Asymmetric synthesis of 8-aminoindolizidine from chiral 2-pyrroleimines

Article abstract of DOI:10.1021/jo8014598

(Chemical Equation Presented) 1-Allyl-2-pyrroleimines obtained from (S)-valinol and (S)-phenylglycinol underwent highly diastereoselective addition of allylmagnesium chloride, used in excess amounts, to give the corresponding secondary amines with concomitant allyl to (Z)-1-propenyl isomerization of the 1-pyrrole substituent. Transformation of the 2-amino alcohol moiety to an oxazolidinone, or its cleavage and subsequent N-protection, followed by ring-closing metathesis of the two alkene groups gave the unsaturated bicyclic compound. Full hydrogenation of the alkene function and the aromatic rings afforded the indolizidine derivative as a mixture of two or three diastereomers with a ratio which was dependent on the nature of both the N-substituent and the catalyst. The two prevalent diastereomers were isolated, and their configuration was determined by X-ray crystallographic analysis.

Full text of DOI:10.1021/jo8014598

Asymmetric Synthesis of 8-Aminoindolizidine from Chiral
2-Pyrroleimines
Vincenzo Giulio Albano, Andrea Gualandi, Magda Monari, and Diego Savoia*
Dipartimento di Chimica “G. Ciamician”, UniVersita` di Bologna, Via Selmi 2, 40126 Bologna, Italy
diego.saVoia@unibo.it
ReceiVed July 4, 2008
1-Allyl-2-pyrroleimines obtained from (S)-valinol and (S)-phenylglycinol underwent highly diastereo-
selective addition of allylmagnesium chloride, used in excess amounts, to give the corresponding secondary
amines with concomitant allyl to (Z)-1-propenyl isomerization of the 1-pyrrole substituent. Transformation
of the 2-amino alcohol moiety to an oxazolidinone, or its cleavage and subsequent N-protection, followed
by ring-closing metathesis of the two alkene groups gave the unsaturated bicyclic compound. Full
hydrogenation of the alkene function and the aromatic rings afforded the indolizidine derivative as a
mixture of two or three diastereomers with a ratio which was dependent on the nature of both the
N-substituent and the catalyst. The two prevalent diastereomers were isolated, and their configuration
was determined by X-ray crystallographic analysis.
SCHEME 1
Introduction
7-Aminopyrrolizidine 1a1 and 8-aminoindolizidine 1b1 are
relatively unexplored compounds, despite the presence in nature
of these motifs and the potential activity of these compounds
and their substituted derivatives as glycosidase inhibitors and
anti-HIV drugs. 8-Aminoindolizidine 1b has been already
prepared from L-proline 3 by a sequence of steps involving the
reductive amination of indolizidin-8-one 2b (Scheme 1). This
was described in a communication2 where the experimental part
was absent and the stereochemistry of both the starting material
and the final product was not detailed, so we assume that the
compound was obtained as a mixture of diastereomers in
racemic form. This seems likely in view of the fact that the
corresponding pyrrolizidin-7-one 2a, obtained from L-proline,
was unstable and was converted to a mixture of optically inactive
diastereomers 1b by reductive amination.3 Derivatives of
8-aminoindolizidin-3-one 2b were regarded as constrained
analogues of bioactive peptides and substitutes of ꢀ-turns, so
they were also prepared from L-ornithine by a synthetic sequence
involving an intramolecular reductive amination step which,
however, occurred with >28% racemisation of the pre-existing
stereocenter.4 7-Alkyl-8-aminoindolizidines have been synthe-
sized by intramolecular imino-ene reactions of L-1-(3-alkene-
1-yl)prolinal imines, so forming the fused six-membered ring.5
* Corresponding author. Fax: +39-051-2099456.
8376 J. Org. Chem. 2008, 73, 8376–8381
10.1021/jo8014598 CCC: $40.75 2008 American Chemical Society
Published on Web 10/01/2008

Asymmetric Synthesis of 8-Aminoindolizidine
TABLE 1. Addition of Allylmagnesium Chloride to the Imines
8a,ba
SCHEME 2
allylMgCl
(equiv)
yield (%) yield (%)
entry imine
time (h) ratio 9/10 of 9 + 10b
of 10c
1
2
3
4
8a
8a
8a
8b
2.5
3
4
48
24
24
24
47:53
24:76
0:100
0:100
98
97
98
98
66
92
96
4
a The Grignard reagent was added to the imine (5.9 mmol) dissolved
in THF (25 mL) at 0 °C, and the temperature was allowed to reach 20
°C during 24 h. b Yield of crude product. c Yield of isolated, pure
product.
reagent (2.2 equiv), a 73:27 mixture of two isomeric amines
were obtained, as evidenced by 1H NMR analysis of the crude
product. The major isomer was identified as the expected
product 9a on the basis of the 1H NMR spectrum, whereas the
minor one 10a was supposed to have an isomerized propenyl
substituent on the pyrrole nitrogen. The base-promoted isomer-
ization was attributed to the action of the Grignard reagent in
excess amount, hence the reaction was carried out with increased
amounts of allylmagnesium chloride in order to optimize the
yield of compound 10a, since it has the required 1,7-octadiene
moiety for the construction of a six-membered cycle by the
RCM methodology. The results of these studies are reported in
Table 1.
The results obtained showed that, by increasing the amount
of the Grignard reagent, a corresponding increased conversion
of 9a to 10a occurred (entries 2 and 3) and the complete
conversion was achieved using four equivalents of allylmag-
nesium chloride (entry 4). The 1H NMR spectrum of the crude
product, obtained in 98% yield, showed the presence of a single
diastereomer, concerning either the newly formed stereocenter
and the double bond geometry, which was determined to be Z
on the basis of the coupling constant of the vinylic protons. On
the other hand, GC-MS and HPLC-MS analyses could not
used to determine the purity and diastereomeric ratio, as the
product was not eluted or underwent massive decomposition.
The pure product 10a was then obtained with 92% yield by
chromatography on a SiO2 column. However, we found that
the crude compound could be used without purification in the
following step. Under the same conditions, the imine 8b was
converted to the homoallylic amine 10b with complete selectiv-
ity and excellent yield.
Before performing the RCM step, it was necessary to protect
the amino functionality. As acidic conditions are not suitable
owing to the presence of the pyrrole ring, we chose to convert
the ꢀ-amino alcohol moiety of 10a into the oxazolidinone 11a
by routine reaction with triphosgene (Scheme 3). The RCM step
was investigated on this compound, exploring the effectiveness
of both first-generation and second-generation Grubbs catalysts
(ruthenium benzylidene complexes I and II, respectively).
The results obtained, reported in Table 2, showed that both
catalysts can be used for that purpose, although II was more
effective and allowed to obtain a complete reaction in less time
with respect to I in the same experimental conditions (entries 1
and 2). Moreover, high yields of compound 12a were obtained
using catalyst II in toluene at 111 °C for 0.5 h with 5 mol %
loading (entry 3) and in dichloromethane at 40 °C for 1.5 h
with 2.5 mol % loading (entry 4). Finally, by working with 1
mol % loading of catalyst II, a high yield of the product 12a
was obtained in dichloromethane at the reflux temperature for
4 h (entry 5). Under the same conditions, the diene 11b in turn
Pyrroles have been used as building blocks for the stereose-
lective synthesis of indolizidines, as the heteroaromatic ring can
be hydrogenated to pyrrolidine and the six membered ring was
formed by diverse cyclization strategies.6 Here, we report the
synthesis of 8-aminoindolizidine 1b by this general strategy,
starting from the pyrroleimine 6 and constructing the six-
membered ring by the ring-closing metathesis (RCM) reaction
of the crucial intermediate diene 5, so affording the unsaturated
bicyclic compound 4. The two unsaturated alkyl substituents
in the intermediate 5 can be introduced exploiting either the
nucleophilic property of the pyrrolide anion and the electrophilic
reactivity of the chiral imine 6. The asymmetric formation of
the benzylic stereocenter in 4 is achieved exploiting the
asymmetric induction of a chiral auxiliary (imine N-substituent)
in 6, whereas in the final hydrogenation step a novel stereocenter
is formed at the ring junction carbon.7
It should be observed that by this route any of the four
possible stereoisomers of compounds 1 can be prepared by the
proper choice of the chiral auxiliary and the other structural
variances, i.e., the nature of the amino substituent or protective
group, and the size of the newly formed ring. As a matter of
fact, rings with different sizes can be obtained in the RCM step,
depending on the values of “n” and “m” of the unsaturated
substituents in the intermediate 5. Particularly, a five membered
ring is formed by RCM when n ) m ) 0, thus leading ultimately
to pyrrolizidines 1a, whereas to prepare indolizidines one has
to build a six-membered ring in intermediate 2 by choosing n
) 1, m ) 0, or vice versa. All the routes appear viable at a first
glance, as we have previously described the highly diastereo-
selective addition of various organometallic reagents to chiral
2-pyrrole imines derived from (S)-valinol and (S)-phenylglyci-
nol, having either unprotected or trimethylsilyl-protected OH
and NH functions.8
Results and Discussion
We started the investigation by routinely preparing in high
yields the 1-allyl-2-pyrroleimines 8a and 8b from 1-allyl-2-
pyrrolealdehyde by reaction with either (S)-valinol and (S)-
phenylglycinol in dry dichloromethane in the presence of
anhydrous magnesium sulfate (Scheme 2). The OH-free imines
8a,b were then treated with allylmagnesium chloride in excess
amounts in anhydrous THF at 0 °C to give the known secondary
homoallylic amines 9a,b.8 Unexpectedly, in the first reaction
run on the imine 8a, using only a slight exess of Grignard
J. Org. Chem. Vol. 73, No. 21, 2008 8377

Albano et al.
sponding pyrrolidines.5,9 The results we have obtained using
10% Pd/C, 10% Pd(OH)2/C, PtO2, and 5% Rh/Al2O3 with the
compounds 12a,b most frequently using methanol as the solvent
are reported in Table 3.
SCHEME 3
In all cases, the hydrogenation occurred with poor diaste-
reoselectivity. This is consistent with the outcomes of several
reports on the hydrogenation of chiral pyrroles bearing stereo-
centers at the benzylic position. Since one stereocenter is formed
under the asymmetric induction of the pre-existing stereocenter,
two diastereomers are expected in this reaction, e.g., (S,S)- and
(S,R)-14a,b. However, in several reactions mixtures a third
diastereomer was observed. Amounts of sufficiently pure
diastereomers (S,S)- and (S,R)-14a,b were obtained by chro-
matographic separation, but assignment of the configuration to
each compounds was difficult by 1H NMR spectroscopy, so that
single crystal X-ray structure analysis of all four compounds
was carried out for determination of their configuration. The
molecular structures of diastereomers (S,R)- and (S,S)-14a,b are
reported in the Supporting Information. Suitable crystals were
not obtained for the minor diastereomers of 14a,b, and their
(R,R)-configuration was assumed on the basis of the following
mechanistic considerations. We assumed that after the partial
saturation of the pyrrole ring to give the pyrrolines 15a,b an
alkene isomerization occurs, particularly using palladium cata-
lysts, leading to the ene-1,2-diamines 16a,b. These intermedi-
ates, where the pre-existing stereocenter has been lost, can
undergo hydrogen addition to both faces, so giving a mixture
of diastereomers (S,S)- and (R,R)-14a,b, assuming the prevalent
syn-addition of hydrogen to the double bond (Scheme 4).
It is noteworthy that (S,R)-14a was the minor diastereomer
when the reaction was performed at 1 atm of H2 in the presence
of 10% Pd/C, even in the presence of acetic acid (Table 3, entries
1 and 2), but it was prevalently obtained when 10% Pd(OH)2
was used, although with low conversion of 12a (entry 3).
Hydrogenation at higher pressure (8 atm of H2) in the presence
of acetic acid gave a mixture of the three diastereomers with
quantitative yield but low stereocontrol (entry 4). The Adam’s
catalyst (PtO2) proved to be ineffective, as only 10% conversion
was observed after 24 h (entry 5).
TABLE 2. Ring-Closing Metathesis of Compounds 11a,ba
Grubbs cat.
(mol %)
time 12, yieldb
(h)
entry compd
solvent T (°C)
(%)
1
2
3
4
5
6
11a
11a
11a
11a
11a
11b
I (5)
CH2Cl2
CH2Cl2
toluene
CH2Cl2
CH2Cl2
CH2Cl2
40
40
111
40
40
40
4
1
0.5
1.5
4
12a, 93
12a, 94
12a, 95
12a, 94
12a, 95
12b, 96
II (5)
II (5)
II (2.5)
II (1)
II (1)
4
a The reactions were carried out on a 2-3 mmol scale. b Yield of
isolated, pure product.
prepared with high yield from the phenylglycinol derivative 10b
was converted to the bicyclic compound 12b with 96% yield
(entry 6).
Rh/Al2O3 (1.2-1.4 mol equiv) gave more satisfactory results,
and only two diastereomers (S,S)- and (S,R)-14a were quanti-
We then directed our efforts to the hydrogenation of the
unsaturated bicyclic compounds 12a,b. The selective hydroge-
nation of the cyclohexene function of 12a,b to give 13a,b was
easily achieved by stirring a solution of 12a,b in methanol under
1 atm of H2 in the presence of 10% Pd/C (Scheme 3). As we
were interested to obtain the fully saturated indolizidine
derivatives, we checked the palladium, platinum and rhodium
heterogeneous catalysts which were previously used for the
hydrogenation of substituted pyrrole rings to give the corre-
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8378 J. Org. Chem. Vol. 73, No. 21, 2008

Asymmetric Synthesis of 8-Aminoindolizidine
TABLE 3. Hydrogenation of Compounds 12a,ba
entry
compd
catalyst (wt %; mol %)
H2 (atm)
solvent
time (h)
convb (%)
14a,b (S,S)/(S,R)/(R,R)b
yieldc (%)
1
2
3
4
5
12a
12a
12a
12a
12a
10% Pd/C (20; 4.7)
10% Pd/C (20; 4.7)
10% Pd(OH)2/C (20; 3.6)
10% Pd(OH)2/C (20; 3.6)
PtO2 (10; 11)
1
1
1
8
1
MeOH
MeOH-AcOH (4:1)
MeOH
MeOH-AcOH (4:1)
MeOH
24
24
24
24
24
100
100
30
100
10
14a, 43:15:42
14a, 38:15:47
14a, 16:73:11
14a, 24:48:28
14a, 14:72:14
(S,S)-14a, 5
(S,R)-14a, 49
(S,S)-14a, 19
(S,R)-14a, 57
(S,S)-14a, 11
(S,R)-14a, 63
6
7
12a
12a
5% Rh/Al2O3 (10; 1.2)
5% Rh/Al2O3 (10; 1.2)
1
8
MeOH
MeOH
24
24
100
100
14a, 31:69:0
14a, 26:74:0
8
9
12a
12b
5% Rh/Al2O3 (10; 1.2)
5% Rh/Al2O3 (10; 1)
8
1
EtOAc
MeOH/AcOH (4:1)
24
24
96
100
14a, 40:60:0
14b, 31:64:5
(S,S)-14b, 24
(S,R)-14b, 56
(S,S)-14b, 20
(S,R)-14b, 58
(S,S)-14a, 11
(S,R)-14a, 65
(S,S)-14a, 11
(S,R)-14a, 62
(S,S)-14a, 29
(S,R)-14a, 48
(S,S)-14b, 18
(S,R)-14b, 53
(S,S)-14b, 19
(S,R)-14b, 50
10
11
12
13
14
15
12b
12a
12a
12a
12b
12b
5% Rh/Al2O3 (10; 1.4)
5% Rh/Al2O3 (10; 1.2)
26% Rh/Gr (1.5; 0.9)
26% Rh/Gr (1.5; 0.9)
26% Rh/Gr (1.5; 1.0)
26% Rh/Gr (1.5; 1.0)
8
1
1
8
1
1
MeOH/AcOH (4:1)
MeOH-Et3N (4:1)
MeOH/Et3N (4:1)
MeOH
24
72
48
11
48
24
100
100
100
100
100
100
14b, 28:69:3
14a, 22:78
14a, 24:76
14a, 39:61
14b, 26:67:7
14b, 29:66:5
MeOH
MeOH/AcOH (4:1)
a The reactions were carried out on a 2-3 mmol scale. b The conversion degree of compounds 12a,b and the dr of the products 14a,b were
determined by GC-MS analysis; the ratio is reported according to the increasing retention times of the diastereomers. c Yield of isolated, pure
diastereomers.
SCHEME 4
phenylglycinol derivative 12b with the same rhodium catalyst
in methanol under 1 and 8 atm of H2 pressure gave complex
mixtures of products after comparable times, as the hydrogena-
tion of the Ph substituents was incomplete. However, the
addition of acetic acid increased the reaction rate, although the
formation of a third diastereomer was observed (entries 9 and
10). It was then found that when hydrogenation was carried
out with Rh/Al2O3 in methanol in the presence of triethylamine
only the (S,R)- and (S,S)-diastereomers were formed with a
slightly better diastereoselectivity, although at the expense of
the rate, as the reaction was complete after 72 h (entry 11).
Finally, we checked 24% rhodium on graphite (Rh/Gr) as a
novel catalyst for the hydrogenation of the pyrrole as well as
arene rings.10 This catalyst proved to be more effective than
previously tested heterogeneous catalysts. As a matter of fact,
using a slightly lower catalyst loading (0.9-1.0 molar equiv)
the complete reduction of 12a,b occurred in shorter times, other
reaction conditions being the same (compare entries 12/11 and
13/7). The reduction of 12b was positively affected by the
presence of acetic acid, although the diastereoselectivity re-
mained low (entries 14 and 15).
We reasoned that the diastereoselectivity of the hydrogenation
step could be affected by the amino substituent, so the
preparation of differently N-substituted derivatives was then
addressed. The removal of the chiral auxiliary from the
ꢀ-aminoalcohols 10a,b was routinely accomplished by treatment
with periodic acid-methylamine system, then the obtained crude
primary amines were benzoylated under Schotten-Baumann
conditions to obtain the benzamide 17a from the valinol
derivative 10a and the N-Boc amine 17b from the phenylgly-
cinol derivative 10b with high overall yields (Scheme 5).
The RCM reactions on these products were then carried out
in the optimized reaction conditions to give the unsaturated
tatively formed with a moderate prevalence of the latter,
especially under 8 atm of H2 pressure (entries 6 and 7), whereas
substitution of methanol by ethyl acetate gave slightly minor
conversion and diastereoselectivity (entry 8). A slightly greater
ratio ((S,R)/(S,S)-14a ) 74:26) was obtained in MeOH at a
pressure of 8 atm of H2 (entry 8). The hydrogenation of the
(10) The preparation of Rh/Gr and its use in hydrogenation of aromatic ring
will be reported in a forthcoming paper.
J. Org. Chem. Vol. 73, No. 21, 2008 8379

Albano et al.
SCHEME 5
2-pyrroleimines derived from (S)-valinol and (S)-phenylglycinol,
RCM reaction, and pyrrole ring hydrogenation as the key steps.
Further optimization of the effectiveness and stereoselectivity
of the hydrogenation step should be in principle accomplished
by modifying the nitrogen substituent. Moreover, the configu-
ration and the chiral auxiliary can be changed, and different
chiral auxiliaries can be tested as well. Moreover, the unsaturated
substituent introduced by the organometallic addition can be
varied in length, so that either a five- or a seven-membered ring
can be constructed in the RCM step. In conclusion, the auxiliary
based methodology starting from 2-pyrrolealdehyde can be
effectively used to prepare all the possible stereoisomers of
amino-substituted fused bicyclic compounds containing the
pyrrolidine nucleus.
Experimental Section
N-Alkylation of Pyrrole- and Indolealdehydes. General Pro-
cedure. To a solution of 2-pyrrolecarbaldehyde (2.42 g, 25.4 mmol)
in dioxane (40 mL) were added allyl bromide (6.6 mL, 9.22 g,
76.2 mmol) and K2CO3 (12.30 g, 89.0 mmol), and the mixture was
stirred at the reflux temperature during 8 h. Then the mixture was
cooled at room temperature, and cyclohexane (40 mL) was added.
The solid was filtered off through a pad of Celite, and the organic
phase was concentrated at reduced pressure. Flash column chro-
matography (SiO2) eluting with cyclohexane/ethyl acetate 9:1
mixture gave the aldehyde 711as a red oil: 3.05 g (89%).
Preparation of Imines. General Procedure. To a solution of
(S)-phenylglycinol (1.50 g, 11.1 mmol) or (S)-valinol (1.14 g, 11.1
mmol) in dry CH2Cl2 (40 mL) were added anhydrous MgSO4 (5
g) and the aldehyde 7 (1.5 g, 11.1 mmol), and the mixture was
stirred overnight. The solid was filtered off through a pad of Celite,
and the organic phase was concentrated at reduced pressure to leave
the crude imine 8a as a red oil, which was used as obtained avoiding
purification: 2.39 g (98%). Compound 8b was similarly obtained
as a red oil: 2.73 g (97%).
bicyclic compounds 18a,b, which were finally submitted to
hydrogenation using Rh/Al2O3 as the catalyst in methanol under
1 atm H2. In both cases, after complete reduction of the aromatic
rings, two diastereomers of the products 19a,b were observed.
They were isolated by column chromatography, then GC
analyses of both diastereomers on a chiral column showed that
the prevalent diastereomers were mixtures of enantiomers,
although with high e.e.’s (89 and 91%), whereas the minor
diastereomers were enantiomerically pure. The incomplete
optical purity of the prevalent diastereomers is certainly due to
the alkene isomerization occurring during hydrogenation, simi-
larly to the step described in Scheme 4 (15a,b to 16a,b), the
only difference is that an achiral intermediate (enediamine) is
formed from 18a,b.
Aiming to determine the relative configuration of the stereo-
centers in the products, we transformed the oxazolidinone (S,R)-
14a into the N-Boc derivative (S,R)-19b through a sequence of
steps which involves the hydrolytic cleavage of the oxazolidi-
none ring, oxidative cleavage of the ꢀ-amino alcohol and N-Boc
protection of the free amine. This correlation demonstrated that
the hydrogenation of the pyrrole rings in the differently
substituted unsaturated bicyclic compounds 12 and 18 occurred
with opposite diastereoselectivity, probably owing to a different
steric bulkiness and orientation of the functionalized amino
substituent of the bicyclic skeleton.
Organometallic Addition to Imines. Typical Procedure.
Allylmagnesium chloride (1.0 M in THF, 23.6 mL, 23.6 mmol)
was added to a magnetically stirred solution of the imine 8b (1.50
g, 5.9 mmol) in THF (25 mL) cooled at 0 °C. After 30 min, the
reaction mixture was slowly warmed until room temperature was
reached, and stirring was continued for 24 h. The mixture was
quenched with a saturated aqueous solution of NaHCO3 (30 mL)
at 0 °C, and then the organic material was extracted with diethyl
ether (3 × 20 mL). The collected ethereal layers were dried over
1
Na2SO4 and concentrated to leave the crude product. H NMR
analysis showed the presence of a single compound. Flash column
chromatography (SiO2) eluting with cyclohexane/ethyl acetate 9:1
mixture gave the product 10b as a yellow oil: 1.69 g, (96%). The
compound decomposed during GC-MS and HPLC-MS analyses.
Compound 10a was similarly obtained as a yellow oil starting from
the imine 8a (1.32 g, 6.0 mmol): 1.45 g (92%).
Preparation of Oxazolidinonones. Typical Procedure. To a
solution of the ꢀ-amino alcohol 10b (1.30 g, 4.4 mmol) in CH2Cl2
(20 mL) cooled at 0 °C were added a saturated aqueous solution
of NaHCO3 (10 mL) and triphosgene (0.65 g, 2.2 mmol) dissolved
in CH2Cl2 (5 mL), and the mixture was stirred overnight. The
mixture was extracted with CH2Cl2 (3 × 20 mL). The collected
organic layers were dried over Na2SO4 and concentrated to leave
the crude product. Flash column chromatography (SiO2) eluting
with cyclohexane/ethyl acetate (8:2) mixtures gave the product 11b
as a yellowish oil: 1.29 g, 4 mmol, 91%. Compound 11a was
similarly obtained as a white solid from 10a (0.79 g, 3.0 mmol):
0.785 g (93%).
Conclusions
(11) (a) Settambolo, R.; Savi, S.; Caiazzo, A.; Lazzaroni, R. J. Organomet.
Chem. 2001, 619, 241–244. (b) Broggini, G.; La Rosa, C.; Pilati, T.; Terraneo,
A.; Zecchi, G. Tetrahedron 2001, 57, 8323–8332.
N-Protected 8-aminoindolizidines have been synthesized by
an efficient route that involves organometallic allylation of
8380 J. Org. Chem. Vol. 73, No. 21, 2008

Asymmetric Synthesis of 8-Aminoindolizidine
Cleavage of the Chiral Auxiliary and N-Benzoylation of
the Secondary Amines. General Procedure. The valinol derivative
10a (0.445 g, 1.7 mmol) was dissolved in MeOH (5 mL), and then
a 40% solution of MeNH2 in H2O (4.0 mL, 5.2 mmol) and
successively a solution of H5IO6 (1.40 g, 6.0 mmol) in H2O (5 mL)
were added dropwise. The mixture was stirred for 2 h at room
temperature, and the organic materials were extracted with Et2O
(3 × 20 mL). The collected ethereal layers were washed with brine,
dried over Na2SO4, and concentrated to leave the primary amine
as a yellow oil. This was dissolved in acetone (5 mL), and then
H2O (5 mL), K2CO3 (0.47 g, 3.4 mmol), and benzoyl chloride (300
µL, 2.6 mmol) were added with magnetic stirring. After 12 h, most
of the solvent was evaporated at reduced pressure and the organic
materials were extracted with Et2O (3 × 20 mL). The collected
ethereal layers were dried over Na2SO4 and concentrated to leave
a white solid, which was crystallized from pentane/Et2O (9:1) to
give pure 17a (0.42 g, 89%).
pressure. Flash column chromatography (SiO2) eluting with ethyl
acetate/methanol/30% NH4OH (9:1:0.1) mixture gave the diaster-
eomers of 14a, which were eluted in the order (R,R), (S,S), (S,R).
The order of elution in GC-MS analysis was found: (S,S), (R,R),
(S,R).
(S,S)-14a was a white solid, 0.096 g (19%). Colorless crystals
were obtained by crystallization from Et2O/CH2Cl2 (10:1).
(S,R)-14a was a white solid, 0.287 g (57%). Colorless crystals
were obtained by crystallization from Et2O/CH2Cl2 (10:1).
(R,R)-14a could not be obtained in a pure state, being contami-
nated by (S,S)-14a. It had the same molecular weight of previous
diastereomers by GC-MS analysis.
Compound 13a was obtained as a yellowish oil from 12a (0.10
g, 0.40 mmol) after a 2 h reaction time: 0.095 g (96%). Compound
13b was similarly obtained as a white solid from 12b (0.10 g, 0.36
mmol) after a 2 h reaction time: 0.098 g (97%).
Full hydrogenation of compound 12b (0.5 g, 1.79 mmol) gave
the following diastereomers:
Cleavage of the Chiral Auxiliary and N-Boc Protection of
the Secondary Amines. General Procedure. The compound 10b
(0.50 g, 1.7 mmol) and a 40% solution of MeNH2 in H2O (4.4 mL,
5.8 mmol) were dissolved in MeOH (5 mL), a solution of H5IO6
(1.35 g, 5.7 mmol) in H2O (5 mL) was added dropwise, and the
mixture was stirred for 2 h at room temperature. The organic
materials were extracted with Et2O (3 × 20 mL), and the collected
ethereal layers were washed with brine, dried over Na2SO4, and
concentrated to leave the primary amine as a yellow oil. This was
dissolved in THF (5 mL), and then a saturated aqueous solution of
NaHCO3 (5 mL) and (Boc)2O (0.75 g, 3.4 mmol) were added while
the mixture was magnetically stirred. After 2 h, Et2O (10 mL) was
added, and the organic materials were extracted with Et2O (3 × 20
mL). The collected ethereal layers were dried over Na2SO4 and
concentrated to leave a white solid, which was washed with pentane
(2 × 5 mL) to give pure 17b as white powder: 0.415 g (91%).
Ring-Closing Metathesis Reactions. General Procedure. The
oxazolidinone 11b (1.29 g, 4.4 mmol) was dissolved in anhydrous
CH2Cl2 (20 mL), and the solution was deaerated by bubbling a
stream of Ar through it during 2 min. The Grubbs catalyst II (0.044
g, 0.01 mmol) was added, and the solution was again deaerated
for 2 min further. The mixture was stirred at the reflux temperature,
and the progress of the reaction was monitored by TLC. Disap-
pearance of the starting material was observed within 4 h. The
solvent was removed at reduced pressure to leave the crude product.
Flash column chromatography (SiO2) eluting with cyclohexane/
ethyl acetate 9:1 mixture gave the product 12b as a white solid:
1.18 g (96%). Colorless crystals were obtained by crystallization
from pentane/Et2O (7:3).
(S,S)-14b: 0.100 g (19%). Colorless crystals were obtained by
crystallization from Et2O/CH2Cl2 (8:2). (S,R)-14b: 0.293 g (56%).
Colorless crystals were obtained by crystallization from Et2O/
CH2Cl2 (8:2). (R,R)-14b could not be obtained in a pure state, being
contaminated by (S,S)-14b.
Full hydrogenation of compound 18a (0.20 g, 0.84 mmol) gave
two diastereomers. Compound (S,S)-19a: white solid, 0.129 g,
(60%). Colorless crystals were obtained by crystallization from
Et2O/CH2Cl2 (9:1). Compound (S,R)-19a: white solid, 0.059 g
(31%). Colorless crystals were obtained by crystallization from
Et2O/CH2Cl2 (9:1). The ee of (S,S)-19a was determined by chiral
GC on a Megadex chiral column (25 m, flow rate: 15 mL/min,
isotherm 150 °C for 2 min then 2 °C/min to 220 °C, FID detection).
Retention times: (S,S)-19a (major enantiomer), 28.2 min; (R,R)-
19a, 28.6 min. Under the same analytical conditions, (S,R)-19a was
found to be enantiomerically pure with a retention time 21.2 min,
Full hydrogenation of compound 18b (0.200 g, 0.86 mmol) gave
two diastereomers. Compound (S,S)-19b: white solid; 0.132 g
(64%). Colorless crystals were obtained by crystallization from
Et2O/CH2Cl2 (9:1). Compound (S,R)-19b: white solid; 0.064 g
(31%). Colorless crystals were obtained by crystallization from
Et2O/CH2Cl2 (9:1). The ee of (S,S)-19b was determined by chiral
GC on a Megadex chiral column (25 m, flow rate 15 mL/min,
isotherm at 100 °C for 2 min, then 5 °C/min to 220 °C, FID
detection). Retention times: (S,S)-19b (major enantiomer), 17.6 min;
(R,R)-19b, 18.3 min; ee 91%. Under the same analytical conditions,
(S,R)-19b resulted enantiomerically pure: retention time 15.8 min.
12a was prepared as a white solid from 11a (0.98 g, 3.4 mmol):
0.795 g (95%). Colorless crystals were obtained by crystallization
from pentane/Et2O (7:3).
18a was similarly obtained as a white solid from 17a (0.260 g,
0.90 mmol) and was purified by washing with pentane: 0.237 g
(94%).
Acknowledgment. This work was carried out in the field of
the Prin Project: “Sintesi e stereocontrollo di molecole organiche
per lo sviluppo di metodologie innovative”. A.G. held a
scholarship from GSK (Verona). We also thank the University
of Bologna for financial support.
18b was similarly obtained as a white solid from 17b (0.25 g,
0.91 mmol) and purified by washing with pentane: 0.195 g (92%).
General Procedure for the Hydrogenation Reactions. To 12a
(0.50 g, 2.0 mmol) dissolved in anhydrous MeOH (20 mL) was
added 5% Rh/Al2O3 (10%, 0.050 g), and the mixture was kept under
hydrogen (1 atm). The progress of the reaction was monitored by
GC-MS analysis, and the disappearance of the starting material
was observed within 24 h. The solid was filtered off through a pad
of Celite, and the organic phase was concentrated at reduced
Supporting Information Available: General methods, ana-
1
lytical data, and copies of H NMR and 13C NMR spectra for
all of the new compounds prepared. ORTEP drawing and CIF
files of compounds (S,R)- and (S,S)-14a and (S,R)- and (S,S)-
14b. This material is available free of charge via the Internet at
http://pubs.acs.org.
JO8014598
J. Org. Chem. Vol. 73, No. 21, 2008 8381