Asymmetric syntheses of (1R,1′R,5′R,7′R) and (1S,1′R,5′R,7′R)-1-hydroxy-exo-brevicomin and a formal synthesis of (+)-exo-brevicomin

Article abstract of DOI:10.1016/j.tetlet.2003.12.157

Asymmetric syntheses of (1R,1′R,5′R,7′R) and (1S,1′R,5′R,7′R)-1-hydroxy-exo-brevicomins 1 and 2, volatiles of the male mountain pine beetle, and a formal synthesis of (+)-exo-brevicomin 3, a component of the attracting pheromone system of several bark beetles have been achieved. The key steps are Birch reduction of commercially available α-picoline, selective Wittig olefination, and Sharpless asymmetric dihydroxylation.

Full text of DOI:10.1016/j.tetlet.2003.12.157

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 2227–2229
Asymmetric syntheses of (1R,10R,50R,70R) and (1S,10R,50R,70R)-1-
hydroxy-exo-brevicomin and a formal synthesis of
(+)-exo-brevicominq
D. Naveen Kumar and B. Venkateswara Rao*
Organic Chemistry Division III, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 24 October 2003; revised 18December 2003; accepted 23 December 2003
Abstract—Asymmetric syntheses of (1R,10R,50R,70R) and (1S,10R,50R,70R)-1-hydroxy-exo-brevicomins 1 and 2, volatiles of the male
mountain pine beetle, and a formal synthesis of (+)-exo-brevicomin 3, a component of the attracting pheromone system of several
bark beetles have been achieved. The key steps are Birch reduction of commercially available a-picoline, selective Wittig olefination,
and Sharpless asymmetric dihydroxylation.
Ó 2004 Elsevier Ltd. All rights reserved.
The 6,8-dioxabicyclo[3.2.1]octane skeleton is a common
structural subunit in the pheromones of a variety of
bark beetle species. In 1989, Prestwich1 discovered
oxygenated 6,8-dioxabicyclo[3.2.1]octane derivatives in
volatiles produced by bark beetles and in 1996, Francke2
et al. identified two diastereomers 1 and 2 along with
some other derivatives in the volatiles of the males of the
mountain pine beetle, Dendroctonus brevicomis. Among
various alkyl derivatives, (+)-exo-brevicomin 3 (7-ethyl-
5-methyl-6,8-dioxabicyclo[3.2.1]octane) a component of
several bark beetle species belonging to the genera
Dendrectonus and Dryocoetes3 is a well known synthetic
target (Fig. 1).
Barbas III and his co-workers5 synthesized enantiomers
of 1 and 2, that is ())-hydroxy brevicomins via enan-
tioselective C–C bond formation using the aldolase
antibody 38C2 catalyst. A number of syntheses6;7 have
been reported and reviewed in the literature for com-
pound 3. Most of the synthetic strategies for the above
targets involved organometallic reagents and protection,
deprotection protocols to construct the required carbon
skeleton. Owing to the commercial potential of these
pheromones and for the preparation of more active
analogues, their efficient synthesis demands great atten-
tion. Herein we report a short and common strategy for
the enantioselective total syntheses of (+)-(1R)-1-hy-
droxy-exo-brevicomin 1, (+)-(1S)-1-hydroxy-exo-brevi-
comin 2, and (+)-exo-brevicomin 3, starting from easily
available a-picoline 4.
To date, two syntheses2;4 have been reported for (+)-1-
hydroxy-exo- brevicomins 1 and 2 applying kinetic res-
olution by Sharpless asymmetric epoxidation and
Sharpless asymmetric dihydroxylation, respectively.
Our synthesis involved Birch reduction of a-picoline 4
and Wittig olefination as key steps. Earlier, a Birch
reduction strategy was utilized in our laboratory for the
synthesis of biologically active compounds.8 Birch
reduction of pyridine and substituted pyridines is known
to give dihydro compounds, which on hydrolysis afford
1,5-diketo products.9 These 1,5-diketo compounds can
undergo intramolecular cyclization to give aldolized
products. Birch, Shaw, and Danishefsky used this
strategy efficiently in targeted natural product synthe-
ses.10 Similarly a-picoline gave cyclohexenone via
5-oxohexanal 6 (not isolated),11 which showed that
a-picoline could be used as a 5-oxohexanal equivalent,
a key fragment in our synthesis.
O
O
O
O
O
O
HO
HO
1
2
3
Figure 1.
q IICT Communication Number: 031008.
* Corresponding author. Tel./fax: +91-40-2716-0512; e-mail: venky@
iict.res.in
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.12.157

2228
D. Naveen Kumar, B. Venkateswara Rao / Tetrahedron Letters 45 (2004) 2227–2229
The synthesis commenced with the Birch reduction of
a-picoline 4 with Na (3 equiv) in liq. NH3 containing
EtOH (10 equiv) using the known procedure.11 The
residue containing dihydro-a-picoline 5, obtained upon
evaporation of the ammonia, was treated with 4 N HCl
to afford 5-oxohexanal 6. Chemoselective Wittig olefin-
ation on crude 6 with PPh3CHCOCH3 in DCM gave the
required carbon skeleton 7 with trans stereoselectivity in
38% overall yield from a-picoline (average yield for each
step is 71%). The resulting a,b-unsaturated ketone 7 was
subjected to asymmetric dihydroxylation with AD-mix-
bâ under Sharpless conditions12 affording compound 8,
which upon treatment with catalytic p-TSA in DCM
gave cyclized product 9. The cyclized compound 9 was
reduced with different reducing agents to give diastereo-
mers 1 and 2 (see Table 1), which were separated by
column chromatography. The physical and spectral data
of these compounds were in good agreement with the
reported values2;4;13 (Scheme 1).
OH
O
O
O
O
ii
i
6
OEt
OEt
OH
11
10
iv
Ref 14
iii
O
O
O
O
O
O
OEt
HO
3
12
O
13
Scheme 2. Reagents and conditions: (i) Ph3PCHCOOEt, DCM 30 min
(overall yield for three steps 25%); (ii) AD mix-b, t-BuOH/H2O, 1:1,
3 h, 0 °C; (iii) catalytic p-TSA, DCM, 56% (for two steps from 10); (iv)
LiCl, NaBH4, EtOH, THF, 77%.
In earlier approaches for the synthesis of (+)-exo-brev-
icomin 3 employing Sharpless asymmetric dihydroxyl-
ation, Weigel and Turpin15, and Soderquest and Rane16
observed that the remote ketone functionality lowers the
enantiomeric excess in asymmetric dihydroxylation of
the isolated double bond. However in the case of 8 and
11 good enantiomeric excess was observed in the AD
reaction.17 In this instance, the presence of a keto or
ester functionality in conjugation with the olefin might
have minimized the interference of the remote ketone. It
is also well known that a,b-unsaturated esters/carbonyl
compounds give diols with good enantiomeric excess in
the AD reaction.
Similarly, when 5-oxohexanol 6 was treated with
Ph3PCHCO2Et, compound 10 was formed in 26%
overall yield (average yield for each step is 65%). This
when subjected to Sharpless asymmetric dihydroxyl-
ation using AD-mix-bâ gave 11, which upon cyclization
with catalytic p-TSA in DCM afforded 12 in good yield.
Cyclized ester 12 on reduction with LiBH4 gave alcohol
13, the spectral data for which matched with the
reported values.13;14Compound 13 has been converted to
(+)-exo-brevicomin 3 in two steps,14 providing a formal
synthesis of target molecule 3 (Scheme 2).
In conclusion, we have developed a short approach for
the synthesis of (1R,10R,50R,70R)-(+)-hydroxy-exo-brev-
icomin 1, (1S,10R,5R,70R)-(+)-1-hydroxy-exo-brevico-
min 2, and (+)-exo-brevicomin 3 starting from cheaply
available a-picoline.
Table 1
Solvents and
temperature
Yield (%)
1a
2a
Acknowledgements
LAH
NaBH4
THF, 0 °C
MeOH, 0 °C
THF, 0 °C
Toluene, )78 °C
THF, 0 °C
8
6
4
32
68
D. Naveen Kumar thanks the UGC New Delhi for
financial assistance (S.R.F). We are grateful to Dr. J. S.
75
92
8
36
64
25
78
Zn(BH4)2
K-Selectride
DIBAL-H
Yadav and Dr. G. V. M. Sharma for their support and
encouragement.
79
92
22
20
8
0
a Calculated from NMR.
References and notes
1. Prestwich, G. D. Pure Appl. Chem. 1989, 61, 551–554.
2. Francke, W.; Schroder, F.; Philipp, P.; Meyer, H.;
Sinnwell, V.; Gries, G. Bioorg. Med. Chem. 1996, 4, 363–
374.
i
iii
ii
O
O
N
N
H
H
4
6
5
3. (a) Wood, D. L.; Browne, L. E.; Ewing, B.; Lindahl, K.;
Bedard, W. D.; Tilden, P. E.; Mori, K.; Pitman, G. B.;
Hughes, P. R. Science 1976, 192, 896–898; (b) Vite, J. P.;
Billings, R. F.; Ware, C. W.; Mori, K. Naturwissenschaften
1985, 72, 99–100.
OH
O
O
O
O
iv
v
7
8
OH
vi
O
O
O
O
O
O
+
4. Yokoyama, Y.; Mori, K. Liebigs Ann./Recueil 1997, 845–
849.
2
9
1
5. Benzamen List; Shabat, D.; Barbas, C. F., III; Lerner, R.
A. Chem. Eur. J. 1998, 4, 881–885.
HO
HO
O
Scheme 1. Reagents and conditions: (i) Na in liq. NH3ÁEtoH; (ii) 4 N
HCl; (iii) Ph3PCHCOCH3, DCM, 3 h (overall yield for three steps
35%); (iv) AD mix-b, t-BuOH/H2O, 1:1, 3 h, 0 °C; (v) catalyst p-TSA,
DCM, 54% (for two steps from 7); (vi) see Table 1.
6. For earlier reported syntheses see: (a) Mori, K. Tetra-
hedron 1989, 45, 3233–3298; (b) Francke, W.; Schroder, W.
Curr. Org. Chem. 1999, 3, 407–443; (c) House, P. F.;
Jones, O. T.; Stevens, I. D. Insect Pheromones and Their

D. Naveen Kumar, B. Venkateswara Rao / Tetrahedron Letters 45 (2004) 2227–2229
2229
Use in Pest Management; Chapmann & Hall London,
1998; (d) Mori, K. Eur. J. Org. Chem. 1998, 1479–1489.
7. (a) For some recent syntheses see: Raghavan, S.; Joseph,
S. C. Tetrahedron Lett. 2003, 44, 8237–8239; (b) de Sousa,
A. L.; Resck, I. S. J. Braz. Chem. Soc. 2002, 13, 233–237;
(c) Mayer, S. F.; Mang, H.; Steinreiber, A.; Saf, R.; Faber,
K. Can. J. Chem. 2002, 80, 362–369; (d) Gallos, J. K.;
Kyaradjoglou, L. C.; Koftis, T. V. Heterocycles 2001, 55,
781–784; (e) Burke, S. D.; Muller, N.; Beaudry, C. M. Org.
Lett. 1999, 11, 1827–1829; (f) Hu, S.; Jayaraman, S.;
Ochlschlager, A. C. J. Org. Chem. 1999, 64, 2524–2526.
8. (a) Shashidhar, A.; Haritha, B.; Rao, B. V. Tetrahedron
Lett. 2003, 44, 4261–4263; (b) Rao, B. V.; Rao, A. S.
Synth. Commun. 1995, 25, 1531–1543.
and 773; 1H NMR (500 MHz, CD3CN): d 1.01 (d, 3H,
J ¼ 6:3 Hz), 1.35 (s, 3H), 1.42–1.48(m, 1H), 1.53–1.63 (m,
3H), 1.67–1.75 (m, 1H), 1.79–1.89 (m, 1H), 2.72 (d, 1H,
J ¼ 3:3 Hz), 3.52 (m, 1H, J ¼ 3:3, 6.3 Hz), 3.75 (d, 1H,
J ¼ 6:3 Hz); 4.22 (br s, 1H); 13C NMR (125 MHz, CD3CN):
d 17.91, 18.65, 25.10, 28.48, 35.56, 69.46, 76.80, 84.38,
108.75; EI-MS m=z: 172 (Mþ), 127, 112, 97, 81, 69, 55, 43.
26:1
D
Compound 12: ½aŠ ¼ þ35:75 (c 1.1, CHCl3); IR (neat
cmÀ1): 2980, 2940, 1750, 1715, 1375, 1295, 1175, 1150, 1095,
1
1050, 1035, 1000, and 825; H NMR (200 MHz, CDCl3): d
1.33 (t, 3H J ¼ 7:4 Hz), 1.54 (s, 3H), 1.60–1.95 (m, 6H), 4.23
(q, 2H, J ¼ 7:4 Hz), 4.43 (s, 1H), 4.61 (br s, 1H) 13C NMR
(50 MHz, CDCl3): d 171.51, 109.87, 79.07, 77.42, 65.05,
34.33, 27.58, 24.07, 16.96, 14.04; FAB-MS m=z: 201 (Mþ +1),
9. (a) Harries, C. Ber. Dtsch. Chem. Ges. 1914, 47, 784–791;
(b) Shaw, B. D. J. Chem. Soc. 1925, 215–216; (c) Shaw, B.
D. J. Chem. Soc. 1937, 300–302.
10. Donohoe, T. J.; McRiner, A. J.; Helliwell, M.; Sheldrake,
P. J. Chem. Soc., Perkin. Trans. 1 2001, 1435–1445, and
references cited therein.
154, 137, 107, 97, 83, 69, 55.
25:9
D
Compound 13: Colorless oil ½aŠ ¼ þ50:25 (c 1.3, CHCl3)
27
{lit.13 ½aŠ ¼ 53:7 ꢀ 2 (c 0.94, CHCl3)}; IR (neat cmÀ1):
D
1
3200, 1450, 1180, and 760; H NMR (200 MHz, CDCl3): d
1.40 (s, 3H), 1.42–1.85 (m, 6H), 3.50 (d, 2H, J ¼ 6 Hz), 4.07
(t, 1H, J ¼ 6 Hz), 4.23 (br s, 1H); 13C NMR (75 MHz,
CDCl3): d 108.34, 79.53, 76.51, 64.91, 34.69, 27.53, 24.87,
17.05; FAB-MS m=z: 159 (Mþ +1), 147, 136, 109, 95, 81, 73,
55.
11. Birch, A. J. J. Chem. Soc. 1946, 1270.
12. (a) Kolb, H. C.; Nieuwenhze, M. S. V.; Sharpless, K. B.
Chem. Rev. 1994, 94, 2483–2547; (b) Carlo, B.; Giuliana,
R. Tetrahedron 2002, 58, 4981–5021, and references cited
therein.
14. Johnston, B. D.; Ochlschlazer, A. C. J. Org. Chem. 1982,
47, 5386–5389.
13. Spectral data for selected compounds: Compound 9:
15. Turpin, J. A.; Weigel, L. O. Tetrahedron Lett. 1992, 33,
6563–6564.
16. Soderquest, J. A.; Rane, A. M. Tetrahedron Lett. 1993, 34,
5031–5034.
17. Enantiomeric purities of 8 and 11 were estimated to be
24:8
½aŠ ¼ À49:8 6 c( 1.23, CHCl3); IR (CHCl3 cmÀ1): 2962,
D
1718, 1382, 1349, 1220, 1015, and 1049; 1H NMR (300 MHz,
CDCl3): d 1.52 (s, 3H), 1.56–1.88 (m, 6H), 2.22 (s, 3H), 4.18
(s, 1H), 4.45 (s, 1H); 13C NMR (75 MHz, CDCl3): d 211.89,
109.90, 84.24, 79.28, 34.61, 27.89, 26.95, 24.37, 17.07; EI-MS
90.1% ee and >97% ee, respectively, by HPLC analysis of
26:5
D
m=z: 170 (Mþ), 155, 141, 127, 99, 81, 69, 43.
the corresponding dibenzoates 8a {½aŠ ¼ þ73:67 (c 1.19,
25:4
D
26:6
D
Compound 1: Low melting solid {lit.2 29 °C}; ½aŠ
¼
CHCl3)} and 11a {½aŠ ¼ þ71:44 (c 1.43, CHCl3)} using
21
þ54:12 (c 1.82, CHCl3) {lit.2 ½aŠ ¼ þ56:7 (c 0.8, CHCl3),
a Chiracel OD-H column. (For 8a 10% i-propanol/
n-hexane, flow rate 0.5 mL/min, k ¼ 254 nm; for 11a 7%
i-propanol/n-hexane, flow rate 0.5 mL/min, k ¼ 254 nm.)
D
26
D
lit.4 ½aŠ ¼ þ55:2 (c 0.82, CHCl3)}; IR (CHCl3 cmÀ1): 3470,
2941, 2853, 1741, 1460, 1380, 1165, 1102, 1087, 1026,
1005, and 827; 1H NMR (500 MHz, CD3CN): d 1.10
(d, 3H, J ¼ 6:4 Hz), 1.31 (s, 3H), 1.45 (m, 1H), 1.52–1.61 (m,
3H), 1.68–1.76 (m, 1H), 1.78–1.88 (m, 1H), 2.60–2.68 (br s,
1H), 3.42 (m, 1H), 3.65 (d, 1H, J ¼ 7:1 Hz), 4.35 (br s 1H).
13C NMR (125 MHz, CD3CN): d 17.97, 19.74, 25.09, 28.54,
OBz
OH
O
O
O
O
benzoyl chloride,
R
R
Et3N, cat DMAP,
DCM.
OBz
OH
35.57, 69.15, 76.91, 84.56, 108.52.
25:9
Compound 2: Colorless oil ½aŠ ¼ þ63:38( c 2.95, CHCl3)
11
11
D
21
8a R = CH3
11a R = OEt
8
R = CH3
{lit.4 ½aŠ ¼ þ61:3 (c 1.18, CHCl3)}; IR (CHCl3 cmÀ1): 3472,
D
2938, 1450, 1384, 1237, 1173, 1115, 1040, 1010, 930, 883, 851,
11 R = OEt