Prins and RCM protocols for the synthesis of the pheromones of the giant white butterfly Idea leuconoe

Article abstract of DOI:10.1016/j.tetlet.2008.08.010

The total syntheses of (6R)-6-[(2R)-2-hydroxyhexyl]tetrahydro-2H-2-pyranone and 7-hydroxy-5-dodecanolide are described utilizing a Prins reaction and ring closing metathesis reaction sequence.

Full text of DOI:10.1016/j.tetlet.2008.08.010

Tetrahedron Letters 49 (2008) 6087–6089
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Tetrahedron Letters
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Prins and RCM protocols for the synthesis of the pheromones
of the giant white butterfly Idea leuconoe
*
Gowravaram Sabitha , Narjis Fatima, E. Venkata Reddy, J. S. Yadav
Organic Division I, Indian Institute of Chemical Technology, 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:
The total syntheses of (6R)-6-[(2R)-2-hydroxyhexyl]tetrahydro-2H-2-pyranone and 7-hydroxy-5-dode-
canolide are described utilizing a Prins reaction and ring closing metathesis reaction sequence.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 28 April 2008
Revised 15 July 2008
Accepted 3 August 2008
Available online 8 August 2008
Keywords:
d-Lactones
Natural products
Pheromones
Prins
RCM
Males of the giant white butterfly Idea leuconoe hairpencils
release a complex mixture of compounds such as dihydropyrroli-
zines, terpenoids, aromatics, lactones, and hydrocarbons amongst
others during courtship.1 Among them, b- and d-lactones with
two chiral centers are considered as important components of
the pheromone system. The chain lengths of lactones, such as
6-hydroxy-4-alkanolides 1 and 7-hydroxy-5-alkanolides 2, vary
between C10 and C13. d-Lactones 2 are the minor components of
the hairpencil secretion, and occur as mixtures of all the possible
enantiomers. Among these, the anti-enantiomers predominate.
Hairpencil components also produce a warning signal against
predators,2 besides their courtship function. To date, a single report
has appeared3 on the synthesis of these lactones, which uses an
enantioselective hydrogenation of a dioxoalkanoate precursor.
The development of efficient Prins cyclizations for the synthesis
of natural products4 has prompted us to explore its utility further.
In this connection and in continuation of our interest on the syn-
thesis of bioactive naturally occurring lactones,5 we herein report
a concise synthesis of lactones 2a and 2b utilizing a Prins cycliza-
tion coupled with RCM (ring closing metathesis) (Fig. 1).
O
O
OH
OH
O
O
R
R
(4 isomers)
1a; R = C4H9
1b; R = C5H11
1c; R = C6H13
2a; R = C4H9
2b; R = C5H11
2c; R = C6H13
Figure 1.
This intermediate 5 can be utilized for the synthesis of both 2a
and 2b using C4H9CHO and C5H11CHO, respectively (Schemes 1
and 2). Accordingly, Prins cyclization of 5 with C4H9CHO in the
presence of TFA followed by hydrolysis of the resulting trifluoro-
acetate yielded the desired trisubstituted pyran 7a. Silyl protection
of the 2° alcohol with TBSCl and imidazole in the presence of a cat-
alytic amount of DMAP afforded 8a in 92% yield, which underwent
debenzylation by hydrogenation at atmospheric pressure, in EtOAc
in the presence of 10% Pd/C as the catalyst to produce primary
alcohol 9a. Alcohol 9a, on exposure to TPP, iodine, and imidazole
in refluxing diethyl ether and acetonitrile (3:1) converted into
the corresponding iodide 10a in 24 h. The iodo compound 10a on
exposure to activated Zn in refluxing EtOH furnished the key ring
opened compound 11a with the anti-1,3-diol system. The second-
ary alcohol was protected as a benzyl ether and a subsequent
removal of the TBDMS group provided 12a. The alkene 12a was
converted readily into acrylate 13a upon exposure to acryloyl
The synthesis commenced from the R-(+)-benzyl glycidyl ether
4, obtained by the Jacobsen resolution6 of racemate 3 using (S,S)-
(salen) Co(II) precatalyst, AcOH and H2O (0.5 equiv) for 12 h. Reg-
ioselective opening of epoxide 4 with the vinyl Grignard reagent
formed by the addition of vinyl bromide to Mg in THF in the pres-
ence of CuCN in THF afforded homoallylic alcohol 5 in 92% yield.
* Corresponding author. Tel./fax: +91 40 27160512.
E-mail address: gowravaramsr@yahoo.com (G. Sabitha).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.08.010

6088
G. Sabitha et al. / Tetrahedron Letters 49 (2008) 6087–6089
(s,s) Co-(salen)
OH
O
O
CH2=CHBr, Mg
AcOH, H2O, THF
OBn
OBn
OBn
º
º
C
º
CuCN, THF, -78 C to -40
0 C-r.t, 12 h
3
5
47%
92%, 4 h
4
OR
OR
O
i) Pd/C, EtOAc, H2
r.t, 80%
i) C4H9-CHO, TFA, CH2Cl2
ii) TPP, I2 , Imidazole
Et2O:CH3CN (3:1)
80%
R1
K2CO3, MeOH
r.t, 0.5 h, 59%
OBn
O
C4H9
C4H9
ii) TBSCl, Imidazole,
DMAP, CH2Cl2
7a; R = H
8a; R = TBS
,
92%
9a; R = TBS, R1 = OH
10a; R = TBS, R1= I
i) NaH, BnBr, THF
r.t, 0.5 h, 95%
OBn OH
OH
OTBS
activated Zn, EtOH,
85%
ii)TBAF, THF,
C4H9
C4H9
º
0
C- r.t, 2 h, 90%
11a
12a
O
O
10 mol%, CH2Cl2,
r.t, 3 h, 76%
Acryloyl chloride, Et3N
OBn
O
OBn
O
º
Grubbs' 2nd
DMAP, 0 C, r.t, 2 h
generation cat
79%
C4H9
C4H9
13a
14a
O
Grubbs' 2nd generation catalyst
H2, Pd/C, EtOAc
2 h, r.t, 96%
OH
O
C4H9
2a
Scheme 1.
OH
O
OH
C5H11CHO
OH
O
OBn
OBn
C5H11
O
7b
C5H11
2b
5
Scheme 2.
2. Nishida, R.; Schulz, S.; Kim, C. S.; Fukami, H.; Kuwahara, Y.; Honda, K.; Hayashi,
N. J. Chem. Ecol. 1996, 22, 949–972.
chloride, Et3N, and DMAP in 79% yield. Next, the ring closing
metathesis reaction was implemented easily by the exposure of a
DCM solution of the diene to Grubbs’ 2nd generation catalyst
(10 mol %), which resulted in clean cyclization to dihydropyran-
2-one 14a in 76% yield.
Removal of the benzyl protecting group with concomitant
reduction of the double bond was accomplished by hydrogenation
at atmospheric pressure, in EtOAc in the presence of 10% Pd/C as
the catalyst to afford target molecule 2a in 96% yield.
Using the abovementioned synthetic approach, optically active
7-hydroxy-5-dodecanolide 2b (Scheme 2) was accessed readily
from 5 and C5H11CHO in 6.4% overall yield.
3. Stritzke, K.; Schulz, S.; Nishida, R. Eur. J. Org. Chem. 2002, 3884–3892.
4. (a) Yadav, J. S.; Reddy, M. S.; Rao, P. P.; Prasad, A. R. Tetrahedron Lett. 2006, 47,
4397–4401; (b) Yadav, J. S.; Reddy, M. S.; Prasad, A. R. Tetrahedron Lett. 2005, 46,
2133–2136; (c) Yadav, J. S.; Reddy, M. S.; Prasad, A. R. Tetrahedron Lett. 2006, 47,
4995–4998; (d) Yadav, J. S.; Rao, P. P.; Reddy, M. S.; Rao, N. V.; Prasad, A. R.
Tetrahedron Lett. 2007, 48, 1469–1471.
5. (a) Sabitha, G.; Sudhakar, K.; Reddy, N. M.; Rajkumar, M.; Yadav, J. S. Tetrahedron
Lett. 2005, 46, 6567–6570; (b) Sabitha, G.; Narjis, F.; Swapna, R.; Yadav, J. S.
Synthesis 2006, 17, 2879–2884; (c) Sabitha, G.; Reddy, E. V.; Yadagiri, K.; Yadav, J.
S. Synthesis 2006, 19, 3270–3274; (d) Sabitha, G.; Sudhakar, K.; Yadav, J. S.
Tetrahedron Lett. 2006, 47, 8599–8602; (e) Sabitha, G.; Bhaskar, V.; Yadav, J. S.
Tetrahedron Lett. 2006, 47, 8179–8181; (f) Sabitha, G.; Swapna, R.; Reddy, E. V.;
Yadav, J. S. Synthesis 2006, 24, 4242–4246; (g) Sabitha, G.; Bhikshapathi, M.;
Yadav, J. S. Synth. Commun. 2007, 561–569; (h) Sabitha, G.; Gopal, P.; Yadav, J. S.
Synth. Commun. 2007, 1495–1502; (i) Sabitha, G.; Yadagiri, K.; Yadav, J. S.
Tetrahedron Lett. 2007, 48, 1651–1652; (j) Sabitha, G.; Yadagiri, K.; Yadav, J. S.
Tetrahedron Lett. 2007, 48, 8065–8068.
In conclusion, we have achieved a total synthesis of two phero-
mones of giant white butterfly I. leuconoe.
6. Tokunaga, M.; Larrow, J. F.; Kukiuchi, F.; Jacobsen, E. N. Science 1997, 277, 936.
Spectral data. (2R)-1-(Benzyloxy)-4-penten-2-ol (5): 1H NMR (CDCl3, 300 MHz): d
7.33 (m, 5H), 5.83 (m, 1H) 5.11 (dt, J = 5.2 Hz, 2H), 4.56 (s, 2H), 3.85 (m, 1H), 3.49
(dd, J = 3.7, 9.0 Hz, 1H), 3.39–3.32 (dd, J = 7.5, 9.0 Hz, 1H), 2.23 (t, J = 6.7 Hz, 2H);
13C NMR (CDCl3, 75 MHz): d 137.9, 134.1, 128.4, 127.7, 127.6, 117.6, 73.9, 73.4,
69.6, 37.8; LCMSD: 215 [M+23]; HRMS 215.1040 [M+23], C12H16O2Na; IR (neat):
3436, 3071, 3031, 2921, 2860, 1718, 1640, 1495, 1452, 1363, 1275, 1209, 997,
Acknowledgment
N.F. thanks IICT for the award of a fellowship.
743, 698, 608, 468 cmꢀ1; ½a D25
ꢀ4.98 (c 1, CHCl3).
ꢁ
References and notes
(2R,4R,6R)-2[(Benzyloxy)- methyl]-6-butyltetrahydro-2H-4-pyranol (7a): 1H NMR
(CDCl3, 300 MHz): d 7.33 (m, 5H), 4.55 (q, J =12.0 Hz, 2H), 3.82–3.68 (m, 1H),
1. Schulz, S.; Nishida, R. Bioorg. Med. Chem. 1996, 4, 341–349.

G. Sabitha et al. / Tetrahedron Letters 49 (2008) 6087–6089
6089
3.55–3.22 (m, 4H), 1.93 (td, J = 2.2, 4.5, 12.8 Hz, 4H), 1.50–1.03 (m, 6H), 0.90 (t,
J = 6.7 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 138.3, 128.3, 127.6, 127.5, 75.8, 74.9,
(td, J = 9.0 Hz, 1H), 4.70–4.51 (ABq, J = 11.3, 4.4 Hz, 2H), 4.43 (d, J = 11.3 Hz, 1H),
3.86–3.75 (m, 1H), 2.32–2.26 (td, J = 4.5, 6.0, 1.5 Hz, 2H), 1.93–1.18 (m, 8H), 0.88
(td, J = 1.7, 7.0 Hz, 3H,); 13C NMR (CDCl3, 75 MHz): d 164.4, 145.2, 138.5, 128.3,
127.8, 127.6, 121.3, 74.9, 74.7, 71.8, 40.5, 33.8, 29.9, 29.6, 26.9, 22.8, 14.0;
73.3, 73.2, 68.1, 41.0, 37.9, 35.6, 27.7, 22.6, 13.9; LCMSD: 279 [M+1]; ½a D25
ꢁ
+23.8
(c 0.75, CHCl3).
((2R,4R,6R)-2-[(Benzyloxy)methyl]-6-butyltetrahydro-2H-4-pyranyloxy)(tert-butyl)-
dimethylsilane (8a): 1H NMR (CDCl3, 300 MHz): d 7.35–7.29 (m, 5H), 4.6–4.52
(ABq, J = 12.0, 18.5 Hz, 2H), 3.98–3.94 (m, 1H), 3.81–3.71 (m, 1H), 3.54–3.38 (m,
3H), 1.77 (td, J = 4.5, 12.0 Hz, 1H), 1.62–1.11 (m, 7H), 0.98–0.87 (m, 14H), 0.11–
0.04 (s, 6H); 13C NMR (CDCl3, 75 MHz): 138.1, 128.0, 127.4, 127.2, 75.6, 73.1,
74.7, 72.0, 70.7, 41.2, 38.2, 35.5, 27.5, 25.4, 22.5, 20.5, 13.8, ꢀ4.5; LCMSD: 393
LCMSD: 301 [M+Na]; HRMS 289.1799 [M+1] C18H23O3;
CHCl3).
½ ꢁ ꢀ15.7 (c 1.75,
a 2D5
(6R)-6-[(2R)-2-Hydroxyhexyl]tetrahydro-2H-2-pyranone (2a): 1H NMR (CDCl3,
300 MHz): d 4.58 (t, J = 9.5 Hz, 1H), 4.05–3.85 (m, 1H), 2.68–2.24 (m, 2H),
2.00–1.82 (m, 2H), 1.81–1.20 (m, 10H), 0.91 (t, J = 6.5 Hz, 3H). 13C NMR (CDCl3,
75 MHz): d 171.9, 77.3, 67.4, 43.2, 37.6, 29.5, 28.3, 27.6, 22.6, 18.4, 13.9; IR
[M+1]; HRMS: 393.2809 [M+1] C23H41O3Si; ½a D25
ꢁ
+2.3 (c 1.21, CHCl3).
(neat): 3441, 2926, 1731, 1457; LCMSD: 223 [M+Na]; HRMS: 223.1310; ½a D25
ꢁ
((2R,4R,6R)-6-Butyl-4-[1-(tert-butyl)-1,1-dimethylsilyl]oxytetrahydro-2H-2-pyran-
yl)methanol (9a): 1H NMR (CDCl3, 300 MHz): d 3.85–3.66 (m, 1H), 3.62–3.14 (m,
4H), 1.95–1.07 (m, 13H), 0.87 (s, 12H), 0.04 (m, 6H); 13C NMR (CDCl3, 75 MHz):
75.89, 75.75, 68.61, 66.10, 41.72, 37.42, 35.71, 27.77, 25.83, 22.70, 18.06, 14.03,
ꢀ12.5 (c 0.2, CHCl3), ꢀ16.5 (c 0.5, diethyl ether).
(2R,4R,6R)-2-[(Benzyloxy)methyl]-6-pentyltetrahydro-2H-4-pyranol (7b): 1H NMR
(CDCl3, 300 MHz): d 7.36–7.22 (m, 5H), 4.56 (q, J = 12.0 Hz, 2H), 3.98–3.70 (m,
1H), 3.56–3.37 (m, 4H), 1.93 (td, J = 4.5, 12.0 Hz, 2H), 1.64–1.06 (m, 11H), 0.97–
0.87 (t, J = 6.7 Hz, 3H); 13C NMR (CDCl3, 75 MHz): d 138.2, 126.3, 127.6, 127.5,
75.7, 73.6, 73.2, 73.0, 68.0, 40.8, 37.8, 35.7, 31.8, 25.1, 22.5, 13.9; LCMSD: 315
ꢀ4.59; LCMSD: 325 [M+Na]; HRMS 325.2165 [M+Na], C16H34O3NaSi; ½a D25
ꢀ2.9
ꢁ
(c 1.4, CHCl3).
(4R,6R)-6-(Benzyloxy)-1-decen-4-ol (12a): 1H NMR (CDCl3, 300 MHz): d 7.44–
7.12 (m, 5H), 5.93–5.66 (m, 1H), 5.17–5.10 (d, J = 12.50 Hz, 2H), 4.67–4.41 (m,
2H), 3.99–3.83 (m, 1H), 3.77–3.59 (m, 1H), 3.48–3.43 (br s, 1H), 2.24–2.14 (t,
J = 6.2 Hz, 2H), 1.74–1.16 (m, 8H), 0.98–0.82 (t, J = 6.2 Hz, 3H); 13C NMR (CDCl3,
75 MHz): 138.3. 134.9, 128.4, 127.8, 117.4, 76.2, 71.1, 67.7, 42.1, 39.3, 33.1, 29.6,
[M+Na]; ½a 2D5
ꢁ
+6.9 (c 1.65, CHCl3).
7-Hydroxy-5-dodecanolide/(6R)-6-[(2R)-2-hydroxyheptyl]tetrahydro-2H-2-pyranone
(2b): 1H NMR (CDCl3, 300 MHz): d 4.60 (t, J = 9.8 Hz, 1H), 3.97 (m, 1H), 2.60 (m,
1H), 2.44 (m, 1H), 1.86–1.99 (m, 2H), 1.53–1.79 (m, 2H), 1.44 (m, 2H), 1.36–1.26
(m, 9H), 0.92 (t, J = 6.0 Hz, 3H); 13C NMR (CDCl3, 75 MHz): d 171.9, 77.3, 67.4,
43.3, 38.0, 31.7, 29.5, 28.4, 25.1, 22.6, 18.5, 13.9; LCMSD: 237 [M+Na], HRMS
27.5, 22.7, 13.9.; LCMSD: 263 [M+1]; ½a D25
ꢀ8.9 (c 2.25, CHCl3).
ꢁ
(6R)-6-[(2R)-2-(benzyloxy)hexyl]-5,6-dihydro-2H-2-pyranone (14a): 1H NMR
(CDCl3, 300 MHz): d 7.34–7.22 (m, 5H), 6.85–6.77 (t, J = 4.5 Hz, 1H), 6.01–5.94
237.1466 (M+Na); IR (neat): 3448, 2925, 1637, 1458 cmꢀ1; ½a D25
ꢀ22.5 (c 0.3,
ꢁ
CHCl3); ꢀ28.0 (c 0.15, diethyl ether), [lit.:3 ꢀ26.5 (c 2.4, diethyl ether)].