Hydrolysis of Substituted 1,3,2-dioxaborolanes and an Asymmetric Synthesis of a Differentially Protected syn,syn-3-Methyl-2,4-hexanediol

Full text of DOI:10.1021/jo960684m

J . Org. Chem. 1996, 61, 6047-6051
6047
Sch em e 1
Hyd r olysis of Su bstitu ted
1,3,2-Dioxa bor ola n es a n d a n Asym m etr ic
Syn th esis of a Differ en tia lly P r otected
syn ,syn -3-Meth yl-2,4-h exa n ed iol
Donald S. Matteson* and Hon-Wah Man
Department of Chemistry, Washington State University,
Pullman, Washington 99164-4630
or conversion to a borinic ester,9 or, if the boronic acid
is water soluble, transesterification with phenylboronic
acid in a two-phase system.8 The method of hydrolysis
reported in this note appears to be generally useful for
boronic esters of C2-symmetrical diols but falls short of
complete hydrolysis of pinanediol esters.
Received April 15, 1996
Carbon chain extension by means of asymmetric bo-
ronic ester chemistry potentially allows free choice of the
absolute configuration of each new stereogenic carbon
introduced,1 and the method is capable of very high
stereoselectivity.2,3 Although many combinations of
configurations of two or three adjacent stereogenic cen-
ters can be achieved with a single asymmetric diol
boronic ester group as chiral director,1-3 other combina-
tions require removal of the first diol and replacement
by its enantiomer,1 or, with pinanediol esters, a double
SN2 inversion sequence.4 Accordingly, an efficient gen-
eral method for hydrolyzing a sterically hindered boronic
ester of a diol to the corresponding boronic acid and
diol would have synthetic application. Such a hydro-
lysis would also be useful for converting boronic ester
precursors to boronic acids of interest as enzyme
inhibitors.5-8
Resu lts
Syn th etic Rou te. A major goal of this work was
synthesis of 1,3-diol derivatives having the stereochem-
ical relationships of (3R,4S,5S)-5-(benzyloxy)-4-methyl-
3-hexanol (11). The precursor 10 has to be a boronic ester
of (S,S)-1,2-dicyclohexylethanediol [(S,S)-DICHED] (6S)
in order to have the correct absolute configurations at
the last two stereogenic centers installed, but precursor
8 is not the diastereomer accessible via reaction of a
boronic ester of 6S with (dichloromethyl)lithium. It was
necessary to make the boronic ester 5, derived from (R,R)-
DICHED (6R), and then to find an efficient means of
cleaving 6R from 5 so that the boronic acid 7 could be
esterified with 6S to form 8.
The preparation of (R,R)-DICHED (R)-[1-(benzyloxy)-
ethyl]boronate (5)10 from (R,R)-DICHED methylboronate
(3)11 via the (S)-(1-chloroethyl)boronate (4) followed well-
established procedures (Scheme 2).11-14 The hydrolysis
of 5 to (R,R)-DICHED (6R) and (R)-[1-(benzyloxy)ethyl]-
boronic acid (7) was carried out with sodium hydroxide
and a tris(hydroxymethyl)methane derivative (17) in a
two-phase system, as described in the next subsection.
The ratio of boronic ester 8 to diastereomeric impurity
(5 + en t-5) was g40:1 by NMR analysis. Chain extension
of 8 with (dichloromethyl)lithium and treatment of the
resulting R-chloro boronic ester with methylmagnesium
bromide yielded 9, and a second chain extension followed
by ethylmagnesium bromide yielded 10, which was
deboronated to 11 with hydrogen peroxide.
The hydrolysis of C2-symmetrical 1,2-diol boronic esters
[(4R,5â)-2-alkyl-4,5-dialkyl-1,3,2-dioxaborolanes] has
proved to be surprisingly difficult, and pinanediol esters
are even more resistant. Unfavorable equilibrium con-
stants are the major obstacle, with slow equilibration
rates a lesser problem.
Transesterification with diethanolamine has been used
to convert (S,S)-2,5-dimethyl-3,4-hexanediol (R)-(1-chlo-
robutyl)boronate (1) to the corresponding diol and di-
ethanolamine ester 2 (Scheme 1), from which the boronic
acid can be generated easily by treatment with dilute
aqueous acid.3 However, this procedure requires that the
diethanolamine ester crystallize from the solution during
the reaction so as to drive the equilibrium toward the
products and is not generally applicable.
The particular target 11 was chosen because it could
serve as a precursor to derivatives of (4R,5S)-5-hydroxy-
4-methyl-3-hexanone (12) used as intermediates for our
Pinanediol boronic esters have been cleaved only by
destruction of the pinanediol with boron trichloride,1,5-7
reduction to borohydride with lithium aluminum hydride,
(9) Brown, H. C.; Rangaishenvi, M. V. J . Organomet. Chem. 1988,
358, 15-30.
(1) (a) Matteson, D. S.; Ray, R. J . Am. Chem. Soc. 1980, 102, 7590-
7591. (b) Matteson, D. S.; Ray, R.; Rocks, R. R.; Tsai, D. J . S.
Organometallics 1983, 2, 1536-1543.
(2) (a) Matteson, D. S.; Sadhu, K. M.; Peterson, M. L. J . Am. Chem.
Soc. 1986, 108, 812-819. (b) Matteson, D. S.; Peterson, M. L. J . Org.
Chem. 1987, 52, 5116-5121. (c) Matteson, D. S.; Kandil, A. A.;
Soundararajan, R. J . Am. Chem. Soc. 1990, 112, 3964-3969.
(3) Tripathy, P. B.; Matteson, D. S. Synthesis 1990, 200-206.
(4) Matteson, D. S.; Kandil, A. A. J . Org. Chem. 1987, 52, 5121-
5124.
(10) Systematic names of DICHED boronic esters: 3, [R-(4R,5â)]-
4,5-dicyclohexyl-2-methyl-1,3,2-dioxaborolane; 4, [4R-(2S*,4R,5â)]-2-
(1′-chloroethyl)-4,5-dicyclohexyl-1,3,2-dioxaborolane; 3, [4R-(2R*,4R,5â)]-
4,5-dicyclohexyl-2-[1′-(phenylmethoxy)ethyl]-1,3,2-dioxaborolane; 6,
[4S-(2S*,4R,5â)]-4,5-dicyclohexyl-2-[1-(phenylmethoxy)ethyl]-1,3,2-di-
oxaborolane; 7, [4S-[2(1S*,2R*),4R,5â]]-2-[2′-(phenylmethoxy)-1′-me-
thylpropyl-4,5-dicyclohexyl-1,3,2-dioxaborolane; 8, [4S-[2(1S*,2R*,3R*),-
4R,5â]]-4,5-dicyclohexyl-2-[1-ethyl-2-methyl-3-(phenylmethoxy)butyl]-
1,3,2-dioxaborolane.
(5) (a) Matteson, D. S.; Sadhu, K. M.; Lienhard, G. E. J . Am. Chem.
Soc. 1981, 103, 5241-5242. (b) Matteson, D. S.; Sadhu, K. M.
Organometallics 1984, 3, 614-618.
(11) Matteson, D. S.; Man, H.-W. J . Org. Chem. 1994, 59, 5734-
5741.
(12) (a) Matteson, D. S.; Man, H.-W. J . Org. Chem. 1993, 58, 6545-
6547. (b) Matteson, D. S.; Man, H.-W.; Ho, O. C. J . Am. Chem. Soc.
1996, 118, 4560-4566.
(6) (a) Matteson, D. S.; Michnick, T. J .; Willett, R. D.; Patterson, C.
D. Organometallics 1989, 8, 726-729.
(7) Martichonok, V.; J ones, J . B. J . Am. Chem. Soc. 1996, 118, 950-
958.
(8) Wityak, J .; Earl, R. A.; Abelman, M. M.; Bethel, Y. B.; Fisher,
B. N.; Kauffman, G. S.; Kettner, C. A.; Ma, P.; McMillan, J . L.;
Mersinger, L. J .; Pesti, J .; Pierce, M. E.; Rankin, F. W.; Chorvat, R.
J .; Confalone, P. N. J . Org. Chem. 1995, 60, 3717-3722.
(13) (a) Ditrich, K.; Bube, T.; Stu¨rmer, R.; Hoffmann, R. W. Angew.
Chem. 1986, 98, 1016-1018; Angew. Chem., Int. Ed. Engl. 1986, 25,
1028. (b) Hoffmann, R. W.; Ditrich, K.; Ko¨ster, G.; Stu¨rmer, R. Chem.
Ber. 1989, 122, 1783-1789.
(14) Matteson, D. S.; Soundararajan, R.; Ho, O. C.; Gatzweiler, W.
Organometallics 1996, 15, 152-163.
S0022-3263(96)00684-6 CCC: $12.00 © 1996 American Chemical Society

6048 J . Org. Chem., Vol. 61, No. 17, 1996
Notes
Sch em e 2
Sch em e 3
a
R1 of 7, CH(OBn)CH3. R1 of 21, a , Ph; b, CH(NHAc)CH2Ph.
R2 of 17, a , HOCH2-; b, -O3S(CH2)3NH-; c, -O3S(CH2)2NH-; d ,
-O2CCH2NH-; e, H2N-; f, H3C-. R1 and R2 of 18-20, intermedi-
ates not isolated, defined by context.
Ta ble 1. Hyd r olysis of (R,R)-1,2-Dicycloh exyleth a n ed iol
[(1R)-1-(Ben zyloxy)eth yl]bor on a te (5) to
(R,R)-1,2-Dicycloh exyleth a n ed iol (6R) in Equ a l Volu m es
of Dieth yl Eth er a n d 1 M Sod iu m Hyd r oxid e
mole ratiosa
NaOH/5 17/5
triol 17
ratio of (6R)/(5)
6.6
100
38
6.6
38
6.6
38
38
38
0
0
3
3
3
none
none
5:1
42:1
242:1
33:1
500:1
10:1
92:1
86:1
99:1
20:1
92:1
43:1
(HOCH2)3CCH2OH (a )
(HOCH2)3CNH(CH2)3SO3- (b)
(HOCH2)3CNH(CH2)3SO3- (b)
recent synthesis of stegobinone.12,15 Our first sample of
pure stegobinone was derived from 12c prepared via
3-11 (Scheme 2). However, oxidation of 11 to the ketone
12a deletes a stereogenic center, and only the route to
12 via boronic ester 13 and (3S,4S,5S)-diol derivative 14,
which requires no change of chiral director, was re-
ported.12
Hyd r olysis of DICHED Ester 5. The hydrolysis of
5 was initially attempted by stirring an ethereal solution
of 5 with excess 10 or 3 M aqueous sodium hydroxide,
which resulted in immediate precipitation of the sodium
salt of the boronic ester 15 instead of the desired boronic
acid salt 16, as indicated by recovery of boronic ester 5
on acidification (Scheme 3). The use of higher dilution
and 1 M sodium hydroxide avoided precipitation of 15,
and monitoring of the contents of the ether phase by
NMR indicated that the equilibrium values (Table 1)
were reached after stirring ∼18 h. The predominant
constituent of the ether phase was (R,R)-DICHED (6R),
but a substantial proportion of unchanged boronic ester
5 remained unless impractically low concentrations
(∼0.01 M) were used (see Table 1).
1.5 (HOCH2)3CNH(CH2)2SO3- (c)
3
3
3
3
(HOCH2)3CNH(CH2)2SO3- (c)
(HOCH2)3CNHCH2CO2- (d )
(HOCH2)3CNH2 (e)
14
38
100
(HOCH2)3CCH3 (f)
(HOCH2)3CCH3 (f)
(HOCH2CH2)2NCH2CO2
3
3b
- b
a
A higher ratio of 1 M NaOH to 5 corresponds to a higher
b
dilution of 5. N,N-Bis(hydroxyethyl)glycine yields the same
equilibrium as observed with no additive.
To increase the ratio of 6R to 5 in the ether phase,
several different water-soluble tris(hydroxymethyl)-
methanes 17 were tested in the hope of transesterifying
15 to a more water-soluble sodium salt and liberating
6R. All of the 17 tested produced the desired effect, as
indicated in Table 1. Pentaerythritol (17a ) or TAPS (3-
{[tris(hydroxymethyl)methyl]amino}propanesulfonic acid,
17b) appeared to yield the best results, though the
differences between these and 17c-f are not necessarily
greater than experimental error. When 1,1,1-tris(hy-
droxymethyl)ethane (17f) was used for preparation of
boronic acid 7, acidification of the aqueous phase and
ether extraction yielded a ∼1:1 mixture of 7 and its ester
with 17f. This problem was not observed with the more
polar 17a ,b.
Recovery of the free (R)-[1-(benzyloxy)ethyl]boronic
acid [21, R1 ) 1-(benzyloxy)ethyl] was readily accom-
plished by acidification of the aqueous solution of 18, 19,
and 20 and extraction with ethyl acetate.
Bor a te An ion s 18-20. For R1 ) -CH(OBn)CH3, the
ratios of monocyclic boronic ester anions 18/19 to bicyclic
(15) Our first attempted route to stegobinone involved esterification
of 12b with (2S,3S)-2-methyl-3-[(tert-butyldimethylsilyl)oxy]pentanoic
acid. Cyclization of a similar ester has been described: Mori, K.; Ebata,
T. Tetrahedron 1986, 42, 4413-4420. However, our attempts at ring
closure failed. Our chiral carboxylic acid had been made via (R,R)-
DICHED (S)-(1-bromopropyl)boronate and tert-butyl lithiopropanoate,
a process subsequently shown to be stereochemically flawed but to have
a viable boronic ester-based alternative.11 A revised carboxylic ester
ring closure route has recently been applied successfully to a homologue
of stegobiol, serricorone: Oppolzer, W.; Rodriguez, I. Helv. Chim. Acta
1993, 76, 1275-1281; 1282-1291.

Notes
J . Org. Chem., Vol. 61, No. 17, 1996 6049
Sch em e 4
showed ∼35% of the TAPS hydroxymethyl CH2 as a
singlet at δ 3.18. There was a partially obscured AB
pattern, J ) 5 Hz, at δ 3.20 and 3.22, consistent with
the ring CH2 groups of monocyclic anion, ∼55%, and the
remaining 10% appeared as a singlet at δ 3.48, typical
of bicyclic TAPS esters 20. Overlapping peaks prevented
further interpretation.
Treatment of pinanediol (1-acetamido-2-phenylethyl)-
boronate (22b) with 6.5 equiv of 1 M sodium hydroxide
and 4 volumes of diethyl ether resulted in ∼50% hydroly-
sis. Inclusion of 3 equiv of TAPS (17b) increased the
proportion of hydrolysis to ∼80%, though the best recov-
ery of boronic acid 21a (as its DICHED ester) was only
59%.16 Diethyl ether extracted free pinanediol (23) from
the basic solution, but part of the 23 was held in the
aqueous solution, presumably in the form of the spiro
borate ester 24. Acidification then liberated unchanged
22b, which was easily extracted into organic solvents,
and the free water-soluble boronic acid 21b. Addition of
DICHED converted 21b to the corresponding ester, which
could be extracted with ethyl acetate.
anions 20 were not determined. However, for R1 ) Ph,
evidence for the presence of both types was obtained from
the 1H NMR spectrum of a solution prepared from
phenylboronic acid (21a ), sodium deuteroxide, and TAPS
(17b-H+) in D2O. In this case, the major species present
was the bicyclic anion 20, as indicated by the singlet
arising from the three identical bridging -CH2O- groups
at δ 3.53. Uncomplexed TAPS appeared as a singlet at
δ 3.21. TAPS bound to boron through only two of the
CH2O groups shows one isomer (18 or 19) as a doublet
at δ 3.47 (J ) 11 Hz) coupled to a doublet near δ 3.15-
3.16, plus a geometric isomer (19 or 18) having a doublet
at δ 3.37 (J ) 11 Hz) coupled to a doublet overlapping
with that of the first isomer at δ 3.15-3.16. In addition,
each geometric isomer shows a singlet for the unbound
CH2OH group, one at δ 3.27 and the other at δ 3.22. The
couplings were determined with the aid of COSY and
HOMO2DJ spectra.
P in a n ed iol P h en ylbor on a te. The hydrolysis of pi-
nanediol phenylboronate (22a ) remained incomplete
under all conditions tested. Even with a 50-fold excess
of sodium hydroxide and 10-fold excess of TAPS (17b),
the ratio of free pinanediol (23) to ester 22a in the ether
phase was only 3.5:1 (Scheme 4). Although the method
lacks synthetic utility for pinanediol esters, the data
obtained were useful for optimizing the general hydroly-
sis conditions.16
Contrary to expectation, increasing the concentration
of sodium hydroxide to 3 M actually decreased the
conversion of 22a to 23, though it was not determined
whether the effect might be kinetic, as the 23/22a ratio
increased from 1:1 after 1 day to 2:1 after 2 days. For
the experiments with 1 M sodium hydroxide, equilibrium
is the limiting factor, as shown by the reverse reaction
of free pinanediol, phenylboronic acid (21a ), TAPS (17b-
H+), and 1 M sodium hydroxide in the ratio 2:2:3:12,
which after 18 h yielded a 0.6:1 ratio of 23/22a . Glycerol
is much less efficient than TAPS for promoting the
liberation of 23 from 22a (Table 2, in the supporting
information).
Discu ssion
Syn th etic Utility. The ability to remove a chiral
director and replace it by its enantiomer allows the
chemist free choice of the absolute configuration of each
carbon atom in a series of several chiral centers. The
approach described here has been demonstrated to be
practical for making syn,syn-diols such as 11 and should
also be applicable to anti,anti-diols by postponing the
change of chiral directors until after the second chiral
center has been installed. For a similar synthetic objec-
tive, the still unsolved impasse in the cleavage of pi-
nanediol boronic esters has been circumvented by a
double SN2 inversion sequence,4 the second inversion of
which would be sterically incompatible with diols of C2-
symmetry.3
Although the route to ketones 12 via 13 and 14
requires only one chiral director, it was not obvious in
advance that this would be more efficient than the route
via 11. Both (R,R)- and (S,S)-DICHED are available and
easily recoverable. Our initial synthetic objective, â-hy-
droxy ketone 12b,15 was reached in three easy steps from
10 but required five steps from 13. Loss of silyl protec-
tion plagued the reported route to 14,12a and a better
route to stegobinone via a keto boronic ester was ulti-
mately found.12b
Th er m od yn a m ics of Liga n d Exch a n ge. Because
the major obstacle to hydrolysis of 1,3,2-dioxaborolanes
is thermodynamic, it is relevant to consider what factors
are involved. Hydrolysis is opposed by the unfavorable
entropy of converting three molecules to two:
RB[O2(CHR′)2] + 2H2O )
(1-Aceta m id o-2-p h en yleth yl)bor on ic ester s. A cy-
clic structure for the sodium salt of (1R)-(1-acetamido-
RB(OH)2 + R′CH(OH)CH(OH)R′
1
2-phenylethyl)boronic acid (21b) is indicated by the H
NMR spectrum, in which the acetyl methyl singlet
appears at δ 1.43, substantially upfield from its position
in the free boronic acid 21b, δ 2.1.
(1-Acetamido-2-phenylethyl)boronic acid (21b, 0.1 M),
sodium deuteroxide (1 M), and TAPS (17b, 0.07 M) in
D2O indicated a preponderance (∼85%) of the monocyclic
TAPS esters, which appear to be better represented by
structure 25 than by 18/19. The 1H NMR spectrum
Hydroxylation of both the boronic ester and acid in basic
solution does nothing to overcome this entropy barrier,
but transesterification to a water-soluble diol keeps the
number of molecules constant, and on acidification, the
water-insoluble boronic acid becomes separable by ex-
traction.
Other factors that affect equilibrium constants include
the influence of steric repulsions on enthalpy and the
entropies of internal rotations of free diols. 1,3,2-Diox-
aborolanes derived from (R*,R*)-DICHED are favored by
(16) Details are included in the supporting information.

6050 J . Org. Chem., Vol. 61, No. 17, 1996
Notes
(benzyloxy)ethyl]boronic acid (7). The mixture was dissolved in
hexane and stirred with (S,S)-DICHED (6S) (36 g, 150 mmol)
(ee ∼99%) for 18 h. The solution was washed with water (3 ×
200 mL) and dried over magnesium sulfate. Distillation of the
solvent gave (S,S)-DICHED (R)-[1-(benzyloxy)ethyl]boronate (8)
[52.88 g, 76% based on (R,R)-DICHED methylboronate (3)],
which was used in the next step without further purification:
minimal steric repulsions between the trans-4,5-substit-
uents, which eclipse hydrogen atoms.17,18 Methyl group
interactions destabilize pinacol esters, which are easily
transesterified with (R*,R*)-DICHED or (R*,R*)-diiso-
propylethanediol.14,17 The extreme hydrolytic resistance
of pinanediol boronic esters results from the orientation
of hydroxyl groups and rigidity of the free diol. Our NMR
data suggest that the favorable entropy of elimination
of water from the monocyclic 1,3,2-dioxaborins 18 and
19 to form the bicyclic ester anions 20 is largely offset
by increased strain. The apparent formation of spiro
esters 24 and 25 from (1-acetamido-2-phenylethyl)boronic
acid (21b) and TAPS (17b) is consistent with the known
structure of an R-amido boronic ester6 as well as the easy
hydrolysis of 3- or 4-(hydroxyalkyl)-1,3,2-dioxaborolanes
to cyclic derivatives.12b,14
1
500-MHz H NMR (CDCl3) δ 0.96-1.40 and 1.56-1.82 (m, 22),
1.34 (d, J ) 7.5 Hz, 3), 3.45 (q, J ) 7.5 Hz, 1), 3.91-3.93 (m, 2),
4.55 (d, J ) 11.5 Hz, 1), 4.58 (d, J ) 11.5 Hz, 1), 7.25-7.37 (m,
5); 125-MHz 13C NMR (CDCl3) δ 17.0, 25.9, 26.0, 26.4, 27.3, 28.4,
43.0, 62 (br), 71.8, 83.9, 127.3, 127.8, 128.2, 139.2; HRMS calcd
for C23H35BO3 (M+) 370.2679, found 370.2687. The ratio of 8 to
its diastereomer (R*,R*)-DICHED (R*)-[1-(benzyloxy)ethyl]bo-
ronate (5 + en t-5) was g40:1 based on 125-MHz 13C NMR
analysis.
(R)-[1-(Ben zyloxy)eth yl]bor on ic Acid (7). The procedure
of the foregoing paragraph carried out with TAPS but without
pentaerythritol allowed isolation of 7, which was not purified:
500-MHz 1H NMR (CDCl3) δ 1.30 (d, J ) 7.5 Hz, 3), 3.34 (q, J
) 7.5 Hz, 1), 4.41 (AB, J ) 12 Hz, 1), 4.60 (d, J ) 12 Hz, 1),
6.4-6.6 (br s, 1), 7.2-7.4 (m, 5).
(S,S)-DICHED (1R,2S)-[2-(Ben zyloxy)-1-m eth ylp r op yl]-
bor on a te (9). Addition of 8 to preformed (dichloromethyl)-
lithium according to the usual procedure yielded the crude
R-chloroboronic ester, which with methylmagnesium bromide
under the usual conditions led to crude 9.12,16
Exp er im en ta l Section
(R,R)-DICH E D (R)-[1-(Ben zyloxy)et h yl]b or on a t e (5).
Similar procedures have been reported elsewhere for synthesis
of the homologous [1-(benzyloxy)propyl]boronate,12 and a de-
tailed procedure is described in the supporting information for
1
this paper. The H NMR spectra are not useful for distinguish-
ing 5 from its diastereomer 8, but chemical shift differences in
the 13C spectra are measurable: for 5, 125-MHz 13C NMR
(CDCl3) δ 16.8, 25.9, 26.0, 26.4, 27.3, 28.2, 42.9, 62.5 (br), 71.7,
83.7, 127.3, 127.8, 128.2, 139.2. The ratio of 5 to its (1S)-
diastereomer (en t-8) estimated by 125-MHz 13C NMR was 250:
1.
(S,S)-DICH E D (1R,2S,3S)-{[3-(Ben zyloxy)-2-m et h yl-1-
eth yl]bu tyl}bor on a te (10). (Dichloromethyl)lithium was pre-
pared from dichloromethane (22 mL) in THF (150 mL) at -100
°C with butyllithium (160 mmol) in the usual manner.2a
A
solution of crude 9 (45.23 g, 114 mmol) was added via cannula,
followed after 10 min by anhydrous zinc chloride (13.1 g, 95.6
mmol). The solution was kept at ambient temperature for 36 h
and then concentrated and worked up in the usual way with
hexanes (200 mL) and aqueous ammonium chloride (2 × 200
mL). The concentrated crude chloroboronic ester (47 g) was used
in the next step without further purification: 500-MHz 1H NMR
(CDCl3) δ 0.87-1.78 (m, 22), 1.13 (d, J ) 6.5 Hz, 3), 1.20 (d, J
) 6.5 Hz, 3), 2.18 (dp, J ) 5, 6.5 Hz, 1), 3.52 (d, J ) 7 Hz, 1),
3.67 (p, J ) 6 Hz, 1), 3.75-3.76 (m, 2), 4.48 (AB, J ) 15 Hz, 1),
4.51 (AB, J ) 15 Hz, 1), 7.30-7.34 (m, 5); 125-MHz 13C NMR
(CDCl3) δ 13.50, 15.86, 25.65, 25.69, 26.26, 27.53, 28.20, 42.37,
42.43, 47 (br), 70.87, 76.78, 84.10, 127.21, 127.45, 128.09, 138.94.
Ethylmagnesium chloride (56 mL, 1.88 M, 105 mmol) was added
dropwise to the crude boronic ester (47 g) in THF (150 mL) at
-78 °C. After 48 h at 20-25 °C, the solution was concentrated
and worked up in the usual way with hexanes (200 mL) and
aqueous ammonium chloride (2 × 200 mL). Concentration of
the organic phase, followed by flash column chromatography
(silica, 5% ether/hexanes), yielded boronic ester 10 (32.3 g, 73.3
Hyd r olysis of (R,R)-1,2-DICHED R-[1-(Ben zyloxy)eth yl]-
bor on a t e (5). A solution of (R,R)-1,2-dicyclohexylethanediol
(R)-1-(benzyloxy)ethyl]boronate (5) (28 g, 75.6 mmol) in diethyl
ether (750 mL) was stirred with 3-{[tris(hydroxymethyl)methyl]-
amino}propanesulfonic acid (TAPS, 17b-H+) (56 g, 230 mmol)
in aqueous 1 M sodium hydroxide (750 mL) at room temperature
for 18 h under argon. The ether phase was separated and
filtered through a short pad of magnesium sulfate. Concentra-
tion of the ether solution yielded (R,R)-1,2-dicyclohexylethanediol
(6R) (17 g, 99%). The aqueous sodium hydroxide solution
containing the boronate salt was acidified to pH < 3 by addition
of 12 M hydrochloric acid and extracted with ethyl acetate (700
mL). The ethyl acetate solution was dried over magnesium
sulfate and concentrated under vacuum to yield (R)-[(1-benzy-
loxy)ethyl]boronic acid (10.6 g, 77%): 500-MHz 1H NMR (CDCl3)
δ 1.30 (d, J ) 7.5 Hz, 3), 3.34 (q, J ) 7.5 Hz, 1), 4.41 + 4.60 (AB
pattern, J ) 12 Hz, 2), 6.5 (br, 2), 7.2-7.4 (m, 5). Further
extraction of the aqueous solution with pinacol (14 g) in pentane
(500 mL), followed by washing the pentane solution with water
and concentration, yielded pinacol (R)-[(1-benzyloxy)ethyl]bor-
onate (2.6 g, 12%); total recovery of 7 plus its pinacol ester, 89%.
(S,S)-DICHED (R)-[1-(Ben zyloxy)eth yl]bor on a te (8). A
solution of crude (R,R)-DICHED (R)-[1-(benzyloxy)ethyl]boronate
(5) (67.73 g) in ether (1 L) was stirred with aqueous sodium
hydroxide (1 L, 1 M), pentaerythritol (17a ) (51 g, 375 mmol),
and TAPS (3-{[tris(hydroxymethyl)methyl]amino}propanesulfonic
acid) (17b-H+) (46 g, 189 mmol) for 18 h at room temperature.
The aqueous layer was separated and washed with ether (300
mL) to remove any (R,R)-DICHED (6R) or (R,R)-DICHED (R)-
[1-(benzyloxy)ethyl]boronate (5). The combined ether phase was
washed with water (500 mL) and dried over magnesium sulfate.
Concentration under vacuum yielded (R,R)-DICHED (6R) [36
g, 150 mmol, 85% based on (R,R)-DICHED methylboronate (3)].
1
mmol, 64% from 9); 500-MHz H NMR (CDCl3) δ 0.85-1.80 (m,
26), 0.89 (t, J ) 7.5 Hz, 3), 0.98 (d, J ) 7 Hz, 3), 1.18 (d, J ) 6
Hz, 3), 3.47 (p, J ) 6 Hz, 1), 3.68-3.70 (m, 2), 4.41 (AB, J ) 12
Hz, 1), 4.55 (AB, J ) 12 Hz, 1), 7.23-7.36 (m, 5); 125-MHz 13C
NMR (CDCl3) δ 12.58, 14.02, 17.27, 22.94, 25.85, 25.92, 26.44,
27.85, 28.64, 40.96, 42.93, 70.76, 78.64, 83.35, 127.16, 127.68,
128.16, 139.57. Anal. Calcd for C28H45O3B: C, 76.35; H, 10.3;
B, 2.45. Found: C, 76.84; H, 10.52; B, 2.47.
(3R,4S,5S)-5-(Ben zyloxy)-4-m eth yl-3-h exa n ol (11). To a
solution of boronate (10) (21.2 g, 48 mmol) in 80 mL of THF
and 17 mL of sodium hydroxide (3 M) was added hydrogen
peroxide (20 mL, 30%) at 0 °C. The solution was allowed to
warm to room temperature, kept for 18 h, and partially
concentrated under reduced pressure to remove THF. The
aqueous solution was extracted with ether (2 × 200 mL). The
combined organic phase was washed with ammonium chloride
(100 mL) and dried over magnesium sulfate and then concen-
trated to a solid residue, which was treated with pentane to
crystallize (S,S)-DICHED and dissolve 11. The (S,S)-DICHED
was filtered, and the mother liquor was concentrated and
separated by flash column chromatography (silica, 20% ethyl
acetate/hexanes) to yield alcohol 11 (9.2 g, 86%): 500-MHz 1H
NMR (CDCl3) δ 0.91 (t, J ) 7.5 Hz, 3), 0.96 (d, J ) 6.5 Hz, 3),
1.24 (d, J ) 6.5 Hz, 3), 1.36-1.41 (m, 2), 1.50-1.58 (m, 1), 3.70-
3.73 (dt, J ) 7, 2 Hz, 1), 3.79 (dq, J ) 2.5, 6 Hz, 1), 4.39 (AB, J
) 11 Hz, 1), 4.65 (AB, J ) 11 Hz, 1), 7.25-7.35 (m, 5); 125-MHz
13C NMR (CDCl3) δ 5.33, 10.46, 16.86, 27.59, 41.82, 70.28,
The sodium hydroxide solution was acidified to pH
3 by
hydrochloric acid (12 M) at 0 °C and extracted with ethyl acetate
(3 × 500 mL). The combined organic phase was dried over
magnesium sulfate. Distillation of the solvent yielded a mixture
of pentaerythritol (R)-[1-(benzyloxy)ethyl]boronate and (R)-[1-
(17) Ho, O. C.; Soundararajan, R.; Lu, J .; Matteson, D. S.; Wang,
Z.; Chen, X.; Wei, M.; Willett, R. D. Organometallics 1995, 14, 2855-
2860.
(18) In
a 4,5-unsubstituted 2-(1-amidoalkyl)-1,3,2-dioxaborolane,
bonding to the amide oxygen makes the boron tetracoordinate and the
CH2 groups staggered,6 geometry which also favors trans-disubstitu-
tion.

Notes
J . Org. Chem., Vol. 61, No. 17, 1996 6051
77.27, 79.90, 127.58, 127.60, 128.41, 138.15. Anal. Calcd for
C14H23O2: C, 75.63 H, 9.97. Found: C, 74.4; H, 9.94.
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails for preparations of compounds 5, 9, and 12a -c, and for
the partial hydrolysis of pinanediol boronic esters (7 pages).
This material is contained in libraries on microfiche, im-
mediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
Ack n ow led gm en t. This work was supported by
NSF Grant CHE-8922672. Support of the WSU NMR
Center by NIH Grant RR 0631401, NSF Grant CHE-
9115282, and Battelle Pacific Northwest Laboratories
Contract No. 12-097718-A-L2 is also gratefully acknowl-
edged.
J O960684M