Synthetic studies on C14 cembranoids: Synthesis of C4-12 fragment of sarcophytonolides E-G and L and C5-11 fragment of sarcophytonolide L

Article abstract of DOI:10.1016/j.tetlet.2010.11.093

An efficient stereoselective synthesis of C4-12 fragment of the cembranoids, sarcophytonolides E-G and L and C5-11 fragment of sarcophytonolide L is described. The C4-12 building block is efficiently assembled starting from chiral pool material (R)-carvon

Full text of DOI:10.1016/j.tetlet.2010.11.093

Tetrahedron Letters 52 (2011) 458–460
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Tetrahedron Letters
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Synthetic studies on C14 cembranoids: synthesis of C4–12 fragment
of sarcophytonolides E–G and L and C5–11 fragment of sarcophytonolide L
⇑
Rodney A. Fernandes , Arun B. Ingle
Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai 400 076, Maharashtra, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient stereoselective synthesis of C4–12 fragment of the cembranoids, sarcophytonolides E–G and
L and C5–11 fragment of sarcophytonolide L is described. The C4–12 building block is efficiently assem-
bled starting from chiral pool material (R)-carvone employing the Baeyer–Villiger oxidation, modified
Knoevenagel condensation and asymmetric dihydroxylation as the key steps. The synthesis of C5–11
fragment is based on orthoester Johnson–Claisen rearrangement as the key step.
Received 26 October 2010
Revised 16 November 2010
Accepted 17 November 2010
Available online 23 November 2010
Ó 2010 Elsevier Ltd. All rights reserved.
This paper is dedicated to Professor
Raymundo Cea Olivares on the occasion of
his 61st birthday
Keywords:
Sarcophytonolides
Stereoselective synthesis
Johnson–Claisen rearrangement
Knoevenagel condensation
Asymmetric dihydroxylation
α-alkylation
R
Cembranoid diterpenes are used as chemical defence
compounds by octocorals against predators such as other corals,
fishes and against settlement of microorganisms such as fungi or
bacteria.1 Most of these 14-membered cembrane diterpenes show
various bioactivities such as ichthyotoxic, cytotoxic, anti-inflam-
matory, antiarthritic, Ca-antagonistic, and antimicrobial proper-
ties.2 Guo and co-workers3 have isolated a series of cembranoid
diterpenes, sarcophytonolides A–L (1–12, Fig. 1) from the soft cor-
als of the genus Sarcophyton. The discovery of farnesyl transferase
inhibition by a cembranoid diterpene 134 has further enhanced the
interest in this group of secondary metabolites. There are no re-
ports on the synthesis of this class of sarcophytonolides. We wish
to report in this communication our initial synthetic studies on
sarcophytonolides E–G and L. Sarcophytonolides E–G (5–7) and L
R' = β -Me; 7,8 -dihydro, R = α −OH,
sarcophytonolide E (5)
R' = Me, R = α−OH, sarcophytonolide F (6)
R' = Me, R = β−OH, sarcophytonolide G (7)
R' = Me, R = H, sarcophytonolide L (12)
O
7
4
O
8
R'
11
3
1
12
RCM
R
O
O
O
I
OMe
O
HO
+
R'
O
O
16
15
O
14
C5-11 fragment
C4-12 fragment
(12) could be targeted from the C4–12 fragment 14 by
a
-alkylation
O
R = H
R' = Me
of the -lactone enolate with C5–11 fragment 15 (R = protected OH
c
MeO
for 5–7, R = H for 12 and R0 = b-Me and 3,4-dihydro for 5) and sub-
sequent b-hydroxy elimination, ketal deprotection, Wittig olefin-
ation, ring-closing metathesis (RCM) and OH deprotection
reactions (Scheme 1). The fragment 14 can be assembled from es-
ter 17 by reduction to aldehyde, modified Knoevenagel condensa-
O
TBDMSO
OTBDMS
O
17
HO
CO2Me
O
O
21
O
20
tion5 to get b,
c-unsaturated ester 16 and subsequent asymmetric
dihydroxylation. The ester 17 could be traced back to the chiral
HO
OTBDMS
22
(R)-carvone (19)
18
⇑
Corresponding author. Tel.: +91 22 25767174; fax: +91 22 25767152.
E-mail address: rfernand@chem.iitb.ac.in (R.A. Fernandes).
Scheme 1. Retrosynthetic analysis of sarcophytonolides E–G and L.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.093

R. A. Fernandes, A. B. Ingle / Tetrahedron Letters 52 (2011) 458–460
459
O
O
O
CO2Me
O
HO
HO
O
O
O
R
O
O
O
O
R
OAc
R = CH3, sarcophytonolide A
1
sarcophytonolide E
5
R = H, sarcophytonolideF
6
R = CO2Me, sarcophytonolide B
2
3
sarcophytonolide C
4
sarcophytonolide D
R = OAc, sarcophytonolideH
8
O
O
O
O
O
O
O
O
HO
O
H
O
H
O
O
O
OAc
R
OAc
OH
OAc
13
9
R = OAc, sarcophytonolide I
11
10
sarcophytonolide J
sarcophytonolide K
sarcophytonolide G
7
R = H, sarcophytonolideL 12
Figure 1. Sarcophytonolides A–L and cembranoid 13.
pool material (R)-carvone (19) through reduction of the diene,
Baeyer–Villiger oxidation, hydroxyl group oxidation and ketal
formation. Thus the C-5 isopropene group in 19 would become
the isopropyl group in the target molecules with the required
stereochemistry. The iodide 15 (R = H, R0 = Me for the synthesis of
12) could be obtained from ester 20 by usual terminal functional
groups manipulation. The Johnson–Claisen rearrangement of
allylalcohol 21 would produce the ester 20. Allylalcohol 21 can
be prepared from 22 by oxidation and isopropenyl-Grignard
addition.
The synthesis of fragment C4–12 (14) was initiated from the
chiral pool material (R)-carvone (19, Scheme 2). Reduction of the
diene unit in 19 through hydrogenation directly to deliver 25 gave
poor yields. In this reaction aromatization is known to be a side
reaction.6 Hence we attempted stepwise synthesis of 25. Reduction
of the keto-group in 19 with NaBH4 delivered the alcohol 23 in
quantitative yield. The hydrogenation of the diene now provided
24 (80%). Further PCC oxidation of 24 afforded the ketone 25
(83%).7 The Baeyer–Villiger oxidation8 of 25 with m-CPBA gave
the
x-lactone 18 (75%). This was converted into the x-hydroxy
methylester 26 (95%). The oxidation of hydroxyl group in 26 to
the ketone 27 (90%) and ketal formation provided the ester 17 in
91% yield. The reduction of ester to the aldehyde and subsequent
modified Knoevenagel condensation5 with the half ester of malonic
a
b
acid gave the b,c-unsaturated ester 16 in 52% yield over two-steps.
The asymmetric dihydroxylation9 of 16 with (DHQ)2PHAL as
OH
O
OH
stereoinducing ligand gave a 10:1 diastereomer mixture10 of the
24
23
-lactone. The diastereomer 1411 was easily separated by flash
(R)-carvone (19)
c
column chromatography in 74% yield. This completed the synthe-
sis of C4–12 fragment having the required stereochemistry at C-1
and C-2 centers with the isopropene group in 19 now efficiently
placed as the isopropyl group of the target molecules 5–7 and
O
e
c
O
d
O
18
25
O
a
O
b
O
HO
OH
HO
OTBDMS
22
MeO
g
MeO
O
MeO
28
f
HO
OTBDMS
O
26
O
OTBDMS
27
d
17
c
HO
O
O
CO2Me
20
O
OMe
21
OTBDMS
h
i
HO
I
OH
O
O
e
f
C4-C12 fragment
O
O
14
16
29
C5-C11 fragment
15
Scheme 2. Synthesis of C4–12 fragment 14. Reagents and conditions: (a) NaBH4
(1.2 equiv), MeOH, 0 °C to rt, 5 h, quant.; (b) H2, Pd/C, MeOH, rt, 24 h, 80%; (c) PCC
(1.5 equiv), mol sieves 4 Å, CH2Cl2, 0 °C to rt, 4 h, 83%; (d) m-CPBA (1.2 equiv), CAN
(10.0 mol %), CH2Cl2, 0 °C to rt, 6 h, 75%; (e) K2CO3 (1.5 equiv), MeOH, rt, 3 h, 95%; (f)
PCC (2.0 equiv), mol sieves 4 Å, CH2Cl2, 0 °C to rt, 4 h, 90%; (g) (CH2OH)2
(10.0 equiv), p-TsOH (catalytic), C6H6, reflux, 14 h, 91%; (h) (i) DIBAL-H (1.1 equiv),
CH2Cl2, ꢀ78 °C to ꢀ40 °C, 4 h; (ii) HO2CCH2CO2Me (2.0 equiv), Et3N, reflux, 12 h,
52% (two-steps); (i) K3Fe(CN)6 (3.0 equiv), K2CO3 (3.0 equiv), MeSO4NH2 (1.0 equiv),
(DHQ)2PHAL (1.0 mol %), K2OsO4ꢁ2H2O (0.4 mol %), t-BuOH:H2O (1:1), 0 °C, 24 h, rt,
12 h, 74%.
30
Scheme 3. Synthesis of C5–11 fragment 15. Reagents and conditions: (a) NaH
(1.05 equiv), TBDMSCl (1.0 equiv), THF, 0 °C to rt, 3 h, 95%; (b) (i) PCC (2.0 equiv),
NaOAc (2.0 equiv), CH2Cl2, 0 °C to rt, 4 h; (ii) isopropenylMgCl (1.2 equiv), THF, 0 °C
to rt, 1 h, 81% (two-steps); (c) (MeO)3CMe (10.0 equiv), toluene, EtCO2H (catalytic),
reflux, 12 h, 92%; (d) (i) DIBAL-H (1.0 equiv), CH2Cl2, ꢀ78 °C, 1.5 h; (ii)
Ph3P+MeIꢀ(1.5 equiv), nBuLi (1.5 equiv), THF, 0 °C to rt, 2 h, 75% (two-steps); (e)
nBu4NF (2.0 equiv), THF, rt, 2 h, 90%; (f) I2 (1.1 equiv), Ph3P (1.2 equiv), imidazole
(1.1 equiv), CH2Cl2, 0 °C to rt, 4 h, 91%.

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R. A. Fernandes, A. B. Ingle / Tetrahedron Letters 52 (2011) 458–460
2. (a) Kusumi, T.; Ohtani, I.; Inouye, Y.; Kakisawa, H. Tetrahedron Lett. 1988, 29,
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12. The b-hydroxyl group in the lactone 14 is correctly placed and
is to be eliminated after
unit.
a-alkylation to generate the c-butenolide
The synthesis of C5–11 fragment 15 (R = H, R0 = Me for 12)
began with the monoprotection of 1,3-propane diol 28 to give alco-
hol 22 (95%, Scheme 3). Oxidation of 22 to the aldehyde and sub-
sequent isopropenyl-Grignard addition afforded the allylalcohol
21 in 81% yield. The orthoester Johnson–Claisen rearrangement
of 21 gave the ester 20 in 92% yield. Reduction of the ester group
to the aldehyde and subsequent Wittig olefination provided the
diene 29 in 75% yield. Removal of the TBDMS group gave the alco-
hol 30 (90%) and conversion of hydroxyl to the iodide afforded the
C5–11 fragment 1512 in 91% yield.
6. Dell’ Anna, M. M.; Gagliardi, M.; Mastrorilli, P.; Suranna, G. P.; Nobile, C. F. J.
Mol. Catal. A: Chem. 2000, 158, 515–520.
In summary we have designed and successfully accomplished
the synthesis of the C4–12 fragment of sarcophytonolides E–G
and L and the C5–11 fragment of sarcophytonolide L. This first syn-
thetic effort towards the target molecules involved the orthoester
Johnson–Claisen rearrangement as the key step in the synthesis
of the C5–11 fragment while the C4–12 fragment was efficiently
assembled from the chiral pool material (R)-carvone which fixes
the isopropyl group of the target molecules and the Baeyer–Villiger
oxidation, modified Knoevenagel condensation and asymmetric
dihydroxylation as the key steps. The completion of total synthesis
of sarcophytonolide L and related molecules is underway in our
laboratory.
7. Ketone 25 is a known compound, see: Furstner, A.; Hannen, P. Chem. Eur. J.
2006, 12, 3006–3019.
8. Goswami, P.; Hazarika, S.; Das, A. M.; Chowdhury, P. Indian J. Chem., Sect B 2004,
43, 1275–1281.
9. Reviews: (a) Zaitsev, A. B.; Adolfsson, H. Synthesis 2006, 1725–1756; (b) Bolm,
C.; Hildebrand, J. P.; Muniz, K. In Catalytic Asymmetric Synthesis; Ojima, I., Ed.,
2nd ed.; Wiley-VCH: New York, 2000; pp 399–428; (c) Kolb, H. C.;
VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483–2547; (d)
Johnson, R. A.; Sharpless, K. B. In Asymmetric Catalysis in Organic Synthesis;
Ojima, I., Ed.; VCH: New York, 1993; pp 227–272. For synthesis of b-hydroxy-c-
lactones see; (e) Wang, Z.-M.; Zhang, X.-L.; Sharpless, K. B.; Sinha, S. C.; Sinha-
Bagchi, A.; Keinan, E. Tetrahedron Lett. 1992, 33, 6407–6410; (f) Mohan, H. R.;
Rao, A. S. Synth. Commun. 1993, 23, 2579–2585; (g) Miyazaki, Y.; Hotta, H.; Sato,
F. Tetrahedron Lett. 1994, 35, 4389–4392; (h) Harcken, C.; Brückner, R. Angew.
Chem., Int. Ed. Engl. 1997, 36, 2750–12752; (i) Fernandes, R. A.; Brückner, R.
Synlett 2005, 1281–1285.
10. Diastereomer ratio was determined by 1H NMR spectroscopy of the mixture.
11. Data for compound 14: ½a D25
ꢀ43.7 (c 2.2, CHCl3). IR (CHCl3): m = 3437, 3019,
ꢂ
Acknowledgements
2961, 2878, 1774, 1520, 1468, 1407, 1370, 1329, 1217, 1167, 1063, 1038, 1024,
981, 950, 900, 848 cmꢀ1 1H NMR (400 MHz, CDCl3/TMS): d = 0.94 (d, J = 7.0 Hz,
.
The authors are indebted to IRCC, IIT-Bombay for financial
support. A.B.I. is grateful to CSIR New Delhi for senior research
fellowship.
3H), 0.97 (d, J = 7.0 Hz, 3H), 1.11–1.19 (m, 1H), 1.32 (s, 3H), 1.40–1.49 (m, 1H),
1.74–1.79 (m, 1H), 1.86–1.96 (m, 2H), 2.06–2.12 (m, 2H, OH), 2.54 (d,
J = 17.4 Hz, 1H), 2.74 (dd, J = 17.4, 5.2 Hz, 1H), 3.83–4.07 (m, 4H), 4.11 (dd,
J = 11.3, 2.7 Hz, 1H), 4.44–4.46 (m, 1H). 13C NMR (100 MHz, CDCl3/CHCl3):
d = 18.2, 19.4, 19.5, 23.4, 28.0, 37.7, 39.0, 41.7, 64.3, 64.5, 68.5, 86.1, 110.4,
176.0. HRMS (ESI-TOF) (m/z) [M++Na] calcd for C14H24O5Na: 295.1521, found
295.1526.
Supplementary data
12. For some of the intermediates towards the synthesis of 15 see: (a) Schinzer, D.;
Limberg, A.; Böhm, O. M. Chem. Eur. J. 1996, 2, 1477–1482; (b) Feducia, J. A.;
Gagne, M. R. J. Am. Chem. Soc. 2008, 130, 592–599; c Data for compound 15: IR
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.11.093.
(CHCl3):
m
= 3077, 2977, 2931 2857, 1694, 1640, 1447, 1378, 1246, 1217, 1167,
1112, 994, 974, 914, cmꢀ1
.
1H NMR (400 MHz, CDCl3/TMS): d = 1.61 (s, 3H),
References and notes
2.05–2.20 (m, 4H), 2.58 (q, J = 7.2 Hz, 2H), 3.11 (t, J = 7.3 Hz, 2H), 5.01 (dd,
J = 17.0, 1.5 Hz, 1H), 5.02 (dd, J = 17.1, 1.5 Hz, 1H), 5.11 (t, J = 7.0 Hz, 1H), 5.75–
5.85 (m, 1H). 13C NMR (100 MHz, CDCl3/CHCl3): d = 6.0, 16.3, 32.1, 32.3, 38.9,
114.5, 123.2, 137.6, 138.4. HRMS (ESI-TOF) (m/z) [M++Na] calcd for C9H15INa:
273.0110, found 273.0108.
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