Studies towards the total synthesis of novel marine diterpene havellockate. Construction of the tetracyclic core

Article abstract of DOI:10.1016/S0040-4039(01)01721-X

The synthesis of the tetracyclic core present in the novel marine diterpenoid havellockate 1 has been accomplished from the readily available endo-dicyclopentadienone-10-ethylene ketal 3 as a prelude to the projected total synthesis of the natural product

Full text of DOI:10.1016/S0040-4039(01)01721-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 8097–8100
Studies towards the total synthesis of novel marine diterpene
havellockate. Construction of the tetracyclic core
Goverdhan Mehta* and R. Senthil Kumaran
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
Received 12 August 2001; revised 6 September 2001; accepted 13 September 2001
Abstract—The synthesis of the tetracyclic core present in the novel marine diterpenoid havellockate 1 has been accomplished from
the readily available endo-dicyclopentadienone-10-ethylene ketal 3 as a prelude to the projected total synthesis of the natural
product. © 2001 Elsevier Science Ltd. All rights reserved.
Diterpenes in general and particularly those of marine
origin are rich in skeletal diversity and structural com-
plexity and many of them possess impressive and wide
ranging biological activities.1 These attributes make
diterpenenoids from marine sources attractive and chal-
lenging targets of synthesis.1 In 1998, a new diterpenoid
named havellockate 1, bearing a novel skeleton, was
isolated from the soft coral species Sinularia granosa
collected from the Havellock island of the Andaman
and Nicobar group of Islands in the Indian ocean.2 The
structure of havellockate 1 was determined on the basis
of spectral data and confirmed by single-crystal X-ray
analysis.2 The skeleton of 1 is biogenetically quite
intriguing and is probably derived from a cembranoid
precursor through extensive restructuring and concomi-
tant oxy-functionalization. The tetracyclic core present
in the complex structure of 1 with eight stereogenic
centers and many functionalities consists of a cis-fused
hydrindane moiety to which two g-lactone units are
appended, one of them being spiro-fused. These struc-
tural features of 1 aroused our interest in its total
synthesis. As the first objective, we targeted the tetra-
cyclic core structure 2, identified through retrosynthetic
considerations indicated in Scheme 1. It was surmized
that with the acquisition of the tetracyclic ketolactone
2, the overall strategy could be tactically modified and
adopted for the synthesis of 1. Herein, we report a
synthesis of tetracyclic ketolactone 2 with complete
regio- and stereocontrol.
For the synthesis of 2, readily available3 endo-dicy-
clopentadienone 3 was chosen as the starting material
as the cis-hydrindane moiety is embedded into this
framework (see bold portion in 3) and can be unrav-
elled by removing the ketal bearing C-10 carbon
bridge.4 Stereoselective epoxidation of the enone moiety
in 3 to exo-epoxide 4 and hydride reduction furnished
the trans 1,3-diol 5 (Scheme 2).5 The endo hydroxyl
group in 5 was protected through intramolecular halo-
etherification to furnish tetracyclic bromoether 6.5 The
exo-hydroxyl group in 6 was now inverted through
oxidation to ketone 7 and stereoselective reduction
O
O
OH
O
CH3
CH3
O
O
O
O
H
OH
H
H
H
H
OH
O
MeO
H
H
O
O
O
O
O
O
1
2
Scheme 1.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01721-X

8098
G. Mehta, R. S. Kumaran / Tetrahedron Letters 42 (2001) 8097–8100
O
O
O
O
O
O
O
O
O
Br
c
b
a
H
H
H
H
H
H
H
H
OH
OH
O
O
HO
O
3
4
5
6
d
O
O
O
O
O
O
O
Br
g ,
h
Br
f
H
e
H
H
H
H
H
OBn
H
H
OH
OH
O
O
O
BnO
10
HO
9
8
7
i
O
OH
OBn
OBn
O
O
H
H
OH
OBn
OBn
OBn
H
H
H
j
k
l
H
H
OBn
H
TBDMSO
OBn
TBDMSO
HO
BnO
11
12
13
14
Scheme 2. Reagents and conditions: (a) 30% H2O2, 6N NaOH, MeOH, 0°C, 30 min, 80%; (b) LAH, THF, 0°C to reflux, 4.5 h,
,
88%; (c) NBS, DCM, rt, 3 h, 90%; (d) PCC, DCM, 4 A molecular sieves, 0°C to rt, 1 h, 85%; (e) NaBH4, MeOH, 0°C, 15 min,
80%; (f) Zn/NH4Cl, THF/H2O (9:1), 50°C, 2 h, 65%; (g) BnBr, NaH, nBu4NI (cat.), 0°C to rt, 10 h, 72%; (h) Amberlyst-15,
CH3COCH3, 65°C, 15 h, 80%; (i) 90% aq. HOAc, 30% H2O2, CH3COONa, 0°C to rt, 6 h, 45%; (j) LAH, THF, 0°C, 2 h, 90%;
,
(k) TBDMSCl, imidazole, DMAP (cat.), DCM, rt, 3 h, 70%; (l) PCC, DCM, 4 A molecular sieves, 0°C to rt, 45 min, 89%.
from the exo-face to deliver the endo-alcohol 8 (Scheme
2).5 On exposure to zinc metal, the olefinic and the
hydroxyl groups could be released back from the bro-
moether 8 to furnish the symmetrical endo,endo-1,3-diol
9.5 Besides having the requisite stereochemistry of the
hydroxyl groups, the symmetrical nature of 9 circum-
vented any regiochemical problems that could surface
during the opening of the C-10 bridge (vide infra). The
two endo-hydroxyl groups in 9 were protected as the
benzyl ethers, then ketal deprotection led to the norbor-
nenone derivative 10 (Scheme 2). Carefully controlled
Baeyer–Villiger oxidation on 10 delivered a single lac-
tone 11, which was reductively cleaved to unravel the
cis-hydrindane 12 with secured stereochemistry at six
stereogenic centers. The primary hydroxyl group in 12
was selectively protected as the TBDMS-ether 13 and
the secondary alcohol oxidized with PCC to deliver
enone 14, a key substrate on which two lactone moi-
eties present in the target compound 2 were to be
installed (Scheme 2).
(Scheme 3). The spiro-fused dihydrofuran moiety in 17
could be further oxidized to the corresponding g-lac-
tone.7 The TBDMS protective group in 17 was now
dispensed with and the resulting primary hydroxyl
group was oxidized in a controlled manner to give the
exo-aldehyde 18. The next task was to invert the alde-
hyde stereochemistry in 18 and for this purpose the
cyclohexene double bond in it was isomerized in the
presence of DBU to deliver the a,b-unsaturated alde-
hyde 19. Catalytic hydrogenation of 19, besides liberat-
ing the benzyl protected hydroxyl groups, also reduced
the a,b-unsaturated aldehyde functionality from the
preferred exo-face to deliver the endo-aldehyde group,
which was concomitantly captured by the appropriately
positioned endo-hydroxyl group resulting in the lactol
20. PCC oxidation of 20 led to the target compound 2,
in the process generating not only the second g-lactone
ring but also the cyclopentanone moiety required to
set-up the tertiary alcohol unit present in the natural
product 1.
For the stereoselective spiro-lactone annulation at the
carbonyl site in 14, a RCM based protocol was pre-
ferred.6 Addition of vinylmagnesium bromide to 14
occurred exclusively from the convex face to give vinyl
alcohol 15 (Scheme 3). Allylation of the tertiary
hydroxy group in 15 was smooth and the allyl-ether 16
was readily realized. Exposure of 16 to Grubbs’ catalyst
gave spiro-annulated dihydrofuran 17 in excellent yield
In short, we have accomplished a synthesis of the
tetracyclic core 2 present in the marine diterpenoid
havellockate 1, with good regio- and stereochemical
control, from a readily available dicyclopentadienone
derivative 3. The overall synthetic strategy delineated
here for havellockate 1 is also amenable to adaptation
for the synthesis of many novel but related diterpenoid

G. Mehta, R. S. Kumaran / Tetrahedron Letters 42 (2001) 8097–8100
8099
O
O
HO
OBn
OBn
OBn
OBn
O
OBn
OBn
OBn
OBn
H
H
H
H
H
H
H
a
b
c
H
TBDMSO
TBDMSO
TBDMSO
TBDMSO
14
15
16
17
d,e
O
O
OH
O
O
O
OBn
OBn
OBn
OBn
H
H
H
H
H
h
f
g
H
H
CHO
H
O
O
OHC
HO
O
2
20
19
18
n
Scheme 3. Reagents and conditions: (a) vinylmagnesium bromide, THF, 0°C to rt, 10 h, 70%; (b) allyl bromide, NaH, Bu4NI
n
(cat.), THF, 0°C, 1 day, 78%; (c) Grubbs’ catalyst (20 mol%), DCM, rt, 2 h 90%; (d) Bu4NF, THF, 0°C to rt, 10 h, 65%; (e)
,
PCC, DCM, 4 A molecular sieves, 10 min, 0°C, 70%; (f) DBU, DCM, 0°C to rt, 1.5 h, 60%; (g) H2, 10% Pd–C, EtOAc, rt, 2 h,
,
50%; (h) PCC, DCM, 4 A molecular sieves, 0°C to rt, 15 h, 70%.
skeleta of marine origin like mandapamate and
isomandapamate.8
5. All new compounds reported here were racemic and char-
acterized on the basis of spectroscopic data (IR, w in cm−1
,
1H and 13C NMR, J in Hz) and elemental analyses.
Selected spectral data. 14: IR: 1674; (300 MHz, CDCl3):
lH 7.37–7.18 (10H, m), 7.10 (1H, dd, J 10, 2), 6.16 (1H,
dd, J 10, 2.5), 4.59–4.35 (4H, m), 4.22–4.20 (1H, m), 4.09
(1H, dd, J 9.5, 3.5), 4.02–3.95 (1H, m), 3.61 (1H, dd, J 9.5,
7.2), 2.96 (1H, m), 2.66–2.58 (2H, m), 2.48–2.38 (1H, m),
1.96 (1H, ddd, J 14, 8.5, 3), 0.87 (9H, s), 0.00 (6H, s); (75
MHz, CDCl3): lC 198.01 (CꢀO), 154.62 (CH), 138.40 (C),
138.24 (C), 129.92 (CH), 128.38 (CH), 128.17 (CH), 127.61
(CH), 127.36 (CH), 127.22 (CH), 127.04 (CH), 100.56 (C),
80.93 (CH), 79.06 (CH), 72.02 (CH2), 71.42 (CH2), 65.28
(CH2), 51.36 (CH), 40.74 (CH), 37.82 (CH), 37.41 (CH2),
25.87 (CH3), 18.24 (C), −5.36 (CH3). 17: IR: 1607; (300
MHz, CDCl3): lH 7.35–7.20 (10H, m), 5.78–5.64 (4H, m),
4.76–4.45 (6H, m), 4.00 (1H, m), 3.96–3.87 (2H, m), 3.58
(1H, dd, J 9.6, 6.6), 2.70–2.66 (1H, m), 2.41–2.34 (2H, m),
1.91–1.82 (2H, m), 0.88 (9H, s), 0.00 (6H, s); (75 MHz,
CDCl3): lC 140.10 (C), 138.84 (C), 135.01 (CH), 130.83
(CH), 130.37 (CH), 128.27 (CH), 127.90 (CH), 127.32
(CH), 127.24 (CH), 126.91 (CH), 126.58 (CH), 124.11
(CH), 88.40 (C), 81.59 (CH), 78.43 (CH), 74.56 (CH2),
71.67 (CH2), 71.43 (CH2), 66.30 (CH2), 50.09 (CH), 38.80
(CH), 37.68 (CH2), 36.62 (CH), 25.97 (CH3), 18.32 (C),
−5.26 (CH3), −5.39 (CH3). 19: IR: 1683, 1647; (300 MHz,
CDCl3): lH 9.46 (1H, s), 7.28–7.20 (10H, m), 6.77 (1H, m),
5.83–5.78 (2H, m), 4.72 (2H, br s), 4.50 (2H, q, J 12.5),
4.47–4.28 (2H, m), 4.18–4.17 (1H, m), 3.41 (1H, t, J 8.4),
3.31 (1H, td, J 18, 3), 2.29–2.17 (3H, m), 1.61–1.52 (2H,
m); (75 MHz, CDCl3): lC 193.69, 147.91, 140.74, 139.21,
138.85, 134.10, 128.03, 127.98, 127.93, 127.30, 127.14,
126.91, 124.92, 90.06, 81.11, 80.01, 74.68, 72.44, 70.83,
49.14, 40.93, 37.14, 36.73. 2: IR: 1766, 1739; (300 MHz,
Acknowledgements
One of us (R.S.K.) thanks CSIR for the award of a
Research Fellowship. We also thank the Chemical Biol-
ogy Unit of the Jawaharlal Nehru Centre for Advanced
Scientific Research for research support.
References
1. Recent reviews: (a) Faulkner, D. J. Nat. Prod. Rep. 2000,
17, 7; (b) Faulkner, D. J. Nat. Prod. Rep. 1999, 16, 155
and earlier reports in this informative series; (c) Hanson, J.
R. Nat. Prod. Rep. 2000, 17, 165 and earlier reports in this
series.
2. Anjaneyulu, A. S. R.; Venugopal, M. J. R. V.; Sarada, P.;
Clardy, J.; Lobkovsky, E. Tetrahedron Lett. 1998, 39, 139.
3. (a) Chapman, N. B.; Key, J. M.; Toyne, K. J. J. Org.
Chem. 1970, 35, 3860; (b) Schuda, P. F.; Ammon, H. L.;
Heimann, M. R.; Bhattachargee, S. J. Org. Chem. 1982,
47, 3434.
4. For the validation of this approach to cis-hydrindanes,
see: (a) Mehta, G.; Reddy, D. S. J. Chem. Soc., Perkin
Trans. 1 2001, 1153; (b) Mehta, G.; Reddy, D. S. J. Chem.
Soc., Perkin Trans. 1 2000, 1399; (c) Mehta, G.; Reddy, D.
S. J. Chem. Soc., Perkin Trans. 1 1998, 2125; (d) Mehta,
G.; Reddy, D. S. Synlett 1997, 612; (e) Mehta, G.; Reddy,
D. S. Synlett 1996, 229; (f) Mehta, G.; Praveen, M. J.
Chem. Soc., Chem. Commun. 1993, 1573.

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G. Mehta, R. S. Kumaran / Tetrahedron Letters 42 (2001) 8097–8100
CDCl3): lH 5.08 (1H, t, J 6.6), 3.67 (2H, m), 3.41–3.32
O
O
(1H, m), 2.92 (1H, t, J 9.9), 2.74–2.52 (3H, m), 2.40 (1H,
d, J 10.8), 2.35–2.24 (1H, m), 2.05–1.61 (5H, m), 1.25 (1H,
td, J 9.9, 14.1); (75 MHz, CDCl3): lC 216.08 (CO), 179.37
(CO), 82.12 (C), 77.12 (CH), 68.35 (CH2), 51.47 (CH),
44.45 (CH2), 38.72 (CH2), 35.86 (CH), 34.15 (CH2), 31.15
(CH2), 25.28 (CH2), 17.45 (CH2).
O
OBn
OBn
OBn
OBn
H
H
PCC, py(cat.), DCM
40%
H
H
TBDMSO
TBDMSO
6. Reviews: (a) Schuster, M.; Blechert, S. Angew. Chem., Int.
Ed. Engl. 1997, 36, 2036; (b) Grubbs, R. H.; Chang, H.
Tetrahedron 1998, 54, 4413.
7. PCC oxidation of 17 readily gave the spiro fused a,b-
unsaturated g-lactone (i). The double bond in (i) was
suitable for the introduction of the hydroxyl group in this
ring as present in the natural product 1.
(i)
17
8. (a) Anjaneyulu, A. S. R.; Sagar, K. S.; Venugopal, M. J.
R. V. Tetrahedron 1995, 51, 10997; (b) Venkateswarlu, Y.;
Farooq Bibani, M. A.; Reddy, M. V. R.; Prabhakar Rao,
T.; Kunwar, A. C.; Faulkner, D. J. Tetrahedron Lett. 1994,
35, 2249.