Homologation of boronic esters with (dialkoxymethyl)lithiums. Asymmetric synthesis of α-alkoxy boronic esters

Full text of DOI:10.1021/jo000457r

J . Org. Chem. 2000, 65, 5403-5408
5403
Notes
Hom ologa tion of Bor on ic Ester s w ith
Dia lk oxym eth yl)lith iu m s. Asym m etr ic
Syn th esis of r-Alk oxy Bor on ic Ester s
(
†
‡
Laurence Carm e` s, Fran c¸ ois Carreaux,* and
Bertrand Carboni
Universit e´ Rennes-I, Synth e` se et Electrosynth e` se organiques,
UMR 6510 associ e´ e au CNRS, campus de Beaulieu,
3
5042 Rennes Cedex, France
francois.carreaux@univ-rennes1.fr
Received March 27, 2000
In tr od u ction
This past decade has witnessed an increased interest
in the chemistry of the R-heterosubstituted boronic acids
and esters. Boronic acid analogues of R-amino acids
represent an interesting class of enzyme inhibitors. The
main results have been hitherto in the field of serine and
1
threonine proteases. We have focused our attention on
the R-alkoxy derivatives because of their synthetic in-
F igu r e 1. Synthetic interest of R-alkoxy boronic esters as
terests. This class of compounds is useful for the synthe-
reagents.
2
3
sis of chiral aldehydes and R-amino boronic acids. The
addition of R-alkoxy allylboronates to aldehydes leads to
compounds to R-hydroxy acids, their biological activities
are interesting, but has so far received little attention
(Figure 1).
4
homoallyl alcohols with good selectivity and this reaction
was used in the total synthesis of the denticulatins. It
5
Different methods are reported for the synthesis of
was also demonstrated that the alkoxy substituents are
9
6
R-alkoxy boronic esters. The most used strategy is the
compatible with chain extension processes. This strategy
substitution of R-chloro boronic esters by a lithium
alkoxide.10 Matteson developed an elegant asymmetric
synthesis of the R-chloro boronic esters by homologation
of boronic esters.11 When pinanediol is used as the chiral
director, the R-chloro derivatives are obtained with high
diastereoselectivity for the majority of boronates, except
for arylboronates. For example, pinanediol phenylbor-
onate often provides lower de’s (88%)12 than other bor-
onates due to the well-documented epimerization of the
resulting benzylic R-chloro boronates in the presence of
LiCl.13 During the substitution of the R-chloro allylbo-
ronic esters, a low stereoselectivity can be observed, the
result of the epimerization of the R-chloro derivatives by
has been extensively employed in syntheses of biologically
important molecules including pheromones and sugars.
Moreover, considering the similarity of this class of
7
8
*
To whom correspondence should be addressed. Fax: (33) 2 99 28
6
9 78.
†
A part of this work was presented at the J ourn e´ es de Chimie
Organique, Soci e´ t e´ Fran c¸ aise de Chimie, Palaiseau (France), Septem-
ber 1998, abstract A-169.
‡
Current address: Department of Chemistry, King’s Buildings,
West Mains Road, Edinburgh EH9 3J J .
(1) For a review of serine protease inhibitor, see: Hiratake, J .; Oda,
J . Biosci. Biotech. Biochem. 1997, 61, 211-218. Threonine protease
inhibitor: Adams, J .; Behnke, M.; Chen, S.; Cruickshank, A. A.; Dick,
L. R.; Grenier, L.; Klunder, J . M.; Ma, Y.-T.; Plamondon, L.; Stein, R.
L. Bioorg. Med. Chem. Lett. 1998, 8, 333-338.
(
2) Brown, H. C.; Imai, T.; Desai, M. C.; Singaram, B. J . Am. Chem.
Soc. 1985, 107, 4980-4983.
3) Carm e` s, L.; Carreaux, F.; Carboni, B.; Mortier, J . Tetrahedron
Lett. 1998, 39, 555-556.
4) (a) Hoffmann, R. W.; Dresely, S. Chem. Ber. 1989, 122, 903-
09. (b) Hoffmann, R. W.; Wolff, J . J . Chem. Ber. 1991, 124, 563-569.
5) Andersen, M. W.; Hildebrandt, B.; Dahmann, G.; Hoffmann, R.
(9) (a) From R-alkoxyorganostannanes: ref 2. (b) By homologation
of boronic esters: Brown, H. C.; Imai, T. J . Am. Chem. Soc. 1983, 105,
6285-6289. (c) From (1-methoxyvinyl)lithium: Matteson, D. S.; Beedle,
E. C. Heteroatom Chem. 1990, 1, 135-140. (d) From (R-alkoxy allyl)-
lithium: Moret, E.; Schlosser, M. Tetrahedron Lett. 1984, 25, 4491-
4494.
(
(
9
(
W. Chem. Ber. 1991, 124, 2127-2139.
(10) (a) Matteson, D. S.; Majumdar, D. J . Am. Chem. Soc. 1980, 102,
7590-7591. (b) Matteson, D. S.; Majumdar, D. Organometallics 1983,
2, 1529-1535. (c) Matteson, D. S.; Kandil, A. A. J . Org. Chem. 1987,
52, 5121-5124. (d) Matteson, D. S.; Soundararajan, R.; Ho, O. C.;
Gatzweiler, W. Organometallics 1996, 15, 152-163.
(
6) Matteson, D. S. J . Organomet. Chem. 1999, 581, 51-65.
(
7) (a) Matteson, D. S.; Sadhu, K. J . Am. Chem. Soc. 1983, 105,
2
077-2078. (b) Matteson, D. S.; Sadhu, K. M.; Peterson, M. L. J . Am.
Chem. Soc. 1986, 108, 810-819. (c) Tripathy, P. B.; Matteson, D. S.
Synthesis 1990, 200-206. (d) Matteson, D. S.; Man, H.-W. J . Org.
Chem. 1993, 58, 6545-6547. (e) Matteson, D. S.; Man, H.-W.; Ho, O.
C. J . Am. Chem. Soc. 1996, 118, 4560-4566.
(11) (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 . Organo-
metallics 1983, 2, 1536-1543.
(
8) (a) Matteson, D. S.; Peterson, M. L. J . Org. Chem. 1987, 52,
116-5121. (b) Matteson, D. S.; Kandil, A. A.; Soundararajan, R. J .
Am. Chem. Soc. 1990, 112, 3964-3969.
(12) Rangaishenvi, M. V.; Singaram, B.; Brown, H. C. J . Org. Chem.
1991, 56, 3286-3294.
(13) Matteson, D. S.; Erdik, E. Organometallics 1983, 2, 1083-1088.
5
1
0.1021/jo000457r CCC: $19.00 © 2000 American Chemical Society
Published on Web 07/11/2000

5
404 J . Org. Chem., Vol. 65, No. 17, 2000
Notes
Sch em e 1
Sch em e 2
lithium chloride liberated during the slow reaction with
alkoxide.14 In light of these facts and due to the potential
of this class of compounds as reagents and as biological
tools, we have initiated a program to develop alternative
routes to chiral R-alkoxy boronic esters.
Str a tegy. A widely used process in organoborane
chemistry is the construction of C-C bonds via the
migration of an organic group from a tetracoordinated
boron atom to an adjacent carbon bearing a leaving
group.15 Different carbenoid reagents bearing a potential
leaving group(s) (such heteroatom substituents as halo-
gen, sulfur) at the R position were used for the one-carbon
homologation of boronic esters.16 One of the most suc-
cessful examples of such transfer reactions is the asym-
metric construction of carbon-carbon bonds by treatment
of a nonracemic boronic esters with (dichloromethyl)-
lithium.17 The diastereotopic differentiation of the chlo-
ductive lithiation of phenylthio-substituted compounds
1
9
or by transmetalation of tri-n-butylstannyl derivatives.
A large variety of R-stannylacetals has been described
2
0
and the simplicity of their preparation make them
attractive reagents. The reaction of (dialkoxymethyl)-
lithium reagents with boronic esters should give access
to the R-alkoxy boronic esters in only one step. Further-
more, if the (+)-pinanediol boronates provides the (RR)-
R-alkoxy boronic esters via the R-chloro derivatives
3
ride groups on an sp carbon is governed by the chirality
2
1
(
displacement of chloride proceeds with inversion), then
of the diol moiety in the borate complexes. As indicated
earlier, homologation of boronic esters of (+)-or (S)-
pinanediol with (dichloromethyl)lithium yields (RS)-R-
chloro boronic esters with excellent diastereomeric purity
in most of the cases.
with the same chiral director, we should obtain the
corresponding epimers. In this paper, we describe the
first results of this methodology (Scheme 2).
Our objective was to find a simple and straightforward
access to chiral R-alkoxy boronic esters. We thus chose
as our strategy to insert a CHOR group in the carbon-
boron bond of boronic esters. The cleavage of these acetals
by nucleophiles is a well-known reaction.18 We envisioned
that the borate intermediate as shown in Scheme 1 could
lead to the homologated boronic ester by 1,2-migration
of an alkyl group from boron to the adjacent atom with
displacement of an alkoxy group. This borate complex
could be prepared by treatment of an alkylboronic ester
with an acyl anion equivalent such as (dialkoxymethyl)-
lithium.
Resu lts a n d Discu ssion
In our preliminary investigation concerning the syn-
thetic utility of these reagents in organoborane chemis-
try, we chose diethoxymethyltributyltin as the starting
2
2
material because of its availability on a large scale. The
(diethoxymethyl)lithium, obtained by transmetalation of
the corresponding dialkoxymethyltributyltin with n-
2
3
butyllithium in THF at -100 °C, was treated with (+)-
pinanediol24 phenylboronate 1a in the absence of a Lewis
acid. The resulting solution was warmed to room tem-
perature and stirred overnight. After workup of the
reaction, the (+)-pinanediol R-(ethoxy)phenylmethylbo-
ronate 4a was isolated by flash chromatography in 58%
yield, with 20% diastereomeric purity (Table 1). Deter-
Shiner and co-workers reported two procedures for the
preparation of (dialkoxymethyl)lithium reagents by re-
(
14) Hoffmann, R. W.; Dresely, S. Tetrahedron Lett. 1987, 28, 5303-
306.
15) (a) Matteson, D. S. Stereodirected Synthesis with organoboranes;
1
mination of diastereomeric excess was based on the H
5
NMR, using integration of the different pinanyl methyl
protons (δ ) 1.34 and 1.37 ppm). To elucidate the
mechanism and to identify the intermediates, the reac-
tion was followed by 11B NMR. At -100 °C, the B NMR
spectrum of the reaction mixture showed that 1a (δ +30
ppm) was completely converted to an “ate” complex (2a ,
δ -4), which can be attributed to complexation of the
reagent on boron. Upon warming, a new peak appeared
(
Springer: Berlin, 1995. (b) Vaultier, M.; Carboni, B. In Comprehensive
Organometallic Chemistry II; Stone, F. G. A., Abel, E. V., Eds.;
Pergamon: Oxford, 1995; Vol. 11, pp 191-276.
11
(16) [Chloro(trimethylsilyl)methyl]lithium: (a) Matteson, D. S.;
Majumdar, D. J . Organomet. Chem. 1980, 184, C41-C43. (b) Matteson,
D. S.; Majumdar, D. Organometallics 1983, 2, 230-236. (c) Tsai, D. J .
S.; Matteson, D. S. Organometallics 1983, 2, 236-241. [Methoxy-
(
phenylthio)methyl]lithium: Reference 9b. (Chloromethyl)lithium: (a)
Sadhu, K. M.; Matteson, D. S. Organometallics 1985, 4, 1687-1689.
b) Brown, H. C.; Singh, S. M.; Rangaishenvi, M. V. J . Org. Chem.
986, 51, 3150-3155. (Bromomethyl)lithium: Michnick, T. J .; Mat-
teson, D. S. Synlett 1991, 631-632. (Iodomethyl)lithium: Wallace, R.
(
1
(
δ +7) with gradual disappearance of the precedent. This
H.; Zong, K. K. Tetrahedron Lett. 1992, 33, 6941-6944. For
comparative study of different (halomethyl)lithiums, see: (a)
a
(19) Shiner, C. S.; Tsunoda, T.; Goodman, B. A.; Ingham, S.; Lee,
S.-H.; Vorndam, P. E. J . Am. Chem. Soc. 1989, 111, 1381-1392.
(20) Duch eˆ ne, A.; Boissi e` re, S.; Parrain, J . L.; Quintard, J .-P. J .
Organomet. Chem. 1990, 387, 153-162.
(21) (a) Midland, M. M.; Zopola, A. R.; Halterman, R. L. J . Am.
Chem. Soc. 1979, 101, 248-249. (b) Matteson, D. S. Acc. Chem. Res.
1970, 3, 186-193.
(22) (a) Quintard, J .-P.; Elissondo, B.; Pereyre, M. J . Organomet.
Chem. 1981, 212, C31-C34. (b) Quintard, J .-P.; Elissondo, B.; Mouko-
Mpegna, D. J . Organomet. Chem. 1983, 251, 175-187.
(23) Parrain, J . L.; Beaudet, I.; Cintrat, J . C.; Duch eˆ ne, A.; Quintard,
J .-P. Bull. Soc. Chim. Fr. 1994, 131, 304-312.
(24) The Chemical Abstracts name for (+)- or (S)-pinanediol is [1S-
(1R,2â,3â,5R)]-2,6,6-trimethylbicyclo[3.1.1]heptane-2,3-diol.
Soundararajan, R.; Li, G.; Brown, H. C. Tetrahedron Lett. 1994, 35,
8
957-8960. (b) Soundararajan, R.; Li, G.; Brown, H. C. Tetrahedron
Lett. 1994, 35, 8961-8964. (1,1-Dichloroethyl)lithium: Matteson, D.
S.; Hurst, G. D. Heteroatom Chem. 1990, 1, 65-74. [(Chloroaryl)-
methyl]lithium: Kabalka, G. W.; Li, N.-S.; Yu, S. Tetrahedron:
Asymmetry 1997, 8, 3843-3846.
(
17) For reviews, see: (a) Matteson. D. S. Tetrahedron 1998, 54,
1
0555-10607. (b) Reference 14a, Chapter 5. (c) Brown, H. C.; Ram-
achandran, P. V. Pure Appl. Chem. 1994, 66, 201-212. (d) Matteson,
D. S. Pure Appl. Chem. 1991, 63, 339-344. (e) Matteson, D. S. Chem.
Rev. 1989, 89, 1535-1551.
(18) Mukaiyama, T.; Murakami, M. Synthesis 1987, 1043-1054.

Notes
Ta ble 1. Hom ologa tion of Bor on ic Ester s to r-Alk oxy
J . Org. Chem., Vol. 65, No. 17, 2000 5405
yield and the diastereomeric excess of the R-chloro
boronic esters improved significantly by addition of Lewis
acids, such as zinc chloride.28 The addition of one
equivalent of this Lewis acid did not bring any significant
improvement (entry 2). Taking into account that our
process takes place with an oxygen-rich reagent, we then
Bor on ic Ester s
boronic
entry esters
Lewis acid
products
a
R
R′ (molar ratio) (yield, %) % deb
1
2
3
4
5
6
7
8
9
0
1
2
3
1a
1a
1a
1a
1a
1b
1c
1d
1e
1f
Ph
Ph
Ph
Ph
Ph
Et
4a (58)
4a (46)
4a (65)
4a (57)
4a (54)
4b (42)
4c (62)
c
4e (66)
4f (65)
4g (63)
4h (44)
4i (40)
20
30
g98
84
48
96
Et ZnCl2 (1)
Et ZnCl2 (3)
Et ZnBr2 (3)
Et BF3‚OEt2(3)
Et ZnCl2 (3)
29
decided to add an excess of zinc chloride. The use of 3
equivalents (entry 3) dramatically improved the stereo-
1
13
selectivity of the reaction (de of 4a g98%; H and
C
4-BrC6H4
1-naphthyl Et ZnCl2 (3)
1-hexenyl Et ZnCl2 (3)
g98
NMR), but had no effect on the yield. Although the use
of an excess of zinc chloride in the homologation with
i-Pr
Et ZnCl2 (3)
Et ZnCl2 (3)
Et ZnCl2 (3)
Me ZnCl2 (3)
Me ZnCl2 (3)
g98
66
66
g98
64
(
dichloromethyl)lithium significantly accelerates the
1
1
1
1
n-C6H13
CH3
Ph
13
epimerization of certain R-chloro boronic esters. This
1g
1a
1g
3
0
is not a problem with the R-alkoxy analogues. The
3
1
CH3
absolute configuration of the new chiral center of 4 was
established unambiguously to be S by comparison to the
optically pure diastereomer of 4e32 using NMR spectros-
copy.
a
b
1
Isolated yield after flash chromatography. Determined by H
1
3
c
NMR and C NMR of the crude product. No R-alkoxy boronate
was obtained; the major product was hydroxyl pinanediol borate.
To find a better procedure, we tested the effects of
several other Lewis acids capable of promoting the
rearrangement of 2 to 3. We then adopted the rule of
thumb that one equivalent of Lewis acid would be added
for each alkoxy group, plus one equivalent for the
rearrangement of 2 to 3. We initially tested zinc bromide,
a more oxophilic Lewis acid than zinc chloride. A diminu-
tion of the diastereomeric excess was observed, 84%
instead of g98% (entry 4). We then tested the effect on
the stereoselectivity of a monodentate Lewis acid such
Sch em e 3
3 2
as BF .OEt . The preferred stereochemistry is the same
as with a bidentate Lewis acid, but a dramatic drop of
the diastereomeric excess was observed (entry 5). How-
ever, it is interesting to note that the diastereoselectivity
was improved compared to the reaction performed with-
out Lewis acid. Although it is a monodentate Lewis acid,
the preferential displacement of one of the prochiral
alkoxide groups is again favored.
Sch em e 4
After identifying the best Lewis acid, we then extended
this process catalyzed by zinc chloride to other boronic
esters. We initially examined arylboronic esters. We have
been agreeably surprised to observe that in all the cases
examined, high diastereoselectivities were obtained (en-
tries 6 and 7). It is important to note that the presence
chemical shift was attributed to an “ate” complex 3a
which results from complexation of the ethoxide, liber-
ated during the 1,2-migration of the phenyl group.25 This
(28) Matteson, D. S.; Sadhu, K. M. J . Am. Chem. Soc. 1983, 105,
2
077-2078.
(29) An excess of zinc chloride is also required during the Matteson
homologation with compounds containing oxygen functionality. Refer-
ence 8a.
observation is consistent with the rearrangement of 2a
to 3a taking place between -100 and -60 °C.26 The
(30) A mixture of 4a , lithium ethoxide and zinc chloride in THF was
stirred overnight at room temperature. No detectable epimerization
is observed only a small degradation of the product (∼2%).
product 3a did not change after standing overnight at
(
31) Systematic names of 4: 4a , {3aS-[2(R*),3aR,4â,6â,7aR]}-2-[1-
room temperature. It is only after addition of a saturated
solution of NH Cl and extraction with diethyl ether that
4
(
ethoxy)phenylmethyl]hexahydro-3a,5,5-trimethyl-4-6-methano-1,3,2-
benzodioxaborole; 4b , {3aS-[2(R*),3aR,4â,6â,7aR]}-2-[1-(ethoxy)(4-
bromophenyl)methyl]hexahydro-3a,5,5-trimethyl-4-6-methano-1,3,2-
benzodioxaborole; 4c, {3aS-[2(R*),3aR,4â,6â,7aR]}-2-[1-(ethoxy)(1-
naphthyl)methyl]hexahydro-3a,5,5-trimethyl-4-6-methano-1,3,2-
benzodioxaborole; 4e, {3aS-[2(R*),3aR,4â,6â,7aR]}-2-[1-(ethoxy)-2-
m et h ylet h yl]h exa h ydr o-3a ,5,5-t r im et h yl-4-6-m et h a n o-1,3,2-
benzodioxaborole; 4f, {3aS-[2(R*),3aR,4â,6â, 7aR]}-2-[1-(ethoxy)-
heptyl]hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborole;
the R-alkoxy derivative 4a was obtained. The stability
of 3a is probably due to a strong coordination with
boron.27 The B NMR of 4a showed a peak (δ +31)
shifted downfield from the starting material 1a (Scheme
11
3
).
We then examined the influence of an added Lewis acid
Scheme 4 and Table 1). We were encouraged in this
approach by the observation made by Matteson that the
4
g, {3aS-[2(R*),3aR,4â,6â,7aR]}-2-[1-(ethoxy)ethyl]hexahydro-3a,5,5-
(
trimethyl-4-6-methano-1,3,2-benzodioxaborole; 4h , {3aS-[2(R*),-
3
4
2
aR,4â,6â,7aR]}-2-[1-(methoxy)phenylmethyl]hexahydro-3a,5,5-trimethyl-
-6-methano-1,3,2-benzodioxaborole; 4i, {3aS-[2(R*),3aR,4â,6â,7aR]}-
-[1-(methoxy)ethyl]hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-
(
25) The same chemical shift was observed when 4a was treated
benzodioxaborole. The 3aS designates the absolute configuration of the
entire molecule by reference to carbon 3a. The 2(R*) indicates that
this is the enantiomer in which the side chain at position 2 would have
the R configuration if position 3a were R, but since position 3a is S,
the side chain is S.
with lithium ethoxide in THF.
(
methylboronate 1g. The migration of the methyl group was observed
at an upper temperature to -60 °C.
(
Handbook of Chemistry, Thirteenth Edition; MacGraw-Hill: New York,
985; pp 3-128.
26) The same NMR study was realized with the (+)-pinanediol
27) B-O; ∆Hf25° ) 188 kcal mol-1. Dean, J . A. Ed. Lange’s
(32) The diastereoisomer of 4e was obtained by substitution of (+)-
7
a
pinanediol-(1S)-1-chloro-2-methylpropylboronate with lithium ethox-
1
ide.

5
406 J . Org. Chem., Vol. 65, No. 17, 2000
Notes
Sch em e 5
reagents. This new process provides a convenient and
one-step method to obtain the R-alkoxy boronic esters.
When the reaction is catalyzed by zinc chloride, a high
diastereoselection has been obtained from aryl and sec-
alkylboronates (g98%).
This new procedure complements the existing meth-
odology described by Matteson, making it possible to
synthesize both (1R)- and (1S)-alkoxy boronic esters with
the same chiral director. With the ready availability of
(dialkoxymethyl)lithium reagents, this method should be
adaptable to the synthesis of a wide variety of R-alkoxy
boronic esters. Studies to further examine the origin of
the stereoselectivity, scope and limitations of the meth-
odology are currently under investigation.
of a bromine atom on the aryl ring was tolerated under
these conditions. We have not observed byproducts
resulting from lithium-halogen exchange. A disappoint-
ing result was obtained with the vinylboronate 1d given
that the expected product was not isolated (entry 8). The
major product was hydroxyl pinanediol borate which may
Exp er im en ta l Section
Gen er a l P r oced u r es. Reactions were performed in oven-
dried glassware under an argon atmosphere. Tetrahydrofuran
3
3
2
be the result of decomposition catalyzed by ZnCl .
(THF) was distilled from deep blue solutions of sodium/ben-
Isopropylboronate gave the R-alkoxy derivative 4e in
g98% de (entry 9) while the n-alkylboronates produced
the corresponding product in 66% de (entries 10, 11).
Clearly, our results indicates that the de of the final
product 4 is dependent upon R. In addition to steric
effects, the high diastereoselectivity obtained with aryl-
boronates may be explained partially by the high migra-
tory aptitude of the aryl groups compared to the n-alkyl
groups.34
We have also experimented (dimethoxymethyl)lithium
in our homologation reaction. The results are similar with
those obtained with (diethoxymethyl)lithium except the
yields are lower (entries 12, 13). It should be noted that
even at -100 °C, the reaction does not take place using
the dibenzyloxymethyltributyltin, presumably due to the
higher acidity of the benzylic proton which preclude the
formation of the prerequisite (dibenzyloxymethyl)lithi-
um.35
From a mechanistic point of view, taking into account
the absolute configuration of the final product, it can be
proposed that the reaction proceeds as depicted in
Scheme 5. According to the litterature,36 we believe that
the dialkoxymethyllithium reagent adds to the (+)-
pinanediol boronate exclusively on the less sterically
hindered side of the boron atom. We can deduce that the
reaction involves complexation of a Lewis acid with one
of the two oxygens of the boronic ester and that the Lewis
acid then assists one of the two prochiral alkoxide groups
zophenone ketyl prior to use. n-BuLi, 1.6 M in hexane, purchased
from Aldrich Chemical Co., Inc., was titrated as indicated by
38
Watson and Eastham. ZnCl
2
was vacuum-dried at 100 °C/0.1
Torr. All boronic acids were purchased (Lancaster Synthesis Ltd)
3
9
40
except 1-(methyl)ethylboronic acid, hexylboronic acid and
-hexenylboronic acid.41 The (+)-pinanediol (used as purchased
from Aldrich Company) was 98% ee. Melting points are uncor-
rected. NMR spectra were recorded in CDCl on a 200- or 300-
MHz spectrometer operating in the Fourier transform mode.
1
3
1
3
C
NMR spectra were obtained with broadband proton decoupling.
Chemical shifts were recorded relative to the internal TMS
(tetramethylsilane) reference signal. For 11B NMR, the chemical
shifts are in ppm relative to BF
3
2
‚OEt . Optical rotations were
measured using 10-cm cell at 20 °C, and the concentration is
expressed in g/dL. HRMS were performed by Centre R e´ gional
de Mesures Physiques de l’Ouest. Microanalysis were done at
the Central Laboratory for Analysis, CNRS, Lyon, (France).
Silica gel 60F254 was used for column chromatography.
(
+)-P in a n ed iol Bor on ic Ester s. A solution of (+)-pinanediol
and 1.1 equivalent of the boronic acid in ether was stirred
overnight at room temperature. The organic phase was washed
with water, dried over magnesium sulfate, concentrated, and
the boronic ester was chromatographied or recrystallized. The
NMR and analytical data of 1a , 1g,1 and 1e have been
1b
42
reported.
(
+)-P in a n ed iol (4-br om op h en yl)bor on a te (1b): mp 83-
20
8
1
5 °C; 95% (R
f
) 0.4, heptane: ethyl acetate 95:5); [R]
D
+7.6 (c
1
.0 in CHCl ); H NMR (200 MHz, CDCl ) δ 7.44 (d, J ) 8.4 Hz,
3
3
2H), 7.23 (d, J ) 8.4 Hz, 2H), 4.44 (dd, J ) 1.8, 8.7 Hz, 1H),
2.41-1.92 (m, 5H), 1.47 (s, 3H), 1.31 (s, 3H), 1.17 (d, J ) 10.6
Hz, 1H), 0.88 (s, 3H); 13C NMR (50 MHz, CDCl
) δ 136.3, 131.0,
26.2, 86.5, 78.4, 51.4, 39.5, 38.2, 35.5, 28.7, 27.1, 26.5, 24.0;
3
1
N
in leaving. The migration is then carried out in an S 2
+
HRMS (EI) calcd for C16
H
20BBrO
2
(M ) 334.0739, found 334.0739.
manner, anti to the departing oxygen. Although the
reactions are different, we were consolidated on this
interpretation by the fact that we obtained the same
Anal. Calcd for C16
H, 6.07.
H20BBrO : C, 57.36; H, 6.02. Found: C, 57.32;
2
(
+)-P in a n ed iol (1-n a p h th yl)bor on a te (1c): mp 73-75 °C;
20
3
7
configuration as during the homologation with LiCHCl
2
.
9
8% (R
f
) 0.28, heptane: ethyl acetate 95:5); [R]
D
+5.1 (c 1.0
) δ 8.75 (m, 1H), 8.08 (dd,
J ) 1.4, 6.8 Hz, 1H), 7.93 (dd, J ) 1.4, 8.2 Hz, 1H), 7.83 (dd, J
1
3 3
in CHCl ); H NMR (300 MHz, CDCl
Con clu sion s
)
1
0
1.7, 7.9 Hz, 1H), 7.54-7.44 (m, 3H), 4.55 (dd, J ) 1.9, 8.7 Hz,
In this paper, we have developed a new homologation
reaction of boronic esters with (dialkoxymethyl)lithium
H), 2.47-1.97 (m, 5H), 1.56 (s, 3H), 1.34 (m, 3H), 1.29 (s, 1H),
13
3
.93 (s, 3H); C NMR (50 MHz, CDCl ) δ 136.9, 135.7, 133.2,
(
33) The R-ethoxy derivative 4d was obtained from the (+)-pi-
nanediol 1-hexenylboronate without Lewis acid in 14% de, yield 50%.
34) No quantitative study of migratory aptitudes was carried out
(38) Watson, S. C.; Eastham, J . F. J . Organomet. Chem. 1967, 9,
165-168.
(39) Brown, H. C.; Srebnik, M.; Cole, T. E. Organometallics 1986,
(
in homologation reaction, contrary to the oxidative deboronation.
However, certain brief replies are given in the ref 15a.
5, 2300-2303.
(
(
35) Sch o¨ llkopf, U. Angew. Chem., Int. Ed. Engl. 1970, 9, 763-773.
(40) Brown, H. C.; Ravindran, N.; Kulkarni, S. U. J . Org. Chem.
36) Tsai, D. J . S.; J esthi, P. K.; Matteson, D. S. Organometallics
1980, 45, 384-389.
1
983, 2, 1543-1545.
37) (a) Corey, E. J .; Barnes-Seeman, D.; Lee, T. W. Tetrahedron:
Asymmetry 1997, 8, 3711-3713. (b) Midland, M. J . Org. Chem. 1998,
3, 914-915.
(41) Brown, H. C.; Campbell, J . B. J . Org. Chem. 1980, 45, 389-
(
395.
(42) Matteson, D. S.; J esthi, P. K.; Sadhu, K. M. Organometallics
1984, 3, 1284-1288.
6

Notes
J . Org. Chem., Vol. 65, No. 17, 2000 5407
1
3
3
3
31.5, 128.4, 128.3, 126.3, 125.5, 125.0, 86.1, 78.1, 51.5, 39.6,
(96 MHz, CDCl
3
) δ 31.5; HRMS (EI) calcd for C21
H
24BO
29BO
3
(M+
-
1
1
5.7, 28.8, 28.2, 27.1, 26.6, 24.0; B NMR (96 MHz, CDCl
3
) δ
(M ) 306.1791, found
2
: C, 78.45; H, 7.57. Found:
C
2
H
5
) 335.1818, found 335.1827. Anal. Calcd for C23
H
3
: C,
+
0.7; HRMS (EI) calcd for C20
H
23BO
2
75.83; H, 8.02. Found: C, 75.77; H, 8.13. An epimeric mixture,
prepared without a Lewis acid, showed the presence of additional
06.1784. Anal. Calcd for C20
H
23BO
1
C, 78.54; H, 7.49.
peaks in the H NMR ((1R) δ 4.87, 4.30, 1.38, 0.72). No evidence
(
+)-P in a n ed iol 1-h exen ylbor on a te (1d ): oil; 95% (R
f
)
of the epimer was seen in the sample of 4c.
2
0
0
.21, heptane: ethyl acetate 99:1); [R]
D
3
+17.1 (c 1.0 in CHCl );
(
S)-P in an ediol (1S)-[1-(eth oxy)-2-m eth ylpr opyl]bor on ate
1
H NMR (200 MHz, CDCl
3
) δ 6.64 (dt, J ) 18.0, 6.4 Hz, 1H),
20
(
4e): oil; 66% (R
f
) 0.19, heptane/ethyl acetate 97:3); [R]
D
+32.8
) δ 4.33 (dd, J ) 2.2,
.8 Hz, 1H), 3.53 (qd, J ) 6.9, 9.1 Hz, 1H), 3.43 (qd, J ) 6.9, 9.1
5
2
1
.45 (dt, J ) 18.0, 1.4 Hz, 1H), 4.29 (dd, J ) 8.7, 1.6 Hz, 1H),
1
3 3
(c 1.0 in CHCl ); H NMR (500 MHz, CDCl
.25-1.84 (m, 7H), 1.44-1.34 (m, 4H), 1.40 (s, 3H), 1.29 (s, 3H),
.15 (d, J ) 10.8 Hz, 1H), 0.89 (t, J ) 7.1 Hz, 3H), 0.85 (s, 3H);
8
Hz, 1H), 2.97 (d, J ) 6.4 Hz, 1H), 2.42-1.83 (m, 6H), 1.40 (s,
1
3
3
C NMR (50 MHz, CDCl ) δ 155.0, 85.1, 78.0, 51.8, 39.9, 38.5,
3
1
3
3
H), 1.29 (s, 3H), 1.20 (t, J ) 6.9 Hz, 3H), 1.18 (d, J ) 10.3 Hz,
3
5.9, 30.8, 29.0, 27.5, 26.8, 26.7, 24.4, 22.6, 14.3; HRMS (EI)
H), 0.98 (d, J ) 6.8 Hz, 3H), 0.96 (d, J ) 6.8 Hz, 3H), 0.85 (s,
+
calcd for C16
for C16 27BO
H
27BO
2
(M ) 262.2104, found 262.2108. Anal. Calcd
: C, 73.29; H, 10.38. Found: C, 73.18; H, 10.31.
) 0.26,
3
); H NMR (200 MHz, CDCl )
13
3
H); C NMR (50 MHz, CDCl ) δ 86.1, 77.9, 66.3, 51.1, 39.5,
11
H
2
8.1, 35.5, 30.5, 28.8, 27.1, 26.7, 24.1, 19.6, 19.5, 15.6; B NMR
(
+)-P in a n ed iol h exylbor on a te (1e): oil; 94% (R
f
+
(96 MHz, CDCl
3
) δ 31.85; HRMS (EI) calcd for C14
H
24BO
3
(M
2
0
1
heptane); [R]
D
+5.1 (c 1.0 in CHCl
3
-
C
2
H
5
) 251.1818, found 251.1818. Anal. Calcd for C16
H
29BO :
3
δ 4.25 (dd, J ) 1.8, 8.6 Hz, 1H), 2.32-1.80 (m, 5H), 1.38 (s, 3H),
C, 68.58; H, 10.43. Found: C, 68.31; H, 10.46. The position of
the epimer peaks was verified by the synthesis of the diastere-
1
.35 (m, 8H), 1.29 (s, 3H), 1.12 (d, J ) 10.7 Hz, 1H), 0.90-0.77
13
(m, 5H), 0.84 (s, 3H); C NMR (50 MHz, CDCl
3
) δ 85.2, 77.7,
32 1
omer of 4e: H NMR ((1R) δ 3.51, 3.46, 1.41, 0.97 instead of
5
1
7
1.3, 39.6, 38.1, 35.6, 32.2, 31.7, 28.7, 27.1, 26.5, 24.1, 24.0, 22.6,
13
3
.53, 3.43, 1.40, 0.98 for (1S)); C NMR ((1R) δ 30.2 and 26.6
4.1. Anal. Calcd for C16
2.80; H, 11.15.
2
H29BO : C, 72.73; H, 11.06. Found: C,
instead of 30.5 and 26.7 for (1S)). No evidence of the epimer was
seen in the sample of 4e.
Gen er a l P r oced u r e for Rea ction of (Dia lk oxym eth yl)-
(
S)-P in a n ed iol (1S)-[1-(eth oxy)h ep tyl]bor on a te (4f): oil;
lith iu m s w ith Bor on ic Ester s in th e P r esen ce of Zin c
Ch lor id e. A solution of dialkoxymethyltributyltin (0.89 mmol)
in 2 mL of THF was cooled to -100 °C in a 95% ethanol/liquid
nitrogen bath and stirred magnetically during the dropwise
addition of 1.07 mmol of n-butyllithium (1.6 M in hexane). After
20
6
5% (R
f
) 0.20, heptane: ethyl acetate 95:5); [R]
3
D
-6.0 (c 1.0
1
in CHCl
); H NMR (200 MHz, CDCl ) δ 4.32 (dd, J ) 2.0, 8.8
3
Hz, 1H), 3.53-3.44 (m, 2H), 3.27 (t, J ) 6.4 Hz, 1H), 2.37-1.86
(
(
(
m, 5H), 1.71-1.59 (m, 2H), 1.40 (s, 3H), 1.38-1.27 (m, 8H), 1.29
s, 3H), 1.20 (t, J ) 7.0 Hz, 3H), 1.15 (d, J ) 10.8 Hz, 1H), 0.87
1
5-20 min at -100 °C, a solution of 0.89 mmol of the boronic
13
3
t, J ) 7.0 Hz, 3H), 0.85 (s, 3H); C NMR (75 MHz, CDCl ) δ
esters 1 in 1 mL of THF was added slowly, and then the solution
of anhydrous zinc chloride (0.27 mmol) in 2-3 mL of THF was
added. The mixture was allowed to warm to room temperature
slowly and stirred overnight. The reaction mixture was quenched
8
6.1, 78.0, 65.5, 51.2, 51.1 (epimer 17%), 39.5, 38.1, 35.5, 35.4
(epimer 17%), 31.8, 31.5, 31.3 (epimer 17%), 29.5, 28.7, 27.1, 26.6,
11
2
6.5 (epimer 17%), 26.4, 24.0, 22.6, 15.6, 14.1; B NMR (96 MHz,
+
CDCl
3
) δ 31.8. HRMS (EI) calcd for C17
H
30BO
3
(M - C
2 5
H )
4
with 5 mL of saturated aqueous NH Cl and the aqueous phase
2
93.2288, found 293.2276. Anal. Calcd for C19
H
35BO
3
: C, 70.81;
was extracted with diethyl ether. The combined organic phases
were washed with brine, dried over magnesium sulfate, filtrated
and concentrated under reduced pressure. The residue was
purified by flash chromatography on silica gel (210-400 mesh),
initially with 100% heptane to remove tin byproducts, followed
by 1-5% ethyl acetate/heptane gradient elution.
H, 10.95. Found: C, 71.08; H, 11.01. The position of the epimer
peaks was verified by the synthesis of the diastereomer of 4f
via the R-chloro derivative.
(
S)-P in a n ed iol (1S)-[1-(eth oxy)eth yl]bor on a te (4 g): oil;
2
0
6
3% (R
f
) 0.17, heptane/ethyl acetate 95:5); [R]
3 3
D
+30.0 (c 1.0
1
in CHCl ); H NMR (200 MHz, CDCl ) δ 4.32 (dd, J ) 1.9, 8.9
Hz, 1H), 3.61-3.43 (m, 2H), 3.38 (q, J ) 7.6 Hz, 1H), 2.37-1.87
(m, 5H), 1.41 (s, 3H), 1.30 (d, J ) 7.6 Hz, 3H), 1.29 (s, 3H), 1.21
(
S)-P in a n ed iol (1S)-[1-(eth oxy)p h en ylm eth yl]bor on a te
2
0
(
4a ): oil; 65% (R
f
) 0.25, heptane/ethyl acetate 95:5); [R]
D
-53.6
1
(c 1.0 in CHCl
3
); H NMR (200 MHz, CDCl
3
) δ 7.39-7.18 (m,
1
3
(
t, J ) 7.0 Hz, 3H), 1.14 (d, J ) 10.8 Hz, 1H), 0.84 (s, 3H);
C
5
2
7
H), 4.33 (s, 1H), 4.29 (dd, J ) 2.0, 8.8 Hz, 1H), 3.59-3.30 (m,
3
NMR (75 MHz, CDCl ) δ 86.2, 78.1, 65.1, 65.0 (epimer 17%),
51.1, 39.4, 38.1, 35.4, 35.3 (epimer 17%), 28.6, 27.1, 26.5, 26.4
(
H), 2.33-1.66 (m, 5H), 1.34 (s, 3H), 1.24 (s, 3H), 1.21 (t, J )
.0 Hz, 3H), 0.90 (m, 1H), 0.80 (s, 3H); 13C NMR (50 MHz, CDCl
3
)
epimer 17%), 24.0, 16.7, 16.5 (epimer 17%), 15.6; 11B NMR (96
δ 139.3, 127.3, 126.0, 125.7, 85.4, 77.3, 64.4, 50.1, 38.2, 37.1,
+
4.2, 27.3, 26.0, 25.1, 22.9, 14.3; 1 B NMR (96 MHz, CDCl
1
MHz, CDCl
3
) δ 31.9; HRMS (EI) calcd for C12
H
20BO
3
(M
-
3
3
3
3
) δ
+
C
2
H
5
) 223.1505, found 223.1510. Anal. Calcd for C14
H
25BO
3
: C,
1.0; HRMS (EI) calcd for C19
H
27BO
3
(M ) 314.2053, found
6
6.68; H, 9.99. Found: C, 66.41; H, 10.15. The position of the
14.2067. Anal. Calcd for C19
H
27BO
3
: C, 72.62; H, 8.66. Found:
epimer peaks was verified by the synthesis of the diastereomer
of 4g via the R-chloro derivative.
(S)-P in an ediol (1S)-[1-(m eth oxy)ph en ylm eth yl]bor on ate
C, 72.70; H, 8.80. An epimeric mixture, prepared without a Lewis
acid, showed the presence of additional peaks in the H NMR
1
1
3
(
(1R) δ 1.37) and C NMR ((1R) δ 64.2 and 24.9). No evidence
of the epimer was seen in the sample of 4a .
S)-P in a n ed iol (1S)-[1-(eth oxy)(4-br om op h en yl)m eth yl]-
2
0
(
4h ): oil; 44% (R
69.8 (c 1.0 in CHCl
m, 5H), 4.22 (dd, J ) 2.0, 8.7 Hz, 1H), 4.12 (s, 1H), 3.21 (s, 3H),
2.17-1.60 (m, 5H), 1.29 (s, 3H), 1.17 (s, 3H), 0.84 (d, J ) 10.2
Hz, 1H), 0.73 (s, 3H); 13C NMR (50 MHz, CDCl
) δ 138.6, 127.4,
26.1, 125.9, 85.5, 77.3, 57.0, 50.1, 38.3, 37.1, 34.1, 27.4, 26.0,
5.1, 22.9; 11B NMR (96 MHz, CDCl
) δ 30.6; HRMS (EI) calcd
300.1897, found 300.1914. Anal. Calcd for C18
f
) 0.23, heptane/ethyl acetate 90:10); [R]
D
1
-
(
3 3
); H NMR (200 MHz, CDCl ) δ 7.27-7.15
(
bor on a te (4b): oil; 42% (R
f
) 0.18, heptane/ethyl acetate 95:
2
0
1
5
7
3
2
1
); [R]
D
3 3
-6.0 (c 1.0 in CHCl ); H NMR (200 MHz, CDCl ) δ
.47-7.19 (m, 4H), 4.29 (dd, J ) 2.0, 8.6 Hz, 1H), 4.28 (s, 1H),
.49 (qd, J ) 7.0, 9.5 Hz, 1H), 3.38 (qd, J ) 7.0, 9.5 Hz, 1H),
.35-1.39 (m, 5H), 1.37 (epimer 2%), 1.34 (s, 3H), 1.25 (s, 3H),
.20 (t, J ) 7.0 Hz, 3H), 0.87 (d, J ) 10.1 Hz, 1H), 0.80 (s, 3H);
3
1
2
3
for C18
H
25BO
3
H
25
-
1
3
BO : C, 72.02; H, 8.39. Found: C, 72.06; H, 8.41. An epimeric
C NMR (50 MHz, CDCl
8.4, 65.6, 51.2, 39.3, 38.1, 35.2, 28.4, 27.0, 26.2, 24.0, 15.3;
) δ 30.9. Anal. Calcd for C19
O: C, 56.24; H, 6.81. Found: C, 56.21; H, 6.57. The position
3
) δ 139.6, 131.4, 128.5, 120.4, 86.6,
3
1
1
mixture, prepared without a Lewis acid showed the presence of
additional peaks in the 1H NMR ((1R) δ 3.20 and 1.30). No
evidence of the epimer was seen in the sample of 4h .
7
B
NMR (96 MHz, CDCl
.7H
3
3
H26BO Br‚
0
2
of the epimer peak was verified by the synthesis of 4b without
a Lewis acid.
(S)-P in a n ed iol (1S)-[1-(m eth oxy)eth yl]bor on a te (4i): oil;
2
0
40% (R +28.0 (c 1.0
f
) 0.18, heptane/ethyl acetate 90:10); [R]
3 3
D
1
(
S)-P in a n ed iol (1S)-[1-et h oxy(1-n a p h t h yl)m et h yl]bor -
in CHCl ); H NMR (200 MHz, CDCl ) δ 4.25 (dd, J ) 1.8, 8.7
on a te (4c): oil; 62% (R
f
) 0.16, heptane/ethyl acetate 95:5);
Hz, 1H), 3.30 (s, 3H), 3.21 (q, J ) 7.5 Hz, 1H), 2.29-1.79 (m,
5H), 1.35 (s, 3H), 1.24 (d, J ) 7.5 Hz, 3H), 1.22 (s, 3H), 1.06 (d,
2
0
1
[R]
D
3 3
-22.1 (c 0.8 in CHCl ); H NMR (300 MHz, CDCl ) δ 8.37-
8
4
5
1
1
6
.32 (m, 1H), 7.88-7.75 (m, 2H), 7.56-7.40 (m, 4H), 4.88 (s, 1H),
.32 (dd, J ) 2.0, 8.8 Hz, 1H), 3.53-3.32 (m, 2H), 2.18-1.61 (m,
H), 1.29 (s, 3H), 1.22 (s, 3H), 1.18 (t, J ) 7.1 Hz, 3H), 0.98 (m,
J ) 10.8 Hz, 1H), 0.77 (s, 3H); 13C NMR (50 MHz, CDCl
3
) δ 86.4,
86.3 (epimer 18%), 78.2, 57.6, 51.1, 39.4, 38.1, 35.4, 35.3 (epimer
1
1
18%), 28.6, 27.1, 26.5, 24.0, 15.9, 15.7 (epimer 18%); B NMR
H), 0.78 (s, 3H); 13C NMR (50 MHz, CDCl
) δ 136.3, 133.9,
(96 MHz, CDCl
CH ) 223.1505, found 223.1465. Anal. Calcd for C13
) δ 31.8; HRMS (EI) calcd for C12
H
20BO
(M
+
-
3
3
3
31.6, 128.4, 127.7, 125.9, 125.6, 125.5, 125.4, 124.9, 86.7, 78.4,
3
H
3
23BO : C,
5.3, 51.0, 39.2, 38.1, 35.2, 28.4, 27.0, 26.3, 23.9, 15.4; 11B NMR
65.57; H, 9.74. Found: C, 65.73; H, 9.99. The position of the

5
408 J . Org. Chem., Vol. 65, No. 17, 2000
Notes
epimer peaks was verified by the synthesis of the diastereomer
of 4i via the R-chloro derivative.
J . P. Quintard. In addition, we thank S. Sinbandhit for
running the NMR spectra.
Ackn owledgm en t. Financial support from the CNRS
and a doctoral fellowship from “Conseil R e´ gional de
Bretagne” to L.C. are gratefully acknowledged. Wethank
Prof. D. S. Matteson for fruitful discussions at the time
of his stay in Rennes as invited Professor, and, too, Prof.
Su p p or tin g In for m a tion Ava ila ble: Copies of H and 13C
NMR spectra of compounds 4a -i. This material is available
free of charge via the Internet at http://pubs.acs.org.
1
J O000457R