An enantiospecific synthesis of (+)-hydroxy-exo-brevicomin

Article abstract of DOI:10.1016/j.tetlet.2005.12.094

A concise enantiospecific synthesis of the pine beetle pheromone (+)-hydroxy-exo-brevicomin was achieved from l-(+)-tartaric acid in high yield. The key step involves the reduction of a keto-Weinreb amide derived from tartaric acid.

Full text of DOI:10.1016/j.tetlet.2005.12.094

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 1433–1435
An enantiospecific synthesis of (+)-hydroxy-exo-brevicomin
Kavirayani R. Prasad* and Pazhamalai Anbarasan
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
Received 3 November 2005; revised 9 December 2005; accepted 15 December 2005
Abstract—A concise enantiospecific synthesis of the pine beetle pheromone (+)-hydroxy-exo-brevicomin was achieved from L-(+)-
tartaric acid in high yield. The key step involves the reduction of a keto-Weinreb amide derived from tartaric acid.
Ó 2006 Elsevier Ltd. All rights reserved.
Several species of the Western pine beetle produce alkyl-
ated 6,8-dioxabicyclo[3.2.1]octanes, which play a major
role in their communication systems. Extensive out-
breaks of bark beetles may result in the destruction of
millions of trees per year causing great ecological and
economic damage. Brevicomin 1, 7-ethyl-5-methyl-6,8-
dioxabicyclo[3.2.1]octane was the first pheromone of
this kind that was identified from the frass of the females
of the Western pine beetle, Dendroctonus brevivomis.1
Similar structures having varied bicyclooctane struc-
tures such as frontalin 2 and multistriatin 3 were isolated
in addition to a number of other compounds from differ-
ent Dendroctonus species. Interestingly, marine tunicates
belonging to the genus Dedemnum produce serinolipids
such as didemniserinolipid 5 which possess the same
bicyclic core2 (Fig. 1). Francke et al. reported the isola-
tion and synthesis of hydroxy-exo-brevicomin 4, 1-(5-
methyl-6,8-dioxabicyclo[3.2.1]oct-7-yl)ethanol from the
head-space extracts from Dendroctonus ponderosae.3
There are only a few approaches for the enantioselective
synthesis of hydroxy-exo-brevicomin reported in the lit-
erature employing either a chiron approach or other
asymmetric methodologies.4,5 In continuation of our
efforts on the utility of chiral pool L-(+)-tartaric acid
in natural product synthesis,6 herein, we report an
efficient enantiospecific synthesis of (+)-hydroxy-exo-
brevicomin starting from chiral pool L-(+)-tartaric acid.
We reasoned that the keto-amide 7, which is produced
by controlled addition of the appropriate Grignard
reagent to the bis-Weinreb amide 6 derived from tartaric
acid, could be elaborated to the title compound (Scheme
1).
Thus, controlled addition of 4-pentenylmagnesium bro-
mide (1.5 equiv) to the bis-Weinreb amide7 6 produced
the mono keto-amide 7 in 92% yield. A highly diastereo-
selective reduction of the ketone group in 7 was achieved
O
O
O
O
O
O
O
O
OH
multistriatin
3
frontalin
2
exo-brevicomin
1
hydroxy-exo-brevicomin
4
OH
O
HO
O
O
O
O
NH2
(+)-didemniserinolipid B
5
Figure 1. Bio-active bicyclic acetals possessing the 6,8-dioxabicyclo[3.2.1]octane skeleton.
Keywords: Stereoselective reduction; L-(+)-Tartaric acid; Hydroxy-exo-brevicomin.
*
Corresponding author. Fax: +91 80 23600529; e-mail: prasad@orgchem.iisc.ernet.in
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.12.094

1434
K. R. Prasad, P. Anbarasan / Tetrahedron Letters 47 (2006) 1433–1435
TBDMSO
O
TBDMSO
O
O
OH
Me
O
O
O
OH
10
4
12
O
Me
O
O
Me
N
O
MeO
N
L-(+)-tartaric acid
N
OMe
OMe
O
Me
O
O
O
7
6
Scheme 1. Retrosynthesis of (+)-hydroxy-exo-brevicomin.
MgBr
(1.5 eq)
O
Me
N
O
O
Me
N
O
L-Selectride, -78 ˚C
THF, 2.5 h
89%
MeO
OMe
N
OMe
THF, -15 oC, 0.5 h
92%
3
O
O
Me
O
O
O
7
6
Me
N
TBDMSO
3
Me
N
O
HO
3
O
NaBH4, MeOH
TBDMSOTf
Pyridine, DCM
0 oC to RT, 1 h
98%
0
oC to RT, 3 h
95%
OMe
OMe
O
O
O
O
9
8
TBDMSO
3
TBDMSO
3
O
TsCl, DMAP
DCM, RT, 5 h
92%
Super hydride
THF, RT, 2 h
94%
OH
O
OTs
O
O
10
11
O
TBDMSO
O
Me
PdCl2, CuCl, O2
DMF/H2O, RT, 6 h
74%
Me
OH
(+)-hydroxy-exo-brevicomin
O
4
12
Scheme 2. Synthesis of (+)-hydroxy-exo-brevicomin.
with L-selectride furnishing a single diastereomer of the
corresponding alcohol 8 with the requisite stereochemis-
Further application of the strategy for the synthesis of
a number of other similar bicyclic systems is currently
underway.
try. Protection of the hydroxy group in 8 as its silyl ether
25
9 (½aꢀD ꢁ6.2 (c 1.3, CHCl3)) was effected with TBDM-
SOTf in almost quantitative yield. The high reactivity
of the Weinreb amide was then exploited by reduction
to the corresponding alcohol with sodium borohydride
to give 10 in 95% yield. The primary alcohol group in
10 was converted to the corresponding tosylate 11,
which on reduction with super hydride8 gave 12 in excel-
lent yield. The trihydroxy-protected alkene 12 under
Acknowledgements
We thank DST, New Delhi, for funding this project.
P.A. thanks IISc, Bangalore, for financial support.
Wacker oxidation9 conditions, produced (+)-hydroxy-
References and notes
25
exo-brevicomin (½aꢀD +61.2 (c 2.4, CHCl3); lit5a
25
1. Silverstein, R. M.; Brownlee, R. G.; Bellas, T. E.; Wood,
D. L.; Browne, L. E. Science 1968, 159, 889–891.
2. Gonzalez, N.; Rodriguez, J.; Jiminez, C. J. Org. Chem.
1999, 64, 5705–5707.
3. Francke, W.; Schroder, F.; Philipp, P.; Meyer, H.;
Sinnwell, V.; Gries, G. Bioorg. Med. Chem. 1996, 4,
363–374.
½aꢀD +61.3 (c 1.18, CHCl3)), via the formation of the
ketone and simultaneous deprotection of the silyl and
acetonide group followed by intramolecular ketalization
(Scheme 2). The synthetic sample exhibited spectral data
identical to that of an authentic sample.10
In conclusion, we have achieved an efficient enantio-
specific synthesis of (+)-hydroxy-exo-brevicomin in an
overall yield of 48% in seven steps starting from the
bis-Weinreb amide 6 derived from L-(+)-tartaric acid.
4. Kumar, D. N.; Rao, B. V. Tetrahedron Lett. 2004, 45,
2227–2229.
5. (a) Yokoyama, Y.; Mori, K. Liebigs Ann. Chem. 1997,
845–849; (b) Kumar, D. N.; Rao, B. V. Tetrahedron Lett.

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2004, 45, 7713–7714; (c) Kumar, D. N.; Rao, B. V.;
Ramanjaneyulu, G. S. Tetrahedron: Asymmetry 2005, 16,
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Asymmetry 2005, 16, 1897–1900; (b) Prasad, K. R.;
Gholap, S. L. Synlett 2005, 2260–2262; (c) Prasad, K.
R.; Anbarasan, P. Tetrahedron: Asymmetry 2005, 16,
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7. Nugiel, D. A.; Jakobs, K.; Worley, T.; Patel, M.;
Kaltenbach, R. F., III; Meyer, D. T.; Jadhav, P. K.; De
Lucca, G. V.; Smyser, T. E.; Klabe, R. M.; Bacheler, L. T.;
Rayner, M. M.; Seitz, S. P. J. Med. Chem. 1996, 39, 2156–
2169.
NMR (400 MHz, CDCl3) d 5.79 (ddt, J = 17, 10.2, 6.6 Hz,
1H), 5.03–4.93 (m, 2H), 4.75 (br s, 1H), 4.36 (br s, 1H),
3.74 (s, 3H), 3.62–3.60 (m, 1H), 3.23 (s, 3H), 2.08–2.04 (m,
2H), 1.68–1.42 (m, 4H), 1.48 (s, 3H), 1.45 (s, 3H);
13C NMR (100 MHz, CDCl3) d 170.6, 138.5, 114.7,
111.1, 80.7, 73.8, 70.2, 61.6, 38.4, 34.0, 33.5, 27.0, 26.1,
25
1
25.1. Compound 10, ½aꢀD +12.1 (c 2.4, CHCl3); H NMR
(300 MHz, CDCl3) d 5.70 (ddt, J = 16.8, 10.2, 6.6 Hz,
1H), 4.96–4.82 (m, 2H), 3.93 (dt, J = 8.1, 4.8 Hz, 1H),
3.80–3.45 (m, 4H), 2.37 (br s, 1H), 1.98–1.94 (m, 2H),
1.60–1.24 (m, 4H), 1.31 (s, 3H), 1.30 (s, 3H), 0.81 (s, 9H),
0.01 (s, 6H); 13C NMR (75 MHz, CDCl3) d 138.5, 114.7,
108.6, 80.5, 77.0, 71.9, 62.9, 33.7, 31.9, 27.0, 26.9, 25.8,
25.3, 18.1, ꢁ4.2, ꢁ4.7. HRMS for C18H36O4Si+Na calcd
25
8. (a) Krishnamurthy, S.; Brown, H. C. J. Org. Chem. 1976,
41, 3064–3066; (b) Krishnamurthy, S. J. Organomet.
Chem. 1978, 156, 171–181.
367.2281; found 367.2281. Compound 12, ½aꢀD +16.0 (c
1.5, CHCl3); 1H NMR (300 MHz, CDCl3) d 5.80 (ddt,
J = 17.1, 10.5, 6.6 Hz, 1H), 5.05–4.9 (m, 2H), 3.99 (dq,
J = 8.4, 6.3 Hz, 1H), 3.80–3.69 (m, 1H), 3.53 (dd, J = 8.4,
4.2 Hz, 1H), 2.06 (m, 2H), 1.59–1.38 (m, 4H), 1.39 (s, 3H),
1.37 (s, 3H), 1.29 (d, J = 6.3 Hz, 3H), 0.89 (s, 9H), 0.07
(s, 6H); 13C NMR (75 MHz, CDCl3) d 138.6, 114.5, 107.7,
84.6, 72.7, 71.9, 33.7, 32.4, 27.3, 26.9, 25.9, 25.1,
18.8, 18.2, ꢁ4.1, ꢁ4.6. (+)-Hydroxy-exo-brevicomin 4:
9. Tsuji, J. Synthesis 1984, 369–384.
10. All the compounds exhibited spectral data consistent with
their structures. Spectral data for selected com-
25
pounds: compound 7, ½aꢀD +6.6 (c 1.8, CHCl3); 1H
NMR (300 MHz, CDCl3) d 5.77 (ddt, J = 17.1,10.2,
6.6 Hz, 1H), 5.06–4.97 (m, 3H), 4.82 (d, J = 5.4 Hz, 1H),
3.71 (s, 3H), 3.23 (s, 3H), 2.77–2.55 (m, 2H), 2.11–2.04
25
½aꢀD +61.2 (c 2.4, CHCl3); 1H NMR (300 MHz, CDCl3) d
(m, 2H), 1.76–1.66 (m, 2H), 1.49 (s, 3H), 1.44 (s, 3H); 13
C
4.23 (s, br, 1H), 3.77 (d, J = 7.2 Hz, 1H), 3.63 (dq, J = 7.2,
6.3 Hz, 1H), 2.58 (s, br, 1H), 1.76–1.94 (m, 2H), 1.62–1.71
(m, 3H),1.47–1.51 (m, 1H), 1.45 (s, 3H), 1.14 (d,
J = 6.3 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 108.4,
83.8, 76.5, 69.2, 34.6, 27.6, 24.8, 18.4, 17.1.
NMR (75 MHz, CDCl3) d 208.1, 169.7, 137.7, 115.3,
112.7, 82.2, 73.9, 61.6, 38.4, 32.9, 32.5, 26.6, 26.2, 22.1.
HRMS for C14H23NO5+Na calcd 308.1474; found
25
308.1480. Compound 8 ½aꢀD ꢁ5.5 (c 1.8, CHCl3); 1H