trans-6-Aminocyclohept-3-enols, a new designed polyfunctionalized chiral building block for the asymmetric synthesis of 2-substituted-4-hydroxypiperidines.

Article abstract of DOI:10.1021/ol025683x

trans-6-Aminocyclohept-3-enols 18 and ent-18 are new designed polyfunctionalized chiral building blocks for piperidine alkaloids synthesis and are prepared in high yields from the enzymatically derived cyclohept-3-ene-1,6-diol monoacetate (-)-8. Efficient highly enantioselective syntheses of cis-4-hydroxypipecolic acid (1) and piperidines 3 and 4, in both enantiomeric forms, are described. [reaction: see text]

Full text of DOI:10.1021/ol025683x

ORGANIC
LETTERS
2
002
Vol. 4, No. 8
367-1370
trans-6-Aminocyclohept-3-enols, a New
Designed Polyfunctionalized Chiral
Building Block for the Asymmetric
Synthesis of
1
2-Substituted-4-hydroxypiperidines
Paolo Celestini, Bruno Danieli, Giordano Lesma,* Alessandro Sacchetti,
Alessandra Silvani, Daniele Passarella, and Andrea Virdis
Dipartimento di Chimica Organica e Industriale, UniVersit a` degli Studi di Milano,
Via Venezian 21, 20133 Milano, Italy
giordano.lesma@unimi.it
Received February 7, 2002
ABSTRACT
trans-6-Aminocyclohept-3-enols 18 and ent-18 are new designed polyfunctionalized chiral building blocks for piperidine alkaloids synthesis
and are prepared in high yields from the enzymatically derived cyclohept-3-ene-1,6-diol monoacetate (−)-8. Efficient highly enantioselective
syntheses of cis-4-hydroxypipecolic acid (1) and piperidines 3 and 4, in both enantiomeric forms, are described.
Piperidine subunits constitute an integral feature of many
chiral natural compounds and synthetic derivatives which
exhibit interesting biological activities and in many cases
have proved to be useful chemotherapeutic agents.
utilized as chiral building blocks of biologically active
2
molecules, and in particular, (2S,4R)-ent-1 was employed
in a recent synthesis of the potent antiviral agent palinavir.2b
In addition, the biologically active 2-alkyl-4-hydroxy-
piperidines 3 and 4 were isolated as cometabolites of a
These reasons have prompted an exceptional growth of
1
3
research resulting in the development of synthetic strategies
piperidine-producing organism and are proposed as inter-
for the preparation of these compounds, and a wide range
of methodologies have been reported in the past decade.
In this regard, several enantiopure naturally occuring cis-
and trans-2-substituted-4-hydroxy-piperidines, for example,
cis- and trans-4-hydroxy-2-pipecolic acids (1 and 2), were
mediates in the biosynthesis of the potent antimicrobial agent
streptazolin. However, to the best of our knowledge, only
3a,4
(2) (a) Bellier, B.; Da Nascimento, S.; Meudal, H.; Gincel, E.; Roques,
B. P.; Garbay, C. Bioorg. Med. Chem. Lett. 1998, 8, 1419. (b) Gillard, J.;
Abraham, A.; Anderson, P. C.; Beaulieu, P. L.; Bogri, T.; Bousquet, Y.;
Grenier, L.; Guse, I.; Lavallee, P. J. Org. Chem. 1996, 61, 2226.
(
3) (a) Grabley, S.; Hammann, P.; Kluge, H.; Wink, J.; Kricke, P.; Zeek,
(
1) For reviews on the synthesis of substituted piperidines, see: (a)
A. J. Antibiot. 1991, 44, 797. (b) Romeyke, Y.; Keller, M.; Kluge, H.;
Grabley, S.; Hammann, P. Tetrahedron 1991, 47, 3335. (c) Keller-Schierlein,
W.; Wuthier, D.; Drautz, H. HelV. Chim. Acta 1983, 66, 1253. (d) Arnone,
A.; Cardillo, R.; Nasini, G.; Vajna de Pava, O.; Quaroni, S. Phytochemistry
1988, 27, 3611. (e) Komoto, T.; Yano, K.; Ono, J.; Okawa, J.; Nakajima,
T. Jpn. Kokai 35788, Feb 2, 1986; Chem. Abstr. 1986, 105, 132137w.
Laschat, S.; Dickner, T. Synthesis 2000, 13, 1781. (b) Bailey, P. D.;
Millwood, P. A.; Smith, P. D. J. Chem. Soc., Chem. Commun. 1998, 633.
c) Leclercq, S.; Daloze, D.; Braekman, J.-C. Org. Prep. Proc. Int. 1996,
8, 499. (d) Wang, C.-L. J.; Wuonola, M. A. Org. Prep. Proc. Int. 1992,
4, 585.
(
2
2
1
0.1021/ol025683x CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/23/2002

two syntheses of the above-mentioned piperidinols in opti-
cally active form have been reported to date. In the first one,
by regioselective intramolecular N-alkylation of a suitable
protected aminotriol 6, which can be prepared by oxidative
cleavage of the C3/C4 bond of a trans-6-aminocyclohept-
3-enol derivative 7. This in turn can be fashioned by selective
functional group modification of the cyclohept-3-ene-1,6-
5
the 2-pentadienylpiperidin-4-ol (3) was prepared, in both
enantiomeric forms, by a diastereoselective intramolecular
Mannich reaction using planar chiral iron dienal complexes.
6
More recently, a biomimetic synthesis of the 2-pent-3-
1
diol monoacetate 8 with C -symmetry, which can be prepared
enylpiperidin-4-ol (4) has been accomplished via the suc-
cessful cyclization of an aminostreptenol precursor.
in both enantiomeric forms from the corresponding meso-
diol 9 and meso-diacetate 10 by employing lipase-mediated
transesterification or hydrolysis, respectively.
9
10
The meso-substrates 9 and 10 were prepared, in line with
1
0,11
established literature precedents,
available tropone (11) (Scheme 2).
from commercially
Scheme 2. Synthesis of meso-Precursors 9 and 10a
As part of a program aimed at the design and preparation
of polyfunctionalized chiral building blocks useful for the
enantiosynthesis of alkaloids, by a chemoenzymatic ap-
7
proach, we introduce here optically pure, protected, trans-
a
6
2
-aminocyclohept-3-enols for the asymmetric synthesis of
-alkyl-4-hydroxypiperidines. The utility of these new syn-
Reagent and conditions: (a) NaBH
MCPBA, CH Cl /H O-NaHCO , 0 °C, 94%; (c) LiAlH
rt, 80%; (d) Ac O, pyridine, rt, 99%.
4
, MeOH/H
2
O, rt, 88%; (b)
2
2
2
3
4
, THF,
2
thons is well illustrated in the concise, high -yielding
enantioselective syntheses of both enantiomers of cis-4-
8
hydroxy-2-pipecolic acid (1) and cis-2-alkyl-4-hydroxy-
piperidines 3 and 4.
Our retrosynthetic analysis was guided by the retrosyn-
thetic symmetrization concept (Scheme 1). The C-2 append-
Thus, controlled reduction of 11 with NaBH
afforded 3,5-cycloheptadienol (12) (88%). Selective mono-
epoxidation of 12 with m-chloroperbenzoic acid in CH Cl
at room temperature, as described earlier, was found to be
unexpectedly low-yielding in our hands (<33%). Fortunately,
we found that epoxidation of 12, as described above, but in
4
in MeOH
2
2
1
0
Scheme 1. Retrosynthetic Symmetrization of 1, 3, and 4
the presence of 1.2 equiv of aqueous NaHCO
predominantly the cis-epoxyalcohol 13 in very high yield
94%). Reduction of 13 with LiAlH in THF afforded diol
(80%), which by further acetylation gave the corresponding
3
, provided
(
4
9
diacetate 10 (99%). Using this procedure, the overall yield
of diol 9 (and diacetate 10) was 64-66%, and multigram
amounts may be prepared with minimal purification.
To obtain first the (1R,6S)-ent-8, we attempted the lipase-
catalyzed transesterification of diol 9, as described by
9
Lautens. Surprisingly, at variance with this report, we found
that acetylation of 9, in isopropenyl acetate in the presence
of Candida cylindracea lipase, afforded selectively the
1
2
(
1S,6R)-8 enantiomer with high ee (>96%), but moderate
yield (58%). Moreover, C. rugosa lipase produced the same
enantiomer with 99% ee, but in very low yield (<30%),
whereas porcine pancreatic lipase (PPL) and Pseudomonas
ages in 1, 3, and 4 can be derived by appropriate elaboration
of the 2-hydroxyethyl side chain of a piperidine 5, accessible
(
8) For recent syntheses of 1, see: (a) Sabat, M.; Johnson, C. R.
Tetrahedron Lett. 2001, 42, 1209. (b) Brooks, C. A.; Comins, D. L.
Tetrahedron Lett. 2000, 41, 3551. (c) Di Nardo, C.; Varela, O. J. Org.
Chem. 1999, 64, 6119. (d) Haddad, M.; Larchev eˆ que, M. Tetrahedron:
Asymmetry 1999, 10, 4231.
(9) Lautens, M.; Ma, S.; Yee, A. Tetrahedron Lett. 1995, 36, 4185.
(10) Kaku, H.; Tanaka, M.; Norimine, Y.; Miyashita, Y.; Suemune, H.;
Sakai, K. Tetrahedron: Asymmetry 1997, 8, 195.
(
4) Mayer, M.; Thiericke, R. J. Org. Chem. 1993, 58, 3486.
(5) Ripoche, I.; Canet, J.-L.; Aboab, B.; Gelas, J.; Troin, Y. J. Chem.
Soc., Perkin Trans. 1 1998, 3485.
6) Dollt, H.; Hammann, P.; Blechert, S. HelV. Chim. Acta 1999, 82,
111.
7) See, for example: (a) Danieli, B.; Lesma, G.; Passarella, D.; Riva,
(
1
(
S. Chiral Synthons via Enzyme-Mediated Asymmetrization of Meso-
Compounds. In AdVances in the Use of Synthons in Organic Chemistry;
Dondoni, A., Ed.; 1993; Vol. 1, pp 143-219. (b) Danieli, B.; Lesma, G.;
Passarella, D.; Silvani, A. Curr. Org. Chem. 2000, 4, 231 and references
therein.
(11) Chapman, O. L.; Pasto, D. J.; Griswold, A. A. J. Am. Chem. Soc.
1962, 84, 1213.
(12) Optical purities of the diol monoacetate 8 and of the diol mono-
1
sililated 14 were determined by H NMR spectra after transformation into
the (R)- and (S)-MTPA esters (see refs 10 and 9, respectively).
Org. Lett., Vol. 4, No. 8, 2002
1368

fluorescens lipase (PFL) were completely ineffective. Al-
though the meso-diol 9 could not be desymmetrized satis-
factorily, the meso-diacetate 10 was desymmetrized in clear-
cut manner under hydrolysis conditions in the presence of
Lipase PS (from P. cepacea) to give the enantiopure
trans-azidoacetate 23, both in satisfactory yields. Having in
hand the key intermediates 18 and ent-18 possessing the
requisite N- and O-protected groups with the correct stereo-
chemistry, our next efforts were devoted to the elaboration
of the cis-2,4-disubstituted piperidine moiety.
monoacetate 8,12 (>97% ee), [R]24
-50.9 (c 2.0, CHCl
Toward this end, cleavage of the cycloheptene ring in 18
D
3
),
in 95% yield. By a sequential functional group protection
and deprotection, starting from 8, a formal enantiomeric
conversion was performed, affording enantiopure mono-
by ozonolysis in MeOH/CH
2
5
Cl
2
at -78 °C followed by in
1
4
situ reduction, with NaBH , of the intermediate dialdehyde
(not isolated) provided the dihydroxy derivative 19 in 72%
yield. The following step involves the critical piperidine ring
formation, utilizing the nitrogen and oxygen functionalities
present at C-3 and C-7 in 19, via a favored 6-exo-tet
intramolecular cyclization. Mesylation of 19 gave the rather
unstable dimesylate 20 (98%) which was not isolated but
directly subjected to cyclization by reaction with NaH (1.3
equiv) in DMF at 0 °C, affording the cis-2,4-disubstituted
piperidine 21 in 59% yield from 19.
12
24
9
silylated diol 14 [R]
D
3
+6.1 (c 1.3, CHCl ); the sequence
involved reaction with TBSCl and imidazole in DMF and
hydrolysis of acetate group with NaOH in MeOH (Scheme
3).
Scheme 3a
With the piperidine ring formation now solved, the
synthesis of hydroxypiperidines 1, 3, and 4 was addressed
(Scheme 4).
Scheme 4a
a
Reagent and conditions: (a) (PhO)
rt, (77% for 15; 72% for 23); (b) SnCl
Boc O, rt, (64% for 16; 66% for ent-18); (c) NaOH, MeOH/H
5 °C, (98% for 17; 95% for 14); (d) TBSCl, DMF, imidazole, 40
C, (99% for 18; 92% for 22); (e) O , CH Cl -MeOH (1:1), -78
C; then Me S, NaBH , -78 f 25 °C, 72%; (f) TsCl, TEA, CH Cl
2
P(O)N
, MeOH, rt, 4 h; then TEA,
O,
3
, DEAD, TPP, THF,
2
2
2
4
°
°
3
2
2
2
4
2
2
,
rt, 98%; (g) NaH, DMF, rt, 59%.
As the first step in our synthetic plan, we devised the
synthesis of the protected trans-6-aminocyclohept-3-enol
intermediates 18 and ent-18.
Enantiopure diol monoacetate 8 was treated under Mit-
13
14
sunobu conditions with diphenylphosphoryl azide to give
cleanly the trans-azidoacetate 15 which furnished the
protected trans-aminoacetate 16, in 64% yield, by a straight-
a
Reagent and conditions: (a) (E)-propenylmagnesium bromide,
2
forward one-pot, two-step reduction (SnCl /MeOH) and
CuI, THF, -78 f 25 °C, 5h; then 3 N HCl-MeOH, rt, (55%); (b)
i) 2-nitrophenyl selenocyanate, NaBH , EtOH, 0 f 24 °C; (ii)
, THF, 76%; (c) O , CH Cl -MeOH (1:1), -78 °C; then
S, -78 f 25 °C, 88%; (d) KMnO , NaH PO , tBuOH/H O;
then 3 N HCl, MeOH, 50 °C, 79%; (e) (i) Me-CHdCH-CHdPPh
THF; (ii) I , benzene, hν, 40 min; (iii) 3 N HCl, MeOH, rt, 64%.
carbamoylation sequence. For the synthesis of the target 21,
which is the synthetic equivalent of 5, the conversion of the
acetate function of 16 into tert-butyldimethylsilyl (TBS) ether
was required. After hydrolysis of the acetate of 16 under
conventional conditions (98%), the resulting protected amino
alcohol 17 was then silylated with TBSCl to afford (1S,6S)-
(
H
Me
4
2
O
2
2
3
2
2
4
2
4
2
3
,
2
1
8, [R]24
similar sequence, the enantiomer (1R,6R)-ent-18, [R]
c 1.0, CHCl ), was obtained from 14 by Mitsunobu azidation
and sequential reduction-carbamoylation of the resulting
D
+3.4 (c 1.0, CHCl
3
), in quantitative yield. By a
24
Treatment of the intermediate 21 with (E)-propenylmag-
nesium bromide/CuI in THF, followed by acidic workup,
afforded the (2S,4S)-(+)-2-pent-3-enylpiperidin-4-ol (4), in
5% yield, possessing spectral properties in accordance with
D
-3.2
1
6
(
3
5
(
13) Mitsunobu, O. Synthesis 1981, 1.
(14) Using the Weinreb amide as amination reagent, product formation
(15) Johnson, C. R.; Golebiowski, A.; Steensma, D. H.; Scialdone, M.
required 2-3 days and resulted in 21% yield.
A. J. Org. Chem. 1993, 58, 7185.
Org. Lett., Vol. 4, No. 8, 2002
1369

the literature {[R]24
c 2.5, MeOH)}.
The aldehyde 25 was considered as a common attractive
6
+6.9 (c 2.0, MeOH); lit. [R]
6
24
+7.3
obtained in 64% yield, as colorless needles {[R]
24
+37.8
3
), mp 67 °C
D
D
D
5
25
(
(c 1.0, CHCl
3
); lit. [R]
D
+39.0 (c 1.0, CHCl
5
1
13
(lit., for the enantiomer, 67-68 °C)}, whose H NMR,
C
intermediate for the synthesis of cis-4-hydroxy-2-pipecolic
acid (1), and 2-pentadienylpiperidin-4-ol (3), by oxidation
and Wittig olefination, respectively.17 Conversion of 21 to
vinylpiperidine 24 was performed (according to Sharpless
procedure ) by reaction wit 2-nitrophenyl selenocyanate
followed by an oxidation-elimination reaction in 76%
combined yield for the two steps.
Ozonolysis of 24 gave smoothly the aldehyde 25 which
was not purified but used directly in the next stage to avoid
compromising the stereochemical integrity at the C-2 carbon
atom.
NMR, and MS spectral data were identical in all respects to
those reported in the literature.
Repetition of the entire reaction sequence described in
Schemes 3 and 4, starting from ent-18, afforded first ent-21
5
18
24
and then the enantiomers ent-4 {[R]
D
-6.1 (c 2.0, MeOH)},
2
4
24
ent-1 {[R]
(c 1.0, CHCl
to note that the naturaly occurring relevant antibacterial and
D
-19.1 (c 1.0, H
2
O)}, and ent-3 {[R]
D
-36
3
)} in comparable yields. It is also interesting
3
a,e
anticonvulsant agent (-)-SS20846A (26) is potentially
available from ent-3 by inversion of the C-4 hydroxy group
by Mitsunobu reaction.
Finally, treatment of 25 with KMnO
4
in aqueous tert-
followed by full
In conclusion, a concise asymmetric enzyme-mediated
preparation of protected trans-6-aminocyclohept-3-enols (18
and ent-18), designed polyfunctionalized chiral building
blocks for the asymmetric synthesis of cis-2-alkyl-4-hydroxy-
piperines, is reported. The utility of these building blocks
was illustrated in efficient enantioselective syntheses of cis-
4-hydroxy-2-pipecolic acid (1) and cis-2-alkyl-4-hydroxy-
piperidines 3 and 4, in both enantiomeric forms. Since the
key intermediates 21 and ent-21 allow the introduction of
various functionalities at the C-2 side chain, the sequence
may be widely applicable to the stereoselective preparation
of a variety of natural and nonnatural cis-2-alkyl-4-hydroxy-
piperidines useful for biologic evaluation.
19
BuOH in the presence of NaH
2
PO
4
deprotection with 3 N HCl in methanol provided (2R,4S)-1
1
as a single stereoisomer (as shown by H NMR spectros-
copy), in 79% yield, possessing spectral properties in
8
c,d
24
accordance with the literature {[R]
D
+21.3 (c 0.5, H
O) for the enantiomer}.
Aldehyde 25 was also subjected to Wittig olefination with
2
O);
2
b
24
lit. [R]
D
-23.5 (c 1, H
2
5
20
n-but-2-enylidenetriphenyl-λ -phosphane, olefin isomer-
ization2 (I
1
/benzene, hν), and deprotection (HCl/MeOH).
2
After recrystallization from diethyl ether, (2R,4S)-(+)-3 was
(16) (a) Bartmann, E.; Bogdanovic, B,; Janke, N.; Liao, S.; Schlichte,
K.; Spliethoff, B.; Treber, J.; Westeppe, U.; Wilczok, U. Chem. Ber. 1990,
1
1
23, 1517. (b) Harmange, J.-C.; Boyle, C. D.; Kishi, Y. Tetrahedron Lett.
994, 35, 6819.
Acknowledgment. This research was supported by CNR,
Centro di Studio per le Sostanze Organiche Naturali.
(17) A similar strategy, describing the use of a related aldehyde for the
synthesis of trans-4-hydroxy-2-pipecolic acid 2 and the antibacterial (-)-
SS20846A (26), has been recently reported, see: Johonson, C. R.; Sabat,
M. Tetrahedron Lett. 2001, 42, 1209.
Supporting Information Available: Experimental pro-
cedure and spectroscopic data for all new compounds. This
material is available free of charge via the Internet at
htpp://pubs.acs.org.
(
(
18) Sharpless, K. B.; Young, M. W. J. Org. Chem. 1975, 40, 947.
19) Abiko, A.; Roberts, J. C.; Takemasa, T.; Masamune, S. Tetrahedron
Lett. 1986, 27, 4537.
20) (a) Boger, D. L.; H u¨ ter, O.; Mbiya, K.; Zhang, M. J. Am. Chem.
Soc. 1995, 117, 11839. (b) Chen, X.; Millar, J. G. Synthesis 2000, 113.
21) Naruse, M.; Aoyagi, S.; Kibayashi, C. J. Org. Chem. 1994, 59, 1358.
(
(
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Org. Lett., Vol. 4, No. 8, 2002