Synthetic studies towards the novel neurotrophic diterpenoids neovibsanins A and B: construction of the ABC core

Article abstract of DOI:10.1016/j.tetlet.2009.03.040

A concise, general approach to the tricyclic furo-furan-based core structure present in the bioactive natural products neovibsanins A and B, from readily available Baylis-Hillman adducts, is delineated.

Full text of DOI:10.1016/j.tetlet.2009.03.040

Tetrahedron Letters 50 (2009) 2474–2477
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Synthetic studies towards the novel neurotrophic diterpenoids neovibsanins
A and B: construction of the ABC core
*
Goverdhan Mehta , Bilal Ahmad Bhat
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A concise, general approach to the tricyclic furo-furan-based core structure present in the bioactive nat-
ural products neovibsanins A and B, from readily available Baylis–Hillman adducts, is delineated.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 26 December 2008
Revised 20 February 2009
Accepted 5 March 2009
Available online 13 March 2009
Vibsane-type diterpenoids constitute a rapidly expanding and
structurally diverse family of natural products that occur exclu-
sively in Viburnum species such as V. awabuki, V. odoratissimum
and V. suspensum.1,2 From a biogenetic perspective, the most impor-
tant vibsane diterpenoid is the ten-membered vibsanin B 1, which
is structurally a higher isoprenologue of the sesquiterpene humu-
lene, with potential to unfold a myriad cyclization patterns.1–3 As
many as ten sub-structural types are known among vibsane diter-
penoids and this impressive collection, 1–10 is displayed in Figure
1. While many vibsanins exhibit some kind of bioactivity profile
ranging from pesticidal and plant growth inhibition to cytotoxic-
ity,1 it is the neovibsanins A and B 10a,b that exhibit the unique
activity of promoting neurite outgrowth of NGF-mediated PC-12
cells.4 This attribute makes 10a,b important therapeutic leads for
mitigating neurodegenerative disorders such as Alzheimer’s.
The isolation of neovibsanins A and B (10a and 10b) from V.
awabuki was reported by Fukuyama in 1996 and their uncommon
tricyclic formulation was arrived at through incisive NMR studies.2
Architectural complexity combined with their unique bioactivity
makes the neovibsanins challenging and attractive targets for total
synthesis. A recent report5 on studies aimed towards the synthesis
of neovibsanins A and B prompts us to disclose our own efforts in
the area. The present report, to our knowledge, constitutes the first
acquisition of the core ABC framework of the neovibsanin natural
products.
be prepared from the Baylis–Hillman product 146 of the corre-
sponding cyclohexenone, Scheme 1.
Initially, the TBS-protected Baylis–Hillman adduct6b of cyclo-
hexenone 15 was reacted with the dianion derived from propargyl
alcohol7 to furnish 16. The triple bond in 16 was regio- and stere-
oselectively reduced to the cis-alkene 17. MnO2-mediated oxida-
tion of 17 led directly to the spiro-fused
c-lactone 18 via the
intermediacy of the corresponding cyclic lactol. Fluoride-mediated
deprotection in 18 triggered the intramolecular Michael addition
to furnish the tricyclic furo-furanone 19 and further methylenation
of the lactone carbonyl with the Tebbe reagent8 led to 20 embody-
ing the ABC core of the natural products, Scheme 2. To demonstrate
the generality of this concise approach to the cyclohexene-fused
furo-furan core, the above sequence was implemented on 5,5-dim-
ethylcyclohex-2-en-1-one 21, as the natural products 10a,b har-
bour geminal dialkyl substitution in the same position. Thus 21
was readily transformed to the Baylis–Hillman adduct 226b and
propargyl alcohol addition delivered 23. Selective hydrogenation
to 24, oxidation to the c-lactone 25 and TBS deprotection/Michael
addition furnished the tricyclic furo-furanone 26, Scheme 3.
Further evolution of our strategy towards neovibsanins re-
quired inclusion of the C-10 side arm. Towards this end, the pro-
tected Baylis–Hillman adduct 22 was allylated under kinetically
controlled conditions to furnish 27. Regioselective oxidative cleav-
age of the allyl group led to the aldehyde 28 with the requisite
two-carbon C-10 side arm. Aldehyde protection in 28 as the acetal
29 set the stage for the acetal side arm-directed propargyl addi-
tion9 and led to a 1:1.2 mixture of 30 and 31, Scheme 4. The forma-
tion of two diastereomers 30 and 31 was considered a satisfactory
outcome and they were individually elaborated to the tricyclic
furo-furanones 36 and 37, respectively, through stereoselective
The initial focus of our synthetic efforts towards the natural
products 10a,b was to devise a rapid and diversity-oriented access
to the cyclohexene-fused tricyclic furo-furan ABC core 11. Retro-
synthetically, it was planned to assemble this from a furo-furanone
precursor 12 which in turn could be assembled through a tandem
intramolecular lactonization-Michael addition protocol from 13.
The functionally embellished cyclohexene derivative 13 was to
hydrogenation to 32 and 33, MnO2-oxidation to the
c-lactones
34 and 35 and fluoride-mediated Michael addition. In the context
of the target natural products, it was important to delineate unam-
biguously the relative stereochemistry at C-4 and C-10 in 36 and
37 and this was achieved through single crystal X-ray structure
* Corresponding author. Tel.: +91 8023600367; fax: +91 8023600283.
E-mail address: gm@orgchem.iisc.ernet.in (G. Mehta).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.040

G. Mehta, B. A. Bhat / Tetrahedron Letters 50 (2009) 2474–2477
2475
O
OH
O
O
OH
OH
O
O
O
HO
5
1
O
OH
4
O
8
7
3
6
RO
O
O
OH
O
10
2
9
RO
RO
RO
RO
Vibsanin B (1)
Vibsanin E (3)
Vibsanin O (4)
Cyclovibsanin A (5)
Vibsanin C (2)
R2
R1
7
4
H
5
O
OCH3
O
OH
O
O
O
O
O
H
RO
O
O
RO
CHO
RO
10
11
OH
RO
H
OHC
OCH3
Neovibsanin A (10a),
R1 = CH3, R2 = OCH3;
Neovibsanin B (10b),
R1 = OCH3, R2 = CH3
Aldolvibsanin B (6)
Furanovibsanin D (7)
Spirovibsanin A (8)
Neovibsanin H (9)
O
R =
Figure 1. Structural diversity in vibsanin diterpenoids.
OH
R
O
O
7
C
H
H
OTBS
OTBS
HO
O
O
O
4
O
O
5 B
b
a
R1
R1
10
11
A
21
22
23
R2
R3
R2
R3
c
OH
11
12
O
O
H
O
O
O
OTBS
d
OTBS
HO
O
e
RO
HO
OH
OH
O
26
25
24
R1
R1
R2
R3 13
R2
R3
14
Scheme 3. Reagents and conditions. (a) (i) HCHO aq (37–41%, w/v), DMAP,
THF:H2O (1:1), rt, 12 h, 65%; (ii) TBSCl, imidazole, DMAP, CH2Cl2, rt, 1 h, 98%; (b)
propargyl alcohol, n-BuLi, THF, 0 °C, 6 h, 56%; (c) Lindlar catalyst, H2 (1 atm), MeOH,
rt, 10 h, 88%; (d) MnO2, CH2Cl2, rt, 24 h, 92%; (e) TBAF, THF, rt, 20 min, 94%.
Scheme 1. Retrosynthetic analysis of the tricyclic core 11.
OH
OH
O
OTBS
a
OTBS
b
OTBS
determination on 37, Figure 2.10 This established that in tricyclic
diastereomer 36, we had achieved the required relative stereo-
chemistry at C-4, C-5 and C-10 as present in the neovibsanin nat-
ural products.
HO
HO
15
16
17
Our next major task was to establish the viability of our concise
furo-furan strategy with a substrate having a preinstalled C-11
quaternary centre bearing the methyl and the homoprenyl moie-
ties. With this objective in mind, the previously reported11 dime-
done derivative 38 was conveniently elaborated to the
cyclohexenone 40 via the intermediacy of the enol ether 39. Bay-
lis–Hillman reaction of 40 led to 41 and the hydroxy group was
protected as the TBS derivative 42, Scheme 5. Addition of the dian-
ion derived from propargyl alcohol to 42 furnished a mixture of
c
O
O
F
Si
H
H
O
O
O
O
O
O
e
d
20
19
18
diastereomers 43 (b–OH:a–OH, 1.2:1). The distal quaternary cen-
Scheme 2. Reagents and conditions. (a) propargyl alcohol, n-BuLi, THF, 0 °C, 4 h,
60%; (b) Lindlar catalyst, H2 (1 atm), MeOH, rt, 2 h, 90%; (c) MnO2, CH2Cl2, rt, 24 h,
88%; (d) TBAF, THF, rt, 20 min, 94%; (e) Tebbe reagent, THF:toluene (1:1), À40 °C to
0 °C, 2 h, 78%.
tre at C-11 only engendered marginal stereoselection in the addi-
tion reaction. Separation of the propargylated diastereomers 43
was difficult at this stage and it was considered prudent to con-

2476
G. Mehta, B. A. Bhat / Tetrahedron Letters 50 (2009) 2474–2477
O
O
O
OTBS
OTBS
OTB S
O
OTB S
O
O
O
a
b
c
22
27
28
29
d
OH
O
OH
OH
O
O
O
O
HO
O
O
HO
O
O
HO
O
OTBS
OTBS
OTBS
OTBS
f
h
+
35
33
31
30
g
e
OH
O
O
O
H
H
O
O
O
O
O
O
O
O
HO
O
O
O
O
4
O
OTB S
OTBS
5
5
4
f
g
10
10
37
36
34
32
Scheme 4. Reagents and conditions. (a) LDA, allyl iodide, THF, À78 to 0 °C, 60%; (b) OsO4, NaIO4, 2,6-lutidine, dioxane:H2O (4:1), 0 °C, 2 h, 62%; (c) 2,2-dimethyl-1,3-
propandiol, PPTS, benzene, reflux, 1 h, 94%; (d) propargyl alcohol, n-BuLi, THF, 0 °C, 12 h, 60% (based on recovered starting material); (e) 5% Pd/C, MeOH, H2, rt, 85%; (f) MnO2,
CH2Cl2, rt, 24 h, 34 (90%), 35 (92%); (g) TBAF, THF, rt, 20 min, 36 (92%), 37 (88%); (h) Lindlar catalyst, H2 (1 atm), MeOH, rt, 10 h, 80%.
O
OEt
O
a
b
O
O
38
39
40
OH
c
OH
OTBS
OTBS
O
OR
HO
HO
f
e
44
43
R = H (41)
d
g
R = TBS (42)
Figure 2. ORTEP diagram of compound 37 with 30% ellipsoidal probability.
O
O
O
O
H
O
H
O
5
O
H 10
O
5
OTBS
tinue with the mixture. Partial hydrogenation of 43 led to cis-al-
kenes 44 and further oxidation with MnO2 delivered the c-spiro-
H 10
4
4
h
H
H
11
11
+
lactones 45, quite uneventfully. Fluoride-mediated deprotection
of 45 resulted in concomitant Michael addition to furnish an easily
separable mixture of 46 and 47. The stereostructures 46 and 47
were assigned on the basis of 2D NMR studies, particularly through
the key NOESY connectivities indicated. Once again, it was gratify-
ing to note that 46 had the requisite stereochemistry at the C-4, C-
5 and C-11 stereogenic centres of the tricyclic furo-furanone ABC
core.12
In conclusion, we have outlined a very short approach of
general utility to the tricyclic furo-furan-based core of neovibsanin
diterpenoids 10a,b. The structural and stereochemical challenges
associated with the construction of the neovibsanin framework
have been addressed and the stage is now set to translate the
45
46
47
Scheme 5. Reagents and conditions. (a) TiCl4, EtOH, 0 °C–rt, 2 h, 90%; (b) (i) DIBAL-
H, CH2Cl2, rt; (ii) HCl, acetone:H2O (20:1), 15 min, 65% (over 2 steps); (c) HCHO aq
(37–41%, w/v), DMAP, sodium dodecyl sulfonate, THF:H2O (1:1), rt, 16 h, 56%; (d)
TBSCl, imidazole, DMAP, CH2Cl2, rt, 1 h, 98%; (e) propargyl alcohol, n-BuLi, THF, 0 °C,
8 h, 52%; (f) Lindlar catalyst, H2 (1 atm), MeOH, rt, 12 h, 84%; (g) MnO2, CH2Cl2, rt,
24 h, 90%; (h) TBAF, THF, rt, 20 min, 90%.
outcomes and experiences of this model study towards the total
synthesis of the natural products.

G. Mehta, B. A. Bhat / Tetrahedron Letters 50 (2009) 2474–2477
2477
least-squares method on F2 using SHELXL-97. Crystallographic data have been
deposited with the Cambridge Crystallographic Data Centre, CCDC-706720.
Compound 37: C19H28O5, MW = 336.41, crystal system: monoclinic, space
group: P21/c, cell parameters: a = 9.0085(3) Å, b = 13.3822(5) Å, c =
Acknowledgements
B.A.B. thanks CSIR for support through a post-doctoral fellow-
ship. X-ray data were collected at the CCD facility at IISc, supported
by DST, India, and we thank Mr. Saikat Sen for his help in crystal
structure determination. This research was also supported by the
CBU of JNCASR, Bangalore. G.M. thanks CSIR for the award of
Bhatnagar Fellowship and research support.
17.5105(6) Å, b = 118.891(2)°, V = 1848.22(11) Å3, Z = 4,
q ,
calc = 1.209 g cmÀ3
F(000) = 728,
l
= 0.086 mmÀ1, number of l.s. parameters = 221, R1 = 0.0886 for
2207 reflections with I > 2r(I) and 0.1290 for all 3672 data. wR2 = 0.2757,
GOF = 0.9550 for all data.
11. Mehta, G.; Bera, M. K. Tetrahedron Lett. 2008, 49, 1417–1420.
12. All new compounds were fully characterized on the basis of IR, 1H NMR, 13C
NMR and HRMS spectral data. Spectral data of selected compounds: 19 IR
(neat) 2952, 2935, 1766, 1253, 1222, 837 cmÀ1 1H NMR (400 MHz, CDCl3) d
;
5.93 (br s, 1H), 4.53–4.58 (m, 1H), 4.38 (dd, J = 2.1, 14.6 Hz, 1H), 4.31 (dd,
J = 1.8, 3.6 Hz, 1H), 2.78 (d, J = 3.6 Hz, 2H), 2.23 (m, 1H), 1.99–2.15 (m, 2H),
1.84–1.91 (m, 2H), 1.53 (m, 1H); 13C NMR (100 MHz, CDCl3) d 175.1, 134.9,
125.6, 88.4, 82.3, 70.2, 37.2, 29.5, 24.3, 17.5; HRMS (ES) m/z calcd for
C10H12O3Na (M+Na+): 203.0684; found: 203.0675; 20 IR (neat) 2925, 2854,
References and notes
1. (a) Kawazu, K. Agric. Biol. Chem. 1980, 44, 1367–1372; (b) Kubo, M.; Chem, I. S.;
Minami, H.; Fukuyama, Y. Chem. Pharm. Bull. 1999, 47, 295–296; (c) Kubo, M.;
Fujii, T.; Hioki, H.; Tanaka, M.; Kawazu, K.; Fukuyama, Y. Tetrahedron Lett. 2001,
42, 1081–1083; (d) Fukuyama, Y.; Kubo, M.; Fujii, T.; Matsuo, A.; Minoshima,
Y.; Minami, H.; Morisaki, M. Tetrahedron 2002, 58, 10033–10041; (e)
Fukuyama, Y.; Minami, H.; Fujii, H.; Tajima, M. Phytochemistry 2002, 60, 765–
768; (f) Duh, C.-Y.; El-Gamal, A. A. H.; Wang, S. K. Tetrahedron Lett. 2003, 44,
9321–9322; (g) Fukuyama, Y.; Morisaki, M.; Minoshima, Y.; Minami, H.;
Takahashi, H.; Asakawa, Y. Lett. Org. Chem. 2004, 1, 189–193.
2. Fukuyama, Y.; Minami, H.; Takeuchi, K.; Kodama, M.; Kawazu, K. Tetrahedron
Lett. 1996, 37, 6767–6770.
3. Vibsanin diterpenoids have evoked considerable interest from synthetic
chemists, see Schwartz, B. D.; Tilly, D. P.; Heim, R.; Wiedemann, S.; Williams,
C. M.; Bernhardt, P. V. Eur. J. Org. Chem. 2006, 3181–3192 and references cited
therein.
4. Fukuyama, Y.; Kubo, M.; Minami, H.; Yuasa, H.; Matsuo, A.; Fujii, T.; Morisaki,
M.; Harada, K. Chem. Pharm. Bull. 2005, 53, 72–80.
5. Esumi, T.; Zhao, M.; Kawakami, T.; Fukumoto, M.; Toyota, M.; Fukuyama, Y.
Tetrahedron Lett. 2008, 49, 2692–2696.
6. (a) Basavaiah, D.; Rao, K. V.; Reddy, R. J. Chem. Soc. Rev. 2007, 36, 1581–1588;
(b) Rezgui, F.; El Gaied, M. M. Tetrahedron Lett. 1998, 39, 5965–5966.
7. Puglisi, C. J.; Elsey, G. M.; Prager, R. H.; Skouroumounis, G. K.; Sefton, M. A.
Tetrahedron Lett. 2001, 42, 6937–6939.
1600, 1447, 887 cmÀ1 1H NMR (300 MHz, CDCl3) d 5.60 (br s, 1H) 4.86 (d,
;
J = 5.7 Hz, 2H), 4.58 (dd, J = 2.7, 12.6 Hz, 1H), 4.25 (dd, J = 2.4, 12.9 Hz, 1H), 3.53
(m, 1H), 2.31–2.49 (m, 2H), 1.97–2.30 (m, 2H), 1.77–1.95 (m, 4H); 13C NMR
(75 MHz, CDCl3) d 142.6, 140.6, 121.5, 112.4, 85.1, 73.9, 68.3, 36.8, 24.9, 22.7,
17.5; HRMS (ES) m/z calcd for C11H14O2K (M+K+): 217.1183; found: 217.0631;
26 IR (neat) 2953, 2870, 1778, 1209, 1137, 914 cmÀ1 1H NMR (400 MHz,
;
CDCl3) d 5.88 (br s, 1H), 4.51–4.56 (m, 1H), 4.35 (d, J = 11.3 Hz, 1H), 4.23 (t,
J = 2.4 Hz, 1H), 2.72 (br s, 2H), 2.09 (d, J = 18.6 Hz, 1H), 1.99 (d, J = 18.6 Hz, 1H),
1.79 (d, J = 14.1 Hz, 1H), 1.58 (d, J = 14.1 Hz, 1H), 1.13 (s, 3H), 1.06 (s, 3H); 13C
NMR (100 MHz, CDCl3) d 175.4, 133.5, 125.6, 88.8, 83.3, 70.1, 42.1, 39.3,
36.9, 31.8, 29.3, 27.1; HRMS (ES) m/z calcd for C12H16O3Na (M+Na+):
231.0997; found: 231.1005; 36 IR (neat) 2926, 1778, 1470, 1141, 1029,
834 cmÀ1 1H NMR (400 MHz, CDCl3) d 5.82 (br s, 1H), 4.75 (d, J = 4.5 Hz,
;
1H), 4.52 (m, 1H), 4.39 (m, 1H), 4.32 (d, J = 12.2 Hz, 1H), 3.56 (d, J = 11.0 Hz,
2H), 3.39 (m, 2H), 2.85 (dd, J = 4.3, 18.8 Hz, 1H), 2.61 (d, J = 17.9 Hz, 1H),
1.67–2.06 (m, 3H), 1.33–1.42 (m, 2H), 1.18 (s, 3H), 1.15 (s, 3H), 1.04 (s, 3H),
0.72 (s, 3H); 13C NMR (100 MHz, CDCl3) d 176.2, 133.7, 124.8, 101.9, 93.2,
81.4, 77.2, 77.1, 69.9, 42.8, 36.4, 35.8, 33.3, 31.4, 30.0, 29.3, 28.1, 22.9, 21.7;
HRMS (ES) m/z calcd for C19H28O5Na (M+Na+): 359.1834; found: 359.1834;
37 IR (neat) 2957, 2854, 1779, 1470, 1141, 1029, 907 cmÀ1
;
1H NMR
(400 MHz, CDCl3) d 5.81 (br s, 1H), 4.56 (d, J = 6.0 Hz, 1H), 4.41 (m, 2H), 4.24
(d, J = 10.8 Hz, 1H), 3.57 (d, J = 11.1 Hz, 2H), 3.38 (m, 2H), 2.99 (dd, J = 5.4,
18.6 Hz, 1H), 2.62 (d, J = 18.6 Hz, 1H), 2.08 (br s, 2H), 1.78–1.86 (m, 2H),
1.37–1.46 (m, 1H), 1.15 (s, 3H), 1.01 (s, 3H), 0.96 (s, 3H), 0.71 (s, 3H); 13C
NMR (100 MHz, CDCl3) d 176.9, 134.8, 124.2, 101.6, 90.5, 83.1, 77.1, 69.4,
43.1, 41.6, 38.2, 33.2, 29.9, 29.6, 23.0, 22.3, 21.7; HRMS (ES) m/z calcd for
C19H28O5Na (M+Na+): 359.1834; found: 359.1834; 46 IR (neat) 2955, 2855,
8. Jung, M. E.; Pontillo, J. Tetrahedron 2003, 59, 2729–2736.
9. In this context, it is important to mention that propargyl addition to the
allylated compound 27 was dominated by steric considerations with preferred
addition from the less hindered opposite face to furnish exclusively 48 having
the undesired stereochemical disposition at C-4 and C-10. Thus, we devised the
tactic of using the acetal oxygen in 29 to coordinate with the organolithium
reagent and deliver the propargyl group from the same face by partially
1781, 1458, 1203, 1036, 912 cmÀ1 1H NMR (400 MHz, CDCl3) d 5.86 (br s,
;
overcoming the steric barrier.
1H), 5.09–5.12 (m, 1H), 4.50–4.55 (m, 1H), 4.34 (dd, J = 1.2, 11.3 Hz, 1H),
4.23 (m, 1H), 2.73 (d, J = 2.4 Hz, 2H), 2.05–2.21 (m, 1H), 1.95 (d, J = 14.3 Hz,
1H), 1.87–2.05 (m, 1H), 1.67 (s, 3H), 1.61 (s, 3H), 1.49 (d, J = 14.3 Hz, 1H),
1.23–1.35 (m, 4H), 1.03 (s, 3H); 13C NMR (100 MHz, CDCl3) d 175.2, 133.6,
131.1, 125.4, 124.7, 88.5, 83.3, 70.2, 39.8, 38.5, 38.3, 36.9, 32.2, 28.1, 25.7,
22.9, 17.1; HRMS (ES) m/z calcd for C17H24O3Na (M+Na+): 299.1623; found:
OH
O
OTBS
OTBS
HO
propargyl alcohol,
º
n-BuLi, THF, 0 C, 8 h
299.1611; 47 IR (neat) 2955, 2856, 1782, 1458, 1145, 1037, 907 cmÀ1 1H
;
56% (based on recovered
starting material)
NMR (400 MHz, CDCl3) d 5.88 (br s, 1H), 5.06–5.10 (m, 1H), 4.52–4.56 (m,
1H), 4.36 (dd, J = 1.3, 11.3 Hz, 1H), 4.24 (t, J = 2.5 Hz, 1H), 2.73 (d, J = 6.1 Hz,
2H), 1.93–2.04 (m, 4H), 1.83 (d, J = 13.9 Hz, 1H), 1.71 (s, 3H), 1.61 (s, 3H),
1.54 (d, J = 14.0 Hz, 1H), 1.23–1.35 (m, 2H), 1.12 (s, 3H); 13C NMR (100 MHz,
CDCl3) d 175.4, 133.7, 131.7, 125.4, 124.3, 88.5, 83.5, 70.2, 44.8, 40.4, 37.9,
36.9, 32.0, 25.6, 24.4, 22.2, 17.6; HRMS (ES) m/z calcd for C17H24O3Na
(M+Na+): 299.1623; found: 299.1611.
27
48
10. X-ray data were collected at 291 K on a Bruker Kappa APEX II diffractometer
with graphite monochromated MoK radiation (k = 0.7107 Å). The crystal
a
structure was solved by direct methods (SIR92) and refined by full-matrix