Synthesis of "Garner" aldehyde-derived cyclopropylboronic esters

Article abstract of DOI:10.1002/ejoc.200300220

The "Garner" aldehyde has been used as a common intermediate for the preparation of the corresponding alkyne 7 and the alkenylboronic esters 12-16 (24-80%). Diastereoselective cyclopropanation afforded cyclopropylboronic esters 17-20 (60-84%, dr 22:78 to 92:8), the configurations of which were determined by chemical correlation (cyclopropanols 22), X-ray structural analysis (of 21a), and characteristic NMR spectroscopic data. The protected amino alcohols 23-26 and amino acids 27 have been synthesised from the cyclopropylboronic esters 19 by oxidation, Matteson homologation or Suzuki coupling. ( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003).

Full text of DOI:10.1002/ejoc.200300220

FULL PAPER
Synthesis of ‘‘Garner’’ Aldehyde-Derived Cyclopropylboronic Esters
Jörg Pietruszka,*[a] Andreas Witt,[a] and Wolfgang Frey[a]
Keywords: Amino acids / Amino alcohols / Boronic esters / Cyclopropanes / Suzuki coupling
The ‘‘Garner’’ aldehyde has been used as a common interme-
diate for the preparation of the corresponding alkyne 7 and
the alkenylboronic esters 12−16 (24−80%). Diastereoselec-
tive cyclopropanation afforded cyclopropylboronic esters
17−20 (60−84%, dr 22:78 to 92:8), the configurations of which
were determined by chemical correlation (cyclopropanols
22), X-ray structural analysis (of 21a), and characteristic
NMR spectroscopic data. The protected amino alcohols
23−26 and amino acids 27 have been synthesised from the
cyclopropylboronic esters 19 by oxidation, Matteson homo-
logation or Suzuki coupling.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2003)
Introduction
in lychee seeds (Litchi chinensis). Its strong hypoglycaemic
effect proved to be fatal in a large number of cases.[16Ϫ19]
Numerous syntheses of individual non-proteinogenic α-
amino acids have been reported, but use of general building
blocks has always been especially versatile. Many prepara-
tive approaches to enantiopure compounds have been based
on radical, cationic and Ϫ more recently Ϫ anionic re-
agents, ultimately derived from the ‘‘chiral pool’’.[20Ϫ24]
While organozinc derivatives have been successful (anionic)
candidates for many (palladium-catalysed) couplings with
electrophiles (e.g., ref.[25Ϫ29]), organoboron reagents have
been used less frequently.[30Ϫ33] We thought to investigate
the potential of the preparation of cyclopropane-containing
Natural and unnatural amino acids containing cyclopro-
pyl groups exhibit various physiological properties, and the
cyclopropane unit is frequently responsible for the observed
biological activity.[1] Apart from fascinating complex natu-
ral products such as the peptidolactone hormaomycin,[2,3]
which influences the secondary metabolite production of
certain bacteria, or the recently isolated belactosin A,[4]
a
novel antitumor antibiotic, simpler amino acids can also
show remarkable features. Among those, 1-aminocyclopro-
panecarboxylic acid (1, R ϭ H) is structurally the simplest
derivative (Figure 1), but it is nevertheless the highly im-
portant precursor of the plant hormone ethylene, which is
formed by enzymatic oxidative degradation.[5,6] Moreover,
substituted derivatives (1, R ϶ H) are generally inhibitors
of the corresponding ethylene-forming enzyme.[7] Another
important issue of the incorporated cyclopropane units is
the inherent conformational constraint in the system, and
they have consequently been used for the synthesis of sev-
eral peptidomimetics.[8Ϫ13] The conformationally con-
strained -glutamate analogue 2, originally synthesised by
Ohfune and co-workers in 1991,[14] was found to be an
agonist for group II metabotropic glutamate receptors.[15]
Of particular interest is hypoglycine A (3), occurring in the
unripe fruits of the Jamaican ackee tree (Blighia sapida) and
amino acids from cyclopropylboronic esters
4
(Figure 2),[34Ϫ41] thus using the synthetic potential of the
boron moiety for further transformations.[42Ϫ48] We recently
described the synthesis of highly stable, enantiomerically
pure boronic esters, the diol 5[49,50] usually being the auxili-
ary and protecting group of our choice.[51Ϫ55] Consequently,
one envisaged target was the ‘‘Garner’’ aldehyde-
derived[56Ϫ60] cyclopropane 6. Upon diastereoselective syn-
thesis the question of matched-mismatched interaction
would need to be addressed. Furthermore, it was a chal-
lenge to perform further transformations to produce either
synthetically useful, orthogonally protected enantiomer-
ically pure amino alcohols or amino acids. Preliminary re-
sults in this area have been published;[61] we now wish to
report our investigations in full.
Figure 1. Natural and nonnatural analogues of amino acids con-
taining a cyclopropyl group
[a]
Institut für Organische Chemie der Universität Stuttgart,
Pfaffenwaldring 55, 70569 Stuttgart, Germany
Fax: (internat.) ϩ 49-(0)711/6854335
E-mail: joerg.pietruszka@po.uni-stuttgart.de
Figure 2. Cyclopropylboronic esters as general building blocks
Eur. J. Org. Chem. 2003, 3219Ϫ3229
DOI: 10.1002/ejoc.200300220
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J. Pietruszka, A. Witt, W. Frey
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Results and Discussion
It is interesting to note that, despite the sluggish cleavage
of the isopropylidene protecting group of 15 (MeOH/
CF3CO2H), the primary alcohol 16 could be isolated in
moderate yield (61%) with 10% recovery of starting mate-
rial, but without any noticeable decomposition of the bo-
ronic ester moiety. Unfortunately, cyclopropanation of 16
could not be achieved under SimmonsϪSmith conditions.
Synthesis of Cyclopropylboronic Esters
As a common starting material for the investigations, al-
kyne 7[62Ϫ64] was needed. This serine derivative is usually
synthesised most conveniently by a one-pot aldehyde-to-al-
kyne one-carbon homologation. In our hands, the best re-
sults were obtained when the intermediate ‘‘Garner’’ alde-
hyde Ϫ obtained either by oxidation of serinol 8[59] with
DessϪMartin periodinane 10[65Ϫ67] or by reduction of ester
9[59] with diisobutylaluminium hydride (DiBAl-H) Ϫ was
not purified (Scheme 1). Instead, the crude product was di-
rectly treated with the BestmannϪOhira reagent 11[68Ϫ73] in
basic methanol, furnishing the alkyne 7 in 58Ϫ64% yield.[74]
Although the overall yield starting from ester 9 would seem
superior, in our experience the alternative proved to be
more reliable. For a high degree of repeatability of the re-
duction step it is essential to make sure that the DiBAl-
H reagent is of high quality. Another requirement is for
meticulous temperature control, as well as precise com-
pliance with the workup procedure.
Scheme 2. Synthesis of alkenylboronic esters 12؊16
Scheme 1. Synthesis of alkyne 7 from alcohol 8 or ester 9 via the
‘‘Garner’’ aldehyde
Cyclopropanation of the remaining alkenylboronic esters
12؊15 was preparatively unproblematic (Scheme 3). The
palladium-catalysed decomposition of diazomethane
(Method A) was most convenient, and the products 17؊20
The synthesis of alkenylboronic esters 12؊16 was next were isolated in 61Ϫ84% yield. The diastereoselectivity of
investigated (Scheme 2). It is well known that direct hydro- the conversion was somewhat surprising (see below for the
boration of sterically demanding alkynes with 1,3,2-di- assignment of configuration). While the configuration of
oxaborolanes such as pinacolborane[75,76] does not allow chiral auxiliary 5/ent-5 was only of minor consequence Ϫ
convenient product isolation.[55,77] The more reactive the diastereoisomers 17a and 18a were preferentially
dicyclohexyl- (Cy2BH)[78] or diisopinocampheylborane formed Ϫ and no pronounced matched-mismatched inter-
(Ipc2BH)[79] should be used, followed by oxidation and actions were observed, the change from pinacol to benzpin-
transesterification with a suitable diol. While the isolation acol gave dramatic results. Cyclopropanation of alkene 14
of the diol 5/ent-5-derived olefins 12 and 13 (69Ϫ80%) was gave the usually preferred diastereoisomer 19a (dr 70:30),
unproblematic, the purification of ester 14 proved trouble- but with benzpinacol derivative 15 the ratio was almost
some: chromatographic separation from side products was completely reversed and cyclopropane 20b (20a/20b, dr
possible, but slow decomposition of 14 decreased the yield 24:76) dominated. The cause for the unusual observation is
(63%). The transesterification with benzpinacol was a slow not clear, but since steric effects predominate in dia-
process,[61] presumably due to the fact that the two hydroxy stereoselective cyclopropanations with diazomethane/PdII,
groups should preferentially exist in an antiperiplanar con- the assumption that the different diols induce a different
formation and that the rotation around the central CϪC preferred reactive conformation would seem reasonable.
bond is hindered. Product isolation was unproblematic, but Unfortunately, attempts to crystallise either starting mate-
the alkenylboronic ester 15 was obtained only in 24% yield. rial or product failed and we could not gain further insights.
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“Garner” Aldehyde-Derived Cyclopropylboronic Esters
FULL PAPER
It is interesting to note that Simmons-Smith-type cyclopro-
panations[80] of pinacol-derived alkenylboronic ester 14
failed at ambient temperature and even at Ϫ20 °C. Product
19 was only isolated (48%) when the conversion was per-
formed at Ϫ78 °C (Method B); in relation to the cyclopro-
panation with diazomethane, the selectivity is Ϫ as would
be expected Ϫ reversed (19a/19b, dr 22:78). Attempts to
separate the diastereoisomers fully failed and only small
amounts of pure fractions could be obtained at this stage.
Scheme 4. Establishing the absolute configuration of cyclopro-
pylboronic esters 19 by an X-ray structural analysis of the Suzuki
cross-coupling product 21a
Scheme 3. Synthesis of cyclopropylboronic esters 17؊20
Figure 3. Gas chromatographic correlation of cyclopropylboronic
esters through the diastereoisomeric cyclopropanols 22
Determination of Configuration
Finally, we were also able to make use of characteristic
NMR spectroscopic data for the correlation of the different
cyclopropylboronic esters 17؊20. Although the chemical
shifts are usually less pronounced than in other esters de-
rived from diol 5, and signals of 2Ј-H or 3Ј-H are not diag-
nostic at all, a certain trend is followed for the two dia-
stereoisomeric series (Figure 4). Independently of the diol
used, the 1Ј-H and the C-3Ј signals could be used to assign
the configuration. In the ЈaЈ diastereoisomer, the 1Ј-H sig-
nal always has a relative (to the ЈbЈ isomer) high-field shift,
while the C-3Ј signal is shifted to lower fields.
First of all we needed to establish a reliable method to
determine the configurations of all cyclopropylboronic es-
ters 17؊20. We thought we might correlate the esters with
the known[81] phenyl derivatives 21. Suzuki coupling of 19
with phenyl iodide gave the product in 54Ϫ76% yield
(Scheme 4). While comparison of the NMR spectroscopic
data allowed the assignment of diastereoisomer 21b (syn-
thesised by an alternative approach by Bernabe et al.[81]),
´
compound 21a was found to crystallise conveniently out of
the crude product mixture, with highly enriched 21b re-
maining as an oil. X-ray structural analysis indirectly estab-
lished the configuration of 19a and so was the foundation
for all following efforts.
Transformations of Cyclopropylboronic Esters 19
A more convenient analytical tool is the correlation and
Cyclopropylboronic esters 19 should be ideal intermedi-
determination of diastereomeric ratios by GLC. We found ates for the syntheses of amino alcohols and amino acids.
that it was most reliable to transform analytical samples of For analytical samples we had already established that oxi-
all cyclopropylboronic esters into cyclopropanols 22 under dation to cyclopropanols 22 was possible. On preparative
standard conditions (Figure 3).[51] Since we had unambigu- scales it was more convenient to isolate not the alcohol,
ously assigned pinacol-derived esters 19, we could now cor- but the tert-butyldiphenylsilyl-protected (TPS) derivative 23
relate the remaining esters 17, 18 and 20 either with 22a or (74%; Scheme 5). Separation of the diastereoisomers was
with 22b.
not possible, but the primary alcohols 24a and 24b were
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J. Pietruszka, A. Witt, W. Frey
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Figure 4. Characteristic NMR spectroscopic data (CDCl3,
300 MHz/75 MHz, 330 K) of cyclopropylboronic esters
Scheme 6. Synthesis of cyclopropane-containing amino acid deriva-
tives 27 and 28
conveniently separated after cleavage of the isopropylidene
acetal (52%). Matteson homologation[47] was also possible,
but the process was rather slow and complete conversion
was not observed. Consequently, oxidation not only gave
the desired product, but also yielded minor amounts of
cyclopropanols 22. Purification was achieved after deriv-
atisation: TPS-protected alcohols 25 were obtained in 61%
yield. Separation of diastereoisomers was not possible
either at this stage or after deprotection of the N,O-acetal.
We did not pursue the approach further.
Conclusion
In conclusion, we have developed a synthetic route to
new cyclopropylboronic esters from the ‘‘Garner’’ aldehyde.
The configurations of all derivatives could be assigned by
chemical correlation by use of glc, NMR and X-ray analy-
sis. With these building blocks to hand, we should now have
a fairly general access to cyclopropane-containing amino
alcohols or amino acids. To test this hypothesis, a number
of transformations were evaluated. Since the separation of
diastereoisomers was most convenient for the phenyl de-
rivatives 21 or 26, respectively, we utilised the intermediates
for their conversion into the unusual amino acids 27 and 28.
Experimental Section
General Remarks: All reagents were used as purchased from com-
mercial suppliers without further purification. Alcohol 8,[59]
ester 9,[57][59] DessϪMartin periodinane 10[65,66] and the
BestmannϪOhira reagent 11[68Ϫ73] were prepared according to the
references given. The reactions were carried out by use of standard
Schlenk techniques under dry nitrogen. Glassware was oven-dried
at 150 °C overnight. Solvents were dried and purified by conven-
tional methods prior to use; diethyl ether (Et2O), 1,2-dimethoxye-
thane (DME) and tetrahydrofuran (THF) were freshly distilled
from sodium/benzophenone. ‘‘Petroleum ether’’ refers to the frac-
tion with a boiling point between 40Ϫ60 °C. Caution: The genera-
tion and handling of diazomethane[83Ϫ86] requires special pre-
cautions. Flash column chromatography: Merck silica gel 60,
0.040Ϫ0.063 mm (230Ϫ400 mesh). TLC: pre-coated sheets, Alug-
ram SIL G/UV254 MachereyϪNagel; detection by UV extinction
or by use of cerium molybdenum solution [phosphomolybdic acid
Scheme 5. Synthesis of cyclopropane-containing amino alcohols
23؊25
Finally, we used the Suzuki coupling products 21a and (25 g), Ce(SO4)2·H2O (10 g), concd. H2SO4 (60 mL), H2O
(940 mL)]. Preparative MPLC: Gilson (Spectrochrom), with a
21b (vide supra) for further transformations (Scheme 6).
While separation of the diastereoisomers by crystallisation
was possible, it was even more convenient to separate the
primary alcohols 26a (87%) and 26b (86%) after deprotec-
tion. The amino acids were obtained either by direct oxi-
dation (by the procedure of Zhao et al.[82]) or by a more
conventional two-step approach. In our hands the direct
conversion into 27 (85%) proved superior; in order to purify
the diastereoisomeric acid, the crude product was treated
with diazomethane to yield the ester 28 (51%).
packed column (49 ϫ 500 mm), LiChroprep, Si60 (15Ϫ25 µm), and
1
UV detector (254 nm). H and 13C NMR spectra were recorded Ϫ
at room temperature in CDCl3 unless otherwise indicated Ϫ with
a Bruker ARX 500/300. Chemical shifts (δ) are given in ppm rela-
tive to resonances of the solvent (1H: CDCl3, δ ϭ 7.25 ppm; 13C:
CDCl3, δ ϭ 77.0 ppm), coupling constants (J) are given in Hertz;
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. Micro-
analysis: performed at the Institut für Organische Chemie,
Stuttgart. Melting points (Büchi 510) were not corrected. Specific
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“Garner” Aldehyde-Derived Cyclopropylboronic Esters
FULL PAPER
rotations were measured at 20 °C unless otherwise stated. [α]D val-
ppm. C12H19NO3 (225.28): calcd. C 63.98, H 8.50, N 6.22; found C
63.70, H 8.73, N 6.10.
ues are given in 10Ϫ1 deg·cm2·gϪ1
.
Alkenylboronic Esters 12؊16. Method A: (With Cy2BH). BH3·SMe2
complex (1.0 equiv. of a 12  solution in dimethyl sulfide) in 1,2-
dimethoxyethane (1 mL/mmol borane) was cooled to 0 °C under
dry nitrogen. After addition of cyclohexene (2.0 equiv.) and re-
moval of the cooling bath, a colourless precipitate formed. After
2 h the reaction mixture was cooled to 0 °C, followed by the ad-
dition of alkyne 7 (1.0 equiv.). The mixture was stirred at this tem-
perature for 15 min, and then warmed to room temperature. While
stirring was continued for 2Ϫ4 h, a clear solution formed. Trimeth-
ylamine N-oxide[88Ϫ90](2 equiv.) was carefully added at a rate suit-
able to keep the reaction under gentle reflux. After 2 h at room
temperature the appropriate diol (1 equiv.) was added. The reaction
mixture was stirred until complete consumption of diol (as judged
by TLC) was indicated. The solvent was removed under reduced
pressure and the crude product was subjected to flash column chro-
matography on silica gel.
X-ray Crystallographic Study:[87] The crystal data for compound
21a were determined by use of a Siemens P4 diffractometer with
graphite monochromator in Omega scan modus with Cu-Kα (λ ϭ
1.54178 A) radiation: C19H27NO3, Mr ϭ 317.4, colourless, T ϭ
293 K, crystal size 0.5 ϫ 0.5 ϫ 0.5 mm, orthorhombic, P212121,
˚
˚
˚
a ϭ 10.9590(5) A, b ϭ 11.9785(7) A, c ϭ 14.1744(14) A, α ϭ β ϭ
3
γ ϭ 90°, V ϭ 1860.7(2) A , Z ϭ 4, dcalcd. ϭ 1.133 g cmϪ3, µ ϭ
˚
0.604 mm Ϫ1, F(000) ϭ 688, Θ range 4.83Ϫ66.00°, 1739 measured/
independent reflections, 1579 reflections with [I Ͼ 2σ(I)]. Solved
by direct methods and refined by full-matrix, least-squares on F2
for all data weights to R ϭ 0.051, Rw ϭ 0.133, S ϭ 1.063, H atoms
Ϫ3
˚
riding, max. shift/error Ͻ 0.001, residual ρmax ϭ 0.172 A
.
(R)-3-tert-Butoxycarbonyl-4-ethynyl-2,2-dimethyl-1,3-oxazolidine
(7). Method A: (From alcohol 8[59]). DessϪMartin periodinane
(10[65,66], 34.0 g, 80.0 mmol) was added in small portions at ambi-
Method B: (With Ipc2BH). BH3·SMe2 complex (1 mL of a 10 
solution in dimethyl sulfide, 10 mmol) in THF (10 mL) was cooled
to 0 °C under dry nitrogen. After addition of α-pinene (3.2 mL,
20 mmol) and removal of the cooling bath, a colourless precipitate
formed. After 2 h the reaction mixture was cooled to Ϫ35 °C, fol-
lowed by the slow addition of alkyne 7 (2.2 g, 10 mmol). The mix-
ture was stirred at this temperature for 15 min, and then warmed
to room temperature. Acetaldehyde (11.0 mL, 200 mmol) was care-
fully added (strongly exothermic reaction!), and the formed solu-
tion was heated at reflux for 12 h. After removal of all volatile
components under reduced pressure, the residue was dissolved in
THF (10 mL) and benzpinacol (3.7 g, 50 mmol) was added. After
5Ϫ6 h at room temperature, the solvent was removed under re-
duced pressure and the crude product was subjected to MPLC.
Method C: (Deprotection). Alkenylboronic ester 15 (1.25 g,
2.00 mmol) in MeOH (20 mL) was treated with trifluoroacetic acid
(1 mL) at ambient temperature. CH2Cl2 was added to the suspen-
sion until a clear solution formed. After 1 day, H2O was added
and the aqueous layer was thoroughly extracted with CH2Cl2. The
combined organic layers were dried with MgSO4 and filtered, and
the solvents were removed under reduced pressure. After flash col-
umn chromatography, pure product 16 was isolated.
ent temperature to
a stirred solution of serinol 8 (12.3 g,
53.0 mmol) in CH2Cl2 (150 mL). Stirring was continued for 3Ϫ4 h
until TLC indicated full consumption of the starting material. The
reaction mixture was poured into an aqueous solution (700 mL) of
sodium bicarbonate (50 g) and sodium thiosulfate (50 g) and stirred
vigorously. The two phases were separated and the aqueous layer
was extracted twice with CH2Cl2 (2 ϫ 300 mL). The combined or-
ganic layers were dried with MgSO4 and filtered, and the solvent
was removed under reduced pressure. The residue was dissolved in
MeOH (150 mL) and the BestmannϪOhira reagent (11,[68Ϫ73]
12.5 g, 65.0 mmol) was added. After the mixture had been cooled
to 0 °C, K2CO3 (13.5 g, 100 mmol) was added in small portions.
The reaction mixture was kept at ambient temperature for 4 h until
TLC indicated full consumption of the starting material. Petroleum
ether (400 mL) was added, and the reaction mixture was quenched
with saturated aqueous NH4Cl solution (300 mL). The aqueous
layer was extracted twice with petroleum ether (2 ϫ 300 mL), the
combined organic layers were dried with MgSO4 and filtered, and
the solvent was removed under reduced pressure. Distillation of the
residue yielded product
(31.0 mmol, 58% over 2 steps).
7 as a colourless oil; yield: 6.95 g
Method B: (From ester 9[57,59]). Ester 9 (13.0 g, 50.0 mmol) in dried
toluene (120 mL) was placed in a three-necked round-bottom flask,
fitted with an addition funnel and a thermometer. The solution
was cooled to Ϫ78 °C and DiBAl-H (88 mL of 1  solution in
heptane, 88 mmol) was slowly added, the temperature never ex-
ceeding Ϫ65 °C. After 2 h at Ϫ70 °C no starting material could be
detected by TLC. Hydrolyses of the complex was achieved by care-
ful addition of pre-cooled MeOH (20 mL). Again, the temperature
should not exceed Ϫ65 °C. The mixture was poured into a cooled
(0 °C) 1  solution of hydrochloric acid and extracted three times
with ethyl acetate (3 ϫ 300 mL). The combined organic layers were
dried with MgSO4 and filtered, and the solvent was removed under
reduced pressure. The residue was further converted into alkyne 7
as described above. Yield: 7.22 g (32.0 mmol, 64% over 2 steps).
Compound 12. Method A: Alkenylboronic ester 12 (950 mg,
1.38 mmol, 69%) was obtained from alkyne 7 (450 mg, 2.00 mmol)
and diol 5 (910 mg, 2.00 mmol) after flash column chromatography
on silica gel (pentane/Et2O, 9:1 to 4:1); m.p. 106 °C. [α]2D0 ϭ Ϫ72.1
(c ϭ 1.32, CHCl3). IR (film, NaCl): ν˜ ϭ 2950 cmϪ1, 2910, 1690,
1635, 1375, 1165, 1060, 740, 680. MS (FAB, NBA ϩ NaI): m/z
(%) ϭ 712 (1) [M ϩ Na]ϩ, 197 (100) [Ph2COCH3ϩ]. 1H NMR
(500 MHz, [D6]DMSO, 373 K): δ ϭ 1.35 [s, 9 H, C(CH3)3], 1.46 (s,
3 H, CH3), 1.50 (s, 3 H, CH3), 2.96 (s, 6 H, OCH3), 3.60 (dd, J ϭ
8.7, J ϭ 2.5 Hz, 1 H, 5"-Ha), 3.92 (dd, J ϭ 8.7, J ϭ 6.5 Hz, 1 H,
5"-Hb), 4.19 (m, 1 H, 4"-H), 5.16 (d, J ϭ 17.9 Hz, 1 H, 1Ј-H), 5.33
(s, 2 H, 4-H/5-H), 6.12 (dd, J ϭ 17.9, J ϭ 6.2 Hz, 1 H, 2Ј-H),
7.21Ϫ7.32 (m, 20 H, arom. CH) ppm. 13C NMR (125 MHz,
[D6]DMSO, 373 K): δ ϭ 26.5 (CH3), 28.5 [C(CH3)3], 51.9 (OCH3),
60.4 (C-4"), 67.9 (C-5"), 77.6 [C(CH3)3], 77.9 (C-4/C-5), 83.4, 83.5
(CPh2OMe), 94.1 (C-2ЈЈ), ഠ 119 (br., C-1Ј), 127.3, 127.8 (2 C),
127.9, 128.7, 129.6 (arom. CH), 141.3, 141.5 (arom. Cipso), 151.0
(C-2Ј), 151.9 (CϭO) ppm. C42H48BNO7 (689.64): calcd. C 73.15,
H 7.02, N 2.03; found C 73.22, H 7.17, N 1.82.
Compound 7: B.p. 75 °C (1Ϫ2 Torr). [α]2D3 ϭ Ϫ90.2 (c ϭ 2.63,
CHCl3). IR (film, NaCl): ν˜ ϭ 3265 cmϪ1, 2968, 2919, 2860, 2089,
1700, 1370, 1065. 1H NMR (500 MHz, [D6]DMSO, 373 K): δ ϭ
0.99 (s, 3 H, CH3), 1.00 [s, 9 H, C(CH3)3], 1.08 (s, 3 H, CH3), 2.50
(br. s, 1 H, 2Ј-H), 3.43 (dd, J ϭ 8.7, J ϭ 2.4 Hz, 1 H, 5-Ha), 3.59
(dd, J ϭ 8.7, J ϭ 6.1 Hz, 1 H, 5-Hb), 4.08 (ddd, J ϭ 6.1, J ϭ 2.4,
J ϭ 2.3 Hz, 1 H, 4-H) ppm. 13C NMR (125 MHz, [D6]DMSO, Compound 13. Method A: Alkenylboronic ester 13 (1.10 g,
373 K): δ ϭ 24.0, 25.6 (CH3), 27.5 [C(CH3)3], 47.5 (C-2Ј), 67.9 (C- 1.60 mmol, 80%) was obtained from alkyne 7 (450 mg, 2.00 mmol)
5), 71.5 (C-4), 79.2 [C(CH3)3], 82.8 (C-1Ј), 93.0 (C-2), 150.3 (CϭO) and diol ent-5 (910 mg, 2.00 mmol) after flash column chromatog-
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J. Pietruszka, A. Witt, W. Frey
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raphy on silica gel (pentane/Et2O, 9:1 to 4:1); m.p. 109 °C. [α]2D3
ϭ
(d, J ϭ 18.2, J ϭ 4.3 Hz, 1 H, 2Ј-H), 7.03Ϫ7.26 (m, 20 H, arom.
Ϫ59.1 (c ϭ 1.43, CHCl3). IR (film, NaCl): ν˜ ϭ 2977 cmϪ1, 1698, CH) ppm. 13C NMR (125 MHz, [D6]DMSO, 373 K): δ ϭ 28.4
1640, 1387, 1178, 1077, 758, 701. MS (EI, 70 eV): m/z (%) ϭ 689
[C(CH3)3], 60.4 (C-3Ј), 65.1 (C-4Ј), 80.0 [C(CH3)3], 96.1
1
(Ͻ 1) [Mϩ], 657 (2) [M Ϫ CH3OH]ϩ, 197 (100) [Ph2COCH3ϩ]. H [C(Ph3)2], ഠ 119 (br., C-1Ј), 127.0, 127.2, 128.5 (arom. CH), 142.4
NMR (500 MHz, [D6]DMSO, 373 K): δ ϭ 1.37 [s, 9 H, C(CH3)3], (2 C, arom. Cipso), 151.5 (C-2Ј), 155.0 (CϭO) ppm. C35H36BNO5
1.44 (s, 3 H, CH3), 1.47 (s, 3 H, CH3), 2.97 (s, 3 H, OCH3), 2.98
(561.48): calcd. C 74.87, H 6.46, N 2.49; found C 74.59, H 6.48,
(s, 3 H, OCH3), 3.62 (dd, J ϭ 8.9, J ϭ 2.5 Hz, 1 H, 5"-Ha), 3.97 N 2.43.
(dd, J ϭ 8.9, J ϭ 6.4 Hz, 1 H, 5"-Hb), 4.29 (m, 1 H, 4"-H), 5.14
Cyclopropylboronic Esters 17؊20. Method A: (With CH2N2). The
alkenylboronic ester (1 equiv.) was dissolved in Et2O (ഠ 1 mL/
mmol boronic ester), and 5Ϫ10 mol % palladium() acetate was
(dd, J ϭ 18.0, J ϭ 1.1 Hz, 1 H, 1Ј-H), 5.33 (s, 2 H, CHCPh2), 6.07
(dd, J ϭ 18.0, J ϭ 5.8 Hz, 1 H, 2Ј-H), 7.29Ϫ7.38 (m, 20 H, arom.
CH) ppm. 13C NMR (125 MHz, [D6]DMSO, 373 K): δ ϭ 23.4,
25.9 (CH3), 27.5 [C(CH3)3], 50.93, 50.96 (OCH3), 59.9 (C-4"), 66.5
(C-5ЈЈ), 77.6 [C(CH3)3], 78.5 (CHCPh2), 82.8 (CPh2OMe), 92.7 (C-
2ЈЈ), 126.6, 126.9, 127.2, 127.7, 128.5, 129.7 (arom. CH), 140.1,
140.5 (arom. Cipso), 150.3 (C-2Ј), 150.6 (CϭO) ppm. C42H48BNO7
(689.64): calcd. C 73.15, H 7.02, N 2.03; found C 72.96, H 6.96,
N 1.96.
added. The suspension was treated for 2 min in an ultrasonic bath.
[83Ϫ86]
After the mixture had been cooled to 0 °C, CH2N2
(25 mL/
mmol boronic ester of an approx. 0.5  solution in Et2O) was
slowly (1.5 mL/min) added with the aid of a syringe-pump.[86] Un-
changed CH2N2 was destroyed by stirring the reaction mixture vig-
orously. Filtration through Celite and evaporation of the solvent
under reduced pressure, followed by chromatographic purification,
gave the cyclopropylboronic esters.
Method B: (With Et2Zn/CH2I2). The alkenylboronic ester (1.0
equiv.) in CH2Cl2 (1 mL/mmol boronic ester) was added to pre-
formed cyclopropanation reagent [6.0 equiv. CH2I2 dissolved in
CH2Cl2 (10 mL/mmol boronic ester), treated at Ϫ78 °C with Et2Zn
solution (3 equiv. of a 1  solution in hexane)]. Stirring was con-
tinued at room temperature for 12 h. After the reaction had been
quenched with saturated aqueous NH4Cl, the aqueous layer was
thoroughly extracted with CH2Cl2. The combined organic layers
were dried with MgSO4 and filtered, and the solvent was removed
under reduced pressure. The crude product was purified by flash
column chromatography.
Determination of dr: For the determination of the dr of the cyclo-
propylboronic esters 17؊20, a sample (0.1Ϫ0.3 mmol) was dis-
solved in THF (5 mL). MeLi (3 equiv., 1  solution in hexane) was
added at Ϫ78 °C, and the mixture was warmed to room tempera-
ture. Stirring was continued while 2Ϫ3 mL of 30% aqueous H2O2
was carefully added. Hydrolysis after 2Ϫ3 h (TLC monitoring)
with saturated aqueous NH4Cl solution, separation of the organic
layer, extraction with CH2Cl2, drying over MgSO4, filtration and
removal of the solvents under reduced pressure furnished the crude
cyclopropanols 22a and 22b. The GLC traces were used to deter-
mine the dr of the corresponding cyclopropanation (conditions and
retention times: see Figure 3).
Compound 14. Method A: Alkenylboronic ester 14 (5.58 g,
16.0 mmol, 63%) was obtained from alkyne 7 (5.60 g, 25.0 mmol)
and pinacol (3.00 g, 25.0 mmol) after flash column chromatogra-
phy on silica gel (petroleum ether/Et2O, 9:1); m.p. 52Ϫ54 °C.
[α]2D3 ϭ Ϫ31.2 (c ϭ 0.98, CHCl3). IR (film, NaCl): ν˜ ϭ 2978 cmϪ1
,
2935, 1691, 1643, 1329, 1293, 1098, 1057, 851, 770. MS (FAB): m/
z (%) ϭ 354 (22) [[M ϩ 1]ϩ], 298 (100), 238 (40), 57 (35). 1H NMR
(500 MHz, [D6]DMSO, 373 K): δ ϭ 1.23 [s, 12 H, C(CH3)2], 1.44
[s, 9 H, C(CH3)3], 1.50 (s, 3 H, CH3), 1.56 (s, 3 H, CH3), 3.75 (dd,
J ϭ 9.02, J ϭ 3.1 Hz, 1 H, 5ЈЈ-Ha), 4.08 (dd, J ϭ 9.0, J ϭ 6.6 Hz,
1 H, 5ЈЈ-Hb), 4.37 (dddd, J ϭ 6.6, J ϭ 3.1, J ϭ 6.2, J ϭ 1.3 Hz, 1
H, 4ЈЈ-H), 5.48 (dd, J ϭ 17.9, J ϭ 1.3 Hz, 1 H, 1Ј-H), 6.46 (dd,
J ϭ 17.9, J ϭ 6.2 Hz, 1 H, 2Ј-H) ppm. 13C NMR (125 MHz,
[D6]DMSO, 373 K): δ ϭ 23.6 (CH3), 24.0 [C(CH3)2], 25.9 (CH3),
27.5 [C(CH3)3], 59.5 (C-4ЈЈ), 66.7 (C-5ЈЈ), 78.6 [C(CH3)3], 82.4 (C-
4/C-5), 92.8 (C-2ЈЈ), ഠ119 (br., C-1Ј), 150.8 (C-2Ј), 150.8 (CϭO)
ppm. C18H32BNO5 (353.26): calcd. C 61.20, H 9.13, N 3.96; found
C 61.35, H 9.09, N 4.24.
Compound 15. Method B: Alkenylboronic ester 15 (1.46 g,
2.40 mmol, 24%) was obtained from alkyne 7 (2.20 g, 10.0 mmol)
and benzpinacol (3.70 g, 50.0 mmol) after MPLC (petroleum ether/
MTBE, 19:1); m.p. 45Ϫ50 °C. [α]2D3 ϭ Ϫ36.2 (c ϭ 1.09, CHCl3).
IR (film, NaCl): ν˜ ϭ 2960 cmϪ1, 2900, 1695, 1643, 1480, 1435,
1360, 1240, 1080, 851, 740, 680. MS (FAB): m/z (%) ϭ 601 (61)
Compounds 17a and 17b. Method A: Products 17a and 17b (720 mg,
1.02 mmol, 79%) were isolated from alkenylboronic ester 12
(900 mg, 1.30 mmol) after flash column chromatography (pentane/
Et2O, 9:1); separation of diastereoisomers (dr 84:16) could not be
achieved by MPLC (all data from mixture): IR (film, NaCl): ν˜ ϭ
2978 cmϪ1, 2935, 1691, 1643, 1329, 1293, 1098, 1057, 851, 770. MS
(FAB, NBA ϩ NaI): m/z (%) ϭ 726 (25) [M ϩ Naϩ], 197 (100).
HRMS: C43H5010BNO7Na: calcd. 725.3624; found 725.3614.
C43H50BNO7 (703.67): calcd. C 73.40, H 7.16, N 1.99; found C
72.82, H 7.26, N 1.85.
1
[Mϩ], 363 (32), 261 (29), 183 (28), 165 (100), 84 (46), 57 (64). H
NMR (500 MHz, [D6]DMSO, 373 K): δ ϭ 1.39 [s, 9 H, C(CH3)3],
1.47 (s, 3 H, CH3), 1.57 (s, 3 H, CH3), 3.86 (m, 1 H, 5ЈЈ-Ha), 4.12
(m, 1 H, 5ЈЈ-Hb), 4.51 (m, 1 H, 4ЈЈ-H), 5.85 (d, J ϭ 17.9 Hz, 1 H,
1Ј-H), 6.87 (dd, J ϭ 17.9, J ϭ 6.1 Hz, 1 H, 2Ј-H), 7.11Ϫ7.20 (m,
20 H, arom. CH) ppm. 13C NMR (125 MHz, [D6]DMSO, 373 K):
δ ϭ 26.4 (CH3), 26.7 (CH3), 28.3 [C(CH3)3], 60.7 (C-4ЈЈ), 67.4 (C-
5ЈЈ), 79.4 [C(CH3)3], 93.4 (C-2ЈЈ), 95.7 [C(Ph3)2], ഠ118 (br., C-1Ј),
127.6, 127.7, 128.2, 128.4 (br., arom. CH), 151.6 (C-2Ј), 154.7 (Cϭ
O) ppm. C38H40BNO5 (601.54): calcd. C 75.87, H 6.70, N 2.33;
found C 75.98, H 7.04, N 2.27.
1
Major Diastereoisomer 17a: H NMR (300 MHz, CDCl3, 330 K):
δ ϭ Ϫ0.69 (ddd, J ϭ 9.9, J ϭ 6.2, J ϭ 5.8 Hz, 1Ј-H), 0.56 (ddd, J ϭ
7.7, J ϭ 6.3, J ϭ 3.7 Hz, 3Ј-Htrans), 0.75 (br., 3Ј-Hcis), 0.80Ϫ0.87 (m,
2Ј-H), 1.45 [s, C(CH3)3], 1.42 (s, CH3), 1.61 (s, CH3), 2.98 (s,
OCH3), 3.03Ϫ3.14 (m, 4ЈЈ-H), 3.68 (dd, J ϭ 8.5, J ϭ 1.4 Hz, 5ЈЈ-
Ha), 3.82 (dd, J ϭ 8.5, J ϭ 5.8 Hz, 5ЈЈ-Hb), 5.26 (s, 4-H/5-H),
Compound 16. Method C: Product 16 (720 mg, 1.30 mmol, 65%)
was obtained from alkenylboronic ester 15 (1.25 g, 2.00 mmol) after
flash column chromatography (petroleum ether/ethyl acetate, 9:1 to
1:1); m.p. 109 °C. [α]2D3 ϭ Ϫ3.4 (c ϭ 1.0, CHCl3). IR (film, NaCl):
ν˜ ϭ 3400 cmϪ1, 2950, 1700, 1635, 1485, 1435, 1360, 1160, 760, 680. 7.19Ϫ7.45 (m, arom. CH) ppm. 13C NMR (75 MHz, CDCl3,
MS (FAB, NBA ϩ NaI): m/z (%) ϭ 584 (7) [M ϩ Na]ϩ, 561 [Mϩ] 330 K): δ ϭ Ϫ3.1 (br., C-1Ј), 11.8 (C-3Ј), 22.1 (C-2Ј), 23.9 (CH3),
(14), 506 (100), 165 (40), 105 (40), 57 (23). 1H NMR (500 MHz, 26.9 [C(CH3)3], 27.3 (CH3), 51.7 (OCH3), 62.3 [C(CH3)3], 68.3 (C-
[D6]DMSO, 373 K): δ ϭ 1.47 [s, 9 H, C(CH3)3], 2.03 (s, 1 H, OH),
5ЈЈ), 78.0 (C-4ЈЈ), 78.2 (C-4/C-5), 83.6 (CPh2OMe), 93.9 (C-2ЈЈ),
3.76 (m, 1 H, 4Ј-Ha), 3.83 (m, 1 H, 4Ј-Hb), 4.49 (m, 1 H, 3Ј-H), 127.2, 127.3, 127.4, 127.7, 128.5, 129.7 (arom. CH), 141.3, 141.5
4.99 (s, 1 H, NH), 6.05 (dd, J ϭ 18.2, J ϭ 1.9 Hz, 1 H, 1Ј-H), 6.94 (arom. Cipso), 152.3 (CϭO).
3224
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 3219Ϫ3229

“Garner” Aldehyde-Derived Cyclopropylboronic Esters
FULL PAPER
1
Minor Diastereoisomer 17b: H NMR (300 MHz, CDCl3, 330 K): H), 1.47 [s, 9 H, C(CH3)3], 1.49 (s, 3 H, CH3), 1.61 (s, 3 H, CH3),
δ ϭ Ϫ0.23 (m, 1Ј-H), 0.06 (ddd, J ϭ 8.0, J ϭ 6.3, J ϭ 3.8 Hz, 3Ј-
H
3.41 (br., 1 H, 4ЈЈ-H), 3.72 (dd, J ϭ 8.7, J ϭ 1.7 Hz, 1 H, 5ЈЈ-Ha),
trans), 0.28 (m, 3Ј-Hcis), 0.8Ϫ0.87 (m, 2Ј-H), 1.38 (s, CH3), 1.43 [s, 3.90 (dd, J ϭ 8.7, J ϭ 5.8 Hz, 1 H, 5ЈЈ-Hb) ppm. 13C NMR
C(CH3)3], 1.52 (s, CH3), 2.99 (s, OCH3), 3.03Ϫ3.14 (m, 4ЈЈ-H), 3.50
(75 MHz, CDCl3, 330 K): δ ϭ 11.0 (C-3Ј), 21.7 (C-2Ј), 23.9 (CH3),
(dd, J ϭ 8.9, J ϭ 1.3 Hz, 5ЈЈ-Ha), 3.76 (dd, J ϭ 8.9, J ϭ 6.0 Hz, 5ЈЈ- 24.7 [C(CH3)2], 27.0 (CH3), 28.5 [C(CH3)3], 60.8 (C-4ЈЈ), 67.4 (C-
Hb), 5.26 (s, 4-H/5-H), 7.19Ϫ7.45 (m, arom. CH) ppm. 13C NMR
5ЈЈ), 79.6 [C(CH3)3], 83.0 (C-4, C-5), 94.0 (C-2ЈЈ), 152.3 (CϭO)
(75 MHz, CDCl3, 330 K): δ ϭ Ϫ3.1 (br., C-1Ј), 8.0 (C-3Ј), 21.2 ppm.
(C-2Ј), 22.8 (CH3), 27.3 (CH3), 28.4 [C(CH3)3], 51.7 (OCH3), 60.1
First Eluted Diastereoisomer 19b: M.p. 58 °C. [α]2D0 ϭ Ϫ46.1 (c ϭ
[C(CH3)3], 67.6 (C-5ЈЈ), 78.5 (C-4ЈЈ), 79.5 (C-4/C-5), 83.5 0.92, CHCl3). 1H NMR (300 MHz, CDCl3, 330 K): δ ϭ 0.02 (ddd,
(CPh2OMe), 93.9 (C-2ЈЈ), 125.8, 127.3, 127.4, 128.6, 129.3, 129.7 J ϭ 9.4, J ϭ 6.4, J ϭ 5.1 Hz, 1 H, 1Ј-H), 0.39 (ddd, 1 H, J ϭ 9.4,
(arom. CH), 141.1, 141.6 (arom. Cipso), 151.8 (CϭO) ppm.
J ϭ 5.5, J ϭ 3.6 Hz, 1 H, 3Ј-Hcis), 0.53 (ddd, J ϭ 7.9, J ϭ 6.4, J ϭ
3.6 Hz, 1 H, 3Ј-Htrans), 1.09 [s, 12 H, C(CH3)2], 1.17 (m, 1 H, 2Ј-
H), 1.38 (s, 3 H, CH3), 1.39 [s, 9 H, C(CH3)3], 1.50 (s, 3 H, CH3),
3.44 (br., 1 H, 4ЈЈ-H), 3.61 (dd, J ϭ 8.7, J ϭ 1.6 Hz, 1 H, 5ЈЈ-Ha),
3.75 (dd, J ϭ 8.7, J ϭ 5.8 Hz, 1 H, 5ЈЈ-Hb) ppm. 13C NMR
(75 MHz, CDCl3, 330 K): δ ϭ 7.6 (C-3Ј), 22.2 (C-2Ј), 24.6
[C(CH3)2], 24.7 (CH3), 27.0 (CH3), 28.5 [C(CH3)3], 61.5 (C-4ЈЈ),
68.2 (C-5ЈЈ), 79.7 [C(CH3)3], 82.9 (C-4, C-5), 94.1 (C-2ЈЈ), 152.3
(CϭO) ppm.
Compounds 18a and 18b. Method A: Products 18a and 18b (500 mg,
0.71 mmol, 84%) were isolated from alkenylboronic ester 13
(590 mg, 0.85 mmol) after flash column chromatography (pentane/
Et2O, 9:1); separation of diastereoisomers (dr 92:8) could not be
achieved by MPLC (all data from mixture): IR (film, NaCl): ν˜ ϭ
2978 cmϪ1, 2935, 1691, 1643, 1329, 1293, 1098, 1057, 851, 770. MS
(FAB, NBA ϩ NaI): m/z (%) ϭ 726 (10) [M ϩ Naϩ], 197 (100).
C43H50BNO7 (703.67): calcd. C 73.40, H 7.16, N 1.99; found C
73.50, H 7.35, N 1.89.
Compounds 20a and 20b. Method A: Products 20a and 20b (75 mg,
0.12 mmol, 61%) were isolated from alkenylboronic ester 15
(120 mg, 0.20 mmol) after flash column chromatography (petro-
leum ether/ethyl acetate, 92.5:7.5); separation of diastereoisomers
(dr 24:76) could not be achieved by MPLC (all data from mixture):
IR (film, NaCl): ν˜ ϭ 2960 cmϪ1, 2900, 1695, 1643, 1480, 1435,
1360, 1240, 1080, 851, 740, 680. MS (FAB): m/z (%) ϭ 616 (18) [M
ϩ 1]ϩ, 560 (27), 377 (35), 212 (100), 165 (81), 105 (38), 57 (45).
C39H42BNO5 (615.57): calcd. C 76.10, H 6.88, N 2.28; found C
76.20, H 7.11, N 2.17.
1
Major Diastereoisomer 18a: H NMR (300 MHz, CDCl3, 330 K):
δ ϭ Ϫ0.86 (ddd, J ϭ 9.9, J ϭ 6.2, J ϭ 5.8 Hz, 1Ј-H), 0.01 (ddd, J ϭ
7.7, J ϭ 6.3, J ϭ 3.7 Hz, 3Ј-Htrans), 0.45 (br., 3Ј-Hcis), 0.76Ϫ0.93 (m,
2Ј-H), 1.20 [s, C(CH3)3], 1.22 (s, CH3), 1.31 (s, CH3), 2.78 (s,
OCH3), 2.90 (ddd, J ϭ 8.6, J ϭ 5.8, J ϭ 1.3 Hz, 4ЈЈ-H), 3.38 (dd,
J ϭ 8.6, J ϭ 1.3 Hz, 5ЈЈ-Ha), 3.55 (dd, J ϭ 8.6, J ϭ 5.8 Hz, 5ЈЈ-
Hb), 5.06 (s, 4-H/5-H), 6.99Ϫ7.39 (m, arom. CH) ppm. 13C NMR
(75 MHz, CDCl3, 330 K): δ ϭ Ϫ3.1 (br., C-1Ј), 11.9 (C-3Ј), 22.2
(C-2Ј), 23.9 (CH3), 26.9 [C(CH3)3], 27.4 (CH3), 51.7 (OCH3), 61.8
(C-4ЈЈ), 67.7 (C-5ЈЈ), 78.0 (C-4/5), 79.5 [C(CH3)3], 83.6 (CPh2OMe),
93.9 (C-2ЈЈ), 127.2, 127.3, 127.4, 127.7, 128.5, 129.7 (arom. CH),
141.3, 141.5 (arom. Cipso), 152.3 (CϭO) ppm.
1
Minor Diastereoisomer 20a: H NMR (300 MHz, CDCl3, 330 K):
δ ϭ 0.24 (mc, 1Ј-H), 1.13Ϫ1.18 (m, 3Ј-Ha and 3Ј-Hb), 1.51 (s, CH3),
1.56 [s, C(CH3)3], 1.65 (s, CH3), 3.68 (mc, 4ЈЈ-H), 3.83 (dd, J ϭ 8.8,
J ϭ 1.6 Hz, 5ЈЈ-Ha), 4.00 (dd, J ϭ 8.8, J ϭ 5.8 Hz, 5ЈЈ-Hb) ppm,
2Ј-H signal (covered). 13C NMR (75 MHz, CDCl3, 330 K): δ ϭ
11.4 (C-3Ј), 23.4 (C-2Ј), 25.0 (CH3), 27.1 (CH3), 28.5 [C(CH3)3],
53.5 (C-4ЈЈ), 68.6 (C-5ЈЈ), 79.9 [C(CH3)3], 94.1 (C-2ЈЈ), 95.8 (C-4,
C-5), 126.9, 2 ϫ 127.2, 2 ϫ 128.4, 128.5 (arom. CH), 142.2, 142.9
(arom. Cipso), 152.1 (CϭO) ppm.
1
Minor Diastereoisomer 18b: H NMR (300 MHz, CDCl3, 330 K):
δ ϭ Ϫ0.38 (m, 1Ј-H), 0.20 (ddd, J ϭ 8.0, J ϭ 6.3, J ϭ 3.7 Hz, 3Ј-
Htrans), 0.64 (m, 3Ј-Hcis), 0.76Ϫ0.93 (m, 2Ј-H), 1.20 [s, C(CH3)3],
1.22 (s, CH3), 1.31 (s, CH3), 2.74 (s, OCH3), 2.75 (m, 4ЈЈ-H), 3.47
(dd, J ϭ 8.6, J ϭ 1.3 Hz, 5ЈЈ-Ha), 3.63 (dd, J ϭ 8.6, J ϭ 6.0 Hz,
5ЈЈ-Hb), 5.02 (s, 4-H/5-H), 6.99Ϫ7.39 (m, 20 H, arom. CH) ppm.
13C NMR (75 MHz, CDCl3, 330 K): δ ϭ Ϫ3.1 (br., C-1Ј), 8.0 (C-
3Ј), 21.2 (C-2Ј), 23.9 (CH3), 27.3 (CH3), 28.4 [C(CH3)3], 51.7
(OCH3), 62.3 (C-4ЈЈ), 67.6 (C-5ЈЈ), 78.3 (C-4/5), 79.7 [C(CH3)3],
83.6 (CPh2OMe), 93.9 (C-2ЈЈ), 125.8, 127.3, 127.4, 128.6, 129.3,
129.6 (arom. CH), 141.4, 141.7 (arom. Cipso), 152.4 (CϭO) ppm.
1
Major Diastereoisomer 20b: H NMR (300 MHz, CDCl3, 330 K):
δ ϭ 0.67Ϫ0.78 (m, 1Ј-H and 3Ј-Ha), 0.98Ϫ1.02 (m, 3Ј-Hb), 1.48 (s,
CH3), 1.54 [s, C(CH3)3], 1.67 (s, CH3), 3.59 (br., 4ЈЈ-H), 3.90 (dd,
J ϭ 8.6, J ϭ 1.3 Hz, 5ЈЈ-Ha), 4.01 (dd, J ϭ 8.6, J ϭ 5.6 Hz, 5ЈЈ-
Hb), 2Ј-H signal (covered) ppm. 13C NMR (75 MHz, CDCl3,
330 K): δ ϭ 8.3 (C-3Ј), 22.7 (C-2Ј), 23.3 (CH3), 26.9 [C(CH3)3],
27.1 (CH3), 53.4 (C-4ЈЈ), 67.8 (C-5ЈЈ), 79.9 [C(CH3)3], 95.7 (C-2ЈЈ),
95.8 (C-4, C-5), 126.9, 2 ϫ 127.2, 2 ϫ 128.4, 128.5 (arom. CH),
142.8, 142.9 (arom. Cipso), 152.1 (CϭO) ppm.
Compounds 19a and 19b. Method A: Products 19a and 19b (640 mg,
1.74 mmol, 69%) were isolated from alkenylboronic ester 14
(900 mg, 2.54 mmol) after kugelrohr distillation; separation of dia-
stereoisomers (dr 70:30) could not be achieved.
Phenylcyclopropanes 21 by Suzuki Coupling of Boronic Esters 19:
Dioxaborolane 19 (400 mg, 1.08 mmol; dr 70:30) was dissolved in
DME (12 mL). After addition of [Pd(PPh3)4] (140 mg, 122 µmol)
and KOtBu (2.8 mL of a 1  solution in tBuOH) the mixture was
carefully deoxygenated by freeze techniques. Phenyl iodide (180 µL,
1.62 mmol) was added. After 48 h at 90 °C the mixture was diluted
with toluene (15 mL) and filtered through a pad of Celite, and the
solvents were removed under reduced pressure. The residue was
purified by flash column chromatography (petroleum ether/Et2O,
19:1 to 4:1). The product 21 (252 mg, 0.82 mmol, 76%) was ob-
tained as colourless oil.
Method B: Products 19a and 19b (80 mg, 0.22 mmol, 48%) were
isolated from alkenylboronic ester 14 (160 mg, 0.45 mmol) after
flash column chromatography (petroleum ether/ethyl acetate, 95:5).
Separation of diastereoisomers (dr 22:78) could not be fully
achieved, but isolation of some pure fractions allowed the assign-
ment of data: IR (film, NaCl): ν˜ ϭ 2979 cmϪ1, 2935, 2872, 1692,
1368, 1255, 1169, 1145, 1089, 1060, 860, 770. MS (FAB): m/z (%) ϭ
368 (51) [M ϩ 1]ϩ, 312 (96), 252 (100), 212 (31), 57 (60).
C19H34BNO5 (367.29): calcd. C 62.13, H 9.33, N 3.81; found C
61.79, H 9.22, N 3.88.
Second Eluted Diastereoisomer 19a: Colourless oil. [α]2D0 ϭ Ϫ2.6
(c ϭ 0.9, CHCl3). 1H NMR (300 MHz, CDCl3, 330 K): δ ϭ Ϫ0.28 21: IR (KBr): ν˜ ϭ 3060 cmϪ1, 3040, 2994, 2970, 2860, 1682, 1670,
(ddd, J ϭ 9.7, J ϭ 6.4, J ϭ 5.6 Hz, 1 H, 1Ј-H), 0.78 (ddd, J ϭ 9.7,
J ϭ 5.3, J ϭ 3.6 Hz, 1 H, 3Ј-Hcis), 0.90 (ddd, J ϭ 7.6, J ϭ 6.4, J ϭ (41) [M ϩ 1]ϩ, 261 (91), 144 (100), 57 (41). C19H27NO3 (317.42):
3.6 Hz, 1 H, 3Ј-Htrans), 1.19 [s, 12 H, C(CH3)2], 1.31 (m, 1 H, 2Ј- calcd. C 71.89, H 8.57, N 4.41; found C 71.68, H 8.55, N 4.41. The
1380, 1242, 1065, 840, 750, 730, 680. MS (FAB): m/z (%) ϭ 318
Eur. J. Org. Chem. 2003, 3219Ϫ3229
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 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3225

J. Pietruszka, A. Witt, W. Frey
FULL PAPER
diastereoisomers could not be separated by chromatography, but
the major product 21a crystallised upon standing and could be
isolated. An X-ray structure analysis was obtained (see Scheme 4).
The experiment was repeated with essentially diastereoisomerically
pure 19b (63 mg, 0.17 mmol; dr Ͼ 98:2); yield 21b: 29 mg
(0.09 mmol, 54%).
Alcohol 24: Oxazolidine 23 (650 mg, 1.30 mmol; dr 70:30) was dis-
solved in MeOH (5 mL), and trifluoroacetic acid (0.5 mL) was ad-
ded at 0 °C. After 3 h the mixture was diluted with CH2Cl2 (15 mL)
and washed with saturated aqueous Na2CO3 solution, and the
aqueous layer was extracted twice with CH2Cl2. The combined or-
ganic layers were dried with MgSO4 and filtered, and the solvents
were removed under reduced pressure. The crude product was puri-
fied by flash column chromatography (petroleum ether/ethyl acet-
ate, 3:1). The product 24 (310 mg, 0.68 mmol, 52%) was obtained
as a colourless oil. IR (KBr): ν˜ ϭ 3413 cmϪ1, 3071, 3050, 2932,
2856, 1712, 1392, 1112, 1055, 889, 742, 701. The diastereoisomers
could be separated by MPLC (petroleum ether/ethyl acetate, 3:1):
Compound 21a: M.p. 109Ϫ111 °C. [α]2D0 ϭ Ϫ20.0 (c ϭ 0.95,
1
CHCl3). H NMR (300 MHz, CDCl3, 330 K): δ ϭ 1.00 (ddd, J ϭ
8.7, J ϭ 5.3, J ϭ 5.3 Hz, 1 H, 3Ј-Ha), 1.25 (m, 1 H, 3Ј-Hb),
1.36Ϫ1.46 (m, 1 H, 1Ј-H), 1.49 [s, 9 H, C(CH3)3], 1.50 (s, 3 H,
CH3), 1.62 (s, 3 H, CH3), 1.80 (m, 1 H, 2Ј-H), 3.68 (m, 1 H, 4-H),
3.85 (dd, J ϭ 8.6, J ϭ 1.2 Hz, 1 H, 5-Ha), 3.97 (dd, J ϭ 8.6, J ϭ
5.7 Hz, 1 H, 5-Hb), 7.04Ϫ7.36 (m, 5 H, arom. CH) ppm. 13C NMR
(125 MHz, CDCl3): δ ϭ 15.4 (C-5), 20.4 (C-4), 23.3 (C-3), 24.6
(CH3), 27.0 (CH3), 28.5 [C(CH3)3], 60.3 (C-4), 67.9 (C-5), 79.8
[C(CH3)3], 125.6, 125.9, 128.3 (arom. CH), 94.1 (C-2), 142.4 (arom.
Cipso), 152.2 (CϭO) ppm.
Compound 24a: [α]2D0 ϭ Ϫ20.0 (c ϭ 0.95, CHCl3). MS (FAB): m/z
(%) ϭ 478 (12) [M ϩ Na]ϩ, 456 (15) [M ϩ 1]ϩ, 199 (73), 144 (100),
135 (93). HRMS: C26H38NO4Si [M ϩ 1]: calcd. 456.2570; found
456.2561. 1H NMR (500 MHz, CDCl3): δ ϭ 0.55 (mc, 1 H, 3-
Htrans), 0.82 (ddd, J ϭ 9.9, J ϭ 5.8, J ϭ 3.1 Hz, 1 H, 3-Hcis), 1.02
[s, 9 H, TPS-C(CH3)3], 1.11 (mc, 1 H, 2-H), 1.38 [s, 9 H, Boc-
C(CH3)3], 2.46 (br., 1 H, OH), 2.82 (m, 1 H, 1Ј-H), 3.28 (dd, J ϭ
11.1, J ϭ 5.9 Hz, 1 H, 2Ј-Ha), 3.37 (ddd, J ϭ 9.9, J ϭ 5.9, J ϭ
5.8 Hz, 1 H, 1-H), 3.43 (dd, J ϭ 11.1, J ϭ 3.4 Hz, 1 H, 2Ј-Hb),
4.69 (d, J ϭ 6.4 Hz, 1 H, NH), 7.37Ϫ7.45 (m, 6 H, arom. CH),
7.68Ϫ7.71 (m, 4 H, arom. CH) ppm. 13C NMR (125 MHz, CDCl3):
δ ϭ 12.7 (C-3), 19.0 [TPS-C(CH3)3], 22.4 (C-2), 26.7 [TPS-
C(CH3)3], 28.3 [Boc-C(CH3)3], 53.3 (C-1), 55.1 (C-1Ј), 65.6 (C-2Ј),
79.6 [Boc-C(CH3)3], 127.7, 129.8, 133.5 (arom. CH), 135.5 (arom.
Cipso), 156.5 (CϭO) ppm.
1
Compound 21b: M.p. 64 °C. [α]2D0 ϭ Ϫ86.8 (c ϭ 1.16, CHCl3). H
NMR (300 MHz, CDCl3, 330 K): δ ϭ 0.79Ϫ0.90 (m, 2 H, 3Ј-Ha/
3Ј-Hb), 1.36Ϫ1.46 (m, 1 H, 1Ј-H), 1.49 [s, 9 H, C(CH3)3], 1.50 (s,
3 H, CH3), 1.60 (s, 3 H, CH3), 2.27 (br., 1 H, 2Ј-H), 3.68 (m, 1 H,
4-H), 3.81 (dd, J ϭ 8.8, J ϭ 1.4 Hz, 1 H, 5-Ha), 3.97 (dd, J ϭ 8.6,
J ϭ 5.7 Hz, 1 H, 5-Hb), 7.04Ϫ7.36 (m, 5 H, arom. CH) ppm. 13C
NMR (125 MHz, CDCl3): δ ϭ 15.4 (C-5), 20.4 (C-4), 23.3 (C-3),
24.6 (CH3), 27.0 (CH3), 28.5 [C(CH3)3], 60.3 (C-4), 67.9 (C-5), 79.8
[C(CH3)3], 125.6, 125.9, 128.3 (arom. CH), 94.1 (C-2), 142.4 (arom.
Cipso), 152.2 (CϭO) ppm.
Compound 24b: [α]2D0 ϭ ϩ21.8 (c ϭ 1.40, CHCl3). MS (FAB): m/z
(%) ϭ 478 (7) [M ϩ Na]ϩ, 456 (17) [M ϩ 1]ϩ, 199 (77), 144 (100),
135 (80). HRMS: C26H38NO4Si [M ϩ 1]: calcd. 456.2570; found
456.2563. 1H NMR (500 MHz, CDCl3): δ ϭ 0.55 (mc, 1 H, 3-
Htrans), 0.87 (ddd, J ϭ 10.0, J ϭ 5.9, J ϭ 3.1 Hz, 1 H, 3-Hcis), 1.02
[s, 9 H, TPS-C(CH3)3], 1.03Ϫ1.08 (m, 1 H, 2-H), 1.38 [s, 9 H, Boc-
C(CH3)3], 2.76 (m, 2 H, 1Ј-H and OH), 3.43 (dd, J ϭ 11.1, J ϭ
6.0 Hz, 1 H, 2Ј-Ha), 3.46 (mc, 1 H, 1-H), 3.43 (dd, J ϭ 11.1, J ϭ
3.0 Hz, 1 H, 2Ј-Hb), 4.40 (d, J ϭ 7.1 Hz, 1 H, NH), 7.37Ϫ7.45 (m,
6 H, arom. CH), 7.68Ϫ7.71 (m, 4 H, arom. CH) ppm. 13C NMR
(125 MHz, CDCl3): δ ϭ 13.6 (C-3), 19.0 [TPS-C(CH3)3], 22.0 (C-
2), 26.7 [TPS-C(CH3)3], 28.3 [Boc-C(CH3)3], 52.6 (C-1), 55.6 (C-
1Ј), 65.7 (C-2Ј), 79.7 [Boc-C(CH3)3], 127.8, 129.9, 133.8 (arom.
CH), 135.5 (arom. Cipso), 156.5 (CϭO).
Silyl-Protected Cyclopropanol 23: Cyclopropylboronic ester 19
(330 mg, 0.90 mmol; dr 70:30) was dissolved in THF (2 mL) and a
mixture of aqueous KHCO3 (2 , 1 mL) and aqueous H2O2 (30%,
1 mL) was added. After 3 h, saturated aqueous NH4Cl solution
(2 mL) was added and the mixture was extracted with CH2Cl2 (3
ϫ 20 mL). The combined organic layers were dried with MgSO4
and filtered, and the solvents were removed under reduced pressure.
The crude product 22 was dissolved in CH2Cl2 (5 mL), and imidaz-
ole (68 mg, 1.0 mmol) was added. After addition of tert-butyldi-
phenylsilyl chloride (275 mg, 1.00 mmol; TPS-Cl), the mixture was
stirred until complete consumption of the alcohol (as judged by
TLC) was indicated. Hydrolysis with saturated aqueous NH4Cl
solution (5 mL) was followed by extraction with CH2Cl2 (3 ϫ
20 mL). The combined organic layers were dried with MgSO4 and
filtered, and the solvents were removed under reduced pressure.
The crude product was purified by flash column chromatography
(petroleum ether/Et2O, 4:1) and MPLC (petroleum ether/MTBE,
19:1); separation of diastereoisomers 23a and 23b could not be
achieved, and complete assignment of data was not possible. Yield:
330 mg (0.67 mmol, 74%), colourless oil.
Silyl-Protected Cyclopropylmethanol 25: Cyclopropylboronic ester
19 (570 mg, 1.50 mmol; dr 70:30) and chloroiodomethane (220 µL,
3.00 mmol) were dissolved in THF (9 mL), and the solution was
cooled to Ϫ78 °C. Butyllithium (1.9 mL of a 1.6  solution in hex-
ane, 3.00 mmol) was slowly added, and the reaction mixture was
warmed to room temperature and stirred for 7 d. A 1:1 mixture of
H2O2 (30%, 5 mL) and aqueous NaOH solution (3 , 5 mL) was
carefully added and stirring was continued until TLC indicated
complete consumption of the intermediate. Dilution with CH2Cl2
Compound 23: IR (film, NaCl): ν˜ ϭ 3064 cmϪ1, 3003, 2982, 2930,
2856, 1686, 1361, 1184, 1055, 859, 741, 702. MS (FAB, NBA ϩ
NaI): m/z (%) ϭ 518 (100) [M ϩ Na]ϩ, 382 (34), 252 (100), 135 (68), (20 mL) was followed by the addition of a saturated aqueous
100 (48), 57 (56). 1H NMR (500 MHz, CDCl3): δ ϭ 0.35Ϫ0.94 (m, NH4Cl solution (20 mL). After extraction of the aqueous layer,
2 ϫ 3-H), 1.03 [s, TPS-C(CH3)3], 1.30Ϫ1.35 (m, 2-H), 1.23 (s, CH3), drying with MgSO4 and evaporation of the organic solvents under
1.43, 1.44 [s, Boc-C(CH3)3], 1.57 (s, CH3), 2.82 (m, 1-H), 3.20Ϫ3.75 reduced pressure, the crude product was dissolved in CH2Cl2
(m, 1Ј-H, 4Ј-H, 5Ј-Ha, 5Ј-Hb), 7.37Ϫ7.45 (arom. CH), 7.36Ϫ7.73 (5 mL), and imidazole (102 mg, 1.50 mmol) was added. After ad-
(arom. CH) ppm. 13C NMR (125 MHz, CDCl3): δ ϭ 12.3 (C-3), dition of tert-butyldiphenylsilyl chloride (412 mg, 1.50 mg; TPS-
19.0 [TPS-C(CH3)3], 24.5 (C-2), 25.3 (CH3), 26.7 [TPS-C(CH3)3],
Cl), the mixture was stirred until complete consumption of the al-
26.9 (CH3), 28.3 [Boc-C(CH3)3], 53.3 (C-1), 58.7 (C-5Ј), 66.8 (C- cohol (as judged by TLC) was indicated. Hydrolysis with saturated
4Ј), 79.6 [Boc-C(CH3)3], 93.8 (C-2Ј), 127.7, 129.8, 133.5 (arom. aqueous NH4Cl solution (5 mL) was followed by extraction with
CH), 135.5 (arom. Cipso), 156.5 (CϭO) ppm. C29H41NO4Si
(495.73): calcd. C 70.26, H 8.34, N 2.83; found C 70.26, H 7.15,
N 2.80.
CH2Cl2 (3 ϫ 20 mL). The combined organic layers were dried with
MgSO4 and filtered, and the solvents were removed under reduced
pressure. The crude product was purified by flash column chroma-
3226
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2003, 3219Ϫ3229

“Garner” Aldehyde-Derived Cyclopropylboronic Esters
FULL PAPER
tography (petroleum ether/Et2O, 4:1) and MPLC (petroleum ether/
MTBE, 19:1); separation of diastereoisomers 25a and 25b could
not be achieved, and complete assignment of data was not possible.
Yield: 465 mg (0.91 mmol, 61%), colourless oil. IR (film, NaCl):
(40 mg, 0.4 mmol), MeCN (198.5 mL) and H2O (1.5 mL). After
30 min no starting material could be detected by TLC. The reaction
mixture was diluted with toluene and quenched with phosphate
buffer (pH ϭ 5.8). The organic layer was washed with brine and
ν˜ ϭ 3064 cmϪ1, 3003, 2977, 2932, 2859, 1694, 1385, 1255, 1172, NaHSO3 solution (0.66 g in 15 mL H2O), dried with MgSO4 and
1087, 703. MS (FAB, NBA ϩ NaI): m/z (%) ϭ 532 (18) [M ϩ
filtered, and the solvent was removed under reduced pressure.
Na]ϩ, 382 (21), 199 (62), 135 (82), 100 (39), 57 (100). HRMS: Yield: 100 mg (0.34 mmol, 85%). [α]2D0 ϭ ϩ25.9 (c ϭ 1.15, CHCl3).
C30H44NO4Si [M ϩ 1]: calcd. 510.3040; found 510.3052. 1H NMR
(500 MHz, CDCl3): δ ϭ 0.34Ϫ0.47, 0.75Ϫ0.97 (m, 1Ј-H, 3Ј-Ha, 3Ј-
Hb), 1.02 [s, TPS-C(CH3)3], 1.26Ϫ1.39 (m, 2Ј-H), 1.41 (s, CH3),
MS (EI, 70 eV): m/z (%) ϭ 291 (4) [Mϩ], 236 (55), 192 (3), 146 (8),
57 (100). HRMS: C16H21NO4: calcd. 291.1471; found 291.1471. 1H
NMR (500 MHz, CDCl3): δ ϭ 0.99 (m, 1 H, 3Ј-Ha), 1.09 (m, 1 H,
1.42 [s, C(CH3)3], 1.55 (s, CH3), 3.20Ϫ3.75 (m, 1-Ha, 1-Hb, 4ЈЈ-H, 3Ј-Hb), 1.37 (br., 1 H, 1Ј-H), 1.45 [s, 9 H, C(CH3)3], 2.09 (br., 1 H,
5ЈЈ-Ha, 5ЈЈ-Hb), 7.37Ϫ7.45 (arom. CH), 7.36Ϫ7.73 (arom. CH) 2Ј-H), 3.92Ϫ4.10 [m, 1 H, 2-H; two rotamers ഠ 2:1], 5.22 and 6.71
ppm. C30H43NO4Si (509.75): calcd. C 70.69, H 8.50, N 2.75; found
C 70.14, H 8.48, N 2.72.
(br., 1 H, NH; two rotamers ഠ 2:1), 7.06Ϫ7. 07 (m, 2 H, arom.
CH), 7.13Ϫ7.16 (m, 1 H, arom. CH), 7.22Ϫ7.25 (m, 2 H, arom.
CH), ഠ 10.5 (br., 1 H, CO2H) ppm. 13C NMR (125 MHz, CDCl3;
two rotamers ഠ 2:1, minor rotamer in italics): δ ϭ 12.5/12.9 (C-
3Ј), 21.0/21.3 (C-2Ј), 24.5/24.7 (C-1Ј), 28.3 [C(CH3)3], 55.9/57.0 (C-
2), 80.3/81.8 [C(CH3)3], 125.9, 126.2, 128.3 (arom. CH), 141.3
(arom. Cipso), 155.6/156.7 (CϭO), 175.8/176.4 (CϭO) ppm.
Amino Alcohol 26a: Oxazolidine 21a (330 mg, 1.04 mmol) in
MeOH (5 mL) was treated at 0 °C with trifluoroacetic acid (1 mL).
After 3 h at ambient temperature, CH2Cl2 (15 mL) was added, the
reaction was quenched with saturated aqueous Na2CO3 solution,
and the aqueous layer was thoroughly extracted with CH2Cl2. The
combined organic layers were dried with MgSO4 and filtered, and
the solvent was removed under reduced pressure. After flash col-
umn chromatography (petroleum ether/ethyl acetate, 9:1 to 2:1),
pure product 26a was isolated. Yield: 250 mg (0.90 mmol, 87%).
M.p. 88Ϫ89 °C. [α]2D0 ϭ ϩ42.4 (c ϭ 1.14, CHCl3). IR (film, NaCl):
ν˜ ϭ 3401 cmϪ1, 3064, 3003, 2977, 2932, 2876, 1684, 1499, 1366,
1248, 1167, 1055, 859, 753, 739, 698. MS (FAB): m/z (%) ϭ 278
(43) [M ϩ 1]ϩ, 222 (100), 252 (100), 178 (23), 143 (23), 104 (43),
α-Amino Ester 28: DessϪMartin periodinane (10,[65,66] 190 mg,
0.45 mmol) was added in small portions at ambient temperature to
a stirred solution of amino alcohol 26b (85 mg, 0.3 mmol) in
CH2Cl2 (0.5 mL). Stirring was continued for 3Ϫ4 h until TLC indi-
cated full consumption of the starting material. The reaction mix-
ture was poured into an aqueous solution of NaHCO3/Na2S2O3
(1 mL) and stirred vigorously. The two phases were separated and
the aqueous layer was extracted twice with CH2Cl2 (2 ϫ 5 mL).
The combined organic layers were dried with MgSO4 and filtered,
and the solvent was removed under reduced pressure. The residue
was dissolved in tBuOH (5 mL), and 2-methyl-2-butene (3 mL) was
added. After slow addition of NaH2PO4 (100 mg) and NaClO2
(70 mg) in H2O (2 mL), the mixture was stirred at ambient tem-
perature until TLC indicated completion of reaction. The mixture
was treated with NaOH (1 mL of a 20% aqueous solution), fol-
lowed by removal of the solvents under reduced pressure. The resi-
due was taken up in H2O, washed twice with Et2O, acidified (pH ϭ
2.5) with diluted H2SO4, and extracted thoroughly with Et2O. The
combined organic layers were washed with saturated Na2S2O3 solu-
tion and water, dried with MgSO4 and filtered, and the solvent was
1
57 (31). H NMR (300 MHz, CDCl3, 330 K): δ ϭ 0.91 (ddd, J ϭ
8.5, J ϭ 5.2, J ϭ 5.2 Hz, 1 H, 3Ј-Ha), 1.01 (ddd, 1 H, J ϭ 8.9, J ϭ
5.2, 2J ϭ 5.2 Hz, 1 H, 3Ј-Hb), 1.12 (m, 1 H, 1Ј-H), 1.40 [s, 9 H,
C(CH3)3], 1.83 (m, 1 H, 2Ј-H), 2.69 (br., 1 H, OH), 3.15 (m, 1 H,
2-H), 3.63 (dd, J ϭ 11.0, J ϭ 6.1 Hz, 1 H, 1-Ha), 3.75 (m, 1 H, 1-
Hb), 5.22 (br., 1 H, NH), 6.97Ϫ7.20 (m, 5 H, arom. CH). 13C NMR
(125 MHz, CDCl3, 330 K): δ ϭ 13.6 (C-3Ј), 21.9 (C-2Ј), 24.6 (C-
1Ј), 28.3 [C(CH3)3], 57.2 (C-2), 66.3 (C-1), 79.9 [C(CH3)3], 125.8,
125.9, 128.4 (arom. CH), 141.9 (arom. Cipso), 156.6 (CϭO) ppm.
C16H23NO3 (277.36): calcd. C 69.29, H 8.36, N 5.05; found C
69.00, H 8.39, N 5.07.
Amino Alcohol 26b: Oxazolidine 21b (490 mg, 1.50 mmol) in
MeOH (5 mL) was treated at 0 °C with trifluoroacetic acid (1 mL).
After the mixture had been kept for 3 h at ambient temperature,
CH2Cl2 (15 mL) was added, the reaction was quenched with satu-
rated aqueous Na2CO3 solution, and the aqueous layer was thor-
oughly extracted with CH2Cl2. The combined organic layers were
dried with MgSO4 and filtered, and the solvent was removed under
reduced pressure. After flash column chromatography (petroleum
ether/ethyl acetate, 9:1 to 2:1) and MPLC (petroleum ether/ethyl
acetate, 3:1) product 26b was isolated, its spectroscopic data in
agreement with those given in the literature.[81] Yield: 353 mg
(1.30 mmol, 85%). [α]2D0 ϭ Ϫ38.2 (c ϭ 1.20, CHCl3). MS (CI, CH4):
m/z (%) ϭ 193 (80), 165 (100), 133 (61), 109 (69), 93 (88). 1H NMR
(500 MHz, CDCl3): δ ϭ 0.92 (m, 2 H, 3Ј-Ha and 3Ј-Hb), 1.12 (m,
1 H, 1Ј-H), 1.37 [s, 9 H, C(CH3)3], 1.99 (m, 1 H, 2Ј-H), 3.12 (br.,
1 H, OH), 3.48 (m, 1 H, 2-H), 3.63 (dd, J ϭ 11.0, J ϭ 5.8 Hz, 1
H, 1-Ha), 3.75 (dd, J ϭ 11.0, J ϭ 3.1 Hz, 1 H, 1-Hb), 4.83 (br., 1
H, NH), 6.97Ϫ7.20 (m, 5 H, arom. CH) ppm. 13C NMR
(125 MHz, CDCl3): δ ϭ 13.6 (C-3Ј), 21.4 (C-2Ј), 24.9 (C-1Ј), 28.3
[C(CH3)3], 58.0 (C-2), 65.8 (C-1), 79.8 [C(CH3)3], 125.8, 126.0,
128.4 (arom. CH), 142.3 (arom. Cipso), 156.6 (CϭO) ppm.
removed under reduced pressure. The crude product was dissolved
[83Ϫ86]
in Et2O (2.5 mL) and CH2N2
(0.5  solution in Et2O) was
carefully added until the solution remained yellow. The excess of
the reagent was destroyed by stirring the solution vigorously. Re-
moval of the solvent under reduced pressure and chromatographic
purification [flash column chromatography (petroleum ether/ethyl
acetate, 9:1) and MPLC (diethyl ether/ethyl acetate, 95:5)] gave
product 28 that still contained some minor unidentified impurities.
Yield: ഠ48 mg (0.16 mmol, 51%). [α]2D0 ϭ Ϫ80.4 (c ϭ 1.20, CHCl3).
IR (film, NaCl): ν˜ ϭ 3369 cmϪ1, 3064, 3004, 2978, 2954, 1745,
1714, 1499, 1165, 1052, 859, 759, 699. MS (CI, CH4): m/z (%) ϭ
306 (25) [M ϩ 1]ϩ, 249 (89), 206 (100), 188 (44), 129 (43). HRMS:
C17H24NO4: calcd. 306.1705; found 306.1697. 1H NMR (500 MHz,
CDCl3; two rotamers ഠ 1:1, 2nd rotamer in italics): δ ϭ 1.05 (ddd,
J ϭ 8.6, J ϭ 5.6, J ϭ 5.6 Hz, 1 H, 3Ј-Ha), 1.16 (ddd, 1 H, J ϭ 9.0,
J ϭ 5.5, J ϭ 5.5 Hz, 1 H, 3Ј-Hb), 1.34 (m, 1 H, 1Ј-H), 1.45/1.46 [s,
9 H, C(CH3)3], 2.02Ϫ2.09 (m, 1 H, 2Ј-H), 3.76/3.78 (s, 3 H, OCH3),
3.98/4.04 (mc, 1 H, 2-H), 5.15Ϫ5.19 (m, 1 H, NH), 7.03Ϫ7. 06 (m,
2 H, arom. CH), 7.14Ϫ7.17 (m, 1 H, arom. CH), 7.23Ϫ7.26 (m, 2
H, arom. CH) ppm. 13C NMR (125 MHz, CDCl3): δ ϭ 13.3 (C-
3Ј), 21.1 (C-2Ј), 24.9 (C-1Ј), 28.3 [C(CH3)3], 52.4 (OCH3), 56.4 (C-
2), 80.0 [C(CH3)3], 125.9, 126.1, 128.3 (arom. CH), 141.6 (arom.
Cipso), 155.2 (CϭO), 172.4 (CϭO) ppm. C17H23NO4 (305.37):
calcd. C 66.86, H 7.59, N 4.59; found C 66.44, H 7.72, N 4.59.
α-Amino Acid 27: Amino alcohol 26a (120 mg, 0.40 mmol) in
MeCN/0.75% H2O (5 mL) was treated dropwise at 0 °C with
2.3 mL of a stock solution containing H5IO6 (20 g, 88 mmol), CrO3
Eur. J. Org. Chem. 2003, 3219Ϫ3229
www.eurjoc.org
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3227

J. Pietruszka, A. Witt, W. Frey
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Acknowledgments
We gratefully acknowledge the Deutsche Forschungsgemeinschaft,
the Fonds der Chemischen Industrie, and the Otto-Röhm-Gedächt-
nisstiftung for their generous support of this project. Donations
from Boehringer Ingelheim KG, Degussa AG, Bayer AG, BASF
AG, Wacker AG, and Novartis AG were greatly appreciated. We
are grateful to the Institut für Organische Chemie der Universität
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 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 3219Ϫ3229

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CCDC-206722 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
at www.ccdc.cam.ac.uk/conts/retrieving.html [or from the
Cambridge Crystallographic Data Centre, 12, Union Road,
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www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3229