Chiron approach for the synthesis of (1S,2R,5R,7S)-2-hydroxy-exo-brevicomin

Article abstract of DOI:10.1016/j.tetasy.2006.02.020

(1S,2R,5R,7S)-2-Hydroxy-exo-brevicomin ent-1 was synthesized from 1,2;5,6-di-O-isopropylidene-d-glucose in seven steps. The key reaction in our synthesis is the formation of bicyclic ketal 7 under acid mediated acetal exchange of a 1,2-acetonide of d-glucose derivative 6.

Full text of DOI:10.1016/j.tetasy.2006.02.020

Tetrahedron: Asymmetry 17 (2006) 819–821
Chiron approach for the synthesis of
(1S,2R,5R,7S)-2-hydroxy-exo-brevicominI
D. Gautam, D. Naveen Kumar and B. Venkateswara Rao*
Organic Division III, Indian Institute of Chemical Technology, Hyderabad 500007, India
Received 20 January 2006; accepted 15 February 2006
Abstract—(1S,2R,5R,7S)-2-Hydroxy-exo-brevicomin ent-1 was synthesized from 1,2;5,6-di-O-isopropylidene-D-glucose in seven steps.
The key reaction in our synthesis is the formation of bicyclic ketal 7 under acid mediated acetal exchange of a 1,2-acetonide of D-glucose
derivative 6.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
synthesized the enantiomers and/or racemates of the
following compounds: (1S,5R,7S)-B, (1R,10R,50R,70R)-D,
( )-D, ( )-E, (1R,2R,5S,7R)-F, (1R,2R,5S,7S)-G, and
( )-1. Amongst these, compound 1 is less abundant and
the absolute configuration of 1 was not determined at
that time. However, comparative NMR studies showed
that 1 could be an exo-isomer with an equatorial OH
group in the second position.2 In 1997, Mori et al.3
synthesized (1R,2S,5S,7R)-1 employing a Sharpless asym-
metric dihydroxylation protocol, and with this reference,
the absolute configuration of 1 is determined as (1R,
2S,5S,7R).
The 6,8-dioxabicyclo[3.2.1]octane skeleton is a common
structural subunit in the pheromones of a variety of bark
beetle species. Brevicomin (7-ethyl-5-methyl-6,8-dioxabi-
cyclo[3.2.1]octane) A was the first of these bicyclic acetals
identified from the frass of female western pine beetles.1
In 1996, Francke et al.2 reported the isolation and iden-
tification of several new 6,8-dioxabicyclo[3.2.1]octane
derivatives, such as B–G, and 1 (Fig. 1) as the compo-
nents of the head-space volatiles obtained from the male
mountain pine beetle, Dendroctonus ponderosae. They
O
O
O
O
O
O
O
O
O
O
A
C
E
B
D
OH
OH
H
H
OH
OH
HO
OH
H
H
O
O
O
O
O
O
O
O
ent-1
(1S,2R,5R,7S)-1
(1R,2S,5S,7R)-1
G
F
Figure 1.
q IICT Communication No. 051108.
*
Corresponding author. Tel.: +91 40 27160123x2614; fax: +91 40 27160512; e-mail: venky@iict.res.in
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.02.020

820
D. Gautam et al. / Tetrahedron: Asymmetry 17 (2006) 819–821
2. Results and discussion
3. Conclusions
As part of our ongoing research, we undertook the syn-
thesis of these hydroxy brevicomins and consequently
reported the asymmetric synthesis of (1R,10R,50R,70R)-D,
(1S,10R,50R,70R)-E using a Sharpless asymmetric dihydr-
oxylation protocol, starting from a-picoline4 and a chiron
approach for the synthesis of (1R,2R,5S,7R)-F5 and
(1R,2R,5S,7S)-G6 starting from D-mannose and D-ribose,
respectively. Herein, we report a short chiron approach
for the synthesis of ent-1.
In conclusion, we have demonstrated a short chiron ap-
proach for the synthesis of (1S,2R,5R,7S)-1 starting from
D-glucose with minimum usage of protecting groups. It
should be noted that within our scheme is the formation
of anticipated bicyclic skeleton 7 in acid hydrolysis of
1,2-acetonide of compound 6.
4. Experimental
Earlier approaches for both ( )-12 and (1R,2S,5S,7R)-13
involved organometallic reagents to construct the required
carbon skeleton for the epoxidation or asymmetric dihydr-
oxylation respectively, whereas in our approach the adja-
cent chiral hydroxy centers of ent-1 were obtained from
D-glucose (Scheme 1).
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 deter-
mined on a Fisher John’s melting point apparatus and
are uncorrected. IR spectra were recorded on a Perkin–
1
Elmer RX-1 FT-IR system. H NMR (200 MHz) spectra
As shown in Scheme 1, our synthesis commenced with re-
moval of the 5,6-O-isopropylidene group in compound 2,
which was prepared from D-glucose according to the
reported procedure,7 to give compound 3. The cleavage of
the glycol moiety in compound 3 by periodate in aqueous
methanol, followed by Wittig olefination of the resulting
1,2-O-isopropylidene-a-D-xylo-pentodialdo-1,4-furanose 4
with (2-oxopropylidene)triphenylphosphorane in DCM,
resulted in the formation of three carbon extended a,b-
unsaturated ketone 5. Hydrogenation of enone 5 in the
presence of catalytic Pd/C gave an equilibrium mixture of
were recorded on a Varian Gemini-200 MHz spectrometer.
1H NMR (300 MHz) and 13C NMR (75 MHz) spectra were
recorded on Bruker Avance-300 MHz spectrometer. Opti-
cal rotations were measured with Horiba-SEPA-300 digital
polarimeter. Accurate mass measurement was performed
on Q STAR mass spectrometer (Applied Biosystems,
USA).
4.1. (E)-5,6,8-Trideoxy-1,2-O-isopropylidene-a-D-xylo-oct-
5-eno-1,4-furanos-7-ulose 5
1
6a and 6b (in 3:7 ratio by H NMR). This mixture was
A solution of compound 2 (5 g, 19.23 mmol) in 60% aque-
ous acetic acid (75 mL) was stirred for 12 h and then con-
centrated to give 1,2-O-isopropylidene-a-D-glucofuranose
3. To a stirred solution of this crude material 3 in methanol
(60 mL) at 0 ꢁC was added an aqueous solution of sodium
periodate (4.52 g, 21.22 mmol, 15 mL). After 1 h, the mix-
ture was concentrated. To the residue was added DCM
(20 mL), and the resultant solids removed by filtration
and then washed with DCM (20 mL · 2). The combined fil-
trate and washings were concentrated to give 1,2-O-isopro-
converted to bicyclic ketal derivative 7 with TFA–water
solution (3:2) and the resultant aldehyde 7 was directly
subjected to a Wittig reaction, without any further purifica-
tion with methylidenetriphenylphosphorane to give the
corresponding olefin 8 in 30% yield from 6 (the average
yield for each step is 67%). Finally, palladium catalyzed
hydrogenation of 8 gave (1S,2R,5R,7S)-1 in 94% yield as
a colorless oil. The spectroscopic data of ent-1 is in accor-
dance with the reported values of 1.2,3
OH
OH
O
ii) aq NaIO4,
MeOH, rt, 1 h
O
i) 60% aq. AcOH
12 h, rt
iii) Ph3PCHCOCH3
DCM, rt, 2 h
CHO
OH
O
O
O
O
O
O
O
O
O
OH
OH
4
3
2
O
iv) cat. Pd/C
H2, THF, rt, 2 h
O
O
O
O
O
O
O
(98%)
O
HO
O
O
OH
OH
O
5 (68% from 2)
6b
6a
v) TFA-H2O
H
H
H
(3:2 solution)
0 oC-rt, 2 h
vi) PPh3=CH2,THF,
-10 oC-rt, 3 h
vii) cat. Pd/C
H2, MeOH, rt, 2 h
HO
HO
HO
O
O
O
O
O
O
OHC
ent-1 (94%)
8 (30% from 6)
7
Scheme 1.

D. Gautam et al. / Tetrahedron: Asymmetry 17 (2006) 819–821
821
pylidene-a-xylo-pentodialdo-l,4-furanose 4 (4 g). A solu-
tion of the crude aldehyde 4 and (2-oxopropylidene)tri-
phenylphosphorane (8.14 g, 25.60 mmol) in DCM (50 mL)
was stirred at room temperature for 2 h and then water
was added (50 mL). The aqueous layer was extracted with
DCM (50 mL · 2) and the combined organic layers dried
over Na2SO4 and concentrated. The residue was then chro-
The combined organic layer was dried over Na2SO4, con-
centrated and purified by chromatography (ethyl acetate/
hexane = 1:4) to give olefin 8 (90 mg, 30%, from compound
26:4
6) as a colorless oil. ½aꢀD ¼ ꢁ42:7 (c 0.53, CHCl3); IR mmax
(neat, cmꢁ1): 3448, 2926, 2854, 1453, 1385, 1232, 1196,
1175, 1042; 1H NMR (300 MHz, CDCl3): d 5.82 (ddd,
1H, J = 6.8, 10.5, 17.3 Hz), 5.28 (td, 1H, J = 1.5,
17.3 Hz), 5.12 (td, 1H, J = 1.5, 9.8 Hz), 4.61 (d, 1H,
J = 6.8 Hz), 3.98 (br d, 1H, J = 3.8 Hz), 3.89 (m, 1H),
1.89 (m, 1H), 1.80–1.60 (m, 3H), 1.46 (s, 3H); 13C NMR
(75 MHz, CDCl3): d 138.1, 115.8, 107.7, 82.0, 76.7, 66.2,
34.9, 26.5, 23.7; ESI-HRMS for [MꢁH]ꢁ: calcd for
C9H13O3 = 169.0864, found: 169.0861.
matographed on silica gel (ethyl acetate/hexane = 1:3)
28
to give compound 5 (3 g, 68%) as a white solid. ½aꢀD
¼
ꢁ59:8 (c 0.57, CHCl3); mp 90–92 ꢁC; IR mmax (neat,
cmꢁ1): 3450, 2928, 1637, 1377, 1218, 1165, 1076; 1H
NMR (300 MHz, CDCl3): d 6.71 (dd, 1H, J = 4.5,
15.9 Hz), 6.47 (br d, 1H, J = 15.9 Hz), 5.92 (d, 1H,
J = 3.7 Hz), 4.81 (m, 1H), 4.52 (d, 1H, J = 3.7 Hz), 4.19
(br s, 1H), 2.27 (s, 3H), 1.48 (s, 3H), 1.31 (s, 3H); 13C
NMR (75 MHz, CDCl3): d 198.1, 139.6, 132.2, 112.1,
104.8, 85.1, 79.8, 76.2, 27.8, 26.7, 26.2; ESI-MS: 229
[M+H]+; ESI-HRMS for [M+Na]+: calcd for C11H16-
O5Na = 251.0895, found: 251.0905.
4.4. (1S,2R,5R,7S)-2-Hydroxy-exo-brevicomin ent-1
The hydrogenation of 8 (40 mg, 0.23 mmol) was carried
out with catalytic amount of Pd/C (5% on carbon) in
MeOH. After being stirred for 2 h at room temperature,
the catalyst was removed by filtration. The filtrate was con-
centrated in vacuo and purified by chromatography (ethyl
acetate/hexane = 1:4) to give ent-1 (38 mg, 94%) as a color-
less oil. The GLC analysis of this compound showed 99.7%
4.2. 5,6,8-Trideoxy-1,2-O-isopropylidene-a-D-xylo-octano-1,
4-furanos-7-ulose 6a and 2,3-O-isopropylidene-5-methylper-
hydrofuro[3,2-b]pyran-5-ol 6b
25
25
purity. ½aꢀD ¼ ꢁ32:0 (c 0.6, CHCl3) {lit.3 for 1, ½aꢀD
¼
þ33:3, (c 1.94, CHCl3)}; IR mmax (neat, cmꢁ1): 3448,
Hydrogenation of compound 5 (0.85 g, 3.73 mmol) was
carried out with a catalytic amount of Pd/C (5% on car-
bon) in THF (10 mL). After being stirred for 2 h at room
temperature, the catalyst was removed by filtration. The
filtrate was concentrated in vacuo and purified by
chromatography (ethyl acetate/hexane = 1:3) to give an
inseparable mixture of 6a and 6b (0.84 g, 98%) in 3:7 ratio.
White solid, mp 68 ꢁC. 1H NMR for minor isomer 6a
(300 MHz, CDCl3): d 5.80 (d, 1H, J = 3.7 Hz), 4.48 (d,
1H, J = 3.7 Hz), 3.92 (m, 1H), 3.83 (br s, 1H), 3.05 (br s,
1H), 2.74 (ddd, 1H, J = 5.2, 6.8, 18.9 Hz), 2.55 (ddd, 1H,
J = 4.5, 8.3, 18.9 Hz), 2.18 (s, 3H), 1.56–1.47 (m, 2H),
1
2926, 1458, 1030; H NMR (200 MHz, C6D6): d 4.16 (t,
1H, J = 6.3 Hz), 3.76 (d, 1H, J = 3.8 Hz), 3.58 (m, 1H),
1.70–1.38 (m, 6H), 1.44 (s, 3H), 0.90 (t, 3H, J = 7.6 Hz),
0.76 (br s, 1H); 13C NMR (75 MHz, C6D6): d 106.8, 80.8,
77.1, 66.1, 35.1, 28.6, 26.7, 24.1, 9.8, [M+H]+; ESI-HRMS
for [M+H]+: calcd for C9H17O3 = 173.1177, found:
173.1173.
Acknowledgements
1
1.45 (s, 3H), 1.28 (s, 3H); H NMR for major isomer 6b
D.N.K. thanks the UGC and D.G. thanks the CSIR, for
financial support. The authors thank Dr. J. S. Yadav, A.
C. Kunwar and T. K. Chakraborthy, for their help and
suggestions.
(300 MHz, CDCl3): d 5.82 (d, 1H, J = 3.7 Hz), 4.41 (d,
1H, J = 3.7 Hz), 4.16–4.12 (m, 2H), 2.16–1.64 (m, 4H),
1.47 (s, 3H), 1.36 (s, 3H), 1.29 (s, 3H); ESI-HRMS for
[M+Na]+: calcd for C11H18O5Na = 253.1051, found:
253.1042.
4.3. (1S,2R,5R,7S)-exo-2-Hydroxy-5-methyl-7-vinyl-6,8-di-
oxabicyclo[3.2.1]octane 8
References
1. Silverstein, R. M.; Brownlee, R. G.; Bellas, T. E.; Wood, D. L.;
Browne, L. E. Science 1968, 159, 889–891.
2. Francke, W.; Schro¨der, F.; Philipp, P.; Meyer, H.; Sinnwell,
V.; Gries, G. Bioorg. Med. Chem. 1996, 4, 363–374.
3. Takikawa, H.; Shimbo, K.; Mori, K. Liebigs Ann./Recueil
1997, 821–824.
4. Kumar, D. N.; Rao, B. V. Tetrahedron Lett. 2004, 45, 2227–
2229.
5. Kumar, D. N.; Rao, B. V. Tetrahedron Lett. 2004, 45, 7713–
7714.
6. Kumar, D. N.; Rao, B. V.; Ramanjaneyulu, G. S. Tetrahedron:
Asymmetry 2005, 16, 1611–1614 (Corrigendum Tetrahedron:
Asymmetry 2005, 16, 2045).
7. Furniss, B. S.; Hannaford, A. J.; Smith, P. W. G.; Tatchell, A.
R. Vogel’s Textbook of Pract. Org. Chem., 5th ed.; p 654.
A solution of 6 (0.40 g, 1.74 mmol) in TFA–water (7.5 mL,
3:2) was stirred from 0 ꢁC to room temperature for 2 h
under a N2 atmosphere. The solvent was removed in vacuo
and the resultant crude aldehyde was taken up in dry
THF (10 mL) and cooled to ꢁ10 ꢁC. To the above alde-
hyde 7 was added methylidene triphenylphosphorane gen-
erated from methyl triphenylphosphonium iodide (3.50 g,
8.66 mmol) and KOtBu (0.78 g, 6.95 mmol) in THF
(50 mL). After being stirred for 3 h at room temperature,
water (15 mL) was added to the reaction mixture and
volatiles removed in vacuo. The residue was partitioned
between water (15 mL) and ethyl acetate (15 mL) and the
aqueous layer extracted with ethyl acetate (2 · 10 mL).