Organoboranes for synthesis. 16. A convenient synthesis of enantiomerically pure isopinocampheylamine, a chiral derivatizing agent for gas chromatographic analysis of optically active carboxylic acids

Article abstract of DOI:10.1021/jo9512158

Both isomers of enantiomerically pure isopinocampheylamine (1) have been synthesized from the corresponding B-chlorodiisopinocampheylborane by treatment with either methylmagnesium bromide or trimethylaluminum to form B-methyldiisopinocampheylborane, followed by treatment of the intermediate with hydroxylamine-O-sulfonic acid. Application of 1 as a derivatizing agent for the gas chromatographic analysis of optically active carboxylic acids has been demonstrated.

Full text of DOI:10.1021/jo9512158

J . Org. Chem. 1996, 61, 341-345
341
Or ga n obor a n es for Syn th esis. 16. A Con ven ien t Syn th esis of
En a n tiom er ica lly P u r e Isop in oca m p h eyla m in e, a Ch ir a l
Der iva tizin g Agen t for Ga s Ch r om a togr a p h ic An a lysis of Op tica lly
Active Ca r boxylic Acid s
P. Veeraraghavan Ramachandran, Milind V. Rangaishenvi,1a Bakthan Singaram,1b
Christian T. Goralski,1c and Herbert C. Brown*
H. C. Brown and R. B. Wetherill Laboratories of Chemistry, Purdue University,
West Lafayette, Indiana 47907
Received J uly 6, 1995X
Both isomers of enantiomerically pure isopinocampheylamine (1) have been synthesized from the
corresponding B-chlorodiisopinocampheylborane by treatment with either methylmagnesium
bromide or trimethylaluminum to form B-methyldiisopinocampheylborane, followed by treatment
of the intermediate with hydroxylamine-O-sulfonic acid. Application of 1 as a derivatizing agent
for the gas chromatographic analysis of optically active carboxylic acids has been demonstrated.
In tr od u ction
encouraged several groups to utilize pinane-based struc-
tures as chiral auxiliaries for asymmetric synthesis.11 On
this basis we believed that isopinocampheylamine (1)
might also find valuable applications for asymmetric
organic synthesis. However, since its original synthesis
some three decades ago,12 no such applications have been
described. The lack of interest in 1 could be due to the
relatively poor yields and inefficient aminating process
utilized in the original synthesis.
The Thalidomide tragedy2 and the new regulations of
the U.S. Food and Drug Administration3 stimulated the
development of asymmetric synthetic methodologies.
Enantiomerically pure primary amines have also received
their share of attention in asymmetric synthesis.4 Tra-
ditionally enantiopure primary amines have been used
for the resolution of racemic carboxylic acids.5 However,
recently they have been utilized as chiral auxiliaries for
the synthesis of optically active molecules. For example,
Sugasawa and Toyoda carried out asymmetric aldol
condensations via chiral vinylaminodichloroboranes.6 Ki-
tamoto and co-workers achieved the synthesis of optically
active 2-alkylcycloalkanones via chiral lithio enamines.7
Bertz and co-workers lithiated chiral amines to prepare
chiral amidocuprates for use in the synthesis of alkyl
cycloalkanones.8 Yamaguchi and co-workers achieved an
asymmetric addition of thiols to diene polymers in the
presence of optically active amines as catalysts.9 Fiorini
and Giongo used chiral aminophosphine-rhodium com-
plexes to catalyze the asymmetric hydrogenation of
olefins.10
The laboratory synthesis of optically pure amines often
involved kinetic resolution13 or synthesis from readily
available optically active precursors.14 Recently, we had
made a systematic study of the conversion of organobo-
ranes to primary amines which identified chloramine and
hydroxylamine-O-sulfonic acid (HSA) as reagents of
choice for achieving such aminations (eqs 1 and 2).15
However, the yields in the reaction were relatively low
and the migratory aptitudes of the alkyl groups posed
problems.
(1)
Our success in asymmetric syntheses via chiral orga-
noboranes based on the superchiral auxiliary R-pinene
(2)
X Abstract published in Advance ACS Abstracts, December 15, 1995.
(1) (a) Current address: Astra Research Center India, Malleswaram,
Bangalore 560 003, India. (b) Current address: Department of Chem-
istry and Biochemistry, University of California at Santa Cruz, Santa
Cruz, CA 90564. (c) Current address: Pharmaceuticals Process
Research, The Dow Chemical Co., Midland, MI 48674.
(2) Thalidomide is a tragic example of one optical isomer being a
safe drug, whereas the other is a potent mutagen. Phocomelia, a
teratogenic effect characterized by the absence of arms and legs, is
ascribed exclusively to the S-isomer. Blaschke, G.; Kraft, H. P.;
Fickentscher, K.; Koehler, F. Arzneim.-Forsch. 1979, 29, 1640.
(3) Stinson, S. C. Chem. Eng. News 1992, 70(39), 46.
We then studied the possibilities for a more effective
utilization of the alkyl groups attached to boron and
discovered that while monoalkylboronic acid derivatives
are essentially inert to HSA, dialkylborinates react
readily with the aminating agent.16 This methodology
became more useful by choosing a nonmigrating blocking
group, such as a methyl group, to transfer the alkyl group
preferentially from boron to nitrogen to provide the
desired amine (eq 3).16
(4) The wide use of a chiral amine, for example R-methylbenzy-
lamine, is evident from the large number of references in the literature.
A
CAS ONLINE (American Chemical Society) search for (S)-R-
(11) Brown, H. C.; Ramachandran, P. V. J . Organomet. Chem. 1995,
500, 1.
(12) (a) Brown, H. C.; Heydkamp, W. R.; Breuer, E.; Murphy, W. S.
J . Am. Chem. Soc. 1964, 86, 3365. (b) Rathke, M. W.; Inoue, N.; Varma,
K. R.; Brown, H. C. Ibid. 1966, 88, 2870.
(13) (a) Thome, L. G. Chem. Ber. 1903, 36, 582. (b) Holm, R. H.;
Chakravorty, A.; Dudek, G. O. J . Am. Chem. Soc. 1964, 86, 379.
(14) (a) Santaniello, E.; Casati, R.; Milani, F. J . Chem. Soc., Perkin
Trans. 1 1985, 919.
methylbenzylamine (Registry No. 2627-86-3) showed ∼1500 references
and (R)-R-methylbenzylamine (Registry No. 3886-69-9) showed ∼1300
references.
(5) Bussche-Hu¨nnefeld, C. v. d.; Cescato, C.; Seebach, D. Chem. Ber.
1992, 125, 2795.
(6) Sugasawa, T.; Toyoda, T. Tetrahedron Lett. 1979, 1423.
(7) Kitamoto, M.; Hiroi, K.; Terashima, S.; Yamada, S. Chem.
Pharm. Bull. 1974, 22, 459.
(8) Bertz, S. H.; Dabbagh, G.; Sundararajan, G. J . Org. Chem. 1986,
51, 4953.
(9) Yamaguchi, K.; Yamada, N.; Minoura, Y. Polymer 1973, 14, 427.
(10) Fiorini, M.; Giongo, G. M. J . Mol. Catal. 1979, 5, 303.
(15) Brown, H. C.; Kim, K. W.; Srebnik, M.; Singaram, B. Tetrahe-
dron 1987, 43, 4071.
(16) Brown, H. C.; Kim, K. W.; Cole, T. E.; Singaram, B. J . Am.
Chem. Soc. 1986, 108, 6761.
0022-3263/96/1961-0341$12.00/0 © 1996 American Chemical Society

342 J . Org. Chem., Vol. 61, No. 1, 1996
Ramachandran et al.
(3)
(7)
Asymmetric organoboranes are converted to the cor-
responding primary amines with complete retention of
configuration.16 As part of our program on chiral syn-
theses via organoboranes, we undertook to improve the
synthesis to obtain 1 in high yield. The modifications
that achieved isolated yields of 96% and the application
of 1 as a chiral derivatizing agent for the gas chromato-
graphic analysis of optically active acids are described
below.
A molar equivalent of methylaluminum dichloride or
dimethylaluminum chloride can also be used for transfer
of the methyl group with equal efficiency (eq 8). The
diisopinocampheylmethylborane was decanted from the
inorganic salts and used without further purification for
the preparation of 1.
Resu lts a n d Discu ssion
Our original synthesis of 1 involved the treatment of
diisopinocampheylborane and HSA in refluxing diglyme
(eq 4). The yield is 45% on the basis of the two
isopinocampheyl groups in Ipc2BH.
(8)
Isop in oca m p h eyla m in e. Having achieved the syn-
thesis of 2 in essentially quantitative yield, we reinves-
tigated the procedure for the preparation of 1 via the
amination reaction using HSA. Using the reported
procedure,16 the amination was performed in tetrahy-
drofuran (THF) at room temperature (rt) using 2 equiv
of HSA (eq 9). After the reaction was over (∼8 h), ethyl
ether (EE) and water were added to the mixture, and the
aqueous layer was separated. Treatment with alkali and
workup furnished (-)-1 in around 50% isolated yield (on
the basis of 2 Ipc groups).
(4)
Our improved synthesis produced a 72% yield of 1
starting with monoisopinocampheylborane (IpcBH2) (eq
5). Considering that the synthesis of IpcBH2 begins with
2 equiv of R-pinene, the yield based on the R-pinene
utilized was not yet satisfactory.
(9)
(5)
As a first modification, THF was removed before the
addition of EE-H2O. This procedure improves the yield
of 1 to 67%. However, a considerable amount of pot
residue remained after distillation. The 11B NMR spec-
trum of this residue dissolved in CDCl3 shows two peaks,
a singlet at δ 31 probably corresponding to MeB(OH)2
and another singlet at δ 0.1 presumably due to a
borazene type of derivative formed by the reaction of
MeB(OH)2 and 1. Attempts to avoid the formation of the
borazene by treatment of the reaction mixture with
aqueous 6 N HCl during the workup did not improve the
yield. Thus, in our second modification, we substituted
THF with EE and treated the mixture with 6 N HCl,
followed by the usual workup. Distillation provided (-)-1
in 70% isolated yield with a large amount of the same
viscous pot residue (eq 10).
B-Meth yld iisop in oca m p h eylbor a n e. On the basis
of our previous experience,15 we designed an improved
synthesis of 1 from B-methyldiisopinocampheylborane
(2), which in turn can be readily prepared from com-
mercially available B-chlorodiisopinocampheylborane (Ipc2-
BCl; Aldrich, DIP-Chloride, 3) of g99% ee.17 Treatment
of 3 with methylmagnesium bromide provides 2 in 94%
yield (eq 6).
(6)
An essentially quantitative yield of 2 is achieved by
using trimethylaluminum for the transfer of the methyl
group to the boron atom of 3. The reaction of 3 with 0.33
equiv of a solution of the aluminum reagent in hexane
provides a 99% yield of 2 (eq 7), which can be used
without further purification for the preparation of 1.
(10)
However, utilization of a mixture of methanol and 12
N HCl improves the yield considerably. Treatment of the
above residue with such methanolic HCl, followed by
extraction with EE, gave a solution whose 11B NMR
(17) Brown, H. C.; Chandrasekharan, J .; Ramachandran, P. V. J .
Am. Chem. Soc. 1988, 110, 1539. DIP-Chloride is a trademark of the
Aldrich Chemical Co.

Organoboranes for Synthesis
J . Org. Chem., Vol. 61, No. 1, 1996 343
Ta ble 1. Colu m n Tem p er a tu r es a n d Reten tion Tim es for th e Sep a r a tion of Isop in oca m p h eyla m id es Usin g Differ en t
Ca p illa r y Colu m n s
Supelcowaxa
tR (min)
SPB-5b
tR (min)
methylsiliconec
tR (min)
temp,
°C
temp,
°C
temp,
acid
t1
t2
t1
t2
°C
t1
t2
(()-R-methoxyphenylacetic acid
(()-2-phenylbutyric acid
165
165
170
135
130
165
80.96
66.63
295.80
65.08
230.00
40.22
85.88
69.49
304.70
66.20
237.84
41.39
180
180
67.32
93.84
no separation
168.15
175.86
52.42
69.45
95.20
180
180
67.60
62.13
69.61
62.99
(()-mandelic acid
(()-tetrahydro-2-furoic acid
(()-N-trifluoroacetylproline
(()-methoxy(trifluoromethyl)phenylacetic acid
130
140
180
171.18
180.07
53.48
a
b
Column inlet pressure, 6 psi; linear flow rate, 20 cm/min; split ratio, 100:1. Column inlet pressure, 26 psi; linear flow rate, 20
cm/min; split ratio, 100:1. c Column inlet pressure, 14 psi; linear flow rate, 20 cm/min; split ratio, 100:1.
spectrum reveals only a sharp singlet at δ 32, probably
due to MeB(OMe)2. The aqueous layer, upon saponifica-
tion followed by fractional distillation furnishes an ad-
ditional 17% yield of (-)-1, without any pot residue.
Thus, a total yield of 87% is realized. Application of this
modificationsthe addition of MeOH-HCl-H2O to the
reaction mixture after the removal of THFsearly in the
workup improves the isolated yield of (-)-1 to 96% (eq
11).
(11)
As with the majority of transfer reactions of organobo-
ranes which proceed with complete stereochemical in-
F igu r e 1. Gas chromatogram of diastereomeric N-
tegrity, this amination reaction provides 1 without loss
(1R,2S,3R,5R)-(-)-3-isopinocampheyl-R-methoxyphenylacet-
of optical activity. Gas chromatographic analysis of its
amides on a methylsilicone (50 m) column at 180 °C.
methoxy(trifluoromethyl)phenylacetamide (MTPA amide)
on a 15 m Supelcowax column reveals an ee of g99%.
Following the same sequence of reactions, (+)-1 is
prepared from (+)-DIP-Chloride derived from (-)-R-
pinene.
(12)
Ch ir a l Der iva tiza tion of Op tica lly Active Ca r -
boxylic Acid s. Having achieved an excellent synthesis
of 1, we tested the utility of this pinane-based chiral
amine as a derivatizing agent for the separation of
racemic carboxylic acids on a gas chromatograph using
a capillary column. (()-R-Methoxyphenylacetic acid, (()-
Con clu sion s
2-phenylbutyric acid, (()-mandelic acid, (()-tetrahydro-
2-furoic acid, (()-methoxy(trifluoromethyl)phenylacetic
In conclusion, we have developed a modified synthesis
acid, and (()-N-(trifluoroacetyl)proline were chosen as
of B-methyldiisopinocampheylborane and an improved
representative examples for this study. Capillary col-
workup procedure for obtaining isopinocampheylamine
umns of different polarities, such as Supelcowax,18a SPB-
in essentially quantitative yield. Application of 1 for the
5,18a or methylsilicone18b were used for the analysis to
preparation of diastereomeric pairs of amides of racemic
show the generality of this procedure. The acids were
carboxylic acids for determining their enantiomeric purity
activated with 1,1'-carbonyldiimidazole (CDI)19 and treated
using capillary gas chromatography has been demon-
with 1 in THF to provide the corresponding amides (eq
strated. Our earlier studies of the hydroboration of a
12). Analyses of the THF solution of the diastereomeric
number of terpenes, such as 2-20a and 3-carene,20b
amides using the above columns showed a 1:1 cor-
respondence with excellent resolution. All of the six
amides tested were separated on the Supelcowax column
sabinene,20c thujene,20c R- and â-cedrene,20d thujopsene,20e
and limonene,20f suggest that there should not be any
significant difficulty in extending this development to the
whereas the non-polar SPB-5 column separated only five
syntheses of other terpene-based chiral amines. The
amides. The details of the gas chromatographic analyses
are presented in Table 1. Figure 1 shows the chromato-
(20) (a) Acharya, S. P.; Brown, H. C. J . Am. Chem. Soc. 1967, 89,
1925. (b) Brown, H. C.; Suzuki, A. J . Am. Chem. Soc. 1967, 89, 1933.
(c) Acharya, S. P.; Brown, H. C.; Suzuki, A.; Nozawa, S.; Itoh, M. J .
Org. Chem. 1969, 34, 3015. (d) Acharya, S. P.; Brown, H. C. J . Org.
gram of N-isopinocampheyl-R-methoxyphenylacetamide
using a methylsilicone column.
(18) Suplecowax and SPB-5 are trademarks of Supelco. (b) The
methylsilicone column was purchased from Hewlett-Packard.
(19) Paul, R.; Anderson, G. W. J . Org. Chem. 1962, 27, 2094.
Chem. 1970, 35, 196. (e) Acharya, S. P.; Brown, H. C. J . Org. Chem.
1970, 35, 3874. (f) Brown, H. C.; Pfaffenberger, C. D. Tetrahedron 1975,
31, 625.

344 J . Org. Chem., Vol. 61, No. 1, 1996
Ramachandran et al.
perature was controlled by the slow addition of HSA. The
mixture was stirred at rt until the initial slurry became a clear
solution (2 h). The 11B NMR spectrum of an aliquot showed a
singlet at δ 10 which shifted to a sharp singlet at δ 31 upon
methanolysis, indicating completion of the reaction. Solvent
THF was pumped off under aspirator. (It is important to pump
off THF.) The white viscous mass was suspended in EE (10
mL) followed by the addition of water (10 mL). The acidic
aqueous layer was separated, cooled to 0 °C, and layered with
EE (20 mL). It was then made strongly alkaline by the
addition of solid sodium hydroxide (40 mmol) with stirring.
The organic phase was separated, and the aqueous layer was
extracted with EE (10 mL). The combined organic phase was
dried over Na2SO4, concentrated, and distilled at 94-96 °C/
16 mmHg to obtain 2.06 g (13.4 mmol, 67% on the basis of the
migration of two Ipc groups during amination reaction) of (-)-1
syntheses of several of these chiral amines are in
progress.
Exp er im en ta l Section
Gen er a l Meth od s. Techniques for handling air-sensitive
compounds have been previously described.21 Analyses of the
N-isopinocampheylamides were performed on
a Hewlett-
Packard 5890A gas chromatograph (GC) using a Supelcowax
(15 m), a SPB-5 (30 m), or a methylsilicone capillary column
(50 m), at appropriate temperatures.
Mater ials. Anhydrous ethyl ether purchased from Mallinck-
rodt, Inc., was used as received. THF was distilled from
sodium benzophenone ketyl. (+)- and (-)-DIP-Chloride, me-
thylmagnesium bromide, trimethylaluminum, methylalumi-
num dichloride, hydroxylamine-O-sulfonic acid, 1,1′-carbon-
yldiimidazole (CDI), and all of the carboxylic acids were
obtained from Aldrich Chemical Co.
1
whose structure was ascertained by H NMR.
A substantial amount of pot residue remained after distil-
lation.
P r epar ation of B-Meth yldiisopin ocam ph eylbor an e (2).
(a ) Usin g Meth ylm a gn esiu m Br om id e. Methylmagnesium
bromide (24.2 mmol, 8.07 mL of 3 M solution in EE) was added,
dropwise, to a stirred solution of Ipc2BCl (7.76 g, 24.20 mmol)
in EE (40 mL) maintained at 0 °C in a 250 mL round-bottom
flask. The reaction mixture was stirred at 0 °C for 0.5 h,
warmed to rt, and stirred for an additional 15 min. A white
precipitate of MgClBr separated, and the 11B NMR spectrum
of an aliquot of the supernatant showed a singlet at δ 81
corresponding to a trialkylborane. Anhydrous n-pentane (10
mL) was added to the reaction mixture to ensure the complete
precipitation of MgClBr. The organic portion was transferred
to another flask by means of a cannula. The precipitate was
washed with n-pentane (2 × 10 mL), and the combined organic
portion was washed with saturated ammonium chloride solu-
tion (20 mL) and dried over MgSO4. Removal of the volatiles
furnished 6.89 g of air-sensitive and pyrophoric 2 as a thick
syrup.
(b) Usin g Tr im eth yla lu m in u m . Trimethylaluminum (9.8
mL of 2 M solution in hexane, 19.54 mmol) was added,
dropwise, to a stirred solution of Ipc2BCl (18.80 g, 58.63 mmol)
in n-pentane (51 mL) at 0 °C. The reaction is mildly exother-
mic, and the temperature was controlled by the slow addition
of Me3Al. Upon addition of Me3Al, the colorless reaction
mixture became pale yellow and a brown viscous mass
(presumably AlCl3) precipitated out of the hexane-pentane
mixture. The reaction mixture was warmed to rt and allowed
to stir for 0.5 h. The 11B NMR spectrum of an aliquot of the
supernatant showed the total disappearance of Ipc2BCl (δ 74)
and the formation of Ipc2BMe (δ 81). The hexane-pentane
mixture was separated by means of a cannula, washed with
saturated NH4Cl solution (20 mL) under nitrogen, and dried
over MgSO4. Upon washing with NH4Cl solution, the pale
yellow solution became colorless. Removal of the volatiles
furnished 17.39 g (57.96 mmol, 98%) of 2.
P r oced u r e b: Mod ified Am in a tion Rea ction Usin g 6
N HCl-EE. Under nitrogen, hydroxylamine-O-sulfonic acid
(5.75 g, 50.82 mmol) was added using a solid addition tube to
a solution of 2 (7.26 g, 24.20 mmol) in THF (25 mL). The
reaction was exothermic, and the temperature of the reaction
mixture was controlled by slow addition of HSA. The reaction
mixture was allowed to stir at rt for 2 h during which period
the initial slurry became a clear solution. The completion of
the reaction was confirmed by 11B NMR spectroscopy, and the
solvent was removed under aspirator. The viscous residue was
treated with 6 N HCl (9 mL), and 25 mL of EE was added.
The acidic aqueous layer was separated, cooled to 0 °C, and
layered with EE (30 mL). It was then made strongly alkaline
by adding solid NaOH with stirring. The organic phase was
separated, and the aqueous layer was extracted with EE (3 ×
25 mL). The combined organic phase was dried over Na2SO4,
concentrated, and distilled to provide 5.18 g (33.88 mmol, 70%)
of (-)-1, bp 94-96 °C/16 mm.
The 11B NMR spectrum of the residue dissolved in CDCl3
showed two major peaks at δ -0.1 and 31. This residue was
treated with MeOH (2 mL), concd HCl (3 mL), and water (2
mL) and stirred at rt for 0.5 h. The organics were extracted
with EE (10 mL). The 11B NMR spectrum of the organic
portion showed a singlet at δ 31 attributed to the presence of
a RB(OMe)2 species. The acidic aqueous layer was separated,
layered with EE (10 mL), and cooled to 0 °C. This was made
strongly alkaline by adding solid NaOH. The organic portion
was separated, and the aqueous layer was extracted with EE
(2 × 10 mL). The combined organic portion was dried over
MgSO4, concentrated, and distilled in vacuo to furnish 1.3 g
of (-)-1 (8.02 mmol, 16.6%), bp 94-96 °C/16 mmHg. There
was no pot residue remaining after distillation. The total yield
of (-)-1 is 6.48 g (41.90 mmol, 86.6%).
(c) Usin g Meth yla lu m in u m Dich lor id e. The prepara-
tion of 2 was carried out by using a similar procedure as
described above, substituting methylaluminum dichloride for
trimethylaluminum. Methylaluminum dichloride (8.2 mL of
1 M solution in hexane, 8.2 mmol) was added, dropwise, to a
stirred solution of Ipc2BCl (2.625 g, 8.18 mmol) in n-pentane
(8 mL) at 0 °C. The reaction was mildly exothermic, and the
temperature was controlled by the slow addition of MeAlCl2
solution. Upon addition of MeAlCl2, the reaction mixture
changed from colorless to pale yellow and a brown viscous
mass precipitated out (AlCl3). The organic portion was
separated, washed with saturated NH4Cl solution under
nitrogen, dried over MgSO4, and concentrated to obtain 2.42
g (8.07 mmol, 98%) of 2. 11B NMR (CDCl3) ) δ 81.
P r oced u r e c: Recom m en d ed Mod ified P r oced u r e Us-
in g Meth a n olic HCl. Hydroxylamine-O-sulfonic acid (13.77
g, 121.8 mmol, 2.1 equiv) was added slowly using a solid
addition tube to 17.39 g (57.96 mmol) of 2 dissolved in freshly
distilled THF (58 mL). The temperature of the reaction was
controlled by the slow addition of HSA. The reaction mixture
was stirred at rt until the initial slurry became a clear solution
(2 h). The completion of the reaction was ascertained by 11B
NMR spectroscopy, and the solvent was pumped off in vacuo
(20 mm). The residual viscous mass was treated with metha-
nol (5 mL), concd HCl (13 mL), and water (10 mL), and to this
mixture was added 60 mL of EE. The reaction mixture was
allowed to stir at 25 °C for 0.5 h. The 11B NMR spectrum of
the organic portion showed a sharp singlet at δ 32 [Me-
B(OMe)2]. The acidic aqueous layer was separated, cooled to
0 °C, and layered with EE (40 mL). It was then made strongly
alkaline by adding solid NaOH with stirring. The EE layer
was separated, and the aqueous layer was extracted with EE
(3 × 40 mL), combined, dried over Na2SO4, concentrated, and
distilled to furnish 17.05 g (111.3 mmol, 96%) of (-)-1, bp 91-
P r ep a r a t ion of (1R,2S,3R,5R)-(-)-Isop in oca m p h ey-
la m in e. P r oced u r e a . Hydroxylamine-O-sulfonic acid (2.37
g, 21 mmol) was slowly added at rt, using a solid addition tube,
to a solution of the above Ipc2BMe (3.0 g, 10 mmol) in THF
(10 mL). The reaction was mildly exothermic, and the tem-
(21) Brown, H. C.; Kramer, G. W.; Levy, A. B.; Midland, M. M.
Organic Syntheses via Boranes; Wiley-Interscience: New York, 1975;
Chapter 9.
92 °C/16 mmHg: [R]23 of (-)-1‚HCl ) -23.68° (c 4, MeOH),
D
mp >250 °C.

Organoboranes for Synthesis
J . Org. Chem., Vol. 61, No. 1, 1996 345
The MTPA amide of this amine was prepared and analyzed
on a Supelcowax glass capillary column (15 m) using a gas
chromatograph (180 °C, isothermal) which showed an ee of
g99%.
h. (In those cases where the acid is a solid, the acid (0.1 mmol)
and CDI (0.1 mmol) were weighed into a vial and dissolved in
3 mL of THF, followed by the addition of (-)-1.) Then 1 µL of
the THF solution of the resulting diastereomeric amides was
injected directly into a gas chromatograph fitted with an
appropriate capillary column maintained isothermally at the
required temperature. The diastereomeric amides revealed a
1:1 correspondence with the corresponding retention times.
The details of the GC analyses are presented in Table 1.
P r ep a r a t ion of (1S,2R,3S,5S)-(+)-Isop in oca m p h ey-
la m in e [(+)-1]. Using procedure c, 6.55 g (96%) of (+)-1 was
prepared from 6.68 g (22.28 mmol) of (+)-Ipc2BMe that was
obtained from 7.24 g (22.63 mmol) of (+)-DIP-Chloride and
7.54 mmol of trimethylaluminum, bp 94-96 °C/16 mmHg:
[R]23 of (+)-1‚HCl ) +23.64° (c 4, MeOH), mp >250 °C.
D
P r ep a r a tion of Ra cem ic N-(1R,2S,3R,5R)-Isop in oca m -
p h eyla m id es. Gen er a l P r oced u r e. The racemic carboxylic
acid (0.1 mmol) was added to a vial containing 0.016 g (0.1
mmol) of CDI in 3 mL of dry THF. To this solution was added
0.015 g (0.1 mmol) of (-)-1, and the solution was stirred for 1
Ack n ow led gm en t . Financial support from the
United States Army Research Office (DAAH-94-G-0313)
is gratefully acknowledged.
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