Stereoselective synthesis of (+)-(1R,2S,5S,7R)-2-hydroxy-exo-brevicomin

Article abstract of DOI:10.1016/j.tetlet.2010.06.011

A stereoselective approach for the synthesis of (+)-(1R,2S,5S,7R)-2- hydroxy-exo-brevicomin from l-ascorbic acid has been described. The key steps are highly stereoselective nucleophilic addition reaction on aldehyde 8 and also a single pot transformation of 15 to (+)-(1R,2S,5S,7R)-2-hydroxy-exo- brevicomin. The later tandem reaction which involves the hydrogenation of double bond, debenzylation, MOM deprotection and bicyclic ketal formation was carried under Pd/C, H₂ followed by acid treatment.

Full text of DOI:10.1016/j.tetlet.2010.06.011

Tetrahedron Letters 51 (2010) 4199–4201
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Stereoselective synthesis of (+)-(1R,2S,5S,7R)-2-hydroxy-exo-brevicomin
*
D. Gautam, B. Venkateswara Rao
Organic Division III, Indian Institute of Chemical Technology, Hyderabad 500 607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A stereoselective approach for the synthesis of (+)-(1R,2S,5S,7R)-2-hydroxy-exo-brevicomin from L-ascor-
Received 5 April 2010
Revised 28 May 2010
Accepted 3 June 2010
Available online 8 June 2010
bic acid has been described. The key steps are highly stereoselective nucleophilic addition reaction on
aldehyde 8 and also a single pot transformation of 15 to (+)-(1R,2S,5S,7R)-2-hydroxy-exo-brevicomin.
The later tandem reaction which involves the hydrogenation of double bond, debenzylation, MOM depro-
tection and bicyclic ketal formation was carried under Pd/C, H2 followed by acid treatment.
Ó 2010 Elsevier Ltd. All rights reserved.
The 6,8-dioxabicyclo[3.2.1]octane skeleton is a common struc-
tural subunit in the pheromones of a variety of bark beetle species.
m-CPBA epoxidation.2,4 The other approaches which used chiral
starting material were for the synthesis of unnatural antipode of
1 but not the natural isomer.3 Therefore a straightforward synthe-
sis for 1 is still to be accomplished. Nevertheless, it is interesting to
note that the 2-hydroxy-exo-brevicomins have been converted to
exo-brevicomin A by deoxygenation of its free hydroxyl group.4,2c
General features of our synthesis of (1R,2S,5S,7R)-2-hydroxy-
exo-brevicomin 1 are illustrated in the retrosynthetic format in
Scheme 1. The key reaction of our synthesis is the tandem hydro-
genation of double bond, deprotection of the protecting groups and
bicyclic ketal formation of compound 2 to give 1. Compound 2 can
be obtained from alcohol 3 by appropriate protections, deprotec-
tions to obtain primary alcohol and then oxidation and Wittig reac-
tion. Whereas, alcohol 3 can be synthesized from appropriately
Brevicomin (7-ethyl-5-methyl-6,8-dioxabicyclo[3.2.1]octane)
A
was the first of these bicyclic acetals identified from the frass of fe-
male western pine beetles.1 In 1996. Francke et al.2a reported the
isolation and identification of several new 6,8-dioxabicy-
clo[3.2.1]octane derivatives such as B-G and 1 (Fig. 1) as the com-
ponents of the head-space volatiles obtained from the male
mountain pine beetle, Dendroctonus ponderosae. They 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. Among these, compound 1 is less abun-
dant and the absolute configuration of 1 was not determined at
that time. However, comparative NMR studies showed that 1 could
be exo-isomer with equatorial OH group in second position.2a In
1997, Mori and co-workers2b synthesized (1R,2S,5S,7R)-1 employ-
ing Sharpless asymmetric dihydroxylation protocol and with this
protected aldehyde
nucleophilic addition of ethyl magnesium bromide. Compound 4
can be easily obtained from -ascorbic acid 5 (Scheme 1).
The synthesis of 1 commenced from 6 which was readily
obtained from -ascorbic acid 5 by following the literature proce-
4 by stereoselective chelation-controlled
L
reference, the absolute configuration of
1 is determined as
(1R,2S,5S,7R).
L
Brevicomins play a major role in the communication system of
the bark beetle species. With the proven importance of single
enantiomer compounds in the inhibition of pheromone response,
there has been a sustained interest in the synthesis of these pher-
omones in their enantiomerically pure form.5 As part of our ongo-
ing research we undertook the synthesis of these hydroxy
brevicomins and consequently reported the asymmetric synthesis
of (1R,10R,50R,70R)-D and (1S,10R,50R,70R)-E6 and chiron approach for
the synthesis of (1R,2R,5S,7R)-F7, (1R,2R,5S,7S)-G8 and ent-1.3a Now
herein we wish to report a highly stereoselective approach for the
synthesis of 1.
dure.9 The secondary hydroxy of 6 was protected as its MOM ether
to give compound 7. The ester functionality in compound 7 was
reduced using DIBAL-H in CH2Cl2 at ꢀ78 °C for 3 h to yield aldehyde
8. The crude aldehyde 8 on treatment with ethyl magnesium
bromide in diethyl ether at ꢀ78 °C to rt overnight gave predomi-
nantly the syn isomer (syn/anti in 18:1 by 1H NMR) (Scheme 2).
The stereoselectivity of the reaction can be explained by the
chelation-controlled addition of the nucleophile as shown in the
Figure 2.10 The two oxygen atoms of methyl oxy methyl group che-
lated with MgBr and then the nucleophile attacked from less hin-
dered side to give syn isomer as major product. These isomers
could not be separated at this stage and proceeded further with
the mixture.
In earlier approaches, 1 has been prepared as a mixture of
diastereomers utilizing the asymmetric dihydroxylation or the
asymmetric aldol reaction and as a racemic mixture utilizing the
The hydroxyl functionality in 9 was protected as its MOM ether
using MOMCl and DIPEA to give compound 10. The acetonide in 10
was deprotected selectively using PPTS in MeOH to give diol 11.
The primary hydroxyl in 11 was protected using TBDMSCl and
* Corresponding author. Tel./fax: +91 40 27193003.
E-mail addresses: venky@iict.res.in, drb.venky@gmail.com (B.V. Rao).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.06.011

4200
D. Gautam, B. V. Rao / Tetrahedron Letters 51 (2010) 4199–4201
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
(1R,2S,5S,7R)-1
G
F
(1S,2R,5R,7S)-1
Figure 1. Brevicomins and hydroxy brevicomins.
OP
H
OP
O
OH
O
O
O
O
OH
P'O
OP
1
2
3
HO
OP
O
O
HO
CHO
O
O
HO
OH
4
L
-ascorbic acid 5
Scheme 1. Retrosynthesis analysis for compound 1.
HO
HO
OH
OMOM
COOEt
O
O
b
a
COOEt
O
O
O
O
HO
OH
6
7
L-Ascorbic acid 5
OMOM
OMOM
H
c
d
O
OH
O
O
O
O
8
9
Scheme 2. Reagents and conditions: (a) (i) AcCl, acetone, rt, 3 h; (ii) H2O2, K2CO3, H2O, 0 °C to rt, 12 h; (iii) EtBr, ACN, reflux, 24 h, 85% (for three steps); (b) MOMCl, DIPEA,
CH2Cl2, ꢀ15 °C to rt, 12 h, 86%; (c) DIBAL-H, CH2Cl2, ꢀ78 °C, 3 h; (d) EtMgBr, ether, ꢀ78 °C to rt, 12 h, 60% for two steps.
imidazole in CH2Cl2 as its TBDMS ether. The major syn isomer 12
has been obtained in its pure form at this stage by column chroma-
tography. The secondary hydroxyl in 12 was protected as its benzyl
ether using benzyl bromide and NaH in THF to give compound 13.
Compound 13 on treatment with TBAF in THF gave the hydroxyl
compound 14. Compound 14 on Swern oxidation and Wittig reac-
tion gave compound 15. Compound 15 on hydrogenation with H2,
Pd/C in MeOH in the presence of aq HCl gave inseparable mixture
of compounds along with required compound 1. But, when the
compound 15 was subjected to hydrogenation with H2, Pd/C in
MeOH for 25 min initially and then treatment with aq. HCl over-
night gave exclusively the target compound 1 in 75% yield (Scheme
3). The spectroscopic data of 1 are in accordance with the reported
O
O
H
H
Nu
O
values.11
½
a 2D5
ꢁ
+30.8 (c 0.52, CHCl3) lit.2b
½
a 2D0
+33.3 (c 1.1, CHCl3).
ꢁ
Mg
Br
O
O
In conclusion we have demonstrated the synthesis of
(1R,2S,5S,7R)-2-hydroxy-exo-brevicomin in a highly stereoselec-
tive fashion starting with chiral pool starting material. The exo-
Figure 2. The chelation-controlled addition of nucleophile.

D. Gautam, B. V. Rao / Tetrahedron Letters 51 (2010) 4199–4201
4201
OMOM
OMOM
OMOM
a
b
O
O
HO
O
OMOM
O
OH
HO
OMOM
11
9
10
OMOM
OMOM
c
d
e
TBSO
TBSO
HO
OMOM
BnO
OMOM
13
12
H
OMOM
OMOM
O
g
f
OH
O
HO
O
BnO
OMOM
14
BnO
OMOM
1
15
Scheme 3. Reagents and conditions: (a) MOMCl, DIPEA, CH2Cl2, ꢀ15 °C to rt, 12 h, 88%; (b) PPTS, MeOH, rt, 24 h, 74%; (c) TBSCl, imidazole, CH2Cl2, rt, 3 h, 90%; (d) BnBr, THF,
0 °C to rt, 2 h, 77%; (e) TBAF, THF, 0 °C to rt, 2 h, 90%; (f) (i) (COCl)2, DMSO, CH2Cl2, Et3N, ꢀ78 °C 2 h; (ii) PPh3CHCOCH3, toluene, reflux, 5 h, (75% for two steps); (g) H2, 10% Pd/
C, MeOH, 25 min, then aq HCl, rt, 12 h, 75%.
7. Kumar, D. N.; Rao, B. V. Tetrahedron Lett. 2004, 45, 7713–7714.
8. Kumar, D. N.; Rao, B. V.; Ramanjaneyulu, G. S. Tetrahedron: Asymmetry 2005, 16,
brevicomin A is also accessible by this route as its synthesis from 1
is already reported. The key steps are the highly stereoselective
1611–1614 (corrigendum Tetrahedron: Asymmetry 2005, 16, 2045).
chelation-controlled nucleophilic addition on carbonyl and the
one-pot double bond reduction, debenzylation, MOM deprotection
and bicyclic ketal formation. The single pot reaction helps in min-
imizing the steps of protections and deprotections which are indis-
pensable in syntheses involving the carbohydrates as starting
material.
9. (a) Abushanab, E.; Vemishetti, P.; Leiby, R. W.; Singh, H. K.; Mikkilineni, A. B.;
Wu, D. C. J.; Saibaba, R.; Panzica, R. P. J. Org. Chem. 1988, 53, 2598; (b) Cho, B. H.;
Kim, J. H.; Jeon, H. B.; Kim, K. S. Tetrahedron 2005, 61, 4341–4346.
10. Iida, H.; Yamazaki, N.; Kibayashi, C. Tetrahedron Lett. 1985, 26, 3255–3258.
11. Physical data for selected compounds. (1S,2R/S)-1-((S)-20,20-Dimethyl-10,30-
dioxolan-40-yl)-1-(methoxymethoxy) butan-2-ol (9):
½ ꢁ ꢀ53.17 (c 2.20,
a 3D0
CHCl3); IR mmax (neat, cmꢀ1): 3464, 2936, 1459, 1376, 1153, 1035, 919, 759;
ESIMS (m/z): 257 (M+Na)+; ESI-HRMS for (M+Na)+: calcd for
(C11H22O5Na) = 257.1364, found = 257.1375; NMR data for major syn isomer of
9: 1H NMR (500 MHz, CDCl3) d: 0.99 (t, J = 7.2 Hz, 3H), 1.36 (s, 3H), 1.43 (s, 3H),
1.53–1.63 (m, 2H), 2.38 (br s, 1H). 3.41–3.50 (m, 2H), 3.43 (s, 3H) 3.80 (dd,
J = 7.2, 8.2 Hz, 1H), 4.06 (dd, J = 6.7 Hz, 8.2 Hz, 1H), 4.36 (ddd, J = 6.2, 6.7, 7.2 Hz,
1H), 4.74 (d, J = 6.7 Hz, 1H), 4.90 (d, J = 6.7 Hz, 1H); 13C NMR (75 MHz, CDCl3) d:
10.1, 25.3, 26.4, 27.0, 56.1, 66.0, 73.1, 76.8, 80.1, 97.5, 109.2.
Acknowledgements
D.G. thanks the CSIR-New Delhi for research fellowship. The
authors also thank Dr. J. S. Yadav, Dr. A. C. Kunwar and Dr. T. K.
Chakraborty for their help and encouragement. They also thank
DST (SR/SI/OC-14/2007), New Delhi, for financial assistance.
(2S,3R,4R)-1-(tert-Butyldimethylsilyloxy)-3,4-bis(methoxymethoxy)hexan-2-ol (12):
½ ꢁ
a 2D5 = 11.04 (c 0.96, CHCl3); IR mmax (neat, cmꢀ1): 3462, 2935, 1400, 1254,
1104, 1034, 840; 1H NMR (300 MHz, CDCl3) d: 0.07 (s, 6H), 0.90 (s, 9H), 0.95 (t,
J = 7.4 Hz, 3H), 1.50–1.80 (m, 2H), 2.52 (d, J = 5.7 Hz, 1H), 3.37 (s, 3H), 3.40 (s,
3H), 3.57–3.77 (m, 5H), 4.62, 4.66 (AB-q, J = 7.0 Hz, 2H), 4.71, 4.74 (AB-q,
J = 6.8 Hz, 2H); 13C NMR (75 MHz, CDCl3) d: ꢀ5.4, 9.9, 18.2, 23.5, 25.8, 55.9,
56.2, 64.2, 71.2, 78.6, 79.6, 96.5, 98.4. ESIMS (m/z): 375 (M+Na)+; ESI-HRMS for
(M+Na)+: calcd for (C16H36O6NaSi) = 375.2178, found = 375.2171.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.06.011.
(5S,6S,7R,E)-5-(Benzyloxy)-6,7-bis(methoxymethoxy)non-3-en-2-one (15): ½a D25
ꢁ
=
12.55 (c 0.8, CHCl3); IR mmax (neat, cmꢀ1): 2934, 1677, 1456, 1104, 1032, 919;
1H NMR (500 MHz, CDCl3) d: 0.91 (t, J = 7.0 Hz, 3H), 1.47–1.57 (m, 1H), 1.61–
1.71 (m, 1H), 2.26 (s, 3H), 3.34 (s, 3H), 3.35 (s, 3H), 3.51–3.56 (m, 1H), 3.63 (dd,
J = 5.0, 6.0 Hz, 1H), 4.20 (dd, J = 5.0, 6.0 Hz, 1H), 4.44 (d, J = 11.9 Hz, 1H), 4.57–
4.60 (m, 2H), 4.62 (d, J = 7.0 Hz, 1H). 4.68 (d, J = 7.0 Hz, 1H), 4.78 (d, J = 7.0 Hz,
1H), 6.26 (d, J = 15.9 Hz, 1H), 6.81 (dd, J = 6.0, 15.9 Hz, 1H), 7.21–7.38 (m, 5H);
13C NMR (75 MHz, CDCl3) d: 9.7, 23.6, 27.0, 55.8, 56.1, 71.9, 78.7, 79.3, 79.8,
96.9, 98.2, 127.8, 128.3, 131.5, 137.5, 144.1, 198.1; ESIMS (m/z): 389 (M+Na)+;
ESI-HRMS for (M+Na)+: calcd (C20H30O6Na) = 389.1940, found = 389.1925.
References and notes
1. Silverstein, R. M.; Brownlee, R. G.; Bellas, T. E.; Wood, D. L.; Browne, L. E. Science
1968, 159, 889–891.
2. (a) Francke, W.; Schröder, F.; Philipp, P.; Meyer, H.; Sinnwell, V.; Gries, G.
Bioorg. Med. Chem. 1996, 4, 363–374; (b) Takikawa, H.; Shimbo, K.; Mori, K.
Liebigs Ann./Recueil 1997, 821–824; (c) List, B.; Shabat, D.; Barbas, C. A., III;
Lerner, R. A. Chem. Eur. J. 1998, 4, 881.
3. (a) Gautam, D.; Kumar, D. N.; Rao, B. V. Tetrahedron: Asymmetry 2006, 819; (b)
Prasad, K. R.; Anbarasan, P. Tetrahedron: Asymmetry 2006, 17, 850–853.
4. Taniguchi, T.; Ohnishi, H.; Ogasawara, K. Chem. Commun. 1996, 1477–1478.
5. Mori, K. Acc. Chem. Res. 2000, 33, 102.
(1R,2S,5S,7R)-2-Hydroxy-exo-brevicomin (1): ½a D25
ꢁ
= 30.77 (c 0.52, CHCl3); IR
m
max (neat, cmꢀ1): 3443, 2922, 1452, 1030; 1H NMR (400 MHz, C6D6) d: 0.76 (br
s, 1H), 0.89 (t, J = 7.6 Hz, 3H), 1.43 (s, 3H), 1.28–1.70 (m, 6H), 3.57 (m, 1H), 3.75
(d, 1H, J = 3.5 Hz), 4.15 (t, 1H, J = 6.3 Hz); 13C NMR (75 MHz, C6D6) d: 10.0, 24.3,
27.0, 28.9, 35.4, 66.3, 77.3, 81.0, 106.9; ESIMS (m/z): 172 (M+).
6. Kumar, D. N.; Rao, B. V. Tetrahedron Lett. 2004, 45, 2227–2229.