A flexible route to chiral 2-endo-substituted 9-oxabispidines and their application in the enantioselective oxidation of secondary alcohols

Article abstract of DOI:10.1021/jo802409x

A new and flexible route to enantiomerically pure bi-and tricyclic 9-oxabispidines has been developed with use of (1R,5S)-7-methyl-2-oxo-9-oxa-3,7- diazabicyclo[33.1]nonane-3-carboxylic acid tert-butyl ester as the common late-stage intermediate. The 9-oxabispidines synthesized were evaluated as the chiral ligands in the Pd(II)-catalyzed oxidative kinetic resolution of secondary alcohols giving good to excellent selectivity factors of up to 19.

Full text of DOI:10.1021/jo802409x

A Flexible Route to Chiral 2-endo-Substituted
9-Oxabispidines and Their Application in the
Enantioselective Oxidation of Secondary Alcohols
Matthias Breuning,* Melanie Steiner, Christian Mehler,
Alexander Paasche, and David Hein
Institute of Organic Chemistry, UniVersity of Wu¨rzburg,
Am Hubland, 97074 Wu¨rzburg, Germany
breuning@chemie.uni-wuerzburg.de
FIGURE 1. Chiral (9-oxa)bispidines and the key intermediate 8.
ReceiVed October 29, 2008
tributed to the (-)-sparteine/Pd(II)-catalyzed oxidative kinetic
resolution of secondary alcohols developed by Stoltz and
Sigman.3-6
Structurally simpler derivatives of 1 that also possess a
chirally modified bispidine (3,7-diazabicyclo[3.3.1]nonane) core
of type 2 are rare since their total synthesis is still a challenging
and laborious task.7-9 The only exception is given by the
tricyclic bispidine 3, which is available in 3 steps from the
natural product (-)-cytisine (4).10,11 Diamine 3 found applica-
tion as a surrogate for the less readily available (+)-sparteine
enantiomer, ent-1.10,12
Our search for novel sparteine substitutes focuses on the
structurally closely related, but only poorly investigated13
9-oxabispidines of type 5. Their cage-like architectures are
comparable to those of the well-known bispidines,14 thus giving
rise to excellent properties as chiral ligands in asymmetric
A new and flexible route to enantiomerically pure bi- and
tricyclic 9-oxabispidines has been developed with use of
(1R,5S)-7-methyl-2-oxo-9-oxa-3,7-diazabicyclo[3.3.1]nonane-
3-carboxylic acid tert-butyl ester as the common late-stage
intermediate. The 9-oxabispidines synthesized were evaluated
as the chiral ligands in the Pd(II)-catalyzed oxidative kinetic
resolution of secondary alcohols giving good to excellent
selectivity factors of up to 19.
(4) (a) Jensen, D. R.; Pugsley, J. S.; Sigman, M. S. J. Am. Chem. Soc. 2001,
123, 7475. (b) Mandal, S. K.; Sigman, M. S. J. Org. Chem. 2003, 68, 7535.
(5) Nielsen, R. J.; Keith, J. M.; Stoltz, B. M.; Goddard, W. A., III J. Am.
Chem. Soc. 2004, 126, 7967.
(6) Ebner, D. C.; Trend, R. M.; Genet, C.; McGrath, M. J.; O’Brien, P.;
Stoltz, B. M. Angew. Chem., Int. Ed. 2008, 47, 6367.
(7) Enantioselective synthesis of 3: (a) Danieli, B.; Lesma, G.; Passarella,
D.; Piacenti, P.; Sacchetti, A.; Silvani, A.; Virdis, A. Tetrahedron Lett. 2002,
43, 7155. (b) Danieli, B.; Lesma, G.; Passarella, D.; Sacchetti, A.; Silvani, A.
Tetrahedron Lett. 2005, 46, 7121. (c) Hermet, J.-P. R.; Viterisi, A.; Wright,
J. M.; McGrath, M. J.; O’Brien, P.; Whitwood, A. C.; Gilday, J. Org. Biomol.
Chem. 2007, 5, 3614.
(8) Enantioselective synthesis of 1 or ent-1: (a) Smith, B. T.; Wendt, J. A.;
Aube´, J. Org. Lett. 2002, 4, 2577. (b) Hermet, J.-P. R.; McGrath, M. J.; O’Brien,
P.; Porter, D. W.; Gilday, J. Chem. Commun. 2004, 1830.
(9) Stereoselective synthesis of other bispidines possessing a chirally modified
core: (a) Phuan, P.-W.; Ianni, J. C.; Kozlowski, M. C. J. Am. Chem. Soc. 2004,
126, 15473. (b) Chau, F. H. V.; Corey, E. J. Tetrahedron Lett. 2006, 47, 2581.
(c) Breuning, M.; Hein, D. Tetrahedron: Asymmetry 2007, 18, 1410.
(10) (a) Dixon, A. J.; McGrath, M. J.; O’Brien, P. Org. Synth. 2006, 83,
141. (b) O’Brien, P. Chem. Commun. 2008, 655.
(11) Synthesis of N-alkyl derivatives of 3 from 4: (a) Dearden, M. J.;
McGrath, M. J.; O’Brien, P. J. Org. Chem. 2004, 69, 5789. (b) Genet, C.;
McGrath, M. J.; O’Brien, P. Org. Biomol. Chem. 2006, 4, 1376. (c) Wilkinson,
J. A.; Rossington, S. B.; Ducki, S.; Leonard, J.; Hussain, N. Tetrahedron 2006,
62, 1833. (d) Johansson, M. J.; Schwartz, L. O.; Amedjkouh, M.; Kann, N. C.
Eur. J. Org. Chem. 2004, 1894. (e) Johansson, M. J.; Schwartz, L.; Amedjkouh,
M.; Kann, N. Tetrahedron: Asymmetry 2004, 15, 3531.
(12) ent-1 is accessible from the naturally occurring alkaloid rac-lupanine
(rac-10-oxosparteine) by reduction and resolution: Ebner, T.; Eichelbaum, M.;
Fischer, P.; Meese, C. O. Arch. Pharm. (Weinheim) 1989, 322, 399.
(13) There is a single lecture abstract, in which an enantioselective route to
6 and some other bicyclic 9-oxabispidines of type 5 is sketched. However, no
yields or characterization data are given, see: Gill, D. M.; Holness, H.; Keegan,
P. S. Abstracts of Papers, 232nd ACS National Meeting, San Francisco, CA;
American Chemical Society: Washington, DC, 2006.
The lupine alkaloid (-)-sparteine (1, Figure 1) belongs to
the privileged ligands in asymmetric synthesis. It is, for example,
the unrivalled chiral auxiliary of choice in almost all enanti-
oselective deprotonation/electrophilic trapping reactions of
weakly C-H acidic compounds using strong organolithium
bases such as s-BuLi.1 The extraordinary complexation proper-
ties of 1 are, however, not restricted to lithium organyls; highly
enantioselective transformations have also been realized in
combination with other metals.2 Particular attention was at-
(1) (a) Hoppe, D.; Hintze, F.; Tebben, P.; Paetow, M.; Ahrens, H.;
Schwerdtfeger, J.; Sommerfeld, P.; Haller, J.; Guarnieri, W.; Kolczewksi, S.;
Hense, T.; Hoppe, I. Pure Appl. Chem. 1994, 66, 1479. (b) Hoppe, D.; Hense,
T. Angew. Chem., Int. Ed. Engl. 1997, 36, 2282. (c) Clayden, J. Organolithiums:
SelectiVity for Synthesis; Pergamon: New York, 2002. (d) Hodgson, D. M. Topics
in Organometallic Chemistry; Springer: Berlin, Germany, 2003; Vol. 5. (e)
Gawley, R. E.; Coldham, I. In The Chemistry of Organolithium Compounds;
Rappoport, Z., Marek, I., Eds.; Wiley: Chichester, UK, 2004; p 997. (f) Hoppe,
D.; Christoph, G. In The Chemistry of Organolithium Compounds; Rappoport,
Z., Marek, I., Eds.; Wiley: Chichester, UK, 2004; p 1055. (g) Chuzel, O.; Riant,
O. In Topics in Organometallic Chemistry; Lemaire, M., Mangeney, P., Eds.;
Springer: Berlin, Germany, 2005; Vol. 15, p 59.
(2) For some examples, see: (a) Shintani, R.; Fu, G. C. Angew. Chem., Int.
Ed. 2002, 41, 1057. (b) Sorger, K.; Petersen, H.; Stohrer, J. U.S. Patent 6924386,
2005. (c) Maheswaran, H.; Prasanth, K. L.; Krishna, G. G.; Ravikumar, K.;
Sridhar, B.; Kantam, M. L. Chem. Commun. 2006, 4066.
(3) (a) Ferreira, E. M.; Stoltz, B. M. J. Am. Chem. Soc. 2001, 123, 7725. (b)
Bagdanoff, J. T.; Ferreira, E. M.; Stoltz, B. M. Org. Lett. 2003, 5, 835. (c)
Bagdanoff, J. T.; Stoltz, B. M. Angew. Chem., Int. Ed. 2004, 43, 353. (d) Caspi,
D. D.; Ebner, D. C.; Bagdanoff, J. T.; Stoltz, B. M. AdV. Synth. Catal. 2004,
346, 185.
(14) Comba, P.; Kerscher, M.; Schiek, W. Prog. Inorg. Chem. 2007, 55,
613.
10.1021/jo802409x CCC: $40.75
Published on Web 12/16/2008
2009 American Chemical Society
J. Org. Chem. 2009, 74, 1407–1410 1407

SCHEME 1. Synthesis of the Key Intermediate 8 from 9
and 11
SCHEME 2. Synthesis of 15 from 16 and 17
SCHEME 3. Preparation of the Bicyclic 9-Oxabispidines
7a,b from 8
synthesis. With the methylene bridge in 2 being replaced by an
ether function, the 9-oxabispidines 5 are often more easily
accessible than the corresponding bispidines. This has recently
been demonstrated in our group by the enantioselective prepara-
tion of a set of bicyclic 2-endo-phenyl-substituted derivatives
(5, R ) Ph; R1, R2 ) H, Me, Bn) from commercially available
(R,R)-phenylglycidol (3-5 steps, 35-41% yield).15 A first
asymmetric synthesis of the tricyclic 9-oxabispidine 6 was
successfully accomplished, too.16
One major problem, inherent to all known syntheses of
bispidines and 9-oxabispidines, still remained unsolved: a late-
stage variation of the appendage at C-2 is not possible since
this part of the molecule (or a precursor to it) is usually
constructed in the very beginning.7-9 The missing synthetic
flexibility in the southern hemisphere, which plays the decisive
role in the chirality transfer, severely hampers more in-depth
structure-selectivity investigations.
Herein we disclose a first solution to this problem by using
the N-Boc-9-oxabispidin-2-one 8 as a common, late-stage
intermediate. This imide, available in 7 steps by two different
routes, was converted in just 4-5 steps and 35-47% yield into
the bicyclic, 2-endo-substituted 9-oxabispidines 7a and 7b and
the tricycle 6. The potential of these diamines in the oxidative
kinetic resolution of secondary alcohols was studied.
Two conceptually different approaches have been realized
for the enantioselective synthesis of the key intermediate 8.
Route 1 (Scheme 1) commenced with methyl glycidate (9),
which was treated with p-methoxybenzylamine to afford the
amide 10 in 99% yield. The morpholine 13 was prepared
following a multistep one-pot sequence developed earlier on
related cyclizations of ꢀ-amino alcohols17 and 3-amino-1,2-
diols.15,16 Heating of 10 with (R)-epichlorohydrin (11) in the
presence of LiClO4 induced a highly regioselective ring opening
of the epoxide at C-3 to give a chlorohydrin intermediate, which,
upon addition of KOtBu, underwent an intramolecular cycliza-
tion to provide 12. Nucleophilic attack of the hydroxy group at
the epoxide function and mesylation delivered 13 as a 52:48
mixture of epimers at C-2 in 31% yield. KOtBu-induced ring
closure of 13, which involved an isomerization of the trans-
epimer to the cis-configured derivative, gave the chiral 9-oxa-
bispidine 14 in excellent 95% yield.18 Hydrogenolytic removal
of the northern PMB group, N-alkylation, and MsOH-induced
cleavage of the amidic PMB substituent delivered the lactam
15, which was converted into the key intermediate 8 by
treatment with Boc2O in pyridine. This route, in which the chiral,
1,2-bis-electrophilic C-3 building block 11 was used, afforded
8 in overall 7 steps and 12% yield.
The second approach (Scheme 2) started with the known acid
16, available in a single step from ethyl 2,3-dibromopro-
panoate.19 Activation of 16 as the acid chloride, amide formation
with (R)-3-aminopropane-1,2-diol (17), and ring closure under
basic conditions afforded the morpholin-3-one 18 as a 67:33
mixture of the epimers at C-2 in 48% yield. O-Debenzylation
and mesylation of the two hydroxy groups provided 19 in 76%
yield and set the stage for the cyclization with methylamine,
which delivered the desired 9-oxabispidin-2-one 15 in 33%
yield. As a byproduct, the R,ꢀ-unsaturated morpholin-2-one 20
was obtained in 34% yield. The final conversion of 15 into 8 is
shown in Scheme 1. Compared to route 1, this 7-step approach
is based on the chiral, 1,2-bis-nucleophilic C-3 building block
17 giving 8 in slightly lower 9% overall yield, but offers the
advantage of more convenient reaction procedures.
The transformation of the key intermediate 8 into the 2-endo-
substituted 9-oxabispidines was straightforward (Scheme 3). The
bicyclic ethyl derivative 7a was obtained in 44% yield by using
a 4-step protocol:20 Treatment of 8 with EtMgBr resulted in a
clean monoaddition at the N-acyl moiety of the unsymmetric
imide function,21 delivering, after ring-opening of the initially
formed semiaminal, the ketone 21a in good 86% yield. Acidic
(19) Ward, R. S.; Pelter, A.; Goubet, D.; Pritchard, M. C. Tetrahedron:
Asymmetry 1995, 6, 469.
(20) For a related protocol starting from achiral 2,4,6,8-tetraoxobispidine,
see: (a) Blakemore, P. R.; Kilner, C.; Norcross, N. R.; Astles, P. C. Org. Lett.
2005, 7, 4721. (b) Norcross, N. R.; Melbardis, J. P.; Solera, M. F.; Sephton,
M. A.; Kilner, C.; Zakharov, L. N.; Astles, P. C.; Warriner, S. L.; Blakemore,
P. R. J. Org. Chem. 2008, 73, 7939.
(21) For additions of organometallic reagents to N-Boc-activated piperidines,
see: (a) Williams, G. D.; Pike, R. A. Org. Lett. 2003, 5, 4227. (b) Giovannini,
A.; Savoia, D.; Umani-Ronchi, A. J. Org. Chem. 1989, 54, 228. (c) Wei, B.-G.;
Chen, J.; Huang, P.-Q. Tetrahedron 2006, 62, 190. (d) Harrison, T. J.; Kozak,
J. A.; Corbella-Pane, M.; Dake, G. R. J. Org. Chem. 2006, 71, 4525. (e) Williams,
G. D.; Wade, C. E.; Wills, M. Chem. Commun. 2005, 4735.
(15) Breuning, M.; Steiner, M. Synthesis 2007, 1702.
(16) Breuning, M.; Steiner, M. Tetrahedron: Asymmetry 2008, 19, 1978.
(17) Breuning, M.; Winnacker, M.; Steiner, M. Eur. J. Org. Chem. 2007,
2100.
(18) The epimers of 13 are easily separable by column chromatography. Ring
closure of the cis-configured derivative (2R,6S)-13 to the bispidin-2-one 14
occurred at rt in 99% yield, the trans-isomer (2S,6S)-13 cyclized in refluxing
toluene (92% yield).
1408 J. Org. Chem. Vol. 74, No. 3, 2009

TABLE 1. Oxidative Kinetic Resolution of the Alcohols 27 and 28
in the Presence of the 9-Oxabispidines 6 and 7
SCHEME 4. Final Stages to the Tricyclic 9-Oxabispidine 6
sm ligand cond.a t (d) conv. (%)b yield (%) er (R:S)c
sd
27
27
27
7a
7b
6
7a
7b
6
6
6
6
6
A
A
A
A
A
A
B
B
C
C
C
C
C
17
17
30
17
17
17
31
25
54
47
41
61
62
53
67
63
58
48
42
50:50
54:46
75:25
50:50
59:41
89:11
80:20
83:17
93:7
99.6:0.4 19
94:6
83:17
76:24
0.0
1.8
3.8
0.0
2.0
6.7
3.7
7.1
6.4
cleavage of the N-Boc group followed by base-induced cycliza-
tion gave the imine 22a, which was hydrogenated and N-
methylated to provide the target diamine 7a. In agreement with
known reductions and nucleophilic alkylations of bispidine-
derived imines,22 the hydrogenation of 22a occurred highly
stereoselectively from the less hindered exo-face thus leading
to the exclusive formation of the endo-substituted isomer 7a.
The 2-endo-phenyl derivative 7b15 was prepared analogously
in 47% overall yield from 8.
28a
28a
28a
27
28a
27
28a
28b
28c
28d
4.5
4.5
0.75
0.8
0.9
2.5
2.5
21
33
35
39
48
6
6
6
12
12
10
The tricyclic 9-oxabispidine 616 was accessed by using a
slightly modified sequence (Scheme 4). Reaction of 8 with
TBSO(CH2)4MgBr and O-deprotection afforded the ketone 23,
which exists in a 20:40:40 ratio with its two diastereomeric lactol
isomers 24A and 24B. Hydroxy/chlorine exchange, acidic
removal of the N-Boc protective group, and filtration through
basic aluminum oxide furnished, probably via the imine 25, the
iminium salt 26, the structure of which was fully established
by two-dimensional NMR measurements. Final reduction with
NaBH4 in methanol delivered 6 in 35% overall yield, again with
full stereocontrol.
a Conditions A: Pd(nbd)Cl2 (5 mol %), 6 or 7 (20 mol %), O2 (1 bar),
mol sieves 3 Å, toluene, 60-80 °C. Conditions B: Pd(nbd)Cl2 (5 mol
%), 6 (12 mol %), O2 (1 bar), Cs2CO3, mol sieves 3 Å, CHCl3, rt.
Conditions C: 29 (5 mol %), 6 (7 mol %), O2 (1 bar), Cs2CO3, mol
sieves 3 Å, CHCl3, rt. b Determined by 1H NMR. c Determined by
HPLC on the chiral phase. d Reference selectivity factors (ligand,
conditions):3,6,26 27: s ) 10 (1, B), s ) 6.8 (3, A); 28a: s ) 17 (1, C), s
) 19 (3, C); 28b: s ) 15 (1, B); 28c: s ) 28 (1, C), s ) 25 (3, C);
28d: s ) 20 (1, C).
As exemplified by the preparations of 7a,b and 6, the imide
8 is well-suited as a late-stage intermediate, from which a variety
of bi- and tricyclic 9-oxabispidines with different 2-endo-
substituents or 2-endo-fused rings should be accessible.
The potential of the 9-oxabispidines as chiral ligands in
asymmetric synthesis was studied on the Pd(II)-catalyzed
oxidative kinetic resolution of the secondary alcohols 27 and
28 (Table 1) with conditions A-C developed by Stoltz et al.3,6
for the analogous (-)-sparteine-catalyzed reactions.23 Even
though only low enantiomer differentiations were found under
conditions A with 1-indanol (rac-27) and 1-(4-methoxyphe-
nyl)ethanol (rac-28a) as the substrates, the results clearly
showed that the tricyclic 9-oxabispidine 6 is superior to the
bicyclic 9-oxabispidines 7a and 7b.24 Good to excellent
selectivity factors s25 of up to 19 were achieved applying
conditions C, in which the preformed Pd(II)-complex 29 (Figure
2), prepared from 6 and [Pd(MeCN)2Br2], in combination with
some additional ligand 6 was used as the catalytic system. The
enantioselective oxidation of rac-28a, for example, delivered
the alcohol (R)-28a in 99.4:0.6 er after 20 h at 63% conversion
and in 33% isolated yield. In this case, the high selectivity factor
of s ) 19 is fully in the range of those obtained with (-)-
FIGURE 2. The chiral PdBr2 complex 29 and the isomer 30.
sparteine (1, s ) 17)6 and the bispidine 3 (s ) 19)6 as the chiral
ligands. Lower differentiations were observed for 27 and 28b-d
(s ) 6.4-12).
According to quantum chemical studies,5 a cationic species
is involved in the rate-limiting step of the catalytic cycle, the
ꢀ-hydride shift from the complexed alcohol to the Pd-metal.
Since this process is facilitated by a stronger electron-donating
ligand, the lower reaction rates (factor 5-10), observed with 6
as compared to 1 and 3, might be a consequence of a reduced
basicity of the 9-oxabispidine, caused by the electron-withdraw-
ing oxygen atom in the bridge. This assumption is supported
by the calculated27 basicity of 6 (pKa,calcd ) 19.5), which is more
than two pKa units lower than these of 1 (pKa,calcd ) 21.7,
pKa,exp.,MeCN ) 22.1) and 3 (pKa,calcd ) 21.9).28
1
The coupling constants found in the H NMR data of the
catalyst 29 strongly support the desired N,N-complexation of
the chiral ligand 6 (chair-chair conformation) to the Pd-metal,
(22) (a) Harrison, J. R.; O’Brien, P. Tetrahedron Lett. 2000, 41, 6167. (b)
Blakemore, P. R.; Norcross, N. R.; Warriner, S. L.; Astles, P. C. Hetreocycles
2006, 70, 609. (c) References 9b and 20.
(23) For a recent study on 9-bispidinones as the ligands, see: Lesma, G.;
Pilati, T.; Sacchetti, A.; Silvani, A. Tetrahedron: Asymmetry 2008, 19, 1363.
(24) The only other application of a chiral bicyclic bispidine (2, R-R2 )
Me) in asymmetric synthesis was reported by Kozlowski et al.9a Low 33% ee
was achieved in the enantioselective deprotonation of N-Boc pyrrolidine.
(25) The selectivity factor s is defined as s ) kfast/kslow ) ln[(1- C)(1-ee)]/
ln[(1- C)(1 + ee)], where C is the conversion.
(26) (a) Dearden, M. J.; Firkin, C. R.; Hermet, J.-P. R.; O’Brien, P. J. Am.
Chem. Soc. 2002, 124, 11870–11871. (b) Reference 11a.
(27) All calculated structures were optimized with the TURBOMOLE
program package on the B3LYP//BLYP-RI level of theory, employing the TZVP
basis set. Solvent effects were taken into account by using the COSMO solvent
model (ꢀ ) 36.64). For details, see the Supporting Information.
(28) pKa values refer to the acidities of the protonated (9-oxa)bispidines. They
were calculated by using a method established by Gogoll et al., see: Toom, L.;
Ku¨tt, A.; Kaljurand, I.; Leito, I.; Ottosson, H.; Grennberg, H.; Gogoll, A. J.
Org. Chem. 2006, 71, 7155.
J. Org. Chem. Vol. 74, No. 3, 2009 1409

120 mg) were added to the residue dissolved in EtOH (30 mL).
The reaction mixture was hydrogenated for 20 h under 1 bar of H2
pressure. The crude product was sucked through a pad of Celite,
washed with MeOH (150 mL), and concentrated under reduced
pressure. The residue was dissolved in H2O (30 mL) and the pH
was adjusted to 11 with 1 N NaOH (ca. 40 mL). After extraction
with CHCl3 (5 × 60 mL), the combined organic layers were dried
over Na2SO4. Removal of the solvent in vacuo yielded the
N-demethylated precursor of 7a (122 mg, 717 µmol, 79%) as a
brownish oil. [R]22D -1.4 (c 0.27 in MeOH). 1H NMR (400 MHz,
CD3OD) δ 0.97 (t, J ) 7.5 Hz, 3H, CH2Me), 1.41 (m, 2H, CH2Me),
2.15 (s, 3H, NMe), 2.36 (ddd, J ) 11.9, 3.6, 1.4 Hz, 1H, 8-H),
2.45 (m, 1H, 6-H), 2.95 (m, 4H, 2-H, 4-H, 6-H, 8-H), 3.15 (ddd,
J ) 13.8, 3.9, 2.5 Hz, 1H, 4-H), 3.56 (t, J ) 3.3 Hz, 1H, 1H), 3.64
(t, J ) 3.8 Hz, 1H, 5-H). 13C NMR (100 MHz, CD3OD) δ 10.9
(CH2Me), 27.0 (CH2Me), 47.1 (NMe), 50.9 (C-4), 56.1 (C-8), 60.6
(C-6), 60.7 (C-2), 68.6 (C-5), 71.4 (C-1). IR (film) 3300, 2933,
2789, 1460, 1269, 1210, 1078, 846 cm-1. HRMS (ESI) calcd for
[C9H18N2O + H]+ 171.1492, found 171.1494.
although, a priori, an N,O-ligation of 6 (boat-chair conformation)
as in 30 cannot fully be excluded (Figure 2). The large difference
in the calculated27 heats of formation [∆Hf ) Hf(29) - Hf(30)
) -43.9 kJ mol-1], however, makes a competing N,O-chelation
as in 30 very unlikely.
In conclusion, a novel enantioselective approach to 9-ox-
abispidines has been developed. Using the N-Boc-activated
9-oxabispidin-2-one 8 as the key intermediate, a flexible
introduction of substituents in the 2-endo position was possible
via a 4-5 step sequence, as demonstrated in the preparation of
the bicyclic derivatives 7a and 7b and the tricycle 6. This route
will permit efficient access to a broader variety of interesting
derivatives for further structure-selectivity investigations. In the
oxidative kinetic resolution of secondary alcohols, selectivity
factors of up to 19 have been achieved with the tricyclic
9-oxabispidine 6. The prolonged reaction times, as compared
to 1 and 3 as the chiral ligands, are probably a consequence of
the electron-withdrawing oxygen atom in 6.
The 9-oxabispidine prepared above (100 mg, 587 µmol) was
dissolved in CH2Cl2 (10 mL) and treated at rt with K2CO3 (162
mg, 1.17 mmol) and MeI (36.5 µL, 83.3 mg, 587 µmol). After 6 h
at rt, 1 N NaOH (50 mL) and brine (50 mL) were added and the
reaction mixture was extracted with CHCl3 (3 × 75 mL). The
combined organic layers were dried over MgSO4 and the solvent
was removed in vacuo. Column chromatography (basic Al2O3,
activity V, EtOAc/MeOH 1:0 f 0:1) gave 7a (69.1 mg, 375 µmol,
64%) as a colorless oil. [R]22D +32.1 (c 0.27 in MeOH). 1H NMR
(400 MHz, CD3OD) δ 0.90 (t, J ) 7.6 Hz, 3H, CH2Me), 1.28 (m,
1H, CHHMe), 1.91 (m, 1H, CHHMe), 2.15 (s, 3H, NMe), 2.18 (s,
3H, NMe), 2.23 (m, 2H, 8-H, 2-H), 2.38 (dd, J ) 11.4, 2.5 Hz,
1H, 6-H), 2.55 (dd, J ) 11.8, 4.2 Hz, 1H, 4-H), 2.84 (d, J ) 11.8
Hz, 2H, 4-H, 6-H), 2.95 (d, J ) 12 Hz, 1H, 8-H), 3.72 (t, J ) 3.7
Hz, 1H, 1-H), 3.82 (t, J ) 4.0 Hz, 1H, 5-H). 13C NMR (100 MHz,
CD3OD) δ 10.6 (CH2Me), 23.3 (CH2Me), 44.4 (3-Me), 47.1 (7-
Me), 54.8 (C-8), 59.5 (C-6), 60.4 (C-4), 68.5 (C-2), 69.7 (C-5),
71.1 (C-1). IR (ATR) 2940, 2800, 1676, 1460, 1176, 1130, 1092,
801 cm-1. HRMS (ESI) calcd for [C10H20N2O + H]+ 185.1648,
found 185.1648.
Experimental Section
The following preparation of 7a from 8 is representative.
(2R,6R)-6-tert-Butoxycarbonylaminomethyl-4-methyl-2-propio-
nylmorpholine (21a). EtMgBr (466 µL, 1.4 mmol, 3.0 M in Et2O)
was added at -78 °C to a solution of 8 (300 mg, 1.17 mmol) in
anhydrous THF (20 mL). After 12 h at -78 °C, the reaction mixture
was quenched with saturated aqueous NH4Cl (20 mL) and water
(80 mL) and extracted with EtOAc (4 × 60 mL). The combined
organic layers were dried over MgSO4 and concentrated in vacuo.
Column chromatography (silica gel, Et2O/MeOH 1:0 f 9:1)
delivered 21a (288 mg, 1.01 mmol, 86%) as a yellowish oil. [R]22
+41.4 (c 0.15 in CH2Cl2). H NMR (400 MHz, CDCl3) δ 1.02 (t,
D
1
3H, J ) 7.3 Hz, CH2Me), 1.44 (s, 9H, CMe3), 1.79 (td, J ) 11.0,
3.7 Hz, 2H, 3-Hax, 5-Hax), 2.29 (s, 3H, NMe), 2.60 (q, J ) 7.3 Hz,
2H, CH2Me), 2.70 (d, J ) 11.3 Hz, 1H, 5-Heq), 2.98 (br d, J )
11.3 Hz, 1H, 3-Heq), 3.16 (m, 1H, 6-CHH), 3.34 (m, 1H, 6-CHH),
3.65 (m, 1H, 6-H), 4.04 (dd, J ) 11.0, 2.7 Hz, 1H, 2-H), 4.88 (br
s, 1H, NH). 13C NMR (100 MHz, CDCl3) δ 6.9 (CH2Me), 28.4
(CMe3), 31.8 (CH2Me), 43.0 (6-CH2), 46.0 (NMe3), 55.7 (C-3), 56.9
(C-5), 75.3 (C-6), 79.5 (CMe3), 80.8 (C-2), 155.9 (CO2), 209.5
(COEt). IR (film) 3361, 2978, 2939, 2800, 1715, 1523, 1467, 1366,
1252, 1173, 1117 cm-1. HRMS (ESI) calcd for [C14H26N2O4 +
H]+ 287.1965, found 287.1966.
Acknowledgment. This work was supported by the Deutsche
Forschungsgemeinschaft DFG (Emmy-Noether fellowship to
M.B.) and Chemetall.
Supporting Information Available: Experimental proce-
dures and quantum chemical calculations, as well as charac-
terization data and NMR spectra for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(1R,2S,5S)-2-Ethyl-3,7-dimethyl-9-oxa-3,7-diazabicyclo[3.3.1]-
nonane (7a). A solution of the morpholine 21a (260 mg, 908 µmol)
in TFA (2 mL) was stirred for 4.5 h at 0 °C. NaOH (11 N, 50 mL)
was added and the reaction was warmed to rt within 15 min. After
extraction with Et2O (3 × 100 mL), the combined organic layers
were washed with brine (100 mL), dried over Na2SO4, and
evaporated. Concentrated HCl (3 mL) and Pd(OH)2/C (20 w/w %,
JO802409X
1410 J. Org. Chem. Vol. 74, No. 3, 2009