Diastereocontrolled synthesis of enantiopure trans- and cis-5-allylprolinols via a ring-contraction protocol

Article abstract of DOI:10.1055/s-2001-9731

A highly diastereocontrolled formation of trans- and cis-5-allyl-N-benzylprolinols from trans- and cis-2-allyl-N-benzyl-5-piperidinols has been achieved by employing a ring-contraction protocol.

Full text of DOI:10.1055/s-2001-9731

LETTER
45
Diastereocontrolled Synthesis of Enantiopure trans- and cis-5-Allylprolinols
via a Ring-Contraction Protocol
Hideki Sakagami, Kunio Ogasawara*
Pharmaceutical Institute, Tohoku University, Aobayama, Sendai 980-8578, Japan
Fax +81-22-217-6845; E-mail: konol@mail.cc.tohoku.ac.jp
Received 18 October 2000
peridine derivatives carrying a leaving group at the 3 po-
sition undergo ring-contraction under appropriate
nucleophilic conditions to give rise to 2-substituted pyrro-
lidines with 3-substituted piperidines through common
aziridinium intermediates generated initially by intramo-
lecular nucleophilic substitution. However, formation of
piperidine derivatives prevails in most cases except some
examples.4,5 We explored conversion of the above isomer-
ic enantiopure 2-allylpiperidines 5 and 6 into the 2,5-dis-
ubstituted pyrrolidines and found practically acceptable
conditions for their diastereospecific conversion into
2,5-disubstituted pyrrolidine derivatives.
Abstract: A highly diastereocontrolled formation of trans- and cis-
5-allyl-N-benzylprolinols from trans- and cis-2-allyl-N-benzyl-5-
piperidinols has been achieved by employing a ring-contraction
protocol.
Key words: chiral building block, ring contraction, 2-allyl-5-pipe-
ridinol, 5-allylprolinol, cesium acetate, Mitsunobu reaction
We have developed an efficient synthesis of N-carboben-
zoxy-5,6-didehydro-5-piperidinol 2 in both enantiomeric
forms from 3-hydroxypyridine 1 through an unprecedent-
ed reductive formation of the racemic didehydropiperidi-
nol (±)-2 followed by lipase-mediated kinetic resolution1,2
(Scheme 1). Moreover, 2 was readily transformed into the
3-acetoxy-6-methoxypiperidine 4 which underwent dia-
stereoselective allylation on exposure to allyltrimethylsi-
lane in the presence of a Lewis acid to give 80% of trans-
5-acetoxy-2-allyl-1-carbobenzoxypiperidine 5 and 10%
of its cis-2,5-epimer 6 (Scheme 2).
In order to secure the cis-acetate 6 which was generated as
a minor component in the Lewis acid-mediated allylation
of the methoxypiperidine 4, conversion of the major
trans-5 into the minor cis-6 was first examined by em-
ploying the Mitsunobu reaction.6 Thus, (+)-5, [a]D32+19.9
(c 0.9, CHCl3), afforded the trans-alcohol (+)-7,
[a]D32+35.3 (c 0.9, CHCl3), on alkaline methanolysis,
which was treated with acetic acid in the presence of triph-
enylphosphine and diisopropyl azodicarboxylate (DIAD)
to furnish the cis-acetate (+)-6, [a]D29+26.3 (c 1.0,
CHCl3). This gave the cis-alcohol (+)-8, [a]D30+26.1 (c
0.8, CHCl3), on alkaline methanolysis. Overall yield of
(+)-8 from (+)-5 was 73% in three steps (Scheme 3).
Since there are a variety of physiologically active natural
products carrying a 2,5-cis-substituted pyrrolidine core in
their molecules,3 we are interested in transformation of
the above 2-allyl-5-piperidinol derivatives into the corre-
sponding 2,5-disubstituted pyrrolidine derivatives by a
ring-contraction pathway.4 It was well established that pi-
OH
OH
OAc
OH
Lipase PS
ClCO2Bn
and
vinyl acetate
CH2Cl2
NaBH4
NaHCO3
(70%)
N
N
N
N
Cbz
Cbz >99%e.e.
>99%e.e.
Cbz
1
(±)-2
(+)-3: R=Ac (47%)
(+)-2 (48%)
K2CO3
MeOH
(95%)
(–)-2: R=H
Scheme 1
OAc
OAc
OAc
TMS
1) p-TsOH (cat.)
+
(+)-2
MeOH
2) Ac2O, Et3N
DMAP (cat.)
CH2Cl2
ZnCl2
MeO
N
N
N
CH2Cl2
–78 °C ~ r.t.
Cbz
4
Cbz (80%)
(+)-5
Cbz (10%)
(–)-6
(78%)
Scheme 2
Synlett 2001, No. 1, 45–48 ISSN 0936-5214 © Thieme Stuttgart · New York

46
H. Sakagami, K. Ogasawara
LETTER
OAc
OH
OH
AcOH
K2CO3
K2CO3
(+)-5
DIAD
PPh3
Et2O
MeOH
(98%)
MeOH
(91%)
N
N
N
Cbz
Cbz
Cbz
(+)-6
(+)-8
(+)-7
(82%)
Scheme 3
OH
OH
OH
BzCl
LiAlH4
50% KOH
(+)-5
1N NaOH
dioxane
THF
(92%)
EtOH
reflux
N
N
H
9
N
Bz
(85%)
Bn
(+)-11
(+)-10
OMs
CsOAc
MsCl
+
N
DMF
Et3N
CH2Cl2
0 °C
N
45 °C
MsO–
Bn
Bn
13
12
OR
+
OAc
N
N
Bn
Bn
(+)-15 : R=Ac (14%)
(+)-11 : R=H
K2CO3
MeOH
(94%)
(+)-14 (64%)
Scheme 4
Having secured both diastereomeric acetates, the trans- after transformation into (+)-11 by alkaline methanolysis
acetate (+)-5 was transformed into the trans-N-benzy- (Scheme 4).
laminoalcohol (+)-11, [a]D29+37.2 (c 0.9, CHCl3), in 78%
On the other hand, the cis-acetate (-)-6 was transformed
overall yield by sequential alkaline hydrolysis, N-benzoy-
into the cis-N-benzylaminoalcohol (-)-17, [a]D30 -89.6 (c
lation, and hydride reduction via the aminoalcohol 9 and
1.0, CHCl3), in 66% overall yield by sequential alkaline
hydrolysis, N-benzoylation, and hydride reduction via the
the N-benzamide (+)-10, mp 174-175 °C, [a]D30+50.0 (c
1.0, CHCl3). Mesylation of (+)-11 in dichloromethane in
benzamide (-)-16, [a]D30 -30.5 (c 0.9, CHCl3), as for the
the presence of triethylamine brought about spontaneous
trans-counterpart (+)-5. Upon mesylation, (-)-17 afford-
intramolecular reaction of the generated mesylate 12 to
ed the aziridinium salt 19, through the mesylate 18, which
give the aziridinium salt 13. Among the conditions exam-
was treated with cesium acetate5,7 to give diastereoselec-
ined, treatment of the salt 13 with cesium acetate5,7 in
29
tively the cis-2,5-substituted pyrrolidine (-)-20, [a]D
DMF at 45 °C for 3 h furnished the ring-contracted prod-
-31.1 (c 1.6, CHCl3), and the cis-2,5-substituted piperi-
uct trans-5-allylprolinol acetate (+)-14, [a]D31+88.2 (c
29
dine (-)-21, [a]D -17.8 (c 1.0, CHCl3), in yields of
1.5, CHCl3), in 64% yield accompanied with the readily
60% and 19%, respectively, after separation by column
separable trans-2-allyl-5-piperidinol acetate (+)-15,
chromatography. The latter was identical with the authen-
[a]D29+40.6 (c 1.1, CHCl3), in 14% yield. Optical rotation
29
tic (-)-21, [a]D -18.6 (c 1.03, CHCl3), obtained from
of the latter was virtually the same as that of the authentic
(-)-17, which may be recycled after conversion into the
acetate (+)-15, [a]D31+40.1 (c 1.2, CHCl3), obtained from
29
alcohol (-)-17, [a]D -91.6 (c 0.8, CHCl3), by alkaline
the starting alcohol (+)-11, indicating the preservation of
methanolysis. Yield of the ring-contraction product from
the original chiral integrity during the double inversion re-
action. Although the ring-contraction did not proceed in a
completely selective manner, the 2,5-disubstituted pyrro-
lidine (+)-14 could be obtained in a practically acceptable
yield and the piperidine byproduct (+)-15 may be recycled
the cis-substrate (-)-17 was somewhat lower than that of
the trans-counterpart (+)-11, but it is still acceptable for
practical utilization (Scheme 5).
Synlett 2001, No. 1, 45–48 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Diastereocontrolled Synthesis of Enantiopure trans- and cis-5-Allylprolinols
47
OH
OH
LiAlH4
1) 50% KOH
(–)-6
EtOH
reflux
THF
(100%)
N
N
Bz
Bn
2) BzCl
1N NaOH
dioxane
(66%)
(–)-16
(–)-17
OMs
CsOAc
MsCl
+
N
DMF
Et3N
CH2Cl2
0 °C
N
45 °C
MsO–
Bn
Bn
19
18
OR
+
OAc
N
N
Bn
Bn
(–)-21 : R=Ac (19%)
(–)-17 : R=H
K2CO3
MeOH
(99%)
(–)-20 (60%)
Scheme 5
In summary, we have achieved diastereoselective trans-
formation of trans- and cis-2-allyl-5-hydroxy-1-benzylpi-
peridines into trans- and cis-5-allylprolinols in a practical
manner by employing a ring-contraction protocol. Al-
though the present procedure is accompanied with an un-
wanted piperidine byproduct, it may be recycled after
deacetylation. Utilization of the 2,5-disubstituted pyrro-
lidines thus obtained for enantiocontrolled synthesis of
pyrrolidine natural products is currently under investiga-
tion.
45 °C for 3 h. The mixture was diluted in brine and extracted
with ether. The extract was washed with 5% aqueous sodium
hydrogen carbonate, dried (MgSO4), evaporated under
reduced pressure, and chromatographed (SiO2, 30 g) to give
the trans-prolinol acetate (+)-14 (647 mg, 64%), [a]D31+88.2
(c 1.5, CHCl3), as a colorless oil from an EtOAc-hexane eluent
(1: 12 v/v) and the trans-piperidinol acetate (+)-15 (145 mg,
14%), [a]D29+40.6 (c 1.1, CHCl3), as a colorless oil from an
EtOAc-hexane eluent (1:10 v/v). (+)-14: IR (film): n = 1740,
1233 cm-1; 1H NMR (300 MHz, CDCl3): d = 7.42 - 7.14 (5H,
m), 5.81 - 5.61 (1H, m), 5.09 - 4.92 (2H, m), 4.11 - 3.89 (3H,
m), 3.84 - 3.70 (1H, m), 3.26 -3.12 (1H, m), 3.12 - 2.99 (1H,
m), 2.44 - 2.28 (1H, m), 2.09 - 1.08 (3H, m), 2.01 (3H, s),
1.69 - 1.54 (2H, m); 13C NMR (125 Hz, CDCl3): d = 171.3,
140.3, 136.3, 128.3, 126.8, 116.5, 65.7, 60.2, 58.8, 51.8, 35.1,
27.7, 26.6, 21.0; MS: m/z = 272 (M+ - 1), 91 (100%); HRMS:
Calcd for C14H18NO2 (M+ - C3H5) = 232.1338,
Acknowledgement
We thank Japan Society for the Promotion of Science for a scholar-
ship (to H.S.).
found = 232.1346. (+)-15: IR (film):n = 1737, 1242 cm-1; 1H
NMR (300 MHz, CDCl3): d = 7.36 - 7.17 (5H, m), 5.97 -
5.77 (1H, m), 5.10 (1H, d, J = 4.1 Hz), 5.09 (1H, s), 4.82 -
4.68 (1H, m), 4.06 (1H, d, J = 13.5 Hz), 3.26 (1H, d, J = 13.5
Hz), 2.89 (1H, ddd, J = 11.3, 4.1, 1.8 Hz), 2.47 - 2.28 (2H,
m), 2.02 (1H, dd, J = 10.8, 9.8 Hz), 1.97 (3H, s), 1.84 - 1.72
(1H, m), 1.57 (3H, m), 1.43 - 1.24 (1H, m); 13C NMR (125
Hz, CDCl3): d = 170.5, 139.2, 135.4, 128.9, 128.4, 127.1,
116.9, 69.7, 59.6, 57.3, 55.1, 36.3, 29.3, 28.0, 21.2; MS : m/
z = 272 (M+ - 1), 91 (100%); HRMS : Calcd for C14H18NO2
(M+ - C3H5) = 232.1338, found = 232.1325. (b) for the cis-
substrate (-)-17-As for (+)-11, (-)-17 (87 mg, 0.38 mmol)
was treated to give the cis-prolinol acetate (-)-20 (61.9 mg,
60%), [a]D29 -31.1 (c 1. 6, CHCl3), as a colorless oil from an
EtOAc-hexane eluent (1:12 v/v) and the cis-piperidinol
acetate (-)-21 (19.6 mg, 19%), [a]D29 -17.8 (c 1.0, CHCl3), as
a colorless oil from an EtOAc-hexane eluent (1:10 v/v).
(-)-20: IR (film):n = 1738, 1234 cm-1; 1H NMR (300 MHz,
CDCl3): d = 7.38 - 7.17 (5H, m), 5.86 - 5.59 (1H, m), 5.17 -
4.93 (2 H, m), 3.88 (1H, d, J = 13.8 Hz), 3.78 (2H, d, J = 6.9
Hz), 3.75 (1H, d, J = 13.8 Hz), 3.09 - 2.96 (1H, m), 2.88 -
2.75 (1H, m), 2.32 - 2.19 (1H, m), 2.08 - 1.92 (1 H, m), 1.95
References and Notes
(1) Sakagami, H.; Kamikubo, T.; Ogasawara, K. Chem. Commun.
1996, 1433.
(2) Sakagami, H.; Ogasawara, K. Synthesis 2000, 521.
(3) Pertinent reviews, see; Liddell, J.R. Nat. Prod. Rep. 1999, 16,
499, and previous reports.
(4) Tehrani, K. A.; Syngel, K. V.; Boelens, M.; Contreras, J.; De
Kimpe, N.; Knight, D. W. Tetrahedron Lett. 2000, 41, 2507,
and references cited therein.
(5) Poitout, L.; LeMerrer, Y.; Depezay, J.-C. Tetrahedron Lett.
1996, 37, 1609.
(6) (a) Mitsunobu, O. Synthesis 1981, 1. (b) Hughes, D. L. Org.
React. 1992, 42, 335.
(7) Typical procedure: (a) for the trans-substrate (+)-11-To a
stirred solution of (+)-11 (860 mg, 3.72 mmol) in
dichloromethane (15 mL) was added triethylamine (1.6 mL,
11.2 mmol) and methanesulfonyl chloride (0.43 mL,
5.6 mmol) at 0 °C and the stirring was continued for 30 min at
the same temperature. After evaporation of the solvent under
reduced pressure, the residue was dissolved in DMF (18 mL)
and was stirred with cesium acetate (2.1 g, 11.2 mmol) at
Synlett 2001, No. 1, 45–48 ISSN 0936-5214 © Thieme Stuttgart · New York

48
H. Sakagami, K. Ogasawara
LETTER
(3H, s), 1.90 - 1.72 (2H, M), 1.64 - 1.42 (2H, m); 13C NMR
(125 Hz, CDCl3): d = 171.2, 140.3, 136.1, 129.0, 128.3, 127.0,
116.3, 67.7, 65.1, 63.0, 58.3, 39.8, 29.3, 27.2, 20.9; MS: m/
z = 272 (M+ - 1), 91 (100%); HRMS : Calcd for C14H18NO2
(M+ - C3H5) = 232.1338, found = 232.1336.
(3H, m), 2.02 (3H, s), 1.83 - 1.57 (4H, m); 13C NMR (125 Hz,
CDCl3): d = 170.8, 139.3, 136.4, 128.7, 128.4, 127.1, 116.6,
69.5, 58.0, 57.4, 51.7, 31.9, 26.2, 25.4, 21.3; MS: m/z = 272
(M+ - 1), 91 (100%); HRMS: Calcd for C14H18NO2 (M+ -
C3H5) = 232.1338, found = 232.1319.
(-)-21: IR (film):n = 1735, 1240 cm-1; 1H NMR (300 MHz,
CDCl3): d = 7.38 - 7.17 (5H, m), 5.88 - 5.67 (1H, m), 5.16 -
4.98 (2H, m), 4.92 - 4.78 (1H, m), 3.82 (1H, d, J = 13.7 Hz),
3.57 (1H, d, J = 13.7 Hz), 2.72 - 2.56 (2H, m), 2.56 - 2.23
Article Identifier:
1437-2096,E;2001,0,01,0045,0048,ftx,en;Y17400ST.pdf
Synlett 2001, No. 1, 45–48 ISSN 0936-5214 © Thieme Stuttgart · New York