Efficient total synthesis of (+)-exo-, (-)-endo-brevicomin and their derivatives via asymmetric organocatalysis and olefin cross-metathesis

Article abstract of DOI:10.1016/j.tetlet.2006.06.170

The catalytic enantioselective synthesis of (+)-exo-, (-)-endo-brevicomin and their derivatives is described herein. This approach involves the use of the organocatalyzed asymmetric α-aminoxylation of aldehyde, in situ indium mediate allyation and olefin

Full text of DOI:10.1016/j.tetlet.2006.06.170

Tetrahedron Letters 47 (2006) 6369–6372
Efficient total synthesis of (+)-exo-, (ꢀ)-endo-brevicomin
and their derivatives via asymmetric organocatalysis
and olefin cross-metathesis
Sung-Gon Kim,* Tae-Ho Park and Bong Jin Kim
Medicinal Science Division, Korea Research Institute of Chemical Technology, PO Box 107, Yuseong-gu,
Daejeon 305-600, Republic of Korea
Received 26 May 2006; revised 29 June 2006; accepted 30 June 2006
Available online 20 July 2006
Abstract—The catalytic enantioselective synthesis of (+)-exo-, (ꢀ)-endo-brevicomin and their derivatives is described herein. This
approach involves the use of the organocatalyzed asymmetric a-aminoxylation of aldehyde, in situ indium mediate allyation and
olefin cross-metathesis. This versatile strategy allows for the rapid synthesis of other members of this class of natural products.
Ó 2006 Elsevier Ltd. All rights reserved.
Derivatives of the 6,8-dioxabicyclo[3.2.1]octanes are
O
O
pheromones of a variety of bark beetle species and play
an important role in the system of chemical communica-
tion amongst them. (+)-exo- and (ꢀ)-endo-Brevicomin
(1a and 2a, respectively, Fig. 1) are typical components
of the attracting pheromone system of several bark beetle
species of the Dendroctonus and Dryocoetes family.1 In
several species, while exo-brevicomin is an aggregation
pheromone of the western pine beetle (Dendroctonus
brevicomis), endo-brevicomin is a minor component
accompanying exo-brevicomin and has been reported
to be an antiaggregation pheromone for the southern
pine beetle (Dendroctonus frontalis).2 Since exo-brevico-
min was first synthesized in racemic form,3 derivatives
of the 6,8-dioxabicyclo[3.2.1]octanes have been the
arget of numerous synthesis in both racemic and
enatiomerically pure forms.4,5 The design of an efficient
synthetic strategy still remains a challenge due to the
preparation of more active analogues. Herein we report
a short and efficient asymmetric synthesis of (+)-exo-,
(ꢀ)-endo-brevicomin and their derivatives, based on
asymmetric organocatalysis and olefin cross-metathesis.
O
O
(+)-exo-brevicomin (1a)
Figure 1.
(-)-endo-brevicomin (2a)
ation of aldehyde and nitrosobenzene as the oxygen
source.6 Recently, Zhong has developed tandem
aminoxylation–allylation reaction, which produced
mono-substituted 1,2-diols.7 We employed their organo-
catalytic a-aminoxylation–allylation reaction in the
synthesis of brevicomin and their derivatives.8
The synthesis of (+)-exo- and (ꢀ)-endo-brevicomin (1a
and 2a, respectively) begins with commercially available
nitrosobenzene and butyraldehyde as illustrated in
Scheme 1. The reaction was conducted by stirring butyr-
aldehyde (1.2 equiv), nitrosobenzene (1.0 equiv) and L-
proline (20 mol %) in DMSO at room temperature.
When the colour of the reaction mixture turned to red
from green, allyl bromide (1.5 equiv), sodium iodide
(1.5 equiv) and indium (1.5 equiv) were added. After
10 min, the product 5 was isolated in 71% yield with
the diastereoselectivity 3:2 (syn/anti).9 The enantioselec-
tivities of syn-5 and anti-5 were obtained with 98% ee
over syn-5 and 99% ee over anti-5. Though these syn-5
and anti-5 were able to separate by column chromato-
graphy, we carried out the next reactions without separa-
tion and separated diastereomers in the final stage.10
Our synthetic approach towards the target molecule was
based on the organocatalytic asymmetric a-aminoxyl-
Keywords: Brevicomin; Isobrevicomin; Total synthesis; Organocata-
lysis; Olefin cross-metathesis.
*
Corresponding author. Tel.: +82 42 860 7115; fax: +82 42 861
1291; e-mail: sgkim@krict.re.kr
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.06.170

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S.-G. Kim et al. / Tetrahedron Letters 47 (2006) 6369–6372
O
L-Proline
(20 mol%),
(I)
OH
H
ONHPh
O
N
DMSO
,
Cu(OAc)2 (30 mol%), MeOH
65% yield
4
Ph
(II) allyl bromide, In, NaI
71% yield
OH
OH
3
5
6
3 : 2 dr
(
syn : anti
)
syn: 98% ee
anti: 99% ee
O
Catalyst 8
OH
O
O
O
,
CH2Cl2
(i) 10% Pd/C, H2, EtOAc
(ii) 2 N HCl in water
(2.5 mol%)
O
OH
O
80% yield
1a
30% yield
2a
45% yield
9
MesN NMes
MesN NMes
Cl
Cl
Ru
Ru
Ph
3
Cl
Cl
8
7
PCy
O
Scheme 1. Synthesis of (+)-exo-brevicomin 1a and (ꢀ)-endo-brevicomin 2a.
The N-phenylamino group from 5 was removed by the
copper (II) catalyzed N–O cleavage reaction to give diol
6 in 65% yield.
Table 1. Asymmetric synthesis of diol derivatives
OH
ONHPh
O
R1
R1
R1
H
OH
OH
The conversion of diol 6 to ketone 9 was achieved by
olefin cross-metathesis with methyl vinyl ketone.11 We
initially examined the olefin cross-metathesis reaction
of diol 6 with methyl vinyl ketone in the presence of cat-
alytic amount (5 mol %) of Grubbs second generation
catalyst (7). However, the desired product 9 was isolated
in low yield (42%) after 24 h under reflux in CH2Cl2. To
address this, we turned our attention to another olefin-
metathesis catalyst (8). In the presence of catalyst (8)
at room temperature, the reaction was fast proceeded
to give ketone 9 in 80% yield after 6 h.12 Finally, palla-
dium catalyzed hydrogenation of 9 followed by dilution
with excess 2 N HCl solution gave 30% of (+)-exo-brev-
4
6
5
Entry
R1
% Yielda
drb (syn:anti)
% eec
(syn/anti)
5
6
1
2
3d
4
Et
71
74
67
72
65
67
61
80
3:2
3:2
3:2
3:2
98
98
99
99
99
Me
Ph
Bn
98
99
99
a Yield was determined on the weight of isolated product.
b The syn:anti ratio was determined by 13C NMR spectra.
c The ee was determined by chiral phase HPLC columns.
d a-Aminoxylation reaction was carried out in CHCl3 at 4 °C.
icomin (1a) and 45% of (ꢀ)-endo-brevicomin (2a) after
24
column chromatography (1a: ½aꢁD +69.5 (c 1.00,
24
Next, having the requisite diols in hand, we subjected to
the olefin cross-metathesis, catalytic hydrogenation and
acid-mediated cyclization. Our results are summarized
in Table 2. The olefin cross-metathesis reaction of diol
6 with other cross-metathesis partners (ethyl vinyl
ketone and benzyl vinyl ketone) allowed to obtain the
desired product 9 in good yield. (+)-exo- and (ꢀ)-endo-
Isobrevicomin were also obtained in this synthetic strat-
egy.15 In most cases, syn-diastereomer was less reactive
than anti-diastereomer at the olefin cross-metathesis
and final stage as mentioned above.
Et2O), 2a: ½aꢁD ꢀ78.8 (c 1.00, Et2O)).13 The physical
and spectroscopic data of 1a and 1b are in full agree-
ment with the literature data. We have also found that
syn-diastereomer was less reactive than anti-diastereo-
mer at the olefin cross-metathesis and final stage.
This strategy could be applied to synthesis of various
brevicomin derivatives, including isobrevicomin.14
First, the scope of organocatalytic a-aminoxylation–
allylation reaction of various aldehydes and the copper-
(II) catalyzed N–O bond cleavage reaction was investi-
gated under same reaction condition (Table 1). In every
case, the reaction gave the products 5 and 6 in good
yields with excellent enantioselectivities (98–99% ee’s).
The aliphatic aldehydes afforded the desired product
in the organocatalytic a-aminoxylation with nitroso-
benzene in DMSO, whereas phenylacetaldehyde did
not give the desired product 5 in the same reaction
condition. However, when this reaction was carried
out in CHCl3 as solvent, followed by allylation in
DMSO, desired product 5 was obtained in good yield
(entry 3).
In conclusion, we have completed the total synthesis of
(+)-exo-, (ꢀ)-endo-brevicomin and their derivatives in
five step, based on the asymmetric organocatalysis and
olefin cross-metathesis, as key steps. This versatile syn-
thetic sequence could be employed for structure activity
studies on brevicomin to determine the biologically rel-
evant components of the architecture. The present
asymmetric route represents potential route to other
members of the 6,8-dioxabicyclo[3.2.1]octane family,
which is now in progress and will be presented in due
course.

S.-G. Kim et al. / Tetrahedron Letters 47 (2006) 6369–6372
6371
Table 2. Synthesis of (+)-exo-and (ꢀ)-endo-brevicomin derivatives
OH OH
R2
O
O
R2
R2
R1
R1
O
O
OH
OH
O
R1
R1
9
1
2
6
24
Entry
R1
R2
% Yielda
½aꢁD (CHCl3) (1 (exo)/2 (endo))
9
1 (exo)
2 (endo)
1
2
3
4
5
6
Et
Et
Et
Me
Ph
Bn
Me
Et
Bn
Et
Me
Me
80
76
95
60
62
75
30
26
60
24
4
45
50
+69.5 (c 1.00)b
+55.0 (c 1.00)
—
ꢀ78.8 (c 1.00)b
ꢀ56.3 (c 1.00)
(1/2 = 2/3)c
—
38
89
62
+56.4 (c 0.45)
ꢀ74.1 (c 0.90)
ꢀ102.3 (c 1.00)
ꢀ21.4 (c 1.00)
d
—
28
+62.9 (c 1.00)
a Yield was determined on the weight of isolated product.
b Et2O was used as solvent.
c Product could not be separated by column chromatography. The 1 (exo)/2 (endo) ratio was determined by 1H NMR spectra.
d Not determined.
Tetrahedron Lett. 2003, 44, 8293–8296; (d) Bøgevig, A.;
Acknowledgements
´
´
Sunden, H.; Codova, A. Angew. Chem., Int. Ed. 2004, 43,
1109–1112; (e) Hayashi, Y.; Yamaguchi, J.; Sumiya, T.;
Shoji, M. Angew. Chem., Int. Ed. 2004, 43, 1112–1115; (f)
Momiyama, N.; Torii, H.; Saito, S.; Yamamoto, H. Proc.
Natl. Acad. Sci. U.S.A. 2004, 101, 5374–5378; (g) Wang,
W.; Wang, J.; Li, H.; Liao, L. Tetrahedron Lett. 2004, 45,
7235–7238; (h) Hayashi, Y.; Yamaguchi, J.; Sumiya, T.;
Hibino, K.; Shoji, M. J. Org. Chem. 2004, 69, 5966–5973;
This work was supported by the Ministry of Commerce,
Industry and Energy (TS-052-03) and we thank the Min-
istry of Science & Technology (KN-0528) for financial
support of this work.
References and notes
´
´
(i) Codova, A.; Sunden, H.; Bøgevig, A.; Johansson, M.;
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7. Zhong, G. Chem. Commun. 2004, 606–607.
8. For recent total synthesis using organocatalyst, see: (a)
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14120–14125; (b) Andrey, O.; Vidonne, A.; Alexakis, A.
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Tetrahedron Lett. 2005, 46, 2437–2439; (f) Chowdari, N.
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´
2. Vite, J. P.; Billings, R. F.; Ware, C. W.; Mori, K.
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Chem. 1999, 3, 407–443; (c) Mori, K. Acc. Chem. Res.
2000, 33, 102–110.
5. For recent syntheses of brevicomin, see: (a) Yusufog˘lu, A.;
Antones, S.; Scharf, H.-D. J. Org. Chem. 1986, 51, 3485–
3487; (b) Oehlschlager, A. C.; Johnston, B. D. J. Org.
Chem. 1987, 52, 940–943; (c) Matsumoto, K.; Suzuki, N.;
Ohta, H. Tetrahedron Lett. 1990, 31, 7163–7166; (d)
Vettel, S.; Diefenbach, L. A.; Haderlein, G.; Hammersch-
9. Attempts to obtain product 5 using other allylation
reagents (allylSiMe3/SnCl4, allylSiMe3/BF3ÆEt2O, allyl-
SnCl3 and allylSiCl3) failed to yield the product.
10. 5-(N-Phenyl-aminooxy)-hept-1-en-4-ol (5). To a solution
of nitrosobenzene 3 (1.07 g, 10 mmol) and butyraldehyde
4 (1.10 ml, 12 mmol) in DMSO (20 ml), L-proline (230 mg,
2.0 mmol) were added. After stirring for 15 min at room
temperature, allyl bromide (1.30 ml, 15 mmol), sodium
iodide (2.25 g, 15 mmol) and indium (1.72 g, 15 mmol)
was added and stirred for 10 min. The reaction mixture
was quenched with 0.5 M aqueous HCl solution and the
aqueous layer was extracted with EtOAc. The combined
organic layers were washed with brine, dried over anhy-
drous MgSO4 and concentrated in vacuo. The crude
residue was purified by flash column chromatography
(15% EtOAc/hexane) to afford 5 (1.57 g, 71%). The
diastereomeric ratio of the product was determined by
13C NMR spectra. The enantiomeric excess of syn- and
anti-diastereomer was measured by HPLC analysis after
the separation of the isomer using column chromato-
graphy. syn-(R,R)-5: 1H NMR (200 MHz, CDCl3) 7.29 (t,
}
midt, S.; Kuhling, K.; Mofid, M.-R.; Zimmermann, T.;
Knochel, P. Tetrahedron: Asymmetry 1997, 8, 779–800; (e)
Burke, S. D.; Muller, N.; Beaudry, C. M. Org. Lett. 1999,
1, 1827–1829; (f) Hu, S.; Jayaraman, S.; Oehlschlager, A.
C. J. Org. Chem. 1999, 64, 2524–2526; (g) Gallos, J. K.;
Kyradjoglou, L. C.; Koftis, T. V. Heterocyles 2001, 55,
781–784; (h) Mayer, S. F.; Mang, H.; Steinreiber, A.; Saf,
R.; Faber, K. Can. J. Chem. 2002, 80, 362–369; (i) Kumar,
D. N.; Rao, B. V. Tetrahedron Lett. 2004, 45, 2227–2229;
(j) Prasad, K. R.; Angarasan, P. Tetrahedron: Asymmetry
2005, 16, 3951–3953.
6. (a) Zhong, G. Angew. Chem., Int. Ed. 2003, 42, 4247–4250;
(b) Brown, S. P.; Brochu, M. P.; Sinz, C. J.; MacMillan,
D. M. C. J. Am. Chem. Soc. 2003, 125, 10808–10809; (c)
Hayashi, Y.; Yamaguchi, J.; Hibino, K.; Shoji, M.

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S.-G. Kim et al. / Tetrahedron Letters 47 (2006) 6369–6372
1
J = 7.4 Hz, 2H), 7.21 (s, 1H), 6.95–7.04 (m, 3H), 5.82–6.02
12. Compound 9: H NMR (200 MHz, CDCl3) 6.69–6.94 (m,
1H), 6.07 (d, J = 15.8 Hz, 1H), 3.23–3.64 (m, 4H), 2.29–
2.41 (m, 2H), 2.17 (s, 3H), 1.27–1.52 (m, 2H), 0.90 (t,
J = 7.4 Hz, 3H); 13C NMR (50 MHz, CDCl3) 199.4,
199.3, 146.3, 145.6, 133.0, 132.9, 76.0, 75.4, 73.2, 72.7,
37.0, 34.7, 26.9, 26.3, 25.0, 10.4, 10.8; MS (EI) m/z = 172
(M+).
(m, 1H), 5.11–5.25 (m, 2H), 4.01–4.09 (m, 1H), 3.78–3.86
(m, 1H), 2.81 (br s, 1H), 2.29–2.38 (m, 2H), 1.53–1.83 (m,
2H), 1.11 (t, J = 7.8 Hz, 3H); 13C NMR (50 MHz, CDCl3)
148.6, 135.3, 129.1, 122.4, 117.7, 114.9þ, 87.4, 72.0, 37.0,
21.4, 11.0; HRMS calcd for C13H19NO2 221.1416, found
221.1414; HPLC (Chiralcel AD-H, 3.0% isopropanol/
hexanes, 1 mL/min); tminor = 30.5 min, tmajor = 35.6 min,
98% ee; anti-(R,S)-5: 1H NMR (200 MHz, CDCl3) 7.29 (t,
J = 7.4 Hz, 2H), 6.95–7.03 (m, 3H), 5.84–6.04 (m, 1H),
5.12–5.24 (m, 2H), 3.84–3.93 (m, 1H), 3.72 (dd, J = 6.2,
11.8 Hz, 1H), 2.23–2.51 (m, 2H), 1.59–1.88 (m, 2H), 1.05
(t, J = 7.8 Hz, 3H); 13C NMR (50 MHz, CDCl3) 148.6,
134.9, 129.1, 122.4, 117.8, 115.9, 86.þ8, 72.3, 38.2, 22.4,
10.1; HRMS calcd for C13H19NO2 221.1416, found
221.1417; HPLC (Chiralcel AD-H, 3.0% isopropanol/
hexanes, 1 mL/min); tminor = 21.6 min, tmajor = 25.1 min,
99% ee.
25
13. Reported rotation values for (+)-exo-brevicomin: ½aꢁD
23
+66.7 (c 1.40, Et2O); Ref. 5c: ½aꢁD +71.5 (c 1.03, Et2O);
23
Ref. 5e: ½aꢁD +67.9 (c 1.41, Et2O); Ref. 5f: [a]D +66.6
20
(c 0.3, Et2O); Ref. 5h: ½aꢁD +65.9 (c 1.90, Et2O); Ref. 5i:
22
reported rotation values for (ꢀ)-endo-brevicomin: ½aꢁD
25
ꢀ78.9 (c 0.99, Et2O); Ref. 5a: ½aꢁD ꢀ78.8 (c 0.8, Et2O);
27
Ref. 5d: ½aꢁD ꢀ77.4 (c 0.2, Et2O); Ref. 5g.
14. For recent syntheses of isobrevicomin, see: (a) Francke,
W.; Schro¨der, W.; Philipp, P.; Meyer, H.; Sinnnwell, V.;
Gries, G. Bioorg. Med. Chem. 1996, 4, 363–374; (b) Mori,
K. Chem. Commun. 1997, 1153–1158; (c) Taniguchi, T.;
Takeuchi, M.; Ogasawara, K. Tetrahedron: Asymmetry
1998, 9, 1451–1456; (d) de Sousa, A. L.; Resck, I. S. J.
Braz. Chem. Soc. 2002, 13, 233–237.
11. For excellent articles on olefin cross-metathesis, see: (a)
Cossy, J.; BouzBouz, S.; Hoveyda, A. H. J. Organomet.
Chem. 2001, 624, 327–332; (b) Chatterjee, A. k.; Choi, T.-L.;
Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc. 2003, 125,
11360–11370; For a recent review: (c) Connon, S. J.;
Blechert, S. Angew. Chem., Int. Ed. 2003, 42, 1900–1923.
24
15. Reported rotation values for (ꢀ)-exo-isobrevicomin: ½aꢁD
28
ꢀ54.3 (c 1.34, CHCl3); Ref. 14a: ½aꢁD ꢀ55.9 (c 1.00,
CHCl3); Ref. 14c.