An improved procedure for the separation of (+) or (-)-isopinocampheol, the major side product of the oxidation workup procedure of Brown's asymmetric crotylborations

Article abstract of DOI:10.1016/j.tetlet.2007.08.075

Separation of (+) or (-)-isopinocampheol, the major side product of the oxidation workup procedure of Brown's asymmetric reactions such as crotylborations from the desired product is quite tedious and often requires repeated column chromatography. It is discovered that a sublimation process can be used to easily separate this major side product.

Full text of DOI:10.1016/j.tetlet.2007.08.075

Tetrahedron Letters 48 (2007) 7695–7697
An improved procedure for the separation of (+) or
À)-isopinocampheol, the major side product of the oxidation
workup procedure of Brown’s asymmetric crotylborations
(
Zhengmao Hua and Zhendong Jin*
Division of Medicinal and Natural Products Chemistry, College of Pharmacy, The University of Iowa,
Iowa City, IA 52242, United States
Received 17 July 2007; revised 10 August 2007; accepted 20 August 2007
Available online 24 August 2007
Abstract—Separation of (+) or (À)-isopinocampheol, the major side product of the oxidation workup procedure of Brown’s asym-
metric reactions such as crotylborations from the desired product is quite tedious and often requires repeated column chromato-
graphy. It is discovered that a sublimation process can be used to easily separate this major side product.
Ó 2007 Elsevier Ltd. All rights reserved.
Over the last two decades, asymmetric allyl- and crot-
ylborane reagents have received a great deal of attention
for their ability to create carbon–carbon bonds in a
the byproduct sometimes can be separated by column
chromatography, difficulty in the isolation and purifica-
tion is often observed when the desired product and the
1
4
highly stereodefined fashion. The asymmetric allylbora-
terpenol byproduct have similar R values.
f
tions and crotylborations developed by Brown are two
of the most popular reactions in organic chemistry2
and numerous natural products were synthesized in
In connection with a total synthesis project in our labo-
ratories, Brown’s asymmetric crotylboration was
employed to convert aldehyde 1 to homoallyl alcohol
3
recent years using these reactions.
3
, which would be protected by a TBS group (Scheme
5
During the application of Brown’s asymmetric allyl- or
crotylboration reaction, the chiral auxiliary is typically
destroyed by hydrogen peroxide oxidation and a large
quantity of terpenol byproduct is produced. Although
1). Although the reaction provided the desired product
3 with excellent diastereoselectivity, it was very tedious
to isolate and purify compound 3 in the presence of
boron-containing side products. We first tried the
Me OPMB
Me
Me OPMB
Me
OPMB
)2
B
+
OHC Me
OH
OTBS
1
2
3
4
oxidation workup 3 M NaOH
procedure
30% H O
column chromatography 62% for 2 steps
2
2
1
. sublimation
Me OPMB
Me OPMB
OH
85% of 5 was removed
OTBS
Me +
+
Me
OTBS
2. TBSOTf, NEt3
OH
3
5
6
7
Scheme 1.
*
0
Corresponding author. Tel.: +1 319 353 5359; fax: +1 319 335 8766; e-mail: zhendong-jin@uiowa.edu
040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.08.075

7696
Z. Hua, Z. Jin / Tetrahedron Letters 48 (2007) 7695–7697
ethanolamine workup procedure,2d but we found that it
was impossible to completely filter off the ethanolamine
adduct, and repeated column chromatography was
needed, which resulted in lower yield of compound 3.
face of the dry-ice condenser, no dry-ice or ice was
added to the condenser, and air-cooling was used. It
was interesting to note that placing a piece of parafilm
between the joints of the condenser and the round-bot-
tom-flask significantly speeded up the sublimation pro-
cess. With this setup, the side product 5 underwent
quick sublimation and crystallized on the surface of
the condenser as beautiful white needles. This procedure
worked very well with large scale, and more than 85% of
the side product 5 was removed. The remaining mixture
(containing about 15% of compound 5) reacted with
TBS triflate, and compound 4 was easily separated from
compound 7 by flash column chromatography (only
once).
2
a
We then employed the oxidation procedure
by
quenching the reaction with 3 M NaOH solution
followed by the addition of 30% H O . However, we
2
2
found that it was very hard to separate compound 3
from the major side product of this procedure, (À)-iso-
pinocampheol 5 by silica gel column chromatography
because they had very close R values on the TLC in
f
various solvent systems. This prompted us to search
for a better method to separate compound 3 from
compound 5.
During the evaporation of the solvent of the crude reac-
tion mixture after the oxidation workup, some white
crystals of compound 5 were found inside the anti-splash
adapter on the rotary evaporator. This observation sug-
gested that isopinocampheol could undergo sublimation
on heating. Therefore, we decided to investigate the pos-
sibility to separate the major side product 5 by the means
of sublimation.
After successfully separating (À)-isopinocampheol 5 via
sublimation, the same procedure was applied to separate
(+)-isopinocampheol 12 from another Brown’s asym-
metric crotylboration as shown (Scheme 2). It also
worked very well, and 70% yield of the desired product
5
10 was isolated.
In summary, we discovered that sublimation is a very
efficient method for the separation of (+) or (À)-iso-
pinocampheol, the major side product of the oxidation
workup procedure of Brown’s asymmetric crotylbora-
tions. In addition, it should be pointed out that this
method is not just limited to Brown’s asymmetric crot-
ylborations. Side product (+) or (À)-isopinocampheol
We found that the sublimation was quite slow when the
crude mixture was heated at 65 °C. The sublimation was
still slow with the combination of heating and reduced
pressure via a vacuum pump. However, the sublimation
was much faster when the crude mixture was heated at
6
6
5 °C under reduced pressure via a water aspirator. A
that is generated in Brown’s other asymmetric reactions
dry-ice condenser was placed on top of a round-bottom
flask as the cooling trap (Fig. 1). To fully utilize the sur-
can also be separated employing this procedure.
The following is our detailed experimental procedure:
After the completion of the reaction, the reaction mix-
ture was treated with 3 M NaOH solution and 30%
H O . Then the mixture was heated at reflux to ensure
2
2
the complete cleavage of borane. Once the oxidation
was complete, the mixture was extracted with CH Cl ,
2
2
Water aspirator
washed with brine, dried over anhydrous Na SO , and
2
4
concentrated by rotary evaporation.
A piece of parafilm was
inserted between the
joints
The crude mixture was placed in a 250 mL round-bot-
tom flask with a 24/40 joint. A dry-ice condenser with
24/40 joint was placed on top of the flask as shown in
Figure 1. A magnetic stirring bar was placed inside the
flask to stir the crude mixture. It is important to place
a small piece of parafilm between the joints to ensure
efficient sublimation. The condenser was connected to
Figure 1. Sublimation apparatus in our procedure.
Me OPMB
Me Me OPMB
Me
Me Me OPMB
Me
)2
B
3M NaOH
30% H O
2
OH
+
+
OHC
Me
OTBS
2
+
OH OTBS
OH OTBS
8
9
10
11
12
1
. sublimation
8
5% of 12 was removed
2. column chromatography
Me Me OPMB
Me Me OPMB
+
Me
Me
OH OTBS
11 11%
OH OTBS
1
0 70%
Scheme 2.

Z. Hua, Z. Jin / Tetrahedron Letters 48 (2007) 7695–7697
7697
a water aspirator and the round-bottom flask was
heated in an oil bath at 65 °C.
2. (a) Brown, H. C.; Jadhav, P. K. J. Am. Chem. Soc. 1983,
1
05, 2092; (b) Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc.
986, 108, 293; (c) Brown, H. C.; Bhat, K. S. J. Am. Chem.
1
Soc. 1986, 108, 5919; (d) Brown, H. C.; Bhat, K. S. J. Org.
Chem. 1989, 54, 1570.
After the white crystal accumulated, the condenser was
removed and washed with acetone to clean out com-
pound 5. Then the condenser was placed on the flask
again and the process was repeated until the sublimation
stopped. About 85% of (+) or (À)-isopinocampheol can
be removed from the mixture by employing this
procedure.
3
. Some published applications of Brown’s asymmetric allyl-
boranate or crotylboronate reagent in total syntheses of
natural products: (a) Ooi, H.; Ishibashi, N.; Iwabuchi, Y.;
Iahihara, J.; Hatakeyama, S. J. Org. Chem. 2004, 69,
7765; (b) Anderson, O. P.; Barrett, G. M.; Edmunds,
J. J.; Hachiya, S-I.; Hendrix, J. A.; Horita, K.; Malecha,
J. W.; Parkinson, C. J.; VanSickle, A. Can. J. Chem. 2001,
7
9, 1562; (c) Crimmins, M. T.; Emmitte, K. A. J. Am.
Acknowledgment
Chem. Soc. 2001, 123, 1533; (d) Nicolaou, K. C.;
Murphy, F.; Barluenga, S.; Ohshima, T.; Wei, H.; Xu, J.;
Gray, D. L. F.; Baudoin, O. J. Am. Chem. Soc. 2000, 122,
This work was supported by a Research Project Grant
RPG-00-030-01-CDD from the American Cancer
Society.
3
830; (e) Nicolaou, K. C.; He, Y.; Vourloumis, D.;
Vallberg, H.; Roschangar, F.; Sarabia, F.; Ninkovic, S.;
Yang, Z.; Trujillo, J. I. J. Am. Chem. Soc. 1997, 119,
7
960.
References and notes
4
5
6
. Brown, H. C.; Racherla, U. S.; Liao, Y.; Khanna, V. V. J.
Org. Chem. 1992, 57, 6608.
. Yu, W.; Zhang, Y.; Jin, Z. Org. Lett. 2001, 3,
1
. (a) Ramachandran, P. V.; Brown, H. C. Recent advances in
borane chemistry. In Organoboranes for Syntheses, ACS
Symposium Series, 2001, 783, pp 1–15; (b) Roush, W. R. In
Comprehensive Organic Synthesis; Heathcock, C. H., Ed.;
Pergamon Press: Oxford, 1991; Vol. 2, pp 1–53.
1
447.
. Brown, H. C.; Ramachandran, P. V. Pure Appl. Chem.
991, 63, 307.
1