Synthesis of enantiomerically pure cis-cyclopropylboronic esters

Article abstract of DOI:10.1002/1099-0690(200007)2000:14<2557::aid-ejoc2557>3.0.co;2-i

Highly stable, enantiomerically pure cyclopropylboronic esters are desirable building blocks for the preparation of a plethora of different cyclopropane derivatives. Whereas trans-configured compounds proved to be readily available, we herein report the f

Full text of DOI:10.1002/1099-0690(200007)2000:14<2557::aid-ejoc2557>3.0.co;2-i

FULL PAPER
Synthesis of Enantiomerically Pure cis-Cyclopropylboronic Esters
Joachim E. A. Luithle[a] and Jörg Pietruszka*[a]
Dedicated to Professor Dr. Dr. h.c. Franz Effenberger on the occasion of his 70th birthday
Keywords: Boron / Chiral auxiliaries / Cycloadditions / Cyclopropanes / Ring opening
Highly stable, enantiomerically pure cyclopropylboronic es-
ters are desirable building blocks for the preparation of a
plethora of different cyclopropane derivatives. Whereas
trans-configured compounds proved to be readily available,
we herein report the first synthesis of the corresponding cis-
cyclopropanes. The scope and limitation of this process will
be discussed. The absolute configuration of the products
could be established by means of chemical and spectro-
scopic correlation.
Introduction
taining a cis-1,2-disubstituted cyclopropane, e.g. cepaciam-
ides[8] or plakosides,[9] establishing a route to this class of
compounds was highly desirable.
Due to the potential of boronic acids and esters,[1] it is
not surprising that an increasing number of reports also
deal with their application in cyclopropane chemistry.[2Ϫ4]
Cyclopropylboronic esters are especially attractive synthetic
targets, since on the one hand, the cyclopropane moiety is
incorporated into pharmaceuticals and natural products,[5]
Results and Discussion
One problem associated with the synthesis of cis-cyclo-
and on the other hand a general method for obtaining en- propylboronic esters is the availability of the starting mat-
antiomerically pure compounds is still elusive.[6] With a erials. Whereas the synthesis of (E)-alkenylboronic acids
plethora of transformations possible, enantiomerically pure and esters is straightforward, routes to the corresponding
cyclopropylboronic esters qualify to be considered as uni- (Z)-products are less direct.[1] The reported alternatives
versal building blocks. Early work in this area suffered from were a) the hydroboration of 1-haloalkynes 4, followed by
the relative lability of this class of compounds; the classical reduction/inversion,[10] b) the selective oxidation of (Z)-1-
advantages of the diastereoselective synthesis, i.e. the sep- alkenylboranes,[11] c) the reaction of (Z)-alkenyllithium with
aration of diastereomers, could not be profitably ex- borates,[12] d) the cis-hydrogenation[13] or hydrozirconation
ploited.[3] By utilizing diol 1,[4,7] we demonstrated that of 1-alkynylboronates,[14] or e) the reaction of lithio(trime-
highly stable boronic esters can be isolated, conveniently thylsilyl)methaneboronic ester with aldehydes (70:30 in
purified and stored. Although we reported a reliable proto- favor of the cis-isomer).[15] In our hands, using the bulky
col for the transformation of alkynes 2 to the trans-1,2-dis- diol 1, we could only successfully apply method c
ubstituted cyclopropanes 3 (Scheme 1), neither the corres- (Scheme 2). Following a sequence first reported by Kluge,
ponding nor other cis-configured cyclopropylboronic esters Untch, and Fried,[16] we synthesized 1-iodoalkyne 4 from
have been synthesized until now. In view of our interest in 1-alkyne 2, followed by the diimide reduction (via the de-
the synthesis of naturally occurring cyclopropanes con- composition of dipotassium azodicarboxylate)[17] to yield
Scheme 1. Synthesis of stable, enantiomerically pure trans-cyclopropylboronic esters 3
(Z)-vinyl iodide 5. Next, lithium-iodide-exchange with
tBuLi,[18] formation of an ate complex, and direct transes-
[a]
Institut für Organische Chemie, Universität Stuttgart,
Pfaffenwaldring 55, D-70569 Stuttgart, Germany
Fax: (internat.) ϩ49(0) 711-685/4269
terification gave the alkenylboronic esters 6. Controlling the
reaction temperature is crucial, especially when adding tri-
isopropyl borate, e.g. transformation of 5b would exclusively
give the (E)-isomer, when performed at ambient temper-
ature. The last step of this sequence is extremely sluggish
E-mail: joerg.pietruszka@po.uni-stuttgart.de
Supporting information for this article is available on the
WWW under http://www.wiley-vch.de/home/eurjoc or from
the author.
Eur. J. Org. Chem. 2000, 2557Ϫ2562
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J. E. A. Luithle, J. Pietruszka
FULL PAPER
Scheme 2. Synthesis of cis-alkenylboronic esters 6 (MOM ϭ me-
thoxymethyl, TBS ϭ tBuMe2Si)
Scheme 4. Synthesis of hydroxymethylcyclopropylboronic esters 10
and 11
and with bulky substituents no product was formed (e.g.
when starting from silyl-protected alcohol 5d).
Hg(CF3CO2)2 in CH2Cl2. In the following step the crude
material was directly reduced to the primary alcohol (S)-
13. This result could be correlated by GLC with a reference
sample that we obtained after the known lipase-catalyzed
acetylation of (rac)-13 with vinyl acetate.[21] In this case,
Barth and Effenberger had observed the preferred forma-
tion of (S)-14 with the alcohol (R)-14 accumulating. Since
one stereogenic center remained untouched during the
whole sequence, we proved the configuration of the boronic
ester 7a. With this result in our hands, we could rely on the
characteristic NMR data of our cyclopropylboronic ester
(Table 1).[4] Again, the chemical shifts for both, proton 3Ј-
Htrans and carbon C-3Ј, follow a distinct pattern for the two
diastereomeric series: the major diastereomer shows a
downfield shift in all cases (1H: 0.21Ϫ0.44 ppm; 13C:
0.12Ϫ1.20 ppm), thus allowing us to assign the configura-
tion of all synthesized cis-1,2-disubstituted cyclopro-
pylboronic esters.
The cyclopropanation of alkenylboronic esters 6 by the
PdII-catalyzed decomposition of diazomethane furnished
cyclopropylboronic esters 7 and 8 in high yields (Scheme 3).
Although we performed the reaction utilizing our improved
protocol,[4] the diastereoselectivity was relatively poor.
Nevertheless, the diastereomeric 1,3,2-dioxaborolanes could
be separated.[19] In view of the high stability of our boronic
esters towards acids, we envisaged deprotection of the
MOM-derivative 6c; the alcohol should have enabled us to
perform a SimmonsϪSmith cyclopropanation. These con-
ditions are known to give complementary diastereoselectivi-
ties.[4] We were surprised to find that although the deprotec-
tion to give alcohol 9 was possible (Scheme 4), the cyclopro-
panation step failed. The PdII-catalyzed reaction led to de-
composition, whereas under SimmonsϪSmith conditions
the starting material was re-isolated. While controlling the
reaction, TLC indicated that diol 1 was formed. We pre-
sume that under basic conditions an intramolecular ate
complex A promotes the hydrolysis, however, upon workup
re-condensation occurs. Finally, the desired building blocks
10 and 11 were synthesized by deprotection of the cyclopro-
pylboronic esters 7c and 8c, respectively. The use of HCl/
MeOH proved to be superior to PPTS (pyridinium toluene-
4-sulfonate) in tBuOH or HCl/NaI/acetone.
Scheme 5. Determination of the absolute configuration of cyclo-
propylboronic ester 7a by chemical correlation
Table 1. Characteristic NMR data (1H: 500 MHz; 13C: 125 MHz;
CDCl3) for diastereomeric cyclopropylboronic esters
Scheme 3. Diastereoselective cyclopropanation of 6 to yield 7 and 8
The absolute configuration of the cyclopropylboronic es-
ters 7 and 8 could not be directly determined; neither were
we able to obtain an X-ray crystal structure. Also, the cor-
responding cyclopropanols were not known. For the chem-
ical correlation of cyclopropylboronic ester 7a (Scheme 5),
we first synthesized cyclopropanol 12 (81%).[20] For a ring-
opening reaction an analytical sample was treated with
2558
Eur. J. Org. Chem. 2000, 2557Ϫ2562

Synthesis of Enantiomerically Pure cis-Cyclopropylboronic Esters
FULL PAPER
(t, J ϭ 7.0 Hz, 3 H, 6Ј-H), 1.08 (mc, 4 H, 4Ј-H and 5Ј-H), 1.91 (mc,
1 H, 3Ј-Ha), 1.95 (mc, 1 H, 3Ј-Hb), 3.00 (s, 6 H, OMe), 4.90 (br d,
J ϭ 13.5 Hz, 1 H; 1Ј-H), 5.31 (s, 2 H, 4-H and 5-H), 6.20 (dt, J ϭ
13.5 Hz, J ϭ 7.6 Hz, 1 H, 2Ј-H), 7.22Ϫ7.39 (m, 20 H, arom.-H).
Conclusion
In summary, we have synthesized cis-configured cyclo-
propylboronic esters for the first time. The stability of the
1,3,2-dioxaborolan unit allowed for the separation of the
diastereomers, thus giving enantiomerically pure cyclopro-
panes, and the acid-catalyzed cleavage of the MOM-pro-
tecting group. The absolute configuration of the products
Ϫ
13C NMR (125 MHz, CDCl3): δ ϭ 13.9 (q, C-6Ј), 22.3, 31.5 (t,
C-5Ј/C-4Ј), 31.6 (t, C-3Ј), 51.8 (q, OMe), 77.3 (d, C-4/C-5), 83.4 (s,
CPh2OMe), 116.8 (br d, C-1Ј), 127.14, 127.18, 127.22, 127.3, 127.4,
127.5, 127.7, 127.80, 128.4, 129.7 (d, arom.-CH), 141.22, 141.28,
141.6 (s, arom.-Cipso), 155.2 (d, C-2Ј). Ϫ MS (EI, 70 eV); m/z (%):
were determined by means of chemical correlation and 546 (Ͻ0.1) [Mϩ], 514 (1.8) [M Ϫ MeOHϩ], 197 (100) [Ph2COMeϩ].
Ϫ C36H39BO4 (546.5): calcd. C 79.12, H 7.19; found C 79.06, H
7.28.
characteristic NMR data. With these new building blocks
in our hands, we finally established a general approach to
enantiomerically pure 1,2-disubstituted cyclopropanes. We
are currently trying to further optimize this sequence and
to apply the described method in natural product synthesis.
6b: Yield 77%, white foam, softening range 72Ϫ77 °C. Ϫ [α]2D1
ϭ
Ϫ274 (c ϭ 0.90, CHCl3). Ϫ IR (film, NaCl): ν˜ ϭ 3057 cmϪ1, 2958,
1
1616, 1197, 1076. Ϫ H NMR (500 MHz, CDCl3): δ ϭ 2.98 (s, 6
H, OMe), 5.14 (br d, J ϭ 14.9 Hz, 1 H; 1Ј-H), 5.32 (s, 2 H, 4-H
and 5-H), 7.01Ϫ7.18 (m, 4 H, 2Ј-H, arom.-H), 7.20Ϫ7.31 (m, 22
H, arom.-H). Ϫ 13C NMR (125 MHz, CDCl3): δ ϭ 51.7 (q, OMe),
77.4 (d, C-4/C-5), 83.3 (s, CPh2OMe), 117.8 (br d, C-1Ј), 127.2,
127.35, 127.39, 127.6, 127.7, 128.9 (d, arom.-CH), 138.0, 141.2,
141.4 (s, arom.-Cipso), 150.2 (d, C-2Ј). Ϫ MS (FAB, NBA ϩ NaI);
m/z (%): 589 (12) [M ϩ Naϩ], 197 (100) [Ph2COMeϩ]. Ϫ HRMS:
C38H3510BO4Na: calcd. 589.2526; found 589.2523. Ϫ C38H35BO4
(566.5): calcd. C 80.57, H 6.23; found C 80.18, H 6.31.
Experimental Section
General Remarks: All reagents were used as purchased from com-
mercial suppliers without further purification. The vinyl iodides 5
were synthesized as described by Dieck and Heck,[12] the spectro-
scopic data are in agreement with published data.[12,22,23] The reac-
tions were carried out using standard Schlenk techniques under
a dry nitrogen atmosphere. Glassware was oven-dried at 150 °C
overnight. Solvents were dried and purified by conventional
methods prior to use; diethyl ether and THF were freshly distilled
from sodium/benzophenone. Caution: The generation and handling
of diazomethane requires special precaution.[24] Ϫ Flash-column
chromatography: Merck silica gel 60, 0.040Ϫ0.063 mm (230Ϫ400
6c: Yield 32%, white foam, softening range 55Ϫ60 °C. Ϫ [α]2D1
ϭ
Ϫ128 (c ϭ 3.5, CHCl3). Ϫ IR (film, NaCl): ν˜ ϭ 3063 cmϪ1, 3039,
1
3005, 2928, 2815, 1627, 1365, 1298, 1249, 1176, 1090, 1061. Ϫ H
NMR (500 MHz, CDCl3): δ ϭ 2.92 (s, 6 H, OMe), 3.09 (s, 3 H,
OMe), 3.73 (ddd, J ϭ 13.6 Hz, J ϭ 5.6 Hz, J ϭ 1.5 Hz, 1 H, 3Ј-
Ha), 3.91 (ddd, J ϭ 13.6 Hz, J ϭ 6.7 Hz, J ϭ 1.5 Hz, 1 H, 3Ј-Hb),
5.02 (dt, J ϭ 13.9 Hz, J ϭ 1.5 Hz, 1 H; 1Ј-H), 5.27 (s, 2 H, 4-H
and 5-H), 6.19 (ddd, J ϭ 13.9 Hz, J ϭ 6.7 Hz, J ϭ 5.6 Hz, 1 H,
2Ј-H), 7.24Ϫ7.28 (m, 20 H, arom.-H). Ϫ 13C NMR (125 MHz,
CDCl3): δ ϭ 51.9 (q, OMe), 55.0 (q, OMe), 66.8 (t, C-3Ј), 77.5 (d,
C-4/C-5), 83.3 (s, CPh2OMe), 95.9 (t, ϪOCH2OϪ), 118.8 (br d, C-
1Ј), 127.24, 127.29, 127.5, 127.8, 128.3, 129.6 (d, arom.-CH), 141.1,
141.3 (s, arom.-Cipso), 150.0 (d, C-2Ј). Ϫ MS (EI, 70 eV); m/z (%):
532 (Ͻ0.1) [M Ϫ MeOHϩ], 519 (0.1) [M Ϫ C2H5Oϩ], 197 (100)
[Ph2COMeϩ]. Ϫ C35H37BO6 (564.5): calcd. C 74.47, H 6.61; found
C 74.46, H 6.77.
mesh).
Ϫ TLC: Pre-coated sheets, Alugram SIL G/UV254
MachereyϪNagel; detection by UV extinction or by cerium molyb-
denium solution [phosphomolybdic acid (25 g), Ce(SO4)2·H2O
(10 g), conc. H2SO4 (60 mL), H2O (940 mL)]. Ϫ Preparative
MPLC: Gilson (Spectrochrom), with a packed column (49 ϫ
500 mm), LiChroprep, Si60 (15Ϫ25 µm), and UV detector
(259 nm). Ϫ 1H and 13C NMR spectra were recorded at room temp.
in CDCl3 unless otherwise indicated on a Bruker A 500. Chemical
shifts are given in ppm relative to resonances of the solvent (1H:
CHCl3, 7.25 ppm; 13C: CDCl3, 77.0 ppm), J in Hz; in spectra of
higher order δs and Js were not corrected. 13C signals were assigned
by means of C-H- and H-H-COSY spectra. Ϫ Microanalysis: Per-
formed at the Institut für Organische Chemie, Stuttgart. Ϫ Melting
points (Fisher Jones) were not corrected.
Cyclopropylboronic Esters 7 and 8: Alkenylboronic ester 6 (1 equiv.)
was dissolved in diethyl ether (1 mL/mmol of 6) and 5 mol-%
Pd(OAc)2 was added. The suspension was treated for 2 min in an
ultrasonic bath. After the mixture was cooled to 0 °C, diazometh-
ane[24] (50 mL/mmol of 6 of an approximately 0.5  solution in
diethyl ether) was slowly added (2 mL/min) by means of a syringe-
pump.[25] Unreacted diazomethane was destroyed by stirring the
reaction mixture vigorously. Filtration through celite and evapora-
tion of the solvent under reduced pressure, followed by chromato-
graphic purification, led to analytically pure cyclopropylboronic es-
ters 7 and 8.
Alkenylboronic Esters (6): Under an atmosphere of nitrogen vinyl
iodide 5 (1.0 equiv.) was dissolved in diethyl ether (2 mL/mmol ol-
efin) and cooled to Ϫ78 °C. After addition of tBuLi (1.5  solution
in diethyl ether; 2.0 equiv.) a white precipitate formed. Stirring was
continued, and after 2 h triisopropyl borate (1.0 equiv.) was syr-
inged into the mixture, which was then allowed to warm to room
temperature. The ate complex was quenched with diol 1 (0.8
equiv.), and the reaction mixture was left at ambient temperature
for 18 h. Diethyl ether (10 mL/mmol olefin) was added and the
organic layer washed with saturated aqueous NH4Cl (5 mL/mmol
olefin), H2O (2 ϫ 5 mL/mmol olefin), and brine (5 mL/mmol ol-
efin), and dried over MgSO4. The solution was concentrated under
reduced pressure and the residue subjected to flash-column chro-
matography on silica gel, eluting with pentane/diethyl ether (10:1
to 4:1), yielding product 6.
7a and 8a: After flash-column chromatography (pentane/diethyl
ether, 10:1), a white foam (yield 96%, dr 87:13) was isolated: Ϫ IR
(film, NaCl): ν˜ ϭ 3060 cmϪ1, 2956, 2928, 2852, 1494, 1447, 1417,
1250, 1188, 1077. Ϫ MS (EI, 70 eV); m/z (%): 560 (Ͻ0.1) [Mϩ], 528
(2.2) [M Ϫ MeOHϩ], 197 (100) [Ph2COMeϩ]. Ϫ C37H41BO4
(560.5): calcd. C 79.28, H 7.37; found C 79.34, H 7.46. By MPLC
(0.4% EtOAc in petroleum ether) the diastereomers 7a and 8a could
be separated. 7a: (first eluted, major diastereomer) Softening range
6a: Yield 68%, colorless crystals, m.p. 109 °C. Ϫ [α]2D0 ϭ Ϫ131 (c ϭ
1.6, CHCl3). Ϫ IR (film, NaCl): ν˜ ϭ 3060 cmϪ1, 3026, 2923, 2849, 60Ϫ65 °C. Ϫ [α]2D0 ϭ Ϫ123 (c ϭ 1.0, CHCl3). Ϫ 1H NMR
1600, 1493, 1453, 1028. Ϫ H NMR (500 MHz, CDCl3): δ ϭ 0.75 (500 MHz, CDCl3): δ ϭ Ϫ0.57 (ddd, J ϭ 10.0 Hz, J ϭ 8.8 Hz, J ϭ
1
Eur. J. Org. Chem. 2000, 2557Ϫ2562
2559

J. E. A. Luithle, J. Pietruszka
6.6 Hz, 1 H, 1Ј-H), Ϫ0.04 (ddd, J ϭ 6.6 Hz, J ϭ 5.6 Hz, J ϭ calcd. 601.2737; found 601.2742. Ϫ C36H39BO6 (578.5): calcd. C
FULL PAPER
3.2 Hz, 1 H, 3Ј-Htrans), 0.50 (ddd, J ϭ 10.0 Hz, J ϭ 7.6 Hz, J ϭ
3.2 Hz, 1 H, 3Ј-Hcis), 0.67 (mc, 1 H, 2Ј-H), 0.77 (t, J ϭ 7.3 Hz, 3
74.74, H 6.80; found C 74.39, H 7.82. By MPLC (4% EtOAc in
petroleum ether) the diastereomers 7c and 8c could be separated.
H, 4ЈЈ-H), 0.72Ϫ0.82 (m, 1 H, 1ЈЈ-Ha), 0.85Ϫ0.94 (m, 2 H, 1ЈЈ-Hb, Ϫ 7c: (second eluted, major diastereomer) Softening range 52Ϫ60
2ЈЈ-Ha), 0.96Ϫ1.03 (m, 1 H, 2ЈЈ-Hb), 1.12 (qt, J ϭ 7.3 Hz, J ϭ °C. Ϫ [α]2D1 ϭ Ϫ125 (c ϭ 0.8, CHCl3). Ϫ 1H NMR (500 MHz,
7.0 Hz, 2 H, 3ЈЈ-H), 2.93 (s, 6 H, OMe), 5.19 (s, 2 H, 4-H and 5-
CDCl3): δ ϭ Ϫ0.40 (ddd, J ϭ 9.6 Hz, J ϭ 9.2 Hz, J ϭ 7.0 Hz, 1
H), 7.15Ϫ7.28 (m, 20 H, arom.-H). Ϫ 13C NMR (125 MHz, H, 1Ј-H), 0.21 (ddd, J ϭ 7.0 Hz, J ϭ 5.5 Hz, J ϭ 3.5 Hz, 1 H, 3Ј-
CDCl3): δ ϭ ഠ Ϫ3 (d, C-1Ј), 11.7 (t, C-3Ј), 13.8 (q, C-4ЈЈ), 18.1 Htrans), 0.68 (dddd, J ϭ 9.6 Hz, J ϭ 7.5 Hz, J ϭ 3.5 Hz, J ϭ 1.1 Hz,
(d, C-2Ј), 22.5 (t, C-3ЈЈ), 30.0 (t, C-1ЈЈ), 31.6 (t, C-2ЈЈ), 51.6 (q,
1 H, 3Ј-Hcis), 1.06 (ddddd, J ϭ 9.9 Hz, J ϭ 9.2 Hz, J ϭ 7.5 Hz,
OMe), 77.0 (d, C-4/C-5), 83.3 (s, CPh2OMe), 127.12, 127.14, 127.3,
J ϭ 5.5 Hz, J ϭ 4.6 Hz, 1 H, 2Ј-H), 2.75 (dd, J ϭ 10.7 Hz, J ϭ
127.6, 128.4, 129.6 (d, arom.-CH), 141.4, 141.6 (s, arom.-Cipso). Ϫ 9.9 Hz, 1 H, 1ЈЈ-Ha), 2.92 (s, 6 H, OMe), 3.14 (ddd, J ϭ 10.7 Hz,
8a: (second eluted, minor diastereomer) Softening range 60Ϫ65 °C.
J ϭ 4.6 Hz, J ϭ 1.1 Hz, 1 H, 1ЈЈ-Hb), 3.22 (s, 3 H, OMe), 4.43
Ϫ [α]2D0 ϭ Ϫ67.8 (c ϭ 0.7, CHCl3). Ϫ 1H NMR (500 MHz, CDCl3): (d, J ϭ 6.4 Hz, 1 H, ϪOCHaHbOϪ), 4.45 (d, J ϭ 6.4 Hz, 1 H,
δ ϭ Ϫ0.54 (ddd, J ϭ 10.0 Hz, J ϭ 8.7 Hz, J ϭ 6.5 Hz, 1 H, 1Ј-H), ϪOCHaHbOϪ), 5.22 (s, 2 H, 4-H and 5-H), 7.16Ϫ7.27 (m, 20 H,
Ϫ0.46 (ddd, J ϭ 6.5 Hz, J ϭ 5.9 Hz, J ϭ 3.2 Hz, 1 H, 3Ј-Htrans),
arom.-H). Ϫ 13C NMR (125 MHz, CDCl3): δ ϭ ഠ Ϫ3 (d, C-1Ј),
0.45 (ddd, J ϭ 10.0 Hz, J ϭ 7.9 Hz, J ϭ 3.2 Hz, 1 H, 3Ј-Hcis), 0.63 11.1 (t, C-3Ј), 17.1 (d, C-2Ј), 51.8 (q, OMe), 54.9 (q, OMe), 69.2
(t, J ϭ 7.3 Hz, 3 H, 4ЈЈ-H), 0.68 (mc, 1 H, 2Ј-H), 0.87 (mc, 1 H, (t, C-1ЈЈ), 77.4 (d, C-4/C-5), 83.3 (s, CPh2OMe), 96.1 (t,
1ЈЈ-Ha), 0.97 (mc, 2 H, 3ЈЈ-H), 0.93Ϫ1.01 (m, 2 H, 2ЈЈ-H), ϪOCH2OϪ), 127.3, 127.5, 127.8, 128.5, 129.6 (d, arom.-CH),
1.05Ϫ1.13 (m, 2 H, 1ЈЈ-Hb), 2.91 (s, 6 H, OMe), 5.15 (s, 2 H, 4-H
141.3, 141.5 (s, arom.-Cipso). Ϫ 8c: (first eluted, minor diastere-
and 5-H), 7.14Ϫ7.30 (m, 20 H, arom.-H). Ϫ 13C NMR (125 MHz, omer) Softening range 55Ϫ60 °C. Ϫ [α]2D0 ϭ Ϫ67.8 (c ϭ 0.70,
CDCl3): δ ϭ ഠ Ϫ2 (d, C-1Ј), 11.6 (t, C-3Ј), 14.0 (q, C-4ЈЈ), 18.4 CHCl3). Ϫ 1H NMR (500 MHz, CDCl3): δ ϭ Ϫ0.33 (ddd, J ϭ
(d, C-2Ј), 22.4 (t, C-3ЈЈ), 30.3 (t, C-1ЈЈ), 32.2 (t, C-2ЈЈ), 51.7 (q,
9.9 Hz, J ϭ 8.7 Hz, J ϭ 6.8 Hz, 1 H, 1Ј-H), Ϫ0.23 (ddd, J ϭ
OMe), 77.4 (d, C-4/C-5), 83.4 (s, CPh2OMe), 127.18, 127.25, 6.8 Hz, J ϭ 5.7 Hz, J ϭ 3.5 Hz, 1 H, 3Ј-Htrans), 0.62 (ddd, J ϭ
127.34, 127.7, 128.4, 128.5, 129.7 (d, arom.-CH), 141.4, 141.6 (s,
arom.-Cipso)
9.9 Hz, J ϭ 7.7 Hz, J ϭ 3.5 Hz, 1 H, 3Ј-Hcis), 1.12 (mc, 1 H, 2Ј-
H), 2.97 (s, 6 H, OMe), 3.15 (s, 3 H, OMe), 3.22 (dd, J ϭ 10.2 Hz,
J ϭ 8.0 Hz, 1 H, 1ЈЈ-Ha), 3.28 (dd, J ϭ 10.2 Hz, J ϭ 6.6 Hz, 1 H,
1ЈЈ-Hb), 4.13 (d, J ϭ 6.5 Hz, 1 H, ϪOCHaHbOϪ), 4.25 (d, J ϭ
6.5 Hz, 1 H, ϪOCHaHbOϪ), 5.22 (s, 2 H, 4-H and 5-H), 7.20Ϫ7.39
(m, 20 H, arom.-H). Ϫ 13C NMR (125 MHz, CDCl3): δ ϭ ഠ Ϫ3
(d, C-1Ј), 9.9 (t, C-3Ј), 17.3 (d, C-2Ј), 51.7 (q, OMe), 55.0 (q, OMe),
69.1 (t, C-1ЈЈ), 77.1 (d, C-4/C-5), 83.3 (s, CPh2OMe), 95.9 (t,
ϪOCH2OϪ), 127.2, 127.3, 127.5, 127.7, 128.5, 129.7 (d, arom.-
.
7b and 8b: After flash-column chromatography (pentane/diethyl
ether, 10:1), a white foam (yield 90%, dr 67:33) was isolated: Ϫ IR
(film, NaCl): ν˜ ϭ 3058 cmϪ1, 3025, 2958, 2938, 2834, 1494, 1446,
1416, 1375, 1254, 11918, 1076. Ϫ MS (EI, 70 eV); m/z (%): 580
(Ͻ0.3) [Mϩ], 548 (8) [M Ϫ MeOHϩ], 197 (100) [Ph2COMeϩ]. Ϫ
C39H37BO4 (580.5): calcd. C 80.69, H 6.42; found C 80.62, H 6.34.
By MPLC (0.5Ϫ1.0% EtOAc in petroleum ether) the diastereomers
7b and 8b could be separated. 7b: (first eluted, major diastereomer)
Softening range 80Ϫ85 °C. Ϫ [α]2D0 ϭ Ϫ144 (c ϭ 1.3, CHCl3). Ϫ
CH), 141.26, 141.35 (s, arom.-Cipso)
.
Alcohols 9؊11. ؊ Method A: The protected boronic ester (1.0
1H NMR (500 MHz, CDCl3): δ ϭ Ϫ0.06 (ddd, J ϭ 10.0 Hz, J ϭ equiv. 6c, 7c or 8c) was dissolved in acetone (100 mL/mmol boronic
9.6 Hz, J ϭ 7.1 Hz, 1 H, 1Ј-H), 0.78 (ddd, J ϭ 7.1 Hz, J ϭ 6.2 Hz, ester), and sodium iodide (5.0 equiv.) and catalytic amounts of
J ϭ 3.8 Hz, 1 H, 3Ј-Htrans), 0.91 (ddd, J ϭ 10.0 Hz, J ϭ 8.0 Hz,
HClg were added. The mixture was heated under reflux for 2 d,
J ϭ 3.8 Hz, 1 H, 3Ј-Hcis), 2.04 (ddd, J ϭ 9.6 Hz, J ϭ 8.0 Hz, J ϭ cooled to room temp., diluted with diethyl ether, washed with water,
6.2 Hz, 1 H, 2Ј-H), 2.83 (s, 6 H, OMe), 5.00 (s, 2 H, 4-H and 5-
H), 6.71Ϫ6.73 (m, 2 H, arom.-H), 7.00Ϫ7.09 (m, 7 H, arom.-H),
saturated aqueous sodium bicarbonate, and brine, and dried over
MgSO4. The solution was concentrated under reduced pressure and
7.11Ϫ7.23 (m, 16 H, arom.-H). Ϫ 13C NMR (125 MHz, CDCl3): the residue subjected to flash-column chromatography on silica gel,
δ ϭ ഠ 2 (d, C-1Ј), 10.8 (t, C-3Ј), 22.3 (d, C-2Ј), 51.7 (q, OMe), 77.0
eluting with petroleum ether/EtOAc (95:5 to 4:1). Ϫ Method B: The
(d, C-4/C-5), 83.2 (s, CPh2OMe), 125.2, 127.1, 127.19, 127.23, protected boronic ester (1.0 equiv. 6c, 7c or 8c) was dissolved in
127.7, 127.8, 128.2, 128.6 (d, arom.-CH), 140.1, 141.5, 141.8 (s, tBuOH (100 mL/mmol boronic ester), and pyridinium toluene-4-
arom.-Cipso)
.
8b (second eluted, minor diastereomer): M.p.
sulfonate (1.0 equiv.) was added. The mixture was heated under
reflux for 18 h, cooled to room temp., and worked-up as usual. Ϫ
Method C: The protected boronic ester (1.0 equiv. 6c, 7c or 8c) was
164Ϫ166 °C. Ϫ [α]2D0 ϭ Ϫ143 (c ϭ 1.6, CHCl3). Ϫ 1H NMR
(500 MHz, CDCl3): δ ϭ Ϫ0.01 (ddd, J ϭ 10.1 Hz, J ϭ 9.6 Hz, J ϭ
7.2 Hz, 1 H, 1Ј-H), 0.57 (ddd, J ϭ 7.2 Hz, J ϭ 6.6 Hz, J ϭ 4.1 Hz, dissolved in MeOH (100 mL/mmol boronic ester), and catalytic
1 H, 3Ј-Htrans), 0.82 (ddd, J ϭ 10.1 Hz, J ϭ 8.0 Hz, J ϭ 4.1 Hz, 1 amounts of conc. HClaq. were added. The mixture was kept for 2 h
H, 3Ј-Hcis), 2.00 (ddd, J ϭ 9.6 Hz, J ϭ 8.0 Hz, J ϭ 6.6 Hz, 1 H,
2Ј-H), 2.84 (s, 6 H, OMe), 5.07 (s, 2 H, 4-H and 5-H), 6.59Ϫ6.66
(m, 3 H, arom.-H), 6.83Ϫ6.87 (m, 6 H, arom.-H), 7.11Ϫ7.28 (m,
16 H, arom.-H). Ϫ 13C NMR (125 MHz, CDCl3): δ ϭ ഠ 5 (d, C-
1Ј), 10.6 (t, C-3Ј), 22.9 (d, C-2Ј), 51.5 (q, OMe), 77.3 (d, C-4/C-5),
83.1 (s, CPh2OMe), 125.3, 127.0, 127.24, 127.27, 127.4, 127.6,
128.3, 129.6, 129.8 (d, arom.-CH), 139.8, 141.1, 141.2 (s, arom.-
at 62 °C, cooled to room temp., and worked-up as usual.
9: The product was isolated as a white foam in 40% yield (method
B). Ϫ Softening range 55Ϫ60 °C. Ϫ [α]2D1 ϭ Ϫ130 (c ϭ 1.8, CHCl3).
Ϫ IR (film, NaCl): ν˜ ϭ 3437 cmϪ1, 3059, 2938, 2835, 1633, 1494,
1447, 1422, 1373, 1308, 1261, 1185, 1077, 1032. Ϫ 1H NMR
(500 MHz, CDCl3): δ ϭ 1.51 (t, J ϭ 6.4 Hz, 1 H, OH), 2.97 (s, 6
H, OMe), 3.76Ϫ3.80 (m, 2 H, 3Ј-H), 5.03 (dt, J ϭ 13.9 Hz, J ϭ
1.4 Hz, 1 H; 1Ј-H), 5.32 (s, 2 H, 4-H and 5-H), 6.30 (dt, J ϭ
13.9 Hz, J ϭ 6.2 Hz, 1 H, 2Ј-H), 7.19Ϫ7.30 (m, 20 H, arom.-H).
Cipso)
.
7c and 8c: After flash-column chromatography (pentane/diethyl
ether, 2:1), a white foam (yield 87%, dr 65:35) was isolated: Ϫ IR
Ϫ
13C NMR (125 MHz, CDCl3): δ ϭ 51.8 (q, OMe), 61.6 (t, C-
(film, NaCl): ν˜ ϭ 3058 cmϪ1, 3025, 2958, 2939, 2834, 1446, 1418, 3Ј), 77.6 (d, C-4/C-5), 83.3 (s, CPh2OMe), 119.0 (br d, C-1Ј), 127.3,
1370, 1194, 1076. Ϫ MS (FAB, NBA ϩ NaI); m/z (%): 601 (35) [M 127.5, 127.65, 127.73, 127.79, 127.9, 129.6 (d, arom.-CH), 141.0,
ϩ Naϩ], 197 (100) [Ph2COMeϩ]. Ϫ HRMS: C36H3910BO6Na: 141.1 (s, arom.-Cipso), 152.0 (d, C-2Ј). Ϫ MS (FAB, NBA ϩ NaI);
2560
Eur. J. Org. Chem. 2000, 2557Ϫ2562

Synthesis of Enantiomerically Pure cis-Cyclopropylboronic Esters
FULL PAPER
m/z (%): 543 (18) [M ϩ Naϩ], 197 (100) [Ph2COMeϩ]. Ϫ HRMS: 4Ј), 18.6 (t, C-2), 23.0, 26.6, 32.6 (t, C-1Ј, C-2Ј, C-3Ј), 50.5 (d, C-
C33H3310BO5Na: calcd. 543.2319; found 543.2310. Ϫ C33H33BO5 1). Ϫ MS (EI, 70 eV); m/z (%): 114 (2) [Mϩ], 96 (12) [M Ϫ H2Oϩ],
(520.4): calcd. C 76.16, H 6.39; found C 76.13, H 6.73.
57 (100) [C4H9ϩ/C3H5Oϩ]. Ϫ HRMS: C7H14O: calcd. 114.1045;
found 114.1042.
10: The product was isolated as a white foam in 86% yield (method
C); the boronic ester could not be obtained in analytically pure
form. Ϫ Softening range 50Ϫ65 °C. Ϫ [α]2D0 ϭ Ϫ116 (c ϭ 2.3,
CHCl3). Ϫ IR (film, NaCl): ν˜ ϭ 3580 cmϪ1, 3060, 3009, 2940,
Alcohol 13. ؊ Determination of Configuration: Under an atmo-
sphere of nitrogen an analytical sample of cyclopropanol 12
(35 mg, 0.31 mmol, 60% ee) was dissolved in CH2Cl2 (1 mL). Mer-
cury trifluoroacetate (185 mg, 0.400 mmol) and MeOH (0.3 mL)
were added, and the resulting mixture stirred at room temp. for
18 h. Sodium chloride (2 g) was added, the slurry stirred for 15 min,
filtered, washed with CH2Cl2, and the solvent evaporated under
reduced pressure. The crude product was dissolved in THF
(1 mL)and LiAlH4 (180 mg, 5.00 mmol) was added, and the re-
sulting mixture stirred for 6 h. After addition of diethyl ether
(5 mL), the reaction was quenched with brine, the layers separated,
and the ethereal phase dried over sodium sulfate. The filtered
sample was directly subjected to GLC analysis, proving the (S)-
configuration of the major enantiomer. A racemic reference (rac)-
13 had been selectively, lipase-catalyzed (Amano PS) acetylated
with vinyl acetate in CH2Cl2 as described by Barth and Effen-
berger,[21] giving predominantly (S)-14 and (R)-13 (47% ee after
4 h). Ϫ Glc: Bondex-un-α-3,8-un-β-3,4-Et116, 0.6 bar H2;[27] 50 °C,
3 min iso, 1 °C/min; tr (R)-13: 13.45 min; tr (S)-13: 13.75 min. Ϫ
IR (film, NaCl): ν˜ ϭ 3338 cmϪ1, 2958, 2928, 2874, 1467, 1379,
1
1494, 1446, 1418, 1365, 1251, 1216, 1187, 1077, 1034. Ϫ H NMR
(500 MHz, CDCl3): δ ϭ Ϫ0.45 (ddd, J ϭ 9.9 Hz, J ϭ 8.6 Hz, J ϭ
6.9 Hz, 1 H, 1Ј-H), 0.18 (ddd, J ϭ 6.9 Hz, J ϭ 5.5 Hz, J ϭ 3.7 Hz,
1 H, 3Ј-Htrans), 0.60 (ddd, J ϭ 9.9 Hz, J ϭ 7.8 Hz, J ϭ 3.7 Hz, 1
H, 3Ј-Hcis), 0.75 (dd, J ϭ 9.4 Hz, J ϭ 4.7 Hz, 1 H, OH), 1.10 (m,
1 H, 2Ј-H), 2.94 (m, 1 H, 1ЈЈ-Ha), 2.95 (s, 6 H, OMe), 3.34 (ddd,
J ϭ 11.9 Hz, J ϭ 9.4 Hz, J ϭ 5.4 Hz, 1 H, 1ЈЈ-Hb), 5.26 (s, 2 H, 4-H
and 5-H), 7.17Ϫ7.34 (m, 20 H, arom.-H). Ϫ 13C NMR (125 MHz,
CDCl3): δ ϭ ഠ Ϫ4 (d, C-1Ј), 9.5 (t, C-3Ј), 20.5 (d, C-2Ј), 51.8 (q,
OMe), 64.0 (t, C-1ЈЈ), 77.3 (d, C-4/C-5), 83.3 (s, CPh2OMe), 127.4,
127.5, 127.7, 127.9, 128.5, 129.6 (d, arom.-CH), 141.0, 141.2 (s,
arom.-Cipso). Ϫ MS (FAB, NBA ϩ NaI); m/z (%): 557 (62) [M ϩ
Naϩ], 197 (100) [Ph2COMeϩ]. Ϫ HRMS: C34H3510BO5Na: calcd.
557.2475; found 557.2460.
11: The product was isolated as a white foam in 67% yield (method
C); the boronic ester could not be obtained in analytically pure
form. Ϫ Softening range 57Ϫ70 °C. Ϫ [α]2D0 ϭ Ϫ116 (c ϭ 0.6,
CHCl3). Ϫ IR (film, NaCl): ν˜ ϭ 3408 cmϪ1, 3060, 3006, 2939,
1
1040. Ϫ H NMR (500 MHz, CDCl3): δ ϭ 0.88 (t, J ϭ 7.1 Hz, 3
H, 6-H), 0.90 (d, J ϭ 6.7 Hz, 3 H, Me), 1.09 (mc, 1 H, 3-Ha),
1.20Ϫ1.42 (m, 6 H, OH, 3-Hb, 4-H, 5-H), 1.59 (mc, 1 H, 2-H), 3.40
(dd, J ϭ 10.5 Hz, J ϭ 6.6 Hz, 1 H, 1-Ha), 3.50 (dd, J ϭ 10.5 Hz,
J ϭ 5.8 Hz, 1 H, 1-Hb). Ϫ 13C NMR (125 MHz, CDCl3): δ ϭ 14.1
(q, C-6), 16.6 (q, Me), 23.0, 29.2, 32.8, 35.7 (C-2, C-3, C-4, C-5),
68.4 (t, C-1). Ϫ MS (EI, 70 eV); m/z (%): 115 (2) [(M Ϫ 1)ϩ], 98
(11) [M Ϫ H2Oϩ], 85 (33) [M Ϫ MeOHϩ], 56 (100) [C4H8ϩ]. Ϫ
C7H16O (116.2): calcd. C 72.35, H 13.88; found C 72.21, H 13.93.
1
2839, 2834, 1494, 1446, 1417, 1368, 1187, 1087, 1076, 1032. Ϫ H
NMR (500 MHz, CDCl3): δ ϭ Ϫ0.49 (ddd, J ϭ 10.3 Hz, J ϭ
8.6 Hz, J ϭ 6.9 Hz, 1 H, 1Ј-H), Ϫ0.16 (ddd, J ϭ 6.9 Hz, J ϭ
5.3 Hz, J ϭ 3.7 Hz, 1 H, 3Ј-Htrans), 0.50 (ddd, J ϭ 10.3 Hz, J ϭ
7.7 Hz, J ϭ 3.7 Hz, 1 H, 3Ј-Hcis), 1.04 (mc, 1 H, 2Ј-H), 1.75 (m, 1
H, OH), 2.77 (dd, J ϭ 11.8 Hz, J ϭ 8.1 Hz, 1 H, 1ЈЈ-Ha), 2.92 (s,
6 H, OMe), 3.40 (dd, J ϭ 11.8 Hz, J ϭ 5.8 Hz, 1 H, 1ЈЈ-Hb), 5.25
(s, 2 H, 4-H and 5-H), 7.18Ϫ7.31 (m, 20 H, arom.-H). Ϫ 13C NMR
(125 MHz, CDCl3): δ ϭ ഠ Ϫ4 (d, C-1Ј), 8.3 (t, C-3Ј), 19.2 (d, C-
2Ј), 51.7 (q, OMe), 64.4 (t, C-1ЈЈ), 77.7 (d, C-4/C-5), 83.4 (s,
CPh2OMe), 127.4, 127.7, 127.9, 128.6, 129.6 (d, arom.-CH), 140.8,
Acknowledgments
140.9 (s, arom.-Cipso). Ϫ MS (FAB, NBA ϩ NaI); m/z (%): 557 (19) We gratefully acknowledge the Deutsche Forschungsgemeinschaft
[M ϩ Naϩ], 197 (100) [Ph2COMeϩ]. Ϫ HRMS: C34H3510BO5Na: (fellowship to J. P.) and the Fonds der Chemischen Industrie (Liebig
calcd. 557.2475; found 557.2460.
fellowships to J. P. and doctoral fellowship to J. E.A. L.) for the
generous support of this project. Donations from the Boehringer
Ingelheim KG, the Degussa AG, the Bayer AG, the Novartis AG,
and Amano Pharmaceutical Co., Ltd. were greatly appreciated. We
are grateful to the Institut für Organische Chemie der Universität
Stuttgart (Prof. Dr. V. Jäger and Prof. Dr. Dr. h. c. Effenberger) for
their ongoing support.
2-Butylcyclopropanol (12): Under an atmosphere of nitrogen, the
cyclopropylboronic ester 7a (485 mg, 0.870 mmol) was dissolved in
THF (2 mL) and cooled to Ϫ78 °C. LiAlH4 (76 mg, 2.0 mmol) was
added and the suspension stirred for 2 h while warming to room
temp. The resulting mixture was cooled to Ϫ78 °C and 30% H2O2
(550 µL, 4.85 mmol) was carefully added (for large-scale reactions
it is highly recommended to filter the excess LiAlH4 off, before
adding H2O2). After slowly warming to room temp., TLC indicated
the complete conversion into the product after 2 h. The reaction
mixture was carefully quenched at 0 °C with brine (5 mL), the
aqueous phase was extracted with diethyl ether (4 ϫ 20 mL), the
combined organic layers dried over sodium sulfate, filtered, and the
solvent evaporated under reduced pressure. Flash column chroma-
tography (pentane/diethyl ether 10:1) yielded diol 1 (380 mg,
0.840 mmol, 97%) and cyclopropanol 12 (80 mg, 0.70 mmol); yield
81%. GLC proved that the product was a 96:2:2 mixture of enantio-
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