A concise synthesis of Hagen's gland lactones

Article abstract of DOI:10.1016/j.tetlet.2014.04.119

A short synthesis of Hagen's gland lactones 1 and 2 from commercially available pentanal and heptanal, respectively, is outlined. The approach relies on sequential ring closing metathesis and intramolecular oxy-Michael addition as the key transformations.

Full text of DOI:10.1016/j.tetlet.2014.04.119

Tetrahedron Letters xxx (2014) xxx–xxx
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Tetrahedron Letters
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A concise synthesis of Hagen’s gland lactones
b
c
Ali Mohd Lone a, Bilal Ahmad Bhat a, , Wajaht Amin Shah , Goverdhan Mehta
⇑
a Indian Institute of Integrative Medicine (CSIR), Sanatnagar, Srinagar 190005, India
b Department of Chemistry, University of Kashmir, Srinagar, India
c School of Chemistry, University of Hyderabad, Hyderabad 500046, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A short synthesis of Hagen’s gland lactones 1 and 2 from commercially available pentanal and heptanal,
respectively, is outlined. The approach relies on sequential ring closing metathesis and intramolecular
oxy-Michael addition as the key transformations.
Received 18 March 2014
Revised 30 April 2014
Accepted 30 April 2014
Available online xxxx
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Hagen’s gland lactones
Biocontrol agents
Ring closing metathesis
Furo[3,2-b]furanone
Oxy-Michael addition
In the chemical ecology of the insect world, exocrine gland
secretions play multiple roles that range from nest building, larval
food, chemical defense, and as communicative agents. In many
instances the secreted volatiles also serve as morphological and
taxonomic markers and as useful semiochemicals.1 For example,
it has been reported that certain parasitic wasps act as biocontrol
agents for fruit fly population in Hawaii and eastern Queensland.2
These wasps from the Braconidae family, Diachasmimorpha longi-
caudata (Ashmead) and Diachasmimorpha tryoni (Cameron), possess
glands (Hagen’s glands) near their abdominal tips that extrude fra-
grance rich volatiles.3 Williams was the first to indicate the pres-
ence of two bicyclic lactones 1 and 2 (Fig. 1), now recognized as
Hagen’s gland lactones, in these wasp secretions besides simple
approach employing diverse carbohydrate precursors,4b–e,g,i,k some
others have either followed chiral auxillary directed approach4h or
deployed tactics like PdCl2-catalyzed oxycarbonylation–lactoniza-
tion strategy,4a base-mediated rearrangement of oxepanone epox-
ide,4f and diastereoselective intramolecular cyclopropanation of
vinylogous carbonates as the key steps.4j While these synthetic
efforts4 toward Hagen’s gland lactones 1 and 2 have their own dis-
tinctive flavor, they also embody limitations in terms of relatively
less accessible starting materials, use of expensive transition metal
catalysts as well as lengthy and low yielding steps in the reaction
sequences. Therefore, a short, simple, and diversity oriented syn-
thesis of 1 and 2, following a different strategy would be a useful
endeavor.
c
-butyrolactones.3a The structure and relative stereochemistry of
Recently, we have delineated methodologies of general applica-
bility to construct sterically encumbered perhydrofuro[3,2-b]fura-
none core present in a diverse range of bioactive natural products.5
1 and 2 were deduced through the application of Karplus equation
to the observed vic-1H–1H coupling constants.3a Subsequently, Kit-
ching and co-workers4a elucidated their absolute stereochemistry
through enantioselective synthesis.
Considering the interesting architecture of Hagen’s gland lac-
tones 1 and 2 and their potential as semiochemicals/biocontrol
agents, these insect derived natural products have drawn sustained
interest and attention from the organic synthesis community and
nearly a dozen total syntheses, both in racemic and enantioselec-
tive versions, have been reported in recent years.4 While a majority
of Hagen’s gland lactones syntheses have been based on chiron
As
a general protocol, one of the approaches employed
Morita–Baylis–Hillman adducts in sequential ring closing metath-
esis and a silicon assisted oxy-Michael addition cascade as key
steps toward the rapid acquisition of perhydrofuro[3,2-b]furanone
scaffolds.5a This approach, with tactical modifications, employing
commercially accessible starting materials appeared quite amena-
ble for the construction of Hagen’s gland lactones 1 and 2, which is
the topic of current communication. We, herein disclose the reali-
zation of such an objective from cheap and commercially available,
pentanal and heptanal in simple and readily scalable reactions.
A retrosynthetic perspective on 1 and 2, depicted in Scheme 1,
helped identify an oxy-Michael addition on b-hydroxy-butenolide
⇑
Corresponding author. Tel.: +91 1942431253; fax: +91 1942441331.
E-mail address: bilal@iiim.acin (B.A. Bhat).
http://dx.doi.org/10.1016/j.tetlet.2014.04.119
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Lone, A. M.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.04.119

2
A. M. Lone et al. / Tetrahedron Letters xxx (2014) xxx–xxx
H
O
O
H
O
O
CHO
TBDPSO
O
TBDPSO
O
O
H
O
a
b
H
O
H
H
8
9
10
1
2
c
Figure 1. Structures of Hagen’s gland lactones 1 and 2.
O
OH
O
TBDPSO
O
(3 ? 1 and 2) and a ring closure metathesis (4 ? 3) as the key
operations to assemble the perhydrofuro[3,2-b]furanone moiety.5a
The RCM precursor 4 could be easily accessed through acrolylation
of vinyl alcohol 5 which could be traced to the hydroxyaldehyde 6
and its precursor ester 7, obtainable via Reformatsky reaction on
an appropriate commercially available alkanal.
TBDPSO
e
O
d
TBDPSO
11
12
13
f
To implement the retrosynthetic theme, pentanal 8 was sub-
jected to Reformatsky reaction with bromoethylacetate in the
presence of zinc activated by trimethylchlorosilane to yield the
corresponding b-hydroxy ester in which the hydroxyl group was
protected as TBDPS ether 9 in excellent yield (Scheme 2). TBDPS
ether 9 was reduced with DIBAL-H in toluene to afford silyl-
protected b-hydroxy aldehyde 10 in good yield.6 With aldehyde
10 in hand, it was further reacted with vinylmagnesium bromide
in THF to furnish a non-separable diastereomeric mixture of vinylic
alcohols 11. Esterification of diastereomers 11 with acrolylchloride
in the presence of triethylamine furnished acrylates 12 which
seemed well poised for the contemplated ring closing metathesis.
Exposure of 12 to Grubbs-I catalyst in degassed dichloromethane
solution at room temperature delivered the silyl-protected
O
O
O
Key NOE
O
H
Ph
O
H
Ph
H
O
H
Si
O
O
O
+
F
H
H
14
1
Scheme 2. Reagents and conditions: (a) (i) ethylbromoacetate, Zn, chlorotrimeth-
ylsilane, Et2O, reflux, 1 h, (ii) TBDPSCl, DMAP, imidazole, DMF, 0 °C to rt, 6 h, 88%
(over two steps); (b) DIBAL-H, toluene, À78 °C, 0.5 h, 82%; (c) vinylmagnesium
bromide, THF, 0 °C, 0.5 h, 92%; (d) acrolylchloride, TEA, THF, 0 °C, 1 h, 88%; (e)
Grubbs-I, dichloromethane, rt, 6 h, 92%; (f) HF-pyridine, CH3CN, rt, 24 h, 1 (62%) and
14 (14%).
b-hydroxy-a-butenolide 13 quite uneventfully and in high yield.
Butenolide 13 was well poised for the silyl-deprotective oxy-
Michael addition protocol.5 However, initially efforts with TBAF-
mediated deprotection and oxy-Michael addition led to some way-
ward products and not to the desired perhydrofuro[3,2-b]furanone
framework. However, recourse to HF-pyridine mediated desilyla-
tion of compound 13 in acetonitrile delivered the required Hagen’s
gland lactone 1 and 5-epi-Hagen’s gland lactone 146 in 4.2:1 ratio
through silyl-deprotection and oxy-Michael addition cascade.
Compounds 1 and 14 were readily separable on flash chromatogra-
phy and the former was identified through spectral comparison (1H
and 13C NMR) with the reported values.4k The stereostructure of
epimer 14 (5-epi-Hagen’s gland lactone) was secured through 2D
NMR analysis, particularly through the observation of key NOE’s.6
In an analogous manner, Hagen’s gland lactone 2 was synthe-
sized from heptanal 15 (Scheme 3) by adopting the reaction
sequence outlined earlier in Scheme 2. Activated zinc metal medi-
ated Reformatsky reaction between 15 and bromoethylacetate and
TBDPS protection of the resulting secondary alcohol led to 16.
DIBAL-H reduction on 16 yielded the corresponding aldehyde
O
O
OH
TBDPSO
O
TBDPSO
CHO
TBDPSO
c
b
a
17
15
16
18
d
O
O
H
O
H
O
O
O
e
f
TBDPSO
O
+ 2
TBDPSO
H
20
19
21
Scheme 3. Reagents and conditions: (a) (i) ethylbromoacetate, Zn, chlorotrimeth-
ylsilane, Et2O, reflux, 1 h, (ii) TBDPSCl, DMAP, imidazole, DMF, 0 °C to rt, 6 h, 82%
(over two steps); (b) DIBAL-H, toluene, À78 °C, 0.5 h, 80%; (c) vinylmagnesium
bromide, THF, 0 °C, 0.5 h, 92%; (d) acrolylchloride, TEA, THF, 0 °C, 1 h, 90%; (e)
Grubbs-I, dichloromethane, rt, 6 h, 88%; (f) HF-pyridine, CH3CN, rt, 24 h, 2 (64%) and
21 (15%).
O
O
O
H
O
R'SiO
O
R'Si O
O
O
H
H
R
H
R
H
H
H
R
17,6 which was further subjected to vinylation to furnish diastereo-
meric alcohols 18. Acrolylation of 18 to 19 and ring closing metath-
esis resulted in the formation of butenolides 20. HF-pyridine
mediated desilylation and concomitant cyclization in 20 delivered
readily separable perhydrofuro[3,2-b]furanones 2 and 216 in 4.2:1
ratio, respectively, in excellent yield. Identity of 2 with the natural
Hagen’s gland lactone was established through spectral compari-
sons (1H and 13C NMR).4k Structure of 21 was unambiguously
secured through incisive 2D NMR studies.6
3
R = n-C4H9 (1)
4
5
2
R = n-C6H13 ( )
R' = -Ph2t-Bu
R'SiO
R
O
R'SiO
R
R'SiO
OH
O
H
R
O
7
6
Scheme 1. Retrosynthetic evaluation of Hagen’s gland lactones 1 and 2.
Please cite this article in press as: Lone, A. M.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.04.119

A. M. Lone et al. / Tetrahedron Letters xxx (2014) xxx–xxx
3
NMR (400 MHz, CDCl3) d 7.76–7.59 (4H, m), 7.51–7.48 (6H, m), 4.26 (1H, m),
4.09 (2H, m), 2.49 (2H, m), 1.48 (2H, m), 1.27–1.10 (7H, m), 1.09 (9H, s), 0.78
(3H, t, J = 8 Hz); 13C NMR (100 MHz, CDCl3) d 171.6, 135.9, 134.1, 129.5, 127.4,
70.5, 60.2, 42.1, 36.7, 26.9, 26.8, 22.4, 19.3, 14.1, 13.9; HRMS (ES) m/z calcd for
In conclusion, we have developed an exceptionally simple and
practical protocol for the synthesis of Hagen’s gland lactones 1
and 2 from cheap, commercially available pentanal and heptanal,
respectively, in six steps involving ring closing-metathesis and
oxy-Michael addition as the key operations.
C
25H36O3Si [M]+: 412.2434; found: 412.2431; Compound 10: IR (CHCl3) 3023,
2926, 2857, 2839, 1739, 1312, 1192, 1021, 925 cmÀ1 1H NMR (400 MHz, CDCl3)
;
d 9.69 (1H, s), 7.69–7.63 (4H, m), 7.49–7.31 (6H, m), 4.25 (1H, m), 2.48 (2H, m),
1.61–1.39 (2H, m), 1.27–1.12 (4H, m), 1.06 (9H, s), 0.79 (3H, t, J = 8 Hz,); 13C
NMR (100 MHz, CDCl3) d 202.4, 135.9, 135.8, 133.9, 133.6, 129.8, 129.7, 127.7,
127.6, 69.3, 50.1, 37.0, 31.9, 27.0, 22.4, 19.3, 13.9; HRMS (ES) m/z calcd for
Acknowledgments
C
23H32O2Si [M+H]+: 369.2172; found: 369.2248; Compound 1: IR (CHCl3) 3016,
2861, 2929, 2858, 1781, 1648, 1471, 1340, 1183, 1062, 908 cmÀ1 1H NMR
;
B.A.B. acknowledges the financial support from the Department
of Science and Technology, India (GAP 1199) and A.M.L. thanks
University Grants Commission, India for the award of senior
research fellowship. We are also highly grateful to the Director
IIIM, Dr. Ram Vishwakarma, for his generous support to setup syn-
thetic chemistry facilities in the Srinagar campus of IIIM.
(400 MHz, CDCl3) d 5.11 (1H, t, J = 4.7 Hz), 4.80 (1H, dt, J = 6.7, 5.1 Hz), 4.09– 4.02
(1H, m), 2.74 (1H, dd, J = 18.8, 6.7 Hz), 2.61 (1H, d, J = 18.8 Hz), 2.35 (1H, dd,
J = 14.0, 4.7 Hz), 1.69–1.58 (2H, m), 1.55–1.48 (1H, m), 1.38–1.21 (4H, m), 0.89
(3H, t, J = 7.2 Hz); 13C NMR (100 MHz, CDCl3) d 175.9, 84.6, 78.0, 77.1, 38.5, 36.3,
34.0, 28.2, 22.3, 13.7; HRMS (ES) m/z calcd for C10H16O3 [M+H]+: 185.1099;
found: 185.1175; Compound 14: IR (CHCl3) 3013, 2958, 2936, 2855, 1773, 1642,
1457, 1353, 1180, 1068, 967, 904, 852 cmÀ1 1H NMR (400 MHz, CDCl3) d 5.01
;
(1H, ddd, J = 6.8, 4.3, 2.2 Hz), 4.49 (1H, dd, J = 7.2, 3.4 Hz), 3.95–3.93 (1H, m),
2.70 (2H, d, J = 3.2 Hz), 2.40 (1H, ddd, J = 14.0, 7.6, 6.5 Hz), 1.87 (1H, ddd, J = 14.0,
7.8, 2.1 Hz), 1.67–1.63 (1H, m), 1.58–1.49 (1H, m,), 1.40–1.20 (4H, m), 0.89 (3H,
t, J = 6.8 Hz); 13C NMR (100 MHz, CDCl3) d 175.5, 84.5, 80.0, 78.0, 38.0, 36.2, 35.1,
28.0, 22.3, 13.9; HRMS (ES) m/z calcd for C10H16O3 [M+H]+: 185.1099; found:
185.1175; Compound 16: IR (CHCl3) 3039, 2864, 2928, 2849, 1745, 1637, 1335,
References and notes
1. Mitra, A. J. Hymenoptera Res. 2013, 35, 33. and references cited therein.
2. (a) Tryon, H. Trans. Nat. Hist. Soc. Qld. 1895, 1, 8; (b) Hagen, K. L. Proc. Hawaii.
Entomol. Soc. 1953, 15, 115; (c) Rungrojwanich, K. Ph.D. Thesis (Entomology),
1994, The University of Queensland.; (d) Vargas, R. I.; Stark, J. D.; Nichida, G. K.;
Purcell, M. Environ. Entomol. 1993, 22, 246.
1139, 1104, 9013 cmÀ1 1H NMR (400 MHz, CDCl3) d 7.79–7.68 (4H, m), 7.44–
;
7.41 (6H, m), 4.22 (1H, m), 4.05 (2H, m), 2.48 (2H, m), 1.22–1.123 (13H, m), 1.06
(9H, s), 0.86 (3H, t, J = 7.8 Hz); 13C NMR (100 MHz, CDCl3) d 171.6, 135.9, 134.3,
129.9, 127.6, 70.5, 60.2, 42.1, 36.7, 26.9, 26.8, 22.4, 19.3, 14.1,13.9; HRMS (ES) m/
z calcd for C27H40O3Si [M]+: 440.2747; found: 440.2743; Compound 17: IR
3. (a) Williams, H. J.; Wong, M.; Wharton, R. A.; Vinson, S. B. J. Chem. Ecol. 1998, 14,
1727; (b) Wheeler, J. W.; Happ, G. M.; Araujo, J.; Pasteels, J. M. Tetrahedron Lett.
1972, 46, 4635; For an early summary of the occurrence of lactones in insects, (c)
Blum, M. S. Chemical Defences of Arthropods; Academic Press: New York, 1981.
4. (a) Paddon-Jones, G. C.; Moore, C. J.; Brecknell, D. J.; Konig, W. A.; Kitching, W.
Tetrahedron Lett. 1997, 38, 3479; (b) Mereyala, H. B.; Gadikota, R. R. Chem. Lett.
1999, 273; (c) Mereyala, H. B.; Gadikota, R. R. Tetrahedron: Asymmetry 2000, 11,
743; (d) Mereyala, H. B.; Gadikota, R. R.; Sunder, K. S.; Shailaja, S. Tetrahedron
2000, 56, 3021; (e) Paddon-Jones, G. C.; McErlean, C. S. P.; Hayes, P.; Moore, C. J.;
Konig, W. A.; Kitching, W. J. Org. Chem. 2001, 66, 7487; (f) Agrawal, D.;
Sriramurthy, V.; Yadav, V. K. Tetrahedron Lett. 2006, 47, 761; (g) Banda, G.;
Chakravarthy, I. E. Tetrahedron: Asymmetry 2006, 17, 1684; (h) Kapitán, P.;
Gracza, T. ARKIVOC 2008, viii, 8; (i) Paz-Morales, E.; Melendres, R.; Sartillo-Piscil,
F. Carbohydr. Res. 2009, 344, 1123; (j) Gharpure, S. J.; Nanda, L. N.; Shukla, M. K.
Eur. J. Org. Chem. 2011, 6632; (k) Rodney, A. F.; Pullaiah, K. J. Org. Chem. 2012, 77,
9357.
(CHCl3) 3021, 2931, 2862, 2843, 1736, 1315, 1187, 1018, 919 cmÀ1 1H NMR
;
(400 MHz, CDCl3) d 9.75 (1H, s), 7.71–7.68 (4H, m), 7.46–7.40 (6H, m), 4.23 (1H,
m), 2.51 (2H, m), 1.62–1.13 (10H, m), 1.04 (9H, s), 0.86 (3H, t, J = 8 Hz); 13C NMR
(100 MHz, CDCl3) d 202.4. 135.8, 135.7, 133.9, 133.7, 129.8, 129.7, 127.7, 127.5,
69.3, 50.1, 37.0, 31.6, 29.6, 26.9, 24.4, 22.4, 19.3, 13.9; HRMS (ES) m/z calcd for
C
25H36O2Si [M+H]+: 397.2485; found: 397.2561; Compound 2: IR (CHCl3) 3018,
2934, 2861, 1775, 1467, 1337, 1168, 1069, 913 cmÀ1 1H NMR (400 MHz, CDCl3)
;
d 5.09 (1H, t, J = 4.5 Hz), 4.80 (1H, t, J = 5.5 Hz), 4.08–4.01 (1H, m), 2.73 (1H, dd,
J = 18.7, 6.4 Hz), 2.62 (1H, d, J = 18.5 Hz), 2.36 (1H, dd, J = 14.0, 4.8 Hz), 1.68–1.55
(1H, m), 1.52À 1.25 (10H, m), 0.87 (3H, t, J = 7.0 Hz); 13C NMR (100 MHz, CDCl3)
d 175.9, 84.7, 78.1, 77.1, 38.6, 36.5, 34.5, 31.4, 29.3, 25.9, 22.4, 13.9; HRMS (ES)
m/z calcd for C12H20O3 [M+H]: 213.1412; found: 213.1487; Compound 21: IR
(CHCl3) 3012, 2931, 2864, 1777, 1638, 1467, 1414, 1347, 1201, 1161, 1082,
903 cmÀ1 1H NMR (400 MHz, CDCl3) d 5.01 (1H, ddd, J = 7.0, 4.5, 2.3 Hz), 4.49
;
5. (a) Lone, A. M.; Bhat, B. A.; Mehta, G. Tetrahedron Lett. 2013, 54, 5619; (b) Mehta,
G.; Bhat, B. A.; Kumara, T. H. S. Tetrahedron Lett. 2010, 51, 4069; (c) Mehta, G.;
Bhat, B. A. Tetrahedron Lett. 2009, 50, 2474; (d) Mehta, G.; Bhat, B. A.; Kumara, T.
H. S. Tetrahedron Lett. 2009, 50, 6597.
(1H, dd, J = 7.0, 3.5 Hz), 3.95–3.89 (1H, m), 2.72 (2H, d, J = 3.5 Hz), 2.40 (1H, ddd,
m, J = 14.0, 7.0, 6.5 Hz), 1.86 (1H, ddd, J = 14.1, 7.8, 2.1 Hz), 1.64–1.59 (1H, m),
1.56–1.53 (1H, m), 1.40–1.26 (8H, m), 0.89 (3H, t, J = 7.1 Hz); 13C NMR (100 MHz,
CDCl3) d 175.5, 84.4, 80.1, 78.3, 38.1, 36.2, 35.3, 31.5, 29.3, 26.2, 22.4, 14.0;
HRMS (ES) m/z calcd for C12H20O3 [M+H]: 213.1456; found: 213.1487.
6. All compounds reported were fully characterized on the basis of IR, 1H NMR, 13
C
NMR, and HRMS data. Spectral data of selected compounds: Compound 9: IR
(CHCl3) 3045, 2863, 2932, 2853, 1748, 1643, 1334, 1133, 1095, 905 cmÀ1 1H
;
Please cite this article in press as: Lone, A. M.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.04.119