A chiron approach to (1R,2R,5S,7S)-2-hydroxy-exo-brevicomin: A component of the volatiles produced by the male mountain pine beetle, Dendroctonus ponderosae

Article abstract of DOI:10.1016/j.tetasy.2005.03.014

A chiron approach for the synthesis of (1R,2R,5S,7S)-2-hydroxy-exo- brevicomin 1, a component of the volatiles obtained from male mountain pine beetles, Dendroctonus ponderosae has been achieved. Our synthesis started with commercially available d-ribose

Full text of DOI:10.1016/j.tetasy.2005.03.014

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 1611–1614
A chiron approach to (1R,2R,5S,7S)-2-hydroxy-exo-brevicomin:
a component of the volatiles produced by the male mountain
pine beetle, Dendroctonus ponderosaeI
D. Naveen Kumar,a B. Venkateswara Raoa,* and G. S. Ramanjaneyulub
aOrganic Division III, Indian Institute of Chemical Technology, Hyderabad 500007, India
bNational Centre for Mass Spectrometry, Indian Institute of Chemical Technology, Hyderabad 500007, India
Received 5 January 2005; accepted 10 March 2005
Available online 14 April 2005
Abstract—A chiron approach for the synthesis of (1R,2R,5S,7S)-2-hydroxy-exo-brevicomin 1, a component of the volatiles obtained
from male mountain pine beetles, Dendroctonus ponderosae has been achieved. Our synthesis started with commercially available
D-ribose and involves a Wittig olefination, an acid catalyzed one pot hydrogenation and the internal acetalization as key steps.
Ó 2005 Elsevier Ltd. All rights reserved.
1.Introduction
2.Results and discussion
In 1996 Francke et al.1 identified several new oxygen-
ated derivatives of 6,8-dioxabicyclo[3.2.1]octane in the
head space volatiles obtained from the male mountain
pine beetle, Dendroctonus ponderosae, which are destruc-
tive pests causing damage to coniferous forests in the
northern hemisphere. These compounds are mainly
stereoisomers of 7-ethyl-5-methyl-6,8-dioxabicyclo-
[3.2.1]octan-2-ol and 1-(5-methyl-6,8-dioxabicyclo-
[3.2.1]octyl)-ethanol such as A–D and 1.
Previously we have reported an asymmetric synthesis of
A and B including the formal synthesis of (+)-exo-brevi-
comin starting from a-picoline2 and a chiron approach
to the synthesis of C starting from D-mannitol.3 With
these successful achievements and in continuation of
our interest in the synthesis of other family members,
herein we report a chiron approach to the synthesis of
1. Francke et al. reported its first synthesis based on a
kinetic resolution using a Sharpless asymmetric epoxid-
ation.1 Herein we report the synthesis of 1 starting from
D-ribose as depicted in Scheme 1.
OH
2,3-O-Isopropylidene-D-ribose 2 was prepared accord-
ing to the literature procedure.4 The primary hydroxyl
group in acetonide 2 was protected as silyl ether using
TBDMSCl, imidazole to give 3 (89%). This was sub-
jected to Wittig reaction with methylene triphenylphos-
phorane to give olefin 4 (82%), which upon benzylation
with benzyl bromide gave 5 (62%). Compound 5 was
desilylated using 1 M TBAF solution in THF to yield
6 (78%). The primary hydroxyl functionality in 6 was
oxidized to the aldehyde using TEMPO conditions,
which was subsequently treated with Ph3PCHCOCH3
to give 7 (60% overall yield for two steps) as a mixture
H
O
O
O
O
O
O
C
B
A
OH
OH
H
OH
OH
H
O
O
O
O
1
D
1
of cis:trans-isomers (1:9 by H NMR). Hydrogenation
q IICT Communication number: 050101.
*
of 7 in the presence of a catalytic amount of Pd–C
and aqueous HCl in MeOH gave target 1 (40%) directly.
The physical and spectral data of compound 1 are in
Corresponding author. Tel./fax: +91 40 27160512; e-mail: venky@
iict.res.in
0957-4166/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.03.014

1612
D. Naveen Kumar et al. / Tetrahedron: Asymmetry 16 (2005) 1611–1614
O
OH
OBn
O
O
OH
OH
TBSO
TBSO
TBSO
HO
ref.4
ii
iii
i
D
-Ribose
O
O
O
3
O
O
O
O
2
4
5
OH
OBn
O
O
OBn
OBn
vi
HO
v
H
iv
O
O
+
O
O
O
O
O
O
6
1
7
Scheme 1. Reagents and conditions: (i) TBDMSCl, imidazole, DCM, rt, 89%; (ii) Ph3PCH2I, KOtBu, THF, ꢀ78 °C, 82%; (iii) NaH, benzyl bromide,
THF, 62%; (iv) 1 M TBAF, THF, 78%; (v) (a) TEMPO, NaOCl, toluene, ethyl acetate, water; (b) Ph3PCHCOCH3, DCM, 60% (for two steps);
(vi) H2–Pd–C and catalytic aq HCl, MeOH, 40%.
good agreement with the reported values.1 The final step
was carried out as per the procedure reported by us
earlier in the synthesis of C, in which hydrogenation,
debenzylation, acetonide deprotection, and internal
acetalization takes place in one step.3
to give 3 (5 g, 89%) as colorless oil (9:1 anomeric mix-
ture). IR mmax (film): 2943, 2863, 2357, 1466, 1376,
1254, 1213, 1156, 1074, 997, 838, 776; 1H NMR
(400 MHz, CDCl3) for major isomer: d 5.20 (d, 1H,
J = 11.9 Hz), 4.63 (d, 1H, J = 6.3 Hz), 4.43 (d, 1H,
J = 6.3 Hz), 4.38 (d, 1H, J = 11.1 Hz), 4.27 (m, 1H),
3.78–3.72 (m, 2H), 1.46 (s, 3H), 1.30 (s, 3H), 0.94 (s,
9H), 0.14 (s, 6H); EIMS = 289 (M+ꢀ15), accurate mass
calcd for [M+Na]+ (C14H28O5Na): 327.1603. Found:
327.1608.
3.Conclusion
In summary we have demonstrated a chiron approach
for the synthesis of 1 starting from D-ribose involving
simple and standard transformations.
4.2. (1R,40R,50S)-(ꢀ)-1-(20,20-Dimethyl-50-vinyl-10,30-
dioxolan-40-yl)-2-(tert-butyldimethylsilyloxy)-1(R)-
ethan-1-ol 4
4.Experimental
TLC was performed on Merck Kiesel gel 60, F254 plates
(layer thickness 0.25 mm). Column chromatography
was performed on silica gel (60–120 mesh) using ethyl
acetate and hexane mixture as eluent. Melting points
were determined on a Fisher JohnÕs melting point appa-
ratus and are uncorrected. IR spectra were recorded
on a Perkin–Elmer RX-1 FT-IR system. 1H NMR
(200 MHz) and 13C NMR (50 MHz) spectra were re-
To a mixture of methyl triphenylphosphonium iodide
(7.170 g, 17.74 mmol) and potassium tert-butoxide
(1.66 g, 14.8 mmol) was added dry THF (100 mL) and
stirred at room temperature under N2 for 4 h. Stirring
was stopped and the solid allowed to settle. The clear
supernatant orange-yellow liquid was then cannulated
into the solution of compound 3 (0.90 g, 2.96 mmol) in
dry THF (10 mL) at ꢀ78 °C. The reaction mixture was
then slowly allowed to attain room temperature. After
3 h the reaction mixture was quenched with crushed
ice and diluted with ethyl acetate. The organic portion
was separated and dried over anhydrous Na2SO4, fil-
tered, and evaporated. The resulting syrup was purified
by silica gel column chromatography (hexane/ethyl
1
corded on a Varian Gemini-200 MHz spectrometer. H
NMR (300 MHz) and 13C NMR (75 MHz) spectra were
recorded on Bruker Avance-300 MHz spectrometer.
Optical rotations were measured with Horiba-SEPA-
300 digital polarimeter. The EI mass spectra were re-
corded on GC–MS system (Agilent Technologies, CA)
equipped with agilent 6890 GC and 5973 GC mass selec-
tive detector. Accurate mass measurement for sodiated
molecular ions 2–7 generated under electrospray ioniz-
ation conditions was performed on Quattro LC mass
spectrometer (Micromass, UK). Accurate mass for the
molecular ion of compound 1 was measured using
VG-Autospec M mass spectrometer, (Micromass, UK)
under electron ionization conditions at 20 eV.
acetate, 85:15) to give 4 (0.73 g, 82%) as a pale yellow
29:6
D
syrup, ½aꢁ = ꢀ3.2 (c 0.69, CHCl3); IR mmax (film):
3562, 2929, 2858, 1465, 1374, 1254, 1217, 1167, 1063,
1009, 927, 840, 780; 1H NMR (300 MHz, CDCl3): d
5.99 (ddd, 1H, J = 6.0, 10.5, 17.0 Hz), 5.38 (td, 1H,
J = 1.5, 17.0 Hz), 5.23 (td, 1H, J = 1.5, 10.5 Hz), 4.64
(t, 1H, J = 6.0 Hz), 3.98 (dd, 1H, J = 6.7, 9.8 Hz), 3.77
(dd, 1H, J = 3.0, 9.8 Hz), 3.71–3.52 (m, 2H), 2.34 (d,
1H, J = 6.0 Hz), 1.44 (s, 3H), 1.33 (s, 3H), 0.91 (s,
9H), 0.08 (s, 6H); 13C NMR (75 MHz, CDCl3, proton
decoupled): d 134.21, 117.46, 108.74, 78.81, 77.43,
69.38, 64.38, 27.82, 25.37, 25.42, 18.32, ꢀ4.7;
EIMS = 287 (M+ꢀ15), accurate mass calcd for
[M+Na]+ (C15H30O4SiNa): 325.1811. Found: 325.1814.
4.1. 2,3-O-Isopropylidene-5-(tert-butyldimethylsilyl)-D-
ribose 3
To a stirred solution of 2 (3.50 g, 18.4 mmol) in dry
DCM (50 mL) was added imidazole (3.13 g, 44.0 mmol)
and tert-butyldimethylsilylchloride (3.22 g, 21.4 mmol)
at room temperature and the mixture stirred for 3 h.
The solvent was removed and the residue partitioned
between ethyl acetate and water. The organic layer
was washed with brine, dried over anhydrous Na2SO4,
and evaporated. The residue was purified by silica gel
column chromatography (hexane/ethyl acetate, 70:30)
4.3. (10R,4R,5S)-(ꢀ)-4-[20-(tert-Butyldimethylsilyloxy)-
10-(benzyloxy)-ethyl]-2,2-dimethyl-5-vinyl-1,3-dioxolane 5
To a stirred solution of sodium hydride (94.0 mg, 60%
wt in mineral oil, 2.35 mmol) in dry THF (2 mL) was

D. Naveen Kumar et al. / Tetrahedron: Asymmetry 16 (2005) 1611–1614
1613
added alcohol 4 (0.60 g, 2.0 mmol) dissolved in dry THF
(3 mL) at 0 °C. After 20 min, benzyl bromide (0.26 mL,
2.19 mmol) was added and stirring continued for 2 h at
room temperature. The reaction was quenched by the
addition of a saturated solution of NH4Cl (5 mL) and
extracted with ethyl acetate. The organic extracts were
washed with water, brine, and dried over anhydrous
Na2SO4. Evaporation of the solvent and purification
of the crude product by column chromatography (hex-
NaOCl solution (1.3 mL, 0.69 mmol, 4% aqueous solu-
tion) was added slowly to the above reaction mixture
at 0 °C. After completion of the reaction the resultant
aldehyde was washed with an aqueous solution of KI
(5 mg), 10% KHSO4 (2 mL) and 10% hypo (2 mL)
followed by water. The organic layer was separated
and concentrated to give the aldehyde (0.15 g) as a light
yellow color oil, which was taken to next step without
any purification.
ane/ethyl acetate, 95:5) afforded benzyl ether 5 (0.48 g,
29:6
D
62%) as a pale yellow liquid, ½aꢁ = ꢀ22.8 (c 0.69,
To the crude aldehyde in dry DCM (5 mL), was added
Ph3PCHCOCH3 (0.25 g, 0.79 mmol) dissolved in dry
DCM (2 mL) slowly at 0 °C. After the addition, the
reaction mixture was brought to room temperature
and stirred for a further 2 h and quenched with water.
The organic layer was separated, dried over anhydrous
Na2SO4 and concentrated. Purification by column chro-
matography (hexane/ethyl acetate, 93:7) afforded 7
(0.13 g, 60% for two steps) as a clear oil (1:9 cis:trans-
CHCl3); IR mmax (film): 3031, 2987, 2931, 2886, 2857,
1728, 1496, 1459, 1377, 1254, 1216, 1093, 1033, 1003,
926, 838, 778, 739; 1H NMR (300 MHz, CDCl3): d
7.33–7.17 (m, 5H), 5.89 (ddd, 1H, J = 6.3, 10.2,
17.3 Hz), 5.32 (td, 1H, J = 1.5, 17.3 Hz), 5.17 (td, 1H,
J = 1.5, 11.0 Hz), 4.79 (d, 1H, J = 11.0 Hz), 4.64 (t,
1H, J = 6.3 Hz), 4.41 (d, 1H, J = 11.0 Hz), 4.15 (dd,
1H, J = 6.3, 8.6 Hz), 3.96 (dd, 1H, J = 2.3, 11.0 Hz),
3.73 (dd, 1H, J = 5.5, 11.0 Hz), 3.45 (ddd, 1H, J = 2.3,
5.5, 8.6 Hz), 1.45 (s, 3H), 1.33 (s, 3H), 0.91 (s, 9H),
0.06 (s, 6H); EIMS = 377 (M+ꢀ15), accurate mass calcd
for [M+Na]+ (C22H36O4SiNa): 415.2280. Found:
415.2293.
1
diastereomeric mixture, by H NMR). IR mmax (film):
2986, 2925, 2861, 2361, 1683, 1633, 1495, 1455, 1419,
1
1370, 1254, 1216, 1167, 1074, 986, 928, 873, 743; H
NMR for major isomer (300 MHz, CDCl3): d 7.35–
7.21 (m, 5H), 6.68 (dd, 1H, J = 6.0, 16.6 Hz), 6.23 (d,
1H, J = 16.6 Hz), 5.88 (m, 1H), 5.39 (td, 1H, J = 1.5,
17.3 Hz), 5.20 (td, 1H, J = 1.5, 10.5 Hz), 4.71 (t, 1H,
J = 6.0 Hz), 4.44 (d, 1H, 10.5 Hz), 4.26 (d,
1H, 10.5 Hz), 4.08 (dd, 1H, J = 6.0, 8.3 Hz), 3.91 (dd,
1H, J = 6.7, 8.3 Hz), 2.28 (s, 3H), 1.46 (s, 3H), 1.33
(s, 3H); EIMS = 301 (M+ꢀ15), accurate mass calcd
for [M+Na]+ (C19H24O4Na): 339.1572. Found:
339.1571.
4.4. (2R,40R,50S)-(ꢀ)-2-(Benzyloxy)-2-[20,20-dimethyl-50-
vinyl-10,30-dioxolan-40-yl]-ethan-1-ol 6
To an ice-cooled solution of 5 (0.40 g, 1.02 mmol) in dry
THF (5 mL) was added a 1 M solution of TBAF
(2.0 mL, 2.0 mmol) and stirred for 2 h at room temper-
ature. After completion of the reaction, water was added
to the reaction mixture and THF was removed under
vacuum. Then the aqueous layer was extracted with
ethyl acetate and washed with saturated aqueous NaH-
CO3 and brine, dried over anhydrous Na2SO4, and
concentrated in vacuum. The residue was purified by
4.6. (1R,2R,5S,7S)-2-Hydroxy-exo-brevicomin 1
To a solution of compound 7 (0.10 g, 0.32 mmol) in
MeOH (2 mL) were added catalytic amounts of Pd–C
and aqueous HCl. The reaction mixture was stirred un-
der hydrogen atmosphere for overnight, filtered, and the
filtrate neutralized with solid NaHCO3 after which the
volatiles were removed under vacuum. The resultant res-
idue was partitioned between ethyl acetate and water.
The organic layer was separated, dried over anhydrous
Na2SO4 and concentrated to give the crude product,
which was purified on column chromatography (hex-
ane/ethyl acetate 75:25) to get the pure compound 1
(0.022 g, 40%) as colorless oil (97.99% pure by GC anal-
column chromatography (hexane/ethyl acetate, 80:20)
29:6
D
to give 6 (0.22 g, 78%) as a colorless oil, ½aꢁ = ꢀ30.5
(c 0.55, CHCl3); IR mmax (film): 3473, 2988, 2931, 1457,
1378, 1250, 1216, 1166, 1071, 926, 874, 742; H NMR
1
(400 MHz, CDCl3): d 7.37–7.26 (m, 5H), 5.92 (ddd,
1H, J = 5.9, 10.4, 17.0 Hz), 5.41 (td, 1H, J = 1.4,
17.0 Hz), 5.24 (td, 1H, J = 1.4, 10.4 Hz), 4.73 (t, 1H,
J = 5.9 Hz), 4.59 (d, 1H, J = 11.1 Hz), 4.45 (d, 1H,
J = 11.1 Hz), 4.26 (dd, 1H, J = 5.9, 8.1 Hz), 3.90–3.73
(m, 2H), 3.47 (m, 1H), 1.95 (br dd, 1H, J = 2.2,
9.6 Hz), 1.5 (s, 3H), 1.4 (s, 3H); 13C NMR (75 MHz,
CDCl3, proton decoupled): d 137.84, 133.83, 128.46,
127.86, 127.73, 117.21, 108.73, 78.51, 77.60, 77.43,
71.36, 61.42, 27.70, 25.25; EIMS = 263 (M+ꢀ15), accu-
rate mass calcd for [M+Na]+ (C16H22O4Na): 301.1415.
Found: 301.1427.
26
1
ysis). ½aꢁ = +91.3 (c 0.4, CHCl3); H NMR (300 MHz,
D
C6D6): d 3.95 (m, 1H), 3.81 (ddd, 1H, J = 4.2, 5.9,
8.0 Hz), 3.39 (m, 1H), 2.15 (br s, 1H), 1.92–1.75 (m,
1H), 1.60–1.26 (m, 4H), 1.40 (s, 3H), 1.07 (m, 1H),
0.75 (t, 3H, J = 7.6 Hz); 13C NMR (75 MHz, C6D6,
proton decoupled): d 107.24, 81.12, 80.11, 63.91, 31.53,
26.41, 24.98, 21.61, 11.07; HR-EIMS calcd for
(C9H16O3): 172.1099. Found: 172.1092.
4.5. (5R,40R,50S)-5-[50-Vinyl-20,20-dimethyl-10,30-dioxo-
lan-40-yl]-5-benzyloxy-E or Z-3-penten-2-one 7
To a stirred solution of 6 (0.19 g, 0.68 mmol) in ethyl
acetate/toluene mixture (1:1, 2 mL) were added sodium
bromide (0.07 g, 0.68 mmol), water (0.3 mL) and TEM-
PO free radical (2.0 mg, 0.013 mmol) at 0 °C simulta-
neously. NaHCO3 (0.16 g, 1.91 mmol) dissolved in
Acknowledgements
D. Naveen Kumar thanks the UGC New Delhi for
financial assistance (S.R.F). We are grateful to

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D. Naveen Kumar et al. / Tetrahedron: Asymmetry 16 (2005) 1611–1614
2. Naveen Kumar, D.; Rao, B. V. Tetrahedron Lett. 2004, 45,
2227–2229.
3. Naveen Kumar, D.; Rao, B. V. Tetrahedron Lett. 2004, 45,
7713–7714.
4. Moon, H. R.; Choi, W. J.; Kim, H. O.; Jeong, L. S.
Tetrahedron: Asymmetry 2002, 13, 1189–1193.
Dr. J. S. Yadav and Dr. A. C. Kunwar for their support
and encouragement.
References
1. Francke, W.; Schroder, F.; Philipp, P.; Meyer, H.; Sinnwell,
V.; Gries, G. Bioorg. Med. Chem. 1996, 4, 363–374.