A configurational switch based on iridium-catalyzed allylic cyclization: Application in asymmetric total syntheses of prosopis, dendrobate, and spruce alkaloids

Article abstract of DOI:10.1002/chem.200901316

A method for the stereoselective synthesis of 2,6-disubstituted piperidines has been developed that is based on the use of an intramolecular iridium-catalyzed allylic substitution as a configurational switch. The procedure allows the preparation of 2-viny

Full text of DOI:10.1002/chem.200901316

DOI: 10.1002/chem.200901316
A Configurational Switch Based on Iridium-Catalyzed Allylic Cyclization:
Application in Asymmetric Total Syntheses of Prosopis, Dendrobate, and
Spruce Alkaloids
Christian Gnamm, Kerstin Brçdner, Caroline M. Krauter, and Gꢀnter Helmchen*[a]
Dedicated to Professor Werner Tochtermann on the occasion of his 75th birthday
Abstract: A method for the stereose-
lective synthesis of 2,6-disubstituted pi-
peridines has been developed that is
based on the use of an intramolecular
iridium-catalyzed allylic substitution as
a configurational switch. The proce-
dure allows the preparation of 2-vinyl-
piperidines with enantiomeric excesses
(ee) of greater than 99%. As applica-
tions, total syntheses of piperidine alka-
loids have been elaborated, most often
by using Ru-catalyzed cross-metatheses
as a key step for introduction of a side
chain. Asymmetric total syntheses of
the prosopis alkaloids (+)-prosopinine,
(+)-prosophylline, (+)-prosopine, and
of the dendrobate alkaloid (+)-241D
and its C6 epimer are described.
Keywords: alkaloids · allylic amina-
tion · heterocycles · iridium · natu-
ral products · total synthesis
Introduction
Piperidine alkaloids[1] often possess potent biological activity
and are therefore of interest for organic and medicinal
chemists.[2] Structural types that were addressed in our work
are described in Figure 1.[3] Commonly, construction of the
À
piperidine involves ring closure by C N bond formation. As
most alkaloids possess chirality centers at C2 and C6, stereo-
selectivity is essential for this step. High levels of diastereo-
selectivity have been achieved in substrate-controlled cycli-
zations, for example, by allylic substitution.[4] However,
there is a drawback of this approach in that the selectivity
of the cyclization process is predetermined by the substrate
configuration and only one of a pair of diastereomers can
usually be provided.
Figure 1. Examples of naturally occuring 2,6-dialkylpiperidine alkaloids.
Recently we have communicated a method using the Ir-
catalyzed allylic substitution[5] as a configurational switch
that allows either of a pair of diastereomeric cyclization
products to be generated selectively by external (reagent)
control (Scheme 1).[6] To the best of our knowledge, such a
configurational switch has not been achieved for an allylic
substitution,[7,8] whereas it has been developed for other re-
agent-controlled reactions such as the Brown allylation,[9]
and most prominently, the Katsuki–Sharpless epoxidation.[10]
In our previous communication,[6] we have presented one
example of the configurational switch, which was used in a
synthesis of the 4-hydroxypiperidine (+)-241D. In the mean-
time this work was considerably extended to include a varie-
ty of 3-hydroxypiperidines such as the prosopis alkaloids
listed in Figure 1. Here we present a full account of our in-
vestigations.
[a] Dipl.-Chem. C. Gnamm, K. Brçdner, C. M. Krauter,
Prof. Dr. G. Helmchen
Organisch-Chemisches Institut der Universitꢀt Heidelberg
Im Neuenheimer Feld 270, 69120 Heidelberg (Germany)
Fax : (+49)6221-544205
E-mail: g.helmchen@oci.uni-heidelberg.de
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FULL PAPER
(Scheme 3).[23a] The present project was used to test the
scale-up capability. The reaction was run on a scale of
50 mmol with a reduced catalyst loading of 1 mol% of Ir.
After cleavage of the formyl group, the allylic amide 2 was
obtained with 96% ee in 79% yield.
Scheme 1. Double stereodifferentiation: interplay between substrate- and
reagent-induced selectivity ([Ir]=Ir catalyst; L*=L1 or L2).
Results and Discussion
Synthesis of prosopis alkaloids: The alkaloids (+)-prosopi-
nine (15b) and (+)-prosopine (18b) were isolated by Ratle
et al. from leaves of a Prosopis africana species in 1966.[11]
They possess antihypertensive and local anesthetic proper-
ties as well as antibiotic activity against Staphyllococcus
aureus and are being used by African natives against tooth-
ache and for the treatment of wounds.[12] Their relative and
absolute configuration was disclosed in 1972 by the same
group,[13] which also reported the isolation of racemic (Æ)-
prosophylline in the same year.[14] Since then, various syn-
theses have been reported for prosopinine,[15,16] prosophyl-
line,[17,18] and their desoxo derivatives.[19,20]
Scheme 3. Synthesis of the epoxides anti-4 and syn-4 (TBD=1,5-
triazabicycloACTHNUTRGNE[NUG 4.4.0]-dec-5-ene).
Synthesis of the cyclization precursor 9: For the introduction
of the OH group of the piperidine ring, epoxidation or dihy-
droxylation of the amination product 2 was planned. Thus,
treatment of 2 with meta-chloroperbenzoic acid (mCPBA)
gave the epoxides 4a and 4b as an 87:13 mixture of diaste-
reoisomers in 78% yield, in favor of syn-4a as expected
(Scheme 3).[27] The epoxides were separated by preparative
HPLC and crystallization, and the relative configuration of
syn-4a was confirmed by single-crystal X-ray structural anal-
ysis.[28] Several other reagents and methods for the epoxida-
tion of 2 as well as various dihydroxylation methods were
tested, but none of them provided a useful access to the
requisite anti-4b or gave otherwise improved results. Similar
results were obtained with the corresponding N-phthaloyl
derivative (formula not shown).
Ir-catalyzed allylic amination: The Ir-catalyzed allylic substi-
tution, introduced in 1997,[21] has emerged as a versatile tool
for the enantioselective construction of allylic stereocen-
ters.[5] High degrees of enantio- and regioselectivity in favor
of the branched substitution products can routinely be ob-
tained (Scheme 2). Of particular value are aminations[22]
Scheme 2. General scheme for iridium-catalyzed allylic substitution.
The epoxides syn-4a and anti-4b were each subjected to
the copper-mediated addition of allylmagnesium chloride,[29]
which generated the alcohols syn-5a and anti-5b in 78 and
83% yield, respectively (Scheme 4). In both cases <10% of
the byproduct, 5a’ and 5b’, respectively, resulting from reac-
tion of the cuprate at C2’ of the epoxide was formed.
with diacylimines, which react with carbonates to give allyl-
ACHTUNGTRENNUNGamines with a broad range of N-protecting groups suitable
in alkaloid synthesis, such as tert-butoxycarbonyl (Boc) and
carbobenzyloxy (Cbz).[23] Furthermore, salt-free reaction
conditions can be applied with diacylimines.[24]
The catalyst was prepared from [{IrCl
(cod)}2] (cod=1,5-
The syn-alcohol 5a was transformed into the anti-alcohol
5b by inversion of configuration using the Mitsunobu reac-
tion followed by saponification of the resultant acetate. Ini-
tially, this seemingly simple task met with difficulties. It
turned out to be crucial, concerning yield and reproducibili-
ty, to add diisopropyl azodicarboxylate after having stirred a
solution of the alcohol, PPh3, and AcOH for a period of
cyclooctadiene) and a chiral phosphoramidite L* by activa-
tion with a strong base. The commercially available ligand
L1, introduced by Feringa,[25] and the usually superior ligand
L2, developed by Alexakis, were used.[26] The Ir-catalyzed
amination of the carbonate 1 with HN
ACHTUNGTREN(NGNU CHO)Boc as ammo-
nia equivalent has already been described by us
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G. Helmchen et al.
Scheme 4. Synthesis of the cyclization precursor 9.
15 min (yield: 85%). Next, 5b was reacted with the bis-car-
bonate 6 (5 equiv) in the presence of Grubbs II catalyst
(5 mol%). The metathesis product 7 was obtained in almost
quantitative yield as an 89:11 mixture of the E and the Z
isomers, which were separated by preparative HPLC.
97.5:2.5 in 85% yield (entry 1). The ligand L2 induced even
higher reactivity and diastereoselectivity (98.5:1.5, entry 2);
the latter was slightly reduced upon heating (entries 3–4).
With a 9:1-mixture of (E)- and (Z)-9, the diastereoselectiv-
ity was slightly reduced (entries 4–5). The configuration of
the cyclization products was as expected according to a gen-
eral rule for the steric course of the Ir-catalyzed substitu-
tions.[5a]
The Ir-catalyzed substitution reaction of the Boc-protect-
ed amide 7 exclusively gave the tetrahydrofuran derivatives
8a and 8b (91–97%). Thus, an intramolecular Ir-catalyzed
etherification[30] rather than an amination had occurred. The
diastereoselectivity of the reaction was very high, both upon
use of ligand L2 (98:2) as well as ligand ent-L2 (5:95).
Hence, a change in the protecting-group strategy was re-
quired for the preparation of the desired piperidines. Using
standard procedures, the amines (E)-9 and (Z)-9 with two
tert-butyldimethylsilyl (TBDMS)-protected OH groups were
prepared from the isomerically pure precursors (E)-7 and
(Z)-7, respectively. It was of interest to investigate the influ-
ence of the double-bond geometry on the cyclization.
Ir-catalyzed cyclizations of (E)- and (Z)-9: Intramolecular
allylic aminations usually give
Scheme 5. Ir-catalyzed cyclizations of the allylic carbonate 9.
excellent results.[7] This was also
Table 1. Iridium-catalyzed allylic cyclizations of carbonate 9 according to Scheme 5.
true for the cyclization of (E)-9,
which proceeded smoothly
under standard conditions to
give the vinylpiperidines in
good yield and with high selec-
tivity (Scheme 5, Table 1).[31]
Entry[a]
Substrate
L*
Ir [mol%]
T [8C]
t [h]
Yield[b] [%]
10a/10b[c]
1
2
3
4
5
6
7
8
(E)-9
(E)-9
(E)-9
(E)-9/(Z)-9 9:1
(E)-9/(Z)-9 9:1
(E)-9
(E)-9
(E)-9
L1
L2
L2
L2
L2
4
4
4
4
2
4
4
4
4
4
4
2
4
RT
RT
50
50
50
RT
RT
50
50
RT
50
22
6.5
2
1
3
24
5.5
3
1.3
22
1
85
89
78
88
76
76 (86)
87
88
92
82
87
77
60 (90)
97.5:2.5
98.5:1.5
97:3
95.5:4.5
94:6
Control
experiments
using
ent-L1
ent-L2
ent-L1
ent-L2
ent-L1
ent-L2
ent-L2
L2
6:94
P
ACHTUNGTRENNUNG
2.5:97.5
4.5:95.5
3:97
5.5:94.5
4.5:95.5
5:95
that substrate control is weak in
this system (10a/10b=60:40).
The use of isomerically pure
(E)-9 in conjunction with ligand
L1 (matched case) furnished
the cyclization product 10a
9
(E)-9
10
11
12
13
(E)-9/(Z)-9 9:1
(E)-9/(Z)-9 9:1
(E)-9/(Z)-9 9:1
(Z)-9
50
RT
3
6
51:49
[a] All reactions were carried out according to GP2 (see Experimental Section). [b] Isolated yield of the major
with
a diastereoselectivity of diastereoisomer; in parentheses: yield corrected for recovered starting material. [c] Determined by GC.
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Iridium-Catalyzed Allylic Cyclization
FULL PAPER
Scheme 6. Synthesis of (+)-prosopinine and (+)-prosophylline.
In the mismatched case (entries 6–9, ent-L*) yields and se-
lectivities were only marginally lower than in the matched
case (L*). Again, yields and selectivities were little affected
by an increase of the reaction temperature, reduced catalyst
loading, and use of the 9:1 mixture of (E)- and (Z)-9 as sub-
strate (entries 10–12).
rived from ketone 13 or adding Lewis acids such as Ti-
AHCTUNGRTENGUN(N OiPr)4 or Cy2BCl (Cy=cyclohexyl) did not give improved
results either.[33] Finally, moderate yields of 14a (58%) and
14b (62%) were obtained, when Grubbs II–Hoveyda cata-
lyst (9–12 mol%) was used and added in 3–6 portions to a
solution of the reactants in CH2Cl2 at reflux.
When isomerically pure (Z)-9 was used as substrate, the
reaction was nonselective (10a/10b=51:49) and slow
(entry 13). This result reflects observations that intermolecu-
lar Ir-catalyzed allylic substitutions of (Z)-allylic substrates
yield linear substitution products[32] and the formation of vi-
nylcyclopropanes by Ir-catalyzed cyclizations of (Z)-allylic
substrates proceed with very poor yield.[24]
The synthesis of (+)-prosopinine was completed by cata-
lytic hydrogenation of the metathesis product 14b using
Pearlmanꢂs catalyst (Pd(OH)2/C).[34] Other than anticipated,
no epimerization occurred within the limits of detection
(1H NMR spectroscopy). After recrystallization from ace-
tone (+)-prosopinine (15b) was obtained as colorless nee-
dles suitable for X-ray structural analysis.[28] The synthesis of
(+)-prosophylline was carried out similarly, except for
workup of the hydrogenation reaction; in this case, a solu-
tion of the crude product had to be washed with aqueous
1n NaOH before the desired compound could be extracted.
Recrystallization from acetone gave analytically pure (+)-
prosophylline (15a) as colorless needles.
Synthesis of (+)-prosophylline (15a) and (+)-prosopinine
(15b): The cyclization products 10a and 10b were trans-
formed into benzyl carbamates 11a or 11b under standard
conditions (Scheme 6). Unexpectedly, the carbamates did
not undergo cross-metathesis with the ketone 13 (10 mol%
Grubbs II or Grubbs II–Hoveyda, CH2Cl2 or ClCH2CH2Cl,
reflux). The same observation was made when the bulky
TBDMS groups of 11b were replaced by acetyl groups (not
shown). Initial attempts with the free diols 12 as substrates
gave only little conversion under standard conditions (cata-
lyst: 5 mol% Grubbs II or Grubbs II–Hoveyda, CH2Cl2,
reflux). The reaction never went to completion, and the
products were isolated in low yields (15–20%). Changing
the solvent and increasing the reaction temperature (1,2-di-
chloroethane or toluene, reflux) led to predominant forma-
tion of an unidentified side product. Using the dioxolane de-
Synthesis of (+)-prosopine (18b) and its C6 epimer (18a):
Various syntheses of prosopinine and prosophylline have
been carried out,[15–20] however, no synthesis of (+)-proso-
pine has been reported. With the piperidine 12b in hand, in-
troduction of an appropriate side chain by means of cross-
metathesis appeared of interest (Scheme 7). Thus, the chiral
alcohol 16[35] was prepared from (À)-(S)-propylene oxide in
analogy to a known procedure.[29,36]
Other than the cross-metatheses with 13, the reaction be-
tween 12b and the unsaturated alcohol 16 (3 equiv) using
Scheme 7. Synthesis of (+)-prosopine and (+)-6-epi-prosopine.
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G. Helmchen et al.
Grubbs–Hoveyda catalyst (7 mol%) was fast (1 h, CH2Cl2,
reflux). However, selectivity was low and only a modest
yield of 57% of 17b was obtained. Subsequent hydrogena-
tion with Pd(OH)2 as catalyst quantitatively gave (+)-proso-
pine, which crystallized from acetone in the form of color-
less needles. To the best of our knowledge, this constitutes
the first synthesis of prosopine (18b).
Furthermore, the heretofore unknown C6 epimer of (+)-
prosopine was synthesized, using cis-piperidine 12a as sub-
strate for the cross-metathesis with 16. Subsequent hydroge-
nation furnished (+)-6-epi-prosopine (18a) as colorless oil
([a]2D0 =+29.9, c=0.84 in MeOH, >99% ee).
Synthesis of dendrobate and spruce alkaloids: Dendrobati-
dae (belonging to the poison or dart frogs) are a family of
small frogs living in the rain forests of Central and South
America. They are usually brightly colored and often show
high toxicity against the central nervous system. From their
skins, numerous alkaloids have been isolated, for example,
batrachotoxines, histrionicotoxines, indolizidines, pumilotox-
ines, decahydrochinolines, and various 2,6-disubstituted pyr-
rolidines and piperidines.[37]
Scheme 8. Synthesis of the cyclization precursor 24 (9-BBN=9-
borabicycloACTHNUTRGNE[UNG 3.3.1]nonane).
fect diastereoselectivity of 25a/25b=98:2 (GC). In the mis-
matched case, upon use of ligand ent-L2, piperidine 25b was
produced in 74% yield with only slightly reduced selectivity
(25a/25b=6:94). The yield was marginally lower with ent-
L1, whereas the diastereoselectivity of 4:96 was even higher
than that achieved with ent-L2.
In contrast to the results in the cyclization of 7, the (Z)-al-
lylic carbonate did not markedly contribute to product for-
mation in this case. In contrast, when isomerically enriched
(Z)-24 (Z/E >90:10) was reacted according to Scheme 9,
using L2 as ligand, the cyclization was slow and nonselective
(25a/25b 63:37) and gave 25a in only approximately 20%
The alkaloid (+)-241D (30a) was isolated by Daly et al.
from the skin of Dendrobates speciosus,[37b,38] and was found
to be a potent inhibitor of binding of [3H]perhydrohistri-
A
Subsequent to a synthesis of the racemate,[39] asymmetric
syntheses of (+)-241D and (À)-241D and their C4 epimers
have been reported.[40]
Synthesis of the cyclization precursor 24: The Ir-catalyzed
amination of trans-crotyl methyl carbonate with HN-
yield. In a control experiment using PACTHNURTGNENUG(OPh3) as achiral
A
ligand, the diastereoselectivity was 65:35 in favor of 25a,
thus showing that substrate control is weak in this system.
The configuration of the cyclization product 25a was veri-
fied by an X-ray crystal structural analysis,[28] which con-
firmed the predicted configuration according to the general
rule.[5a]
carried out on a submillimol scale.[41] In the present project,
the catalyzed reaction was conducted on a preparatively sig-
nificant scale of 77 mmol with a reduced catalyst loading of
1 mol% of L1. After cleavage of the formyl group, the Boc-
protected amine 19 was obtained in 81% yield with
94% ee.[42] Hydroboration/oxidation[43] and Swern reaction
of the resultant primary alcohol 20[44] furnished the sensitive
aldehyde 21 in 89% yield over two steps.[45] Treatment of 21
with (+)-B-allyldiisopinocampheylborane[46] ((+)-Ipc2B-
ACHTUNGTRENNUNG(allyl)) at low temperature gave a 93:7 mixture (GC) of the
homoallylic alcohols 22 and 3-epi-22, which were separated
by flash chromatography. Pure 22[28] was obtained in 88%
yield with >99% ee.[31] As before, the allylic unit was intro-
duced by cross-metathesis (Grubbs II catalyst) of 22 and the
bis-carbonate 6 (5 equiv), which gave allylic carbonate 23 in
87% yield as a 9:1 mixture (1H NMR spectroscopy) of E
and Z isomers. Cleavage of the Boc group under standard
conditions gave the cyclization precursor 24 in 96% yield
(Scheme 8).
Scheme 9. Ir-catalyzed cyclizations of amine 24.
Ir-catalyzed cyclizations of 24: Under standard conditions,
the Ir-catalyzed cyclization of amine 24 (E/Z=9:1) gave
very satisfactory results (Scheme 9). Using L2 as ligand, the
piperidine 25a was isolated in 90% yield with almost per-
Synthesis of the dendrobate alkaloid (+)-241D (30a) and its
C6 epimer 30b: A cross-metathesis was considered as a key
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Iridium-Catalyzed Allylic Cyclization
FULL PAPER
Scheme 10. Synthesis of (+)-241D (30a) and its C6 epimer 30b.
step for the synthesis of (+)-241D from 25a (Scheme 10).
Attempts to use an ammonium salt of 25a as substrate were
not successful, mainly because of low solubility of the salts
tried in dichloromethane. Hence, the OH and the NH group
were protected by formation of 27a using standard proce-
dures. The reaction of 27a with 1-nonene in the presence of
Grubbs II catalyst (10 mol%) furnished the cross-metathesis
product 28a in 71% yield, together with some starting mate-
rial (20%). Catalytic hydrogenation (Rh/C) gave the amine
29a in 92% yield without epimerization according to
1H NMR spectroscopy. Hydrolysis of the acetate gave the
natural product (+)-241D (30a) in an overall yield of 27%.
The spectroscopic data were in full agreement with those re-
ported.
curring in conifers possess the same absolute configuration
at the methylated center C2.[47]
In our synthesis of 34, aldehyde 31 was prepared from car-
bamate 27a by oxidative cleavage of the double bond (O3/
SMe2). This was subjected to a Wittig olefination, which
gave the olefin 32 in 81% yield as a mixture of isomers (Z/
1
E=87:13, H NMR spectroscopy). After catalytic hydroge-
nation using Pd(OH)2/C as catalyst and subsequent hydroly-
sis of the acetate 33, compound 34 was obtained in form of
colorless polyhedra ([a]2D0 =+8.8, c=0.43 in MeOH,
>99% ee), suitable for X-ray crystal structural analysis,[28] in
an overall yield of 24%.[48]
For the synthesis of the C6 epimer of (+)-241D by means
of an analogous route, piperidine 25b was transformed into
27b, which was significantly less reactive than 27a in the
cross-metathesis reaction. After testing several reaction con-
ditions, we had to settle with incomplete conversion and a
moderate yield of 28b of 46%; fortunately, the starting ma-
terial was fully recovered (53%). Similarly, hydrogenation
of 28b using Rh/C as catalyst was not possible; Pd(OH)2 on
charcoal was used instead, and amine 29b was obtained in
86% yield. Other than anticipated, no epimerization oc-
curred (1H NMR spectroscopy). Hydrolysis gave the amino
alcohol 30b in 95% yield, the relative configuration of
which was verified by X-ray crystal structural analysis.[28]
This concluded the first synthesis of the C6 epimer of the al-
kaloid (+)-241D. The overall yield was 15%.
Scheme 11. Synthesis of the spruce alkaloid 34.
Conclusion
In conclusion, we are reporting the first examples of a con-
figurational switch for Ir-catalyzed allylic cyclizations, which
allows each of two possible diastereomeric cyclization prod-
ucts to be prepared with a very high degree of diastereose-
lectivtiy. The concept has been applied in syntheses of 2,6-
disubstituted hydroxypiperidine alkaloids. Examples are
(+)-prosopinine (15b), (+)-prosophylline (15a), and (+)-
241D (30a), which have been synthesized before. The first
asymmetric syntheses are reported here for (+)-prosopine
(18b), (+)-6-epi-prosopine (18a), (+)-6-epi-241D (30b), and
the spruce alkaloid (+)-34.
Synthesis of the spruce alkaloid 34: This compound has
been identified as a trace alkaloid in extracts from Colorado
blue spruce (Picea pungens) by Stermitz et al.
(Scheme 11).[47] They deduced the structure and the relative
configuration of 34 from GC–MS data and on the basis of
analogy to similar alkaloids and verified it by a synthesis of
the racemic compound. The absolute configuration and opti-
cal rotation were unknown. The assignment shown in
Scheme 11 was based on the observation that, with one ex-
ception (euphococcinine), 2,6-disubstituted piperidines oc-
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G. Helmchen et al.
(+)-tert-butyl formyl[(R)-1-methylprop-2-en-1-yl] carbamate,[41,55] (+)-
tert-butyl [(R)-1-methylprop-2-en-1-yl] carbamate ((+)-(R)-19),[55,56,57]
and (À)-tert-butyl [(R)-3-hydroxy-1-methylpropyl]carbamate ((À)-(R)-
20).[43,44]
Experimental Section
General remarks: 1H NMR spectra were recorded at room temperature
using Bruker DRX-200 (199.92 MHz), Bruker Avance DRX-300
(300.13 MHz), Bruker Avance DRX-500 (500.13 MHz), or Bruker
Avance III 600 (600.13 MHz) spectrometers. Chemical shifts are reported
in d relative to the solvent residual peak (CHCl3 in CDCl3 at dH =
7.26 ppm; CD2HOD in CD3OD at dH =3.31 ppm).[49] The following ab-
breviations are used for description of the signal multiplicity: s (singlet),
d (doublet), t (triplet), q (quartet), dd (doublet of doublet), dt (doublet
of triplet), ddd (doublet of doublet of doublet), and so forth, brs (broad
signal), m (multiplet). Diastereotopic hydrogen atoms are described with
indices a and b (CHaHb) or, if applicable, with the indices ax (axial) and
eq (equatorial). Chemical shifts are not reported for acidic protons (NH,
OH) when CD3OD was used as solvent. 13C NMR spectra were recorded
at room temperature using Bruker DRX-200 (50.27 MHz), Bruker
Avance DRX-300 (75.47 MHz), Bruker Avance DRX-500 (125.76 MHz),
and Bruker Avance III 600 (150.90 MHz) spectrometers. Chemical shifts
are reported in d relative to the solvent signal: CDCl3 (dC =77.16 ppm
(central line of the triplet)), CD3OD (dC =49.00 ppm (central line of the
septet)).[49] The following abbreviations were used: s (singlet, quaternary
C atom), d (doublet, CH group), t (triplet, CH2 group), q (quartet, CH3
group). The multiplicity stated refers to {1H}-decoupled spectra. In every
case, the assignments of signals were confirmed by 1H,1H-COSY, 1H,13C-
COSY, and DEPT spectra.
(À)-tert-Butyl {(S)-1-[(trityloxy)methyl]prop-2-en-1-yl}carbamate ((À)-
(S)-2): A flame-dried Schlenk tube was charged with a solution of [{IrCl-
AHCTUNGTERG(NNNU cod)}2] (336 mg, 0.50 mmol) and (S,S,aS)-L1 (540 mg, 1.00 mmol) in dry
THF (50 mL). Anhydrous TBD (278 mg, 2.00 mmol) was added, and the
mixture was stirred for 1 h at room temperature. The carbonate 1 (19.4 g,
50.0 mmol) and the pronucleophile NHACTHUNTGRNEUNG(CHO)Boc (9.44 g, 65.0 mmol)
were then added, and the reaction mixture was stirred at 508C for 26 h
until TLC control (petroleum ether/ethyl acetate 3:1, Rf(1)=0.44,
Rf(2’)=0.50, Rf(3’)=0.44, KMnO4) showed complete conversion. The
mixture was concentrated in vacuo, and the residue was dissolved in dry
MeOH (150 mL). KOH (2.81 g, 50.0 mmol) was added, and the mixture
was stirred at room temperature for 1.5 h when TLC control showed
complete conversion (petroleum ether/diethyl ether 4:1, Rf(2’)=0.19,
Rf(2)=0.15)). An acidic ion exchange resin (Amberlite IR-120, Merck)
was added in portions until pH 7 was reached. The mixture was filtered,
and the filtrate was concentrated in vacuo. The residue was subjected to
flash chromatography (100 g of silica gel, petroleum ether/ethyl acetate
9:1) to give (À)-(S)-2 (17.1 g, 79%, 96% ee) and 3 (2.9 g, 13%). (À)-(S)-
2: Colorless solid; m.p. 93–958C; [a]2D0 =À19.3 (c=0.99 in CHCl3,
95% ee); 1H NMR (300 MHz, CDCl3): d=7.53–7.49 (m, 6H; Ph), 7.38–
7.25 (m, 9H; Ph), 5.95 (ddd, J=17.2, 10.5, 5.3 Hz, 1H; CH=CH2), 5.30
(ddd, J=17.3, 1.4, 1.4 Hz, 1H; CH=CHEHZ), 5.23 (ddd, J=10.5, 1.3,
1.3 Hz, 1H; CH=CHEHZ), 4.91 (brs, 1H; NH), 4.44 (brs, 1H; CHN),
3.28 (dd, J=9.1, 4.2 Hz, 1H; CHaHbO), 3.23 (dd, J=9.0, 4.9 Hz, 1H;
Melting points are uncorrected. Optical rotations were measured using a
Perkin–Elmer 341 polarimeter using a mercury lamp. High-resolution
mass spectra were recorded using a JEOL JMS-700 (EI+, FAB+) or
using a Bruker ApexQe FT-ICR (ESI+) mass spectrometer. Elemental
analyses were carried out at the Organisch-Chemisches Institut, Universi-
tꢀt Heidelberg. Kugelrohr distillations were carried out using a Bꢃchi B-
580 instrument; boiling points correspond to air-bath temperatures.
CHaHbO), 1.53 ppm (s, 9H; C
155.43 (s, CO2), 143.83 (s, Ph), 136.68 (d, =CH), 128.72, 127.88, 127.12
(3d, Ph), 115.52 (t, =CH2), 86.53 (s, CPh3), 79.41 (s, C(CH3)3), 65.71 (t,
CH2O), 52.90 (d, CHN), 28.50 ppm (q, C(CH3)3); elemental analysis
(CH3)3); 13C NMR (75 MHz, CDCl3): d=
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
calcd (%) for C28H31NO3: C 78.29, H 7.27, N 3.26; found C 78.15, H 7.27,
N 3.24; HRMS (FAB+): m/z: calcd for C28H32NO3+: 430.2377; found:
430.2378 [M+H]+; HPLC (Chiralpak AD-H, n-hexane/iPrOH 99:1, flow
0.5 mLminÀ1, RT, l=210 nm): tR((+)-(R)-2)=34.1 min, tR((À)-(S)-2)=
47.0 min.
Determination of enantiomeric excess by HPLC was accomplished using
an HP 1100 instrument equipped with a Daicel, Chiralpak AD-H column
(250ꢄ4.6 mm, 5 mm) with guard cartridge AD-H (10ꢄ4 mm, 5 mm). GC
was carried out on a HP 5890 Series II instrument using helium as carrier
gas. As achiral column an HP-1 cross-linked methylsilicon gum (HP-1)
(25 mꢄ0.2 mm, 0.33 mm film thickness) was used (injector temperature
2508C, detector temperature 2808C). For determination of enantiomeric
excess the following column was used: Varian Chrompack-Chirasil-Dex
permethyl-b-cyclodextrin (b-CD) (25 mꢄ0.25 mm, 25 mm film thickness)
(injector temperature 2008C, detector temperature 2508C). Preparative
HPLC was carried out using a ProntoSIL (250ꢄ20 mm, 5 m silica gel) or
a LATEK (250ꢄ21 mm, 5 m silica gel) column using a Gilson-305 pump
coupled with a Knauer Smartline UV detector 2600. Analytical thin-layer
chromatography was performed on precoated TLC plates (Polygram SIL
G/UV254, from Machery & Nagel) using the solvents stated.
(À)-tert-Butyl
((À)-(1R,2’S)-4a) and (À)-tert-butyl [(1R)-1-[(2’R)-oxiran-2’-yl]-2-(trityl-
oxy)ethyl]carbamate ((À)-(1R,2’R)-4b): flame-dried Schlenk tube
[(1R)-1-[(2’S)-oxiran-2’-yl]-2-(trityloxy)ethyl]carbamate
A
under argon was charged with a solution of (À)-(S)-2 (50 mg, 117 mmol)
in dry CH2Cl2 (1 mL). Then 3-chloroperoxybenzoic acid (ca. 70 wt%)
(43 mg, 175 mmol) was added, and the mixture was heated at reflux for
24 h when TLC control (petroleum ether/ethyl acetate 3:1, Rf(2)=0.68,
Rf(4)=0.56, MPA) showed complete conversion. The reaction mixture
was allowed to cool to room temperature and a saturated aqueous solu-
tion of Na2SO3/NaHCO3 (prepared by mixing saturated aqueous Na2SO3
with saturated aqueous NaHCO3 in a 1:1 ratio) was added slowly until
gas evolution ceased (ca. 1 mL). The mixture was extracted with CH2Cl2
(4ꢄ3 mL), and the combined organic layers were dried over Na2SO4. The
solvent was evaporated under reduced pressure, and the residue was sub-
jected to flash chromatography on silica gel (1 g, petroleum ether/ethyl
acetate 6:1) to yield an 87:13 mixture (1H NMR spectroscopy) of (À)-
(1R,2’S)-4a and (À)-(1R,2’R)-4b (40 mg, 78%).
Visualization of spots was carried out using UV light (l=254 nm) or dip-
ping into the following solutions and heating: aqueous KMnO4 (1.5 g
KMnO4, 2.5 gK2CO3 in 250 mL of H2O; referred to as KMnO4), molyb-
datophosphoric acid (5 g H3[PACHTNUTGRNEUNG(Mo3O10)4]·xH2O in 250 mL of EtOH; re-
ferred to as MPA), p-anisaldehyde (45 mL p-anisaldehyde, 810 mL of
EtOH, 45 mL H2SO4, 9 mL HOAc; referred to as PAA). Flash-column
chromatography was carried out with silica gel (0.032–0.062) of Macher-
ey, Nagel, and Co. Allylamines are prone to decomposition on column;
this can be minimized by the addition of triethylamine (ca. 1%) to the
solvent, use of a small column, and fast elution. Tetrahydrofuran was
dried over benzophenone ketyl, and the water content was determined
Analytically pure samples of (À)-(1R,2’S)-4a and (À)-(1R,2’R)-4b were
obtained by repeated crystallization from diethyl ether/petroleum ether
and repeated preparative HPLC (petroleum ether/ethyl acetate 9:1,
column: ProntoSIL, 250ꢄ20 mm, 5 m silica gel, 18 mLminÀ1, 50 bar). The
relative configuration of (À)-(1R,2’S)-4a was verified by X-ray crystal
structural analysis.
by Karl Fischer titration. 1,5,7-TriazabicycloACTHNUTRGENUG[N 4.4.0]dec-5-ene (TBD) was
stored in an desiccator over KOH (alternatively, small amounts were
stored under argon in a Schlenk tube) and weighed under air. IUPAC
names were generated by the ACD/Labs 6.0 program from Advanced
Chemistry Development Inc.
Analytical data for (À)-(1R,2’S)-4a: Colorless columns; m.p. 141–1428C;
[a]2D0 =À37.0 (c=0.87 in CHCl3, 95% ee); 1H NMR (300 MHz, CDCl3):
d=7.48–7.44 (m, 6H; Ph), 7.34–7.22 (m, 9H; Ph), 4.65 (d, J=9.0 Hz,
1H; NH), 4.13 (brs, 1H; CHN), 3.29–3.22 (m, 2H; CH2OCPh3), 3.20
(brs, 1H; 2’-H), 2.74 (dd, J=4.4, 4.4 Hz, 1H; 3’-Ha), 2.65–2.60 (m, 1H;
The following compounds were prepared according to published proce-
dures: methyl (E)-4-(trityloxy)but-2-en-1-yl carbonate (1),[23a] tert-butyl
(CH3)3); 13C NMR (75 MHz, CDCl3): d=
ACHTUNGTRENNUNG
formyl carbamate (HNACTHNUTRGNEUNG
(CHO)Boc),[50] (Z)-but-2-ene-1,4-diyl dimethyl
3’-Hb), 1.44 ppm (s, 9H; C
155.71 (s, CO2), 143.83 (s, Ph), 128.81, 128.01, 127.24 (3d, Ph), 86.88 (s,
CPh3), 79.76 (s, C(CH3)3), 64.72 (t, CH2OCPh3), 51.84 (d, C-2’), 49.41 (d,
bis-carbonate (6),[51] 11-dodecen-3-one (13),[52] 9-bromonon-1-ene,[53] (+)-
(S)-dodec-11-en-2-ol ((+)-(S)-16),[35,36] trans-crotyl methyl carbonate,[54]
AHCTUNGTRENNUNG
10520
www.chemeurj.org
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 10514 – 10532

Iridium-Catalyzed Allylic Cyclization
FULL PAPER
CHN), 43.71 (t, C-3’), 28.49 ppm (q, C
G
644 mmol) with allylmagnesium chloride was complete after 18 h accord-
(%) for C28H31NO4: C 75.48, H 7.01, N 3.14; found C 75.21, H 7.07, N
3.09; HRMS (FAB+): m/z: calcd for C28H32NO4+: 446.2326; found:
446.2334 [M+H]+.
ing to TLC analysis (petroleum ether/diethyl ether 3ꢄ(3:1), R
fACHTUNGTRENNUNG(4b)=
0.22, RfA(5b)=0.16, RfA(5b’)=0.13, UV, KMnO4, MPA). The crude product
C
CHTUNGTRENNUNG
was subjected to flash chromatography on silica gel (4 g, petroleum
ether/ethyl acetate 4:1) to give (+)-(1R,2S)-5b (262 mg, 83%) and (À)-
(1S,2S)-5b’ (8 mg, 2.5%).
Analytical data for (À)-(1R,2’R)-4b: Colorless crystals; m.p. 122–1248C;
[a]2D0 =À3.7 (c=1.01 in CHCl3, 95% ee); 1H NMR (600 MHz, CDCl3):
d=7.46 (d, J=7.5 Hz, 6H; Ph), 7.33 (t, J=7.8 Hz, 6H; Ph), 7.26 (t, J=
7.3 Hz, 3H; Ph), 4.91 (brs, 1H; NH), 3.51 (brs, 1H; CHN), 3.48 (dd, J=
9.3, 3.6 Hz, 1H; CHaHbOCPh3), 3.25–3.19 (m, 2H; CHaHbOCPh3, 2’-H),
2.86 (dd, J=4.2, 4.2 Hz, 1H; 3’-Ha), 2.79 (brs, 1H; 3’-Hb), 1.46 ppm (s,
Analytical data for (+)-(1R,2S)-5b: Colorless needles; m.p. 105–1068C;
[a]2D0 =+4.5 (c=1.13 in CHCl3, 95% ee); 1H NMR (300 MHz, CDCl3):
d=7.44–7.40 (m, 6H; Ph), 7.33–7.21 (m, 9H; Ph), 5.72 (dddd, J=17.0,
10.3, 6.6, 6.6 Hz, 1H; =CH), 5.37 (d, J=7.5 Hz, 1H; NH), 4.99–4.90 (m,
2H; =CH2), 3.71–3.59 (m, 2H; CHN, CHOH), 3.51 (dd, J=9.7, 2.5 Hz,
1H; CHaHbO), 3.20 (dd, J=9.8, 3.2 Hz, CHaHbO), 2.71 (d, J=8.1 Hz,
1H; OH), 2.25–2.13 (m, 1H; 4-Ha), 2.07–1.94 (m, 1H; 4-Hb), 1.49 (s, 9H;
9H; C
(s, Ph), 128.74, 128.06, 127.32 (3d, Ph), 86.96 (s, CPh3), 79.76 (s, C
63.31 (t, CH2OCPh3), 52.68 (d, CHN), 51.78 (d, C-2’), 47.17 (t, C-3’),
28.49 ppm (q, C(CH3)3); elemental analysis calcd (%) for C28H31NO4: C
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
G
CACHTUNGTRENNUNG
75.48, H 7.01, N 3.14; found C 75.20, H 6.98, N 3.10; HRMS (FAB+):
m/z: calcd for C28H31KNO4+: 484.1885; found: 484.1901 [M+K]+.
AHCTUNGTRENNUNG
(+)-tert-Butyl {(1R,2R)-2-hydroxy-1-[(trityloxy)methyl]hex-5-en-1-yl}car-
bamate ((+)-(1R,2R)-5a) and (À)-tert-butyl {(1S,2R)-2-(hydroxymethyl)-
AHCTUNGTRENNUNG
76.36, H 7.65, N 2.87; found C 76.36, H 7.66, N 2.82; HRMS (FAB+):
m/z: calcd for C31H37NNaO4+: 510.2615; found: 510.2614 [M+Na]+.
1-[(trityloxy)methyl]pent-4-en-1-yl}-carbamate ((À)-(1S,2R)-5a’): In
a
flame-dried Schlenk tube under an argon atmosphere, a solution of allyl-
magnesium chloride (ca. 0.65m in THF, 19.8 mL, ca. 12.9 mmol) was di-
luted with dry THF (58 mL) and cooled to À408C. Then CuI (123 mg,
644 mmol) was added. The resultant yellow suspension was stirred for
30 min and was then treated with the epoxide (À)-(1R,2’S)-4a (2.87 g,
6.44 mmol). The mixture was stirred for 6.5 h at À408C and was then al-
lowed to warm slowly to room temperature overnight. After 24 h, TLC
Analytical data for (À)-(1S,2S)-5b’: Colorless oil; [a]2D0 =À10.7 (c=0.65
in CHCl3, 95% ee); 1H NMR (300 MHz, CDCl3): d=7.44–7.40 (m, 6H;
Ph), 7.33–7.20 (m, 9H; Ph), 5.65 (dddd, J=16.7, 10.2, 7.5, 6.5 Hz, 1H;
CH=CH2), 4.90 (d, J=9.4 Hz, 1H; CH=CHEHZ), 4.88 (d, J=17.0 Hz,
1H; CH=CHEHZ), 4.53 (d, J=9.2 Hz, 1H; NH), 4.21–4.10 (m, 1H;
CHN), 3.62–3.51 (m, 1H; CHaHbOH), 3.49–3.41 (m, 1H; OH), 3.39–3.28
(m, 1H; CHaHbOH), 3.20 (d, J=9.7 Hz, 1H; CHaHbOCPh3), 3.14 (d, J=
10.0 Hz, 1H; CHaHbOCPh3), 2.00–1.89 (m, 2H; 2-H, 3-Ha), 1.80–1.69 (m,
1H; 3-Hb), 1.45 ppm (s, 9H; C
157.12 (s, CO2), 143.76 (s, Ph), 136.68 (d, =CH), 128.77, 128.05, 127.30
(3d, Ph), 116.49 (t, =CH2), 86.99 (s, CPh3), 80.14 (s, C(CH3)3), 64.03 (t,
CH2OCPh3), 62.73 (t, CH2OH), 50.40 (d, CHN), 42.38 (d, C-2), 31.11 (t,
control (petroleum ether/diethyl ether 3:1, R
fACHUTGTNREN(NUG 4a)=0.23, RfACHTUNGTRNEN(UGN 5a)=0.18,
RfACHTUNGTRENNUNG(5a’)=0.15, UV, KMnO4, MPA) showed complete consumption of the
substrate. Saturated aqueous NH4Cl (50 mL) was added, and the mixture
was extracted with ethyl acetate (4ꢄ50 mL). The organic phases were
combined, dried over Na2SO4, and concentrated under reduced pressure.
The crude product was subjected to flash chromatography on silica gel
(47 g, petroleum ether/ethyl acetate 4:1) to give (+)-(1R,2R)-5a (2.44 g,
78%) and the regioisomer (À)-(1S,2R)-5a’ (286 mg, 9%).
(CH3)3); 13C NMR (75 MHz, CDCl3): d=
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
+
C-3), 28.52 (q, C
ACHTUNGNRETN(UGN CH3)3); HRMS (FAB+): m/z: calcd for C31H37NNaO4 :
510.2615; found: 510.2654 [M+Na]+.
Analytical data for (+)-(1R,2R)-5a: Colorless oil; [a]2D0 =+2.5 (c=1.13
in CHCl3, 97% ee); 1H NMR (300 MHz, CDCl3): d=7.44–7.40 (m, 6H;
Ph), 7.35–7.22 (m, 9H; Ph), 5.80 (dddd, J=17.0, 10.2, 6.8, 6.8 Hz, 1H;
CH=CH2), 5.22 (d, J=8.9 Hz, 1H; NH), 5.03 (dd, J=17.2, 1.4 Hz, 1H;
CH=CHEHZ), 4.96 (d, J=10.2 Hz, 1H; CH=CHEHZ), 3.85–3.79 (m;
CHOH), 3.73–3.64 (m, 1H; CHN), 3.46 (dd, J=9.2, 4.1 Hz, 1H;
CHaHbO), 3.19 (dd, J=9.3, 3.5 Hz, 1H; CHaHbO), 2.79 (brs, 1H; OH),
2.24–2.07 (m, 2H; 4-H), 1.68–1.52 (m, 2H; 3-H), 1.48 ppm (s, 9H; C-
Synthesis of (+)-(1R,2S)-5b) by means of Mitsunobu reaction/saponifica-
tion: A cooled (08C) solution of (+)-(1R,2R)-5a (36 mg, 74 mmol) in tol-
uene (Tol; 1.5 mL) was treated with triphenylphosphine (39 mg,
150 mmol) and acetic acid (1m in toluene, 150 mL, 150 mmol). After
15 min diisopropyl azodicarboxylate (DIAD) (30 mL, 150 mmol) was
added to give a yellow solution, which became slightly turbid after some
time. As TLC control (petroleum ether/ethyl acetate 3:1, RfACTHUNRTGNEUN(G 5a)=0.41,
Rf(acetate of 5b)=0.49, PAA) still showed starting material after 30 min,
further PPh3 (39 mg), AcOH (150 mL), and DIAD) (30 mL were added.
This was repeated after 1.5, 3, and 5 h. The reaction was complete after
22 h. The reaction mixture was concentrated in vacuo and the residue
subjected to flash chromatography on silica gel (4 g, petroleum ether/
ethyl acetate 9:1). This gave 58 mg of a mixture of the acetate of 5b and
diisopropyl hydrazine-1,2-dicarboxylate, which was dissolved in methanol
(6 mL). The solution was treated with K2CO3 (9 mg, 90 mmol) at room
temperature (TLC: petroleum ether/ethyl acetate 3:1, Rf(acetate of
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
CHN), 33.00 (t, C-3), 29.96 (t, C-4), 28.56 ppm (q, CACHTNUGTRNEG(UN CH3)3); HRMS
(FAB+): m/z: calcd for C31H38NO4+: 488.2795; found: 488.2853 [M+H]+.
Analytical data for (À)-(1S,2R)-5a’: Colorless rectangular plates; m.p.
99–1018C; [a]2D0 =À7.0 (c=1.09 in CHCl3, 97% ee); 1H NMR (500 MHz,
CDCl3): d=7.45–7.43 (m, 6H; Ph), 7.33 (t, J=7.6 Hz, 6H; Ph), 7.28–7.25
(m, 3H; Ph), 5.82 (dddd, J=17.1, 10.0, 7.7, 6.6 Hz, 1H; CH=CH2), 5.08
(d, J=9.1 Hz, 1H; NH), 5.01 (d, J=8.2 Hz, 1H; CH=CHEHZ), 4.99 (d,
J=16.8 Hz, 1H; CH=CHEHZ), 3.76–3.70 (m, 1H; CHN), 3.67 (ddd, J=
11.9, 3.5, 3.5 Hz, 1H; CHaHbOH), 3.61 (ddd, J=11.8, 8.3, 3.1 Hz, 1H;
CHaHbOH), 3.36 (dd, J=9.4, 3.5 Hz, 1H; CHaHbOCPh3), 3.29 (dd, J=
9.5, 3.7 Hz, 1H; CHaHbOCPh3), 2.91 (dd, J=8.0, 4.7 Hz, 1H; OH), 2.12
(ddd, J=13.9, 8.5, 8.5 Hz, 1H; 3-Ha), 1.99 (ddd, J=13.6, 5.2, 5.2 Hz, 1H;
5b)=0.49,
RfACHTUNGTERNNU(G 5b)=0.41, PAA). After 1 h additional K2CO3 (6 mg,
60 mmol) was added. After 4 h the conversion was complete, and saturat-
ed aqueous NH4Cl (3 mL) was added. The mixture was extracted with
ethyl acetate (4ꢄ5 mL), and the combined organic layers were dried
over Na2SO4 and concentrated under reduced pressure. The residue was
subjected to flash chromatography on silica gel (5 g, petroleum ether/
ethyl acetate 4:1) to give the alcohol (+)-(1R,2S)-5b (31 mg, 86%). For
analytical data, see the previous procedure.
3-Hb), 1.85–1.79 (m, 1H; 2-H), 1.47 ppm (s, 9H; CACTHNUTRGNEUNG
(CH3)3); 13C NMR
(125 MHz, CDCl3): d=156.96 (s, CO2), 143.76 (s, Ph), 136.73 (d, =CH),
128.75, 128.06, 127.33 (3d, Ph), 116.70 (t, =CH2), 86.79 (s, CPh3), 79.91 (s,
CACHTUNGTRENNUNG(CH3)3), 63.32 (t, CH2OCPh3), 61.32 (t, CH2OH), 51.49 (d, CHN), 41.83
General procedure 1 (GP1, cross-metathesis with the bis-carbonate 6): In
a flame-dried Schlenk tube under an argon atmosphere Grubbs II cata-
lyst (0.03–0.05 mmol) was added to a solution of the olefinic substrate
(1 mmol) and 6 (5 mmol) in dry CH2Cl2 (20 mL). The mixture was stirred
at room temperature until complete conversion was indicated by TLC
analysis. Concentration of the mixture under reduced pressure and flash
chromatography of the residue gave clean reaction products.
(d, C-2), 32.73 (t, C-3), 28.54 ppm (q, CACTHNUGTRNEG(UN CH3)3); HRMS (FAB+): m/z:
calcd for C31H37NNaO4+: 510.2615; found: 510.2616 [M+Na]+.
(+)-tert-Butyl {(1R,2S)-2-hydroxy-1-[(trityloxy)methyl]hex-5-en-1-yl}car-
bamate ((+)-(1R,2S)-5b) and (À)-tert-butyl {(1S,2S)-2-(hydroxymethyl)-
1-[(trityloxy)methyl]pent-4-en-1-yl}-carbamate ((À)-(1S,2S)-5b’): The
title compounds were prepared as described above for the preparation of
(+)-(1R,2R)-5a. The reaction of the epoxide (À)-(1R,2’R)-4b (287 mg,
(À)-(E,6S,7R)-7-[(tert-Butoxycarbonyl)amino]-6-hydroxy-8-(trityloxy)-
oct-2-en-1-yl methyl carbonate ((À)-(E,6S,7R)-7) and (+)-(Z,6S,7R)-7-
[(tert-butoxycarbonyl)amino]-6-hydroxy-8-(trityloxy)oct-2-en-1-yl methyl
Chem. Eur. J. 2009, 15, 10514 – 10532
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
10521

G. Helmchen et al.
carbonate ((+)-(Z,6S,7R)-7): Following GP1, Grubbs II catalyst (148 mg,
174 mmol) was added to a solution of alcohol (+)-(1R,2S)-5b (1.70 g,
3.49 mmol) and carbonate 6 (3.56 g, 17.4 mmol) in dry CH2Cl2 (60 mL),
and the mixture was stirred at room temperature for 3.5 h when complete
conversion of the substrate was detected by TLC control (petroleum
Rf(7)=0.19, R
was analyzed by HPLC (Chiralpak AD-H (n-hexane/iPrOH 95:5, flow
0.5 mLminÀ1, RT, l=220 nm): t
RA(8a)=12.3, tRA(8b)=21.0 min) with re-
fACHTUNGTRENN(UNG 8a)=0.48, KMnO4). After workup, the crude product
C
CHTUNGTRENNUNG
spect to the diastereomeric ratio (8a/8b=98:2). The major diastereoiso-
mer (À)-(1R)-d-erythro-8a (88 mg, 97%) was obtained after flash chro-
matography on silica gel (17 g, petroleum ether/diethyl ether 9:1 to 4:1)
as a colorless oil. [a]2D0 =À21.7 (c=0.48 in CHCl3, >99% ee); 1H NMR
(500 MHz, CDCl3): d=7.49–7.48 (m, 6H; Ph), 7.33–7.30 (m, 6H; Ph),
7.26–7.23 (m, 3H; Ph), 5.75 (ddd, J=17.0, 10.3, 6.5 Hz, 1H; CH=CH2),
5.17 (d, J=17.2 Hz, 1H; CH=CHEHZ), 5.03 (d, J=10.1 Hz, 1H; CH=
CHEHZ), 4.82 (d, J=8.7 Hz, 1H; NH), 4.36–4.32 (m, 1H; 1-H), 4.16–4.12
(m, 1H; 4-H), 3.77 (brs, 1H; NCH), 3.49–3.46 (m, 1H; CHaHbO), 3.20–
3.18 (m, 1H; CHaHb), 2.05–1.97 (m, 2H; 2-Ha, 3-Ha), 1.94–1.88 (m, 1H;
ether/ethyl acetate 3:1, RfACHTNUTRGNE(UGN 5b)=0.31, Rf(7)=0.16, KMnO4, PAA). The
mixture was filtered through a pad of Celite and the filtrate was concen-
trated in vacuo. The residue was subjected to flash chromatography on
silica gel (86 g, petroleum ether/ethyl acetate 5:1 to ethyl acetate), which
yielded an 89:11 mixture (1.97 g, 98%; 1H NMR spectroscopy) of (À)-
(E,6S,7R)-7 and (+)-(Z,6S,7R)-7 as a colorless oil. Separation of the dia-
stereomers was accomplished by repeated preparative HPLC (petroleum
ether/ethyl acetate 4:1, column: ProntoSIL, 250ꢄ20 mm, 5 m silica gel,
15 mLminÀ1, 90 bar). Analytically pure (À)-(E,6S,7R)-7 (1.54 g, 76%)
and (+)-(Z,6S,7R)-7 (144 mg, 7%), both colorless oils, and a mixed frac-
tion (211 mg, 10%) were obtained.
3-Hb), 1.65–1.58 (m, 1H; 2-Hb), 1.46 ppm (s, 9H; CACTHNUTRGNEUNG
(CH3)3); 13C NMR
(125 MHz, CDCl3): d=155.68 (s, CO2), 143.96 (s, Ph), 139.08 (d, =CH),
128.67, 127.73, 126.91 (3 d, Ph), 114.88 (t, =CH2), 86.58 (s, CPh3), 80.67
(d, C-1), 80.04 (s, C
CHN), 31.45 (t, C-2), 28.41 (t, C-3), 28.37 ppm (q, CAHCTUNGTRENNUNG
(FAB+): m/z: calcd for C32H37NNaO4
[M+Na]+.
ACHTUNGTRENNUNG
Analytical data for (À)-(E,6S,7R)-7: Colorless oil; [a]2D0 =À10.1 (c=0.97
in acetone, 96% ee); 1H NMR (300 MHz, CDCl3): d=7.43–7.39 (m, 6H;
Ph), 7.33–7.21 (m, 9H; Ph), 5.72 (ddd, J=15.3, 6.8, 6.8 Hz, 1H; 2-H),
5.51 (ddd, J=15.1, 6.5, 6.5 Hz, 1H; 3-H), 5.37 (d, J=7.5 Hz, 1H; NH),
4.54 (d, J=6.2 Hz, 2H; CH2OCO2), 3.76 (s, 3H; CO2CH3), 3.66–3.58 (m,
2H; 6-H, 7-H), 3.51 (dd, J=9.8, 2.6 Hz, 1H; CHaHbOCPh3), 3.18 (dd, J=
9.8, 3.0 Hz, 1H; CHaHbOCPh3), 2.76 (d, J=8.1 Hz, 1H; OH), 2.26–2.15
+
:
(À)-(1S)-1,4-Anhydro-5-[(tert-butoxycarbonyl)amino]-2,3,5-trideoxy-6-O-
trityl-1-vinyl-d-erythro-hexitol ((À)-(1S)-d-erythro-8b): According to
GP2, anhydrous TBD (3.9 mg, 27.8 mmol) was added to a solution of
[{IrClACTHUNGRTENUNG(cod)}2] (4.7 mg, 7.0 mmol) and (R,R,aR)-L2 (8.3 mg, 13.9 mmol) in
(m, 1H; 4-Ha), 2.07–1.95 (m, 1H; 4-Hb), 1.49 (s, 9H; CACHTNUGTRNEUNG(CH3)3), 1.34–
1.25 ppm (m, 2H; 5-H); 13C NMR (75 MHz, CDCl3): d=155.88 (s,
dry THF (750 mL), and the mixture was stirred for 5 min. Then a solution
of the carbonate (À)-(E,6S,7R)-7 (188 mg, 327 mmol) in dry THF
(1.5 mL) was added, and the mixture was heated at reflux for 3.5 h when
complete conversion was indicated by TLC analysis (petroleum ether/
ethyl acetate 3:1, Rf(7)=0.19, R
crude product was analyzed by HPLC (Chiralpak AD-H (n-hexane/
iPrOH 95:5, flow 0.5 mLminÀ1, RT, l=220 nm): t
RA(8a)=12.3, tRA(8b)=
NCO2), 155.77 (s, OCO2), 143.42 (s, Ph), 136.40 (d, C-3), 128.57, 128.17,
127.42 (3d, Ph), 123.83 (d, C-2), 87.39 (s, CPh3), 79.72 (s, CACHTNUGRTNEUNG(CH3)3), 73.09
(d, CHOH), 68.58 (t, CH2OCO2), 63.33 (t, CH2OCPh3), 54.81 (q,
CO2CH3), 53.97 (d, CHN), 33.27 (t, C-5), 28.58 ppm (1t, 1q, C-4, C-
ACHTUNGTRENNUNG(CH3)3); elemental analysis calcd (%) for C34H41NO7: C 70.93, H 7.18, N
fACHTUNGERTN(NUNG 8b)=0.45, KMnO4). After work up the
E
CHTUNGTRENNUNG
2.43; found C 71.12, H 7.29, N 2.44; HRMS (FAB+): m/z: calcd for
C34H42NO7+: 576.2956; found: 576.2944 [M+H]+.
21.0 min) with respect to the diastereomeric ratio (8a/8b=5:95). The
major diastereomer (À)-(1S)-d-erythro-8b (148 mg, 91%) was obtained
after flash chromatography on silica gel (15 g, petroleum ether/diethyl
ether 9:1 to 4:1) as a colorless oil. [a]2D0 =À14.9 (c=0.32 in CHCl3,
Analytical data for (+)-(Z,6S,7R)-7: Colorless oil; [a]2D0 = +1.7 (c=0.99
in CHCl3, 96% ee); 1H NMR (300 MHz, CDCl3): d=7.44–7.40 (m, 6H;
Ph), 7.34–7.21 (m, 9H; Ph), 5.61–5.50 (m, 2H; CH=CH), 5.27 (d, J=
7.3 Hz, 1H; NH), 4.73–4.59 (m, 2H; CH2OCO2), 3.72 (s, 3H; CO2CH3),
3.68–3.60 (m, 2H; 6-H, 7-H), 3.46 (dd, J=9.5, 2.7 Hz, 1H;
CHaHbOCPh3), 3.24 (dd, J=9.7, 3.3 Hz, 1H; CHaHbOCPh3), 2.83 (d, J=
1
>99% ee); H NMR (300 MHz, CDCl3): d=7.49–7.46 (m, 6H; Ph), 7.34–
7.21 (m, 9H; Ph), 5.85 (ddd, J=17.1, 10.4, 6.2 Hz, 1H; CH=CH2), 5.23
(ddd, J=17.1, 1.5, 1.5 Hz, 1H; CH=CHEHZ), 5.09 (ddd, J=10.4, 1.4,
1.4 Hz, 1H; CH=CHEHZ), 4.86 (d, J=8.7 Hz, 1H; NH), 4.34 (ddd, J=
7.2, 6.2, 6.2 Hz, 1H; 1-H), 4.27 (ddd, J=7.2, 7.2, 7.2 Hz, 1H; 4-H), 3.76–
3.68 (m, 1H; NCH), 3.49 (dd, J=9.2, 3.7 Hz, 1H; CHaHbO), 3.15 (dd, J=
9.2, 3.3 Hz, 1H; CHaHbO), 2.13–2.01 (m, 2H; 2-Ha, 3-Ha), 1.93–1.80 (m,
6.2 Hz, 1H; OH), 2.24–2.17 (m, 2H; 4-H), 1.48 (s, 9H; CACHTNUGTRNEG(UN CH3)3), 1.39–
1.22 ppm (m, 2H; 5-H); 13C NMR (75 MHz, CDCl3): d=155.91 (s,
OCO2), 155.88 (s, NCO2), 143.54 (s, Ph), 135.16 (d, =CH), 128.63, 128.14,
127.39 (3d, Ph), 123.68 (d, =CH), 87.31 (s, CPh3), 79.67 (s, C
ACHTUGNRTNE(NUNG CH3)3),
1H; 3-Hb), 1.72–1.63 (m, 1H; 2-Hb), 1.45 ppm (s, 9H;
CACHTUNGTRENNUNG(CH3)3);
72.54 (d, CHOH), 63.74 (t, CH2OCO2), 63.26 (t, CH2OCPh3), 54.86 (q,
13C NMR (75 MHz, CDCl3): d=155.67 (s, CO2), 143.96 (s, Ph), 139.20 (d,
=CH), 128.68, 127.74, 126.93 (3d, Ph), 114.70 (t, =CH2), 86.54 (s, CPh3),
CO2CH3), 54.24 (d, CHN), 33.62 (t, C-5), 28.59 (q, CACHTNUGTRNEUGN(CH3)3), 24.00 ppm
(t, C-4); HRMS (ESI+): m/z: calcd for C34H41NNaO7+: 598.2775; found:
598.2771 [M+Na]+.
80.05 (d, C-1), 79.20 (s, C
(d, CHN), 32.13 (t, C-2), 28.92 (t, C-3), 28.37 ppm (q, CAHCTUNGTRENNUNG
ACHTUNGTRENNUNG
+
General procedure 2 (GP2, Ir-catalyzed allylic cyclization): Success with
the following procedures requires dry THF (<30 mgLÀ1 of H2O, Karl–
Fischer titration). A Schlenk tube was dried under argon with a heat gun
(FAB+): m/z: calcd for C32H37NNaO4
:
[M+Na]+. For HPLC data see (À)-(1R)-d-erythro-8a.
(+)-(E,6S,7R)-7-Amino-6,8-bis{[tert-butylACTHNUGRTENUNG(dimethyl)silyl]oxy}oct-2-en-1-
and charged with a solution of [{IrClACHTNUGRTENUNG(cod)}2] (13.4 mg, 0.02 mmol) and L*
yl methyl carbonate ((+)-(E,6S,7R)-9): A solution of (À)-(E,6S,7R)-7
(578 mg, 1.00 mmol) in CH2Cl2 (12 mL) was treated with trifluoroacetic
acid (TFA; 12 mL, 162 mmol), and the yellow reaction mixture was
stirred at room temperature. After 1 h all volatiles were removed under
reduced pressure, and the yellow-brownish residue was dissolved in
methanol (10 mL). The pale brown solution was concentrated under re-
duced pressure, and the residue was treated with diethyl ether (5 mL)
and water (5 mL). The phases were separated and the organic phase was
extracted repeatedly with water (5ꢄ5 mL). The combined aqueous
phases were washed with diethyl ether (2ꢄ3 mL) and concentrated in
vacuo to give the TFA salt of the amino diol as a colorless, highly viscous
oil. This was treated with CH2Cl2 (20 mL), and the mixture was cooled to
08C. Imidazole (813 mg, 11.9 mmol) and tert-butyldimethylsilyl chloride
(1.21 g, 8.04 mmol) were added, whereupon a white precipitate was
formed. The ice bath was removed, and the mixture was allowed to
warm to room temperature. After being stirred for 18 h, water (15 mL)
was added. The phases were separated, and the aqueous layer was ex-
tracted with CH2Cl2 (3ꢄ20 mL). The combined organic layers were dried
over Na2SO4 and concentrated under reduced pressure. Analytically pure
(0.04 mmol) in dry THF (1 mL). Anhydrous TBD (11.1 mg, 0.08 mmol)
was added, and the mixture was stirred for 5 min (L2) or 1 h (L1). Then
the carbonate (1 mmol) and if necessary dry THF (3 mL) was added and
the mixture was stirred for the time and at the temperature stated until
TLC control indicated complete conversion. For workup, saturated aque-
ous NH4Cl (4 mL) was added, and the mixture was extracted with ethyl
acetate (3ꢄ5 mL). The combined organic layers were dried over Na2SO4,
concentrated under reduced pressure, and the crude product was ana-
lyzed by GC with respect to the diastereomeric ratio. Pure products were
obtained by flash chromatography on silica gel.
(À)-(1R)-1,4-Anhydro-5-[(tert-butoxycarbonyl)amino]-2,3,5-trideoxy-6-
O-trityl-1-vinyl-d-erythro-hexitol ((À)-(1R)-d-erythro-8a): According to
GP2, anhydrous TBD (2.0 mg, 14.6 mmol), was added to a solution of
[{IrClACHTUNGTRENNUNG(cod)}2] (2.5 mg, 3.7 mmol) and (S,S,aS)-L2 (4.4 mg, 7.3 mmol) in dry
THF (300 mL), and the mixture was stirred for 5 min. Then a solution of
the carbonate (À)-(E,6S,7R)-7 (105 mg, 182 mmol) in dry THF (900 mL)
was added, and the mixture was heated at reflux for 3 h when complete
conversion was indicated by TLC (petroleum ether/ethyl acetate 3:1,
10522
www.chemeurj.org
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 10514 – 10532

Iridium-Catalyzed Allylic Cyclization
FULL PAPER
(+)-(E,6S,7R)-9 (388 mg, 84% over two steps) was obtained after purifi-
cation of the crude product by flash chromatography on silica gel (12 g,
petroleum ether/ethyl acetate 3:1) as a colorless oil. [a]2D0 =+2.8 (c=1.10
in CHCl3, 96% ee); 1H NMR (300 MHz, CDCl3): d=5.80 (ddd, J=15.4,
6.6, 6.6 Hz, 1H; 3-H), 5.58 (ddddd, J=15.3, 6.5, 6.5, 1.3, 1.3 Hz, 1H; 2-
H), 4.54 (d, J=6.4 Hz, 2H; CH2OC), 3.75 (s, 3H; CO2CH3), 3.67 (ddd,
J=6.9, 4.6, 4.6 Hz, 1H; CHOSi), 3.62 (dd, J=9.8, 5.1 Hz, 1H;
CHaHbOSi), 3.43 (dd, J=9.8, 7.3 Hz, 1H; CHaHbOSi), 2.87 (ddd, J=7.0,
5.0, 5.0 Hz, 1H; CHN), 2.22–1.98 (m, 2H; 4-H), 1.69–1.56 (m, 1H; 5-Ha),
1.53–1.42 (m, 1H; 5-Hb), 1.33 (brs, 2H; NH2), 0.87, 0.87 (2s, 18H; C-
(+)-(2R,3S,6S)-3-{[tert-Butyl
(dimethyl)silyl]oxy}methyl)-6-vinylpiperidine ((+)-(2R,3S,6S)-10b): Fol-
lowing GP2, a solution of [{IrCl(cod)}2] (1.5 mg, 2.2 mmol) and (R,R,aR)-
L2 (2.6 mg, 4.3 mmol) in dry THF (300 mL) was treated with anhydrous
TBD (1.2 mg, 8.6 mmol), and the mixture was stirred for 5 min at room
temperature. Then a solution of carbonate (+)-(E,6S,7R)-9 (50.0 mg,
108 mmol) in dry THF (700 mL) was added, and the mixture was heated
at 508C for 1.25 h when conversion was complete according to TLC con-
ACHTUNGTRENUN(NG dimethyl)silyl]oxy}-2-({[tert-butyl-
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
trol (petroleum ether/ethyl acetate 1:1, Rf(9)=0.23,
RfACTHNGUTERNNU(G 10b)=0.39,
KMnO4). After workup, the crude product was analyzed by GC with re-
spect to the diastereomeric ratio (10b/10a=97:3). Purification of the
crude product by flash chromatography on silica gel (5 g, petroleum
ether/ethyl acetate 10:1) yielded the major diastereomer (+)-(2R,3S,6S)-
10b (35.7 mg, 92%) as colorless oil. [a]2D0 =+48.5 (c=1.04 in CHCl3,
>99% ee); 1H NMR (300 MHz, CDCl3): d=5.99 (ddd, J=17.8, 10.3,
5.0 Hz, 1H; CH=CH2), 5.15 (ddd, J=10.3, 1.7, 1.7 Hz, 1H; CH=CHEHZ),
5.15 (ddd, J=17.7, 1.5, 1.4 Hz, 1H; CH=CHEHZ), 3.90 (dd, J=9.4,
3.8 Hz, 1H; CHaHbO), 3.55–3.50 (m, 1H; 6-H), 3.44 (dd, J=9.4, 8.1 Hz,
1H; CHaHbO), 3.39 (ddd, J=9.8, 8.5, 3.8 Hz, 1H; 3-H), 2.80 (ddd, J=
8.1, 8.1, 3.7 Hz, 1H; 2-H), 1.96 (brs, 1H; NH), 1.79–1.71 (m, 3H; 4-Ha, 5-
ACHTUNGTRENNUNG
(CH3)3), 0.04 (s, 3H; SiCH3), 0.03 ppm (s, 9H; SiCH3); 13C NMR
(75 MHz, CDCl3): d=155.76 (s, CO2), 137.22 (d, C-3), 123.45 (d, C-2),
73.16 (d, CHOSi), 68.68 (t, CH2OCO2), 65.08 (t, CH2OSi), 56.64 (d,
CHN), 54.77 (q, CO2CH3), 31.33 (t, C-5), 27.90 (t, C-4), 26.01, 25.97 (2q,
C
G
G
(4q, SiCH3); elemental analysis calcd (%) for C22H47NO5Si2: C 57.22, H
10.26, N 3.03; found C 57.29, H 10.30, N 2.98; HRMS (ESI+): m/z: calcd
for C22H48NO5Si2+: 462.3066; found: 462.3063 [M+H]+.
(+)-(Z,6S,7R)-7-Amino-6,8-bis{[tert-butylACTHNUGRTENUNG(dimethyl)silyl]oxy}oct-2-en-1-
yl methyl carbonate ((+)-(Z,6S,7R)-9): This compound was prepared
analogously to (+)-(E,6S,7R)-9 from (+)-(Z,6S,7R)-7 (129 mg, 224 mmol).
Purification by flash chromatography on silica gel (3 g, petroleum ether/
ethyl acetate 3:1) gave pure (+)-(Z,6S,7R)-9 (60 mg, 58% over two
H), 1.59–1.45 (m, 1H; 4-Hb), 0.89, 0.87 (2s, 18H; CACHTNUGTRNEUGN(CH3)3), 0.05 (s, 6H;
SiCH3), 0.03, 0.03 ppm (2s, 6H; SiCH3); 13C NMR (75 MHz, CDCl3): d=
140.33 (d, =CH), 114.97 (t, =CH2), 70.10 (d, C-3), 64.76 (t, CH2O), 58.26
(d, C-2), 53.00 (d, C-6), 29.99 (t, C-4), 28.56 (t, C-5), 26.07, 25.95 (2q, C-
steps) as
a
colorless oil. [a]2D0 = +3.7 (c=1.21 in CHCl3, 96% ee);
1H NMR (300 MHz, CDCl3): d=5.68 (ddd, J=10.8, 7.3, 7.3 Hz, 1H; 3-
H), 5.55 (ddd, J=11.1, 6.7, 6.7 Hz, 1H; 2-H), 4.74–4.62 (m, 2H;
CH2OCO2), 3.77 (s, 3H; CO2CH3), 3.72–3.66 (m, 1H; CHOSi), 3.66 (dd,
J=9.9, 5.0 Hz, 1H; CHaHbOSi), 3.45 (dd, J=9.9, 7.3 Hz, 1H; CHaHbOSi),
2.90 (ddd, J=7.2, 5.0, 5.0 Hz, 1H; CHN), 2.31–2.20 (m, 1H; 4-Ha), 2.18–
2.05 (m, 1H; 4-Hb), 1.70–1.58 (m, 1H; 5-Ha), 1.54–1.42 (m, 1H; 5-Hb),
A
C
A
SiCH3); elemental analysis calcd (%) for C20H43NO2Si2: C 62.27, H 11.24,
N 3.63; found C 62.28, H 11.24, N 3.60; HRMS (ESI+): m/z: calcd for
C20H44NO2Si2+: 386.2905; found: 386.2905 [M+H]+. For GC data see
(+)-(2R,3S,6R)-10a.
General procedure 3 (GP3, Cbz-protection): A solution of the piperidine
1.40 (brs, 2H; NH2), 0.89 (s, 18H; CACHTUNGRTNEUNG(CH3)3), 0.06, 0.06 (2s, 6H; SiCH3),
0.05 ppm (s, 6H; SiCH3); 13C NMR (75 MHz, CDCl3): d=155.88 (s,
CO2), 135.90 (d, C-3), 123.08 (d, C-2), 73.28 (d, CHOSi), 65.20 (t,
CH2OSi), 63.74 (t, CH2OC), 56.63 (d, CHN), 54.85 (q, CO2CH3), 32.13 (t,
(0.1 mmol) in CH2Cl2 (1 mL) was added to
a solution of Na2CO3
(159 mg, 1.5 mmol) in H2O (1.5 mL). The mixture was vigorously stirred
and cooled to 08C. Benzyl chloroformate (85 mg, 0.5 mmol) was added
dropwise. After complete addition the ice bath was removed, and the
mixture was allowed to warm to room temperature. When conversion
was complete according to TLC, the mixture was extracted with CH2Cl2.
The combined organic layers were dried over Na2SO4 and concentrated
in vacuo. Pure products were obtained by flash chromatography on silica
gel.
C-5), 26.06, 26.00 (2q, CACTHNUTRGNEUNG(CH3)3), 23.31 (t, C-4), 18.40, 18.21 (2s, C-
A
calcd (%) for C22H47NO5Si2: C 57.22, H 10.26, N 3.03; found C 57.49, H
10.35, N 3.07; HRMS (ESI+): m/z: calcd for C22H48NO5Si2+: 462.3066;
found: 462.3067 [M+H]+.
(+)-(2R,3S,6R)-3-{[tert-Butyl
(dimethyl)silyl]oxy}methyl)-6-vinylpiperidine ((+)-(2R,3S,6R)-10a): Ac-
cording to GP2, anhydrous TBD (1.2 mg, 8.6 mmol) was added to a solu-
tion of [{IrCl(cod)}2] (1.5 mg, 2.2 mmol) and (S,S,aS)-L2 (2.6 mg,
ACHTUNGTRENUN(NG dimethyl)silyl]oxy}-2-({[tert-butyl-
ACHTUNGTRENNUNG
(+)-Benzyl (2R,3S,6R)-3-{[tert-butyl
ACHTUNGTRENUN(NG dimethyl)silyl]oxy}-2-({[tert-butyl-
A
((+)-
ACHTUNGTRENNUNG
(2R,3S,6R)-11a): Following GP3,
a
solution of (+)-(2R,3S,6R)-10a
4.3 mmol) in dry THF (300 mL), and the mixture was stirred for 5 min.
Then a solution of the carbonate (+)-(E,6S,7R)-9 (50.0 mg, 108 mmol) in
dry THF (700 mL) was added, and the mixture was stirred at room tem-
perature for 6.5 h when TLC control (petroleum ether/ethyl acetate 1:1,
(55.8 mg, 145 mmol) in CH2Cl2 (1.5 mL) was added to a solution of
Na2CO3 (230 mg, 2.17 mmol) in H2O (1.5 mL). The mixture was cooled
to 08C and benzyl chloroformate (123 mg, 721 mmol) was added drop-
wise. After complete addition the ice bath was removed, and the mixture
was allowed to warm to room temperature. After 2.5 h conversion was
complete according to TLC control (petroleum ether/diethyl ether 4:1,
Rf(9)=0.23, RfACHTUNGTRENNUNG(10a)=0.61, KMnO4) showed complete conversion. After
workup, the crude product was analyzed by GC with respect to the dia-
stereomeric ratio (10a/10b=98:2). The major diastereomer (+)-
(2R,3S,6R)-10a (34.6 mg, 89%) was obtained after flash chromatography
on silica gel (5 g, petroleum ether/ethyl acetate 10:1) as a colorless oil.
RfACHTNUTRGENNUG(10a)=0.19, RfCAHTUNGTREN(NUNG 11a)=0.48), and the mixture was extracted with
CH2Cl2 (4ꢄ3 mL). The combined organic layers were dried over Na2SO4
and concentrated in vacuo. The residue was subjected to flash chroma-
tography on silica gel (5 g, petroleum ether/diethyl ether 20:1) to give
pure (+)-(2R,3S,6R)-11a (73.1 mg, 97%) as a colorless oil. [a]2D0 =+26.2
1
[a]2D0 =+38.8 (c=0.94 in CHCl3, >99% ee); H NMR (300 MHz, CDCl3):
d=5.81 (ddd, J=17.0, 10.5, 6.4 Hz, 1H; CH=CH2), 5.14 (d, J=17.1 Hz,
1H; CH=CHEHZ), 5.01 (d, J=10.4 Hz, 1H; CH=CHEHZ), 3.96 (dd, J=
9.5, 2.9 Hz, 1H; CHaHbO), 3.47 (dd, J=8.9, 8.9 Hz, 1H; CHaHbO), 3.29
(ddd, J=10.3, 9.0, 4.6 Hz, 1H; 3-H), 3.12–3.06 (m, 1H; 6-H), 2.56 (ddd,
J=8.7, 8.7, 3.0 Hz, 1H; 2-H), 2.05 (brs, 1H; NH), 1.96–1.89 (m, 1H; 4-
Ha), 1.69 (ddd, J=12.4, 5.9, 2.9 Hz, 1H; 5-Ha), 1.50–1.35 (m, 1H; 4-Hb),
1
(c=1.06 in CHCl3, >99% ee); H NMR (300 MHz, CHCl3): d=7.38–7.28
(m, 5H; Ph), 5.76 (ddd, J=17.4, 10.7, 4.9 Hz, 1H; =CH), 5.21–5.06 (m,
4H; CH2Ph, =CH2), 4.81 (brs, 1H; 6-H), 4.23–4.08 (m, 2H; 2-H, 3-H),
3.54–3.48 (m, 2H; CH2OSi), 2.23 (dddd, J=13.6, 13.6, 6.2, 3.5 Hz, 1H; 5-
Ha), 1.77 (dddd, J=13.6, 13.6, 2.7, 2.7 Hz, 1H; 4-Ha), 1.64–1.42 (m, 2H;
1.34–1.21 (m, 1H; 5-Hb), 0.87, 0.86 (2s, 18H; CACTHNUTGRNEG(UN CH3)3), 0.04, 0.04, 0.02,
0.01 ppm (4 s, 12H; SiCH3); 13C NMR (75 MHz, CDCl3): d=141.34 (d, =
CH), 114.09 (t, =CH2), 70.05 (d, C-3), 64.81 (t, CH2O), 64.08 (d, C-2),
4-Hb, 5-Hb), 0.86 (s, 18H; C
N
58.45 (d, C-6), 34.45 (t, C-4), 31.70 (t, C-5), 26.09, 25.90 (2q, C
18.47, 18.07 (2s, C
(CH3)3), À3.94, À4.77, À5.21, À5.22 ppm (4q, SiCH3);
elemental analysis calcd (%) for C20H43NO2Si2: C 62.27, H 11.24, N 3.63;
ACHTUGNRTNE(NUNG CH3)3),
ACHTUNGTRENNUNG
(d, C-6), 25.97, 25.91 (2q, C
18.17 (2s, C
(CH3)3), À4.71, À4.80, À5.26, À5.47 ppm (4q, SiCH3); ele-
mental analysis calcd (%) for C28H49NO4Si2: C 64.69, H 9.50, N 2.69;
ACHTUGNTRNEN(UNG CH3)3), 22.56 (t, C-4), 20.39 (t, C-5), 18.29,
AHCTUNGTRENNUNG
found
C 62.31, H 11.24, N 3.68; HRMS (ESI+): m/z: calcd for
C20H44NO2Si2+: 386.2905; found: 386.2905 [M+H]+. GC (achiral: HP-1,
2008C isothermal): tR((+)-(2R,3S,6R)-10a)=15.1 min, tR((+)-(2R,3S,6S)-
10b)=16.1 min.
found
C 64.61, H 9.43, N 2.63; HRMS (ESI+): m/z: calcd for
C28H49NNaO4Si2+: 542.3092; found: 542.3087 [M+Na]+.
Chem. Eur. J. 2009, 15, 10514 – 10532
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
10523

G. Helmchen et al.
(+)-Benzyl
(2R,3S,6S)-3-{[tert-butyl
G
(m, 1H; CH=CHEHZ), 5.16 (d, J=12.4 Hz, 1H; CHaHbPh), 5.11 (d, J=
12.4 Hz, 1H; CHaHbPh), 4.92–4.86 (m, 1H; 6-H), 4.62 (brs, 1H;
CH2OH), 4.13–3.99 (m, 2H; CH2OH), 3.91–3.81 (m, 1H; CHOH), 3.19
(ddd, J=9.6, 4.0, 3.0 Hz, 1H; 2-H), 3.11 (brs, 1H; CHOH), 1.98–1.85 (m,
2H; 4-Ha, 5-Ha), 1.82–1.58 ppm (m, 2H; 4-Hb, 5-Hb); 13C NMR (75 MHz,
CDCl3): d=156.30 (s, CO2), 136.54 (d, =CH), 136.35 (s, Ph), 128.70,
128.31, 127.94 (3d, Ph), 117.15 (t, =CH2), 67.58 (t, CH2Ph), 67.09 (d, C-
ACHTUNGTRENNUNG(dimethyl)silyl]oxy}methyl)-6-vinylpiperidine-1-carboxylate
(2R,3S,6S)-11b): According to GP3, a solution of (+)-(2R,3S,6S)-10b
(183 mg, 475 mmol) in CH2Cl2 (4.0 mL) was added to a solution of
Na2CO3 (754 mg, 7.11 mmol) in H2O (4.0 mL). The mixture was cooled
to 08C and benzyl chloroformate (405 mg, 2.37 mmol) was added drop-
wise. When the addition was complete, the ice bath was removed, and
the mixture was allowed to warm to room temperature. After 15 min the
reaction was complete according to TLC analysis (petroleum ether/ethyl
3), 61.17 (d, C-2), 60.08 (t, CH2OH), 55.30 (d, C-6), 28.75 (t, C-4),
+
26.40 ppm (t, C-5); HRMS (ESI+): m/z: calcd for C16H22NO4
292.1543; found: 292.1546 [M+H]+.
:
acetate 4:1, RfACHTUNGTRENNUNG(10b)=0.31, RfCAHTUNGTRENN(UGN 11b)=0.65, KMnO4), and the mixture was
extracted with CH2Cl2 (4ꢄ10 mL). The combined organic layers were
dried over Na2SO4, concentrated under reduced pressure, and the crude
product was purified by flash chromatography on silica gel (5 g, petrole-
um ether/diethyl ether 20:1) to give (+)-(2R,3S,6S)-11b (233 mg, 94%)
as a colorless oil. [a]2D0 =+10.7 (c=0.99 in CHCl3, >99% ee); 1H NMR
(300 MHz, CDCl3): d=7.36–7.27 (m, 5H; Ph), 6.24 (ddd, J=17.3, 10.3,
7.1 Hz, 1H; CH=CH2), 5.16 (d, J=12.6 Hz, 1H; CHaHbPh), 5.12–5.05 (m,
1H; CH=CHEHZ), 5.09 (d, J=12.6 Hz, 1H; CHaHbPh), 5.02 (ddd, J=
10.4, 1.8, 1.8 Hz, 1H; CH=CHEHZ), 4.24–4.20 (m, 2H; 3-H, 6-H), 4.00
(ddd, J=8.5, 4.3, 3.9 Hz, 1H; 2-H), 3.73 (dd, J=9.6, 4.5 Hz, 1H;
CHaHbOSi), 3.56 (dd, J=9.5, 9.5 Hz, 1H; CHaHbOSi), 1.98–1.87 (m, 1H;
CH2CHaHb), 1.84–1.61 (m, 3H; CH2CHaHb), 0.87, 0.87 (2s, 18H; C-
General procedure 4 (GP4, cross-metathesis): In a flame-dried Schlenk
tube under an argon atmosphere, a solution of the piperidine derivative
(0.1 mmol) and the olefin representing the side chain (0.3–1.0 mmol) in
dry CH2Cl2 (1 mL) was treated with Grubbs II or Grubbs II–Hoveyda
catalyst (1–10 mmol) and heated at reflux. If necessary, further portions
of the catalyst and the side chain olefin were added until TLC control in-
dicated complete or no further conversion (1–24 h). The mixture was
concentrated and purified by flash chromatography on silica gel and, if
necessary, by preparative HPLC.
(+)-Benzyl (2R,3S,6R)-3-hydroxy-2-(hydroxymethyl)-6-[(E)-10’-oxodo-
dec-1’-en-1’-yl]piperidine-1-carboxylate ((+)-(2R,3S,6R,E)-14a): Follow-
ing GP4, Grubbs II–Hoveyda catalyst (2.0 mg, 3.2 mmol) was added to a
solution of (+)-(2R,3S,6R)-12a (46.2 mg, 159 mmol) and 13 (145 mg,
797 mmol) in dry CH2Cl2 (1.5 mL), and the mixture was heated at reflux.
An additional 5 portions of the catalyst (each 2.0 mg, 3.2 mmol) were
added after intervals of 2 h each, and stirring was continued at reflux
overnight. After 25 h no further conversion was detected by TLC control
ACHTUNGTRENNUNG
(CH3)3), 0.05, 0.04 (2s, 6H; SiCH3), 0.00 ppm (s, 6H; SiCH3); 13C NMR
(75 MHz, CDCl3): d=156.44 (s, CO2), 140.33 (d, =CH), 137.05 (s, Ph),
128.46, 127.95, 127.87 (3d, Ph), 113.63 (t, =CH2), 66.85 (t, CH2Ph), 65.55
(d, C-3), 62.86 (t, CH2OSi), 60.91 (d, C-2), 55.12 (d, C-6), 26.15,§ 25.97,#
25.94,§ 25.90# (2ꢄ2q, C
G
G
À5.29, À5.47 ppm (4q, SiCH3) (the CH3 resonances of the tert-butyl
groups appear as a pair of each two sharp (#) and two smaller and slight-
ly broadened (§) signals); elemental analysis calcd (%) for C28H49NO4Si2:
C 64.69, H 9.50, N 2.69; found C 64.77, H 9.53, N 2.67; HRMS (ESI+):
m/z: calcd for C28H50NO4Si2+: 520.3273; found: 520.3281 [M+H]+.
(ethyl acetate, RfACHTUNTRGENN(UG 12a)=0.33, RfCAHTUNGTRNE(NNGU 14a)=0.39, KMnO4), and the mixture
was concentrated under reduced pressure. The residue was subjected to
flash chromatography on silica gel (3 g, ethyl acetate) and subsequent
preparative HPLC (ethyl acetate, column: ProntoSIL, 250ꢄ20 mm, 5 m
silica gel, 15 mLminÀ1
, 100 bar) to give pure (+)-(2R,3S,6R,E)-14a
(+)-Benzyl (2R,3S,6R)-3-Hydroxy-2-(hydroxymethyl)-6-vinylpiperidine-
1-carboxylate ((+)-(2R,3S,6R)-12a): A solution of (+)-(2R,3S,6R)-11a
(222 mg, 427 mmol) in methanol (1.0 mL) was treated with 20% HCl/
MeOH (2.0 mL, prepared from concentrated aqueous HCl (ca. 12m,
0.4 mL) and methanol (1.6 mL)) and stirred at room temperature for
2.5 h when complete conversion was indicated by TLC control (petro-
(40.8 mg, 58%) as colorless needles (m.p. 50–518C); [a]2D0 =+41.7 (c=
1
0.82 in CHCl3, >99% ee); H NMR (500 MHz, CDCl3): d=7.34–7.27 (m,
5H; Ph), 5.51 (ddd, J=14.9, 6.8, 6.8 Hz, 1H; 2’-H), 5.36 (dd, J=15.6,
5.2 Hz, 1H; 1’-H), 5.15 (d, J=12.3 Hz, 1H; CHaHbPh), 5.05 (d, J=
12.3 Hz, CHaHbPh), 4.74 (brs, 1H; 6-H), 4.32 (dd, J=7.1, 7.1 Hz, 1H; 2-
H), 4.10 (brs, 1H; 3-H), 3.57 (dd, J=10.7, 6.0 Hz, 1H; CHaHbOH), 3.53
(dd, J=11.0, 8.5 Hz, 1H; CHaHbOH), 3.32 (brs, 2H; OH), 2.40 (q, J=
7.7 Hz, 2H; CH2CH3), 2.37 (t, J=7.8 Hz, 2H; 9’-H), 2.19–2.11 (m, 1H; 5-
Ha), 1.95 (ddd, J=6.9, 6.9, 6.9 Hz, 2H; 3’-H), 1.85–1.78 (m, 1H; 4-Ha),
1.65–1.60 (m, 1H; 4-Hb), 1.56–1.51 (m, 3H; 5-Hb, 8’-H), 1.31–1.20 (m,
8H; (CH2)4), 1.03 ppm (t, J=7.3 Hz, 3H; CH3); 13C NMR (125 MHz,
CDCl3): d=212.31 (s, C=O), 157.28 (s, CO2), 136.61 (s, Ph), 132.27 (d, C-
2’), 130.38 (d, C-1’), 128.54, 128.05, 127.88 (3d, Ph), 67.56 (t, CH2Ph),
64.15 (d, C-3), 63.44 (t, CH2OH), 60.37 (d, C-2), 51.03 (d, C-6), 42.47 (t,
C-9’), 35.99 (t, C-11’), 32.43 (t, C-3’), 29.27, 29.27, 29.10, 29.01 (4 t, C-4’,
C-5’, C-6’, C-7’), 23.93 (t, C-8’), 22.10 (t, C-4), 21.35 (t, C-5), 7.94 ppm (q,
CH3); HRMS (ESI+): m/z: calcd for C26H39NNaO5+: 468.2720; found:
468.2717 [M+Na]+.
leum ether/ethyl acetate 4:1,
RfACTHUNGTREN(UNG 11a)=0.63, RfCAHTUNGTREN(NGNU 12a)<0.1, KMnO4).
NaHCO3 was added in small portions until gas evolution ceased and the
mixture was extracted with ethyl acetate (4ꢄ5 mL). The combined or-
ganic phases were dried over Na2SO4 and concentrated in vacuo. The
crude product was purified by flash chromatography on silica gel (3 g, pe-
troleum ether/ethyl acetate 1:1 to 1:2) to give the pure diol (+)-
(2R,3S,6R)-12a (123 mg, 99%) as a colorless oil. [a]2D0 = +28.0 (c=0.68
1
in CHCl3, >99% ee); H NMR (300 MHz, CDCl3): d=7.37–7.27 (m, 5H;
Ph), 5.81 (ddd, J=17.4, 10.6, 4.9 Hz, 1H; CH=CH2), 5.17–5.09 (m, 2H;
CH=CH2), 5.16 (d, J=12.4 Hz, 1H; CHaHbPh), 5.08 (d, J=12.4 Hz, 1H;
CHaHbPh), 4.83–4.76 (m, 1H; 6-H), 4.35 (dd, J=7.3, 7.3 Hz, 1H; 2-H),
4.08 (brs, 1H; CHOH), 3.59 (dd, J=10.9, 6.8 Hz, 1H; CHaHbOH), 3.54
(dd, J=10.8, 8.6 Hz, 1H; CHaHbOH), 3.19 (brs, 2H; OH), 2.25–2.12 (m,
1H; 5-Ha), 1.86–1.74 (m, 1H; 4-Ha), 1.68–1.60 ppm (m, 2H; 4-Hb, 5-Hb);
13C NMR (75 MHz, CDCl3): d=157.42 (s, CO2), 139.13 (d, =CH), 136.47
(s, Ph), 128.62, 128.15, 127.91 (3d, Ph), 115.79 (t, =CH2), 67.74 (t,
CH2Ph), 64.13 (d, CHOH), 63.33 (t, CH2OH), 60.41 (d, C-2), 51.58 (d, C-
6), 22.15 (t, C-4), 20.60 ppm (t, C-5); HRMS (ESI+): m/z: calcd for
C16H22NO4+: 292.1543; found: 292.1545 [M+H]+.
(À)-Benzyl
(2R,3S,6S)-3-hydroxy-2-(hydroxymethyl)-6-[(E)-10’-oxodo-
dec-1’-en-1’-yl]piperidine-1-carboxylate ((À)-(2R,3S,6S,E)-14b): Follow-
ing GP4, a solution of (À)-(2R,3S,6S)-12b (39.0 mg, 134 mmol) and 13
(122 mg, 670 mmol) in dry CH2Cl2 (750 mL) was treated with Grubbs II–
Hoveyda catalyst (2.5 mg, 4 mmol) and heated at reflux. A second and a
third portion of the catalyst (each 2.5 mg, 4 mmol) was added after 2 h
and 5 h reaction time, respectively. After 8.5 h the mixture was allowed
to cool to room temperature, and stirring was continued overnight. After
(À)-Benzyl (2R,3S,6S)-3-hydroxy-2-(hydroxymethyl)-6-vinylpiperidine-1-
carboxylate ((À)-(2R,3S,6S)-12b): This compound was prepared analo-
gously to (+)-(2R,3S,6R)-12a from (+)-(2R,3S,6S)-11b (195 mg,
375 mmol). After 2.5 h, when the starting material was no longer detected
24 h TLC control (ethyl acetate, RfACHTUNRGTENNUG(12b)=0.40, RfACHTUGNTREN(NUGN 14b)=0.47, KMnO4)
showed almost complete conversion. The mixture was concentrated in
vacuo, and the residue was subjected to flash chromatography on silica
gel (4 g, petroleum ether/ethyl acetate 1:1) and preparative HPLC (ethyl
by TLC control (petroleum ether/ethyl acetate 4:1, RfACHTUNGTRENUN(NG 11b)=0.65, Rf-
ACHTUNGTRENNUNG
acetate, column: ProntoSIL, 250ꢄ20 mm, 5 m silica gel, 15 mLminÀ1
,
and extraction with ethyl acetate. The pure diol (À)-(2R,3S,6S)-12b
(103 mg, 94%) was obtained after purification by flash chromatography
on silica gel (3 g, petroleum ether/ethyl acetate 1:1 to 1:2) as a colorless
oil. [a]2D0 =À19.7 (c=1.08 in CHCl3, >99% ee); 1H NMR (300 MHz,
CDCl3): d=7.40–7.29 (m, 5H; Ph), 5.78 (ddd, J=17.5, 10.7, 3.6 Hz, 1H;
CH=CH2), 5.27 (ddd, J=10.7, 2.4, 0.9 Hz, 1H; CH=CHEHZ), 5.20–5.12
54 bar) to give pure (À)-(2R,3S,6S,E)-14b (36.8 mg, 62%) as a colorless
oil together with some recovered starting material (À)-(2R,3S,6S)-12b
(2.7 mg, 7%). [a]2D0 =À41.3 (c=1.43 in CHCl3, >99% ee); 1H NMR
(300 MHz, CDCl3): d=7.37–7.30 (m, 5H; Ph), 5.55 (dddd, J=15.6, 6.8,
6.8, 1.8 Hz, 1H; 2’-H), 5.38 (dd, J=15.6, 4.1 Hz, 1H; 1’-H), 5.14 (d, J=
10524
www.chemeurj.org
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 10514 – 10532

Iridium-Catalyzed Allylic Cyclization
FULL PAPER
12.3 Hz, 1H; CHaHbPh), 5.11 (d, J=12.3 Hz, 1H; CHaHbPh), 4.85 (brs,
1H; 6-H), 4.61 (brs, 1H; CH2OH), 4.08–4.00 (m, 2H; CH2OH), 3.86–
3.82 (m, 1H; 3-H), 3.22–3.17 (m, 1H; 2-H), 3.00 (brs, 1H; CHOH), 2.40
(q, J=7.7 Hz, 2H; CH2CH3), 2.38 (t, J=7.8 Hz, 2H; 9’-H), 2.02 (dt, J=
7.0, 7.0 Hz, 2H; 3’-H), 1.94–1.90 (m, 1H; 4-Ha), 1.85–1.81 (m, 1H; 5-Ha),
1.75–1.62 (m, 2H; 4-Hb, 5-Hb), 1.58–1.52 (m, 2H; 8’-H), 1.37–1.30 (m,
2H; 4’-H), 1.30–1.22 (m, 6H; 5’-H, 6’-H, 7’-H), 1.04 ppm (t, J=7.3 Hz,
3H; CH3); 13C NMR (125 MHz, CDCl3): d=212.08 (s, C=O), 156.26 (s,
CO2), 136.47 (s, Ph), 133.69 (d, C-1’), 128.67, 128.25, 127.90 (3 d, Ph),
127.75 (d, C-2’), 67.45 (t, CH2Ph), 67.27 (d, C-3), 60.96 (d, C-2), 60.15 (t,
CH2OH), 54.74 (d, C-6), 42.48 (t, C-9’), 35.99 (t, CH2CH3), 32.53 (t, C-3’),
29.30, 29.29, 29.17, 29.07, 28.80 (5 t, C-4, C-4’, C-5’, C-6’, C-7’), 27.03 (t,
C-5), 23.97 (t, C-8’), 7.97 ppm (q, CH3); elemental analysis calcd (%) for
data.[11,15,58] Recrystallization from acetone afforded colorless needles
(m.p. 100.0–100.58C; ref. [15b]: 96–998C ((À)-prosopinine (CHCl3/
Et2O))). The relative configuration of the product was confirmed by X-
ray crystal structural analysis. [a]2D0 =+11.7 (c=0.70 in CHCl3, >99% ee)
(refs. [11,12b,13]: [a]D20 =+12 (c=0.01, CHCl3)); 1H NMR (600 MHz,
CDCl3): d=3.74 (brs, 3H; NH, OH), 3.66 (dd, J=10.9, 7.1 Hz, 1H;
CHaHbOH), 3.63 (dd, J=10.9, 5.0 Hz, 1H; CHaHbOH), 3.53 (ddd, J=6.6,
6.6, 3.8 Hz, 1H; 5’-H), 2.86 (ddd, J=6.0, 6.0, 6.0 Hz, 1H; 6’-H), 2.83–2.79
(m, 1H; 2’-H), 2.39 (q, J=7.3 Hz, 2H; CH2CH3), 2.36 (t, J=7.5 Hz, 2H;
4-H), 1.73–1.68 (m, 1H; 4’-Ha), 1.64–1.57 (m, 2H; 3’-Ha, 4’-Hb), 1.56–1.46
(m, 4H; 5-H, 12-Ha, 3’-Hb), 1.43–1.37 (m, 1H; 12-Hb), 1.30–1.19 (m,
12H; (CH2)6), 1.01 ppm (t, J=7.4 Hz, 3H; CH3); 13C NMR (151 MHz,
CDCl3): d=212.33 (s, C=O), 67.45 (d, C-5’), 61.84 (t, CH2OH), 58.14 (d,
C-6’), 50.39 (d, C-2’), 42.50 (t, C-4), 35.94 (t, C-2), 33.05 (t, C-12), 29.67,
29.57, 29.45, 29.44, 29.30 (5t, CH2), 28.24 (t, C-4’), 26.86 (t, C-3’), 26.40 (t,
CH2), 23.98 (t, C-5), 7.93 ppm (q, CH3); HRMS (ESI+): m/z: calcd for
C18H36NO3+: 314.2690; found: 314.2689 [M+H]+.
C26H39NO5: C 70.08, H 8.82, N 3.14; found C 69.90, H 8.80, N 3.10;
+
HRMS (ESI+): m/z: calcd for C26H39NNaO5
468.2719 [M+Na]+.
: 468.2720; found:
General procedure 5 (GP5, catalytic hydrogenation on Pd(OH)2/C):
Under an atmosphere of hydrogen (1 bar) in a flame dried Schlenk tube,
palladium hydroxide (ca. 10–20 wt% (dry) on activated charcoal, wet, ca.
50% H2O) (5 mg, 3.6 mmol) was suspended in dry methanol (0.5 mL),
(+)-Benzyl (2R,3S,6R)-3-hydroxy-6-[(E,11’S)-11’-hydroxydodec-1’-en-1’-
yl]-2-(hydroxymethyl)piperidine-1-carboxylate ((+)-(2R,3S,6R,E,11’S)-
17a): Following GP4, Grubbs II–Hoveyda catalyst (8.4 mg, 13.4 mmol)
was added to a solution of (+)-(2R,3S,6R)-12a (80.0 mg, 275 mmol) and
(+)-(S)-16 (237 mg, 1.29 mmol) in dry CH2Cl2 (1.5 mL), and the mixture
and the mixture was stirred for 30 min.
A solution of the olefin
(0.1 mmol) in dry methanol (0.5 mL) was added and the mixture was
stirred at room temperature until TLC control showed complete conver-
sion (1–4 h). The mixture was filtered through a pad of silica gel, and the
filtrate was concentrated under reduced pressure.
was heated at reflux. After 2 h TLC control (ethyl acetate, R
fACHTUNGTRENNUNG(12a)=
0.23, RfA(17a)=0.20, KMnO4) still showed some starting material, and an-
CTHUNGTRENNUNG
other portion of the catalyst (3.4 mg, 5.4 mmol) was added. After 5.5 h
conversion was complete, and the mixture was concentrated in vacuo,
and the residue subjected to flash chromatography on silica gel (3 g, pe-
troleum ether/ethyl acetate 1:1 to ethyl acetate). The product obtained
(105 mg, 85%) was still contaminated with unidentified side products
and purified by repeated preparative HPLC (ethyl acetate, column:
ProntoSIL, 250ꢄ20 mm, 5 m silica gel, 15 mLminÀ1, 58 bar) to furnish an-
alytically pure (+)-(2R,3S,6R,E,11’S)-17a (41.5 mg, 34%) as a colorless
oil. [a]2D0 =+34.2 (c=1.18 in CHCl3, >99% ee); 1H NMR (500 MHz,
CDCl3): d=7.36–7.28 (m, 5H; Ph), 5.52 (ddd, J=14.8, 7.1, 7.1 Hz, 1H;
2’-H), 5.38 (dd, J=15.5, 5.6 Hz, 1H; 1’-H), 5.16 (d, J=12.3 Hz,
CHaHbPh), 5.07 (d, J=12.6 Hz, 1H; CHaHbPh), 4.75 (m, 1H; 6-H), 4.34–
4.26 (m, 1H; 2-H), 4.10 (brs, 1H; 3-H), 3.77 (qt, J=6.0, 5.9 Hz, 1H; 11’-
H), 3.62–3.51 (m, 2H; CH2OH), 3.13 (brs, 2H; OH), 2.19–2.12 (m, 1H;
5-Ha), 2.03 (brs, 1H; OH), 1.96 (dt, J=7.0, 7.0 Hz, 2H; 3’-H), 1.86–1.79
(m, 1H; 4-Ha), 1.66–1.61 (m, 1H; 4-Hb), 1.58–1.52 (m, 1H; 5-Hb), 1.48–
1.19 (m, 14H; (CH2)7), 1.16 ppm (d, J=6.3 Hz, 3H; CH3); 13C NMR
(126 MHz, CDCl3): d=157.32 (s, CO2), 136.61 (s, Ph), 132.46 (d, C-2’),
130.33 (d, C-1’), 128.59, 128.10, 127.94 (3d, Ph), 68.21 (d, C-11’), 67.61 (t,
CH2Ph), 64.19 (d, C-3), 63.49 (t, CH2OH), 60.47 (d, C-2), 51.11 (d, C-6),
39.36 (t, C-10’), 32.40 (t, C-3’), 29.61, 29.58, 29.33, 29.10, 29.09, 25.79 (6t,
CH2), 23.51 (q, CH3), 22.14 (t, C-4), 21.45 ppm (t, C-5); HRMS (ESI+):
m/z: calcd for C26H41NNaO5+: 470.2877; found: 470.2879 [M+Na]+.
(+)-12-[(2’S,5’S,6’R)-5’-Hydroxy-6’-(hydroxymethyl)piperidin-2’-yl]dode-
can-3-one ((+)-(2’S,5’S,6’R)-prosophylline; (+)-15a): According to GP5,
a suspension of palladium hydroxide (2.5 mg) in methanol (400 mL) was
stirred under an atmosphere of hydrogen (1 bar) for 30 min. Then a solu-
tion of (+)-(2R,3S,6R,E)-14a (24.9 mg, 55.9 mmol) in methanol (500 mL)
was added, and the mixture was stirred at room temperature for 1 h
when the starting compound was consumed according to TLC control
(ethyl acetate, RfACHTUNGTRENNUNG(14a)=0.39, Rf(prosophylline)<0.1, KMnO4). The mix-
ture was filtered through a pad of Celite and the filtrate concentrated
under reduced pressure to give a colorless oil, which was dissolved in
ethyl acetate (5 mL). The resulting solution was washed with aqueous
NaOH (2ꢄ2 mL, 1n), and the aqueous layer was re-extracted with ethyl
acetate (2ꢄ1 mL). The combined organic layers were dried over Na2SO4
and concentrated in vacuo to give pure (by NMR spectroscopy) (+)-
(2’S,5’S,6’R)-prosophylline (17.4 mg, 99%) as a colorless solid showing
physical properties that matched those reported.[14,17] Recrystallization
from acetone afforded colorless crystals. M.p. 85.5–868C (ref. [17a]: 77–
798C ((À)-prosophylline); ref. [17e]: 82–838C ((Æ)-prosophylline));
[a]2D0 =+10.3 (c=1.30 in CHCl3, >99% ee) (ref. [15a]: [a]2D6 =À12.9 (c=
2.54, CHCl3 ((À)-prosophylline))); 1H NMR (600 MHz, CDCl3): d=3.81
(dd, J=10.8, 4.5 Hz, 1H; CHaHbOH), 3.69 (dd, J=10.8, 5.4 Hz, 1H;
CHaHbOH), 3.44 (ddd, J=10.0, 9.9, 4.5 Hz, 1H; 5’-H), 2.71 (brs, 3H;
OH, NH), 2.54 (ddd, J=9.3, 4.8, 4.8 Hz, 1H; 6’-H), 2.53–2.48 (m, 1H; 2’-
H), 2.41 (q, J=7.3 Hz, 2H; CH2CH3), 2.38 (t, J=7.3 Hz, 2H; 4-H), 2.04–
2.00 (m, 1H; 4’-Ha), 1.75–1.71 (m, 1H; 3’-Ha), 1.57–1.52 (m, 2H; 5-H),
1.40–1.31 (m, 3H; 12-H, 4’-Hb), 1.31–1.22 (m, 12H; (CH2)6), 1.11 (dddd,
J=13.5, 13.5, 10.9, 3.2 Hz, 1H; 3’-Hb), 1.03 ppm (t, J=7.4 Hz, 3H; CH3);
13C NMR (151 MHz, CDCl3): d=212.32 (s, C=O), 70.43 (d, C-5’), 64.47
(t, CH2OH), 63.35 (d, C-6’), 56.14 (d, C-2’), 42.55 (t, C-4), 36.60 (t, C-12),
35.99 (t, C-2), 33.96 (t, C-4’), 31.15 (t, C-3’), 29.83, 29.60, 29.50, 29.48,
29.36, 26.29 [6t, (CH2)6), 24.04 (t, C-5), 7.98 ppm (q, CH3); HRMS
(ESI+): m/z: calcd for C18H36NO3+: 314.2690; found: 314.2691 [M+H]+.
(+)-(2R,3S,6S)-6-[(11’S)-11’-Hydroxydodecyl]-2-(hydroxymethyl)piperi-
din-3-ol ((+)-6-epi-prosopine; (+)-18a)): According to GP5, as suspen-
sion of palladium hydroxide (2.2 mg) in methanol (500 mL) was stirred
for 30 min under an hydrogen atmosphere (1 bar). A solution of (+)-17a
(23.6 mg, 52.8 mmol) in methanol (400 mL) was added, and the mixture
was stirred at room temperature. After 3 h conversion was incomplete ac-
cording to TLC (ethyl acetate, RfACTHNUTRGENNUG(17a)=0.20, RfCAHTUNGTRENN(UGN 18a)<0.1), and another
portion of the palladium catalyst (2.5 mg) was added. After being stirred
for another 1 h, complete conversion was reached, and the mixture was
filtered through a pad of Celite. Evaporation of all volatiles gave (+)-18a
(16.5 mg, 99%) as
a
colorless oil. [a]D20 =+29.9 (c=0.84 in MeOH,
>99% ee); 1H NMR (600 MHz, CD3OD): d=3.94 (dd, J=11.5, 3.0 Hz,
1H; CHaHbOH), 3.74 (dd, J=11.5, 6.3 Hz, 1H; CHaHbOH), 3.72–3.68
(m, 1H; 11’-H), 3.54 (ddd, J=10.7, 10.2, 4.6 Hz, 1H; 3-H), 2.90–2.86 (m,
1H; 6-H), 2.79–2.76 (m, 1H; 2-H), 2.11–2.07 (m, 1H; 4-Ha), 1.99–1.95
(m, 1H; 5-Ha), 1.68–1.63 (m, 1H; 1’-Ha), 1.51–1.27 (m, 21H; (CH2)9, 1’-
Hb, 4-Hb, 5-Hb), 1.14 ppm (d, J=6.2 Hz, 3H; CH3); 13C NMR (151 MHz,
CD3OD): d=68.53 (d, C-11’), 67.26 (d, C-3), 64.68 (d, C-2), 60.90 (t,
CH2OH), 58.03 (d, C-6), 40.20 (t, C-10’), 34.98 (t, C-1’), 33.51 (t, C-4),
30.84, 30.75, 30.70, 30.65, 30.61, 30.55 (6t, CH2), 29.13 (t, C-5), 26.90,
26.82 (2t, CH2), 23.53 ppm (q, CH3); HRMS (ESI+): m/z: calcd for
C18H37NNaO3+: 338.2666; found: 338.2668 [M+Na]+.
(+)-12-[(2’R,5’S,6’R)-5’-Hydroxy-6’-(hydroxymethyl)piperidin-2’-yl]dode-
can-3-one ((+)-(2’R,5’S,6’R)-prosopinine (+)-15b): Following GP5, a sus-
pension of palladium hydroxide (3.4 mg) in methanol (500 mL) was
stirred under an atmosphere of hydrogen (1 bar) for 30 min. A solution
of (À)-(2R,3S,6S,E)-14b (28.5 mg, 64.0 mmol) in methanol (750 mL) was
added, and the mixture was stirred for 1 h when TLC analysis (ethyl ace-
tate, RfACHTUNGTRENNUNG(14b)=0.45, RfACHTUNGTRENNUNG(15b)<0.1, KMnO4) indicated complete consump-
tion of the substrate. The mixture was filtered through a pad of Celite
and all volatiles were evaporated to give analytically pure (+)-
(2’R,5’S,6’R)-prosopinine (20.1 mg, quant.) as a colorless crystalline solid,
the spectroscopic data of which were in accordance with the reported
Chem. Eur. J. 2009, 15, 10514 – 10532
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
10525

G. Helmchen et al.
(À)-Benzyl (2R,3S,6S)-3-hydroxy-6-[(E,11’S)-11’-hydroxydodec-1’-en-1’-
yl]-2-(hydroxymethyl)piperidine-1-carboxylate
17b): According to GP4, Grubbs II–Hoveyda catalyst (5.0 mg, 8.0 mmol)
was added to a solution of (À)-12b (32.0 mg, 110 mmol) and (+)-(S)-16
(59.0 mg, 320 mmol) in dry CH2Cl2 (600 mL). The solution was heated at
1H; NH), 4.16–4.03 (m, 1H; CHN), 2.65–2.49 (m, 2H; CH2), 1.39 (s, 9H;
((À)-(2R,3S,6S,E,11’S)-
CACTHNGUTERNNUG
(CH3)3), 1.20 ppm (d, J=6.8 Hz, 3H; CH3CH); 13C NMR (75 MHz,
CDCl3): d=201.03 (d, CHO), 155.21 (s, CO2), 79.65 (s, C
(t, CH2), 42.48 (d, CHN), 28.45 (q, C(CH3)3), 21.06 ppm (q, CH3CH);
HRMS (EI+): m/z: calcd for C8H14NO3+: 172.0968; found: 172.0974
[M-CH3]+.
(+)-tert-Butyl
((+)-(1R,3R)-22) and (+)-tert-butyl [(1R,3S)-3-hydroxy-1-methylhex-5-
en-1-yl]carbamate ((+)-3-epi-22): According to a general procedure,[46b]
ACHTUGNTRNEN(UNG CH3)3), 50.66
AHCTUNGTRENNUNG
reflux for 1 h when TLC control (ethyl acetate, RfACHTNUGRTENN(UG 12b)=0.38, RfACHTUNGTERN(NUGN 17b)=
AHCTUNGTRENNUNG
0.32, Rf(16)=0.58, KMnO4) showed complete conversion. The mixture
was concentrated in vacuo, and the residue was subjected to flash chro-
matography on silica gel (2 g, ethyl acetate) and subsequent preparative
HPLC (ethyl acetate, column: ProntoSIL, 250ꢄ20 mm, 5 m silica gel,
15 mLminÀ1, 100 bar) to yield pure (À)-17b (28 mg, 57%) as a colorless
oil. [a]2D0 =À38.6 (c=0.81 in CHCl3, >99% ee); 1H NMR (500 MHz,
CDCl3): d=7.37–7.30 (m, 5H; Ph), 5.55 (dddd, J=15.5, 6.8, 6.8, 1.6 Hz,
1H; 2’-H), 5.39 (dd, J=15.8, 4.0 Hz, 1H; 1’-H), 5.14 (d, J=12.3 Hz, 1H;
CHaHbPh), 5.10 (d, J=12.3 Hz, 1H; CHaHbPh), 4.85 (brs, 1H; 6-H), 4.73
(brs, 1H; CH2OH), 4.08–3.99 (m, 2H; CH2OH), 3.85–3.80 (m, 1H; 3-H),
3.77 (qt, J=6.0, 6.0 Hz, 1H; 11’-H), 3.34 (brs, 1H; 3-OH), 3.20–3.18 (m,
1H; 2-H), 2.02 (dt, J=7.0, 7.0 Hz, 2H; 3’-H), 1.95–1.90 (m, 2H; 4-Ha,
11’-OH), 1.84–1.78 (m, 1H; 5-Ha), 1.74–1.62 (m, 2H; 4-Hb, 5-Hb), 1.49–
1.22 (m, 14H; (CH2)7), 1.17 ppm (d, J=6.0 Hz, 3H; CH3); 13C NMR
(126 MHz, CDCl3): d=156.25 (s, CO2), 136.47 (s, Ph), 133.76 (d, C-2’),
128.65, 128.23, 127.88 (3d, Ph), 127.68 (d, C-1’), 68.15 (d, C-11’), 67.45 (t,
CH2Ph), 67.03 (d, C-3), 61.02 (d, C-2), 60.02 (t, CH2OH), 54.74 (d, C-6),
39.42 (t, C-10’), 32.54 (d, C-3’), 29.68, 29.62, 29.43, 29.21, 29.20 (5t, CH2),
28.82 (t, C-4), 27.05 (t, C-5), 25.83 (t, CH2), 23.55 ppm (q, CH3); HRMS
(ESI+): m/z: calcd for C26H42NO5+: 448.3058; found: 448.3054 [M+H]+.
[(1R,3R)-3-hydroxy-1-methylhex-5-en-1-yl]carbamate
a
flame-dried flask equipped with a coolable dropping funnel was charged
with a solution of aldehyde (+)-(R)-21 (3.017 g, 16.11 mmol) in dry di-
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
20.0 mmol) in dry diethyl ether (150 mL) and cooled to À788C. The
borane solution was added dropwise over a period of 30 min to the solu-
tion of the aldehyde, and the mixture was then allowed to warm to
À458C over a period of 1.5 h. Methanol (30 mL), aqueous NaOH (3m,
15 mL) and aqueous hydrogen peroxide (30%, 15 mL) were added to
give a white suspension, which was allowed to warm up to room tempera-
ture overnight. After 18 h the phases were separated and the organic
layer was washed with aqueous NaOH (1m, 2ꢄ70 mL) and saturated
aqueous NH4Cl (2ꢄ70 mL). The combined aqueous layers were extract-
ed with diethyl ether (3ꢄ100 mL), and the combined organic phases
were dried over Na2SO4 and concentrated under reduced pressure to give
the crude product, which was analyzed by GC with respect to the diaste-
reomeric ratio ((+)-22/(+)-3-epi-22=93:7). Flash chromatography on
silica gel (19 g, petroleum ether/ethyl acetate 7:1 to 4:1 to 2:1, Rf(22)=
(+)-(2R,3S,6R)-6-[(11’S)-11’-Hydroxydodecyl]-2-(hydroxymethyl)piperi-
din-3-ol ((+)-(2R,3S,6R,11’S)-prosopine; (+)-18b): According to GP5, a
suspension of palladium hydroxide (2.6 mg) in methanol (100 mL) was
stirred under an atmosphere of hydrogen (1 bar) for 30 min. Then a solu-
tion of (À)-17b (19.0 mg, 42.5 mmol) in methanol (250 mL) was added,
and the mixture was stirred for 2 h when complete conversion was indi-
0.24, RfACTHNUGTRNE(NUG 3-epi-22)=0.11 (petroleum ether/ethyl acetate 3:1), KMnO4)
gave pure (+)-3-epi-22 (317 mg, 8.6%) and pure (+)-(1R,3R)-22 (415 mg,
11.2%), both colorless oils, together with a fraction of (+)-(1R,3R)-22
(8.489 g), which was contaminated with degradation products of the
chiral borane. This fraction was purified by slow sublimation of the
borane impurities in a Kugelrohr distillation apparatus (0.2 mbar, 40–
508C) to yield pure (+)-(1R,3R)-22 (2.81 g, 76%) as a colorless oil,
which crystallized over a period of a few days as colorless polyhedra
(m.p. 39.5–40.58C) that were subjected to X-ray crystal structural analy-
sis.
Analytic data for (+)-(1R,3R)-22: [a]2D0 =+4.6 (c=0.92 in CHCl3,
>99% ee); 1H NMR (300 MHz, CDCl3): d=5.85 (ddd, J=17.2, 10.1,
7.1 Hz, 1H; =CH), 5.11–5.04 (m, 2H; =CH2), 4.50 (d, J=8.0 Hz, 1H;
NH), 3.92 (brs, 2H; CHN, OH), 3.67 (brs, 1H; CHOH), 2.32–2.14 (m,
cated by TLC control (ethyl acetate, RfACHTUNRTGNEUNG(17b)=0.32, Rf(prosopine)<0.1,
KMnO4). Filtration through cotton and a pad of Celite and evaporation
of all volatiles gave (+)-(2R,3S,6R)-prosopine as colorless solid (13.4 mg,
quant.), the analytical data of which agreed with the data reported in the
literature.[11, 12b,13,58] Recrystallization from acetone gave fine colorless
needles. M.p. 127.5–128.58C (ref. [12b]: 126–1278C). [a]2D0 =+21.0 (c=
1.00 in MeOH, >99% ee) (ref. [12b]: [a]2D0 =+25 (c=1, MeOH));
1H NMR (600 MHz, CD3OD): d=3.83 (dd, J=11.0, 4.2 Hz, 1H;
CHaHbOH), 3.70 (qt, J=6.3, 5.8 Hz, 1H; 11’-H), 3.56 (dd, J=10.9,
7.8 Hz, 1H; CHaHbOH), 3.45 (ddd, J=7.8, 7.5, 4.1 Hz, 1H; 3-H), 2.95–
2.91 (m, 1H; 6-H), 2.83 (ddd, J=7.5, 7.5, 4.2 Hz, 1H; 2-H), 1.82–1.78 (m,
1H; 4-Ha), 1.73–1.68 (m, 1H; 5-Ha), 1.67–1.58 (m, 3H; 1’-Ha, 4-Hb, 5-Hb),
1.54–1.48 (m, 1H; 1’-Hb), 1.45–1.29 (m, 18H; (CH2)9), 1.14 ppm (d, J=
6.2 Hz, 3H; CH3); 13C NMR (151 MHz, CD3OD): d=68.56 (d, C-11’),
68.15 (d, C-3), 62.51 (t, CH2OH), 59.07 (d, C-2), 52.07 (d, C-6), 40.22 (t,
C-10’), 32.65 (t, C-1’), 30.84, 30.76, 30.72, 30.72, 30.71, 30.67 (6t, CH2),
28.89 (t, C-4), 27.33, 27.25 (2t, C-5, CH2), 26.91 (t, CH2), 23.51 ppm (q,
CH3); HRMS (ESI+): m/z: calcd for C18H38NO3+: 316.2846; found:
316.2846 [M+H]+.
2H; 4-H), 1.57–1.30 (m, 2H; 2-H), 1.43 (s, 9H; C
J=6.7 Hz, CH3CH); 13C NMR (75, CDCl3): d=156.97 (s, CO2), 135.50 (d,
=CH), 117.05 (t, =CH2), 79.92 (s, C(CH3)3), 67.32 (d, CHOH), 45.70 (t,
C-2), 43.45 (d, CHN), 41.54 (t, C-4), 28.49 (q, C(CH3)3), 21.69 ppm (q,
ACHTUGNTRENUN(NG CH3)3), 1.16 ppm (d,
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
CH3CH); elemental analysis calcd (%) for C12H23NO3: C 62.85, H 10.11,
N 6.11; found C 62.84, H 10.26, N 6.07; HRMS (ESI+): m/z: calcd for
C12H23NNaO3+: 252.1570; found: 252.1572 [M+Na]+. GC (achiral: HP-1,
1408C isothermal): tR((+)-(1R,3R)-22)=17.6 min, tR((+)-3-epi-22). GC
(chiral: b-CD, 1258C isothermal): tR((+)-(1R,3R)-22)=42.0 min, tR((À)-
(1S,3S)-22)=45.8 min.
(+)-tert-Butyl [(R)-1-methyl-3-oxopropyl]carbamate ((+)-(R)-21):[45] In a
flame-dried Schlenk tube under argon, a solution of oxalyl chloride
(800 mL, 9.3 mmol) in dry CH2Cl2 (10 mL) was cooled to À788C. Dry di-
methyl sulfoxide (2.0 mL, 28 mmol) was added dropwise, and the solution
was stirred at À788C for 40 min. Then a solution of (À)-(R)-20 (1.19 g,
6.28 mmol) in dry CH2Cl2 (20 mL) was added dropwise. The solution was
allowed to warm to À308C over a period of 4.5 h and stirred for 4.5 h.
The mixture was then again cooled to À788C and NEt3 (4.4 mL,
31 mmol) was added. After stirring for 30 min the cooling bath was re-
moved, and stirring was continued overnight. The mixture was washed
with saturated aqueous NH4Cl (2ꢄ100 mL), and the combined aqueous
layers were extracted with CH2Cl2 (2ꢄ50 mL). The combined organic
layers were dried over Na2SO4 and concentrated under reduced pressure
to give a yellow oil, which was subjected to flash chromatography on
silica gel (5 g, petroleum ether/ethyl acetate 4:1, Rf(20)=0.47, Rf(21)=
0.55 (ethyl acetate), KMnO4) to give aldehyde (+)-(R)-21 (1.10 g, 93%)
as a colorless oil. [a]2D0 =+27.6 (c=1.12 in CHCl3, 97% ee); 1H NMR
(300 MHz, CDCl3): d=9.72 (t, J=2.0 Hz, 1H; CHO), 4.73 (d, J=6.0 Hz,
Analytical data for (+)-3-epi-22: [a]2D0 =+12.6 (c=1.00 in CHCl3,
96% ee); 1H NMR (300 MHz, CDCl3): d=5.81 (dddd, J=17.4, 9.8, 7.5,
6.9 Hz, 1H; =CH), 5.15–5.07 (m, 2H; =CH2), 4.61 (brs, 1H; NH), 3.82–
3.69 (m, 2H; CHN, CHOH), 2.46 (brs, 1H; OH), 2.30 (ddd, J=13.8, 6.5,
5.0 Hz, 1H; 4-Ha), 2.18 (ddd, J=14.0, 7.5, 7.5 Hz, 1H; 4-Hb), 1.64–1.53
(m, 2H; 2-H), 1.43 (s, 9H; C
CH3CH); 13C NMR (75 MHz, CDCl3): d=155.83 (s, CO2), 134.79 (d, =
CH), 118.20 (t, =CH2), 79.46 (s, C(CH3)3), 69.20 (d, CHOH), 45.20 (d,
CHN), 44.31 (t, C-2), 42.39 (t, C-4), 28.55 (q, C(CH3)3), 21.95 ppm (q,
ACHTUGNTERN(NUNG CH3)3), 1.16 ppm (d, J=6.6 Hz, 3H;
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
CH3CH); elemental analysis calcd (%) for C12H23NO3: C 62.85, H 10.11,
N 6.11; found C 62.69, H 10.08, N 5.97; HRMS (EI+): m/z: calcd for
C12H23NO3+: 229.1673; found: 229.1672 [M]+. For GC data see isomer
(+)-(1R,3R)-22.
(+)-(E,5R,7R)-7-[(tert-Butoxycarbonyl)amino]-5-hydroxyoct-2-en-1-yl
methyl carbonate ((+)-(E,5R,7R)-23) and (+)-(Z,5R,7R)-7-[(tert-butoxy-
carbonyl)amino]-5-hydroxyoct-2-en-1-yl
methyl
carbonate
((+)-
(Z,5R,7R)-23): According to GP1, a solution of (+)-(1R,3R)-22 (300 mg,
10526
www.chemeurj.org
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 10514 – 10532

Iridium-Catalyzed Allylic Cyclization
FULL PAPER
1.308 mmol),
6
(1.30 g, 6.4 mmol) and Grubbs II catalyst (33 mg,
155.77 (s, CO2), 133.65 (d, C-3), 125.78 (d, C-2), 68.65 (d, CHOH), 68.62
(t, CH2O), 54.82 (q, CO2CH3), 44.82 (d, CHN), 42.12 (t, C-6), 40.78 (t, C-
4), 23.39 ppm (q, CH3CH); elemental analysis calcd (%) for C10H19NO4:
C 55.28, H 8.81, N 6.45; found C 55.57, H 8.87, N 6.33; HRMS (ESI+):
m/z: calcd for C10H20NO4+: 218.1387; found: 218.1387 [M+H]+.
39 mmol) in dry CH2Cl2 (30 mL) was stirred at room temperature for
3.5 h when complete conversion was indicated by GC (HP-1; temperature
program: isothermal 508C (1 min), heating rate 208CminÀ1 (10 min), iso-
thermal 2508C (14 min); tR(22)=8.90 min, tR(6)=8.12 min, tR(23)=
12.47 min). The mixture was concentrated in vacuo and the residue sub-
jected to flash chromatography on silica gel (21 g, petroleum ether/ethyl
acetate 5:1 to 3:1, Rf(22)=0.43, Rf(6)=0.43, Rf(23)=0.29 (petroleum
ether/ethyl acetate 1:1), KMnO4) to give 23 (359 mg, 86%) as a 88:12
mixture of E and Z isomers (1H NMR spectroscopy) as a colorless oil.
Separation of the isomers was possible on a small scale by preparative
HPLC (petroleum ether/ethyl acetate 3:1, column: ProntoSIL, 250ꢄ
20 mm, 5 m silica gel, 15 mLminÀ1, 50 bar).
Analytical data for (Z,5R,7R)-24: Rf(24)=0.4 (CH2Cl2/MeOH 4:1); col-
orless oil; 1H NMR (200 MHz, CDCl3): d=5.78 (ddd, J=10.9, 7.0,
7.0 Hz, 1H; 3-H), 5.67 (ddd, J=11.2, 6.3, 6.3 Hz, 1H; 2-H), 4.71 (d, J=
6.1 Hz, 2H; CH2O), 4.05–3.93 (m, 1H; CHOH), 3.78 (s, 3H; CO2CH3),
3.47–3.33 (m, 1H; CHN), 2.74 (brs, 3H; NH2, OH), 2.44–2.19 (m, 2H; 4-
H), 1.58 (ddd, J=14.5, 7.8, 3.6 Hz, 1H; 6-Ha), 1.45 (ddd, J=14.3, 6.4,
3.5 Hz, 1H; 6-Hb), 1.17 ppm (d, J=6.5 Hz, 3H; CH3CH).
(À)-(2R,4S,6R)-2-Methyl-6-vinylpiperidin-4-ol
Following GP2, anhydrous TBD (30.0 mg, 216 mmol) was added to a solu-
tion of [{IrCl(cod)}2] (36.2 mg, 53.9 mmol) and (S,S,aS)-L2 (64.6 mg,
((À)-(2R,4S,6R)-25a):
Analytical data for (+)-(E,5R,7R)-23: Colorless needles; m.p. 63.5–
64.58C; [a]2D0 =+10.6 (c=1.32 in CHCl3, >99% ee); 1H NMR (300 MHz,
CDCl3): d=5.85 (ddd, J=15.3, 7.1, 7.1 Hz, 1H; 3-H), 5.63 (ddd, J=15.3,
6.4, 6.4 Hz, 1H; 2-H), 4.57 (dd, J=6.4, 0.8 Hz, 2H; CH2O), 4.49 (d, J=
8.7 Hz, 1H; NH), 4.13–4.07 (m, 1H; OH), 3.97–3.83 (m, 1H; CHN), 3.75
(s, 3H; CO2CH3), 3.69–3.58 (m, 1H; CHOH), 2.27 (ddd, J=14.2, 6.8,
6.8 Hz, 1H; 4-Ha), 2.17 (ddd, J=14.0, 6.8, 6.8 Hz, 1H; 4-Hb), 1.54–1.21
(m, 2H; 6-H), 1.42 (s, 9H; C
CH3CH); 13C NMR (75 MHz, CDCl3): d=157.04, 155.74 (2s, CO2),
133.58 (d, C-3), 125.65 (d, C-2), 80.00 (s, C(CH3)3), 68.58 (t, CH2O), 67.18
(d, CHOH), 54.80 (q, CO2CH3), 45.84 (t, C-6), 43.34 (d, CHN), 39.84 (t,
C-4), 28.46 (q, C(CH3)3), 21.69 ppm (q, CH3CH); elemental analysis
calcd (%) for C15H27NO6: C 56.77, H 8.57, N 4.41; found C 56.89, H 8.65,
N 4.46; HRMS (ESI+): m/z: calcd for C15H28NO6+: 318.1911; found:
318.1913 [M+H]+. For GC data see experimental procedure.
Analytical data (+)-(Z,5R,7R)-23: Colorless oil; [a]2D0 =+6.6 (c=1.14 in
CHCl3, >99% ee); 1H NMR (500 MHz, CDCl3): d=5.77 (ddd, J=10.8,
7.6, 7.6 Hz, 1H; 3-H), 5.65 (ddd, J=11.0, 6.7, 6.7 Hz, 1H; 2-H), 4.72–4.65
(m, 2H; CH2O), 4.48 (d, J=8.3 Hz, 1H; NH), 4.09 (brs, 1H; OH), 3.95–
3.87 (m, 1H; CHN), 3.76 (s, 3H; CO2CH3), 3.65 (brs, 1H; CHOH), 2.32
(ddd, J=14.9, 7.5, 7.5 Hz, 1H; 4-Ha), 2.25 (ddd, J=14.4, 7.0, 7.0 Hz, 1H;
AHCTUNGTRENNUNG
108 mmol) in dry THF (3.0 mL). After 5 min, a solution of the carbonate
(5R,7R)-24 (E/Z=9:1) (585 mg, 2.69 mmol) in dry THF (2.0 mL) was
added, and the mixture was stirred at room temperature for 6 h when the
reaction was complete according to TLC (CH2Cl2/MeOH 4:1, Rf(24)=
0.4, RfACTHNUGTRENNUG(25a)=0.3, RfACHTUNGTERNN(UGN 25b)=0.3, KMnO4). The mixture was concentrated
ACHTUGNTERN(NUNG CH3)3), 1.15 ppm (d, J=6.8 Hz, 3H;
in vacuo and analyzed by GC with respect to the ratio of diastereomers
((À)-25a/(+)-25b=98:2). Purification by flash chromatography on silica
gel (3 g, CH2Cl2/MeOH 4:1 to 3:1) gave (À)-25a (342 mg, 90%) as a col-
orless solid. An analytically pure sample was obtained by sublimation
under reduced pressure, which gave (À)-25a as colorless needles (m.p.
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
82–838C) that were suitable for X-ray crystal structural analysis. [a]D20
=
À4.7 (c=0.34 in acetone, >99% ee); 1H NMR (300 MHz, CDCl3): d=
5.82 (ddd, J=17.1, 10.5, 6.6 Hz, 1H; =CH), 5.16 (ddd, J=17.3, 1.3,
1.3 Hz, 1H; =CHEHZ), 5.04 (ddd, J=10.4, 1.1, 1.1 Hz, 1H; =CHEHZ),
3.69 (dddd, J=11.1, 11.1, 4.6, 4.6 Hz, 1H; CHOH), 3.20–3.13 (m, 1H; 6-
H), 2.80–2.69 (m, 1H; 2-H), 2.11 (brs, 2H; NH, OH), 2.01–1.90 (m, 2H;
3-Ha, 5-Ha), 1.22–0.99 (m, 2H; 3-Hb, 5-Hb), 1.13 ppm (d, J=6.2 Hz, 3H;
CH3); 13C NMR (75 MHz, CDCl3): d=140.28 (d, =CH), 114.96 (t, =CH2),
68.99 (d, CHOH), 57.74 (d, C-6), 50.26 (d, C-2), 43.33, 41.16 (2t, C-3, C-
5), 22.36 ppm (q, CH3); elemental analysis calcd (%) for C8H15NO: C
68.04, H 10.71, N 9.92; found C 67.87, H 10.70, N 9.62; HRMS (EI+):
m/z: calcd for C8H15NO+: 141.1148; found: 141.1142 [M]+; GC (achiral
HP-1, 908C isothermal): tR((À)-(2R,4S,6R)-25a)=15.5 min, tR((+)-
(2R,4S,6S)-25b)=18.2 min.
4-Hb), 1.53 (ddd, J=13.8, 10.9, 2.8 Hz, 1H; 6-Ha), 1.43 (s, 9H; CACTHNUGTRNEG(UN CH3)3),
1.32 (dd, J=11.9, 11.9 Hz, 1H; 6-Hb), 1.16 ppm (d, J=6.7 Hz, 3H;
CH3CH); 13C NMR (126 MHz, CDCl3): d=157.04 (s, NCO2), 155.89 (s,
OCO2), 132.27 (d, C-3), 124.81 (d, C-2), 80.00 (s, C
CHOH), 63.88 (t, CH2O), 54.86 (q, CO2CH3), 45.91 (t, C-6), 43.39 (d,
ACHTUGNTRENN(UNG CH3)3), 67.37 (d,
CHN), 34.99 (t, C-4), 28.46 (q, CACTHNUTGRNE(UNG CH3)3), 21.67 ppm (q, CH3CH); HRMS
(+)-(2R,4S,6S)-2-Methyl-6-vinylpiperidin-4-ol (25b): According to GP2,
anhydrous TBD (11.9 mg, 85.6 mmol) was added to a solution of [{IrCl-
AHCTUNGTRENNUNG
(ESI+): m/z: calcd for C15H28NO6+: 318.1911; found: 318.1914 [M+H]+.
For GC data see experimental procedure.
ACHTUNGTRENNUNG(5R,7R)-7-Amino-5-hydroxyoct-2-en-1-yl methyl carbonate ((5R,7R)-24):
a
A solution of (5R,7R)-23 (E/Z=91:9) (631 mg, 1.988 mmol) in CH2Cl2
(4.0 mL) was treated with trifluoracetic acid (4.0 mL) at room tempera-
ture. After 1.5 h, the solution was cooled to 08C and saturated aqueous
NaHCO3 (ca. 200 mL) was added until gas evolution had ceased. Aque-
ous NaOH (2m) was added dropwise until pH 9–10 was reached. The
mixture was carefully extracted with CH2Cl2 (15ꢄ50 mL), and the com-
bined organic layers were dried over Na2SO4 and concentrated in vacuo
to give pure (NMR spectroscopy) (5R,7R)-24 (E/Z=91:9) (416 mg,
96%) as a colorless oil, which was directly used in the next step.
AHCTUNGTRENNUNG
CHTUNGTRENNUNG
CTHUNGTRENNUNG
by GC with respect to the ratio of diastereomers ((+)-25b:(À)-25a=
94:6). Purification by flash chromatography on silica gel (2 g, CH2Cl2/
MeOH 5:1 to 3:1) gave (+)-25b (113 mg, 74%) as a brownish solid. An
analytically pure sample was obtained by sublimation under reduced
pressure, which gave (+)-25b as a colorless solid (m.p. 38–408C). [a]D20
=
+69.2 (c=0.27 in acetone, >99% ee); 1H NMR (500 MHz, CDCl3): d=
5.97 (ddd, J=17.3, 10.8, 5.6 Hz, 1H; =CH), 5.13 (ddd, J=17.4, 1.4,
1.4 Hz, 1H; =CHEHZ), 5.12 (ddd, J=10.5, 1.4, 1.4 Hz, 1H; CH=CHEHZ),
3.84 (dddd, J=11.0, 11.0, 4.5, 4.5 Hz, 1H; CHOH), 3.80–3.76 (m, 1H; 6-
H), 3.01–2.94 (m, 1H; 2-H), 2.05–1.98 (m, 3H; 5-Ha, OH, NH), 1.95–1.91
(m, 1H; 3-Ha), 1.58 (ddd, J=12.4, 11.3, 5.5 Hz, 1H; 5-Hb), 1.10–1.02 (m,
1H; 3-Hb), 1.08 ppm (d, J=6.4 Hz, 3H; CH3); 13C NMR (125 MHz,
CDCl3): d=140.06 (d, =CH), 115.20 (t, =CH2), 65.52 (d, CHOH), 54.46
(d, C-6), 44.93 (d, C-2), 44.18 (t, C-3), 38.68 (t, C-5), 22.76 ppm (q, CH3);
HRMS (EI+): m/z: calcd for C8H15NO+: 141.1148; found: 141.1167
[M]+. For GC data see (À)-(2R,4S,6R)-25a.
(À)-(E,5R,7R)-7-Amino-5-hydroxyoct-2-en-1-yl methyl carbonate ((À)-
(E,5R,7R)-24) and (Z,5R,7R)-7-amino-5-hydroxyoct-2-en-1-yl methyl
carbonate ((Z,5R,7R)-24): Isomerically pure (À)-(E,5R,7R)-24 (15 mg,
71%) and isomerically enriched (Z,5R,7R)-24 (Z/E>90:10) (13 mg,
90%) were synthesized in analogy to (5R,7R)-24 from isomerically pure
starting material (+)-(E,5R,7R)-23 and isomerically enriched starting ma-
terial (+)-(Z,5R,7R)-23 (Z/E>90:10), respectively.
Analytical data for (À)-(E,5R,7R)-24: Rf(24)=0.4 (CH2Cl2/MeOH 4:1);
colorless oil; [a]2D0 =À2.5 (c=0.86 in CHCl3, >99% ee); 1H NMR
(300 MHz, CDCl3): d=5.86 (ddd, J=15.3, 7.1, 7.1 Hz, 1H; 3-H), 5.66
(ddd, J=15.4, 6.4, 6.4 Hz, 1H; 2-H), 4.58 (dd, J=6.5, 0.7 Hz, 2H;
CH2O), 4.02–3.95 (m, 1H; CHOH), 3.77 (s, 3H; CO2CH3), 3.45–3.31 (m,
1H; CHN), 2.73 (brs, 3H; NH2, OH), 2.29 (ddd, J=14.1, 7.0, 7.0 Hz,
1H; 4-Ha), 2.19 (ddd, J=13.9, 6.7, 6.7 Hz, 1H; 4-Hb), 1.54 (ddd, J=14.3,
8.4, 3.5 Hz, 1H; 6-Ha), 1.43 (ddd, J=14.4, 6.5, 3.2 Hz, 1H; 6-Hb),
1.16 ppm (d, J=6.6 Hz, 3H; CH3CH); 13C NMR (75 MHz, CDCl3): d=
(À)-Benzyl (2R,4S,6R)-4-Hydroxy-2-methyl-6-vinylpiperidine-1-carboxyl-
ate ((À)-(2R,4S,6R)-26a): Following GP3, a solution of (À)-(2R,4S,6R)-
25a (53.3 mg, 377 mmol) in CH2Cl2 (2 mL) was cooled to 08C with an ice
bath and treated with a solution of Na2CO3 (590 mg, 5.62 mmol) in H2O
(1.5 mL) and benzyl chloroformate (265 mL, 1.86 mmol). The ice bath
Chem. Eur. J. 2009, 15, 10514 – 10532
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
10527

G. Helmchen et al.
was removed and the heterogeneous mixture was vigorously stirred for
3 h when TLC (CH2Cl2/MeOH 4:1, fA(25a)=0.3, fA(26a)=0.77,
H), 1.80 (ddd, J=14.3, 4.1, 4.0 Hz, 1H; 3-Hb), 1.40–1.19 (m, 10H;
(CH2)5), 1.35 (d, J=7.2 Hz, 3H; CH3CH), 0.87 ppm (t, J=6.8 Hz, 3H;
CH3CH2); 13C NMR (75 MHz, CDCl3): d=170.34 (s, CH3CO2), 155.69 (s,
NCO2), 136.95 (s, Ph), 132.11, 131.95 (2d, CH=CH), 128.50, 127.96,
127.93 (3d, Ph), 67.40 (d, CHOAc), 67.13 (t, CH2Ph), 50.78 (d, C-6),
45.51 (d, C-2), 33.36 (t, C-3), 32.71, 32.36 (2t, C-5, CH2), 31.91, 29.22,
29.19, 29.18 (4t, CH2), 22.95 (q, CH3CH), 22.73 (t, CH2), 21.54 (q,
CH3CO2), 14.17 ppm (q, CH3CH2); elemental analysis calcd (%) for
C25H37NO4: C 72.26, H 8.97, N 3.37; found C 72.06, H 9.09, N 3.34;
HRMS (FAB+): m/z: calcd for C25H38NO4+: 416.2795; found: 416.2843
[M+H]+.
R
U
R CHTUNGTRENNUNG
KMnO4) showed complete conversion. The mixture was extracted with
CH2Cl2 (3ꢄ3 mL), and the combined extracts were dried over Na2SO4
and concentrated in vacuo. Purification by flash chromatography on silica
gel (3 g, petroleum ether/ethyl acetate 3:1 to 2:1) yielded pure (À)-26a
(95.7 mg, 92%) as
a
colorless oil. [a]D20 =À16.4 (c=0.73 in MeOH,
>99% ee); 1H NMR (300 MHz, CDCl3): d=7.39–7.28 (m, 5H; Ph), 6.16
(ddd, J=17.1, 10.4, 6.6 Hz, 1H; CH=CH2), 5.15 (ddd, J=17.0, 1.2,
1.2 Hz, 1H; CH=CHEHZ), 5.14 (s, 2H; CH2Ph), 5.07 (ddd, J=10.4, 1.3,
1.3 Hz, 1H; CH=CHEHZ), 4.85–4.78 (m, 1H; 6-H), 4.36 (ddq, J=7.1, 7.1,
4.2 Hz, 1H; 2-H), 4.09 (dddd, J=5.9, 5.9, 4.3, 4.3 Hz, 1H; 4-H), 2.13–1.95
(m, 2H; 3-Ha, 5-Ha), 1.88 (dddd, J=14.5, 5.5, 4.0, 1.1 Hz, 1H; 5-Hb), 1.84
(brs, 1H; OH), 1.67 (dddd, J=13.9, 6.1, 4.4, 1.1 Hz, 1H; 3-Hb), 1.38 ppm
(d, J=7.0 Hz, 3H; CH3); 13C NMR (75 MHz, CDCl3): d=155.92 (s,
CO2), 141.47 (d, =CH), 136.94 (s, Ph), 128.56, 128.02, 127.92 (3d, Ph),
115.11 (t, =CH2), 67.23 (t, CH2Ph), 65.10 (d, CHOH), 52.04 (d, C-6),
46.27 (d, C-2), 36.91 (t, C-3), 35.77 (t, C-5), 23.68 ppm (q, CH3); elemen-
(À)-(2R,4S,6S)-2-Methyl-6-nonylpiperidin-4-yl acetate ((À)-(2R,4S,6S)-
29a): In a Schlenk tube under hydrogen atmosphere (1 bar), a suspension
of rhodium (5 wt% (dry) on charcoal, wet, Degussa type G106B/W)
(7.0 mg) in dry methanol (500 mL) was stirred for 30 min. A solution of
(À)-28a (28.1 mg, 67.6 mmol) in dry methanol (1.5 mL) was added, and
the mixture was stirred at room temperature for 1.5 h when TLC control
(petroleum ether/ethyl acetate 3:1, RfACHTNUTRGENN(UG 28a)=0.41, RfAHCUTTGNREN(NGUN 29a)<0.1, KMnO4)
tal analysis calcd (%) for C16H21NO3: C 69.79, H 7.69, N 5.09; found C
showed complete conversion. The mixture was filtered through a pad of
Celite, and the filtrate was concentrated in vacuo. Flash chromatography
of the residue on silica gel (1 g, ethyl acetate) furnished analytically pure
(À)-(2R,4S,6S)-29a (17.6 mg, 92%) as a colorless oil. [a]2D0 =À6.7 (c=
0.81 in acetone, >99% ee); 1H NMR (500 MHz, CDCl3): d=4.74 (dddd,
J=11.3, 11.3, 4.7, 4.7 Hz, 1H; CHOAc), 2.72 (dqd, J=11.2, 6.2, 2.3 Hz,
1H; 2-H), 2.58 (dddd, J=11.1, 6.4, 6.4, 2.1 Hz, 1H; 6-H), 2.00 (s, 3H;
CH3CO2), 1.98–1.91 (m, 2H; 3-Ha, 5-Ha), 1.45 (brs, 1H; NH), 1.42–1.35
(m, 2H; 1’-H), 1.33–1.20 (m, 14H; (CH2)7), 1.12–1.02 (m, 2H; 3-Hb, 5-
Hb), 1.09 (d, J=6.4 Hz, 3H; CH3CH), 0.85 ppm (t, J=7.0 Hz, 3H;
CH3CH2); 13C NMR (126 MHz, CDCl3): d=170.72 (s, CO2), 71.93 (d,
CHOAc), 54.79 (d, C-6), 50.12 (d, C-2), 39.94 (t, C-3), 37.84 (t, C-5),
36.94 (t, C-1’), 31.99, 29.83, 29.65, 29.63, 29.41, 26.05, 22.78 (7t, (CH2)7),
22.53 (q, CH3CH), 21.48 (q, CH3CO2), 14.21 ppm (q, CH3CH2); elemen-
+
69.85,
276.1594; found: 276.1593 [M+H]+.
(À)-Benzyl (2R,4S,6R)-4-(acetyloxy)-2-methyl-6-vinylpiperidine-1-car-
H
7.64,
N
4.86; HRMS (EI+): m/z: calcd for C16H22NO3
:
boxylate ((À)-(2R,4S,6R)-27a):
A
solution of (À)-26a (106 mg,
385 mmol) in pyridine (700 mL) was treated with acetic anhydride
(300 mL, 3.17 mmol) at room temperature. After 1 h TLC (ethyl acetate,
RfACHTUNGTRENNUNG(26a)=0.33, RfACHTUNGTRENNUNG(27a)=0.57, KMnO4) still showed some starting materi-
al. More pyridine (100 mL) and acetic anhydride (100 mL, 1.06 mmol)
were added, and stirring was continued overnight. After 19 h conversion
was complete, and the mixture was cooled to 08C. Water (2 mL) and
ethyl acetate (5 mL) were added, the phases were separated, and the
aqueous layer was extracted with ethyl acetate (3ꢄ10 mL). The com-
bined organic layers were dried over Na2SO4, concentrated under re-
duced pressure, and the residue was subjected to flash chromatography
on silica gel (3 g, petroleum ether/ethyl acetate 4:1) to give (À)-27a
tal analysis calcd (%) for C17H33NO2: C 72.03, H 11.73, N 4.94; found C
+
71.80, H 11.69, N 4.68; HRMS (EI+): m/z: calcd for C17H33NO2
283.2511; found: 283.2531 [M]+.
:
(106 mg, 87%) as
a
colorless oil. [a]2D0 =À24.3 (c=0.87 in CHCl3,
>99% ee); 1H NMR (300 MHz, CDCl3): d=7.39–7.29 (m, 5H; Ph), 6.07
(ddd, J=17.1, 10.5, 6.6 Hz, 1H; CH=CH2), 5.17–5.04 (m, 3H; CHOAc,
CH=CH2), 5.15 (s, 2H; CH2Ph), 4.89–4.82 (m, 1H; 6-H), 4.42 (qdd, J=
7.1, 7.1, 3.3 Hz, 1H; 2-H), 2.07–2.02 (m, 2H; 5-H), 2.04 (s, 3H; CH3CO2),
1.97 (ddd, J=14.4, 7.3, 4.0 Hz, 1H; 3-Ha), 1.81 (dddd, J=14.4, 4.9, 3.5,
1.2 Hz, 1H; 3-Hb), 1.35 ppm (d, J=7.0 Hz, 3H; CH3CH); 13C NMR
(75 MHz, CDCl3): d=170.49 (s, CH3CO2), 155.83 (s, NCO2), 140.69 (d,
=CH), 136.89 (s, Ph), 128.61, 128.10, 128.03 (3d, Ph), 115.34 (t, =CH2),
67.34 (t, CH2Ph), 67.25 (d, CHOAc), 51.35 (d, C-6), 45.65 (d, C-2), 33.34
(t, C-3), 32.23 (t, C-5), 22.95 (q, CH3CH), 21.62 ppm (q, CH3CO2); ele-
(+)-(2R,4S,6S)-2-Methyl-6-nonylpiperidin-4-ol ((+)-241D; (+)-30a): A
solution of (À)-29a (16.0 mg, 56.5 mmol) in methanol (400 mL) was treat-
ed with methanolic NaOH (1m, 400 mL, 400 mmol) at room temperature
for 15 min until starting material was not detected by TLC control (ethyl
acetate/MeOH 5:1, RfACTHNUTRGNE(UNG 29a)=0.48, Rf((+)-241D)=0.10, KMnO4). Water
(1 mL) was added, and the mixture was repeatedly extracted with
CH2Cl2 (4ꢄ2 mL). The combined organic phases were washed with H2O
(1ꢄ1 mL) and dried over Na2SO4. Evaporation of the solvent gave virtu-
ally pure (+)-241D (13.4 mg, 98%) as a colorless solid. An analytically
pure sample was obtained after flash chromatography on silica gel
(100 mg, ethyl acetate to ethyl acetate/MeOH 5:1) as a colorless solid
(m.p. 106–1078C), the spectroscopic properties of which were in full ac-
cordance with the literature.[38–40] Recrystallization from ethyl acetate by
addition of petroleum ether at 08C furnished (+)-241D as colorless nee-
dles. M.p. 108–1098C (ref. [40a]: 108–1098C). [a]2D0 =+5.9 (c=0.65 in
mental analysis calcd (%) for C18H23NO4: C 68.12, H 7.30, N 4.41; found
+
C 68.02, H 7.35, N 4.48; HRMS (FAB+): m/z: calcd for C18H24NO4
:
318.1700; found: 318.1695 [M+H]+.
(À)-Benzyl (2R,4S,6R)-4-(acetyloxy)-2-methyl-6-[(E)-non-1’-en-1’-yl]pi-
peridine-1-carboxylate ((À)-(2R,4S,6R)-28a): According to GP4, a mix-
ture of (À)-(2R,4S,6R)-27a (61.4 mg, 194 mmol), 1-nonene (150 mL,
869 mmol) (500 mL) and Grubbs II catalyst (8.2 mg, 9.7 mmol) in dry
CH2Cl2 was heated at reflux. After 3 h TLC (petroleum ether/ethyl ace-
1
MeOH, >99% ee) (ref. [40d]: [a]2D0 =+6.5 (c=1.20 in MeOH)); H NMR
(500 MHz, CDCl3): d=3.66 (dddd, J=11.0, 11.0, 4.6, 4.6 Hz, 1H;
CHOH), 2.71 (dqd, J=11.1, 6.3, 2.3 Hz, 1H; 2-H), 2.56 (dddd, J=11.0,
6.4, 6.4, 2.2 Hz, 1H; 6-H), 2.01–1.93 (m, 4H; 3-Heq, 5-Heq, NH, OH),
1.49–1.37 (m, 2H; 1’-H), 1.36–1.21 (m, 14H; CH2(n-nonyl)), 1.14 (d, J=
6.4 Hz, 3H; CH3CH), 1.05 (ddd, J=11.6, 11.6, 11.6 Hz, 1H; 3-Hax), 1.00
(ddd, J=11.5, 11.5, 11.5 Hz, 1H; 5-Hax), 0.88 ppm (t, J=7.0 Hz, 3H;
CH3CH2); 13C NMR (125 MHz, CDCl3): d=69.43 (d, CHOH), 55.02 (d,
C-6), 50.36 (d, C-2), 43.86 (t, C-3), 41.63 (t, C-5), 36.73 (t, C-1’), 32.04,
29.87, 29.71, 29.69, 29.46, 26.15 (6t, CH2(n-nonyl)), 22.81 (t, CH2CH3), 22.41
(q, CH3CH), 14.26 ppm (q, CH3CH2); HRMS (FAB+): m/z: calcd for
C15H32NO+: 242.2478; found: 242.2453 [M+H]+.
tate 3:1, RfACHTUNGTRENNUNG(27a)=0.42, RfACHUTNTGREN(NUGN 28a)=0.53, MPA) indicated incomplete con-
version and 1-nonene (150 mL, 869 mmol) together with a second portion
of the catalyst (8.0 mg, 9.4 mmol) were added. After additional 2 h no fur-
ther conversion was detected, and the mixture was cooled to room tem-
perature and concentrated under reduced pressure. The residue was sub-
jected to flash chromatography on silica gel (12 g, petroleum ether/ethyl
acetate 9:1) and subsequent preparative HPLC (petroleum ether/ethyl
acetate 9:1, column: ProntoSIL, 250ꢄ20 mm, 5 m silica gel, 20 mLminÀ1
,
70 bar) to give pure (À)-28a (56.8 mg, 71%) as a colorless oil together
with some starting material (À)-27a (13.8 mg, 22%). [a]2D0 =À8.9 (c=1.06
1
(À)-Benzyl (2R,4S,6S)-4-Hydroxy-2-methyl-6-vinylpiperidine-1-carboxyl-
in CHCl3, >99% ee); H NMR (300 MHz, CDCl3): d=7.35–7.28 (m, 5H;
ate ((À)-(2R,4S,6S)-26b): According to GP3,
a solution of (+)-25b
Ph), 5.68 (dddd, J=15.4, 7.0, 1.1, 1.1 Hz, 1H; 1’-H), 5.52 (dddd, J=15.4,
6.6, 6.6, 1.0 Hz, 1H; C-2’), 5.17 (d, J=12.4 Hz, 1H; CHaHbPh), 5.11 (d,
J=12.4 Hz, 1H; CHaHbPh), 5.05 (dddd, J=4.5, 4.5, 4.5, 4.5 Hz, 1H;
CHOAc), 4.81 (ddd, J=6.0, 5.9, 4.8 Hz, 1H; 6-H), 4.40 (qdd, J=7.1, 7.1,
3.3 Hz, 1H; 2-H), 2.05 (s, 3H; CH3CO2), 2.01–1.91 (m, 5H; 3-Ha, 5-H, 3’-
(16.6 mg, 118 mmol) in CH2Cl2 (1.0 mL) was cooled to 08C and treated
with a solution of Na2CO3 (187 mg, 1.76 mmol) in H2O (1.0 mL) and
benzyl chloroformate (84 mL, 0.59 mmol). The cooling bath was removed,
and the mixture was vigorously stirred for 4.5 h when TLC control
10528
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ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 10514 – 10532

Iridium-Catalyzed Allylic Cyclization
FULL PAPER
(CH2Cl2/MeOH 4:1, R
(25b)=0.3, R
E
H 8.97, N 3.37; found C 72.15, H 8.96, N 3.42; HRMS (EI+): m/z: calcd
for C25H37NO4+: 415.2717; found: 415.2719 [M]+.
plete conversion. The mixture was extracted with CH2Cl2 (3ꢄ3 mL), and
the combined extracts were dried over Na2SO4 and concentrated in
vacuo. The residue was subjected to flash chromatography on silica gel
(1 g, petroleum ether/ethyl acetate 2:1) to give (À)-26b (30.6 mg, 94%)
as a colorless oil. [a]2D0 =À9.6 (c=0.74 in MeOH, >99% ee); 1H NMR
(300 MHz, CDCl3): d=7.37–7.27 (m, 5H; Ph), 5.79 (ddd, J=17.2, 10.6,
4.2 Hz, 1H; CH=CH2), 5.17–5.02 (m, 4H; CH=CH2, CH2Ph), 4.75–4.70
(m, 1H; 6-H), 4.08 (dddd, J=9.8, 6.6, 6.6, 3.5 Hz, 1H; CHOH), 3.98
(qdd, J=6.7, 5.0, 5.0 Hz, 1H; 2-H), 2.28 (ddd, J=13.8, 7.2, 3.0 Hz, 1H; 5-
Ha), 2.15 (ddd, J=14.6, 6.1, 4.9 Hz, 1H; 3-Ha), 2.06 (brs, 1H; OH), 1.90
(ddd, J=13.8, 9.6, 5.4 Hz, 1H; 5-Hb), 1.56 (ddd, J=14.6, 4.9, 3.9 Hz, 1H;
3-Hb), 1.44 ppm (d, J=6.8 Hz, 3H; CH3); 13C NMR (300 MHz, CDCl3):
d=155.96 (s, CO2), 138.60 (d, =CH), 136.89 (s, Ph), 128.52, 127.99, 127.93
(3 d, Ph), 114.81 (t, =CH2), 67.01 (t, CH2Ph), 63.20 (d, CHOH), 53.18 (d,
C-6), 47.65 (d, C-2), 38.22 (t, C-3), 35.62 (t, C-5), 22.44 ppm (q, CH3); ele-
(+)-(2R,4S,6R)-2-Methyl-6-nonylpiperidin-4-yl acetate ((+)-(2R,4S,6R)-
29b): According to GP5, a suspension of palladium hydroxide (4.5 mg) in
dry methanol (500 mL) was stirred for 30 min under an atmosphere of hy-
drogen (1 bar). A solution of (À)-28b (13.2 mg, 31.8 mmol) in dry metha-
nol (1.2 mL) was added, and the mixture was stirred for 50 min when
conversion was complete according to TLC (petroleum ether/ethyl ace-
tate 3:1, RfACTHNUGTRENN(UG 28b)=0.57, RfAHCTUTGNREN(NUNG 29b)<0.1, KMnO4). The mixture was filtered
through a pad of Celite, concentrated under reduced pressure, and the
residue was subjected to flash chromatography on silica gel (1 g, ethyl
acetate to ethyl acetate/MeOH 10:1), which furnished (+)-29b (8.5 mg,
94%) as a colorless oil. [a]D20 =+21.0 (c=0.38 in CHCl3, >99% ee);
1H NMR (500 MHz, CDCl3): d=4.98 (dddd, J=10.4, 10.4, 4.5, 4.5 Hz,
1H; CHOAc), 3.15–3.11 (m, 1H; 6-H), 3.04–2.98 (m, 1H; 2-H), 2.02 (s,
3H; CH3CO2), 1.97 (d, J=12.6 Hz, 1H; 3-Ha), 1.81 (d, J=12.6 Hz, 1H;
5-Ha), 1.63 (ddd, J=12.3, 11.0, 5.1 Hz, 1H; 5-Hb), 1.62–1.54 (m, 1H;
CHaHb), 1.49–1.40 (m, 1H; CHaHb), 1.34–1.22 (m, 15H; (CH2)7, NH),
1.17 (ddd, J=11.4, 10.9, 10.9 Hz, 1H; 3-Hb), 1.10 (d, J=6.4 Hz, 3H;
CH3CH), 0.87 ppm (t, J=7.0 Hz, 3H; CH3CH2); 13C NMR (126 MHz,
CDCl3): d=170.74 (s, CO2), 68.88 (d, CHOAc), 51.87 (d, C-6), 44.22 (d,
C-2), 39.69 (t, C-3), 34.80 (t, C-5), 32.50, 32.02, 29.74, 29.72, 29.70, 29.44,
26.99, 22.81 (8t, (CH2)8), 22.58 (q, CH3CH), 21.57 (q, CH3CO2),
14.24 ppm (q, CH3CH2); elemental analysis calcd (%) for C17H33NO2: C
72.03, H 11.73, N 4.94; found C 71.74, H 11.73, N 4.86; HRMS (ESI+):
m/z: calcd for C17H34NO2+: 284.2584; found: 284.2589 [M+H]+.
mental analysis calcd (%) for C16H21NO3: C 69.79, H 7.69, N 5.09; found
C 69.50, H 7.79, N 4.92; HRMS (EI+): m/z: calcd for C16H21NO3
275.1516; found: 275.1521 [M]+.
(+)-Benzyl (2R,4S,6S)-4-(acetyloxy)-2-methyl-6-vinylpiperidine-1-carbox-
ylate ((+)-(2R,4S,6S)-27b): This compound was prepared from (À)-
(2R,4S,6S)-26b analogously to (À)-(2R,4S,6R)-27a (30.6 mg, 111 mmol)
using pyridine (500 mL) and acetic anhydride (200 mL, 2.11 mmol). After
16 h workup and purification by flash chromatography on silica gel (2 g,
petroleum ether/ethyl acetate 4:1) furnished (+)-27b (34.4 mg, 97%) as
a colorless oil. RfACHTUNGTRENNUNG =
(27b)=0.61 (petroleum ether/ethyl acetate 1:1); [a]D20
+2.7 (c=1.00 in MeOH, >99% ee); 1H NMR (300 MHz, CDCl3): d=
7.35–7.27 (m, 5H; Ph), 5.82 (ddd, J=17.2, 10.6, 4.1 Hz, 1H; CH=CH2),
5.18–5.02 (m, 5H; CH=CH2, CH2Ph, CHOAc), 4.71 (ddd, J=8.9, 5.3,
2.1 Hz, 1H; 6-H), 4.07 (qdd, J=6.6, 4.6, 4.6 Hz, 1H; 2-H), 2.40 (ddd, J=
14.0, 7.8, 3.0 Hz, 1H; 5-Ha), 2.25 (ddd, J=15.2, 6.7, 5.2 Hz, 1H; 3-Ha),
2.03 (s, 3H; CH3CO2), 1.98 (ddd, J=14.2, 9.2, 5.2 Hz, 1H; 5-Hb), 1.65
(ddd, J=15.3, 3.9, 2.9 Hz, 1H; 3-Hb), 1.39 ppm (d, J=6.9 Hz, 3H;
CH3CH); 13C NMR (75 MHz, CDCl3): d=170.58 (s, CH3CO2), 155.71 (s,
NCO2), 138.38 (d, =CH), 136.88 (s, Ph), 128.54, 128.03, 127.99 (3d, Ph),
115.09 (t, =CH2), 67.06 (t, CH2Ph), 66.07 (d, CHOAc), 52.36 (d, C-6),
47.06 (d, C-2), 34.08 (t, C-3), 32.04 (t, C-5), 22.16 (q, CH3CH), 21.44 ppm
(q, CH3CO2); elemental analysis calcd (%) for C18H23NO4: C 68.12, H
7.30, N 4.41; found C 68.02, H 7.48, N 4.45; HRMS (EI+): m/z: calcd for
C18H23NO4+: 317.1622; found: 317.1646 [M]+.
(+)-(2R,4S,6R)-2-Methyl-6-nonylpiperidin-4-ol ((+)-6-epi-241D; (+)-
30b): A solution of (+)-(2R,4S,6R)-29b (6.5 mg, 23 mmol) in methanol
(1 mL) was treated with methanolic NaOH (1m, 1 mL, 1 mmol) at room
temperature for 15 min when no starting material was detected by TLC
(ethyl acetate/MeOH 5:1, RfACTHNUGTRENN(UG 29b)=0.38, RfCAHTUNGTREN(NUGN 30b)<0.1, KMnO4). Aque-
ous NH4Cl (1 mL) and H2O (1 mL) were added, and the mixture was ex-
tracted with ethyl acetate (4ꢄ3 mL). The combined organic layers were
dried over Na2SO4 and concentrated under reduced pressure. Purification
of the residue by flash chromatography on silica gel (600 mg, ethyl ace-
tate to ethyl acetate/MeOH 5:1) gave (+)-6-epi-241D (5.2 mg, 95%) as
colorless needles (m.p. 88.5–89.58C), suitable for X-ray crystal structural
analysis, which confirmed the relative configuration of the compound.
[a]2D0 =+10.0 (c=0.57 in MeOH, >99% ee); 1H NMR (600 MHz,
CDCl3): d=3.87 (dddd, J=10.7, 10.7, 4.5, 4.5 Hz, 1H; CHOH), 3.13–3.10
(m, 1H; 6-H), 2.94–2.88 (m, 1H; 2-H), 1.97–1.93 (m, 1H; 3-Ha), 1.88–
1.84 (m, 1H; 5-Ha), 1.82 (brs, 2H; NH, OH), 1.55–1.45 (m, 1H; 1’-Ha),
1.48 (ddd, J=11.9, 11.6, 5.2 Hz, 1H; 5-Hb), 1.44–1.38 (m, 1H; 1’-Hb),
1.30–1.22 (m, 14H; CH2(n-nonyl)), 1.08 (d, J=6.3 Hz, 3H; CH3CH), 1.03
(ddd, J=11.4, 11.4, 11.4 Hz, 1H; 3-Hb), 0.87 ppm (t, J=7.0 Hz, 3H;
CH3CH2); 13C NMR (150 MHz, CDCl3): d=65.71 (d, CHOH), 52.50 (d,
C-6), 44.27 (d, C-2), 44.16 (t, C-3), 38.65 (t, C-5), 32.44 (t, C-1’), 32.02,
29.76, 29.76, 29.71, 29.45, 27.16 (6t, CH2(n-nonyl)), 22.91 (t, CH2CH3), 22.81
(q, CH3CH), 14.25 ppm (q, CH3CH2); HRMS (ESI+): m/z: calcd for
C15H32NO+: 242.2478; found: 242.2483 [M+H]+.
(À)-Benzyl (2R,4S,6S)-4-(acetyloxy)-2-methyl-6-[(E)-non-1’-en-1’-yl]pi-
peridine-1-carboxylate ((À)-(2R,4S,6S)-28b): According to GP4, a solu-
tion of (+)-27b (15.0 mg, 47.3 mmol), 1-nonene (80 mL, 0.51 mmol) and
Grubbs II catalyst (4.0 mg, 4.7 mmol) in dry CH2Cl2 was heated at reflux
for 8 h when no further conversion was detected by TLC (petroleum
ether/ethyl acetate 3:1, RfACTHNUTRGNNEG(U 27b)=0.46, RfACHUTNGTREN(NNGU 28b)=0.62, MPA). The mix-
ture was concentrated under reduced pressure, and the residue was sub-
jected to flash chromatography on silica gel (2 g, petroleum ether/ethyl
acetate 9:1) to give (À)-28b (9.0 mg, 46%) as a colorless oil Additionally
some starting material (+)-27b (8.0 mg, 53%) was recovered. An analyti-
cally pure sample was obtained by preparative HPLC (petroleum ether/
ethyl acetate 9:1, column: ProntoSIL, 250ꢄ20 mm, 5 m silica gel,
(+)-Benzyl
(2R,4S,6R)-4-(acetyloxy)-2-formyl-6-methyliperidine-1-car-
boxylate ((+)-(2R,4S,6R)-31): A solution of (À)-27a (106 mg, 333 mmol)
in CH2Cl2/MeOH (4:1, 2.5 mL) was treated with a small amount of
Sudanꢅ III red as indicator, and the resulting red mixture was cooled to
À788C. Ozone was bubbled through for 3 min when the red color disap-
peared. Dimethylsulfide (ca. 200 mL, ca. 2.7 mmol) was added and stirring
was continued for 10 min at À788C. Then the mixture was allowed to
warm to room temperature and stirring was continued for 1 h. Volatiles
were removed under reduced pressure, and the crude product was sub-
jected to flash chromatography on silica gel (5 g, petroleum ether/ethyl
20 mLminÀ1
,
60 bar). [a]2D0 =À7.1 (c=0.75 in CHCl3, >99% ee);
1H NMR (300 MHz, CDCl3): d=7.35–7.28 (m, 5H; Ph), 5.48 (dddd, J=
15.3, 6.3, 6.3, 1.1 Hz, 1H; 2’-H), 5.38 (dd, J=15.4, 4.1 Hz, 1H; 1’-H), 5.17
(d, J=12.3 Hz, 1H; CHaHbPh), 5.12–5.04 (m, CHOAc), 5.10 (d, J=
12.5 Hz, 1H; CHaHbPh), 4.67 (brs, 1H; C-6), 4.04 (qdd, J=6.6, 4.6,
4.6 Hz, 1H; 2-H), 2.35 (ddd, J=13.8, 7.8, 2.9 Hz, 1H; 5-Ha), 2.26 (ddd,
J=15.2, 6.5, 5.0 Hz, 1H; 3-Ha), 2.03 (s, 3H; CH3CO2), 2.02–1.90 (m, 3H;
5-Hb, 3’-H), 1.64 (ddd, J=15.2, 3.9, 3.0 Hz, 1H; 3-Hb), 1.38 (d, J=6.9 Hz,
3H; CH3CH), 1.35–1.20 (m, 10H; (CH2)5), 0.88 ppm (t, J=6.7 Hz, 3H;
CH3CH2); 13C NMR (75 MHz, CDCl3): d=170.64 (s, CH3CO2), 155.72 (s,
NCO2), 137.00 (s, Ph), 131.67 (d, C-2’), 129.65 (d, C-1’), 128.53, 127.98,
127.98 (3d, Ph), 66.95 (t, CH2Ph), 66.31 (d, CHOAc), 51.85 (d, C-6),
46.97 (d, C-2), 34.24 (t, C-3), 32.58 (t, C-5), 32.32 (t, C-3’), 31.91, 29.28,
29.28, 29.23, 22.77 (5t, (CH2)5), 22.17 (q, CH3CH), 21.48 (q, CH3CO2),
14.21 ppm (q, CH3CH2); two signals coincide at 127.98 ppm (d, Ph) and
29.28 ppm (t, CH2); elemental analysis calcd (%) for C25H37NO4: C 72.26,
acetate 4:1 to 3:1, RfACTHNUTRGENUNG(27a)=0.62, Rf(31)=0.52 (petroleum ether/ethyl
acetate 1:1), KMnO4), which gave aldehyde (+)-(2R,4S,6R)-31 (99 mg,
93%) as a colorless oil. [a]2D0 =+2.9 (c=1.03 in CHCl3, >99% ee);
1H NMR (500 MHz, CDCl3): d=9.67 (s, 1H; CHO), 7.37–7.30 (m, 5H;
Ph), 5.20 (d, J=12.3 Hz, 1H; CHaHbPh), 5.17 (d, J=12.3 Hz, CHaHbPh),
5.07 (dddd, J=3.4, 3.4, 3.4, 3.4 Hz, 1H; CHOAc), 4.70 (d, J=7.2 Hz, 1H;
2-H), 4.46 (qdd, J=7.0, 7.0, 1.6 Hz, 1H; 6-H), 2.61 (d, J=14.7 Hz, 1H; 3-
Ha), 1.96 (s, 3H; CH3CO2), 1.89–1.84 (m, 2H; 3-Hb, 5-Ha), 1.79 (d, J=
Chem. Eur. J. 2009, 15, 10514 – 10532
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
10529

G. Helmchen et al.
14.7 Hz, 1H; 5-Hb), 1.29 ppm (d, J=7.1 Hz, 3H; CH3CH); 13C NMR
(126 MHz, CDCl3): d=201.28 (d, CHO), 169.98 (s, CH3CO2), 156.01 (s,
NCO2), 136.29 (s, Ph), 128.63, 128.27, 128.05 (3d, Ph), 67.79 (t, CH2Ph),
65.90 (d, CHOAc), 57.37 (d, C-2), 45.39 (d, C-6), 32.52 (t, C-5), 27.41 (t,
C-3), 21.71 (q, CH3CH), 21.29 ppm (q, CH3CO2); HRMS (ESI+): m/z:
calcd for C17H22NO5+: 320.1493; found: 320.1498 [M+H]+.
concentrated in vacuo to give pure (NMR spectroscopy) (+)-34 (10.0 mg,
85%) as a colorless solid. An analytically pure sample was obtained after
purification by flash chromatography on silica gel (ethyl acetate to ethyl
acetate/MeOH 10:1) as colorless polyhedra (m.p. 94–958C; ref. [47]: 88–
898C ((Æ)-34, (ethyl acetate))), suitable for X-ray crystal structural anal-
ysis. [a]2D0 =+8.8 (c=0.43 in MeOH, >99% ee); 1H NMR (500 MHz,
CDCl3): d=3.63 (dddd, J=11.0, 11.0, 4.6, 4.6 Hz, 1H; CHOH), 2.68
(dqd, J=11.0, 6.3, 2.3 Hz, 1H; 2-H), 2.58–2.53 (m, 1H; 6-H), 1.98–1.90
(m, 2H; 3-Ha, 5-Ha), 1.85 (brs, 2H; NH, OH), 1.43–1.30 (m, 4H;
CH2CH2), 1.11 (d, J=6.3 Hz, 3H; CH3CH), 1.05–0.93 (m, 2H; 3-Hb, 5-
Hb), 0.90 ppm (t, J=7.1 Hz, 3H; CH3CH2); 13C NMR (75 MHz, CDCl3):
d=69.34 (d, CHOH), 54.66 (d, C-6), 50.28 (d, C-2), 44.00 (t, C-3), 41.78
(t, C-5), 39.06 (t, CH2CH2CH3), 22.55 (q, CH3CH), 19.29 (t, CH2CH3),
14.28 ppm (CH3CH2); HRMS (ESI+): m/z: calcd for C9H20NO+:
158.1539; found: 158.1539 [M+H]+.
Benzyl (2R,4S,6R)-4-(acetyloxy)-2-methyl-6-(prop-1’-en-1’-yl)piperidine-
1-carboxylate ((2R,4S,6R)-32): A solution of potassium hexamethyldisila-
zane (KHMDS; 0.5m in toluene, 830 mL, 415 mmol) was added dropwise
at 08C to a suspension of ethyltriphenylphosphonium bromide (149 mg,
401 mmol) in dry THF (1.5 mL) to give an initially yellow solution, which
was stirred at 08C for 30 min when the color changed to red. A solution
of the aldehyde (+)-31 (44.6 mg, 140 mmol) in dry THF (2.0 mL) was
added dropwise, and stirring was continued for 1.5 h at 08C until TLC
(petroleum ether/ethyl acetate 3:1, Rf(31)=0.15, Rf(32)=0.30, MPA)
showed complete conversion. Brine (2 mL) was added, and the mixture
was extracted with ethyl acetate (4ꢄ5 mL). The combined organic layers
were dried over Na2SO4 and concentrated in vacuo. The residue was sub-
jected to flash chromatography on silica gel (4 g, petroleum ether/ethyl
acetate 4:1) to give (2R,4S,6R)-32 (37.6 mg, 81%) as a 87:13 mixture of
Z and E isomers (1H NMR spectroscopy), which could not be separated;
colorless oil. Analytical data refers to this mixture: 1H NMR (E isomer,
500 MHz, CDCl3): d=7.36–7.28 (m, 5H; Ph), 5.75 (ddq, J=10.9, 9.3,
1.7 Hz, 1H; CH=CHCH3), 5.43 (dqd, J=10.8, 6.9, 1.2 Hz, 1H; =CHCH3),
5.18–5.10 (m, 3H; 6-H, CH2Ph), 5.06 (dddd, J=4.7, 4.7, 4.4, 4.2 Hz, 1H;
CHOAc), 4.42 (qdd, J=7.1, 7.1, 3.2 Hz, 1H; 2-H), 2.04 (s, 3H; CH3CO2),
2.03–1.97 (m, 2H; CH2), 1.91–1.85 (m, 1H; CH2), 1.84–1.77 (m, 1H;
CH2), 1.59 (dd, J=7.0, 1.6 Hz, 3H; =CHCH3), 1.39 ppm (d, J=7.0 Hz,
3H; CH3CHN); 13C NMR (126 MHz, CDCl3): d=170.43 (s, CH3CO2),
155.63 (s, NCO2), 136.87 (s, Ph), 133.00 (d, CH=CHCH3), 128.52, 128.02,
128.01 (3 d, Ph), 124.75 (d, =CHCH3), 67.27 (d, CHOAc), 67.25 (t,
CH2Ph), 46.55 (d, C-6), 45.47 (d, C-2), 33.33, 33.33 (2 t, CH2), 23.06 (q,
CH3CHN), 21.58 (q, CH3CO2), 12.60 ppm (q, CH3CH=CH); two signals
(t, CH2) coincide at 33.33 ppm; elemental analysis calcd (%) for
C19H25NO4: C 68.86, H 7.60, N 4.23; found C 68.69, H 7.69, N 4.27;
HRMS (FAB+): m/z: calcd for C19H26NO4+: 332.1856; found: 332.1884
[M+H]+.
Acknowledgements
This work was supported by the Studienstiftung des deutschen Volkes.
We thank Prof. Frank R. Stermitz (Colorado State University) for send-
ing us a sample of racemic 34, Dr. Frank Rominger (Universitꢀt Heidel-
berg) for the crystal structural analyses, and Prof. Dr. K. Ditrich (BASF
AG) for enantiomerically pure 1-arylethylamines.
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(À)-(2R,4S,6S)-2-Methyl-6-propylpiperidin-4-yl acetate ((À)-(2R,4S,6S)-
33): Following GP5, a suspension of palladium hydroxide (6.8 mg) in dry
methanol (0.5 mL) was stirred for 30 min under an atmosphere of hydro-
gen (1 bar). A solution of (2R,4S,6R)-32 (21.0 mg, 63.4 mmol) in dry
methanol (1.2 mL) was added, and the mixture was stirred for 1 h when
TLC control (petroleum ether/ethyl acetate 3:1, Rf(32)=0.40, Rf(33)<
0.1, KMnO4) showed complete conversion. The mixture was filtered
through a pad of silica gel and concentrated under reduced pressure to
give (À)-(2R,4S,6S)-33 (11.0 mg, 87%) as a colorless oil. An analytically
pure sample was obtained by flash chromatography on silica gel (1 g,
ethyl acetate). [a]2D0 =À3.0 (c=0.75 in CHCl3, >99% ee); 1H NMR
(300 MHz, CDCl3): d=4.76 (dddd, J=11.3, 11.3, 4.7, 4.7 Hz, 1H;
CHOAc), 2.75 (dqd, J=11.1, 6.2, 2.0 Hz, 1H; 2-H), 2.67–2.58 (m, 1H; 6-
H), 2.03 (s, 3H; CH3CO2), 2.01–1.91 (m, 2H; 3-Ha, 5-Ha), 1.45–1.30 (m,
5H; CH2CH2, NH), 1.16–1.01 (m, 2H; 3-Hb, 5-Hb), 1.11 (d, J=6.4 Hz,
3H; CH3CH), 0.91 ppm (t, J=6.9 Hz, 3H; CH3CH2); 13C NMR (75 MHz,
CDCl3): d=170.66 (s, CO2), 71.58 (d, CHOAc), 54.59 (d, C-6), 50.28 (d,
C-2), 39.59 (t, C-3), 38.69 (t, CH2), 37.40 (t, C-5), 22.19 (q, CH3CH),
21.43 (q, CH3CO2), 19.15 (t, CH2), 14.19 ppm (q, CH3CH2); HRMS
(EI+): m/z: calcd for C11H21NO2+: 199.1572; found: 199.1615 [M]+; GC
(chiral: b-CD, 1458C isothermal): tR((À)-(2R,4S,6S)-33)=50.5 min,
tR((+)-(2S,4R,6R)-33)=56.4 min.
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Received: June 17, 2009
Published online: September 3, 2009
10532
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Chem. Eur. J. 2009, 15, 10514 – 10532