 (d,
3
3
J=7.0 Hz, 3H, Me), 1.25–1.40 (m, 2H, CH(Me)2 and
CHCHMe) ), 1.68 (s, 3H, CHꢀCMe), 1.70 (s, 3H,
2
−
1 1
1
472, 1072, 1016 cm ; H NMR (400 MHz, CDCl ): l
CHꢀCMe), 1.90–2.00 (m, 8H, 4×CH ), 2.43–2.46 (m, 1H,
2
3
0
.78–0.91 (m, 21H, Sn(CH CH CH CH )
and
CHHCꢀCHH), 4.85 (br s, 1H, CꢀCHH), 4.90 (br s, 1H,
CꢀCHH), 5.09 (t, J=7.0 Hz, 1H, CHꢀC), 5.19 (t, J=7.0
Hz, 1H, CHꢀC), 5.50 (dd, J=15.6, 9.6 Hz, 1H,
2
2
2
3 3
CH(Me) ), 1.22–1.29 (m, 6H, Sn(CH CH CH CH ) ),
2
2
2
2
3 3
1
1
.39–1.66 (m, 7H, Sn(CH CH CH CH ) and CH(Me) ),
.90–2.00 (m, 8H, 4×CH2), 2.20–2.28 (m, 2H,
2 2 2 3 3 2
CHꢀCHCH), 5.94 (d, J=15.6 Hz, 1H, CH
ꢀCCHꢀCH);
C NMR (100 MHz, CDCl ): l 146.0, 137.8, 135.8,
3
2
13
CH C(OTf)ꢀC), 4.85 (d, J=3.4 Hz, 1H, cis-
2
TfOCꢀCHH), 5.02 (d, J=3.4 Hz, 1H, trans-
TfOCꢀCHH), 5.09–5.13 (m, 2H, 2×CHꢀC), 5.65 (dd,
J=18.9, 8.7 Hz, 1H, CHꢀCHSn), 5.75 (d, J=18.9 Hz,
134.0, 132.3, 124.9, 123.8, 113.6, 50.0, 34.2, 33.0, 32.6,
32.2, 29.6, 28.4, 28.0, 24.0, 23.5, 20.7, 19.8; EIMS m/z:
+
+
272 (M , 5), 257 (M −Me, 12); HRMS (ESI): calcd for
+
1
H, ꢀCHSn). Anal. calcd for C H F O SSn: C, 55.70;
C H32+H (M +H) 273.2577, found 273.2571.
20
33
59
3
3