Synthesis of PDE IVb Inhibitors. 1. asymmetric synthesis and stereochemical assignment of (+)- and (-)-7-[3-(Cyclopentyloxy)-4-methoxyphenyl]hexahydro-3H- pyrrolizin-3-one

Article abstract of DOI:10.1021/jo201331h

Asymmetric synthesis of Glaxo Smith Kline's highly potent phosphodiesterase inhibitor 1 has been accomplished in nine steps and 16% overall yield. The original strategy suggested involves as a key step the silylation of enantiopure six-membered cyclic nit

Full text of DOI:10.1021/jo201331h

ARTICLE
pubs.acs.org/joc
Synthesis of PDE IVb Inhibitors. 1. Asymmetric Synthesis and
Stereochemical Assignment of (+)- and (ꢀ)-7-[3-(Cyclopentyloxy)-4-
methoxyphenyl]hexahydro-3H-pyrrolizin-3-one
Alexey Yu. Sukhorukov,*,† Yaroslav D. Boyko,† Sema L. Ioffe,† Yulia A. Khomutova,† Yulia V. Nelyubina,‡ and
Vladimir A. Tartakovsky†
†N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991, Leninsky prosp. 47, Moscow, Russian Federation
‡A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 119991, Vavilov str. 28, Moscow,
Russian Federation
S Supporting Information
b
ABSTRACT: Asymmetric synthesis of GlaxoSmithKline’s highly
potent phosphodiesterase inhibitor 1 has been accomplished in
nine steps and 16% overall yield. The original strategy suggested
involves as a key step the silylation of enantiopure six-membered
cyclic nitronates 4 obtained by a highly stereoselective [4 + 2]-
cycloaddition of an appropriate nitroalkene 5 to trans-1-phenyl-
2-(vinyloxy)cyclohexane. Functionalization of the resulting 5,6-
dihydro-4H-1,2-oxazine and subsequent stereoselective reduction
of 1,2-oxazine ring in intermediate 2 furnished the pyrrolizidinone
framework with the recovery of chiral auxiliary alcohol.
’ INTRODUCTION
the reduction of C-3-functionalized 5,6-dihydro-4H-1,2-oxazine
2. The latter can be obtained by substitution of bromine by
dimethyl malonate residue in product 3, which in turn can be
synthesized by silylation of six-membered cyclic nitronate 4 with
trimethylsilyl bromideviatheintermediacyofN,N-bis(oxy)enamine
A.7c Similarly to other cyclic nitronates, intermediate 4 is assembled
by the [4 + 2]-cycloaddition between nitroalkene 5 and a vinyl
ether.9
Recently, we reported a successful realization of this scheme in
racemic variant (with R = Et in Scheme 1) starting from ethyl
vinyl ether, isovanillin, and nitroethane.8 The most reasonable
approach to accomplish the asymmetric synthesis of pyrrolizidi-
none 1 seems to be the application of a chiral vinyl ether in the
[4 + 2]-cycloaddition with nitroalkene 5 (Denmark’s procedure9).
In this case, the problem of enantioselectivity comes to the facial
stereoselectivity of the [4 + 2]-cycloaddition reaction. Further-
more, in this approach, the chiral auxiliary alcohol ROH can be
recovered at the stage of 1,2-oxazine ring reduction in product 2.
Denmark studied in detail the [4 + 2]-cycloaddition of chiral
vinyl ethers to nitroalkenes.9 In these studies, vinyl ethers of (+)-
and (ꢀ)-trans-2-phenylcyclohexanols proved to be the most
efficient chiral auxiliaries providing the corresponding cyclic
nitronates with high stereoselectivity. Thus, vinyl ethers of (+)-
and (ꢀ)-trans-2-phenylcyclohexanols were chosen as 2π-compo-
nents for the synthesis of enantiopure nitronates 4 (Scheme 2).
Inhibitors of type IV phosphodiesterase (PDE) are considered
as perspective anti-inflammatory and antidepressant drugs,1
among which are well-known rolipram2 (IC50 = 175 nM), Ro
20-17242c,3 (IC50 = 1590 nM) and cilomilast1a,2c,4 (IC50 = 92
nM). 7-[3-(Cyclopentyloxy)-4-methoxyphenyl]hexahydro-3H-
pyrrolizin-3-one 1 (Scheme 1) introduced by GlaxoSmithKline
is a highly selective PDE IV inhibitor (IC50 = 63 nM) several
times more potent than rolipram.5 However, the synthesis of
pyrrolizidinone 1 proposed by GlaxoSmithKline is not stereo-
selective and cannot be accomplished in asymmetric variant.5
It cannot be ruled out that only one of pyrrolizidinone’s 1
enantiomers is able to efficiently bind to the protein, thus being
an active PDE inhibitor. Therefore, to determine the active
enantiomer one needs to develop an efficient synthesis of both
pyrrolizidinones (+)-1 and (ꢀ)-1 and conduct in vitro inhibition
experiments for each of them.6
In the present work, the asymmetric synthesis of pyrrolizidi-
nones (+)-1 and (ꢀ)-1 was developed, and the absolute config-
uration of stereocenters in these enantiomers was unambiguously
determined. To accomplish this synthesis, an original strategy
based on the process of silylation of cyclic nitronates7 was
exploited. This strategy has never been used in asymmetric
synthesis before.
’ RESULTS AND DISCUSSION
Scheme 1 shows a possible retrosynthetic analysis of pyrroli-
zidinone 1. The bicyclic core of molecule 1 can be constructed by
Received: June 24, 2011
Published: August 25, 2011
r
2011 American Chemical Society
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Scheme 1. Retrosynthetic Analysis of Pyrrolizidinone 1
from minor isomers 40 by the catalytic hydrogenation followed
by separation of nitrogen-containing products on DOWEX-
50WX2 (H-form) exchange resin (Scheme 3, eq 1).
Silylation of enantiomeric nitronates (+)-4 and (ꢀ)-4 with a
mixture of trimethylsilyl bromide and triethylamine7c,d furnished
relatively labile bromomethyloxazines 3 (30) in 39% yield and
unreacted nitronates 4 (35%) (Scheme 2). The latter could be
again subjected to the silylation process. After two cycles, 52%
yield of target bromides 3 (30) was achieved. However, in the
silylation of nitronates 4 a partial epimerization at C-6 atom took
place, apparently, under the action of trimethylsilyl bromide (cf.
with ref 7d). Consequently, bromides3 are formed asa mixtures of
necessary 4,6-trans-3 and minor 4,6-cis-30 stereoisomers (ratio
2.9:1.0). In addition, the formation of some amount of trans-2-
phenylcyclohexanol (22%) was observed, whichispossibly formed
by the trimethylsilyl bromide induced oxazine ring-opening in
intermediate A and subsequent hemiacetalic oxime fragmentation
(cf. with ref 7d). Isomers 3 and 30 were readily separated by
column chromatography on silica gel. The unnecessary minor
bromide 30 like nitronate 40 could be hydrogenated to recover
enantiopure trans-2-phenylcyclohexanol (Scheme 3, eq 2).12
Nucleophilic substitution of bromine by dimethyl malonate
moiety in each product (4S,6S,7S,8R)-3 and (4R,6R,7R,8S)-3 furn-
ished dihydrooxazines (+)-(4S,6S,7S,8R)-2 and (ꢀ)-(4R,6R,7R,8S)-
2, respectively, in high yield (Scheme 2). Reduction of these
products with sodium cyanoborohydride in acetic acid pro-
duces corresponding tetrahydrooxazines (+)-8 and (ꢀ)-8 also
in high yield. The latter are formed exclusively as 3,4-trans
isomers. This predictable stereochemical result is in accor-
dance with a mechanistic model of dihydrooxazine’s reduction
process suggested recently.7a,13
The catalytic hydrogenation of each tetrahydrooxazine’s 8
enantiomers ((+)-8 and (ꢀ)-8) with Raney nickel led to a mixture
of diastereomeric pyrrolizidinones 10 with a good recovery of
enantiopure trans-2-phenylcyclohexanol (Scheme 2). The plausi-
ble mechanism of this transformation includes the hydrogenolysis
of the NꢀO bond, elimination of the chiral auxiliary alcohol from
the resulting semiacetal, subsequent cyclization, and reduction of
the resulting aldimine to give pyrrolidine 9 and its lactamization
into products 10.7a,8 The latter without purification were decar-
boxylated by refluxing in wet DMSO with sodium bromide to
furnish target pyrrolizidinones (+)-1 and (ꢀ)-1 in 79% yield over
two steps from tetrahydrooxazines 8. Pyrrolizidinone (ꢀ)-1 was
obtained from tetrahydrooxazine (+)-8, and pyrrolizidinone (+)-1
was prepared from tetrahydrooxazine (ꢀ)-8. Optical rotation
angles of the enantiomers 1 obtained in (+) and (ꢀ) series are
close by the absolute value and have opposite signs. Enantiopure
(+)- and (ꢀ)-trans-2-phenylcyclohexanols were recovered in
89% yield.
The starting nitroalkene 5 was synthesized by the condensa-
tion with nitroethane of aldehyde 6, readily available from
isovanillin and cyclopentyl bromide10 (Scheme 2). The synthesis
of enantiopure vinyl ethers 7 was achieved by transvinylation of
commercially available (+)- and (ꢀ)-trans-2-phenylcyclohexa-
nols (>98% ee) with ethyl vinyl ether catalyzed by Hg(OAc)2 at
ambient temperature.
The [4 + 2]-cycloaddition of nitroalkene 5 with vinyl ethers
(+)-7 and (ꢀ)-7 promoted by SnCl4 furnished the cyclic
nitronates (+)-4 and (ꢀ)-4, respectively, in high yield (Scheme 2).
Interestingly, only two of four possible stereoisomers were
formed with high predominance of isomer 4 (ratio 4/40 = 13:1).
These isomers were readily separated by column chromatogra-
phy (nitronates (+)-4 and (ꢀ)-4 were isolated with de >98%
according to NMR 1H 600 MHz analysis). According to 1D and
2D NMR data, both isomers 4 and 40 have a relative 4,6-trans
configuration. Thus, the cycloaddition of trans-2-phenylcyclo-
hexanol vinyl ether 7 to nitroalkene 5 proceeds with excellent
exo-selectivity and high facial selectivity. It is noteworthy that
enantiopure trans-2-phenylcyclohexanols can be partially recovered
The structures of previously unknown enantiopure products
2, 3, 4, and 8 were confirmed by 1D 1H and 13C NMR, 2D NMR
(COSY, HSQC), HRMS data, and elemental analysis.
The determination of the absolute configuration of stereo-
centers in pyrrolizidinones (+)-1 and (ꢀ)-1 represented a
challenging task. Data in the literature are contradictory on this
point. In the original report5 on the synthesis of racemic
pyrrolizidinone rac-1 by GlaxoSmithKline, the relative config-
uration of stereocenters is reported as (7R*,7aR*)-1. On the
other hand, in the recently published asymmetric synthesis of
pyrrolizidinone (+)-1 by Chen’s group,6 the absolute configura-
1
tion (7S,7aR) is assigned for this product, though its H NMR
spectra match data given in ref 5 for rac-1. In this situation, an
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Scheme 2. Total Synthesis of Pyrrolizidinones (+)-1 and (ꢀ)-111
unambiguous determination of the absolute stereochemistry in
pyrrolizidinones (+)-1 and (ꢀ)-1 is essential.
for the pyrrolizidinone (+)-1 the true configuration is (7R,7aR),
not (7S,7aR), as was reported in ref 6 previously.15
However, we were not able to perform X-ray crystallographic
analysis for the final pyrrolizidinones (+)-1 and (ꢀ)-1 as well as
for any of enantiopure intermediates 2, 3, 4, and 8, since they
were not crystalline. Only when the synthesis was repeated starting
from the racemic trans-2-phenylcyclohexanol (Scheme 2, race-
mic series) was a crystalline racemic tetrahydrooxazine rac-8
obtained. X-ray analysis of rac-814 (see the Supporting In-
formation) revealed the relative configuration of all five
stereocenters in the molecule of tetrahydrooxazine 8 that
allowed us to establish the relationship between the absolute
configuration of starting trans-2-phenylcyclohexanol and the
absolute configuration of the final enantiomer of pyrrolizidi-
none 1. Thus, enantiomer (+)-(7R, 7aR)-1 was obtained from
(ꢀ)-(1R, 2S)-2-phenylcyclohexanol, and (ꢀ)-(7S,7aS)-1 was
obtained from (+)-(1S,2R)-2-phenylcyclohexanol. Accordingly,
’ CONCLUSIONS
In conclusion, the asymmetric synthesis of both enantiomers
of highly potent PDE IV inhibitor 1 was accomplished, and the
absolute configuration of stereocenters was unambiguously
determined. The suggested strategy provides target pyrrolizidi-
nones (+)-1 and (ꢀ)-1 in a 16% yield over nine steps (eight steps
in the longest lineal sequence) starting from nitroethane and
isovanillin. Inhibition of PDE IV enzyme with (+)-1 and (ꢀ)-1
will be studied in the near future. The suggested strategy for the
asymmetric assembly of pyrrolizidinone unit is novel, and it
can be applied in the total synthesis of some pyrrolizidine
alkaloids. Furthermore, the silylation of chiral six-membered
cyclic nitronates realized here for the first time can be employed
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Scheme 3. Recovery of trans-2-Phenylcyclohexanol from
Minor Isomers 30 and 40
Figure 1. Atom numbering in products 1ꢀ4.
phenylcyclohexanol (0.20 g, 20%). 1H NMR spectra of products 7 is in
accordance with literature data.9b
trans-4-[3-(Cyclopentyloxy)-4-(methyloxy)phenyl]-3-met-
hyl-6-[trans-(2-phenylcyclohexyl)oxy]-5,6-dihydro-4H-1,2-oxa-
zine 2-Oxide (4). A solution of nitroalkene 5 (0.39 g, 1.4 mmol)
and enantiopure or racemic trans-2-phenylcyclohexanol vinyl ether
7 (0.37 g, 1.83 mmol) in CH2Cl2 (18.5 mL) was cooled to ꢀ90 °C
(acetone/liquid nitrogen) in a Schlenk flask, and SnCl4 (0.165 mL,
0.368 g, 1.4 mmol) was added under argon with intensive stirring. The
resulting dark-colored solution was stirred at the same temperature for
10 min and poured into a mixture of EtOAc (200 mL) and saturated
solution of K2CO3 (200 mL). The aqueous layer was back-extracted
with EtOAc (2 ꢁ 50 mL). The combined organic layers were then
washed with a saturated solution of K2CO3 (100 mL), water (100 mL)
and brine (100 mL), dried with Na2SO4, and evaporated in vacuum. The
rac-4 was isolated by recrystallization of the final residue from a mixture
Et2O/hexane = 5:1 (0.40 g of pure rac-4). The filtrate was evaporated,
and the residue was preadsorbed on silica gel and subjected to a column
chromatography on silica gel to give 51 mg of rac-4 and 36 mg of rac-40
(eluent EtOAc/heptane = 10:1 f 5:1 f 3:1 f 1:1). Enantiopure
nitronates (+)-4 and (ꢀ)-4, which are not crystalline, were isolated and
separated from the respective minor isomers 40 by column chromatog-
raphy on silica gel. Overall yield of nitronates 4 + 40: 75% (based on
nitroalkene), 57% (based on vinyl ether). Ratio 4/40 = 13:1.
Rf = 0.33 (hexane/EtOAc = 1:1). HRMS (for rac-4): m/z = 480.2734
in the synthesis of other enantiomerically pure PDE IV inhibitors
(cf. with ref 5).
’ EXPERIMENTAL SECTION
Catalytic hydrogenations were carried out in a steel autoclave with
external stirring and heating. Column chromatography was performed
using Kieselgel 40ꢀ60 μm 60A silica gel or basic Brockmann I aluminum
oxide, 50ꢀ200 μm. Glacial acetic acid was recrystallized two times.
CH2Cl2 (technical grade), MeCN (technical grade), Et3N, ethyl vinyl
ether, and Me3SiBr were redistilled from CaH2. THF was redistilled
from sodium diphenyl ketyl. Hexane and EtOAc for chromatography
and extractions and methanol for hydrogenation were distilled without
drying agents. Nitroalkene 58 and racemic trans-2-phenylcyclohexanol17
were synthesized according to known procedures.
1D and 2D NMR spectra were recorded at room temperature in
CDCl3. The chemical shifts (1H, 13C) are given in ppm (δ) and relative
to the solvent signal.16 Multiplicities are indicated by s (singlet), d
(doublet), t (triplet), q (quadruplet), m (multiplet), br (broad). Atom
numbering is depicted in Figure 1. |δ| values in the HR mass spectra data
correspond to the accuracy of the measurement in ppm. Concentrations
c in the optical rotation angles are given in g/100 mL. Analytical thin-
layer chromatography was performed on silica gel plates with QF-254.
Visualization was accomplished with UV light, a standard solution of
ninhydrin in ethanol, or a solution of anisaldehyde/H2SO4 in ethanol.
trans-1-Phenyl-2-(vinyloxy)cyclohexane (7). Ethyl vinyl
ether (18 mL) was added to a mixture of (+)-, (ꢀ)-, or rac-trans-2-
phenylcyclohexanol (1.00 g, 5.68 mmol) and Hg(OAc)2 (0.56 g, 1.73
mmol), and the mixture was kept at 25 °C for 24 h. The resulting
solution was filtered through an Al2O3 column (diameter = 3.5 cm,
height = 4 cm, eluent, hexane) to remove mercury acetate. After the
product was washed off the column (eluent, hexane; TLC control), the
filtrate was evaporated under reduced pressure and the residue was
subjected to a flesh chromatography on Al2O3 (eluent, hexane; the same
column can be used) to give trans-2-phenylcyclohexanol vinyl ether 7
(0.81 g, 71% yield, >95% purity by NMR with external standard).
Further elution (hexane/EtOAc = 3:1) provided the unreacted trans-2-
+
(positive ions); calcd for [C29H38NO5 ]: 480.2744, /δ/ = 2.1 ppm. 1H
NMR (300 MHz, COSY, HSQC): 1.24 (ddd, J = 11.8, 11.0, 8.3 Hz, 1 H,
12-CHax), 1.30 (s, 3 H, 13-CH3), 1.32ꢀ1.58 (m, 1 H, 11-CH),
1.59ꢀ1.64 (m, 2 H, 23-CH), 1.78ꢀ1.89 (m, 11 H, 9-CH2, 10-CH2,
11-CH, 22-CH2 and 23-CH), 1.92 (ddd, J = 12.9, 11.1, 2.3 Hz, 1 H,
5-CHax), 2.01 (ddd, J = 12.9, 8.7, 1.7 Hz, 1 H, 5-CHeq), 2.36 (ddd, J =
11.8, 4.0, 3.1 Hz, 1 H, 12-CHeq), 2.61 (ddd, J = 12.2, 10.7, 3.3 Hz, 1 H,
8-CHax), 3.11 (dd, J = 11.1, 8.7 Hz, 1 H, 4-CHax), 3.80 (s, 3 H, 20-CH3),
4.19 (ddd, J = 11.0, 10.7, 4.0 Hz, 1 H, 7-CHax), 4.70 (m, 1 H, 21-CH),
5.53 (dd, J = 2.3, 1.7 Hz, 1 H, 6-CHeq), 6.47 (d, J = 1.8 Hz, 1 H, 15-CH),
6.54 (dd, J = 8.2, 1.8 Hz, 1 H, 19-CH), 6.75 (d, J = 8.2 Hz, 1 H, 18-CH),
7.16 (t, J = 7.1 Hz, 1 H, 27-CH), 7.28 (d, J = 7.2 Hz, 2 H, 25-CH), 7.33
(dd, J = 7.2, 7.1 Hz, 2 H, 26-CH). 13C NMR (75.47 MHz, HSQC): 17.2
(13-C), 24.0 (9-C), 24.6 (23-C), 26.2 (10-C), 30.2 (12-C), 32.7 and
32.8 (22-C), 33.9 and 34.2 (5-C and 11-C), 39.5 (4-C), 51.1 (8-C), 56.2
(20-C), 76.1 (7-C), 80.6 (21-C), 95.1 (6-C), 112.4 (18-C), 114.7 (15-C),
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120.5 (19-C), 123.1 (C-3), 126.1 (27-C), 127.7 (25-C), 128.3 (26-C),
132.4 (14-C), 144.3 (24-C), 148.2 and 149.7 (16-C and 17-C). Anal.
Calcd for C29H37NO5: C, 72.62; H, 7.78; N, 2.92. Found (for rac-4): C,
72.45; H, 7.96; N, 2.89.
HSQC): 24.1 (9-C), 24.8 and 26.3 (11-C and 23-C), 30.2 (13-C), 31.0
(12-C), 32.1 (5-C), 32.8 and 32.9 (22-C), 33.5 (4-C), 34.5 (10-C), 50.6
(8-C), 56.2 (20-C), 77.0 (7-C), 80.6 (21-C), 91.8 (6-C), 112.4 (18-C),
115.7 (15-C), 120.9 (19-C), 126.1 (27-C), 127.8 (25-C), 128.3
(26-C), 130.9 (14-C), 144.2 (24-C), 148.0 and 149.6 (16-C and 17-C),
156.4 (3-C).
rac-4 (obtained from rac-7): mp 110ꢀ114 °C (crystallized from
Et2O/hexane).
(+)-(4S,6S,7S,8R)-4 (obtained from (+)-7): white foam; [α]D
+243.0 (CH2Cl2, c = 1, 28 °C).
=
=
rac-3 (obtained from rac-4): unstable oil.
(4S,6S,7S,8R)-3 (obtained from (+)-4): unstable oil.
(ꢀ)-(4R,6R,7R,8S)-4 (obtained from (ꢀ)-7): white foam; [α]D
(4R,6R,7R,8S)-3 (obtained from (ꢀ)-4): unstable oil.
ꢀ235.6 (CH2Cl2, c = 1, 21 °C).
cis-3-(Bromomethyl)-4-[3-(cyclopentyloxy)-4-(methyloxy)-
phenyl]-6-[trans-(2-phenylcyclohexyl)oxy]-5,6-dihydro-4H-
1,2-oxazine (30). Rf = 0.45 (hexane/EtOAc = 3:1). HRMS: m/z =
trans-4-[3-(Cyclopentyloxy)-4-(methyloxy)phenyl]-3-
methyl-6-[trans-(2-phenylcyclohexyl)oxy]-5,6-dihydro-4H-
1,2-oxazine 2-Oxide (40). rac-40 (obtained from rac-7). Unstable
oil. Rf = 0.43 (hexane/EtOAc = 1:1). HRMS: m/z = 480.2747 (positive
ions), calcd for [C29H38NO5+] 480.2744, |δ| = 0.6 ppm. 1H NMR (300
MHz, COSY, HSQC): 1.34 (m, 1 H, 11-CH), 1.54ꢀ1.64 and
1.84ꢀ1.95 (2 m, 10 H, 10-CH2, 22-CH2 and 23-CH2), 1.48 (m, 1 H,
12-CH), 1.60 (m, 1 H, 9-CH), 1.65 (ddd, J = 11.7, 10.5, 2.8 Hz, 1 H,
5-CHax), 1.72 (ddd, J = 11.7, 8.5, 2.0 Hz, 1 H, 5-CHeq), 1.79 (m, 1 H,
11-CH), 1.82 (s, 3 H, 13-CH3), 1.92 (m, 1 H, 9-CH), 2.23 (m, 1 H, 12-
CH), 2.57 (ddd, J = 12.5, 10.9, 3.6 Hz, 1 H, 8-CHax), 3.65 (dd, J = 10.5,
8.5 Hz, 1 H, 4-CHax), 3.83 (s, 3 H, 20-CH3), 3.86 (m, 1 H, 7-CH), 4.48
(dd, J = 2.8, 2.0 Hz, 1 H, 6-Heq), 4.72 (m, 1 H, 21-CH), 6.56 (d, J = 2.0
Hz, 1 H, 15-CH), 6.64 (dd, J = 8.1, 2.0 Hz, 1 H, 19-CH), 6.78 (d, J = 8.1
Hz, 1 H, 18-CH), 7.16ꢀ7.30 (2 m, 5 H, 25-CH, 26-CH and 27-CH).
13C NMR (75.47 MHz, HSQC): 17.4 (13-C), 24.0 (9-C), 25.2 (23-C),
25.8 (11-C), 32.7 (10-C), 32.8 (22-C), 34.0 (5-C), 34.3 (12-C), 40.2
(4-C), 51.6 (8-C), 56.2 (20-C), 80.6 (21-C), 82.8 (7-C), 101.6 (6-C),
112.4 (18-C), 114.6 (15-C), 120.4 (19-C), 123.6 (C-3), 126.7 (27-C),
127.9 (25-C), 128.4 (26-C), 132.5 (14-C), 143.9 (24-C), 148.3 and
149.7 (16-C and 17-C).
+
542.1898 (positive ions), calcd for [C29H37BrNO4 ] 542.1900, |δ| =
1
0.4 ppm. H NMR (300 MHz, COSY, HSQC): 1.33ꢀ1.37 (m, 1 H,
11-C), 1.47 (m, 1 H, 12-CH), 1.52ꢀ1.56 and 1.83ꢀ1.95 (3 m, 14 H,
5-CH, 9-CH2, 10-CH2, 11-CH, 22-CH2, 23-CH2), 1.79 (dd, J = 13.2,
8.1, 6.6 Hz, 1 H, 5-CHax), 2.34 (m, 1 H, 12-CH), 2.51 (ddd, J = 12.5,
10.3, 3.7 Hz, 1 H, 8-CHax), 3.56 (dd, J = 7.3, 8.1 Hz, 1 H, 4-CHeq), 3.60
(d, J = 9.5 Hz, 1 H, 13-CH), 3.70 (ddd, J = 10.3, 10.3, 4.4 Hz, 1 H, 7-CH),
3.84 (s, 3 H, 20-CH3), 3.91 (d, J = 9.5 Hz, 1 H, 13-CH), 4.29 (dd, J = 6.6,
2.9 Hz, 1 H, 6-CHeq), 4.76 (m, 1 H, 21-C), 6.73ꢀ6.76 (m, 2 H, 15-CH
and 19-CH), 6.81 (d, J = 8.8 Hz, 1 H, 18-CH), 7.18ꢀ7.30 (m, 5 H, 25-C,
26-C and 27-CH). 13C NMR (75.47 MHz, HSQC): 24.1 (9-C), 25.3
(23-C) and 25.8 (11-C), 30.9 (13-C), 32.4 (10-C), 32.8 and 32.9 (C-
22), 33.2 (5-C), 34.7 (12-C), 37.7 (4-C), 51.6 (8-C), 56.2 (20-C), 80.6
(21-C), 84.5 (7-C), 99.7 (6-C), 112.3 (18-C), 115.3 (15-C), 121.1 (19-
C), 126.5 (27-C), 128.1 and 128.3 (25-C and 26-C), 131.5 (14-C), 144.0
(24-C), 148.1 and 149.6 (16-C and 17-C), 158.2 (3-C). Anal. Calcd for
C29H36BrNO4: C, 64.20; H, 6.69; N, 2.58. Found: C, 64.27; H, 6.69;
N, 2.48.
rac-30 (obtained from rac-4): mp 118ꢀ126 °C (crystallized from
Et2O/hexane).
trans-3-(Bromomethyl)-4-[3-(cyclopentyloxy)-4-(methy-
loxy)phenyl]-6-[trans-(2-phenylcyclohexyl)oxy]-5,6-dihydro-
4H-1,2-oxazine (3). Me3SiBr (1.0 mL, 7.6 mmol) was added to a
solution of racemic or enantiopure nitronate 4 (750 mg, 1.56 mmol) and
Et3N (0.33 mL, 2.4 mmol) in 4.3 mL of MeCN at ꢀ30 °C under argon.
The mixture was kept at ꢀ30 °C for 24 h with occasional stirring, and
then it was diluted with EtOAc (10 mL) and poured into a mixture of
EtOAc (200 mL) and a saturated solution of K2CO3 (200 mL). The
aqueous layer was back-extracted with EtOAc (2 ꢁ 50 mL). The
combined organic layers were washed with a saturated solution of
K2CO3 (100 mL), water (100 mL), and brine (100 mL), dried
(Na2SO4), and evaporated in vacuum. The residue was preadsorbed
on silica gel and subjected to a column chromatography (eluent:
heptane/EtOAc = 20:1 f 10:1 f 5:1 f 1:1). Four fractions were
collected: the first one contained minor isomer 30 (85 mg, 10%), the
second contained trans-2-phenylcyclohexanol (60 mg, 22%), the third
one contained major isomer 3 (241 mg, 29%), and the last one contained
initial nitronate 4 (260 mg, 35%). The recycled nitronate 4 was silylated
again by the same procedure to yield 87 mg of bromide 3 and 30 mg of
bromide 30. Overall yield of bromides 3 + 30 (after 2 cycles): 52%, ratio
3/30 = 2.9:1.0. Rf = 0.39 (hexane/EtOAc = 3:1). HRMS: m/z = 542.1905
(+)-(4S,6R,7S,8R)-30 (obtained from (+)-4): mp 117ꢀ120 °C
(crystallized from Et2O/hexane); [α]D = +61.0 (MeOH, c = 0.75, 22 °C).
(ꢀ)-(4R,6S,7R,8S)-30 (obtained from (ꢀ)-4): mp 118ꢀ120 °C
(crystallized from Et2O/hexane).
Dimethyl 2-[trans-[4-[3-(Cyclopentyloxy)-4-(methyloxy)-
phenyl]-6-[(trans-2-phenylcyclohexyl)oxy]-5,6-dihydro-4H-
1,2-oxazin-3-yl]methyl]propanedioate (2). NaH (41 mg, 1.03
mmol, 60% in mineral oil) was added to stirred solution of dimethyl
malonate (0.088 mL, 0.775 mmol) in 2.1 mL of THF at 0 °C under
argon. After 5 min, a solution of enantiopure or racemic bromide 3
(258 mg, 0.48 mmol) in 3.1 mL of THF was added, and the resulting
mixture was heated at 50ꢀ60 °C for 2 h. Then the mixture was cooled to
rt and quenched with MeOH (ca. 5 mL). The resulting solution was
poured into a mixture of EtOAc (100 mL) and water (100 mL). The
aqueous layer was back-extracted with EtOAc (2 ꢁ 50 mL). The
combined organic layers were washed with water (50 mL) and brine
(50 mL), dried with Na2SO4, and evaporated in vacuum. The residue
was subjected to column chromatography on silica gel (eluent EtOAc/
hexane = 1:10 f 1:5) to yield dihydrooxazine 2 (274 mg, 97%). Rf =
0.63 (hexane/EtOAc = 1:1). HRMS: m/z = 594.3057 (positive ions),
+
+
(positive ions), calcd for [C29H37BrNO4 ] 542.1900, |δ| = 0.9 ppm. 1H
calcd for [C34H44NO8 ] 594.3061, |δ| = 0.7 ppm. 1H NMR (300 MHz,
NMR (300 MHz, COSY, HSQC): 1.38 (m, 1 H, 12-CH), 1.52 (m, 1 H,
9-CH), 1.56ꢀ1.65 and 1.77ꢀ1.91 (2 m, 13 H, 9-CH, 10-CH2, 11-CH2,
22-CH2, 23-CH2), 1.93 (ddd, J = 13.2, 12.5, 2.3, 1 H, 5-CHax), 2.04
(ddd, J = 13.2, 8.1, 2.0 Hz, 1 H, 5-CHeq), 2.36 (m, 1 H, 12-CHeq), 2.61
(ddd, J = 11.7, 10.3, 3.7 Hz, 1 H, 8-CHax), 3.24 (dd, J = 12.5, 8.1 Hz, 1 H,
4-CHax), 3.41 (d, J = 10.3 Hz, 1 H, 13-CH), 3.48 (d, J = 10.3 Hz, 1 H, 13-
CH), 3.82 (s, 3 H, 20-CH3), 4.02 (ddd, J = 10.3, 10.3, 3.7 Hz, 1 H,
7-CHax), 4.72 (m, 1 H, 21-CH), 5.37 (dd, J = 2.3, 2.0 Hz, 1 H, 6-CHeq),
6.59 (s, 1 H, 15-CH), 6.61 (dd, J = 8.1, 2.2 Hz, 1 H, 19-CH), 6.78 (d, J =
8.1 Hz, 1 H, 18-CH), 7.18 (t, J = 7.3 Hz, 1 H, 27-CH), 7.24 (d, J = 6.6 Hz,
2 H, 25-CH), 7.32 (dd, J=8.1, 6.6Hz, 2H, 26-CH). 13C NMR (75.47 MHz,
COSY, HSQC): 1.22 (m, 1 H, 12-CH), 1.33ꢀ1.46, 1.57ꢀ1.65 and
1.78ꢀ2.00 (3 m, 2 H, 3 and 10 H, 5-CH2, 9-CH, 10-CH2, 11-CH2, 22-
CH2, 23-CH2), 1.54 (m, 1 H, 9-CH), 1.73 (dd, J = 17.6, 2.9 Hz, 1 H, 13-
CH), 2.37 (m, 1 H, 12-CH), 2.42 (dd, J = 17.6, 11.5 Hz, 1 H, 13-CH),
2.57 (ddd, J = 12.5, 10.3, 3.7 Hz, 1 H, 8-CHax), 2.72 (dd, J = 12.5, 7.3 Hz,
1 H, 4-CHax), 3.65 (dd, J = 11.5, 2.9 Hz, 1 H, 28-CH), 3.71 and 3.72 (2 s,
6 H, 30-CH3), 3.82 (s, 3 H, 20-CH3), 3.91 (ddd, J = 11.0, 10.3, 3.7 Hz,
1 H, 7-CHax), 4.79 (m, 1 H, 21-CH), 5.31 (dd, J = 2.2, 2.0 Hz, 1 H,
6-CHeq), 6.53 (d, J = 2.2 Hz, 1 H, 15-CH), 6.55 (dd, J = 8.1, 2.2 Hz, 1 H,
19-CH), 6.79 (d, J = 8.1 Hz, 1 H, 18-CH), 7.16 (t, J = 7.3 Hz, 1 H, 27-
CH), 7.27 (d, J = 8.1 Hz, 2 H, 25-CH), 7.31 (dd, J = 8.1, 7.3 Hz, 2 H,
7897
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The Journal of Organic Chemistry
ARTICLE
26-CH). 13C NMR (75.47 MHz, HSQC): 24.1 (9-C), 24.7 and 26.2 (11-
C and 23-C), 30.4 (12-C), 32.1 (13-C), 32.8 and 32.9 (22-C), 33.0 and
33.7 (5-C and 10-C), 35.4 (4-C), 47.2 (28-C), 51.0 (8-C), 52.4 and 52.6
(30-C), 56.2 (20-C), 75.8 (C-7), 80.6 (21-C), 90.3 (6-C), 112.5 (18-C),
115.3 (15-C), 120.8 (19-C), 126.1 (27-C), 127.9 (25-C and 26-C),
132.2 (14-C), 144.8 (24-C), 148.1 and 149.4 (16-C and 17-C), 156.9 (3-
C), 169.2 and 170.0 (29-C). Anal. Calcd for C34H43NO8: C, 68.78; H,
7.30; N, 2.36. Found: C, 68.92; H, 7.21; N, 2.32.
1 H, 15-CH), 6.60 (dd, J = 2.2 Hz, 8.1 Hz, 1 H, 19-CH), 6.77 (d, J = 8.1
Hz, 1 H, 18-CH), 7.23 (m, 1 H, 27-CH), 7.41 (m, 4 H, 25-CH and 26-
CH). 13C NMR (75.47 MHz, HSQC): 24.1 (9-C), 24.8 and 26.1 (11-C
and 23-C), 29.4 (12-C), 31.2 and 32.7 (5-C and 10-C), 32.8 and 32.9
(22-C), 37.6 (13-C), 41.0 (4-C), 47.4 (28-C), 50.9 (8-C), 52.2 and 52.4
(30-C), 56.2 (20-C), 58.1 (3-C), 77.3 (7-C), 80.6 (21-C), 93.4 (6-C),
112.5 (18-C), 114.7 (15-C), 119.8 (19-C), 126.9 (27-C), 128.3 and
128.8 (25-C and 26-C), 134.7 (14-C), 144.7 (24-C), 147.9 and 149.0
(16-C and 17-C), 169.3 and 170.1 (29-C). Anal. Calcd for C34H45NO8:
C, 68.55; H, 7.61; N, 2.35. Found: C, 68.85; H, 7.68; N, 2.35.
rac-2 (obtained from rac-3): mp 108ꢀ110 °C (crystallized from
Et2O/hexane).
(+)-(4S,6S,7S,8R)-2 (obtained from (4S,6S,7S,8R)-3): white foam;
[α]D = +257.5 (MeOH, c = 1, 27 °C).
rac-8 (obtained from rac-2): white crystals; mp 137ꢀ141 °C
(crystallized from MeOH).
(ꢀ)-(4R,6R, 7R,8S)-2 (obtained from (4R,6R,7R,8S)-3): white foam;
(+)-(3S,4S,6S,7S,8R)-8 (obtained from (+)-2): white solid; mp
129ꢀ130 °C; [α]D = +144.0 (MeOH, c = 1, 22 °C).
[α]D = ꢀ263.0 (MeOH, c = 1, 20 °C).
Dimethyl 2-[cis-[4-[3-(Cyclopentyloxy)-4-(methyloxy)phenyl]-
6-[trans-(2-phenylcyclohexyl)oxy]-5,6-dihydro-4H-1,2-oxa-
zin-3-yl]methyl]propanedioate (20). rac-20 was obtained in 51%
yield from rac-30 according to the procedure given above for the
synthesis of dihydrooxazine 2. Oil. Rf = 0.58 (hexane/EtOAc = 1:1).
(ꢀ)-(3R,4R,6R,7R,8S)-8 (obtained from (ꢀ)-2): white solid; mp
127ꢀ130 °C; [α]D = ꢀ142.0 (MeOH, c = 1, 21 °C).
Dimethyl 2-[[3,4-trans-3,6-trans-4-[3-(Cyclopentyloxy)-4-
(methyloxy)phenyl]-6-[trans-(2-phenylcyclohexyl)oxy]-1,2-
oxazinan-3-yl]methyl]propanedioate (rac-80) and Dimethyl
2-[[3,4-cis-3,6-cis-4-[3-(Cyclopentyloxy)-4-(methyloxy)phenyl]-
6-[trans-(2-phenylcyclohexyl)oxy]-1,2-oxazinan-3-yl]methyl]-
propanedioate (rac-800). NaBH3CN (10 mg, 0.15 mmol) was added
to a solution of racemic dihydroooxazine rac-20 (30 mg, 0.05 mmol) in
AcOH (1.0 mL), and the mixture was stirred under argon for 1 h. Then a
second portion of NaBH3CN (10 mg, 0.15 mmol) was added, and the
mixture was stirred for additional 0.5 h. An additional portion of
NaBH3CN (10 mg, 0.15 mmol) was added to the mixture to reach
the full conversion of starting material (TLC control). The resulting
solution was poured into a mixture EtOAc (50 mL)/saturated solution
of K2CO3 (50 mL). The aqueous layer was back-extracted with EtOAc
(2 ꢁ 20 mL). The combined organic layers were washed with saturated
solution of K2CO3 (20 mL), water (20 mL), and brine (20 mL), dried
with Na2SO4, and evaporated in vacuum. The residue was subjected to a
column chromatography on silica gel (eluent EtOAc/hexane =1:10 f
1:5 f1:3) to yield 23 mg (76%) of an unseparable mixture of racemic
tetrahydrooxazines rac-80 and rac-800 (ratio 1.0: 1.7). Colorless oil. Rf =
0.57 (hexane/EtOAc = 1:1). HRMS: m/z = 596.3211 (positive ions),
+
HRMS: m/z = 594.3066 (positive ions), calcd for [C34H44NO8 ]
1
594.3061, |δ| = 0.8 ppm. H NMR (300 MHz, COSY, HSQC): 1.45
(m, 2 H, 11-CH and 12-CH), 1.56ꢀ1.65 and 1.84ꢀ1.98 (2 m, 13 H,
9-CH2, 10-CH2, 11-CH, 22-CH2, 23-CH2), 1.70 (ddd, J = 13.9, 8.1, 6.6
Hz, 1 H, 5-CHax), 1.82 (ddd, J = 13.9, 8.1, 2.7 Hz, 1 H, 5-CHeq), 2.30 (m,
1 H, 12-CH), 2.45 (dd, J = 17.6, 7.3 Hz, 1 H, 13-CH), 2.49 (ddd, J = 12.5,
10.0, 3.9 Hz, 1 H, 8-CHax), 2.60 (dd, J = 17.6, 7.3 Hz, 1 H, 13-CH), 3.07
(dd, J = 8.1, 8.1 Hz, 1 H, 4-CHeq), 3.68 and 3.70 (2 s and m, 7 H, 7-CH
and 30-CH3), 3.84 (s, 3 H, 20-CH3), 3.88 (dd, J = 7.3, 7.3 Hz, 1 H, 28-
CH), 4.18 (dd, J = 6.6, 2.7 Hz, 1 H, 6-CHeq), 4.79 (m, 1 H, 21-CH), 6.67
(dd, J = 8.1, 1.5 Hz, 1 H, 19-CH), 6.71 (d, J = 1.5 Hz, 1 H, 15-CH), 6.79
(d, J = 8.1 Hz, 1 H, 18-CH), 7.15ꢀ7.27 (m, 5 H, 25-CH, 26-CH and 27-
CH). 13C NMR (75.47 MHz, HSQC): 24.1 (9-C), 25.3 (11-C), 25.9
(23-C), 32.6 and 32.7 (10-C and 13-C), 32.8 and 32.9 (22-C), 34.2 (5-
C), 34.7 (12-C), 41.0 (4-C), 48.0 (28-C), 51.6 (8-C), 52.5 and 52.6 (30-
C), 56.2 (20-C), 80.6 (21-C), 83.8 (7-C), 98.8 (6-C), 112.2 (18-C),
115.4 (15-C), 121.2 (19-C), 126.4 (27-C), 128.1 and 128.2 (25-C and
26-C), 132.4 (14-C), 144.1 (24-C), 148.1 and 149.5 (16-C and 17-C),
158.7 (3-C), 169.3 and 169.5 (29-C).
calcd for [C34H46NO8 ] 596.3218, |δ| = 1.2 ppm. rac-80. 1H NMR (300
+
MHz, COSY, HSQC, selected signals): 2.05 (ddd, J = 6.0, 4.2, 1.5 Hz,
1 H, 4-CHeq), 2.23 (m, 1 H, 12-CH), 2.56 (ddd, J = 12.5, 9.5, 3.7, 1 H,
8-CHax), 3.01 (dddd, J = 11.0, 6.0, 4.2, 3.7 Hz, 1 H, 3-CHeq), 3.52 (dd,
J = 9.5, 5.1 Hz, 1 H, 28-CH), 3.64 and 3.66 (2 s and m, 8 H, 2-NH, 7-CH
and 30-CH3), 3.97 (dd, J = 3.9 Hz, 1.5 Hz, 1 H, 6-Heq), 3.81 (s, 3 H, 20-
CH3), 4.72 (m, 1 H, 21-CH), 6.58 (s, 1 H, 15-CH), 6.59 (d, J = 8.1 Hz,
1 H, 19-CH), 6.79 (d, J = 8.1 Hz, 1 H, 18-CH). 13C NMR (75.47 MHz,
HSQC): 24.0, 25.0, and 25.8 (C-9, C-11 and C-23), 35.1 (12-C), 43.1
(4-C), 49.0 (28-C), 51.6 (8-C), 56.2 (20-C), 57.2 (3-C), 80.5 (21-C),
84.1 (7-C), 105.3 (6-C), 112.3 (18-C), 114.3 (15-C), 119.5 (19-C),
126.5 (27-C), 128.1 and 128.3 (25-C and 26-C), 132.4 (14-C), 144.1
(24-C). rac-800. 1H NMR (300 MHz, COSY, HSQC, selected signals):
2.03 (ddd, J = 7.3, 7.3, 2.0 Hz, 1 H, 4-CHeq), 2.23 (m, 1 H, 12-CH), 2.51
(ddd, J = 13.2, 9.5, 3.7, 1 H, 8-CHax), 2.91 (dddd, J = 10.3, 9.5, 7.3, 2.2
Hz, 1 H, 3-CHax), 3.40 (dd, J = 7.3, 7.3 Hz, 1 H, 28-CH), 3.62 (s and m, 8
H, 2-NH, 7-CH and 30-CH3), 3.81 (s, 3 H, 20-CH3), 3.98 (dd, J = 3.7
Hz, 1.5 Hz, 1 H, 6-Heq), 4.72 (m, 1 H, 21-CH), 6.58 (s, 1 H, 15-CH),
Dimethyl 2-[[3,4-trans-3,6-cis-4-[3-(Cyclopentyloxy)-4-(methy-
loxy)phenyl]-6-[trans-(2-phenylcyclohexyl)oxy]-1,2-oxazi-
nan-3-yl]methyl]propanedioate (8). NaBH3CN (76 mg, 2.3
mmol) was added to a solution of enantiopure or racemic dihydrooox-
azine 2 (240 mg, 0.4 mmol) in AcOH (1.75 mL), and the mixture was
stirred under argon for 1 h. Then a second portion of NaBH3CN (76 mg,
2.3 mmol) was added, and the mixture was stirred for an additional 0.5 h.
The resulting solution was poured into a mixture of EtOAc (100 mL)/
saturated solution of K2CO3 (100 mL). The aqueous layer was back-
extracted with EtOAc (2 ꢁ 50 mL). The combined organic layers were
washed with a saturated solution of K2CO3 (50 mL), water (50 mL), and
brine (50 mL), dried with Na2SO4, and evaporated in vacuum. The
residue was subjected to column chromatography on silica gel (eluent
EtOAc/hexane = 1:10 f 1:5 f1:3) to yield 228 mg (95%) of
tetrahydrooxazine 8. Rf = 0.51 (hexane/EtOAc = 1:1). HRMS: m/z =
+
596.3218 (positive ions); calcd for [C34H46NO8 ]: 596.3218, |δ| = 0.0
ppm. 1H NMR (300 MHz, COSY, HSQC): 0.68 (ddd, J = 14.7, 11.0, 3.7
Hz, 1 H, 13-CH), 1.26 (m, 1 H, 12-CH), 1.31ꢀ1.45, 1.60ꢀ1.65 and
1.82ꢀ2.01 (3 m, 15 H, 5-CH, 9-CH2, 10-CH2, 11-CH2, 22-CH2, 23-
CH2), 1.72 (ddd, J = 14.7, 12.2, 2.2 Hz, 1 H, 13-CH), 1.78 (dd, J = 5.3,
1.5 Hz, 1 H, 5-CHeq), 2.14 (ddd, J = 11.7, 10.3, 5.3 Hz, 1 H, 4-CHax),
2.20 (m, 1 H, 12-CH), 2.67 (ddd, J = 12.5, 10.3, 3.7 Hz, 1 H, 8-CHax),
2.91 (dddd, J = 12.2, 11.0, 10.3, 2.2 Hz, 1 H, 3-CHax), 3.39 (dd, J = 11.7,
3.7 Hz, 1 H, 28-CH), 3.63 and 3.72 (2 s, 7 H, 2-NH and 30-CH3), 3.69
(ddd, J = 10.3, 9.5, 4.4 Hz, 1 H, 7-CHax), 3.81 (s, 3 H, 20-CH3), 4.78 (m,
1 H, 21-CH), 4.93 (dd, J = 2.0, 1.5 Hz, 1 H, 6-CHeq), 6.59 (d, J = 8.1 Hz,
6.59 (d, J = 8.1 Hz, 1 H, 19-CH), 6.75 (d, J = 8.1 Hz, 1 H, 18-CH). 13
C
NMR (75.47 MHz, HSQC): 24.0, 25.3, and 25.8 (9-C, 11-C and 23-C),
35.1 (12-C), 46.6 (4-C), 48.9 (28-C), 51.5 (8-C), 56.2 (20-C), 60.4 (3-
C), 80.6 (21-C), 84.0 (7-C), 104.6 (6-C), 112.3 (18-C), 114.7 (15-C),
120.1 (19-C), 126.4 (27-C), 128.1 and 128.3 (25-C and 26-C), 133.6
1
(14-C), 144.1 (24-C). Unassigned Signals of Both Isomers. H NMR
(300 MHz, COSY, HSQC): 1.27ꢀ1.52, 1.55ꢀ1.68 and 1.75ꢀ1.93 (3 m,
17 H, 5-CH2, 9-CH2, 10-CH2, 11-CH2, 12-CH, 13-CH2, 22-CH2, 23-CH2),
7.17ꢀ7.30 (m, 5 H, 25-CH, 26-CH and 27-CH). 13C NMR (75.47 MHz,
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The Journal of Organic Chemistry
ARTICLE
HSQC): 29.5, 29.8, 30.1, 30.4, 32.8, 32.9, and 37.4 (5-C, 10-C, 22-C and
13-C), 52.4, 52.5, and 52.6 (30-C), 147.8, 147.9, 149.1, and 149.2 (16-C and
(MeOH, c = 1.83, 23 °C) [lit.18 [α]D = ꢀ56.8 (MeOH, c = 1.42)].
1H NMR spectra were in accordance with literature data.17,18
17-C), 169.6, 169.8, and 170.0 (29-C).
trans-7-[3-(Cyclopentyloxy)-4-(methyloxy)phenyl]hexahydro-
3H-pyrrolizin-3-one (1). Raney nickel (c.a. 50 mg, washed with
MeOH) was placed in a test tube equipped with a magnetic stirrer and
charged with a solution of enantiopure or racemic tetrahydrooxazine 8
(180 mg, 0.3 mmol) in MeOH (7.2 mL). The test tube was placed in a
steel autoclave which was then flushed and filled with H2 to a pressure of
40 bar. After the mixture was stirred at rt for 3 h, the autoclave was slowly
depressurized and the catalyst was filtered off. The solvent was evapo-
rated, and the residue was dried in vacuum. The product was dissolved in
DMSO (7 mL). Then NaBr (31 mg, 0.3 mmol) and H2O (0.011 mL, 0.6
mmol) were added. The mixture was gently refluxed for 45 min, and
then the solvent was evaporated in vacuo (c.a. 100 °C/10 Torr) and the
residue was subjected to column chromatography on silica gel (eluent
EtOAc/hexane = 1:10 f 1:5 f 1:1 f MeOH/EtOAc = 0: 1 f 1:10).
Two fractions were collected: the EtOAc/hexane fraction contained
trans-2-phenylcyclohexanol (47 mg, 89%) and the EtOAc/MeOH
fraction contained target pyrrolizidinone 1 (75 mg, 79%). Rf = 0.71
’ ASSOCIATED CONTENT
S
Supporting Information. NMR spectra of new com-
b
pounds and crystallographic data of compound rac-8 (CIF).
This material is available free of charge via the Internet at http://
pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: sukhorukov@server.ioc.ac.ru.
’ ACKNOWLEDGMENT
Support from the Russian Foundation for Basic Research
(Grant No. 11-03-00737-a), the Federal Agency for Science and
Innovations (Grant No. MK-1361.2011.3) and the Foundation
for the Support of Small Scale Enterprises in Science and
Technology (project 12628) is greatly acknowledged. We also
thank Mr. S. Zalessky for performing 600 MHz 1H NMR analysis
and Prof. K. Pivnitsky for useful discussions.
1
(EtOAc/MeOH, 1:3). H NMR (CDCl3, 300 MHz, COSY, NOESY,
HSQC): δ = 1.54ꢀ1.65 and 1.76ꢀ1.95 (2 m, 2 and 7 H, 1-CH, 16-CH2
and 17-CH2), 2.15ꢀ2.30 (m, 2 H, 6-CH00 and 1-CH), 2.43ꢀ2.53 (m,
2 H, 6-CH0 and 2-CH), 2.63ꢀ2.79 (m, 2 H, 7-CH and 2-CH), 3.31 (dd,
J = 11.0, 10.3 Hz, 1 H, 5-CH00), 3.61 (ddd, J = 11.0, 9.2, 8.8 Hz, 1 H,
5-CH0), 3.81 (s, 3 H, 14-CH3), 3.89 (ddd, J = 9.5, 7.3, 7.0 Hz, 1 H, 7a-
CH), 4.75 (m, 1 H, 15-CH), 6.72 (s, 1 H, 9-CH), 6.73 (d, J = 8.1 Hz, 1 H,
13-CH), 6.82 (d, J = 8.1 Hz, 1 H, 12-CH). 13C NMR (CDCl3, 75 MHz,
INEPT, HSQC): δ = 23.9 (17-C), 25.5 (1-C), 32.7 (16-C), 34.7 (2-C),
35.2 (6-C), 40.9 (5-C), 50.8 (7-C), 56.0 (14-C), 67.7 (7a-C), 80.5 (15-
C), 112.1, 114.3, and 119.1 (9-C, 12-C and 13-C), 131.5 (8-C), 147.7
and 149.1 (10-C and 11-C), 174.7 (3-C). Characteristic 2D-NOESY
correlations: 9-CH/7a-CH, 9-CH/6-CH00, 6-CH00/5-CH00, 6-CH0/5-
CH0. NMR data were consistent with those previously reported for
pyrrolizidinone rac-1.5,6,8
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(3) Begany, D. P.; Carcillo, J. A.; Herzer, W. A.; Mi, Z.; Jackson, E. K.
J. Pharmacol. Exp. Ther. 1996, 278, 37–41.
(4) Giembycz, M. Br. J. Clin. Pharmacol. 2006, 62, 138–152.
(5) Brackeen, M. F.; Cowan, D. J.; Stafford, J. A.; Schoenen, F. J.;
Veal, J. M.; Domanico, P. L.; Rose, D.; Strickland, A. B.; Verghese, M.;
Feldman, P. L. J. Med. Chem. 1995, 38, 4848.
(6) Recently, the first asymmetric synthesis of pyrrolizidinone (+)-1
was reported: Feng, X.; Cui, H.-L.; Xu, S.; Wu, L.; Chen, Y.-C. Chem.—
Eur. J. 2010, 16, 10309. However, pyrrolizidinone (ꢀ)-1 has not been
obtained before.
(7) (a) Sukhorukov, A. Yu.; Ioffe, S. L. Chem. Rev. 2011,
111, 5004–5041. (b) Ioffe, S. L. In Nitrile Oxides, Nitrones, and Nitronates
in Organic Synthesis: Novel Strategies in Synthesis, 2nd ed.; Feuer, H., Ed.;
Wiley: Hoboken, 2008; pp 704. (c) Sukhorukov, A. Yu.; Klenov, M. S.;
Ivashkin, P. E.; Lesiv, A. V.; Khomutova, Yu. A.; Ioffe, S. L. Synthesis
2007, 97–107. (d) Klenov, M. S.; Lesiv, A. V.; Khomutova, Yu. A.;
Nesterov, I. D.; Ioffe, S. L. Synthesis 2004, 1159–1170.
(8) Sukhorukov, A. Yu.; Lesiv, A. V.; Khomutova, Yu. A.; Ioffe, S. L.;
Tartakovsky, V. A. Synthesis 2009, 1999–2008.
(9) (a) Denmark, S. E.; Thorarensen, A. Chem. Rev. 1996,
96, 137–166. (b) Denmark, S. E.; Schnute, M. E.; Senanayake, C. B. W.
J. Org. Chem. 1993, 58, 1859–1874.
rac-1 (obtained from rac-8): mp 67ꢀ68 °C (lit.5 mp 64ꢀ66 °C).
(+)-(7R,7aR)-1 (obtained from (ꢀ)-8): colorless oil; [α]D = +64.2
(CHCl3, c = 0.35, 23 °C) [lit.6 [α]D = +62.6 (97% ee, CHCl3, c = 0.35,
20 °C)].
(ꢀ)-(7S,7aS)-1 (obtained from (+)-8): colorless oil; [α]D = ꢀ65.9
(CHCl3, c = 0.35, 24 °C).
rac-trans-2-Phenylcyclohexanol (obtained from rac-8): mp 54ꢀ56 °C
(lit. 53ꢀ55 °C, Sigma-Aldrich). 1H NMR spectra are in accordance with
literature data.17,18
(+)-trans-2-Phenylcyclohexanol (obtained from (+)-8): [α]D
=
+55.9 (MeOH, c = 1.83, 20 °C) [lit.19 [α]D = +57.3 (MeOH, c = 5,
20 °C)]. 1H NMR spectra are in accordance with literature data.17,18
(ꢀ)-trans-2-Phenylcyclohexanol (obtained from (ꢀ)-8): [α]D
=
ꢀ54.8 (MeOH, c = 0.5, 24 °C) [lit.18 [α]D = ꢀ56.8 (MeOH, c =
1.42)]. 1H NMR spectra is in accordance with literature data.17,18
Regeneration of trans-2-Phenylcyclohexanol from Minor
Isomers 30 and 40. Raney nickel (ca. 50 mg, washed with MeOH) was
placed in a test tube equipped with a magnetic stirrer and charged with a
solution of nitronate (4S,6S,7R,8S)-40 (48 mg, 0.1 mmol) or bromide
(4R,6S,7R,8S)-30 (54 mg, 0.1 mmol) in 2.7 mL of MeOH. The test tube
was placed in a steel autoclave which was then flushed and filled with H2
to a pressure of 40 bar. After the mixture was stirred at 50 °C for 1 h, the
autoclave was slowly depressurized and the catalyst was filtered off.
DOWEX-50WX2 (150 mg) was added to the resulting solution, and the
mixturewas kept with occasional shaking for 24 h. Then theion-exchange
resin was filtered off, and the solution was concentrated in vacuum. The
residue contained crude(ꢀ)-trans-2-phenylcyclohexanol, which couldbe
purified by flash chromatography on silica gel or recrystallization from
hexane (yield 52ꢀ54%). (ꢀ)-trans-2-Phenylcyclohexanol: [α]D = ꢀ56.3
(10) Barnes, D. M.; Ji, J.; Fickes, M. G.; Fitzgerald, M. A.; King, S. A.;
Morton, H. E.; Plagge, F. A.; Preskill, M.; Wagaw, S. H.; Wittenberger,
S. J.; Zhang, J. J. Am. Chem. Soc. 2002, 124, 13097–13105.
(11) The formulas in Scheme 2 correspond to the synthesis of
pyrrolizidinone (ꢀ)-1 from (+)-trans-2-phenylcyclohexanol.
(12) The minor bromide 30 cannot be used in the synthesis of
pyrrolizidinones 1. Dihydrooxazine 20 obtained from bromide 30
analogously to product 2, upon the reduction with NaBH3CN produces
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ARTICLE
an unseparable mixture of diastereomeric tetrahydrooxazines 80 and 800
(demonstrated on racemic substrates).
(13) Sukhorukov, A. Yu.; Lesiv, A. V.; Khomutova, Yu. A.; Ioffe, S. L.
Synthesis 2009, 741–754.
(14) CCDC 827039 contains the supplementary crystallographic
data for rac-8. These data can be obtained free of charge via http://www.
ccdc.cam.ac.uk/conts/retrieving.html (or from the CCDC, 12 Union
Road, Cambridge, CB21EZ, UK; or deposit@ccdc.cam.ac.uk).
(15) 1H NMR spectra and the optical rotation angle of the obtained
pyrrolizidinone (+)-1 matched those reported in ref 6 ([α]D = +62.6
(97% ee, CHCl3, c = 0.35, 20 °C)).
(16) Gottlieb, H. E.; Kotlyar, V.; Nudelman, A. J. Org. Chem. 1997,
62, 7512–7515.
(17) Basavaiah, D.; Rao, P. D. Tetrahedron: Asymmetry 1994, 5,
223–234.
(18) King, S. B.; Sharpless, K. B. Tetrahedron Lett. 1994, 35, 5611–
5612.
(19) Cravotto, G.; Giovenzana, G. B.; Pilati, T.; Sisti, M.; Palmisano,
G. J. Org. Chem. 2001, 66, 8447–8453.
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