L-Proline derived nitrogenous steroidal systems: An asymmetric approach to 14-azasteroids

Article abstract of DOI:10.1039/c3ra42272k

An efficient chiral pool approach using l-proline to access 14-azasteroids under mild reaction conditions has been described. The key step involves the intramolecular S_N2′ cyclization reaction for the construction of critical C-ring in the nitrogen impregnated steroidal architectures bearing unsaturation at Δ⁹⁽¹¹⁾ position. In the endeavour to synthesize some new congeners, the remote electronic impact of the electron donating groups in A ring and heteroatoms like oxygen in B ring, on the propensity of C-ring cyclization was also observed.

Full text of DOI:10.1039/c3ra42272k

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L-Proline derived nitrogenous steroidal systems: an
asymmetric approach to 14-azasteroids3
Cite this: RSC Advances, 2013, 3,
1
9533
Ritesh Singh and Gautam Panda*
An efficient chiral pool approach using L-proline to access 14-azasteroids under mild reaction conditions
has been described. The key step involves the intramolecular S
N
29 cyclization reaction for the construction
Received 9th May 2013,
Accepted 26th July 2013
9(11)
of critical C-ring in the nitrogen impregnated steroidal architectures bearing unsaturation at D
position. In the endeavour to synthesize some new congeners, the remote electronic impact of the
electron donating groups in A ring and heteroatoms like oxygen in B ring, on the propensity of C-ring
cyclization was also observed.
DOI: 10.1039/c3ra42272k
www.rsc.org/advances
9
l,m
with simultaneous incorporation of nitrogen.
However,
Introduction
ring opening, ring closing sequences generally involve several
steps. Besides, no asymmetric synthesis of steroidal systems
with nitrogen at 14-position has been accounted. Thus the
development of efficient and convergent methodologies
towards the asymmetric synthesis of azasteroids is an
important area to explore.
The total synthesis of natural products and natural product
like molecules have been the cynosure among synthetic
chemists, as it not only provides opportunity to refine the
general strategies delineated previously, but also to innovate
new synthetic pathways to accomplish the architecturally
complex molecules. In this context, steroids pose an impress-
ive synthetic challenge, owing to their rigid framework with
varying levels of functionalization. Steroids with one or more
heteroatoms embedded in their skeletons have been an area of
considerable interest in the past few years due to their
11
Meanwhile, working on the synthesis of heteroatom
1
2
impregnated natural product like architectures and utiliza-
tion of amino acids as chiral pool to access biologically
1
1
3
important molecules, we thought to employ proline and its
derivative as chiral synthon for the incorporation of nitrogen
at the desired 14-position and to utilize their inherent chirality
to induce specific stereo orientation in the steroidal system for
2
,3
profound pharmacological profile. In particular, azasteroids
have received much attention owing to their wide range of
4
a
4b,c
14
bioactivities viz., hypotensive, antifungal,
hypocholester-
GABA receptor antagonists like RU-
135 and neuromuscular blocking agents like pancuronium
our studies. Thus, we envisioned to have diverse nitrogenous
4
a
4a,d
9(11)
olemic, antibacterial,
5
steroidal core 1 with unsaturation at D
as an ideal target.
4
e
4
f
and chandonium. Besides, their activities also include
inhibition of steroid biosynthesis, which comprises blocking
the action of enzyme 5a-reductase involved in the conversion
Results and discussion
8
of testosterone (T) to dihydrotestosterone (DHT), thus
As depicted in Scheme 1, the retrosynthetic analysis revealed
providing
a
possible therapeutic approach towards the
that the target core 1 could be accomplished from the
treatment of prevalent human diseases like benign prostatic
5
6a,b
hyperplasia, acne, male pattern baldness
and alopecia
6
c
(
Fig. 1). Several azasteroids have also shown antiproliferative
activity in breast cancer cell lines.
7
In view of such broad biological profile, several syntheses of
azasteroids with nitrogen at various centers has been
9
,10
reported.
Most asymmetric strategies utilize the degrada-
tion of available chiral steroids followed by reconstruction
Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute,
Chattar Manzil Palace, M. G. Marg, Lucknow-226001, India.
E-mail: gautam.panda@gmail.com; gautam_panda@cdri.res.in;
Fax: 91-522-2623405; Tel: 91-522-2612411-18 (8 lines), Ext. 4385, 4603
3
Electronic supplementary information (ESI) available. See DOI: 10.1039/
Fig. 1 Representative biologically important azasteroids and our target 1 (14-
c3ra42272k
azasteroids).
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Scheme 3 Synthesis of azasteroids 1a and 1a9.
Scheme 1 Retrosynthetic analysis.
a-methyl- L-proline and trans-4-/3-hydroxy L-proline, respec-
tively, using standard reaction conditions. a-methyl- L-proline
2
and trans-4-/3-hydroxy L-proline were esterified (SOCl /MeOH)
at 0 uC followed by Boc protection which furnished ester
derivatives 7, 10 and 11. Benzylation of hydroxyl group in 10
intermediate 2, which in turn could be obtained by coupling of
bromo derivative 3 with L-proline derived aldehyde 4. The
1
5
bromo derivatives 3a–e were obtained by the reaction of
substituted/unsubstituted 1-tetralone/chromanone with PBr3
in dry benzene (Scheme 2), whereas the optically pure
and 11 was performed under neutral reaction conditions using
18
2
Ag O and BnBr to prevent racemization, which provided fully
protected L-proline derivatives 12 and 13, respectively.
Reduction of ester moiety in 7, 12 and 13 using LiBH4
1
6
aldehyde 4a was synthesized from commercially available
1
7a
17b
N-(Boc)-S-proline by carboxyl reduction, Swern oxidation,
followed by Dess–Martin periodinane (DMP) oxidation pro-
1
7c
Wittig olefination, and enol ether hydrolysis with 2 M HCl
vided aldehydes 8, 14 and 15, respectively, in good yields.
Homologation of aldehydes 8, 14 and 15 was then performed
by employing methoxy methyl triphenyl phosphonium ylide
(Scheme 2).
With the starting materials in hand, substrate 3a was
lithiated using n-BuLi at 278 uC and was treated with aldehyde
a which provided the intermediate carbinols 2a and 2a9 as
(
Ph P = CH(OMe) which provided enol ether intermediates 9,
3
4
16 and 17 (an inseparable mixture of Z and E isomers),
two separable diastereoisomers (2 : 1) in 66% yield. However,
as the newly generated stereocenter is lost at the cyclization
stage, therefore diastereomeric mixture was employed directly
without any need for their separation. At this stage, substrates
respectively. Careful hydrolysis of enol ethers with 2 M HCl in
acetone at room temperature provided optically pure alde-
1
9
hydes 4b, 4c and 4d in good yields.
To the best of our knowledge, no reports for the synthesis
of enantiomerically pure homologated aldehydes 4b, 4c and 4d
are present in literature. However, the optically pure aldehyde
2a and 2a9 seemed well poised to undergo 6-endo trig
cyclization to achieve our target cores 1. Thus, removal of
the NHBoc group using 1 : 1 mixture of DCM and TFA at 0 uC
2
0
4e
was synthesized from commercially available N-(Boc)-S-
followed by treatment with NaHCO solution furnished the
3
pipecolic acid 18 by carboxyl reduction, modified Swern
9
(11)
unsaturated D
14-azasteroidal core 1a and 1a9. Cyclization
29 reaction involving the
2
1
oxidation, Wittig olefination, and enol ether 19 hydrolysis
with 2 M HCl (eqn 3; Scheme 4).
proceeds through intramolecular S
N
attack of proline derived pyrrolidine nitrogen atom onto a
tetralone derived allylic alcohol.
Under optimized conditions, removal of the NHBoc group
3
using 4 M HCl in dioxane followed by cyclization using Et N as
base afforded the separable mixture of azasteroids 1a and 1a9
in 1.2 : 1 ratio with 75% yield (Scheme 3).
Thereafter, to explore the scope and limitation of this
strategy as well as to introduce diversity in D–ring, optically
pure aldehydes 4b, 4c, 4d and 4e were synthesized (Scheme 4).
Aldehydes 4b, 4c and 4d (eqn 1 and 2; Scheme 4) were
prepared from commercially available proline derivatives
Following the similar reaction conditions as shown in
Scheme 3, reaction of lithiated bromo derivatives 3 with
aldehydes 4a–e furnished intermediate carbinols 2b–j in
satisfactory yields (55–69%, Table 1). The resulting carbinols
2
(b + b9 2 j + j9) were then subjected to previously optimized
cyclization conditions (4 M HCl in dioxane followed by Et N)
14-azasteroidal skele-
tons as separable diastereomers 1b + b9(73%), 1d + d9(71%), 1e
e9(76%), 1g + g9(78%), 1h + h9(44%) and 1j + j9(71%) as
3
9
(11)
which furnished the unsaturated D
+
depicted in Table 1. Unfortunately, substrates 2c + c9, 2f + f9
and 2i + i9 failed to provide any cyclized product. The
reluctance shown by the substrates 2c + c9, 2f + f9 and 2i + i9
to undergo cyclization could be rationalized by the fact, that
the presence of electron donating methoxy (OMe) group at the
3-position (according to steroidal numbering) in A ring and/or
the presence of oxygen at 6-position (in B ring) considerably
8
(9)
reduces the electrophilicity of the double bond at D
towards
nucleophilic attack.
The structural analysis and stereochemical assignment as
9
(11)
depicted in unsaturated D
14-azasteroids 1 (Table 1) were
1
13
done through incisive analysis of 1D, 2D NMR, via H, C,
H– H)/( H– C) COSY and NOESY of selected compounds
1
1
1
13
(
Scheme 2 Synthesis of bromo derivatives 3a–e and optically pure aldehyde 4a.
1
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Scheme 4 Synthesis of optically pure 4b, 4c, 4d and 4e.
(
see supporting information
3
). Stereochemistry of the rest of
assignment was done on the basis of similar reports in the
literature (Scheme 5).
2
3
the target structures was assigned analogously.
The syn relationship between 13 b-methyl and the C-8
proton in the isomer 1b was predicted by close observation of
its NOESY spectra which showed conspicuous interaction
between them along with other visible interactions. The other
isomer 1b9 was therefore assigned with having an anti
relationship between 13 b-methyl and C-8 proton as no such
interactions were observed in its NOESY spectra (Fig. 2).
Besides, a healthy confirmation comes from the fact that, in
cyclic systems, the protons adjacent to the nitrogen atom and
on the same side of the N lone pair undergo a strong
deshielding effect, whereas the protons on the opposite side
Conclusion
In summary, we have developed a short, efficient and versatile
synthetic route towards the synthesis of 14-azasteroids using
intramolecular S 29 cyclization. The developed strategy may
N
prove beneficial to produce several new azasteroidal scaffolds,
considering the easy availability of L- as well as D-amino acids.
Importantly, the final molecules bear the double bond at
9
(11)
D
, which could well be exploited to produce a large pool of
2
2 1
are strongly shielded. H NMR of 1g shows only one signal in
the region of 3–4 ppm, i.e., at 3.8 ppm, due to the effect of
nitrogen lone pair, which is attributable to 15a-H which being
cis to the lone pair is deshielded. The lack of other signals in
this region of the other adjacent protons is consistent of trans
fusion of the C–D ring system. Thus, the protons at 13b, 8b
and 15b are shielded being anti-periplanar to the nitrogen lone
biologically relevant chiral azasteroids. The biological evalua-
tion of the synthesized molecules is currently underway.
Experimental section
General methods
1
pair. However, in contrast, H NMR of 1g9 shows two signals in
All dry reactions were carried out under an argon or nitrogen
atmosphere in oven-dried glassware using standard gas-light
syringes, cannulas and septa. All reagents and solvents were
dried prior to use according to standard methods. Commercial
reagents were used without further purification unless other-
wise stated. Reactions were monitored on silica gel TLC plates
the region of 3–4 ppm, one at 3.53 ppm and another at 3.33
ppm attributable to 15a-H and 8a-H (generated stereocenter),
respectively, based on above arguments. A similar trend was
observed in other cases too.
9
(11)
We also subjected one of the D
hydrogenation conditions (Pd/C, H
dehydroazasteroid 1g to
(coated with TLC grade silica gel). Detecting agent used (for
2
), which furnished fully
TLC) were iodine vapors. Column chromatography was
saturated azasteroid 1g9 in 74% yield. The stereochemical
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9(11)
a
Table 1 Synthesis of D
14-azasteroidal skeletons 1
b
c
b
c
Entry
Bromo 3
Aldehyde 4
Intermediate Carbinol 2, (d.r.) , yield%
Target 1, (d.r.) , yield%
1
3a
3b
3c
4b
d
2b + 2b9, (3 : 1), 69%
1b + 1b9, (1.5 : 1), 73%
2
3
4a
4c
—
2c + 2c9, (1.5 : 1), 58%
2d + 2d9, (1.4 : 1), 55%
1d + 1d9, (1.3 : 1), 71%
4
3c
4d
2
2
e + 2e9, (1.1 : 1), 58%
1e + 1e9, (1.1 : 1), 76%
5
6
3e
3a
4a
4c
—
f + 2f9, (1.4 : 1), 62%
2g + 2g9, (1.3 : 1), 57%
2h + 2h9, (1.2 : 1), 64%
2i + 2i9, (1.3 : 1), 63%
1g + 1g9, (1.3 : 1), 78%
7e
3c
3d
3c
4e
4a
4a
e
1h + 1h9, (1.4 : 1), 44%
8
—
9
2j + 2j9, (1.3 : 1), 61%
1j + 1j9, (1.3 : 1), 71%
a
b
c
Reactions were carried out as depicted in Scheme 3. d.r. was determined from the isolated yield/crude nmr. Combined yield of both
d
e
3 3
diastereoisomers. 2b, R = Boc; 2b9, R = H. Products 1h + h9 were inseparable in pure form.
1
9536 | RSC Adv., 2013, 3, 19533–19544
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(300 MHz, CDCl
3
): d 7.63–7.60 (m, 1H), 7.17–7.08 (m, 3H),
6
2
.37–6.36 (m, 1H), 3.58–3.52 (m, 1H), 3.00–2.90 (m, 3H), 2.48–
.19 (m, 6H), 2.12–2.02 (m, 1H), 2.00–1.90 (m, 1H), 1.87–1.80
1
3
(m, 1H), 1.78–1.69 (m, 1H), 1.66–1.56 (m, 1H); C NMR (75
MHz, CDCl ): d 135.4, 135.3, 133.4, 128.9, 126.8, 125.9, 123.9,
3
1
18.6, 63.3, 59.8, 52.4, 32.6, 30.6, 29.1, 28.7, 21.3; HRMS(ESI/Q-
+
TOF) [M + H] calcd for C16
H20N 226.159, found 226.159.
(4aS,12aS)-1,2,3,4a,5,6,12,12a-octahydrobenzo[f]pyrrolo[1,2-
a]quinoline (1a9)
2
8
[
(
a] 23.46 (c 0.10, CHCl ); R 0.44 (10% MeOH in CHCl ); IR
D
3 f 3
2
1 1
Neat): 2932, 2347, 1630, 1221, 769, cm ; H NMR (300 MHz,
): d 7.50–7.47 (m, 1H), 7.18–7.08 (m, 3H), 6.28–6.26 (m,
H), 3.63–3.60 (m, 1H), 3.34–3.23 (m, 2H), 3.08–2.94 (m, 3H),
.64–2.55 (m, 1H), 2.41–2.33 (m, 1H), 2.27–2.10 (m, 2H), 2.04–
CDCl
3
1
2
1
3
Fig. 2 NOESY interactions as observed in 1b.
1.88 (m, 3H), 1.71–1.60 (m, 1H); C NMR (75 MHz, CDCl
): d
3
1
5
35.7, 134.9, 134.5, 128.6, 127.4, 126.2, 123.8, 118.9, 56.9, 54.9,
0.7, 29.7, 29.1, 28.6, 26.2, 21.7; HRMS(ESI/Q-TOF) [M + H]
+
calcd for C H N 226.159, found 226.160.
performed over silica gel (230–400 mesh) using freshly
distilled solvents. Mass spectra were recorded using electron
spray ionization (ESI-MS) or fast atom bombardment spectra
16 20
(
4aR,12aS)-12a-methyl-1,2,3,4a,5,6,12,12a-
octahydrobenzo[f]pyrrolo[1,2-a]quinoline (1b)
As described for 1a/1a9, 2b/2b9 (80 mg, 0.22 mmol) in dioxane
2 mL), 4 M HCl in dioxane (1.5 mL), Et N (0.16 mL, 1.1 mmol)
(FAB-MS) using argon/xenon as the FAB gas. HRMS spectra
were recorded using ESI/Q-TOF conditions. IR spectra were
1
13
(
recorded as thin films on salt (NaCl) plates. H NMR and
NMR spectra were recorded using CDCl as solvent.
Tetramethylsilane (0.00 ppm) served as an internal standard
C
3
in MeOH (2 mL) furnished 1b and 1b9 (39 mg, 73%) as viscous
3
2
8
colorless oil, For 1b, [a]D = +31.78 (c 0.22, CHCl ); R 0.52 (10%
3
f
1
13
MeOH in CHCl
3
); IR (Neat): 2924, 2855, 2375, 1634, 1261, 771,
cm ; H NMR (300 MHz, CDCl ): d 7.54–7.51 (m, 1H), 7.10–
.02 (m, 3H), 6.24–6.22 (m, 1H), 3.34–3.30 (m, 1H), 3.18–3.11
m, 1H), 2.90–2.84 (m, 2H), 2.69 (m, 1H), 2.42–2.36 (m, 1H),
3
in H NMR and CDCl (77.0 ppm) in C NMR. All spectra were
2
1 1
recorded at 25 uC. Coupling constants (J values) are given in
hertz (Hz). Chemical shifts are expressed in parts per million.
3
7
(
Typical procedure for 6-endo trig cyclization (S
the azasteroids (4aR, 12aS)-1,2,3,4a,5,6,12,12a-
octahydrobenzo[f]pyrrolo[1,2-a]quinoline (1a)
N
29) to access
2
1
1
4
.31–2.27 (m, 1H), 2.18–2.09 (m, 1H), 1.91–1.83 (m, 3H), 1.77–
.64 (m, 2H), 1.02 (s, 3H); C NMR (75 MHz, CDCl ): d
35.4(2C), 132.9, 129.1, 127.1, 126.1, 123.7, 117.4, 59.2, 55.9,
1
3
3
6.9, 38.2, 37.1, 28.8, 28.1, 19.7, 16.5; HRMS(ESI/Q-TOF) [M +
To a solution of allylic alcohol 2a/2a9 (50 mg, 0.14 mmol) in
anhydrous dioxane (2 mL) at 0 uC, a solution of HCl in dioxane
+
H] calcd for C17
H
22N 240.174, found 240.175.
(
4 M, 1 mL) was added; the resulting yellow solution was
(
4aS,12aS)-12a-methyl-1,2,3,4a,5,6,12,12a-
stirred at r.t for 30 min. Reaction mixture was concentrated
and the crude residue was dissolved in methanol (2 mL) and
then treated with Et
temperature. Stirring was continued for 15 min. After the
completion of reaction, the solvent was removed under
vacuum followed by usual workup with DCM/water. The
combined organic extracts were washed with brine and dried
over Na SO . The residue was purified by flash column
octahydrobenzo[f]pyrrolo[1,2-a]quinoline (1b9)
2
8
[a] 29.88 (c 0.23, CHCl ); R 0.45 (10% MeOH in CHCl ); IR
D
3 f 3
3
N (0.10 mL, 0.73 mmol) at room
2
1 1
(Neat): 2931, 2373, 1636, 1219, 771, cm ; H NMR (300 MHz,
CDCl ): d 7.54–7.51 (m, 1H), 7.17–7.07 (m, 3H), 6.29–6.27 (m,
1
2
3
H), 3.47–3.44 (m, 1H), 3.42–3.38 (m, 1H), 2.93–2.82 (m, 3H),
.42–2.31 (m, 2H), 2.15 (dd, 1H, J = 6.9, J = 17.0), 2.02–2.00
1
2
1
3
(
m, 1H), 1.97–1.74 (m, 4H), 1.28(s, 3H); C NMR (75 MHz,
CDCl ): d 135.5, 134.6, 133.8, 128.9, 127.2, 126.1, 123.5, 117.5,
9.1, 57.9, 53.9, 38.5, 32.2, 30.12, 29.8, 26.4, 20.3; HRMS(ESI/Q-
2
4
chromatography (230–400 mesh silica) using MeOH : CHCl3
10 : 90) as eluent which furnished the cyclized products 1a
and 1a9 (26 mg, 75%) as viscous oil.
3
5
(
+
TOF) [M + H] calcd for C H N 240.174, found 240.175.
17 22
2
8
3 f
For 1a[a]D = +69.58 (c 0.10, CHCl ); R 0.58 (10% MeOH in
(2R,4aR,12aR)-2-(benzyloxy)-9-methoxy-1,2,3,4a,5,6,12,12a-
2
1 1
CHCl ) IR (Neat): 2928, 2854, 2362, 1629, 769, cm ; H NMR
3
octahydrobenzo[f]pyrrolo[1,2-a]quinoline (1d)
As described for 1a/1a9, 2d/2d9 (80 mg, 0.17 mmol) in dioxane
(2 mL), 4 M HCl in dioxane (1.2 mL), Et
3
N (0.12 mL, 0.83
mmol) in MeOH (2 mL) furnished 1d and 1d9 (43 mg, 71%) as
2
8
viscous colorless oil, For 1d; [a]D = +6.76 (c 0.22, CHCl ); R
3
f
0
1
5
2
.57 (3% MeOH in CHCl ); IR (Neat): 2963, 2853, 2361, 1637,
3
2
1 1
219, 772, cm ; H NMR (300 MHz, CDCl
H), 7.09 (d, 1H, J = 2.5), 7.00 (d, 1H, J = 8.4), 6.73 (dd, 1H, J
.5, J = 8.4), 6.32–6.30 (m, 1H), 4.50 (dd, 2H, J = 11.7, J
2
3
): d 7.34–7.26 (m,
1
=
=
2
1
Scheme 5 Hydrogenation of 1g.
17.1), 4.30–4.25 (m, 1H), 3.90–3.83 (m, 1H), 3.80 (s, 3H), 3.04–
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2.96 (m, 1H), 2.83–2.66 (m, 3H), 2.45–2.38 (m, 2H), 2.37–2.18
for 2 h under H
2
(balloon) at r.t. Reaction mixture was then
(
m, 2H), 2.16–2.12 (m, 1H), 1.82–1.71 (m, 1H), 1.65–1.54 (m,
filtered through silica pad followed by concentration of the
organic solvent under vacuum. Flash column chromatogarphy
of obtained crude furnished the fully saturated diastereomeri-
1
3
1
1
7
H); C NMR (75 MHz, CDCl ): d 157.9, 138.2, 135.4, 134.2,
3
29.9, 128.4 (2C), 127.9, 127.7, 127.6 (2C), 118.4, 113.7, 108.3,
6.9, 71.2, 62.9, 59.6, 57.7, 55.3, 38.6, 32.4, 29.3, 27.8;
cally pure azasteroid 1g9 (3.6 mg, 74%) as viscous colorless oil.
+
28
HRMS(ESI/Q-TOF) [M + H] calcd for C24
found 362.211.
H
28NO
2
362.211,
3 f 3
[a]D = +69.16 (c 0.20, CHCl ); R 0.82 (1% MeOH in CHCl ); IR
2
1 1
(Neat): 2930, 2807, 2357, 1217, 770, cm ; H NMR (300 MHz,
CDCl ): d 7.37–7.30 (m, 6H), 7.18–7.10 (m, 3H), 4.51 (dd, 2H, J1
3
(
2R,4aS,12aR)-2-(benzyloxy)-9-methoxy-1,2,3,4a,5,6,12,12a-
=
2
11.5, J = 16.4), 4.27–4.25 (m, 1H), 3.82–3.77 (m, 1H), 2.95–
.92 (m, 2H), 2.65–2.54 (m, 2H), 2.43–2.42 (m, 1H), 2.31–2.29
2
octahydrobenzo[f]pyrrolo[1,2-a]quinoline (1d9)
2
D
8
[a] = +2.83 (c 0.20, CHCl ); R 0.50 (10% MeOH in CHCl ); IR
(m, 1H), 2.28–2.03 (m, 4H), 2.01–1.83 (m, 4H); HRMS(ESI/Q-
3
f
3
2
1
1
+
(
Neat): 2925, 2356, 1634, 1223, 771, cm ; H NMR (300 MHz,
): d 7.35–7.30 (m, 5H), 6.70–6.94 (m, 2H), 6.73 (dd, 1H, J
2
2.7, J = 8.4), 6.13–6.16 (m, 1H), 4.51 (dd, 2H, J = 11.4, J =
TOF) [M + H] calcd for C23
H28NO 334.217, found 334.217.
CDCl
3
1
(1S,4aR,12aR)-1-(benzyloxy)-9-methoxy-1,2,3,4a,5,6,12,12a-
=
1
3
2
1
1
1
2
2
1
octahydrobenzo[f]pyrrolo[1,2-a]quinoline (1e)
4.1), 4.30–4.27 (m, 1H), 3.80 (s, 3H), 3.56–3.52 (m, 1H), 3.40–
.35 (m, 1H), 3.17 (m, 1H), 3.05–2.96 (m, 1H), 2.91–2.86 (m,
H), 2.58–2.46 (m, 1H), 2.27–2.24 (m, 1H), 2.11–2.02 (m, 3H),
As described for 1a/1a9, 2e/2e9 (40 mg, 0.08 mmol) in dioxane
(1 mL), 4 M HCl in dioxane (0.6 mL), Et
N (0.06 mL, 0.42
3
1
3
.84–1.74 (m, 1H); C NMR (75 MHz, CDCl ): d 157.9, 138.1,
mmol) in MeOH (1 mL) furnished 1e and 1e9 (21 mg, 70%) as
3
2
8
37.2, 136.6, 129.6, 128.4(2C), 127.7(2C), 127,6, 127.2, 118.9,
viscous colorless oil, For 1e; [a]D = +4.16 (c 0.10, CHCl
0.59 (4% MeOH in CHCl ); IR (Neat): 2965, 2863, 2367, 1636,
1218, 772, cm ; H NMR (300 MHz, CDCl ): d 7.36–7.28 (m,
5H), 7.09 (d, J = 2.6, 1H), 7.00 (d, J = 8.4, 1H), 6.74 (dd, J = 2.4,
= 8.4, 1H), 6.33–6.31 (m, 1H), 4.54 (dd, J = 11.7, J = 22.6,
); R
3 f
13.8, 108.3, 77.2, 71.4, 56.3, 55.5, 55.3, 52.1, 37.7, 31.9, 29.3,
3
+
21 1
8.0; HRMS(ESI/Q-TOF) [M + H] calcd for C24
H28NO
2
362.211,
3
found 362.211.
1
J
2
1
2
(
2R,4aR,12aR)-2-(benzyloxy)-1,2,3,4a,5,6,12,12a-
2
3
H), 3.92–3.89 (m, 1H), 3.80 (s, 3H), 3.48–3.45 (m, 1H), 3.04–
.00 (m, 1H), 2.85–2.81 (m, 2H), 2.63–2.61 (m, 1H), 2.56–2.42
octahydrobenzo[f]pyrrolo[1,2-a]quinoline (1g)
As described for 1a/1a9, 2g/2g9 (80 mg, 0.18 mmol) in dioxane
2 mL), 4 M HCl in dioxane (1.2 mL), Et N (0.12 mL, 0.90
mmol) in MeOH (2 mL) furnished 1g and 1g9 (46 mg, 78%) as
(m, 1H), 2.31–2.27 (m, 3H), 2.01 (m, 1H), 1.86–1.84 (m, 1H);
+
(
3
HRMS(ESI/Q-TOF) [M + H] calcd for C24
found 362.214.
H28NO 362.211,
2
2
D
8
viscous colorless oil, For 1g; [a] = +72.86 (c 0.20, CHCl
3
); R
); IR (Neat): 2931, 2801, 2355, 1636,
218, 771, cm ; H NMR (300 MHz, CDCl ): d 7.53–7.50 (m,
f
(1S,4aS,12aR)-1-(benzyloxy)-9-methoxy-1,2,3,4a,5,6,12,12a-
0
1
1
4
1
2
2
.62 (1% MeOH in CHCl
3
2
1 1
octahydrobenzo[f]pyrrolo[1,2-a]quinoline (1e9)
3
2
D
8
H), 7.28–7.20 (m, 5H), 7.08–7.00 (m, 3H), 6.27–6.25 (m, 1H),
[a] = +1.21 (c 0.05, CHCl
3
); R
(Neat): 2923, 2357, 1631, 1222, 771, cm ; H NMR (300 MHz,
CDCl ): d 7.35–7.29 (m, 5H), 6.99 (d, J = 8.7, 1H), 6.94 (d, J = 2.3,
1H), 6.74 (dd, J = 2.6, J = 8.2, 1H), 6.14 (m, 1H), 4.54 (dd, J
11.7, J = 21.2, 2H), 3.86–3.83 (m, 1H), 3.79 (s, 3H), 3.57–3.53
f 3
0.53 (10% MeOH in CHCl ); IR
2
1 1
.43 (dd, 2H, J = 11.3, J = 17.5), 4.24–4.18 (m, 1H), 3.81 (dd,
1
2
H, J = 6.8, J = 9.8), 3.01–2.97 (m, 1H), 2.85–2.83 (m, 1H),
3
1
2
.82–2.80 (m, 1H), 2.38–2.28 (m, 2H), 2.24–2.17 (m, 2H), 2.12–
1
2
1
=
1
3
.06 (m, 1H), 1.76–1.70 (m, 1H), 1.66–1.56 (m, 1H); C NMR
): d 138.3, 135.4(2C), 133.4, 128.9, 128.4(2C),
2
(75 MHz, CDCl
3
(m, 1H), 3.21–3.18 (m, 1H), 2.97–2.86 (m, 3H), 2.61–2.55 (m,
+
1
5
27.7(2C), 127.6, 126.9, 126.0, 123.9, 118.1, 76.9, 71.2, 62.9,
9.6, 57.7, 38.6, 32.6, 29.1, 28.6; HRMS(ESI/Q-TOF) [M + H]
1H), 2.27–2.34 (m, 3H), 2.02–1.91 (m, 3H); HR-MS [M + H]
+
calcd for C24
H28NO 362.211, found 362.211.
2
calcd for C H NO 332.200, found 332.201.
2
3
26
(4aR,12aS)-9-methoxy-1,2,3,4a,5,6,12,12a-
(
2R,4aS,12aR)-2-(benzyloxy)-1,2,3,4a,5,6,12,12a-
octahydrobenzo[f]pyrrolo[1,2-a]quinoline (1j)
octahydrobenzo[f]pyrrolo[1,2-a]quinoline (1g9)
As described for 1a/1a9, 2j/2j9 (80 mg, 0.21 mmol) in dioxane (2
2
D
8
[
(
a] 22.83 (c 0.22, CHCl
3
); R
f
0.54 (1% MeOH in CHCl
3
); IR
mL), 4 M HCl in dioxane (1.3 mL), Et
3
N (0.14 mL, 1.05 mmol)
2
1 1
Neat): 2939, 2353, 1629, 1212, 759, cm ; H NMR (300 MHz,
in MeOH (2 mL) furnished 1j/1j9 (38 mg, 71%) as viscous
2
8
CDCl
3
): d 7.44–7.41 (m, 1H), 7.35–7.30 (m, 5H), 7.14–7.07 (m,
colorless oil, [a]D = +45.86 (c 0.20, CHCl
); R 0.66 (1% MeOH
3 f
2
1
3
4
3
2
H), 6.12–6.10 (m, 1H), 4.51 (dd, 2H, J = 11.6, J = 14.4), 4.28–
.26 (m, 1H), 3.55–3.51 (m, 1H), 3.33 (dd, 1H, J = 6.3, J = 9.7),
in CHCl ); IR (Neat): 2932, 2811, 2345, 1637, 1218, 771, cm
H NMR (300 MHz, CDCl
= 8.3), 6.68 (dd, J = 2.3, J
3
;
1
2
1
): d 7.02(d, 1H, J = 2.4), 6.93 (d, 1H, J
1
2
3
.11–3.08 (m, 1H), 3.01–2.92 (m, 2H), 2.50–2.41 (m, 1H), 2.28–
.24 (m, 1H), 2.11–2.04 (m, 2H), 1.83–1.73 (m, 2H), 1.60–1.50
1
2
= 8.2, 1H), 6.28 (m, 1H), 3.73(s, 3H),
3.49 (m, 1H), 2.93 (m, 1H), 2.79–2.76 (m, 2H), 2.35–2.23 (m,
1
3
(
1
7
m, 1H); C NMR (75 MHz, CDCl
3
): d 138.3, 137.6, 136.0,
34.9, 128.6, 128.4, 127.7, 127.6, 127.0, 125.9, 123.8, 118.8,
7.0, 71.3, 56.3, 55.7, 51.7, 38.0, 31.2, 28.9, 24.8; HRMS(ESI/Q-
5H), 1.99–1.90 (m, 2H), 1.78–1.67 (m, 2H), 1.60–1.58 (m, 1H);
+
HRMS(ESI/Q-TOF) [M + H] calcd for C17
256.170.
H22NO 256.170, found
+
TOF) [M + H] calcd for C23
H
26NO 332.200, found 332.201.
For 1j9: this isomer was inseparable in pure form.
(
2R,4aR,10bR,12aR)-2-(benzyloxy)-1,2,3,4a,5,6,10b,11,12,12a-
tert-butyl 2-(2-hydroxy-2-(1,2,3,4-tetrahydronaphthalen-1-
yl)ethyl)pyrrolidine-1-carboxylate (2a/2a9)
decahydrobenzo[f]pyrrolo[1,2-a]quinoline (1g9)
To a stirred solution of 1g (5 mg, 0.015 mmol) in ethyl acetate
To a stirred solution of bromo substrate 3a (300 mg, 1.45
at r.t. was added Pd/C (10 mol%), and reaction was left stirring
2
mmol) in anhydrous THF (15 mL) at 278 uC and under N , n-
1
9538 | RSC Adv., 2013, 3, 19533–19544
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BuLi (1.6 M in hexane, 0.90 mL, 1.45 mmol) was added. The
resulting yellow solution was stirred at 278 uC for 30 min after
which aldehyde 4a (278 mg, 1.30 mmol) in THF (2 mL) was
added and stirred at 278 uC for 1 h followed by overnight
stirring at room temperature. It was then quenched with sat.
(2R,4R)-tert-butyl 4-(benzyloxy)-2-(2-hydroxy-2-(7-methoxy-3,4-
dihydronaphthalen-1-yl)ethyl)pyrrolidine-1-carboxylate (2d/
2d9)
As described for 2a/2a9, 3c (300 mg, 1.25 mmol) in THF (15
mL), n-BuLi (0.78 mL, 1.25 mmol), aldehyde 4c (358 mg, 1.12
mmol) in THF (2 mL) furnished 2d/2d9 (330 mg, 55%) as
NH
4
Cl solution (10 mL), and was extracted with ethyl acetate (3
6
20 mL), washed with brine and dried over Na SO . The
2
4
2
8
colorless semisolid, For 2d: [a]D 28.22 (c 0.54, MeOH); R 0.58
f
extract was subjected to column chromatography on silica gel
and elution with 20% ethyl acetate in hexane furnished
(
20% EtOAc in hexane); IR (Neat): 3436, 3021, 2330, 1564, 1219
21
1
cm ; H NMR (300 MHz, CDCl ): d 7.31–7.30 (m, 5H), 7.04 (d,
3
2
8
alcohol 2a/2a9 (325 mg, 66%) as semi solid. For 2a: [a]D = +2.02
c 0.46, CHCl ); R 0.62 (15% EtOAc in hexane), IR (Neat): 3430,
362, 1559, 1219, 761, 670 cm ; H NMR (300 MHz, CDCl
.27 (m, 1H), 7.20–7.13 (m, 3H), 6.25 (m, 1H), 5.23 (s, 1H), 4.70
1
1
4
H, J = 8.3), 6.90 (s, 1H), 6.67 (dd, 1H, J = 2.2, J = 8.0), 6.25 (m,
1 2
H), 5.01–4.90 (m, 1H), 4.65 (br, s, 1H), 4.47–4.43 (m, 2H),
.15–4.14 (m, 2H), 3.78 (s, 3H), 3.61–3.58 (m, 1H), 3.44–3.42
(
2
7
3
f
2
1 1
3
): d
(
m, 1H), 2.67–2.62 (m, 2H), 2.28–2.21 (m, 2H), 2.04–1.70 (m,
H), 1.48 (s, 9H); C NMR (50 MHz, CDCl ): d 158.1, 156.7,
3
(s, 1H), 4.30 (br, s, 1H), 3.38–3.34 (m, 2H), 2.74–2.70 (m, 2H),
13
4
1
1
2
2
9
1
4
.31–2.27 (m, 2H), 2.04–1.81 (m, 4H), 1.74–1.65 (m, 2H),1.50 (s,
H); C NMR (75 MHz, CDCl ): d 156.8, 138.4, 136.8, 133.8,
3
38.1, 137.8, 134.6, 128.9, 128.3, 128.1, 127.6, 127.5, 125.0,
11.2, 109.2, 80.3, 76.8, 71.2, 66.9, 55.1, 52.8, 51.1, 43.3, 37.8,
1
3
27.6, 126.4, 126.2, 124.2, 122.7, 80.0, 67.9, 66.8, 53.9, 46.5,
+
+
8.3, 27.3, 23.1; ESI-MS m/z 423 [M-tBu] , 462 [M-OH] ,
+
2.8. 31.2, 28.4, 28.3, 23.6; ESI-MS m/z 225 [M-OH-Boc] ,
+
5
HRMS(ESI/Q-TOF) [M + H] calcd for C29H37NO 479.267,
+
HRMS(ESI/Q-TOF) [M + H] calcd for C21
3
H29NO 343.215,
found 479.268.
found 343.213.
28
For 2d9: [a]D 232.22 (c 0.2, CHCl ); R 0.46 (20% EtOAc in
3
f
2
8
For 2a9: [a]D 220.62 (c 0.24, CHCl
hexane), IR (Neat): 3432, 2359, 1563, 1220, 760, 671 cm ; H
NMR (300 MHz, CDCl ): d 7.27 (m, 1H), 7.22–7.14 (m, 3H), 6.23
m, 1H), 4.80–4.76 (m, 1H), 4.14–4.11 (m, 1H), 3.34–3.28 (m,
3
); R
f
0.46 (15% EtOAc in
21 1
hexane); IR (Neat): 3433, 2328, 1565, 1217 cm ; H NMR (300
2
1 1
MHz, CDCl ): d 7.31–7.30 (m, 5H), 7.06 (d, 1H, J = 8.7), 6.92 (s,
3
3
1
2
2
9
1
7
H), 6.68 (d, 1H, J = 7.8), 6.24 (m, 1H), 4.73 (br, s, 1H), 4.48 (m,
H), 4.24 (m, 2H), 4.11–4.08 (m, 1H), 3.78 (s, 3H), 3.54–3.39 (m,
(
2
1
1
7
H), 2.74–2.66 (m, 2H), 2.31–2.25 (m, 2H), 2.07–1.95 (m, 3H),
H), 2.63–2.61 (m, 2H), 2.25 (m, 3H), 2.04–1.80 (m, 3H), 1.46 (s,
1
3
.88–1.76 (m, 4H),1.46 (s, 9H); C NMR (75 MHz, CDCl
3
): d
13
3
H); C NMR (50 MHz, CDCl ): d 158.1, 155.5, 139.1, 137.9,
55.6, 139.3, 136.9, 133.6, 127.7, 126.5, 126.2, 124.0, 122.6,
9.7, 69.7, 55.9, 54.8, 46.3, 43.4, 32.1, 28.5, 28.3, 23.8; ESI-MS
34.4, 129.0, 128.3, 128.2, 127.5, 124.9, 110.9, 109.5, 79.9, 76.4,
0.9, 69.9, 55.2, 54.7, 51.3, 43.3, 38.3, 28.4, 27.3, 23.1; ESI-MS
+
+
m/z 225 [M-OH-Boc] , HRMS(ESI/Q-TOF) [M + H] calcd for
343.215, found 343.214.
+
+
+
m/z 361 [M-OH-Boc] , 462 [M-OH] , HRMS(ESI/Q-TOF) [M + H]
calcd for C29 479.267, found 479.269.
21 3
C H29NO
H37NO
5
(
S)-tert-butyl 2-(2-(3, 4-dihydronaphthalen-1-yl)-2-
(
2R,4R)-tert-butyl 4-(benzyloxy)-2-(2-(3,4-dihydronaphthalen-1-
hydroxyethyl)-2-methylpyrrolidine-1-carboxylate (2b/2b9)
yl)ethyl)pyrrolidine-1-carboxylate (2g/2g9)
As described for 2a/2a9, 3a (300 mg, 1.45 mmol) in THF (15
mL), n-BuLi (0.9 mL, 1.45 mmol), aldehyde 4b (295 mg, 1.30
mmol) in THF (2 mL) furnished 2b/2b9 (353 mg, 69%) as
As described for 2a/2a9, 3a (300 mg, 1.45 mmol) in THF (15
mL), n-BuLi (0.90 mL, 1.45 mmol), aldehyde 4c (416 mg, 1.30
mmol) in THF (4 mL) furnished 2g/2g9 (354 mg, 57%) as
2
8
colorless semisolid. For 2b: [a] 241.04 (c 0.45, CHCl
3
); R
f
0.56
28
D
colorless semisolid, For 2g: [a]D = +19.21 (c 0.50, CHCl ); R
3
f
(
15% EtOAc in hexane); IR (Neat): 3428, 3029, 2331, 1569, 1217
0
.61 (20% EtOAc in hexane); IR (Neat): 3439, 3018, 2328, 1559,
2
1 1
cm ; H NMR (300 MHz, CDCl ): d 7.40 (m, 1H), 7.20–7.14 (m,
21 1
3
1217 cm ; H NMR (300 MHz, CDCl ): d 7.24 (m, 6H), 7.06 (m,
3
3
=
3
1
7
H), 6.21 (m, 1H), 4.88 (m, 1H), 3.95–3.42 (m, 3H), 2.71 (t, 2H, J
3
4
2
H), 6.16 (m, 1H), 4.93 (br, s, 1H), 4.61 (s, 1H), 4.40 (m, 3H),
7.9), 2.28–2.23 (m, 2H), 2.13–2.00 (m, 3H), 1.81–1.76 (m,
.08–4.06 (m, 2H), 3.51–3.36 (m, 3H), 2.66–2.26 (t, 2H, J = 7.8),
1
3
H),1.47 (s, 9H), 1.43 (s, 3H); C NMR (50 MHz, CDCl
3
): d
13
.23–2.20 (m, 2H), 1.66–1.63 (m, 2H), 1.42 (s, 9H); C NMR (50
54.7, 137.0, 136.9, 127.7, 126.6, 126.3, 126.2, 124.9, 123.0,
9.59, 69.2, 62.6, 62.3, 48.7, 48.5, 28.5, 28.3, 26.0, 22.8, 21.7;
MHz, CDCl
3
): d 156.8, 138.2, 137.8, 136.8, 133.7, 128.4(3C),
27.7(2C), 127.5, 126.4, 126.2, 124.3, 122.7, 80.4,77.2, 71.2,
6.8, 52.9, 51.1, 43.4, 37.8, 28.3, 28.2, 22.7; ESI-MS m/z 331[M-
1
6
+
+
ESI-MS m/z 239 [M-OH-Boc] , 340 [M-OH] , HRMS(ESI/Q-TOF)
+
+
+
+
[M + H] calcd for C H NO 357.230, found 357.232.
22 31 3
OH-Boc] , 432[M-OH] , HRMS(ESI/Q-TOF) [M + H] calcd for
449.257, found 449.258.
2
8
For 2b9: [a]D 249.84 (c 0.12, CHCl
hexane); IR (Neat): 3427, 3028, 2329, 1571, 1216 cm ; H NMR
300 MHz, CDCl ): d 7.17 (m, 4H), 6.36 (m, 1H), 5.45 (d, 1H, J =
1.3), 3.81–3.71 (m, 2H), 3.56–3.50 (m, 1H), 2.76–2.71 (m, 2H),
.36–2.27 (m, 3H), 2.03–1.95 (m, 3H), 1.87–1.83 (m, 1H), 1.68–
3 f
); R 0.46 (50% EtOAc in
28 4
C H35NO
2
1 1
28
For 2g9:[a]D 258.52 (c 0.20, CHCl
hexane); IR (Neat): 3436, 3021, 2327, 1579, 1216 cm ; H NMR
300 MHz, CDCl ): d 7.24 (m, 6H), 7.06 (m, 3H), 6.14 (m, 1H),
3 f
); R 0.56 (20% EtOAc in
2
1 1
(
3
1
2
1
1
4
(
3
4
1
.70 (br, s, 1H), 4.41 (s, 2H), 4.18 (s, 1H), 4.02 (m, 1H), 3.80 (m,
H), 3.47–3.32 (m, 2H), 2.65–2.61 (m, 2H), 2.20 (m, 3H), 1.94
1
3
3
.59 (m, 2H), 1.38 (s, 3H); C NMR (50 MHz, CDCl ): d 136.7,
34.3, 132.4, 128.0, 127.1, 126.5, 126.4, 121.8, 73.4, 59.8, 46.1,
0.7, 40.5, 27.9, 25.00, 22.6, 21.3; ESI-MS m/z 241 [M-OH + 1] ,
1
3
(m, 1H), 1.68 (m, 2H), 1.42 (s, 9H); C NMR (50 MHz, CDCl3):
+
d 155.6, 139.2, 137.9, 136.9, 133.4, 130.0, 128.9(3C), 127.7(2C),
+
HRMS(ESI/Q-TOF) [M + H] calcd for C H NO 357.230,
2
2
31
3
127.6, 126.2, 124.1, 122.6, 79.9, 76.4, 71.0, 69.8, 54.8, 51.4,
+
found 357.233.
43.4, 38.3, 28.4, 28.2, 22.7; ESI-MS m/z 331 [M-OH-Boc] ,
+
HRMS(ESI/Q-TOF) [M + H] calcd for C28
found 449.259.
4
H35NO 449.257,
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(
2R,3S)-tert-butyl 3-(benzyloxy)-2-(2-hydroxy-2-(7-methoxy-3,4-
dihydronaphthalen-1-yl)ethyl)pyrrolidine-1-carboxylate (2e/
e9)
1H), 4.27 (m, 1H), 3.77 (s, 3H), 3.39–3.35 (m, 2H), 2.00–1.85 (m,
3H), 1.76–1.68 (m, 1H), 1.62–1.58 (m, 2H), 1.50 (s, 9H), 1.44 (s,
1
3
2
3H), 1.38 (s, 3H); C NMR (50 MHz, CDCl
3
): d 160.0, 156.7,
54.4, 133.4, 123.7, 122.9, 114.0, 106.3, 102.2, 80.0, 76.0, 65.9,
5.0, 53.6, 46.4, 42.7, 31.1, 28.3, 28.1, 27.1, 23.4 ESI-MS m/z 285
1
5
As described for 2a/2a9, 3c (300 mg, 1.25 mmol) in THF (15
mL), n-BuLi (0.78 mL, 1.25 mmol), aldehyde 4d (358 mg, 1.12
mmol) in THF (2 mL) furnished 2e/2e9 (348 mg, 58%) as
+
+
+
[
M-OH-Boc] , 386 [M-OH] , HRMS(ESI/Q-TOF) [M + H] calcd
for C23 403.236, found 403.237.
For 2f9: [a]D 226.33 (c 1.0, MeOH); R
hexane); IR (Neat): 3437, 3021, 2315, 1585, 1211 cm ; H NMR
300 MHz, CDCl ): d 7.10 (d, 1H, J = 6.1), 6.44–6.41 (m, 2H),
.67 (s, 1H), 4.70 (s, 1H), 4.32 (br, s, 1H), 4.10–4.08 (m, 1H),
.76 (s, 3H), 3.35–3.32 (m, 2H), 2.07–1.98 (m, 1H), 1.86–1.68
H
33NO
5
2
D
8
colorless semisolid; For 2e: [a] = +2.23 (c 0.20, MeOH); R 0.61
f
28
f
0.42 (25% EtOAc in
(25% EtOAc in hexane); IR (Neat): 3431, 3019, 2334, 1567, 1216
2
1 1
2
1 1
cm ; H NMR (300 MHz, CDCl ): d 7.33–7.27 (m, 5H), 7.05 (d,
3
(
5
3
3
1
2
3
1
H, J = 8.0), 6.90 (s, 1H), 6.87 (d, 1H, J
.4, J = 8.1), 6.30–6.27 (m, 1H), 4.70–4.37 (m, 4H), 3.78 (s, 3H),
.73–3.37 (m, 3H), 2.67–2.61 (m, 2H), 2.30–2.25 (m, 2H), 2.03–
1 1
= 2.1), 6.68 (dd, 1H, J =
2
1
3
1
3
(m, 5H), 1.47 (s, 9H), 1.43 (s, 3H), 1.37 (s, 3H); C NMR (50
.96 (m, 3H), 1.80–1.70 (m, 2H), 1.51 (s, 9H); C NMR (50
): d 158.2, 157.1, 138.1, 134.7, 129.0, 128.4(3C),
28.2, 127.6(2C), 127.5(2C), 125.1, 111.4, 109.2, 82.4, 80.3, 70.5,
6.5, 59.2, 55.2, 44.9, 41.3, 28.4, 27.4, 23.2; ESI-MS m/z 423 [M-
MHz, CDCl ): d 160.2, 155.5, 154.6, 134.3, 123.6, 122.9, 113.9,
3
MHz, CDCl
1
6
3
1
2
06.5, 102.3, 79.8, 76.6, 68.8, 56.0, 55.1, 46.4, 43.6, 32.2, 28.5,
+
+
8.1, 27.3, 23.7; ESI-MS m/z 285 [M-OH-Boc] , 386 [M-OH] ,
+
+
+
+
HRMS(ESI/Q-TOF) [M + H] calcd for C23
found 403.239.
H33NO 403.236,
5
tBu] , 462 [M-OH] , HRMS(ESI/Q-TOF) [M + H] calcd for
C H NO 479.267, found 479.268.
2
9
37
5
For 2e9: this isomer was inseparable from column in pure
form.
(
S)-tert-butyl 2-(2-hydroxy-2-(6-methoxy-3,4-
dihydronaphthalen-1-yl)ethyl)pyrrolidine-1-carboxylate (2c/2c9)
(
S)-tert-butyl 2-(2-hydroxy-2-(7-methoxy-3,4-
As described for 2a/2a9, 3b (300 mg, 1.25 mmol) in THF (15
mL), n-BuLi (0.78 mL, 1.25 mmol), aldehyde 4a (240 mg, 1.12
mmol) in THF (2 mL) furnished 2c/2c9 (271 mg, 58%) as
dihydronaphthalen-1-yl)ethyl)piperidine-1-carboxylate (2h/2h9)
As described for 2a/2a9, 3c (300 mg, 1.25 mmol) in THF (15
mL), n-BuLi (0.78 mL, 1.25 mmol), aldehyde 4e (255 mg, 1.12
mmol) in THF (2 mL) furnished 2h/2h9 (310 mg, 64%) as
2
8
viscous colorless oil; For 2c: [a]D 23.24 (c 0.7, CHCl
3 f
); R 0.59
(
25% EtOAc in hexane); IR (Neat): 3432, 3016, 2330, 1572, 1211
2
1 1
2
8
cm ; H NMR (300 MHz, CDCl
.70 (m, 2H), 6.11 (m, 1H), 5.20 (s, 1H), 4.64 (br, s, 1H), 4.30 (s,
1H), 3.80 (s, 3H), 3.37–3.34 (m, 2H), 2.72–2.67 (m, 2H), 2.30–
.25 (m, 2H), 2.04–1.85 (m, 4H), 1.71–1.66 (m, 2H), 1.50 (s, 9H);
3
): d 7.23–7.20 (m, 1H), 6.71–
colorless semisolid; For 2h: [a] 22.24 (c 0.60, CHCl ); R 0.61
D
3
f
6
(25% EtOAc in hexane); IR (Neat): 3430, 3017, 2331, 1567, 1213
2
1 1
cm ; H NMR (300 MHz, CDCl
3
): d 7.08 (d, 1H, J = 8.2), 6.91
= 2.4, J = 8.1), 6.30 (m, 1H),
2
(d, 1H, J
1
= 2.6), 6.70 (dd, 1H, J
1
2
+
+
ESI-MS m/z 396 [M + Na] , 300 [M-OH-tBu] , HRMS(ESI/Q-TOF)
4
3
1
1
8
1
.63 (br, s, 1H), 4.53–4.47 (m, 1H), 4.13–4.03 (m, 1H), 3.80 (s,
H), 2.84–2.77 (m, 1H), 2.70–2.65 (m, 2H), 2.30–2.26 (m, 2H),
+
[M + H] calcd for C22
H31NO
4
373.225, found 373.226.
2
8
1
3
For 2c9: [a]D 223.68 (c 0.48, CHCl ); R 0.51 (25% EtOAc in
3
f
3
.74 (m, 2H), 1.53–1.46 (m, 16H); C NMR (50 MHz, CDCl ): d
2
1 1
hexane); IR (Neat): 3433, 3015, 2329, 1571, 1213 cm ; H NMR
300 MHz, CDCl ): d 7.26 (m, 1H), 6.72–6.70 (m, 2H), 6.10 (m,
58.2, 156.7, 138.2, 134.6, 129.0, 128.2, 125.1, 111.2, 109.2,
0.3, 71.0, 55.2, 46.6, 39.8, 37.2, 29.4, 28.4, 27.4, 25.5, 23.1,
(
3
+
+
1H), 4.73 (s, 1H), 4.12 (s, 1H), 3.80 (s, 3H), 3.31 (m, 2H), 2.71–
2.66 (m, 2H), 2.25 (m, 2H), 2.05 (m, 3H), 1.85–1.81 (m, 3H),
9.2; ESI-MS m/z 331 [M-tBu] , 370 [M-OH] , HRMS(ESI/Q-TOF)
+
[M + H] calcd for C H NO 387.241, found 387.243.
23 33 4
1
3
2
8
1.47 (s, 9H); C NMR (50 MHz, CDCl ): d 158.1(2C), 138.8(2C),
3
For 2h9: [a]D 280.34 (c 1.20, CHCl
hexane); IR (Neat): 3431, 3019, 2329, 1566, 1213 cm ; H NMR
300 MHz, CDCl ): d 7.07 (d, 1H, J = 8.1), 6.93 (d, 1H, J = 1.8),
= 2.5, J = 8.3), 6.23–6.20 (m, 1H), 4.73 (m, 1H),
3 f
); R 0.53 (25% EtOAc in
2
1
1
123.8, 121.5, 113.9, 110.8(2C), 79.7, 70.0, 55.9, 55.2, 46.3, 36.6,
+
3
2.1, 31.9, 28.8, 28.5, 23.8; ESI-MS m/z 396 [M + Na] , 300[M-
(
3
1
+
+
OH-tBu] , HRMS(ESI/Q-TOF) [M + H] calcd for C22
73.225, found 373.227.
H31NO
4
6
4
2
1
1
3
.69 (dd, 1H, J
1
2
3
.47 (br, s, 1H), 3.92 (m, 1H), 3.80 (s, 3H), 2.76–2.62 (m, 3H),
.26–2.25 (m, 2H), 1.97–1.93 (m, 2H), 1.63–1.57 (m, 4H), 1.46–
(
S)-tert-butyl 2-(2-(2,2-dimethyl-2H-chromen-4-yl)-2-
1
3
.44 (m, 12H); C NMR (50 MHz, CDCl ): d 158.1, 155.5, 138.7,
3
hydroxyethyl)pyrrolidine-1-carboxylate (2i/2i9)
34.3, 129.1, 128.2, 125.1, 111.2, 109.5, 79.8, 70.2, 55.3, 48.6,
As described for 2a/2a9, 3d (300 mg, 1.25 mmol) in THF (15
mL), n-BuLi (0.80 mL, 1.25 mmol), aldehyde 4a (243 mg, 1.14
mmol) in THF (2 mL) furnished 2i/2i9 (295 mg, 63%) as viscous
9.5, 37.2, 29.2, 28.5, 27.3,25.4, 23.2, 19.1; ESI-MS m/z 269 [M-
+
+
+
OH-Boc] , 370 [M-OH] , HRMS(ESI/Q-TOF) [M + H] calcd for
387.241, found 387.245.
23 4
C H33NO
2
8
colorless oil; For 2i: [a]D 23.67 (c 1.2, CHCl ); R 0.47 (25%
3
f
(
2
S)-tert-butyl 2-(2-hydroxy-2-(7-methoxy-2,2-dimethyl-
H-chromen-4-yl)ethyl)pyrrolidine-1-carboxylate (2f/2f9)
EtOAc in hexane); IR (Neat): 3435, 3018, 2331, 1570, 1214
2
1 1
cm ; H NMR (300 MHz, CDCl
.81 (m, 2H), 5.82 (s, 1H), 5.44 (s, 1H), 4.63 (d, 1H, J = 8.6), 4.29
m, 1H), 3.38 (m, 2H), 2.01–1.60 (m, 6H), 1.52 (s, 9H), 1.46 (s,
3
): d 7.14–7.08 (m, 2H), 6.88–
6
(
As described for 2a/2a9, 3e (300 mg, 1.11 mmol) in THF (15
mL), n-BuLi (0.70 mL, 1.11 mmol), aldehyde 4a (213 mg, 1.00
mmol) in THF (2 mL) furnished 2f/2f9 (278 mg, 62%) as viscous
colorless oil; For 2f: [a] 26.24 (c 1.7, MeOH); R
EtOAc in hexane); IR (Neat): 3431, 3014, 2330, 1569, 1213
1
3
3
3
H), 1.39 (s, 3H); C NMR (50 MHz, CDCl ): d 156.8, 153.2,
2
8
133.6, 128.5, 125.6, 122.8, 120.9, 120.4, 116.8, 80.1, 75.7, 65.7,
3.7, 46.5, 42.9, 31.1, 28.4, 28.2, 27.1, 23.5; ESI-MS m/z 255 [M-
D
f
0.53 (25%
5
+
+
+
2
1 1
OH-Boc] , 317 [M-tBu] , HRMS(ESI/Q-TOF) [M + H] calcd for
cm ; H NMR (300 MHz, CDCl
3
): d 7.04 (d, 1H, J = 8.0), 6.44–
C
22
H31NO
4
373.225, found 373.226.
6.41 (m, 2H), 5.67 (s, 1H), 5.40 (d, 1H, J = 3.6), 4.58–4.55 (m,
1
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2
8
For 2i9: [a]D 28.76 (c 1.6, CHCl
3
); R
f
0.42 (25% EtOAc in
3.43–3.65 (m, 2H), 2.74–2.63 (m, 1H), 2.34–2.27 (m, 1H), 1.99–
2
1 1
hexane); IR (Neat): 3437, 3022, 2316, 1595, 1213 cm ; H NMR
300 MHz, CDCl
2.10 (m, 1H), 1.46 and 1.41 (2s, 9H), rotamers. ESI-MS m/z 246
+
(
3
): d 7.14–7.09 (m, 2H), 6.88–6.81 (m, 2H), 5.81
[M + H] .
(
s, 1H), 4.73 (m, 1H), 4.52 (br, s, 1H), 4.12 (br, s, 1H), 3.34 (m,
(
2S,3S)-1-tert-butyl 2-methyl 3-hydroxypyrrolidine-1,2-
2
3
1
5
H), 2.08–1.99 (m, 1H), 1.87–1.69 (m, 5H), 1.48 (s, 9H), 1.45 (s,
1
3
dicarboxylate (11)
3
H), 1.38 (s, 3H); C NMR (50 MHz, CDCl ): d 155.7, 153.2,
34.4, 128.6, 125.7, 122.7, 120.7, 120.4, 116.9, 79.8, 75.8, 68.6,
Following similar procedure as for 10, trans-3-hydroxy-L-
proline (2 g, 8.73 mmol) provided 11 (3.45 g, 95%, after two
steps) as colorless oil; mixture of rotamers, R 0.53 (30% EtOAc
6.1, 46.4, 43.7, 32.4, 28.5, 28.1, 27.2, 23.7; ESI-MS: m/z 255 [M-
+
+
+
OH-Boc] , 317 [M-tBu] , HRMS(ESI/Q-TOF) [M + H] calcd for
C H NO 373.225, found 373.225.
f
1
2
2
31
4
in hexane); H NMR of major rotamer (300 MHz, CDCl ): d
3
4
.44–4.19 (m, 2H), 3.75 (s, 3H), 3.66–3.56 (m, 2H), 2.78–2.72
(
S)-tert-butyl 2-(2-hydroxy-2-(7-methoxy-3,4-
(m, 1H), 2.14–2.03 (m, 1H), 1.95–1.85 (m, 1H), 1.47 and 1.42
dihydronaphthalen-1-yl)ethyl)pyrrolidine-1-carboxylate (2j/2j9)
+
(2s, 9H); ESI-MS m/z 268 [M + Na] ; other paramaters were in
2
4
As described for 2a/2a9, 3c (300 mg, 1.25 mmol) in THF (15
mL), n-BuLi (0.78 mL, 1.25 mmol), aldehyde 4a (240 mg, 1.12
mmol) in THF (2 mL) furnished 2j/2j9 (285 mg, 61%) as viscous
colorless oil; For 2j: [a] 24.23 (c 0.8, CHCl ); R 0.60 (25%
EtOAc in hexane); IR (Neat): 3431, 3014, 2331, 1572, 1211
full agreement with the literature reports.
(
S)-1-tert-butyl 2-methyl 2-methylpyrrolidine-1,2-dicarboxylate
(7)
Following a similar procedure as described for 10, a-methyl-L-
proline (1 g, 7.75 mmol), SOCl (0.64 mL, 8.52 mmol), in
MeOH (15 mL) and Boc O (1.8 mL, 7.6 mmol), Et N (2.1 mL,
14.56 mmol) provided 7 (1.80 g, 96%, after two steps) as
2
8
D
3
f
2
1 1
cm ; H NMR (300 MHz, CDCl
3
): d 6.97 (d, J = 8.3, 1H), 6.83
2
(m, 1H), 6.60 (dd, J = 2.5, J = 8.3, 1H), 6.19 (m, 1H), 4.56 (d, J =
2
3
1
2
8
2
.1, 1H), 4.23 (br, s, 1H), 3.70 (s, 3H), 3.30–3.27 (m, 2H), 2.59–
.54 (m, 2H), 2.21–2.18 (m, 2H), 1.97–1.78 (m, 4H), 1.67–1.50
1
3
colorless viscous liquid; H NMR (300 MHz, CDCl ): d 3.66 (s,
3H), 3.55–3.42 (m, 2H), 2.15–2.07 (m, 1H), 1.88–1.80 (m, 3H),
1.52–1.47(m, 3H), 1.40 and 1.37 (2s, total 9H), rotamers; ESI-
MS m/z 244 [M + H] ;other paramaters were in agreement with
the literature reports.
1
3
(m, 3H), 1.42 (s, 9H); C NMR (50 MHz, CDCl ): d 158.1(2C),
3
1
6
38.3, 129.0, 128.1(2C), 124.9, 111.4, 109.2, 80.0, 74.0,70.1,
6.8, 55.1, 53.9, 46.5, 43.4, 31.2, 29.6, 28.4, 27.4, 23.1 ESI-MS:
+
+
+
25
m/z 396 [M + Na] , 300 [M-OH-tBu] , HRMS(ESI/Q-TOF) [M +
+
H] calcd for C22
H31NO
4
373.225, found 373.227.
For 2j9: [a]D 221.14 (c 0.54, CHCl ); R 0.50 (25% EtOAc in
hexane); IR (Neat): 3423, 3012, 2330, 1572, 1213 cm ; H NMR
(2S,4R)-1-tert-butyl 2-methyl 4-(benzyloxy)pyrrolidine-1,2-
2
8
3
f
2
1
1
dicarboxylate (12)
(300 MHz, CDCl
3
): d 6.98 (d, J = 7.9, 1H), 6.84 (m, 1H), 6.60 (dd,
To a solution of 10 (1.0 g, 4.08 mmol) in CH Cl (15 mL) was
2 2
J
1
= 2.4, J = 8.2, 1H), 6.17 (m, 1H), 4.65 (d, J = 7.4, 1H), 4.04 (br,
2
added benzyl bromide (0.60 mL, 4.90 mmol), silver oxide (2.83
g, 12.24 mmol) and the mixture was refluxed for 24 h. The
contents were filtered (Celite), concentrated and chromato-
graphed over silica gel (10% ethyl acetate in hexane) to obtain
s, 1H), 3.71 (s, 3H), 3.23 (m, 2H), 2.58–2.53 (m, 2H), 2.18–2.17
m, 2H), 1.99–1.90 (m, 2H), 1.77–1.60 (m, 4H), 1.39 (s, 10H);
(
1
3
C NMR (50 MHz, CDCl ): d 158.1, 155.4, 139.1, 128.2(2C),
3
28
1
2
24.8, 110.9, 109.4, 79.7, 74.0, 69.9, 55.8, 55.2, 46.3,43.4, 32.3,
12 (1.25 g, 92%) as colorless viscous liquid; [a]D 217.65 (c
1.50, CHCl ); R 0.65 (30% EtOAc in hexane); IR (Neat): n 2978,
1743, 1686, 1419, 1159 cm ; H NMR (300 MHz, CDCl
7.34–7.30 (m, 5H), 4.56–4.32 (m, 3H), 4.17–4.10 (m, 1H), 3.72
s, 3H), 3.70–3.52 (m, 2H), 2.43–2.33 (m, 1H), 2.11–2.02 (m,
+
+
8.5, 27.3, 23.1; ESI-MS: m/z 396 [M + Na] , 300 [M-OH-tBu] ,
3
f
+
21 1
HRMS(ESI/Q-TOF) [M + H] calcd for C H NO 373.225,
found 373.228.
3
): d
2
2
31
4
(
1
N-Boc-trans-4-hydroxy-L-proline methyl ester (10)
+
H), 1.45 and 1.41 (2s, 9H), rotamers. ESI-MS m/z 336 [M + H] .
To a stirred slurry of trans-4-hydroxy-L-proline (2 g, 8.73 mmol)
in methanol (20 mL) was added thionyl chloride (0.70 mL, 9.60
mmol) at 0 uC. After the completion of the addition, the
resulting slurry was heated to 60 uC and stirred for 6 h to give a
clear light brown solution. The mixture was evaporated under
reduced pressure to give methyl ester as a light-brown solid
(
2S,3S)-1-tert-butyl 2-methyl 3-(benzyloxy)pyrrolidine-1,2-
dicarboxylate (13)
Following similar procedure as for 12, 11(1.0 g, 4.08 mmol),
BnBr (0.60 mL, 4.90 mmol) and Ag
furnished 13 (1.25 g, 92%) as colorless oil; mixture of
rotamers, H NMR (300 MHz, CDCl
4.67–4.34 (m, 3H), 4.11 (m,1H), 3.72 (s, 3H), 3.68–3.48 (m, 2H),
2.04 (m, 2H), 1.47 and 1.41 (each s, total 9H); C NMR (50
MHz, CDCl ): d 154.5, 153.7, 137.4, 128.4, 127.8, 127.7, 127.5,
81.8, 80.8, 79.9, 71.0, 65.1, 64.3, 52.2, 52.1, 44.8, 44.4, 30.8,
29.9, 28.3, 28.2; ESI-MS m/z 336 [M + H] .
2
O (2.83 g, 12.24 mmol)
1
(
2.71 g, 98%), which was used in the next step without further
purification. Boc O (3.68 mL, 15.15 mmol) was added to a
stirred suspension of crude methyl ester in CH Cl (25 mL). To
): d 7.33–7.27 (m, 5H),
3
2
1
3
2
2
the mixture was added slowly a solution of triethylamine (4.2
mL, 29.56 mmol). After completion of the starting material as
observed by TLC analysis (approximately 3.5 h), the reaction
mixture was quenched with 1 N HCl solution (10 mL). The
organic layer was separated and evaporated under reduced
pressure to give a brown viscous liquid. Purification of the
crude over silica gel provided 10 as yellowish syrup (3.63 g,
3
+
(
2S,4R)-tert-butyl 4-(benzyloxy)-2-formylpyrrolidine-1-
carboxylate (14)
To a well stirred solution of 12 (2.0 g, 5.97 mmol) in dry THF
(30 mL) at 0 uC was added LiBH4 (138 mg, 6.57 mmol) in
portions, the reaction mixture was stirred at r.t. until the
completion of reaction (observed from TLC). The reaction
2
8
9
9%); [a]D 266.53 (c 1.00, CHCl ); R 0.43 (30% EtOAc in
3 f
2
1
hexane); IR (Neat): n 3440, 2976, 1746, 1685, 1416, 1160 cm
H NMR (300 MHz, CDCl ): d 4.47–4.37 (m, 2H), 3.73 (s, 3H),
3
;
1
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mixture was then quenched with acetone followed by water,
after the usual workup (with ethyl acetate and water), the
organic layer was concentrated and the alcohol obtained was
used for the next step without any purification.
was separated by decantation. The resulting organic layer was
concentrated to oily residue. Flash chromatography of the
residue over silica gel (2 6 15 cm), (68% EtOAc/hexane as
eluent), gave enol ethers 16 (1.44 g, 88%) as a colorless oil,
which was used further without characterization. To the
stirred enol ether 16 (1.44 g, 4.33 mmol), in acetone (10 mL)
was added 2 N HCl (3.24 mL, 6.48 mmol) at r.t. and was stirred
for 10 min. The reaction mixture was then neutralized by sat.
To the ice cooled solution of obtained alcohol (1.8 gm, 5.86
mmol) in dry CH Cl (25 mL) was added Dess–Martin
2
2
periodinane (3.24 gm, 7.62 mmol) and the solution was stirred
at r.t. for 2 h. After the completion of reaction, it was quenched
with 100 mL solution of Na
2
S
2
O
4
and Na
2
CO
3
(1 : 1). After the
Na
2
CO
3
(pH = 7) and extracted with diethylether. The ether
SO ) and concentrated, followed by
usual workup with CH Cl (25 6 3 mL) and water, the organic
layer was dried (over Na
2
4
2
2
layer was concentrated in vacuum and the crude obtained was
purified by column chromatography over silica gel (15% ethyl
acetate in hexane), which furnished aldehyde 14 (1.65 g, 93%)
purification on silica gel (100–200 mesh) (using 7% EtOAc/
hexane as eluent), which furnished homoprolinal 4c (1.42 g,
2
8
96% yield) as colorless oil, [a]D 233.28 (c 0.16, CHCl
3 f
); R 0.70
2
8
as colorless viscous liquid; [a] 226.65 (c 0.17, CHCl ); R 0.69
(20% EtOAc in hexane); IR (Neat): n 3064, 3031, 2978, 2931,
D
3
f
2
1 1
(
2
30% EtOAc in hexane); IR (Neat): n 3064, 3031, 2977, 2930,
2718, 1701, 1685, cm ; H NMR (300 MHz, CDCl
1H), 7.25 (m, 5H), 4.43 (m, 2H), 4.27 (m, 1H), 4.01 (m, 1H),
3.37–3.33 (m, 2H), 2.95–2.80 (m, 1H), 2.48 (dd, J = 6.4, J = 7.2,
1H), 2.29 (m, 1H), 1.73–1.68 (m, 1H), 1.38 (s, 9H); C NMR (50
MHz, CDCl ): d 200.6, 154.7, 137.8, 128.4, 127.7, 127.6, 80.6,
3
): d 9.70 (s,
2
1 1
716, 1704, 1695, 1456, 1397, 1256, 1162 cm ; H NMR (300
): d 9.47, 9.37 (d, J = 2.2, 3.5, total 1H), 7.30–7.20
m, 5H), 4.50–4.40 (dd, J = 11.6, J = 16.8, 2H), 4.27–4.12 (m,
MHz, CDCl
(
3
1
2
1
3
1
2
1
1
H), 4.05 (m, 1H), 3.73–3.42 (m, 2H), 2.24–2.08 (m, 1H),1.94–
3
.81 (m, 1H), 1.39 and 1.35 (2s, 9H), rotamers. ESI-MS m/z 306
79.9, 70.8, 51.6, 51.3, 48.7, 37.5, 28.4(3C); ESI-MS m/z 320 [M +
+
+
[M + H] .
H] .
(
2S, 3S)-tert-butyl 3-(benzyloxy)-2-formylpyrrolidine-1-
(2R,3S)-tert-butyl 3-(benzyloxy)-2-(2-oxoethyl)pyrrolidine-1-
carboxylate (15)
carboxylate (4d)
Following the similar procedure as described for 14, 13 (2.0 g,
Following the similar procedure as described for 4c, 15 (750
5
.97 mmol) furnished 15 (1.65 g, 77%, after two steps) as
mg, 2.47 mmol), furnished 4d (710 mg, 96%) via enolether 17
(720 mg, 88%) as colorless syrup; [a]D 267.34 (c 0.20, CHCl );
3
2
8
28
colorless oil; mixture of rotamers, [a] 230.13 (c 0.15, CHCl
3
);
D
R
f
0.72 (30% EtOAc in hexane); IR (Neat): n 3062, 3031, 2978,
R 0.72 (20% EtOAc in hexane); IR (Neat): n 3063, 3032, 2978,
f
2930, 2718, 1706, 1685, cm ; H NMR (300 MHz, CDCl ): d
3
2
1
1
21 1
2
=
931, 2716, 1707, cm ; H NMR (300 MHz, CDCl
3
): d 9.50 (d, J
24.3, 1H), 7.34–7.32 (m, 5H), 4.63–4.50 (m, 3H), 4.21–4.15
9.76 (s, 1H), 7.35–7.30 (m, 5H), 4.63–4.54 (m, 2H), 4.38–4.27
(m, 1H), 3.82 (m, 1H), 3.56–3.45 (m, 2H), 2.92–2.71 (m, 1H),
(m,1H), 3.63–3.56 (m, 2H), 2.10–2.06 (m, 1H), 1.94–1.82 (m,
1
3
13
1H), 1.48 and 1.43 (2s, 9H), rotamers; C NMR (50 MHz,
2.44–2.36 (m, 1H), 2.00 (m, 2H), 1.45 (s, 9H); C NMR (50
CDCl ): d 199.7, 199.45, 154.9, 153.8, 137.3, 128.5, 127.9, 127.7,
MHz, CDCl ): d 200.1, 154.1, 137.9, 128.4, 127.6, 82.7, 81.5,
3
3
8
0.7, 80.4, 79.7, 76.4, 71.2, 70.6, 45.0, 44.7, 31.1, 30.3, 28.2; ESI-
80.1,79.7, 70.7, 57.5, 47.8, 47.1, 44.6, 28.4, mixture of rotamers;
ESI-MS m/z 320 [M + H] .
+
+
MS m/z 306 [M + H] .
S)-tert-butyl 2-formyl-2-methylpyrrolidine-1-carboxylate (8)
Following similar procedure as described for 14, 7 (1.0 g, 4.69
(
(S)-tert-butyl 2-methyl-2-(2-oxoethyl)pyrrolidine-1-carboxylate
(4b)
mmol), LiBH (108 mg, 5.16 mmol) in dry THF (15 mL),
followed by DMP (1.77 g, 5.44 mmol) in dry CH Cl furnished 8
4
Following similar procedure asdescribed for 4c, 8 (1.5 g, 7.04
2
2
1
mmol), (Me Si) NK (1M, 17.6 mL, 12.27 mmol), (methoxy-
3
2
(780 mg, 88%, after two steps) as colorless syrup; H NMR (300
methyl)-triphenyl phosphonium chloride (5.18 g, 14.04 mmol)
in anhydrous THF (30 mL) at 278 uC, furnished 4b (1.32 g,
96%) as colorless oil via enolether 9 (1.46 g, 85%); IR n 2927,
3
MHz, CDCl ): d 9.29 (d, J = 23.9, 1H), 3.60–3.43 (m, 2H), 1.98–
1
.83 (m, 3H), 1.60–1.44 (m,1H), 1.38–1.26 (m,1 2H), rotamers;
+
21 1
ESI-MS m/z 214 [M + H] ; other paramaters were in good
agreement with the literature reports.
2831, 1685 cm ; H NMR (CDCl , 300 MHz) D 9.73 (s, 1 H),
3
2
5
3.62–3.35 (m, 2 H), 3.11–2.74 (m, 2 H), 2.07–1.79 (m, 4 H),
1
3
1
.50–1.44 (m, 12 H); C NMR (50 MHz, CDCl
3
): d 175.8, 154.0,
(
2S, 4R)-tert-butyl 4-(benzyloxy)-2-(2-oxoethyl)pyrrolidine-1-
7
9.2, 60.5, 51.6, 48.2, 39.3, 28.4, 24.9, 21.8; ESI-MS m/z 228[M +
carboxylate (4c)
+
H] , other paramaters were in good agreement with the
literature reports.
2
5
(
Me Si) NK (1 M, 12.27 mL, 12.27 mmol) was added over a
3
2
period of 0.5 h under inert atmosphere to a suspension of
methoxymethyl)-triphenyl phosphonium chloride (3.36 g, 9.8
(
S)-tert-butyl 2-formylpiperidine-1-carboxylate (19)
(
mmol) in anhydrous THF (30 mL) at 278 uC. The reaction
mixture was stirred at 278 uC for 0.5 h and was brought to 0 uC
in the next 0.5 h, then a solution of aldehyde 14 (1.5 g, 4.91
mmol) in anhydrous THF was added gradually over 20 min
and the reaction mixture was left for 2 h overnight at r.t. with
continuous stirring. It was quenched by water and was
extracted using ether. Cooling the organic layer to 230 uC
led to the crystallization of triphenylphosphine oxide, which
To a stirred solution of commercially available 18 (1.0 g, 4.1
mmol) in THF (2.5 mL) cooled with an ice bath was added
BH ?THF (1.0 M in THF, 6.3 mL, 6.3 mmol). The reaction was
3
warmed to room temperature while stirring. After 3 h the
solution was cooled and water (1 mL) was added dropwise.
Sodium carbonate (0.8 g) was added and the mixture was
vigorously stirred for 30 min. The layers were separated and
the aqueous layer was extracted with ether (3 6 3 mL). The
1
9542 | RSC Adv., 2013, 3, 19533–19544
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combined ether layers were washed with brine (2.0 mL) and
dried (Na SO ). The solvent was evaporated to give oil that was
2 4
2 (a) L. Lazar, H. Kivela, K. Pihlaja and F. Fulop, Tetrahedron
Lett., 2004, 45, 6199–6201; C. M. Marson, J. H. Pink and
C. Smith, Tetrahedron, 2003, 59, 10019–10023; (b) A.
V. Karnik, N. J. Malviya, A. M. Kulkarni and B.
L. Kulkarni, Eur. J. Med. Chem., 2006, 41, 891–895; (c)
J. Burbiel and F. Bracher, Steroids, 2003, 68, 587–594; (d)
For reviews see P. F. Morand and J. Lyall, Chem. Rev., 1968,
filtered through silica gel using ethyl acetate as eluent. The
solvent was evaporated to give an oil that crystallized to
intermediate alcohol (product was spectroscopically compar-
1
13
26
able to the H NMR and C NMR to literature values) as a
white solid, which was used directly in the next step.
A solution of oxalyl chloride (0.218 mL, 2.51 mmol) in
6
1
8, 85–124; (e) H. O. Huisman, Angew. Chem. Int. Ed., 1971,
0, 450–459; (f) H. O. Huisman and W. N. Speckamp, Int.
CH
stirred for 15 min. A solution of DMSO (0.323 mL, 4.57 mmol)
in CH Cl 0.5 mL was added and the solution was stirred for
0 min. A solution of alcohol (0.50 g, 2.09 mmol) in CH Cl
2.3 mL) was added dropwise and the reaction was stirred for 1
2 2
Cl (5.7 mL) under nitrogen was cooled to 278 uC and
Rev. Sci.: Org. Chem. Ser.,Two, 1976, 8, 207–236.
3
4
A. G. Romero, J. A. Leiby and S. A. Mizsak, J. Org. Chem.,
2
2
1996, 61, 6974–6979.
1
2
2
(a) R. E. Dolle, H. S. Allaudeen and L. I. Kruse, J. Med.
Chem., 1990, 33, 877–880; (b) W. E. Solomons and N.
J. Doorenbos, J. Pharm. Sci., 1974, 63, 19–23; (c) N.
J. Doorenbos and W. E. Solomons, J. Pharm. Sci., 1973,
(
h at 278 uC. Diisopropylethylamine (1.45 mL, 8.32 mmol) was
added dropwise and the mixture was allowed to warm to room
temperature. The mixture was washed with 1 M HCl (2 6 2
6
2, 638–640; (d) R. W. Chesnut, N. N. Durham, R. A. Brown,
E. A. Mawdsley and R. A. Berlin, Steroids, 1976, 27, 525–541;
e) H. Singh, D. Jindal, M. Yadar and M. Kumar, Prog. Med.
mL), water (4 6 2 mL), brine (2 6 2 mL) and dried (MgSO
4
).
Concentration of the solvent provided 19 (0.435 g, 98%) as a
(
2
8
27
light yellow oil; [a]D 274.31 (c 1.5, CHCl , lit. 277.4, c 1.4,
3
1
Chem., 1991, 28, 233–300; (f) H. Singh, T. R. Bhardwaj, N.
K. Ahuja and D. Paul, J. Chem. Soc. Perkin Trans 1, 1979,
305–307.
CHCl ); R 0.74 (30% EtOAc in hexane), H NMR (300 MHz,
3
f
CDCl ): d 9.60 (s, 1H), 4.57 (m, 1H), 3.93 (m, 1H), 2.92 (m, 1H),
3
2
2
.18–2.14 (m, 1H), 1.68–1.24 (m, 5H), 1.47 (s, 9H); ESI-MS m/z
36 [M + Na] .
5
6
(a) G. H. Rasmusson, G. F. Reynolds, T. Utne, R. B. Jobson,
R. L. Primka, C. Berman and J. R. Brooks, J. Med. Chem.,
+
1984, 27, 1690–1701; (b) G. H. Rasmusson, G. F. Reynolds,
(
S)-tert-butyl 2-formylpyrrolidine-1-carboxylate
N. G. Steinberg, E. Walton, G. F. Patel, T. Liang, M.
A. Cascieri, A. H. Cheung, J. R. Brooks and C. Berman, J.
Med. Chem., 1986, 29, 2298–2315; (c) B. Kenny, S. Ballard,
J. Blagg and D. Fox, J. Med. Chem., 1997, 40, 1293–1315.
(a) J. R. Brooks, C. Berman, R. L. Primka, G. F. Reynolds
and G. H. Rasmusson, Steroids, 1986, 47, 1–19; (b) J.
R. Brooks, C. Berman, D. Garnes, D. Giltinan, L. R. Gordon,
P. F. Malatesta, R. L. Primka, G. F. Reynolds and G.
H. Rasmusson, Prostate, 1986, 9, 65–75; (c) R. C. Gadwood
and V. C. Fiedler, Annu. Rep. Med. Chem., 1989, 24, 187–196;
Spectral data were found to be in good agreement with
1
9
literature report.
S)-tert-butyl 2-(2-oxoethyl)pyrrolidine-1-carboxylate (4a)
Spectral data were found to be in good agreement with
(
1
9
literature report.
S)-tert-butyl 2-(2-oxoethyl)piperidine-1-carboxylate (4e)
Following the similar procedure as described for 4c, 19 (1.82 g,
(
(
d) A. Guarna, E. G. Occhiato, F. Machetti, A. Marrucci,
G. Danza, M. Serio and P. Paoli, J. Med. Chem., 1997, 40,
466–3477.
8
(
1
.50 mmol), (Me Si) NK (1 M, 21.2 mL, 21.25 mmol),
methoxymethyl)-triphenyl phosphonium chloride (6.29 g,
7.01 mmol) in anhydrous THF (40 mL) at 278 uC to r.t.,
3
2
3
2
8
7 (a) J. P. Wiebe, L. Souter and G. Zhang, Journal of Steroid
Biochemistry & Molecular Biology, 2006, 100, 129–140; (b) L.-
H. Huang, Y.-G. Wang, G. Xu, X.-H. Zhang, Y.-F. Zheng, H.-
L. He, W.-Z. Fu and H.-M. Liu, Bioorg. & Med. Chem. Lett.,
2011, 21, 6203–6205.
furnished 4e (1.73 g, 83%, after two steps) as colorless oil via
its enol ether (1.78 g, 85%); [a] 253.71 (c 1.0, CHCl3);
2
D
8
1
H
NMR (300 MHz, CDCl ): d 9.73 (dd, J = 2.3, J = 3.0, 1H), 4.84–
3
1
2
4
2
.83 (m, 1H), 4.01–3.97 (bd, J = 12.7, 1H), 2.83–2.70 (m, 2H),
.57–2.50 (m, 1H), 1.76–1.46 (m, 6H), 1.45 (s, 9H); C NMR (50
1
3
8
J. P. Wiebe, Endocr. Relat. Cancer, 2006, 13, 717–38.
MHz, CDCl ): d 200.8, 154.6, 79.9, 45.8, 44.6, 39.2, 28.8, 28.3,
3
+
9 Selected examples (a) M. Ibrahim-Ouali, E. Romero and
H. Bouleghlem, Tetrahedron, 2011, 67, 3668–3676; (b)
F. Cachoux, M. Ibrahim-Ouali and M. Santelli, Syn.
Commun., 2002, 32, 3549–3560; (c) D. Fortin, F. Gaudette,
E. Marsault and P. Deslongchamps, Tetrahedron, 2001, 57,
2
5.2, 18.9; ESI-MS m/z 228 [M + H] .
Acknowledgements
4167–4177; (d) T. R. Kasturi and V. K. Sharma, Ind J. Chem,
Ritesh thanks the Council of Scientific and Industrial Research
Sec B, 1976, 14B, 731–734; (e) W. N. Speckamp, H. de
Koning, U. K. Pandit and H. O. Huisman, Tetrahedron,
(CSIR), New Delhi, for fellowship. The Department of Science
and Technology, is also thanked for financial assistance. We
also thank SAIF, CDRI for providing analytical data. This has
CDRI communication no. 8503.
1965, 21, 2517–2527; (f) A. I. Meyers and N. K. Ralhan, J.
Org. Chem., 1963, 28, 2950–2953; (g) S. V. Kessar, A. Kumar
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9544 | RSC Adv., 2013, 3, 19533–19544
This journal is ß The Royal Society of Chemistry 2013