Asymmetric synthesis of 2,4,5-trisubstituted piperidines from sulfinimine-derived δ-amino β-ketoesters. Formal synthesis of pseudodistomin B triacetate

Article abstract of DOI:10.1021/jo050373o

N-Sulfinyl δ-amino β-ketoester enaminones, a new sulfinimine-derived chiral building block, undergoes, on hydrolysis in one pot, an intramolecular Michael addition followed by a retro-Michael-type elimination to give enantiopure 2,4,5-trisubstituted piper

Full text of DOI:10.1021/jo050373o

Asymmetric Synthesis of 2,4,5-Trisubstituted Piperidines from
Sulfinimine-Derived δ-Amino â-Ketoesters. Formal Synthesis of
Pseudodistomin B Triacetate
Franklin A. Davis,* Junyi Zhang, Yingxin Li, He Xu, and Charles DeBrosse
Department of Chemistry, Temple University, Philadelphia, Pennsylvania 19122
fdavis@temple.edu
Received February 28, 2005
N-Sulfinyl δ-amino â-ketoester enaminones, a new sulfinimine-derived chiral building block,
undergoes, on hydrolysis in one pot, an intramolecular Michael addition followed by a retro-Michael-
type elimination to give enantiopure 2,4,5-trisubstituted piperidines, a structural motif found in
numerous biologically active alkaloids. This new chiral building block is readily prepared by treating
N-sulfinyl δ-amino â-ketoesters with dimethylformamide dimethyl acetal. This new protocol was
illustrated with a concise formal asymmetric synthesis of marine alkaloid pseudodistomin B
triacetate.
SCHEME 1
Piperidines are among the most common structure
features of many alkaloid natural products, bioactive
compounds, drugs, and drug candidates. As a conse-
quence, numerous methods have been devised for their
synthesis, and they are the subject of several recent
reviews.1 Currently, the challenge is to develop asym-
metric syntheses of multisubstituted piperidines that are
not only concise but also have the necessary substitution
patterns and functionalities for the synthesis of more
elaborate derivatives. Recent efforts in our laboratory
have exploited the intramolecular Mannich2 reaction of
the free amine derived from N-sulfinyl δ-amino â-ke-
toesters 1 and diverse aldehydes (R′CHO) for the highly
diastereoselective asymmetric synthesis of 2,3,4,6 tetra-
substituted 4-piperidones 2 (Scheme 1).3 This chiral
building block was employed in concise asymmetric
syntheses of monosubstituted piperidines such as (R)-
(+)-2-phenylpiperidine;4 disubstituted piperidines such
as the four isomers of 4-hydroxypipecolic acid5 and (-)-
SS20846A;4 and trisubstituted piperidines including the
frog skin toxin (+)-241D6 and the quinolizidine alkaloids
(-)-lasubine I,7 (+)-lasubine II,8 and (-)-epimyrtine.9 In
(1) For reviews on the asymmetric synthesis of piperidines, see: (a)
Laschat, S.; Dickner, T. Synthesis 2000, 1781. (b) Felpin, F.-X.;
Lebreton, J. Eur. J. Org. Chem. 2003, 3693. (c) Weintraub, P. M.; Sabol,
J. S..; Kane, J. M.; Borcherding, D. R. Tetrahedron 2003, 59, 2953. (d)
Buffat, M. G. P. Tetrahedron 2004, 60, 1701.
(2) For a review of the application of the Mannich reaction in
alkaloid synthesis, see: Arend, M.; Westermann, B.; Risch, N. Angew.
Chem., Int. Ed. 1998, 37, 1044.
(5) Davis, F. A.; Fang, T.; Chao, B.; Burns, D. M. Synthesis 2000,
2106.
(6) Davis, F. A.; Chao, B.; Rao, A. Org. Lett. 2001, 3, 3169.
(7) Davis, F. A.; Chao, B. Org. Lett. 2000, 2, 2623.
(8) Davis, F. A.; Rao, A.; Carroll, P. J. Org. Lett. 2003, 5, 3855.
(3) For a review, see: Zhou, P.; Chen, B.-C.; Davis, F. Tetrahedron
2004, 60, 8030.
(4) Davis, F. A.; Chao, B.; Fang, T.; Szewczyk, J. M. Org. Lett. 2000,
2, 1041.
10.1021/jo050373o CCC: $30.25 © 2005 American Chemical Society
Published on Web 05/27/2005
J. Org. Chem. 2005, 70, 5413-5419
5413

Davis et al.
TABLE 1. Reaction of 5 with TFA and Dimethoxymethane
isolated yield (%)
entry
CH2(OMe)2 (equiv)
TFA (equiv)
solvent
scale (mmol)
T (°C)
7
(+)-8
(-)-9
1
2
3
4
5
6
7
8
9
2
2
6
3
6
6
6
6
6
6
6
PhMe
PhMe
PhMe
PhMe
PhMe
DCM
PhMe
PhMe
DCM
0.15
0.15
0.15
0.15
0.15
0.15
0.3
80
80
80
80
60
40
80
80
40
10-30
40
15
40
20
10
15
15a
70
5
50
10
20
0
30
30
0
2
20
2
2
2
2
0.3
0
0.15
a Reaction run in a sealed tube.
SCHEME 2
FIGURE 1. Examples of 2,4,5-trisubstituted piperidines.
a similar fashion, the intramolecular Mannich reaction
of aldehydes (R′CHO) with enantiopure â-amino ketones
3 afforded 2,4,6-trisubstituted10 and 2,3,4,6-tetrasubsti-
tuted 4-piperidones 4 (Scheme 1).11 An example of this
latter type of piperidone, one which has a methyl group
in the 3-position, was concisely elaborated into indolizi-
dine 209B, a 2,3,6-trisubstitued piperidine moiety.11
Numerous piperidine alkaloid natural products have
the 2,4,5-trisubstituted pattern and a few examples are
given in Figure 1. To access these types of piperidines
using the Mannich protocol and N-sulfinyl δ-amino
â-ketoesters 1 requires reaction with formaldehye (CH2O)
or its equivalent. Described herein are studies aimed at
this objective that result in a formal asymmetric synthe-
sis of pseudodistomin B triacetate.
with the aldehyde and the Mannich cyclization.4-7 How-
ever, we discovered that the intramolecular Mannich
reaction works without purification of 6, and the presence
of the sulfinyl byproducts has no influence on the reaction
outcome.12 Therefore, to affect the Mannich cyclization
5 was treated with TFA, formaldehyde, and various
formaldehyde precursors with the goal of preparing 2,4,5-
trisubstituted piperidone 7 (Scheme 2).
All attempts to affect the Mannich cyclization using
formaldehyde gas, generated by heating paraformalde-
hyde, or aqueous formaldehyde resulted in complex
mixtures of products in which 7 was not detected.
Dimethoxymethane, which has been reported to be a
useful source of formaldehyde, proved to be successful.13
Thus, heating 5 with dimethoxymethane and TFA in
toluene resulted in a crude yield of enol 7, in 10-30%
yield (Table 1, entry 1). However, this material proved
to be difficult to isolate and purify. Therefore, following
chromatography 7 was immediately converted into N-Boc
derivative (-)-9 by treatment with (Boc)2O/Et3N. Another
product, bicyclic pyridine (+)-8, was also isolated (Scheme
2). It soon became apparent that the yields of these
products were very sensitive to the solvent, the concen-
tration, and the reaction temperature. These results are
summarized in Table 1.
Result and Discussion
(SS,R)-(+)-Methyl 3-oxo-5-phenyl-5-(p-toluenesulfinyl-
amino)pentanoate (5) was prepared, as previously de-
scribed, and treated with 5 equiv of TFA in MeOH to
remove the N-sulfinyl auxiliary (Scheme 2).5 This pro-
vides the free amine as the triflate salt 6 (Scheme 2).
We previously reported that a short column was neces-
sary to remove the sulfinyl byproducts prior to reaction
(9) Davis, F. A.; Zhang, Y.; Anilkumar, G. J. Org. Chem. 2003, 68,
8061.
(10) (a) Ripoche, I.; Canet, J.; Gelas, J.; Troin, Y. Tetrahedron:
Asymmetry 1999, 10, 2213. (b) Ciblat, S.; Besse, P.; Canet, J.; Troin,
Y.; Veschambre, H.; Gelas J. Tetrahedron: Asymmetry 1999, 10, 2225.
(c) Besse, P.; Ciblat, S.; Canet, J.; Troin, Y.; Veschambre H. Tetrahe-
deron: Asymmetry 2000, 11, 2211. (d) Glasson, S. R.; Canet, J.-L.;
Troin, Y. Tetrahedron Lett. 2000, 41, 9797. (e) Ciblat, S.; Calinaud,
P.; Canet, J.-L.; Troin, Y. J. Chem. Soc., Perkin Trans. 1 2000, 353. (f)
Carbonnel, S.; Troin, Y. Heterocycles 2002, 57, 1807. (g) Lamazzi, C.;
Carbonnel, S.; Calinaud, P.; Troin Y. Heterocycles 2003, 60, 1447.
(11) Davis, F. A.; Yang, B. Org. Lett. 2003, 5, 5011.
With less than 6 equiv of TFA or temperatures lower
than 80 °C the yield of (-)-7/9 was reduced (Table 1,
(12) Unpublished results from these laboratories.
(13) Plate, R.; Hermkens, P. H. H.; Smits, J. M. M.; Ottenheijm, H.
C. J. J. Org. Chem. 1986, 51, 309.
5414 J. Org. Chem., Vol. 70, No. 14, 2005

Formal Synthesis of Pseudodistomin B Triacetate
SCHEME 3
SCHEME 4
entries 2, 5, and 6). The best yield of (-)-9, 50%, was
obtained on a 0.15 mmol scale, with 6.0 equiv of TFA at
80 °C in toluene (Table 1, entry 3). However, attempts
to increase the scale of this to maximize the yield of this
product were unsuccessful (Table 1, entries 7 and 8). The
best yield of pyridine (+)-8 was 70% when the dimeth-
oxymethane was excluded (Table 1, entry 9).
The structure of piperidone (-)-9 and the bicyclic
pyridine (+)-8 are based on the HRMS and NMR spectra.
In (-)-9, the enol proton appears at δ 12.0 ppm and
exchanges with MeOD. The 2D-HMBC spectrum sup-
ports the bicyclic structure of (+)-8 by the observed long-
range couplings of carbon C3 to the NH proton and H9
and both CH2 protons at C5 and C11. The substitution
pattern is supported by NOE difference spectroscopy that
requires separation of protons 1(NH)-6(CH, δ 5.0)-
5(CH2, δ 3.5) from the network of 11(CH2, δ 4.21)-pyridyl
H9 (δ 7.55, s)-15(2H, ortho, phenyl attached to C8). This
experiment showed H9 to be placed central to H11 and
H15.14
A plausible mechanism for the formation of the bicyclic
pyridine (+)-8 is outlined in Scheme 3. Intermolecular
condensations of two molecules of δ-amino â-ketoester
10 gave 11 which cyclizes to the 4-imino piperidone 12.
Both transformations are well precedent in the chemistry
of δ-amino â-ketoesters.5-7 Next, enamine 13 cyclizes to
give the bicyclic dehydropyridine 14, which in turn
undergoes air oxidation affording (+)-8. The fact that the
highest yield of (+)-8 results from the absence of
dimethoxymethane (Table 1, entry 9), where it competes
for the formation of 7, is consistent with this mechanistic
hypothesis.
conditions. As a consequence, enaminones have been
widely used in the preparation of heterocycles.15 However,
to the best of our knowledge, there appears to be only a
single example of their use in the asymmetric synthesis
of piperidines. Here, Bousquet and co-workers employed
an intramolecular Michael addition reaction of a â-ke-
toester enaminone to construct the piperidine ring.16
Treatment of (+)-5 or (+)-15 with 10 equiv of dimeth-
ylformamide dimethyl acetal17 at rt for 6 h followed by
removal of the solvent gave the crude δ-amino â-ketoester
enaminones 16 (Scheme 4). The absorptions appearing
in the proton NMR of 16 at δ 7.68 and 2.68 ppm are
attributed to vinyl and N,N-dimethyl protons, respec-
tively, and suggest that a single isomer was formed, but
of unknown stereochemistry. Because of the hydrolytic
instability of 16 it was used without purification and
treated with 4 N HCl in dioxane to remove the N-sulfinyl
group. Concentration gave presumably 17. The structure
of 17 is supported by the fact that when treated with
(Boc)2O/Et3N it afforded dihydropyridones 18a and 18b
in 65 and 60% isolated yields, respectively, for the five-
step one-flask sequence (Scheme 4). The formation of 17
is consistent with an intramolecular Michael addition of
the free δ-amino group to the enaminone unit in 16
followed by a retro-Michael type elimination. The struc-
ture of 18 is supported by the absorption of the vinyl
proton at 8.5-9.0 ppm. Hydrogenation, H2/Pt, gave the
desired piperidone/enols (-)-9 and (-)-19 in 94 and 93%
isolated yields, respectively (Scheme 4).
Pseudodistomin B. Pseudodistomin A (20) and
pseudodistomin B (21) were isolated by Kobayashi and
co-workers from the Okinawan truncate Pseruodistoma
δ-Amino â-Ketoester Enaminones. Enaminones (â-
amino-R,â-unsaturated carbonyl compounds) are versa-
tile structural motifs capable of reacting with either
electrophiles or nucleophiles depending on the reaction
(15) For reviews on the chemistry of enaminones, see: (a) Elassar,
A.-Z. A.; El-Khair, A. A. Tetrahedron 2003, 59, 8463. (b) Stanovinik,
B.; Svete, J. Chem. Rev. 2004, 104, 2433.
(16) Bousquet, Y.; Anderson, P. C.; Bogri, T.; Duceppe, J.-S.; Grenier,
L.; Guse, I. Tetrahedron 1997, 53, 15671.
(14) A more detailed discussion of the NMR studies can be found in
the Supporting Information.
(17) For a review on formamide acetals, see: Abdulla, R. F.;
Brinkmeyer, R. S. Tetrahedron 1979, 35, 1675.
J. Org. Chem, Vol. 70, No. 14, 2005 5415

Davis et al.
SCHEME 5
Summary. Efficient and general methodology has
been introduced for the asymmetric synthesis of 2,4,5-
trisubstituted piperidines, a structural motif found in
numerous biologically active alkaloids. This new proce-
dure employs N-sulfinyl δ-amino â-ketoester enaminones
16, a new sulfinimine derived chiral building block that
is readily prepared by reaction of N-sulfinyl δ-amino
â-ketoesters with dimethylformamide dimethyl acetal.
On treatment with acid, 16 undergoes an intramolecular
Michael addition followed by a retro-Michael-type elimi-
nation to afford the 2,4,5-trisubstituted piperidine in good
yield for the one-pot, five-step sequence. This new
methodology was illustrated with a concise formal asym-
metric synthesis of the triacetate of pseudodistomin B.
In the course of these studies, a novel dimerization-
rearrangement of δ-amino â-ketoesters to bicyclic pyri-
dine (+)-8 was discovered.
kanoko in 1987 and were the first piperidine alkaloids
to be isolated from a marine source (Scheme 5).18 These
alkaloids exhibited potent cytotoxic activity against
L1210 and L51178 leukemia cells, as well as inhibition
of calmodulin-activated brain phosphodiesterase.18,19 As
a consequence of their important biological activity a
number of asymmetric syntheses have been described.20,21
We were particularly attracted to the synthesis of the
triacetate of pseudodistomin B described by Ma and
Sun.21 Using the Curtius rearrangement, these workers
developed an efficient methodology for conversion of the
piperidine 4-oxo-5-carboxymethyl groups, i.e., 9 and 19,
into the syn-4-hydroxy-5-amino groups required for the
syntheses of 20 and 21. To construct the 2,4,5-piperidone
moiety they employed a Dieckmann condensation of a
derived â-amino ester. However, their condensation
resulted in a 2:1 mixture of isomers that could not be
separated and necessitated further synthetic transforma-
tions on the mixture. This resulted in lower overall yields.
Our formal synthesis of the triacetate of pseudo-
distomin B (21) begins with the preparation of the
requisite (R)-(-)-N-(7-benzyloxyheptylidene)-p-toluene-
sulfinamide (24) by condensation of aldehyde 22, pre-
pared by oxidation of 7-benzyloxyheptan-1-ol,22 with (R)-
(-)-p-toluenesulfinamide (23) (Scheme 6). The sulfinimine
(R)-24, isolated in 78% yield, was transformed, as previ-
ously described, into the N-sulfinyl δ-amino â-ketoester
(RS,R)-(-)-26 by reaction of the â-amino ester (RS,R)-
(-)-25 with an excess of the sodium enolate of methyl
acetate.5,7,9 Using our new δ-amino â-ketoester enami-
none methodology (see above), treatment of (-)-26 with
dimethylformamide dimethyl acetal, hydrolysis, and N-
Boc protection afforded (R)-(-)-27 in 63% yield for the
five-step one-flask sequence (Scheme 6). Hydrogenation
of (R)-(-)-27 gave the key enol intermediate (R)-(+)-28
in 93% isolated yield. This enol, 28, was the same
intermediate that was obtained by Ma and Sun as an
inseparable mixture of products.21 As described by these
workers, pure (R)-(-)-28 was converted in our laboratory
into the silyl enol ether (-)-29, hydrogenated, and
deprotected to give (-)-30 in 77% yield for the three steps.
This completes our formal asymmetric synthesis of
pseudodistomin B triacetate (Scheme 6).
Experimental Section
(SS,R)-(+)-Methyl 3-oxo-5-phenyl-5-(p-toluenesulfinylami-
no)pentanoate (5)5 and methyl (SS,R)-(+)-6,6-dimethyl-3-oxo-
5-(p-toluenesulfinylamino)heptanoate (15)23 were prepared as
previously described.
(6R)-(-)-4-Hydroxy-6-phenyl-5,6-dihydro-2H-pyridine-
1,3-dicarboxylic Acid 1-tert-Butyl Ester 3-Methyl Ester
(9). In a 25-mL, single-necked, round-bottom flask equipped
with a magnetic stirring bar, rubber septum, and argon balloon
was placed (+)-5 (0.05 g, 0.14 mmol) in methanol (2 mL).
Trifluoroacetic acid (0.065 mL, 0.84 mmol) was added, and the
reaction was stirred at rt for 30 min and concentrated. The
residue was dissolved in toluene (3 mL), and dimethoxymethane
(0.025 mL, 0.28 mmol) was added. The solution was refluxed
for 8 h, the solution was concentrated, and the residue was
extracted with EtOAc (3 × 5 mL), ethyl acetate, and aqueous
Na2CO3 (3 × 5 mL). The organic phases were combined, dried
(Na2SO4), and concentrated. Chromatography (hexanes/EtOAc,
1:1) afforded 0.008 g (15%) of bicyclic pyridine (+)-9 (see below)
and piperidine 7 in crude form. Crude 7 was dissolved in THF
(3 mL) and treated with triethylamine (0.04 mL, 0.28 mmol)
and di-tert-butyl dicarbonate (0.034 g, 0.15 mmol). After the
reaction mixture was stirred for 3 h, aqueous NH4Cl (5 mL)
was added, and the solution was extracted with EtOAc (2 ×
15 mL). The combined organic phases were dried (Na2SO4) and
concentrated. Chromatography (hexanes/EtOAc, 3:2) gave
0.024 g (50%) of a colorless oil: [R]20 -13.3 (c 0.22, CHCl3);
D
IR (neat) 1736, 1697, 1551, 1462 cm-1; 1H NMR (CDCl3) δ 1.51
(s, 9 H), 2.78 (d, J ) 13.0 Hz, 1 H), 2.92 (m, 1 H), 3.30 (m, 1
H), 3.71 (s, 3 H), 4.47 (m, 1 H), 5.67 (brs, 1 H), 7.27 (m, 5 H),
12.05 (s, 1 H); 13C NMR (CDCl3) δ 28.5, 28.7, 31.5, 37.1, 51.8,
80.8, 95.9, 126.8, 127.7, 128.8, 129.1, 139.4, 154.9, 168.9, 170.9;
HRMS (FAB) calcd for C18H23NO5Na (M + Na) 356.1474, found
356.1483.
(7R)-(+)-(5-Oxo-2,7-diphenyl-5,6,7,8-tetrahydro[1,6]-
naphthyridin-4-yl)acetic Acid Methyl Ester (8). In a 25-
mL, single-necked, round-bottom flask equipped with a mag-
netic stirring bar, rubber septum,and condenser was placed
(+)-5 (0.05 g, 0.15 mmol) in methanol (3 mL), and trifluoro-
acetic acid (0.073 mL, 0.96 mmol) was added. After 30 min,
the solvent was concentrated, the residue was dissolved in
DCM (3 mL), and the solution was heated at 40 °C for 6 h. At
this time the solution was cooled to rt, DCM (10 mL) was
added, the solution was washed with aqueous Na2CO3 (10 mL),
and the organic phase was dried (Na2SO4) and concentrated.
Chromatography (hexanes/EtOAc, 3:2) gave 0.0188 g (70%) of
(18) Ishibashi, M.; Ohizumi, Y.; Sasaki, T.; Nakamura, H.; Hirata,
Y.; Kobayashi, J. J. Org. Chem. 1987, 52, 450.
(19) Ishibashi, M.; Keki, K.; Kobayashi, J. J. Nat. Prod. 1995, 58,
804.
(20) (a) Kiguchi, T.; Yuumoto, Y.; Ninomiya, I.; Naito, T. Tetrahedron
Lett. 1992, 33, 7389. (b) Kiguchi, T.; Yuumoto, Y.; Ninomiya, I.; Naito,
T. Chem. Pharm. Bull. 1997, 45, 1212.
(21) Ma, D.; Sun, H. J. Org. Chem. 2000, 65, 6009.
(22) Bessodes, M.; Boukarim, C. Synlett 1996, 1119.
a solid: mp 61-63 °C; [R]20 +70 (c 0.23, CHCl3); IR (neat)
D
1
3200, 1736, 1659, 1555, 1458 cm-1; H NMR (CDCl3) δ 3.40
(m, 2 H), 3.70 (s, 3 H), 4.15 (d, J ) 16.4 Hz 1 H), 4.23 (d, J )
(23) Davis, F. A.; Yang, B.; Deng, J. J. Org. Chem. 2003, 68, 5147.
5416 J. Org. Chem., Vol. 70, No. 14, 2005

Formal Synthesis of Pseudodistomin B Triacetate
SCHEME 6
16.4 Hz 1 H), 4.98 (dd, J ) 10.7, 5.4 Hz 1 H), 5.98 (s, 1 H),
7.32 (m, 8 H), 7.48 (s, 1 H), 7.97 (d, J ) 6.5 Hz 2 H); 13C NMR
(CDCl3) δ 40.4, 41.1, 52.2, 54.9, 120.9, 123.2, 126.4, 127.4,
128.9, 129.1, 129.2, 129.9, 138.1, 140.4, 145.8, 158.8, 159.5,
166.1, 171.2; HRMS calcd for C23H20N2O3Na (M + Na) 395.1372,
found 395.1382.
(60%) of a colorless oil: [R]23D +113.4 (c 4.6, CHCl3); IR (neat)
1
3020, 1689, 1456 cm-1; H NMR (CDCl3) δ 0.88 (s, 9 H), 1.51
(s, 9 H), 2.71 (m, 2 H), 3.73 (s, 3 H), 4.38 (brs, 1 H), 8.85 (s, 1
H); 13C NMR (CDCl3) δ 27.6, 28.2, 38.1, 38.2, 52.1, 60.8, 85.5,
108.2, 151.5, 152.4, 165.0, 189.2; HRMS (FAB) calcd for C16H25-
NO5Na (M + Na) 334.1630, found 334.1638.
General Procedure for Preparing Dihydropyridones
Using Dimethylforamide Dimethyl Acetal. (6R)-(-)-4-
Oxo-6-phenyl-5,6-dihydro-4H-pyridine-1,3-dicarboxylic
Acid 1-tert-Butyl Ester 3-Methyl Ester (18a). In a 100-
mL, single-necked, round-bottom flask equipped with a mag-
netic stirring bar, rubber septum, and argon balloon were
placed â-ketoester 5 (0.9 g, 2.5 mmol) and dimethylformamide
dimethyl acetal (3.4 mL, 25 mmol) in toluene (20 mL). The
reaction was stirred at rt for 6 h before the solvent was
removed. The residue was redissolved in 4 N HCl (in dioxane,
10 mL) and stirred at rt for 2 h. The solvent was removed in
vacuo, and the residue was redissolved in acetonitrile (15 mL)
with TEA (1.8 mL, 12.9 mmol), DMAP (0.06 g, 0.5 mmol), and
di-tert-butyl dicarbonate (0.55 g, 2.5 mmol). The reaction was
stirred at rt for 3 h before it was quenched with aqueous NH4-
Cl (10 mL). The mixture was extracted with EtOAc (3 × 10
mL). The combined organic phase was washed with brine (30
mL), dried over Na2SO4, concentrated, and chromatographed
(6R)-(-)-4-Hydroxy-6-tert-butyl-5,6-dihydro-2H-pyri-
dine-1,3-dicarboxylic Acid 1-tert-Butyl Ester 3-Methyl
Ester (19). In a 25-mL, single-necked, round-bottom flask
equipped with a magnetic stirring bar, rubber septum, and
hydrogen balloon were placed 18b (0.3 g, 0.96 mmol) and Pt
(5wt % on C, 0.1 g) in methanol (5 mL). After 3 h, the solution
was filtered and concentrated. Chromatography (hexanes/
EtOAc, 5:1) gave 0.28 g (93%) of a colorless oil: [R]20D -47.7 (c
1.6, CHCl3); IR (neat) 1656, 1493, 1472 cm-1; 1H NMR (CDCl3)
(rotamer) δ 0.85 (s, 9 H), 1.40 (s, 9 H), 2.26 (m, 1 H), 2.48 (m,
1 H), 3.60 (m, 1 H), 3.68 (d, 1.4 H), 3.71 (d, 1.6 H), 4.07 (d, J
) 8.1 Hz, 0.55 H), 4.28 (d, J ) 8.1 Hz, 0.45 H), 4.43 (d, J )
16.8 Hz, 0.55 H), 4.63 (d, J ) 16.8 Hz, 0.45 H), 11.86 (s, 0.55
H), 11.89 (s, 0.45 H); 13C NMR (CDCl3) (rotamer) δ 27.4, 27.7,
27.8, 28.7, 28.9, 37.1, 38.8, 39.5, 51.7, 51.8, 54.7, 56.2, 80.3,
80.4, 95.0, 95.4, 155.3, 155.7, 169.4, 170.3, 171.1,171.2; HRMS
(FAB) calcd for C16H27NO5Na (M + Na) 336.1787, found
336.1792.
7-Benzyloxyheptanal (22). In a 100-mL, single-necked,
round-bottom flask equipped with a magnetic stirring bar,
rubber septum, and argon balloon were placed 7-benzyloxy-
heptan-1-ol22 (1.2 g, 5.5 mmol) and PCC (3.5 g, 16.2 mmol) in
dichloromethane (30 mL). After 2 h, the reaction was diluted
with ether (30 mL) and filtered. The filtrate was concentrated
and chromatographed (hexanes/EtOAc, 1:1) to give 1.1 g (89%)
of a colorless oil: IR (neat) 3127, 2806 cm-1; 1H NMR (CDCl3)
δ 1.32 (m, 4 H), 1.57 (m, 4 H), 2.36 (m, 2 H), 3.42 (t, J ) 6.5
Hz, 2 H), 4.45 (s, 2 H), 7.26 (m, 5 H), 9.70 (t, J ) 1.8 Hz, 1 H);
13C NMR (CDCl3) δ 22.4, 26.3, 29.3, 29.9, 44.1, 70.6, 73.3, 127.8,
(hexanes/EtOAc, 2:1) to give 0.5 g (65%) of a colorless oil: [R]23
D
-146.0 (c 3.1, CHCl3); IR (neat) 3150, 1701, 1652, 1532 cm-1
;
1H NMR (CDCl3) δ 1.25 (s, 9 H), 2.81 (dd, J ) 16.0, 1.5 Hz, 1
H), 3.16 (dd, J ) 16.0, 7.8 Hz, 1 H), 3.81 (s, 3 H), 5.64 (d, J )
7.5 Hz, 1 H), 7.15 (m, 2 H), 7.30 (m, 3 H), 9.03 (s, 1 H); 13C
NMR (CDCl3) δ 28.1, 43.2, 52.1, 57.0, 85.8, 108.3, 125.8 128.6,
129.4, 138.4, 150.7, 151.2, 164.7, 187.5; HRMS (FAB) calcd
for C18H21NO5Na (M + Na) 332.1498, found 332.1507.
(6R)-(+)-6-tert-Butyl-4-oxo-5,6-dihydro-4H-pyridine-
1,3-dicarboxylic Acid 1-tert-Butyl Ester 3-Methyl Ester
(18b). Chromatography (hexanes/EtOAc, 2:1) gave 0.21 g
J. Org. Chem, Vol. 70, No. 14, 2005 5417

Davis et al.
128.0, 128.7, 139.1, 203.0; HRMS (FAB) calcd for C14H19O2
reaction mixture was stirred at room temperature for 6 h and
quenched with aqueous NH4Cl (10 mL). The solution was
extracted with EtOAc (3 × 10 mL), the combined organic
phases were washed with brine (30 mL), dried over Na2SO4,
concentrated. Chromatography (hexanes:EtOAc, 1:1) afforded
0.197 g (68%) of colorless oil. Chromatography (hexanes:
EtOAc, 1:1) afforded 0.24 g (68%) of colorless oil; [R]23D -26.1
(c 1.3, CHCl3); IR (neat) 3210, 1891, 1654, 1560 cm-1; 1H NMR
(CDCl3) δ 1.30 (m, 7 H), 1.56 (s, 9 H), 1.61 (m, 3 H), 2.52 (dd,
J ) 15.8, 1.8 Hz, 1 H), 2.79 (dd, J ) 15.8, 6.3 Hz, 1 H), 3.44 (t,
J ) 6.8 Hz, 2 H), 3.81 (s, 3 H), 4.49 (s, 2 H), 4.52 (m, 1 H),
7.31 (m, 5 H), 8.76 (brs, 1 H); 13C NMR (CDCl3) δ 25.9, 26.3,
28.2, 29.4, 29.9, 31.1, 40.5, 52.1, 53.9, 70.5, 73.2, 85.4, 107.5,
127.8, 127.9, 128.7, 139.0, 150.4, 150.7, 164.9, 188.7; HRMS
(FAB) calcd for C25H35NO6Na (M + Na) 468.2362, found
468.2374.
(M - H) 219.1385, found 219.1383.
(R)-(-)-7-Benzyloxyheptylidene-p-toluenesufina-
mide (24). In a 100-mL, single-necked, round-bottom flask
equipped with a magnetic stirring bar, rubber septum and
argon balloon was placed aldehyde 22 (1.1 g, 4.8 mmol), (R)-
(-)-23 (0.75 g, 4.8 mmol), and Ti(OEt)4 (4.5 mL, 22.5 mmol)
in dichloromethane (20 mL). The reaction was stirred at room
temperature for 3 h and crushed ice (10 g) was added. The
reaction mixture was filtered and the filtrate was concentrated
and chromatographed (hexanes:EtOAc, 10:1) to give 1.33 g
(78%) of a colorless oil; [R]23D -158.0 (c 1.5, CHCl3); IR (neat)
3214, 2930, 2670 cm-1; 1H NMR (CDCl3) δ 1.44 (m, 3 H), 1.68
(m, 5 H), 2.48 (s, 3 H), 2.55 (m, 2 H), 3.52 (m, 2 H), 4.57 (s, 2
H), 7.38 (m, 7 H), 7.64 (m, 2 H), 8.29 (m, 1 H); 13C NMR (CDCl3)
δ 21.5, 25.4, 26.0, 29.0, 29.6, 35.9, 70.3, 72.9, 124.6, 127.6,
127.7, 128.4, 129.9, 138.7, 141.7, 167.3; HRMS (FAB) calcd
for C21H27NO2SNa (M + Na) 380.1660, found 380.1667.
(SR,R)-(-)-Methyl-3-(6-benzyloxyhexyl)-3-(p-toluene-
sulfinylamino)-propanoate (25). In a 250-mL, single-
necked, round-bottom flask equipped with a magnetic stirring
bar, rubber septum, and argon balloon was placed NaHMDS
(2.4 mL, 4.8 mmol, 2 M in THF) and methyl acetate (0.38 mL,
4.8 mmol) in ether (20 mL) at -78 °C. The solution was stirred
at this temperature for 1 h before a solution of sulfinimine
(-)-24 (1.14 g, 3.2 mmol) in ether (15 mL) was added slowly.
After 1 h the reaction was quenched with aqueous NH4Cl (20
mL) and the solution was extracted with EtOAc (3 × 20 mL).
The combined organic phases were dried (Na2SO4), and
concentrated. Chromatography (hexanes:EtOAc, 2:1) gave 1.15
g (83%) of a colorless oil; [R]23D -57.9 (c 0.51, CHCl3); IR (neat)
3280, 2870, 1789 cm-1; 1H NMR (CDCl3) δ 1.42 (m, 10 H), 2.33
(s, 3 H), 2.53 (m, 2 H), 3.40 (t, J ) 6.6 Hz, 2 H), 3.59 (s, 3 H),
3.62 (m, 1 H), 4.45 (m, 3 H), 7.24 (m, 7 H),7.50 (m, 2 H); 13C
NMR (CDCl3) δ 21.7, 26.3, 26.4, 29.5, 30.0, 36.1, 40.8, 52.0,
53.0, 70.7, 73.2, 125.9, 127.8, 128.0, 128.7, 129.9, 139.0, 141.6,
142.8, 172.3; HRMS (FAB) calcd for C20H33NO4SNa (M + Na)
454.2028, found 454.2024.
(6R)-(+)-6-(6-Benzyloxyhexyl)-4-hydroxy-5,6-dihydro-
2H-pyridine-1,3-dicarboxylic acid 1-tert-butyl ester 3-
methyl ester (28). In a 25-mL, single-necked, round-bottom
flask equipped with a magnetic stirring bar, rubber septum,
and hydrogen balloon was placed (-)-27 (0.177 g, 0.40 mmol)
and Pt (0.0015 g, 5wt % on carbon) in methanol (5 mL). After
30 min, the solution was filtered, concentrated, and chromato-
graphed (hexanes:EtOAc, 5:1) to give 0.167 g (93%) of a
colorless oil; [R]23D +52.9 (c 0.33, CHCl3); IR (neat) 1798, 1656,
1
1548, 1482 cm-1; H NMR (CDCl3) δ 1.31 (m, 6 H), 1.47 (s, 9
H), 1.57 (m, 4 H), 2.09 (m, 1 H), 2.65 (m, 1 H), 3.48 (m, 3 H),
3.77 (s, 3 H), 4.41 (m, 4 H), 7.31 (m, 5 H), 12.1 (s, 1 H); 13C
NMR (CDCl3) δ 26.4, 26.5, 28.6, 28.7, 28.8, 29.5, 30.1, 31.9,
51.9, 70.7, 73.2, 80.3, 127.8, 128.0, 128.7, 139.1, 155.1, 171.3;
HRMS (FAB) calcd for C25H37NO6Na (M + Na) 470.2519, found
470.2524.
(R)-(+)-6-(6-Benzyloxyhexyl)-4-(tert-butyldimethylsi-
lanyloxy)-5,6-dihydro-2H-pyridine-1,3-dicarboxylic Acid
1-tert-Butyl Ester 3-Methyl Ester (29). In a 25-mL, single-
necked, round-bottom flask equipped with a magnetic stirring
bar, rubber septum, and argon balloon were placed (+)-28
(0.026 g, 0.058 mmol), TBDMSCl (0.018 g, 0.12 mmol), and
DBU (0.018 mL, 0.12 mmol) in DCM (2 mL). The reaction was
stirred at rt for 30 min and quenched with aqueous NH4Cl (3
mL). The organic phase was dried over Na2SO4 and concen-
trated. Chromatography (hexanes/EtOAc, 5:1) gave 0.03 g
(91%) of a colorless oil: [R]23D +19.1 (c 0.71, CHCl3); IR (neat)
(RS,R)-(-)-Methyl-3-oxo-5-(6-benzyloxyhexyl)-5-(p-tol-
uenesulfinylamino)pentanoate (26). In a 250-mL, single-
necked, round-bottom flask equipped with a magnetic stirring
bar, rubber septum and argon balloon was placed NaHMDS
(12.3 mL, 12.3 mmol, 1 M in THF,) and methyl acetate (0.98
mL, 12.3 mmol) in THF (30 mL) at -78 °C. The solution was
stirred at this temperature for 1 h before a solution of (-)-25
(1.06 g, 2.46 mmol) in THF (20 mL) was added slowly. After 7
h at -78 °C the reaction mixture was quenched with aqueous
NH4Cl (20 mL). The reaction mixture was extracted with
EtOAc (3 × 20 mL). The combined organic phase was dried
over Na2SO4, concentrated, and chromatographed (hexanes:
EtOAc, 1:1) to give 0.85 g (73%) of a colorless oil; [R]23D -49.6
1
3124, 1806, 1597 cm-1; H NMR (CDCl3) δ 0.17 (s, 3 H), 0.18
(s, 3 H), 0.95 (s, 9 H), 1.31 (m, 7 H), 1.46 (s, 9 H), 1.61 (m, 4
H), 1.94 (m, 1 H), 2.59 (m, 1 H), 3.28 (t, J ) 6.6 Hz, 2 H), 3.56
(m, 1 H), 3.70 (s, 3 H), 4.34 (brs, 1 H), 4.49 (s, 2 H), 7.30 (m,
5 H); 13C NMR (CDCl3) δ -3.4, -3.3, -3.2, 18.7, 25.8, 26.0,
26.5, 26.6, 28.8, 29.6, 30.1, 31.9, 51.3, 70.7, 73.2, 80.2, 127.8,
128.0, 128.7, 139.1, 155.1; HRMS (FAB) calcd for C31H51NO6-
SiNa (M + Na) 584.3383, found 584.3383.
(c 1.1, CHCl3); IR (neat) 3170, 2659, 1896 cm-1 1H NMR
;
(3S,4R,6R)-(-)4-Hydroxy-6-(6-hydroxyhexyl)piperidine-
1,3-dicarboxylic Acid 1-tert-Butyl Ester 3-Methyl Ester
(30). In a 250-mL Parr 4601 high-pressure/high-temperature
vessel were placed 29 (0.06 g, 0.107 mmol) and 10% Pd/C (0.1
g) in EtOAc (15 mL). The solution was stirred under 30 atm
of H2 at 50 °C for 24 h. At this time, the solution was filtered
and to the filtrate was added Raney Ni (0.2 g). The solution
was stirred under 90 atm of H2 at 80 °C for 24 h. At this time,
the solution was filtered, the filtrated was concentrated, and
the residue was dissolved in THF (2 mL). To the solution was
added TBAF (0.155 mL, 0.155 mmol, 1 M solution in THF) at
0 °C, and the reaction mixture was slowly warmed to rt and
stirred for 30 min. At this time, the reaction was quenched
with 1 N HCl (4 mL) and the solution was extracted with
EtOAc (3 × 5 mL). The combined organic phases were washed
with brine (10 mL), dried (Na2SO4), and concentrated. Chro-
(CDCl3) δ 1.22 (m, 6 H), 1.47 (m, 4 H), 2.26 (s, 3 H), 2.72 (t,
J ) 5.2 Hz, 2 H), 3.27 (s, 2 H), 3.32 (t, J ) 6.6 Hz, 2 H), 3.53
(m, 1 H), 3.57 (s, 3 H), 4.24 (d, J ) 9.2 Hz, 1 H), 4.36 (s, 2 H),
7.16 (m, 7 H),7.41 (m, 2 H); 13C NMR (CDCl3) δ 21.7, 26.4,
29.4, 30.0, 36.1, 49.1, 49.9, 52.4, 52.6, 70.7, 73.2, 125.9, 127.8,
127.9, 128.7, 129.9, 139.0, 141.6, 142.7, 167.7, 201.8; HRMS
(FAB) calcd for C26H35NO5SNa (M + Na) 496.2134, found
496.2150.
(R)-(-)-6-(6-Benzyloxyhexyl)-4-oxo-5,6-dihydro-4H-py-
ridine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl
ester (27). In a 25-mL single-necked, round-bottom flask
equipped with a magnetic stirring bar, rubber septum, and
argon balloon was placed (-)-26 (0.31 g, 0.65 mmol) and
dimethylformamide dimethylacetal (0.87 mL, 6.5 mmol) in
toluene (5 mL). The reaction was stirred at room temperature
for 5 h, concentrated, and the residue was dissolved in 4 N
HCl (in dioxane, 6 mL). After stirring for 2 h the solvent was
removed in vacuo, the residue was dissolved in acetonitrile (5
mL) containing TEA (0.27 mL, 1.9 mmol), DMAP (0.016 g, 0.13
mmol), and di-tert-butyl dicarbonate (0.28 g, 1.28 mmol). The
matography gave 0.03 g (77%) of a colorless oil: [R]23 -18.6
D
(c 1.2, CHCl3), [lit.21 [R]23 -17.3 (c 1.44, CH3Cl)]; IR (neat)
D
1
3304, 1720 cm-1; H NMR (CDCl3) δ 1.32 (m, 6 H), 1.43 (s, 9
H), 1.60 (m, 4 H), 1.80 (m, 1 H), 1.98 (m, 1 H), 2.85 (brs, 1 H),
2.96 (dd, J ) 14.5, 3.5 Hz, 1 H), 3.34 (brs, 1 H), 3.63 (t, J )
5418 J. Org. Chem., Vol. 70, No. 14, 2005

Formal Synthesis of Pseudodistomin B Triacetate
6.5 Hz, 2 H), 3.72 (s, 3 H), 3.96 (m, 1 H), 4.32 (brs, 1 H), 4.54
(d, J ) 14.0 Hz, 1 H); 13C NMR (CDCl3) δ 26.0, 26.7, 28.7, 29.4,
30.1, 30.8, 33.0, 34.5, 40.1, 45.8, 51.0, 52.2, 63.2, 66.2, 80.0,
154.9, 173.6; HRMS (FAB) calcd for C18H33NO6Na (M + Na)
382.2206, found 382.2203.
from the National Institute of General Medical Sciences
(GM51982).
Supporting Information Available: 1H and 13C NMR
spectra for all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
Acknowledgment. We thank Ashwin Rao for pre-
liminary studies. This work was supported by a grant
JO050373O
J. Org. Chem, Vol. 70, No. 14, 2005 5419