Progress towards the total synthesis of 2,3-dihydroxytrinervitanes

Article abstract of DOI:10.1016/j.tetlet.2010.03.065

Intramolecular Diels-Alder approach to construct the fused AB ring of trinervitane has been demonstrated efficiently. The key intermediate for the Diels-Alder cyclization has been achieved following highly stereoselective Julia-Kocienski olefination, Shar

Full text of DOI:10.1016/j.tetlet.2010.03.065

Tetrahedron Letters 51 (2010) 4014–4016
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Progress towards the total synthesis of 2,3-dihydroxytrinervitanes
*
Jhillu Singh Yadav , Swapan Kumar Biswas, Sandip Sengupta
Organic Chemistry Division-I, Indian Institute of Chemical Technology (CSIR), Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Intramolecular Diels–Alder approach to construct the fused AB ring of trinervitane has been demon-
strated efficiently. The key intermediate for the Diels–Alder cyclization has been achieved following
highly stereoselective Julia–Kocienski olefination, Sharpless epoxidation and Evan’s asymmetric alkyl-
ation as the key reactions.
Received 17 December 2009
Revised 13 March 2010
Accepted 17 March 2010
Available online 9 April 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Trinervitanes
Intramolecular Diels–Alder reaction
Julia–Kocienski olefination
Evan’s asymmetric alkylation
Diterpenoid compounds play a key role in chemical communi-
cations and defense of nasute termite soldiers by squirting at
potential predators. More than two decades ago, characterization
of 2,3-dihydroxytrinervitanes 1a and 1b (Fig. 1) was reported as
the typical defensive substances from several species of termite
soldiers inhabiting the tropics.1 Recently, trinervitanes 1a and 1b
have entered into phase I clinical trials though they are ten times
less potent than any clinically practiced antibiotic and the potency
can be improved by structural optimization.2 To the best of our
knowledge there are only a few reports of its biogenetic-type syn-
thesis but no chemical synthesis has been known so far.3 Because
of its unique structural features and interesting biological activity,
an effort towards the total synthesis of 2,3-dihydroxytrinervitanes
(1a) was considered attractive.
achieved with ( )-10-camphorsulfonic acid (CSA) (0.1 equiv) in
MeOH and CH2Cl2 (1:1).7 The free hydroxyl group was then
H
H
H
H
HO
OH
HO
OH
1b
1a
Figure 1. Typical trinervitanes from termites.
The key compound 3 was prepared following standard protocol
starting from geraniol 2 (Scheme 1).4 Chlorination of hydroxyl
group of 3 with triphenylphosphine (TPP) and catalytic amount
of NaHCO3 in CCl4 at reflux temperature afforded the epoxychloro
compound 4 in 90% yield.
Double elimination reaction of epoxy-chloride 4 to secondary
propargylic alcohol 5 was achieved with Li/liq.NH3 and catalytic
amount of ferric nitrate at ꢀ78 °C.5 The hydroxyl group was pro-
tected as its tert-butyl diphenylsilyl (TBDPS) ether, and formylation
with formaldehyde in the presence of n-butyllithium (n-BuLi) fol-
lowed by its methoxyethoxymethyl (MEM) ether formation with
MEM-Cl and N,N-diisopropylethylamine (DIPEA) in dichlorometh-
ane afforded 6 in 72% yield over three steps.6 Selective deprotec-
tion of the TBDPS group on primary hydroxyl functionality was
ref. 3
O
a
TBDPSO
OH
OH
3
Geraniol (2)
OH
O
b
TBDPSO
TBDPSO
OTBDPS
Cl
4
5
c, d, e
f, g, h
TBDPSO
OMEM
6
N
N
OTBDPS
O
S
N
N
O
Ph
OMEM
7
Scheme 1. Reagents and conditions: (a) TPP, NaHCO3, CCl4, 90%; (b) LiNH2, cat.
Fe(NO3)3 ꢀ78 °C, 95%; (c) TBDPS-Cl, imidazole, CH2Cl2, 90%; (d) n-BuLi, THF, ꢀ78 °C
to rt, CH2O, 0 °C to rt, 89%; (e) MEM-Cl, DIPEA, CH2Cl2, 0 °C to rt, 90%; (f) CSA, MeOH/
CH2Cl2 (1:1), 12 h, 90%; (g) DEAD, TPP, tetrazole, THF, 80%; (h) (NH4)2MoO4, H2O2,
EtOH, 0 °C to rt 70%.
* Corresponding author. Tel.: +91 40 27193128; fax: +91 40 27160387.
E-mail addresses: yadav@iict.res.in, yadavpub@iict.res.in (J.S. Yadav).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.03.065

J. S. Yadav et al. / Tetrahedron Letters 51 (2010) 4014–4016
4015
BnO
OH
BnO
a, b
OTES
ref. 8
OBn
HO
OH
O
4
H
TESO
9
a, b
H
H
1,6-Hexane diol (8)
EtO2C
H
c
OBn
OBn
15
16
O
OH
11
10
Scheme 4. Reagents and conditions: (a) 0.1 equiv BHT, toluene, 180 °C, sealed tube,
20 h; (b) NaBH4, MeOH, 0 °C, 70% (two steps).
Scheme 2. Reagents and conditions: (a) NaBH4, NiCl2ꢁ6H2O, MeOH; (b) LiAlH4, THF,
0 °C, 80% (two steps); (c) IBX, DMSO, THF, 91%.
OBn
(H2C)4
OBn
(H2C)4
CHO
N
N
H
7
OTBDPS
Endo [4+2]
Cis-fusion
O
N
4
H
Et3SiO
5
9
8
OBn
H
N
S
Et3SiO
+
10
11
O
O
Ph
O
OMEM
12
7
6
2
3
11
1
H
H
H3C
a, b
H
H3C
16a
OH
H
OBn
15a
BnO
OBn
OH
(H2C)4
CHO
12
(H2C)4
H
H
Et3SiO
4
H
c
H
Et3SiO
11
H
CH3
OH
10
Exo [4+2]
Cis-fusion
BnO
BnO
BnO
OH
OH
O
5
1
3
2
H
6
7
O
13
14
9
H
H3C
H
8
15b
d, e
16b
OTES
OTES
Scheme 5. Transition states of cyloaddition reaction.
f
Et3Si
HC
CH3
H
O
H
A
H
B
15
(CH2)4OBn
H
H
OH
H
Scheme 3. Reagents and conditions: (a) KHMDS, THF, ꢀ78 °C; (b) 2 N HCl, MeOH,
55% (two steps); (c) Red-Al, ether, 89%; (d) TES-Cl, Et3N; (e) TBAF, 0 °C, 5 min, 68%
(two steps); (f) IBX, DMSO, THF, 1 equiv NaHCO3, 82%.
H
H
H
Me
16
converted to sulfide following Mitsunobu protocol with 1-phenyl-
1H-tetrazole-5-thiol, TPP and diethyl azodicarboxylate (DEAD) in
THF at room temperature followed by oxidation with ammonium
molybdate and H2O2 in ethanol to provide sulfone 7 in 53% yield
over three steps.8,9
Figure 2. NOESY interaction between the protons HA, HB and HC.
Table 1
Relative energies (kJ/mol) at AM1, PM3, MNDO and B3LYP/6-31G(d) levels of theory
Compound 9 was obtained from 1,6-hexane diol 8 following a
Structure
16a(
16b(b,b)
AM1
PM3
MNDO
B3LY/6-31G(d)
reported protocol (Scheme 2).10 Compound 10 was obtained in a
a
,a)
0.0
18.3
0.0
22.8
0.0
15.0
0.0
5.14
two-step sequence from
9 by treatment with NaBH4 and
NiCl2ꢁ6H2O in methanol for 10 min. at 0 °C followed by work-
up11 and reduction of saturated ester with lithium aluminium hy-
dride (LiAlH4) in THF. The alcohol 10 was oxidized with 2-iodoxy-
benzoic acid (IBX) in DMSO and THF at ambient temperature to
afford the aldehyde 11.12
Having fragments 7 and 11 in hand, Julia–Kocienski olefination
was next performed to obtain compound 12 as the only product. As
retention time for both the coupled product and aldehyde was
same, both MEM and TBDPS groups were deprotected to obtain
the pure product 12 in 55% yield over two steps (Scheme 3).13
The allyl alcohol 13 was obtained by treatment of 12 with Red-Al
in diethyl ether.14,15 Both the hydroxyl groups were protected as
triethylsilyl (TES) ether with TES-Cl and Et3N in CH2Cl2 followed
by selective deprotection to afford 14. The primary hydroxyl group
of 14 was oxidized with IBX to obtain the aldehyde 15,16,17 which is
the key intermediate for the intramolecular Diels–Alder
cyclization.
Compound 15 underwent intramolecular Diels–Alder cycliza-
tion upon heating with 10 mol % of butylated hydroxytoluene
(BHT) at 180 °C with toluene in a sealed tube. Reduction of the
crude bicyclic aldehyde with NaBH4 in MeOH afforded the fused
ring system 16 of trinervitanes as the sole product (Scheme
4).18,19 The proposed transition states indicated that half chair con-
formation 15a is more favourable than 15b as the latter intermedi-
ate exerts more steric hindrance between H3, H4, CH3 and H10
(Scheme 5).
The stereochemistry of the fused ring system 16 was supported
by NOESY experiment which showed strong interaction between
HA, HB and HC protons (Fig. 2).
Quantum mechanical energy minimized studies suggest that
molecule 16b with exo-fusion shows a substantial preference for

4016
J. S. Yadav et al. / Tetrahedron Letters 51 (2010) 4014–4016
2. Rouhi, M. A. C & EN WASHINGTON, October 13, 2003, Vol. 81, Number 41
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Kato, T.; Hoshikawa, M. Helv. Chem. Acta 2004, 87, 925; (c) Kato, T.; Hirukawa,
T.; Suzuki, T.; Tanaka, M.; Hoshikawa, M.; Yagi, M.; Tanaka, M.; Takagi, S.; Saito,
N. Helv. Chem. Acta 2001, 84, 47.
4. Marshall, J. A.; Mikowski, A. M. Org. Lett. 2006, 8, 4375.
5. Yadav, J. S.; Deshpande, P. K.; Sharma, G. V. M. Tetrahedron 1990, 46, 7033.
6. Corey, E. J.; Gras, J.-L.; Ulrich, P. Tetrahedron Lett. 1976, 17, 809.
7. Nakata, T.; Nomural, S.; Matsukura, H.; Morimotol, M. Tetrahydron Lett. 1996,
37, 217.
8. Blakemore, P. R. J. Chem. Soc., Perkin Trans. 1 2002, 2563; (b) Blakemore, P. R.;
Cole, W. J.; Kocienski, P. J.; Morley, A. Synlett 1998, 26; (c) Pospısil, J.; Marko, E.
Org. Lett. 2006, 8, 5983.
9. Spectral and analytical data of 7. ½a D25
ꢂ
ꢀ15.7 (c 1.0, CHCl3); IR (Neat):
m
max 3314,
3066, 2927, 2857, 1733, 1594, 1498, 1385, 1229, 1106, 1045, 700, 503 cmꢀ1
;
1H
NMR (300 MHz, CDCl3): d 7.69–7.50 (m, 8H), 7.46–7.25 (m, 7H), 5.27–5.16 (m,
1H), 4.98–4.85 (m, 2H), 4.56 (s, 2H), 4.37–4.24 (m, 1H), 3.60–3.54 (m, 2H),
3.46–3.41 (m, 2H), 3.31 (s, 3H), 2.21 (t, 2H, J = 7.5 Hz), 1.74–1.68 (m, 2H), 1.67
(s, 3H), 1.05 (s, 9H); 13C NMR (75 MHz, CDCl3): d 135.9, 135.7, 131.3, 129.8,
129.6, 127.6, 127.3, 125.1, 119.2, 106.9, 93.6, 86.7, 80.9, 71.7, 70.0, 67.0, 63.1,
58.9, 56.0, 54.2, 36.0, 35.0, 29.6, 26.8, 21.9, 19.2; LC–MS: m/z 725 [M+Na]+;
HRMS calcd for C37H46N4NaO6SSi:725.2805; found: 725.2807.
16a (α,α)-OSiEt3 down 0.0 kJ/mol
10. (a) Gowravaram, M. R.; Johnson, J. S.; Delecki, D.; Cook, E. R.; Tomczuk, B. E.;
Ghose, A. K.; Mathiowetz, A. M.; Spurlino, J. C.; Rubin, B.; Smith, D. L.; Pulvino,
T.; Wahl, R. C. J. Med. Chem. 1995, 38, 2570; (b) Bhagwat, S. S.; Gude, C.; Cohen,
D. S.; Dotson, R.; Mathis, J.; Lee, W.; Furness, P. J. Med. Chem. 1993, 36, 205; (c)
Chakraborty, T. K.; Dutta, S. Tetrahedron Lett. 1998, 39, 101; (d) Sasakia, S.;
Hamadab, Y.; Shioiri, Y. Tetrahedron Lett. 1997, 38, 3013.
11. Satoh, T.; Nanba, K.; Suzuki, S. Chem. Pharm. Bull. 1971, 19, 817.
12. Spectral and analytical data of 11. ½a D25
ꢂ
ꢀ0.7 (c 1.0, CHCl3); IR (Neat):
mmax 2930,
2861, 1714, 1651, 1455, 1275, 1103, 742, 698 cmꢀ1
;
1H NMR (300 MHz, CDCl3):
d 9.72 (t, 1H, J = 2.93 Hz), 7.34–7.21 (m, 5H), 4.45 (s, 2H), 3.42 (t, 2H, J = 6.6 Hz),
2.38 (t, 2H, J = 6.6 Hz), 1.71–1.05 (m, 9H), 0.89 (d, 3H, J = 5.87 Hz) ppm; 13C
NMR (75 MHz, CDCl3): d 202.8, 138.6, 128.2, 127.5, 127.4, 72.8, 70.2, 41.6, 36.4,
32.3, 29.9, 28.9, 28.7, 23.5; ESIMS: m/z 271 [M+Na]+, 249 [M+H]+; HRMS calcd
for C16H25O2: 249.1854, found: 249.1855.
16b (β,β)-OSiEt3 down 5.14 kJ/mol
13. Charette, A. B.; Berthelette, C.; David St-Martin, D. Tetrahedron Lett. 2001, 42,
5149.
Figure 3.
14. Wang, Y.; Janjic, J.; Kozmin, S. A. Pure Appl. Chem. 2005, 77, 1161.
15. Spectral and analytical data of 13. ½a D25
ꢂ
ꢀ1.8 (c 1.0, CHCl3); IR (Neat):
mmax 3448,
2923, 2852, 1637, 1457, 1427, 1216, 1118, 1021, 759 cmꢀ1
;
1H NMR (300 MHz,
endo-cyclization compared to exo-cyclization (Table 1). The opti-
mized minimum structure obtained at B3LYP/6-31G(d) level of
theory is depicted in Figure 3.
CDCl3): d 7.38–7.17 (m, 5H), 6.19–6.10 (m, 1H), 5.78 (d, 1H, J = 11.0 Hz), 5.56–
5.40 (m, 1H), 4.47 (s, 2H), 4.35 (t, 1H, J = 5.1 Hz), 4.33–4.21 (m, 2H), 3.42 (t, 2H,
J = 5.8 Hz), 2.35–1.94 (m, 4H), 1.89–1.78 (m, 1H), 1.75 (s, 3H), 1.67–1.15 (m,
10H), 0.87 (d, 3H, J = 5.8 Hz); 13C NMR (75 MHz, CDCl3): d 138.6, 135.9, 135.7,
133.4, 129.4, 128.2, 127.5, 127.3, 87.0, 80.5, 72.7, 70.3, 67.0, 54.2, 41.6, 35.9,
34.7, 32.3, 29.9, 29.6, 26.8, 23.5, 22.0, 19.3, 19.2; ESIMS): m/z 421 [M+Na]+;
HRMS calcd for C26H38NaO3: 421.5756; found: 421.5759.
In conclusion, we have demonstrated a stereoselective synthe-
sis of the fused bicyclic ring framework of the diterpene, 2,3-
dihydroxytrinervitanes, following intramolecular Diels–Alder ap-
proach. The key intermediate for Diels–Alder cyclization has been
executed in a highly stereoselective manner utilizing Julia–Kocien-
ski olefination for the construction of the conjugated E-alkene,
Sharpless asymmetric epoxidation and Evan’s asymmetric alkyl-
ation. This simple and practical approach can be applied for the to-
tal synthesis of trinervitanes and other related bioactive natural
products.
16. Frigerio, M.; Gostino, M. S. Tetrahedron Lett. 1994, 35, 8019.
17. Spectral and analytical data of 15. ½a D25
ꢂ
ꢀ1.2 (c 1.0, CHCl3); IR (Neat)
mmax 2921,
2852, 1733, 1461, 1377, 1100, 1021, 726 cmꢀ1
;
1H NMR (300 MHz, CDCl3): d
9.55 (d, 1H, J = 8.0 Hz), 7.31–7.23 (m, 5H), 6.72 (dd, 1H, J = 6.6, 11.0 Hz), 6.28–
6.01 (m, 2H), 5.73 (d, 1H, J = 10.2 Hz), 5.58–5.43 (m, 1H), 4.46 (s, 2H), 4.44–4.36
(m, 1H), 3.47 (t, 2H, J = 6.6 Hz), 2.22–2.00 (m, 2H), 1.71 (s, 3H), 1.70–1.55 (m,
5H), 1.52–1.15 (m, 4H), 1.01–0.88 (m, 12H), 0.67–0.53 (m, 6H); 13C NMR
(75 MHz, CDCl3): d 202.4, 161.4, 137.8, 130.8, 130.2, 128.5, 128.0, 126.2, 125.8,
125.6, 124.8, 74.6, 72.8, 64.2, 37.5, 32.8, 32.6, 30.2, 30.0, 25.3, 25.1, 24.2, 19.9,
17.5, 8.1, 4.9; ESIMS: m/z 513 [M+1]+.
18. Brocksom, T. J.; Nakamura, J.; Ferreira, M. C.; Brocksom, U. J. Braz. Chem. Soc.
2001, 12, 597.
Acknowledgements
19. Spectral and analytical data of 16. IR (Neat):
mmax 3448, 2924, 2855, 1633, 1459,
1376, 1106 cmꢀ1 1H NMR (300 MHz, CDCl3): d 7.30–7.22 (m, 5H), 5.50 (d, 1H,
;
S.K.B. and S.S. thank the Council of Scientific & Industrial Re-
search (CSIR), New Delhi, India, for the award of fellowships. We
thank the NMR Division for their constant support and Dr. G. N.
Sastry for helping in quantum mechanical studies.
J = 2.2 Hz), 5.47 (dd, 1H, J = 2.2, 3.0 Hz), 4.49 (s, 2H), 3.98–3.88 (m, 1H), 3.70–
3.55 (m, 2H), 3.49 (t, 2H, J = 6.7 Hz), 2.33–2.02 (m, 1H), 2.00–1.91 (m, 1H),
1.92–1.80 (m, 2H), 1.1.76–1.52 (m, 7H), 1.50–1.22 (m, 8H), 1.05 (s, 3H), 1.02–
0.82 (m, 12H), 0.67–0.55 (m, 6H); 13C NMR (75 MHz, CDCl3): d 138.9, 135.8,
135.7, 129.7, 128.0, 127.5, 127.4, 71.8, 67.4, 63.8, 59.5, 54.2, 43.2, 40.9, 36.5,
34.8, 30.9, 30.8, 29.85, 29.75, 27.1, 24.7, 23.0, 19.5, 16.3, 7.8, 4.7; ESIMS: m/z
515 [M+1]+, 514 [M]+, 513 [Mꢀ1]+; HRMS calcd for C32H54NaO3Si: 537.8542;
found: 537.8546.
References and notes
1. Prestwich, G. D.; Tanis, S. P.; Springer, J. S.; Clardy, J. J. Am. Chem. Soc. 1976, 98,
6061.