Enantiomerically pure cyclopropylamines from cyclopropylboronic esters

Article abstract of DOI:10.1002/ejoc.200900882

Cyclopropylamines are versatile intermediates and products both in organic synthesis in general and for active substances in particular. Although the synthesis of the corresponding enantiomerically pure cyclopropylboronic esters had been established previously, the C-B to C-N transformation was elusive. A detailed, study directed towards the synthesis of several enantiomerically pure cyclopropylamines is disclosed; tranylcypromine [(1S, 2R)-36] and the known belactosin A intermediate 43 were both obtained by use of trifluoroborates as key intermediates.

Full text of DOI:10.1002/ejoc.200900882

FULL PAPER
DOI: 10.1002/ejoc.200900882
Enantiomerically Pure Cyclopropylamines from Cyclopropylboronic Esters
Jörg Pietruszka*[a] and Gemma Solduga[a]
Keywords: Cyclopropane / Boron / Asymmetric synthesis / Amines / Natural products
Cyclopropylamines are versatile intermediates and products
both in organic synthesis in general and for active substances
in particular. Although the synthesis of the corresponding en-
antiomerically pure cyclopropylboronic esters had been es-
tablished previously, the C–B to C–N transformation was
elusive. A detailed study directed towards the synthesis of
several enantiomerically pure cyclopropylamines is dis-
closed; tranylcypromine [(1S,2R)-36] and the known belacto-
sin A intermediate 43 were both obtained by use of trifluoro-
borates as key intermediates.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
Introduction
The importance of cyclopropanes as synthetic intermedi-
ates, as well as the occurrence of the substructure in physio-
logically active natural products,[1] is well documented, and
an impressive number of synthetic methods directed
towards this motif have consequently been reported.[2]
Furthermore, aminocyclopropanes in particular are incor-
porated in a number of drugs such as tranylcypromine[3]
and trovafloxacin[4] or in aminocyclopropanecarboxylic ac-
ids,[5] but also as key elements in natural products such as
coronatine[6] or belactosin A (Figure 1).[7] A number of syn-
theses have been disclosed, including the cyclopropanation
of enamines and aminonitriles,[8] the amidocyclopropan-
ation of alkenes,[9] the Curtius rearrangement,[10] the re-
ductive amination of cyclopropanone acetals[11] or the re-
duction of nitrocyclopropanes,[12] although not every
method has been widely applied. For enantiomerically pure
products – essential for drug synthesis – a number of ap-
proaches have been successfully applied,[13] one of the most
prominent recent examples being the de Meijere[14] varia-
tion of the Kulinkovich[15] hydroxycyclopropanation.
Figure 1. Selected physiologically active aminocyclopropanes.
aminations do not affect boronic acids or esters, but tend
to require the intermediacy of more electrophilic boron sub-
strates such as trialkylboranes, borinic acids or dichloro-
boranes.[17] However, our recent progress with the corre-
sponding trifluoroborates[18] encouraged us to pursue the
strategy. We had previously demonstrated that cyclo-
Our own synthetic efforts are based on the utilisation of
enantiomerically pure and highly stable cyclopropylboronic
esters (Figure 2).[16] We envisaged two alternative ap-
proaches towards cyclopropylamines 1: The first approach
was a Curtius sequence in the presence of a boronic ester
leading to intermediate 2, followed by conversion of the bo-
ron functionality. In a second alternative we utilised the bo-
ronic ester 3 in a C–B to C–N conversion. It should be
noted that methods and reagents commonly used for
[a] Institut für Bioorganische Chemie der Heinrich-Heine-Uni-
versität Düsseldorf im Forschungszentrum Jülich,
Stetternicher Forst Geb. 15.8, 52428 Jülich, Germany
Fax: +49-2461-616196
E-mail: j.pietruszka@fz-juelich.de
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900882.
Figure 2. Cyclopropylamines from cyclopropylboronic esters 4 and
5.
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Enantiomerically Pure Cyclopropylamines
propylboronic esters 4 and 5[19] could indeed be utilised
for both routes;[20] here we describe the full details of our
findings.
Results and Discussion
Cyclopropylamines by Curtius Rearrangement
The substrates for the Curtius rearrangement were read-
ily synthesised by a two-step sequence starting from the pri-
mary alcohols 4 or its diastereomer 5 (Scheme 1). Oxidation
provided the corresponding carboxylic acids 6 (89%) and 7
(90%), respectively. The acyl azides 8 and 9 were obtained
in high yield (quant./95%) after mixed anhydride activation
followed by treatment with sodium azide.
Scheme 1. Conditions: (a) NaIO4 (3 equiv.), RuCl3·H2O (5%),
CCl4/CH3CN/H2O, room temp., 15 h; (b) (i) Et3N (1.5 equiv.),
ClCO2Et (1.5 equiv.), THF, 0 °C, 30 min, (ii) NaN3 (50 equiv.),
0 °C, 30 min.
Scheme 2. Curtius rearrangements of acyl azides 8 and 9.
We next investigated Curtius rearrangements of the acyl
azides, directly introducing different protecting groups at
The same route was also tested for the cis series, starting
the amine moiety. When starting from azide 8, heating in from the diastereoisomerically pure alcohol 11.[16c] Oxi-
toluene (100 °C) in the presence of benzyl alcohol furnished dation to the acid 12 and formation of the acyl azide 13
the carbamate 10a in high yield (Scheme 2, Entry 1). To es- was straightforward, furnishing the intermediates in 76%
tablish a route towards the phthalimide-protected aminocy- and 96% yields, respectively (Scheme 3). However, it should
clopropylboronate 10b, the free amine was trapped with be noted that the formation of the acid 12 was somewhat
phthalic anhydride after neutralisation of the reaction mix- sluggish and the intermediate aldehyde more stable than ex-
ture with triethylamine (Entry 2). It should be noted that pected. Furthermore, the acid 12 decomposed upon treat-
the isolation of free amine proved difficult and was conse- ment with acetic acid, addition of which to the mobile
quently omitted. The product 10b was obtained in moderate phase during chromatographic purification consequently
yield (67%) after column chromatography, but the crude had to be omitted. Curtius rearrangement with water as
product (obtained in 92% yield) could also be directly used nucleophile did not lead to the desired product; neither the
for further transformations. When isocyanate formation in intermediate nor the trapped product could be detected.
the presence of tert-butyl alcohol was examined, more Only the more reactive benzyl alcohol would react with the
equivalents of the nucleophile were found to be needed. The isocyanate, forming the desired benzylcarbamate 14 in
best results for the carbamate 10c (Entry 3, 84%) were ob- moderate yield (51%). These findings are in good agree-
tained in neat alcohol; the yield was significantly lower ment with previous observations for cis-substituted com-
when only 6 equiv. were used (39%). This was obviously pounds and might be due to the proximity of the nucleo-
not a problem with the diastereomer 9, and hence the ben- phile to the boron group.
zylcarbamate 10d was again obtained in high yield (90%,
In order to take advantage of the potential transforma-
Entry 4) under standard conditions (1 equiv. BnOH, tolu- tions on the boron moiety, the esters 10a–d had to be con-
ene, 100 °C, 4 h). In a last experiment, we formed the corre- verted into more active species. The method of choice was
sponding free amine from azide 9 and treated it directly our previously established conversion into the correspond-
with anisaldehyde under Dean–Stark conditions; after ing trifluoroborates 15.[18] Under the reported conditions
workup, the crude imine was reduced with NaBH4 to give [KHF2 (50 equiv.), MeOH, 80 °C] products 15a–c were all
the PMB-protected (PMB: p-methoxybenzyl) aminocyclo- obtained in good to excellent yields (Scheme 4, 78–95%;
propane 10e in 66% yield over three steps (Entry 5).
PG = protecting group). However, all attempts to convert
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J. Pietruszka, G. Solduga
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can be conveniently stored for a long time at 4 °C under
dry nitrogen; it also crystallised from CDCl3, allowing for
an X-ray structure analysis.[24] First attempts to perform
cross-coupling reactions with 10 mol-% catalyst were disap-
pointing (Scheme 5, Entry 1). In order to evaluate whether
the transformation took place at all, 1 equiv. of Pd(PPh3)4
was added. Although no product 16b was observed at
100 °C after 1 h (Entry 2), minor amounts (20% yield, En-
try 3) were isolated after 36 h. Obviously, the purification
was hampered by the large amounts of ligand present, also
accounting for the low yield. We tried to reduce the Pd0
loading (Entries 4 and 5), but were not able to increase the
yield beyond 40% [Entry 4, 0.5 equiv. Pd(PPh3)4]. In sum-
mary, although the desired aminocyclopropylboronates
could be synthesised and used for Suzuki couplings, they
proved to be impractical for large-scale syntheses of a li-
brary of enantiomerically pure aminocyclopropanes. An al-
ternative route utilizing the C–B to C–N conversion was
hence pursued.
Scheme 3. Conditions: (a) NaIO4 (3 equiv.), RuCl3·H2O (5%),
CCl4/CH3CN/H2O, room temp., 15 h; (b) (i) Et3N (1.5 equiv.),
ClCO2Et (1.5 equiv.), THF, 0 °C, 30 min, (ii) NaN3 (50 equiv.),
0 °C, 30 min; (d) (i) toluene, 100 °C, (ii) BnOH (1.1 equiv.), 100 °C,
15 h.
the borates into the cyclopropanes 16 failed, even when the
most reliable coupling partner iodobenzene was used, and
optimised protocols from our own group or alternative cat-
alyst systems (e.g., from the Buchwald[21] or the Glorius[22]
groups) were applied. It is noteworthy that in all cases in
which an acidic proton on the nitrogen atom was involved
(carbamates 15a, 15c) the NMR spectra of the crude prod-
ucts did not show any cyclopropane signals after the trans-
formation, making ring-opening under basic conditions
likely. With the phthalimide-substituted cyclopropane 15b
the product was also not obtained, but deboronation was
observed to a minor extent when Deng conditions[18b] were
applied.
Scheme 5. Conditions: (a) (i) SiCl4 (2.0 equiv.), THF, room temp.,
1 h, (ii) MeOH (11.0 equiv.), 0 °C, 10 min, (iii) propane-1,3-diol
(1.1 equiv.), 0 °C to room temp.
Cyclopropylamines by C–B to C–N Conversion
The fact that trifluoroborates could readily be converted
into dichloroboranes stimulated the second approach, be-
cause it had been well established by Matteson et al. that
these could be further transformed by treatment with azides
Scheme 4. Potasium trifluoroborates 15 and attempted cross-cou-
pling.
The side-reactions could obviously only be avoided un- in a one-pot procedure.[23a] In order to apply the method,
der nonprotic conditions, a prerequisite that could not be all starting materials were first synthesised by standard pro-
met with trifluoroborates. Matteson et al. have recently re- cedures.[25–27]
ported a convenient alternative in which trifluoroborates
For the optimisation study, the cyclopropyl trifluorobor-
were transformed into more reactive dichloroboranes.[23] ate 18a was converted into the dichloride 19a, followed by
We utilised this approach and converted the phthalimide treatment with benzyl azide[27] (20a, Scheme 6). The first
15b with SiCl4; the intermediate dichloride was then directly experiment was run at room temperature in pure toluene,
treated first with MeOH and then with propane-1,3-diol, and we were pleased to obtain a 65% yield of the spectro-
leading to the corresponding 1,3,2-dioxaborinane 17 in scopically pure racemic amine 21a directly (Entry 1). How-
87% yield (Scheme 5). The ester 17 is a colourless solid that ever, when acetonitrile (approximately 11%) was added to
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Enantiomerically Pure Cyclopropylamines
the reaction mixture the solubility of trifluoroborate 18a
was increased, as was the yield (72%, Entry 2). An increase
in the temperature to 60 °C improved the yield further and
allowed for a shorter reaction time (Entry 3), but some im-
purities were observed. Consequently, 40 °C was taken as
the temperature of choice for the second step, and for con-
venience we increased the amount of acetonitrile for all sub-
sequent experiments to 20%. We next checked the yield as
a function of reaction time (Entries 4–8) and obtained the
highest yield when the reaction was quenched after 10–15 h
(Entry 7); prolonged reaction times did not increase the
yield further.
Scheme 7. Conditions: (i) SiCl4 (2 equiv.), toluene/CH3CN (4:1),
room temp., (ii) 20a (1.4 equiv.), 40 °C, 15 h.
sired side-products. The reaction of the cis-cyclopropane
22[18b] also proceeded smoothly, affording amine 23 in 82%
yield.
In view of the results obtained with the trans series, we
next investigated enantiomerically pure functionalised cis-
substituted cyclopropanes. Protected (hydroxymethyl)cyclo-
propanes are ideal model compounds with the flexibility
for the introduction of a number of functional groups. For
obvious reasons, neither silyl or benzyl ethers nor acetals
were chosen, but again the benzoate was selected, because
none of the other groups would tolerate the Lewis acidic
conditions (or the fluoride reagent). The target compound
was not known prior to the present investigation; it was
synthesised from the established[16c,16q] (Z)-allyl alcohol 24
through the introduction of the protecting group
(Scheme 8, 93% yield). Cyclopropanation was – as ex-
pected – only possible with the Pd(OAc)2-catalysed decom-
position of diazomethane, furnishing the cyclopropanes 26a
Scheme 6. Optimisation of the aminocyclopropane synthesis
(* contained impurities).
The optimised reaction conditions [toluene/acetonitrile and 26b in 63% yield as a separable 1:1 mixture. It had
(4:1), 40 °C, 15 h] were applied in other amine syntheses already been shown that the diastereoselectivity in the cis
(Scheme 7). After the alkyl-substituted cyclopropane 18a series was relatively low,[17c] and consequently we did not
(Entry 1, for comparison), the phenylcyclopropane 18b was attempt to optimise the diastereomeric ratio of the conver-
used. Independently of the azide used, high yields were ob- sion, because both isomers were required anyway. However,
tained [Entry 2: 21b (86%) from benzyl azide (20a); En- the following investigation was disappointing: after success-
try 3: 21c (80%) from p-methoxybenzyl azide (20b); En- ful conversion into the trifluoroborate 27 (Scheme 9, 87%
try 4: 21d (85%) from allyl azide (20c)]. In order to avoid yield), all attempts to perform the amination (desired prod-
possible evaporation of allyl azide (20c), the reaction was uct 28) failed. We speculated that the high reactivity of the
carried out at room temperature.
dichloroborane species 29, with the proximity of the car-
Although the benzyl-protected trifluoroborate 18c could bonyl group, was enhancing the intramolecular reaction
not be successfully converted into amine 21a – Lewis acidic leading to ring-opening and decomposition. In order to
conditions at elevated temperatures were not tolerated – the confirm the result, we also investigated the transformation
benzoyl-protected derivative 18d could be used conve- via 29 into the 1,3,2-borinane 30, which – as expected –
niently, furnishing the benzylamine 21f in 73% yield (En- failed. Omitting the electrophilic boron intermediate, we
try 6). However, the transformation was stopped after 5 h, also performed a Suzuki coupling to afford cyclopropane
because prolonged heating caused the formation of unde- 31, which proceeded as expected (67% yield).
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J. Pietruszka, G. Solduga
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possible protecting groups to use and thus the limitations,
especially for the cis-substituted cyclopropanes, was demon-
strated. In the final section two applications of the devel-
oped approach are discussed.
Applications
Tranylcypromine (36, Parnate®, Jatrosom®; see Figure 1)
is a clinically useful agent for the treatment of mental de-
pression and certain phobic anxieties in patients who do
not respond to other therapies; they must be either closely
supervised or hospitalised.[3b,28] The drug acts as a mono-
amine oxidase (MAO) inhibitor, and the mechanism in-
volved in MAO inhibition has been studied in detail.[29] Al-
though the drug is commercially available as racemic mix-
ture, it has been shown that the (1S,2R) isomer is four times
more potent than its enantiomer.[30] Tranylcypromine is
commonly synthesised from the corresponding acid by a
Curtius rearrangement,[13h] but for the synthesis of enantio-
merically pure products, kinetic enzymatic resolutions have
been used as key steps.[3c,3d,30b,31]
Scheme 8. Conditions: (a) BzCl (1.2 equiv.), DMAP (3 mol-%),
Et3N (1.0 equiv.), CH2Cl2, 15 h; (b) CH2N2 (12 equiv.), Pd(OAc)2
(0.1 equiv.), Et2O, 0 °C.
Before proceeding with attempts directed towards the en-
antiomerically pure drug, we examined the deprotection of
the synthesised racemic amines 21b–d (Scheme 11). Obvi-
ously, the task at hand was not unproblematic, because at-
tempted hydrogenolysis of benzylamine 21b (even at
–20 °C) led to ring-opening, as did the oxidative cleavage of
the PMB group in amine 21c – probably through a mecha-
nism similar to that of the MAO inhibition. A variety of
conditions were tested for the isomerisation/hydrolysis se-
quence necessary to deprotect the allylamine 21d, but the
high temperatures needed for the isomerisation led to de-
composition of the formed product 36. Because Boc-pro-
tected tranylcypromine is stable up to high temperatures,
this protection of the allylamine was assumed to be the
method of choice for the following investigation.
Scheme 9. Conditions: (a) KHF2 (50 equiv.), MeOH, 80 °C; (b)
PhBr (1.2 equiv.), Cs2CO3 (3 equiv.), PdCl2(dppf)·CH2Cl2 (7 mol-
%), THF/H2O (3:1), 60 °C, 15 h; (c) (i) SiCl4 (2 equiv.), toluene/
CH3CN (4:1), room temp., (ii) BnN3 (1.4 equiv.), 40 °C, 5 h; (d) (i)
SiCl4 (2.0 equiv.), THF, room temp., 1 h, (ii) MeOH (11.0 equiv.),
0 °C, 10 min, (iii) propane-1,3-diol (1.1 equiv.) , 0 °C to room temp.
The same argument of a proximity effect should also
hold true for a related derivative that was synthesised from
the known[19,16q] 2-substituted allyl alcohol 32 (Scheme 10):
the three-step sequence – protection (ester 33 in 79% yield),
cyclopropanation (cyclopropane 34 in 93% yield) and for-
mation of trifluoroborate 35 (70% yield) – was uneventful.
Again, the following steps failed to provide the desired
amine, with only decomposition being observed.
Scheme 11. Attempts to deprotect amines 21b–d.
Scheme 10. Conditions: (a) BzCl (3.0 equiv.), Et3N (2.0 equiv.),
DMAP (0.1 equiv.), CH2Cl2, room temp., 15 h; (b) Pd(OAc)2
(5 mol-%), CH2N2 (12 equiv.), Et2O, 0 °C, 30 min; (c) KHF2
(50 equiv.), MeOH, 80 °C, 2 d; (d) (i) SiCl4 (2 equiv.), toluene/
CH3CN (4:1), room temp., (ii) BnN3 (1.4 equiv.), room temp., 5 h.
Scheme 12 summarises the successful synthesis of enan-
tiomerically pure tranylcypromine (36). From the starting
enantio- and diastereoisomerically pure cyclopropylboronic
In summary, we have devised a method for the synthesis ester 37,[19a] the corresponding trifluoroborate (S,S)-18b
of cyclopropylamines from cyclopropylboronic esters was first obtained in 89% yield. As expected, the amine
through a C–B to C–N conversion. The scope in view of synthesis proceeded smoothly, yielding the allylamine
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Enantiomerically Pure Cyclopropylamines
(1S,2R)-21d in 85% yield. The Boc group was readily intro-
duced by a standard procedure with Boc2O, furnishing car-
bamate 38 in 89% yield, and the isomerisation to the en-
amine 39 was conveniently achieved with an Ru catalyst[32]
in deoxygenated xylene in 73% yield. The subsequent hy-
drolysis of enamine 39 with HCl in THF failed to give the
desired product 36. Nevertheless, when trifluoroacetic acid
(TFA) in a dioxane/H2O (2:1) mixture as solvent at 50 °C
was used instead, the corresponding TFA salt of tranylcy-
promine was obtained in quantitative yield. Treatment of
the salt with aqueous KOH and extraction with Et2O liber-
ated the enantiomerically pure tranylcypromine [(1S,2R)-
36] (quant.).
Scheme 13. Conditions: (a) KHF2 (50 equiv.), MeOH, 80 °C, 2 d;
(b) (i) SiCl4 (2 equiv.), toluene/CH3CN (4:1), room temp., (ii) BnN3
(1.4 equiv.), 20, room temp., 5 h; (c) (i) Boc2O (1.5 equiv.), Et3N
(1.5 equiv.), MeOH, room temp., 20 h, (ii) Pd/C (10 mol-%), H2,
3 d; (d) DMAP (0.3 equiv.), Boc2O (3 equiv.), CH3CN, room temp.,
15 h; (e) NaOH (7 equiv.), MeOH, 30 min.
Conclusions
Scheme 12. Conditions: (a) KHF2 (50 equiv.), MeOH, 80 °C, 2 d;
(b) (i) SiCl4 (2 equiv.), toluene/CH3CN (4:1), room temp., (ii) Al-
lylN3 (1.4 equiv.), room temp., 15 h; (c) Et3N (1.3 equiv.), DMAP
(0.3 equiv.), Boc2O (3 equiv.), CH3CN, room temp., 2 d; (d)
HRu(PPh3)3·toluene (1–10 mol-%), xylene, 138 °C, 15 h; (e) TFA,
dioxane/H2O (2:1), 50 °C, 15 h.
The versatility of highly stable enantio- and dia-
stereomerically pure cyclopropylboronic esters was con-
firmed, and the scope was extended by (a) their conversion
into the corresponding trifluoroborates and (b) exploitation
of the boron moiety for the synthesis of amines. The high-
yielding transformations could be successfully applied to
the partial and total synthesis of the biologically active
products belactosin A and tranylcypromine (36). The
limitations with respect to cis- and 1,1-disubstituted cyclo-
propanes were shown, forming the foundation for future
endeavours.
A second application was devised for a known key inter-
mediate of the belactosin A synthesis.[7b] Belactosin A is a
Streptomyces metabolite that displays inhibitory activity
towards cyclin–cyclin-dependent kinase complexes;[7a] it has
been demonstrated to inhibit the cell cycle progression of
human tumour cells at the G2/M phase. It has also been
shown to be a ubiquitin-proteasome inhibitor.[7e,7f] The to-
tal synthesis has been accomplished by different
groups,[7b–7d] but the cyclopropane-containing core amino
acid in particular has been the object of several stud-
ies.[13a,33] The amination of trifluoroborates reported in this
manuscript offers an alternative (Scheme 13).
Experimental Section
General Remarks: All reagents were used as purchased from com-
mercial suppliers without further purification. The reactions were
carried out by standard Schlenk techniques under dry nitrogen.
Glassware was oven-dried at 112 °C overnight. Solvents were dried
and purified prior to use. 1,2-Dimethoxyethane (DME) and tetra-
The pure benzoate 40[16d] was again readily converted
into the enantiomerically pure (S,S)-18d (90% yield), fol-
lowed by the established amination via the dichloroborane hydrofuran (THF) were freshly distilled from sodium/benzophe-
none. Toluene, dichloromethane (CH2Cl2) and diethyl ether (Et2O)
were dried with the aid of a Solvent Purification System (MBraun,
MB SPS-800). Petroleum ether refers to the fraction with a boiling
range of 40–60 °C. Flash-column chromatography: Macherey–Na-
gel silica gel 0.040–0.063 mm (400–230 mesh). TLC: pre-coated
sheets of silica gel 60 with a fluorescence indicator (Alugram®
with benzyl azide (20a) [(S,S)-21f, 73% yield]. Removal of
the benzyl group by hydrogenolysis in the presence of
Boc2O[34] led directly to carbamate 41; however, the two-
step sequence (Boc protection followed by hydrogenolysis)
proved to be more reliable, giving the desired product 41 in
86% yield. Two consecutive protecting group manipulations
(Boc protection; 42: 92% yield; saponification; 43: 85%
yield) led to the desired enantiomerically pure building
block that has been used previously in the total synthesis
of belactosin A.[7b]
SIL G/UV245
, Macherey–Nagel), detection by UV extinction
(245 nm) or with cerium molybdenum solution [phosphomolybdic
acid (25 g), Ce(SO4)2·H2O (10 g), concd. H2SO4 (60 mL), H2O
(940 mL)], with ninhydrin solution [ninhydrin (3.2 g), acetone
(200 mL)] or with vanillin solution. Preparative MPLC: Labomatic
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J. Pietruszka, G. Solduga
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(MD80/100), with
a
packed column (39ϫ400 mm or
3), 27.5 (C-2), 65.1 (C-1Ј), 53.3 (C-1ЈЈ), 127.9, 128.7 (arom. CH),
138.0 (arom. Cipso), 157.1 (CO) ppm (C-1 not detectable). 19F
NMR ([D6]DMSO, 376 MHz): δ = –136.6 (s, 1 F, BF2OMeK; im-
23ϫ250 mm), LiChroprep, Si60 (15–25 µm) and UV detector
(254 nm). 1H and 13C NMR spectra were recorded at room tem-
perature in CDCl3 unless otherwise stated with a Bruker ARX 300,
ARX 500 or DRX 600, or a Varian Inova 400. Chemical shifts (δ)
are given in ppm relative to internal standard TMS (1H: δ =
0.00 ppm) or relative to the resonance of the solvent (e.g., 1H:
CHCl3, δ = 7.25 ppm; 13C: CHCl3, δ = 77.0 ppm). In the case of
19F and 11B NMR spectra the external standard BF3·OEt2 (δ =
0.0 ppm) was used. J values (coupling constants) are given in Hz;
in spectra of higher order the δ and J values were not corrected.
The multiplicities of the signals are given as the following abbrevi-
ations: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet),
mc (centred multiplet), br. (broad signal). The NMR signals were
assigned by means of DEPT, H-H and C-H COSY spectroscopy.
The diastereomeric ratios were determined by the integration of the
corresponding signals in the 1H or 13C NMR spectra. Microanaly-
ses were performed at the Institut für Organische Chemie, Stutt-
gart. Melting points (Büchi Melting Point SMP-20, Büchi Melting
Point B-540 and Stuart Melting Point SMP3) are not corrected.
Specific rotations were measured at 20 °C unless otherwise stated.
purity), –140.2 (s, 14 F, BF K) ppm. IR (film): ν = 3639, 3579,
˜
3
3361, 3306, 3028, 2943, 2898, 1714, 1672, 1534, 1514, 1454, 1389,
1299, 1266, 1217, 1177, 1096, 1048, 990, 940, 912, 869, 779, 734,
696 cm–1. MS (ESI, positive ion): m/z (%) = 270.7 [M + OMe –
KF]+ (100), 239.4 [M – KF]+ (63).
Representative Procedure for the C–B to C–N Conversion
Amine 21a (HCl Salt): Cyclopropyl trifluoroborate 18a (45.0 mg,
0.22 mmol) was suspended in toluene (2.20 mL)/CH3CN (0.55 mL)
under dry nitrogen. SiCl4 (0.44 mL of a 1  solution in CH2Cl2,
0.44 mmol) was added at room temp., and the mixture was stirred
for 20 min. Benzyl azide (20a, 0.04 g, 0.31 mmol) was added, and
the reaction mixture was stirred at 40 °C for 15 h. The reaction was
quenched with water (2.20 mL), and the layers were separated. The
organic layer was extracted with HCl (1 , 5ϫ2.20 mL). The com-
bined aqueous layers were strongly basified with aq. KOH (40%).
The amine was extracted with diethyl ether (4ϫ10 mL). The com-
bined ether layers were dried with Na2CO3, and the solvent was
removed under reduced pressure. The amine 21a (36.0 mg,
0.77 mmol, 81%) was obtained as yellow oil. For convenience dur-
ing characterisation, the hydrochloride was formed upon titration
with HCl as a colourless solid, m.p. 126–128 °C. 1H NMR (CDCl3,
600 MHz): δ = 0.52 (mc, 1 H, 3-Ha), 0.84 (t, J = 7.0 Hz, 3 H, 4Ј-
H), 1.02 (mc, 1 H, 1Ј-Ha), 1.23 (mc, 1 H, 3-Hb), 1.23–1.29 (m, 5 H,
1Ј-Hb, 2Ј-H, 3Ј-H), 1.48 (mc, 1 H, 2-H), 2.03 (mc, 1 H, 1-H), 4.04
(s, 2 H, CH2Ph) 7.34–7.42 (m, 3 H, arom. CH), 7.58–7.63 (m, 2 H,
arom. CH), 9.91 (br., 2 H, NH2) ppm. 13C NMR (CDCl3,
151 MHz): δ = 0.4 (C-3), 13.9 (C-4Ј), 17.6 (C-2), 22.3 (C-3Ј), 30.6
(C-2Ј), 31.2 (C-1Ј), 34.4 (C-1), 51.3 (CH2Ph), 128.9, 129.3, 130.6
Representative Procedure for the Curtius Rearrangement
Benzyl Carbamate 10a: Acyl azide 8 (0.62 g, 1.08 mmol) was dis-
solved in dry toluene (5.00 mL) under dry nitrogen, and benzyl
alcohol (1.11 mL, 1.10 mmol) was added. The mixture was stirred
under reflux at 110 °C for 4 h and was then allowed to cool to
room temp., and toluene was removed under reduced pressure. The
crude product was purified by column chromatography [silica gel
(60 g), PE/EtOAc (85:15)] to yield amine 10a (0.59 g, 0.90 mmol,
84%) as a colourless solid, m.p. 88–89 °C. [α]2D0 = –26.3 (c = 0.30,
1
CHCl3). H NMR (CDCl3, 500 MHz): δ = –0.36 (ddd, J = 10.5, J
= 7.3, J = 4.1 Hz, 1 H, 1Ј-H), 0.58 (ddd, J = 10.5, J = 4.1, J =
4.1 Hz, 1 H, 3Ј-Hb), 0.63 (ddd, J = 10.7, J = 7.3, J = 4.1 Hz, 1 H,
3Ј-Ha), 2.16 (ddd, J = 10.7, J = 4.1, J = 4.1 Hz, 1 H, 2ЈЈ-H), 2.99
(s, 6 H, OCH3), 4.67 (br., 1 H, NH), 5.05 (s, 2 H, 1ЈЈ-H), 5.27 (s,
2 H, 4-H, 5-H), 7.33–7.28 (m, 25 H, arom. CH) ppm. 13C NMR
(CDCl3, 125 MHz): δ = 2.0 (C-1Ј), 13.1 (C-3Ј), 28.9 (C-2Ј), 51.7
(OCH3), 66.6 (C-1ЈЈ), 77.7 (C-4 and C-5), 83.2 (CPh2OCH3), 127.3,
127.4, 127.6, 127.8, 128.1, 128.4, 128.5, 129.7 (arom. CH), 136.5,
(arom. CH), 130.2 (arom. Cipso) ppm. IR (film): ν = 2957, 2923,
˜
2857, 2700, 25¸2430, 1584, 1493, 1467, 1455, 1443, 1410, 1392, 1377,
1246, 1215, 1153, 1085, 1055, 1026, 993, 917, 874, 749, 729,
694 cm–1. MS (ESI, positive ion): m/z (%) = 204.3 [M – Cl]+ (100).
C14H22ClN (239.78): calcd. C 70.13, H 9.32, N 5.84; found C 69.88,
H 9.10, N 5.81.
Synthesis of Tranylcypromine (36)
141.1 (arom. Cipso), 156.4 (CO) ppm. IR (film): ν = 3316, 3061,
˜
3031, 1709, 1417, 1185, 1075, 906, 729, 697 cm–1. MS (FAB, NBA
+ NaI): m/z (%) = 676.3 (100) [M + Na]+, 197.1 (76) [Ph2CO-
CH3]+. C41H40BNO6 (653.57): calcd. C 75.35, H 6.17, N 2.14;
found C 75.19, H 6.17, N 2.16.
Trifluoroborate 18b: Cyclopropylboronic ester 37[19a] (0.56 g,
0.96 mmol) was treated with KHF2 (3.77 g, 48.2 mmol) in MeOH
(200 mL) for 2 d according to the procedure described for com-
pound (S,S)-15a. The cyclopropyl trifluoroborate (S,S)-18b (0.19 g,
0.86 mmol, 89%) was obtained as a colourless solid, m.p. 222–
234 °C (decomposition). [α]2D0 = +35.0 (c = 1.25, MeOH). 1H NMR
([D4]MeOH, 600 MHz): δ = –0.05 (ddd, J = 7.4, J = 3.6, J =
5.3 Hz, 1 H, 1-H), 0.53 (ddd, J = 10.0, J = 2.6, J = 3.6 Hz, 1 H,
3-Ha), 0.80 (ddd, J = 7.4, J = 2.6, J = 7.4 Hz, 1 H, 3-Hb), 1.66
(ddd, J = 10.0, J = 5.3, J = 7.4 Hz, 1 H, 2-H), 6.99–7.17 (m, 5 H,
arom. CH) ppm. 13C NMR ([D4]MeOH, 151MHz): δ = 14.7 (C-
Representative Procedure for the Trifluoroborate Formation
Trifluoroborate (S,S)-15a: Cyclopropylboronic ester 10a (0.59 g,
0.90 mmol) was dissolved in a minimum amount of CH2Cl2 in a
Teflon flask. KHF2 (3.53 g, 45.2 mmol) and MeOH (100 mL) were
added, and the mixture was stirred at 80 °C for 4 d. After full con-
version, the solvent was removed under reduced pressure. The
cleaved diol was removed from the cake by filtration with Et2O.
The trifluoroborate was then dissolved in abundant CH3CN, and
the remaining KHF2 was filtered through a Büchner funnel with
CH3CN. After concentration of the solvent under reduced pressure,
the trifluoroborate (S,S)-15a (0.21 g, 0.71 mmol, 78%) was ob-
tained as a colourless solid, m.p. 185–188 °C. [α]2D0 = +32.0 (c =
3), 19.94 (C-2), 125.0, 126.2, 128.8 (arom. CH), 148.9 (arom. Cipso
)
ppm (C-1 not detectable). 19F NMR ([D4]MeOH, 564 MHz): δ =
–144.6 (br. s, BF3K) ppm. 10B NMR ([D4]MeOH, 64 MHz): δ =
4.0 (br., BF K) ppm. IR (film): ν = 3061, 3002, 3018, 2987, 2960,
˜
3
1602, 1494, 1457, 1391, 1315, 1276, 1184, 1162, 1123, 1107, 1072,
1057, 1102, 987, 952, 925, 902, 884, 861, 757, 696 cm–1. MS (ESI,
negative ion): m/z (%) = 184.3 [M – K]– (57). Spectroscopic data
are in full agreement with those previously reported.[18b]
1
0.50, MeOH). H NMR ([D6]DMSO, 60 °C, 400 MHz): δ = –0.50
(ddd, J = 10.8, J = 7.5, J = 4.5 Hz, 1 H, 1-H), 0.03 (ddd, J = 7.5,
J = 6.1, J = 3.0 Hz, 1 H, 3-Ha), 0.17 (ddd, J = 10.8, J = 3.0, J =
3.0 Hz, 1 H, 3-Hb), 2.21 (ddd, J = 6.1, J = 4.5, J = 3.0 Hz, 1 H, 2-
H), 4.99 (s, 2 H, 1Ј-H), 6.70 (br., 1 H, NH), 7.28–7.37 (m, 5 H,
arom. CH) ppm. 13C NMR ([D6]DMSO, 100 MHz): δ = 10.3 (C-
(1S,2R)-Amine 21d (HCl Salt): Phenylcyclopropyl trifluoroborate
(S,S)-18b (0.17 g, 0.76 mmol) was treated with SiCl4 (0.52 mL of a
1  solution in CH2Cl2, 0.52 mmol) according to the procedure
6004
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 5998–6008

Enantiomerically Pure Cyclopropylamines
described for compound 21a. Allyl azide (20c, 0.25 g, 1.06 mmol)
was then added, and the mixture was stirred at room temp. for
14 h. The amine 21d (0.11 g, 0.65 mmol, 85%) was obtained as yel-
low oil. The hydrochloride (0.09 g, 0.44 mmol, 58%) was obtained
as a brown solid, m.p. 107–109 °C. [α]2D0 = +64.6 (c = 0.35, CHCl3).
1H NMR (CDCl3, 600 MHz): δ = 1.26 (ddd, J = 7.7, J = 6.6, J =
6.5 Hz, 1 H, 3-Hb), 1.86 (ddd, J = 10.2, J = 6.6, J = 4.4 Hz, 1 H,
3-Ha), 2.73 (ddd, J = 7.7, J = 4.4, J = 3.6 Hz, 1 H, 1-H), 2.83 (ddd,
J = 10.2, J = 6.5, J = 3.6 Hz, 1 H, 2-H), 3.72 (mc, 2 H, 1Ј-H), 5.44
(dd, J = 10.2, J = 1.0 Hz, 1 H, 3Ј-Ha), 5.50 (dd, J = 17.1, J =
1.0 Hz, 1 H, 3Ј-Hb), 6.15 (ddt, J = 17.1, J = 10.2, J = 6.9 Hz, 1 H,
2Ј-H), 7.09–7.31 (m, 5 H, arom. CH), 10.14 (br., 2 H, NH2) ppm.
13C NMR (CDCl3, 151 MHz): δ = 12.9 (C-3), 21.4 (C-2), 37.1 (C-
1), 50.5 (CH2Ph), 124.3 (C-3Ј), 126.6, 126.9, 128.5, 128.7 (arom.
1290, 1247, 1168, 1144, 1116, 1092, 1070, 1032, 1012, 999, 946,
915, 860, 813, 789, 768, 748, 696 cm–1. MS (ESI, positive ion): m/z
(%) = 296.2 (100) [M + Na]+. HRMS (ESI, positive ion): calcd. for
C17H23NNaO2 296.1621; found 296.1622.
(1S,2R)-2-Phenylcyclopropylamine [Tranylcypromine (36), HCl
Salt]: Enamine 39 (17.0 mg, 60.0 µmol) was dissolved in dioxane
(0.31 mL) and H2O (0.15 mL) in a round-bottomed flask. After
addition of TFA (0.15 mL), the reaction mixture was stirred at
50 °C for 15 h. After removal of the solvents under reduced pres-
sure, the TFA amine salt (18 mg, 70 µmol, quant.) was obtained as
a light yellow oil. The salt was dissolved in Et2O (1 mL) and
strongly basified with aqueous KOH (40%, 0.5 mL). The layers
were separated, and the aqueous layer was extracted with Et2O
(4ϫ1 mL). The combined organic layers were dried with MgSO4,
and the solvents were removed under reduced pressure (not below
100 mbar!) to furnish tranylcypromine (36, 8.00 mg, 60.0 µmol,
quant.) as a light yellow oil. The amine was precipitated (as de-
scribed above for other amines) with concd. HCl vapours to yield
the hydrochloride salt as a solid. [α]2D0 = +138 (c = 0.40, CHCl3)
[ref.[3d] ent-36: [α]2D0 = –135 (c = 0.81, CHCl3)]. 1H NMR (CD3OD,
600 MHz): δ = 1.00 (ddd, J = 9.4, J = 5.3, J = 4.4 Hz, 1 H, 3-Ha),
1.04 (ddd, J = 7.4, J = 5.8, J = 5.3 Hz, 1 H, 3-Hb), 1.90 (ddd, J =
9.4, J = 5.8, J = 3.1 Hz, 1 H, 2-H), 2.49 (ddd, J = 7.4, J = 4.4, J
= 3.1 Hz, 1 H, 1-H), 4.64 (br., 2 H, NH2), 7.04–7.25 (m, 5 H, arom.
CH) ppm. 13C NMR (CD3OD, 151 MHz): δ = 18.0 (C-3), 26.3 (C-
CH), 127.6 (C-2Ј), 137.9 (arom. Cipso) ppm. IR (film): ν = 3090,
˜
3042, 2951, 2895, 2849, 2780, 2739, 2717, 2687, 2605, 2513, 2437,
2417, 1604, 1585, 1497, 1464, 1454, 1440, 1423, 1183, 1047, 989,
941, 909, 838, 762, 739, 695 cm–1. MS (ESI, positive ion): m/z (%)
= 174.2 [M – Cl]+ (100). C12H16ClN (209.72): calcd. C 68.73, H
7.69, N 6.68; found C 68.69, H 7.70, N 6.67.
(1S,2R)-Carbamate 38: Allylamine 21d (0.23 g, 1.32 mmol) was dis-
solved in dry CH3CN (15.0 mL) under dry nitrogen. Boc2O (0.86 g,
3.96 mmol) and DMAP (48 mg, 0.39 mmol) were added, and the
mixture was stirred at room temp. overnight. After complete con-
version (as judged by TLC), the solvents were removed under re-
duced pressure, and the crude product was purified by column
chromatography [silica gel (20 g), PE/EtOAc (90:10)] to yield carba-
mate 38 (0.32 g, 1.17 mmol, 89%) as a colourless oil. [α]2D0 = +49.0
2), 35.7 (C-1), 126.5, 126.7, 129.3 (arom. CH), 143.5 (arom. Cipso
)
ppm. IR (film): ν = 2848, 2744, 2625, 2594, 1605, 1580, 1497, 1467,
˜
1442, 1163, 1081, 1063, 1048, 1024, 937, 901, 800, 743, 698 cm–1.
MS (ESI, positive ion): m/z (%) = 133.9 (100) [M + H]+. Spectro-
scopic data are in full agreement with those previously reported.[3d]
1
(c = 1.00, CHCl3). H NMR (CDCl3, 600 MHz): δ = 1.18 (ddd, J
= 7.4, J = 6.3, J = 5.9 Hz, 1 H, 3-Ha), 1.29 (ddd, J = 9.7, J = 5.9,
J = 4.5 Hz, 1 H, 3-Hb), 1.43 (s, 9 H, CH3), 2.14 (ddd, J = 9.7, J =
6.3, J = 3.3 Hz, 1 H, 2-H), 2.74 (ddd, J = 7.4, J = 4.5, J = 3.3 Hz,
1 H, 1-H), 3.84 (dddd, J = 15.9, J = 5.6, J = 1.5, J = 1.5 Hz, 1 H,
1Ј-Ha), 3.95 (mc, 1 H, 1Ј-Hb), 5.11 (ddd, J = 10.2, J = 3.0, J =
1.5 Hz, 1 H, 3Ј-Ha), 5.14 (ddd, J = 17.1, J = 3.0, J = 1.5 Hz, 1 H,
3Ј-Hb), 5.84 (ddd, J = 17.1, J = 10.2, J = 5.6 Hz, 1 H, 2Ј-H), 7.09–
7.27 (m, 5 H, arom. CH) ppm. 13C NMR (CDCl3, 151 MHz): δ =
17.4 (C-3), 26.2 (C-2), 28.5 (CH3), 38.9 (C-1), 50.3 (C-1Ј), 79.8
[C(CH3)3], 115.9 (C-3Ј), 125.9, 126.2, 128.2 (arom. CH), 134.4 (C-
Synthesis of Belactosin A Intermediate 43
Trifluoroborate 18d: Cyclopropylboronic ester 40[16d] (1.28 g,
2.00 mmol) was treated with KHF2 (7.81 g, 100 mmol) in MeOH
(300 mL) for 3 d according to the procedure described for com-
pound (S,S)-15a. The trifluoroborate 18d (1.01 g, 3.59 mmol, 90%)
was obtained as a colourless solid, m.p. 195–199 °C. [α]2D0 = +23.7
[c
=
0.50, MeOH/acetone (15:1)]. 1H NMR ([D6]acetone,
600 MHz): δ = –0.52 (ddd, J = 9.9, J = 6.8, J = 3.4 Hz, 1 H, 1-H),
0.11 (ddd, J = 9.9, J = 3.6, J = 3.0 Hz, 1 H, 3-Hb), 0.35 (dddd, J
= 6.8, J = 6.8, J = 3.0, J = 1.0 Hz,1 H, 3-Ha), 1.00 (ddddd, J =
8.6, J = 6.8, J = 5.9, J = 3.6, J = 3.4 Hz, 1 H, 2-H), 3.85 (dd, J =
11.1, J = 8.6 Hz, 1 H, 1Ј-Ha), 4.34 (ddd, J = 11.1, J = 5.9, J =
1.0 Hz 1 H, 1Ј-Hb), 7.48–7.51 (m, 2 H, arom. CH), 7.60–7.62 (m,
1 H, arom. CH), 8.03–8.05 (m, 2 H, arom. CH) ppm. 13C NMR
([D6]acetone, 151 MHz): δ = 7.8 (C-3), 13.9 (C-2), 73.0 (C-1Ј),
129.3, 130.2, 133.5 (arom. CH), 132.1 (arom. Cipso), 168.1 (CO)
ppm (C-1 not detectable). 19F NMR ([D6]acetone, 564 MHz): δ =
–143.5 (br. s, BF3K) ppm. 10B NMR ([D6]acetone, 64 MHz): δ =
2Ј), 141.0 (arom. Cipso), 156.4 (CO) ppm. IR (film): ν = 2977, 2930,
˜
1695, 1644, 1605, 1500, 1477, 1438, 1386, 1365, 1279, 1243, 1165,
1146, 1071, 1032, 992, 916, 861, 812, 774, 746, 696 cm–1. MS (ESI,
positive ion): m/z (%) = 312.0 (100) [M + K]+. C17H23NO2 (273.37):
calcd. C 74.69, H 8.48, N 5.12; found C 74.49, H 8.45, N 5.05.
(1S,2R)-Enamine 39: Allylamine 38 (26.0 mg, 0.10 mmol) was dis-
solved in xylene (0.30 mL) under dry argon. After the solution had
been deoxygenated by the freeze technique, HRuCl(PPh3)3·toluene
(1–10 mol-%) was added, and the reaction mixture was stirred at
138 °C for 15 h. The crude product was directly subjected to col-
umn chromatography [silica gel (5 g), PE/EtOAc (98:2)], yielding
the enamine 39 (19.0 mg, 70.0 µmol, 73%) as a colourless oil.
[α]2D0 = +18.0 (c = 0.90, CHCl3). 1H NMR (CDCl3, 600 MHz): δ =
1.36 (ddd, J = 9.9, J = 5.9, J = 4.5 Hz, 1 H, 3-Hb), 1.39 (ddd, J =
4.1 (br., BF K) ppm. IR (film): ν = 3062, 2993, 2942, 1706, 1600,
˜
3
1553, 1454, 1400, 1315, 1277, 1096, 1067, 1023, 954, 925, 882, 869,
836, 814, 707, 686 cm–1. MS (ESI, positive ion): m/z (%) = 243.6
(100) [M – K + H]+.
7.5, J = 6.7, J = 5.9 Hz, 1 H, 3-Ha), 1.47 (s, 9 H, CH3), 1.67 (dd, (1S,2S)-Amine 21f (HCl Salt): Trifluoroborate (S,S)-18d (0.10 g,
J = 6.6, J = 1.6 Hz, 1 H, 3Ј-H), 2.08 (ddd, J = 9.9, J = 6.7, J = 0.35 mmol) was treated with SiCl4 (0.71 mL of a 1  solution in
3.4 Hz, 1 H, 2-H), 2.58 (ddd, J = 7.5, J = 4.5, J = 3.4 Hz, 1 H, 1- CH2Cl2, 0.71 mmol) for 5 min according to the procedure de-
H), 5.03 (dd, J = 20.6, J = 6.6 Hz, 1 H, 2Ј-H), 6.72 (br. d, 1 H, 1Ј-
H), 7.11–7.30 (m, 5 H, arom. CH) ppm. 13C NMR (CDCl3,
151 MHz): δ = 15.5 (C-3Ј), 19.4 (C-3), 26.9 (C-2), 28.4 (CH3), 35.9
scribed for compound 21a. Benzyl azide (20a, 0.07 g, 0.49 mmol)
was then added, and the mixture was stirred at 40 °C for 5 h. The
amine 21f (0.07 mg, 0.26 mmol, 73%) was obtained as a yellow
(C-1), 80.8 [C(CH3)3], 105.7 (C-2Ј), 125.9, 126.0, 128.3 (arom. CH), oil. The hydrochloride (0.08 g, 0.26 mmol, 73%) was obtained as a
128.4 (C-1Ј), 140.9 (arom. Cipso), 153.8 (CO) ppm. IR (film): ν = colourless solid, m.p. 135–138 °C (decomposition). [α]2D0 = –9.50 (c
˜
1
2977, 2930, 1703, 1665, 1605, 1501, 1476, 1455, 1387, 1363, 1308,
= 0.25, CHCl3). H NMR (CDCl3, 300 MHz): δ = 0.86 (ddd, J =
Eur. J. Org. Chem. 2009, 5998–6008
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6005

J. Pietruszka, G. Solduga
FULL PAPER
7.5, J = 6.6, J = 6.4 Hz, 1 H, 3-Hb), 1.49 (ddd, J = 10.4, J = 6.6,
J = 4.2 Hz, 1 H, 3-Ha), 2.05 (ddddd, J = 10.4, J = 7.2, J = 6.4, J
= 6.3, J = 3.8 Hz, 1 H, 1-H), 2.41 (ddd, J = 7.5, J = 4.2, J = 3.8 Hz,
C5H9O2]+. C21H29NO6 (391.46): calcd. C 64.43, H 7.47, N 3.58;
found C 64.20, H 7.45, N 3.43.
1 H, 2-H), 4.00 (dd, J = 11.8, J = 7.2 Hz, 1 H, 1Ј-Ha), 4.07 (s, 2 (1S,2S)-Alcohol 43: Carbamate 42 (0.10 g, 0.26 mmol) was dis-
H, CH2Ph), 4.16 (dd, J = 11.8, J = 6.3 Hz, 1 H, 1Ј-Hb), 7.33–7.59
(m, 8 H, arom. CH), 8.00–8.03 (m, 2 H, arom.), 10.19 (br., 2 H,
solved in MeOH (10.0 mL) in a round-bottomed flask. NaOH
(70.0 mg, 1.76 mmol) was added, and the mixture was stirred at
NH2) ppm. 13C NMR (CDCl3, 151 MHz): δ = 8.9 (C-3), 16.2 (C- room temp. for 30 min. CH2Cl2 was added, and the reaction mix-
1), 33.3 (C-2), 51.6 (CH2Ph), 64.5 (C-1Ј), 128.4, 129.1, 129.7, 130.6,
133.2 (arom. CH), 129.7, 129.9 (arom. Cipso), 166.3 (CO) ppm. IR
ture was quenched with satd. aq. NH4Cl (3 mL). The layers were
separated, and the aqueous layer was extracted with CH2Cl2
(3ϫ5 mL). The combined organic layers were washed with satd.
aq. NaHCO3 (5 mL). The aqueous phase was extracted with
CH2Cl2 (5 mL). The combined organic phases were dried with
MgSO4, and the solvents were removed under reduced pressure.
The crude product was purified by column chromatography [silica
gel (10 g), PE/EtOAc (81:19)], yielding the alcohol 43 as a colour-
less oil (62.0 mg, 0.22 mmol, 85%). [α]2D2 = +3.9 (c = 3.3, CHCl3)
[ref.[33b] ent-43: [α]2D2 = –3 (c = 2, CHCl3)]. 1H NMR (CDCl3,
600 MHz): δ = 0.94 (mc, 2 H, 3-H), 1.31 (dddd, J = 12.8, J = 9.7,
J = 4.8, J = 3.3 Hz, 1 H, 1-H), 1.51 (s, 18 H, CH3), 2.46 (ddd, J =
6.8, J = 4.7, J = 3.3 Hz, 1 H, 2-H), 3.03 (br., 1 H, OH), 3.10 (dd,
J = 10.9, J = 9.7 Hz, 1 H, 1Ј-Ha), 3.89 (dd, J = 10.9, J = 4.8 Hz,
1 H, 1Ј-Hb) ppm. 13C NMR (CDCl3, 151 MHz): δ = 13.7 (C-3),
24.9 (C-1), 28.0 (CH3), 33.7 (C-2), 65.0 (C-1Ј), 82.9 [C(CH3)3],
(film): ν = 2901, 2708, 2595, 2445, 1714, 1600, 1584, 1492, 1451,
˜
1408, 1316, 1290, 1270, 1215, 1176, 1115, 1097, 1085, 1069, 1026,
1014, 999, 960, 882, 752, 696 cm–1. MS (ESI, positive ion): m/z (%)
= 282.2 (100) [M – Cl]+. C18H20ClNO2 (317.8): calcd. C 68.03, H
6.34, N 4.41; found C 67.86, H 6.36, N 4.25.
(1S,2S)-Benzoate 41: Amine (S,S)-21f (0.10 g, 0.36 mmol) was dis-
solved in MeOH (1.85 mL). Boc2O (0.12 g, 0.53 mmol) and Et3N
(0.07 mL, 0.50 mmol) were added, and the mixture was stirred at
room temp. overnight. After the conversion was complete (as
judged by TLC), the solvents were removed under reduced pres-
sure, and the crude product was purified by column chromatog-
raphy [silica gel (10 g), PE/EtOAc (95:5)]. The product was dis-
solved in MeOH (4.00 mL) under dry nitrogen, and Pd/C (10%)
(35 mg, 0.33 mmol) was added. The flask was then evacuated and
flushed with hydrogen (repeated five times). The reaction mixture
was stirred under H2 for 3 d. After full conversion, the mixture was
filtered through a pad of Celite® and silica gel that was thoroughly
rinsed with CH2Cl2. The solvents were removed under reduced
pressure, and the carbamate 41 (95.0 mg, 0.33 mmol, 86% over two
steps) was obtained as a colourless solid, m.p. 94–96 °C (ref.[13g]
m.p. 94–97 °C). [α]2D0 = +23.1 (c = 0.62, CHCl3). 1H NMR (CDCl3,
600 MHz): δ = 0.84–0.88 (m, 2 H, 3-H), 1.45 (s, 9 H, CH3), 1.45
(mc, 1 H, 1-H), 2.55–2.63 (mc, 1 H, 2-H), 4.12–4.23 (m, 1 H, 1Ј-
Ha), 4.30 (dd, J = 11.7, J = 6.9 Hz, 1 H, 1Ј-Hb), 4.42 (br., 1 H,
NH), 7.42–7.59 (m, 4 H, arom. CH), 8.05–8.08 (m, 1 H, arom. CH)
ppm. 13C NMR (CDCl3, 150 MHz): δ = 12.4 (C-3), 19.3 (C-1), 28.3
(C-2, CH3), 66.5 (C-1Ј), 79.7 [C(CH3)3], 128.4, 129.6 (arom. CH),
130.3 (arom. Cipso), 132.9 (arom. CH), 156.3 (NHCO), 166.6 (CO)
153.5 (CO) ppm. IR (film): ν = 3506, 2980, 2937, 1738, 1706, 1687,
˜
1478, 1457, 1429, 1365, 1326, 1274, 1248, 1231, 1158, 1118, 1093,
1047, 1021, 999, 940, 842, 788, 767, 756, 742 cm–1. MS (ESI, posi-
tive ion): m/z (%) = 309.9 (100) [M + Na]+. Spectroscopic data are
in full agreement with those reported previously.[33b]
Supporting Information (see footnote on the first page of this arti-
cle) Full experimental details for all compounds (6–18, 20–27, 31,
33–36, 38, 39, 41–43).
Acknowledgments
We gratefully acknowledge the Deutsche Forschungsgemeinschaft
and the Otto-Röhm-Gedächtnisstiftung for the generous support
of our projects. Donations from BASF AG, Chemetall GmbH and
Wacker AG are greatly appreciated. Furthermore, we thank the an-
alytical departments at the University of Stuttgart and the FZ
Jülich as well as Vera Ophoven and Truc Pham for their support.
We are especially grateful for the X-ray crystallographic analyses
continuously provided by Dr. Wolfgang Frey.
ppm. IR (film): ν = 3365, 2983, 1713, 1683, 1601, 1586, 1508, 1469,
˜
1452, 1392, 1366, 1316, 1283, 1268, 1247, 1168, 1158, 1116, 1069,
1027, 974, 946, 831, 796, 781, 708, 686, 672 cm–1. Spectroscopic
data are in full agreement with those reported previously.[13g]
(1S,2S)-Bis(carbamate) 42: Carbamate 41 (0.12 g, 0.40 mmol) was
dissolved in dry CH3CN (4.00 mL) under dry nitrogen. Boc2O
(0.26 g, 1.21 mmol) and DMAP (15.0 mg, 0.12 mmol) were added,
and the mixture was stirred at room temp overnight. The solvents
were removed under reduced pressure, and the crude product was
purified by column chromatography [silica gel (20 g), PE/EtOAc
(95:5)] to provide the carbamate 42 (0.14 g, 0.37 mmol, 92%) as a
colourless solid, m.p. 98–99 °C. [α]2D0 = +35.5 (c = 0.55, CHCl3).
1H NMR (CDCl3, 600 MHz): δ = 0.96 (ddd, J = 9.4, J = 6.2, J =
4.0 Hz, 1 H, 3-Ha), 1.09 (ddd, J = 7.2, J = 6.8, J = 6.2 Hz, 1 H, 3-
Hb), 1.51 (s, 18 H, CH3), 1.51 (ddddd, J = 9.4, J = 8.0, J = 6.8, J
= 5.4, J = 3.4 Hz, 1 H, 1-H), 2.63 (ddd, J = 7.2, J = 4.0, J = 3.4 Hz,
1 H, 2-H), 4.06 (dd, J = 11.5, J = 8.0 Hz, 1 H, 1Ј-Ha), 4.59 (dd, J
= 11.5, J = 5.4 Hz, 1 H, 1Ј-Hb), 7.43–7.46 (m, 2 H, arom. CH),
7.55–7.57 (m, 1 H, arom. CH), 8.06–8.07 (m, 2 H, arom. CH) ppm.
13C NMR (CDCl3, 151 MHz): δ = 14.8 (C-3), 21.7 (C-1), 28.1
(CH3), 32.7 (C-2), 65.9 (C-1Ј), 82.5 [C(CH3)3] 128.3, 129.7 (arom.
CH), 130.3 (arom. Cipso), 132.9 (arom. CH), 152.9 (CO), 166.6
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1332, 1296, 1269, 1253, 1156, 1090, 1068, 1041, 1025, 969, 951,
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6006
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 5998–6008

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6007

J. Pietruszka, G. Solduga
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Received: August 3, 2009
Published Online: October 14, 2009
6008
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 5998–6008