General Route to 2,4,5-Trisubstituted Piperidines from Enantiopure ss-Amino Esters. Total Synthesis of Pseudodistomin B Triacetate and Pseudodistomin F

Article abstract of DOI:10.1021/jo000447q

The Michael addition reaction of enantiopure ss-amino esters with methyl acrylate followed by Dieckmann condensation and enol silylation affords the enol ethers 6, which are hydrogenated with catalysis by Raney-Ni at 80 atm and 80°C to provide 2,4,5-trisubstituted piperidines with high diastereoselectivity. In this case Ni-H attacks the C-C double bond from the direction of the 2-alkyl group to provide the products in which 2,4,5-trisubstrited groups are all cis to each other. While hydrogenation of enol ether 13 without a N-Boc protecting group gives the product 15 in which the 4-hydroxy group and 5-ester moiety are trans to the 2-alkyl group. By using the diastereoselective hydrogenation products 9d and 9e as key intermediates, pseudodistomin B triacetate and pseudodistomin F are synthesized. The key steps for these transformations include Curtius rearrangement and Julia olefination.

Full text of DOI:10.1021/jo000447q

J . Org. Chem. 2000, 65, 6009-6016
6009
Gen er a l Rou te to 2,4,5-Tr isu bstitu ted P ip er id in es fr om
En a n tiop u r e â-Am in o Ester s. Tota l Syn th esis of P seu d od istom in B
Tr ia ceta te a n d P seu d od istom in F
Dawei Ma* and Haiying Sun
State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
madw@pub.sioc.ac.cn
Received March 24, 2000
The Michael addition reaction of enantiopure â-amino esters with methyl acrylate followed by
Dieckmann condensation and enol silylation affords the enol ethers 6, which are hydrogenated
with catalysis by Raney-Ni at 80 atm and 80 °C to provide 2,4,5-trisubstituted piperidines with
high diastereoselectivity. In this case Ni-H attacks the C-C double bond from the direction of the
2-alkyl group to provide the products in which 2,4,5-trisubstrited groups are all cis to each other.
While hydrogenation of enol ether 13 without a N-Boc protecting group gives the product 15 in
which the 4-hydroxy group and 5-ester moiety are trans to the 2-alkyl group. By using the
diastereoselective hydrogenation products 9d and 9e as key intermediates, pseudodistomin B
triacetate and pseudodistomin F are synthesized. The key steps for these transformations include
Curtius rearrangement and J ulia olefination.
Sch em e 1
In tr od u ction
Although R-amino acids have been widely used as
chiral building blocks for several decades,1 little attention
has been directed to the synthesis from enantiopure
â-amino acid derivatives because of their inconvenient
availability. In 1991 Davies and Ichihara reported a
convenient method to prepare N,N-disubstituted â-amino
ester through a highly diastereoselective Michael addi-
tion reaction of a lithium amide with a suitable R,â-
unsaturated ester.2 This method makes it possible to
assemble some complex molecules employing enantiopure
â-amino esters as a chiral pool. Recently, several groups
have demonstrated that this strategy could be applied
in the synthesis of polyfunctionalized â-amino acid
moieties that exist in many biologically important mol-
ecules,3 chiral alcohols,4 and chiral carbocycles.5 Our
interest in this field is based on the analysis shown in
Scheme 1. The â-amino esters B can be regarded as the
anion-cation synthons C or dianion synthons D. They
can connect with either a suitable anion-cation reagent
or a suitable dication reagent to form N-containing
heterocycles E or F . We have found that polyfunctional-
ized pyrrolidinones G could be obtained diastereo-
selectively using ethyl glycoxalate or an R-ketoester as
a dication reagent.6 These polyfunctionalized pyrrolidi-
nones have been successively used to synthesize necine
alkaloids tussilagine, isotussilagine and (-)-petasine-
cine,7 and plakoridine A, a fully substituted, functionally
diverse pyrrolidine.8 In this article we discuss how to
build piperidines H employing methyl acrylate as an
anion-cation reagent.9 The polyfunctionlized piperidines
(1) For reviews, see (a) Sardina, F. J .; Rapoport, H. Chem. Rev. 1996,
96, 1825. (b) Coppola, G. M.; Schuster, H. F. Asymmetric Synthesis.
Construction of Chiral Molecules Using Amino Acids; Wiley: New York,
1987.
(2) Davies, S. G.; Ichihara, O. Tetrahedron: Asymmetry, 1991, 2,
183. (b) Davies, S. G.; Ichihara, O.; Walters, I. A. S. J . Chem. Soc.,
Perkin Trans. 1 1994, 1141. (c) Davies, S. G.; Smyth, G. D. Tetrahe-
dron: Asymmetry, 1996, 7, 1001. (e) Davies, S. G.; Ichihara, O.
Tetrahedron Lett. 1998, 39, 6045.
(3) Tsukada, N.; Shimada, T.; Gyoung, Y. S.; Asao, N.; Yamamota,
Y. J . Org. Chem. 1995, 60, 143. (b) Burke, A. J .; Davies, S. G.;
Hedgecock, C. J . R. Synlett. 1996, 621. (c) Davies, S. G.; Fenwick, D.
R.; Ichihara, O. Tetrahedron: Asymmetry, 1997, 8, 3387. (d) Davies,
S. G.; Ichihara, O. Tetrahedron Lett. 1999, 40, 9313. (e) Davies, S. G.;
Smyth, G. D.; Chippindale, A. M. J . Chem. Soc., Perkin Trans. 1 1999,
3089.
(6) Ma, D.; J iang, J . Tetrahedron: Asymmetry 1998, 9, 575.
(7) Ma, D.; Zhang, J . Tetrahedron Lett. 1998, 39, 9067. (b) Ma, D.;
Zhang, J . J . Chem. Soc., Perkin Trans. 1 1999, 1703.
(8) Ma, D.; Sun, H. Tetrahedron Lett. 2000, 41, 1947.
(9) Part of these results was reported as a communication; see Ma,
D.; Sun, H. Tetrahedron Lett. 1999, 40, 3609.
(4) Davies, S. G.; Smyth, G. D. Tetrahedron: Asymmetry, 1996, 7,
1005.
(5) Urones, J . G.; Garrido, N. M.; Diez, D.; Dominguez, S. H.; Davies,
S. G.; Tetrahedron: Asymmetry 1997, 8, 2683.
10.1021/jo000447q CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/30/2000

6010 J . Org. Chem., Vol. 65, No. 19, 2000
Ma and Sun
Sch em e 2
Sch em e 3
H are obviously valuable intermediates for assembling
pseudodistomins A-F (1a -f, Scheme 2)10 and sialidases
inhibitor (2R,4S,5S)-5-acetamido-4-hydroxypipecolinic acid
2.11
Pseudodistomins A 1a and B 1b are two piperidine
alkaloids that were isolated from the Okinawan tunicate
Pseudodistoma kanoko and shown to have potent in vitro
antineoplastic activity against L1210 and L5178 leuke-
mia cells. In addition, they also displayed the inhibition
of calmodulin-activated brain phosphodiesterase.10a,10b
Four other pseudodistomins, C (1c), D (1d ), E (1e), and
F (1f), were isolated later from the same source, and they
were found to be active in a cell-based assay for DNA
damage induction.10c,d Their significant biological activity
has made them targets of many synthetic studies.12
Several asymmetric routes to these compounds or their
analogues have appeared in which the enantiopure
R-amino acids were employed to construct the piperidine
systems.12b-d However, a more efficient synthetic protocol
is still needed.
mann condensation of 5 mediated by sodium/methanol
provided the cyclization products as two regioisomers,
which were treated with tert-butyldimethylsilyl chloride
to give a mixture of enol ethers 6 and 7. These two
isomers could not be separated by column chromatogra-
phy, but their ratio could be determined by 1H NMR.
Thus, we could establish that the regioselectivity in the
Dieckmann condensation step was about 1.5, 3.8, 1.7, 2.0,
and 1.6 for 5a , 5b, 5c, 5d , and 5e, respectively. For
further conversion of 6 into the useful intermediates for
synthesizing pseudodistomins, the key problem was how
to reduce its C-C double bond diastereoselectively to
create two stereogenic centers. After some experimenta-
tion, it was found that hydrogenation of the mixture of 6
and 7 at 80 atm and 80 °C under the action of Raney-Ni
gave 8a -c as a single isomer together with unreacted
7a -c. Under these conditions, 100% conversion of 6 could
be achieved while no hydrogenation of 7 was detected.
However, it was found that part of 7 could be reduced by
prolonging the reaction time and increasing the reaction
temperature to 100 °C. The difference in reactivity of 6
and 7 might result from steric hindrance. It is notable
that if the tert-butyl carbamate of 5 was changed to a
methyl carbamate, much lower diastereoselectivity was
observed. These results indicated that the Boc protecting
group plays a crucial role in the diastereoselective
hydrogenation.
Resu lts a n d Discu ssion
Our detailed studies are outlined in Scheme 3. N,N-
Disubstituted â-amino esters 4 could be obtained in high
diastereoselectivity according to Davies’s procedure.2
Deprotection of 4 by Pd/C-catalyzed hydrogenation fol-
lowed by Michael addition of the amine to methyl
acrylate afforded the amino diesters, which were pro-
tected with a Boc group to yield 5a -d . From the alcohol
3 derived from L-aspartic acid, diester 5e was obtained
by a four-step reaction shown in Scheme 3. Next, Dieck-
(10) Ishibashi, M.; Ohizumi, Y.; Sasaki, T.; Nakamura, H.; Hirata,
Y.; Kobayashi, J . J . Org. Chem., 1987, 52, 450. For studies on the
structure revision, see (b) Ishibashi, M.; Deki, K.; Kobayashi, J . J . Nat.
Prod. 1995, 58, 804. (c) Kobayashi, J .; Naitoh, K.; Doi, Y.; Deki, K.;
Ishibashi, M. J . Org. Chem., 1995, 60, 6941. (d) Freyer, A. J .; Patil, A.
D.; Killmer, L.; Troupe, N.; Mentzer, M.; Carte, B.; Faucette, L.;
J ohnson, R. K. J . Nat. Prod. 1997, 60. 986.
(11) Clinch, K.; Vasella, A.; Schauer, R. Tetrahedron Lett., 1987, 28,
6425. (b) Glanzer, Gyorgydeak, Z.; Bernet, B.; Vasella, A. Helv. Chim.
Acta, 1991, 74, 343.
For diastereoselective hydrogenation of 6d , its O-
benzyl protecting group should be removed prior to
Raney-Ni catalyzed hydrogenation because it was found
that the phenyl ring was also hydrogenated under the
reaction condition mentioned above. Thus, the benzyl
ether moiety in the mixture of 6d and 7d was first
cleaved under Pd/C-catalyzed hydrogenation, and then
(12) Kiguchi, T.; Ikai, M.; Shirakawa, M.; Fujimoto, K.; Ninomiya,
I.; Naito, T. J . Chem. Soc., Perkin Trans. 1 1998, 893. (b) Naito, T.;
Yuumoto, Y.; Kiguchi, T.; Ninomiya, I. J . Chem. Soc., Perkin Trans. 1
1996, 281. (c) Doi, Y.; Ishbashi, M.; Kobayashi, J . Tetrahedron 1996,
52, 4573. (d) Naito, T.; Ikai, M.; Shirakawa, M.; Fujimoto, K.; Ninomiya,
I.; Kiguchi, T. J . Chem. Soc., Perkin Trans. 1, 1994, 773. (e) Knapp,
S.; Hale, J . L. J . Org. Chem. 1993, 58, 2650. (f) Naito, T.; Yuumoto,
Y.; Ninomiya, I.; Kiguchi, T. Tetrahedron Lett. 1992, 33, 4033. (g)
Utsunomiya, I.; Ogawa, M.; Natsume, M. Heterocycles 1992, 33, 349.

General Route to 2,4,5-Trisubstituted Piperidines
J . Org. Chem., Vol. 65, No. 19, 2000 6011
F igu r e 2. Stereochemistry analysis for hydrogenation of 6
(A) and 13 (B, C, and D).
F igu r e 1. The X-ray structure of 11a .
Sch em e 6
Sch em e 4
Sch em e 5
Thus, we concluded that the â-hydroxy acid 11a has the
(2R,4R,5S)-configuration.
The X-ray structure of 11a also suggested an explana-
tion for the diastereoselectivity in the Raney-Ni-catalyzed
hydrogenation. As shown in Figure 2, because the Boc
group and n-propyl are trans to each other, the active
species Ni-H may attack the C-C double bond from the
direction of n-propyl group (less-hindered face) to give
the present stereochemistry. On the basis of this analysis,
we realized that if a substrate without a N-protecting
group at the 1-position was used, the active species Ni-H
would attack the C-C double from the face with the
2-alkyl group (less-hindered face for either the normal
case (B) or the case of N-chelation to the Ni (C and D)).
This could lead to a change in stereochemistry of the
hydrogenation products. With this idea in mind, we
attempted the strategy that is outlined in Scheme 6.
From the alcohol 4, the diester 12 was prepared, and this
diester was converted into the enol ether 13 in the
following three steps: (1) Dieckmann condensation of 12
mediated by sodium/methanol provided the cyclization
products; (2) treatment of the cyclization products with
tert-butyldimethylsilyl chloride to give the corresponding
enol ethers; (3) removal of the Cbz protecting group to
produce the separable enol ethers 13 and 14. As we
the C-C double bond was reduced by Raney-Ni catalyzed
hydrogenation to afford a mixture of 8d and unreacted
7d . This mixture was not easy to separate, and it was
therefore treated with TsOH in methanol to provide
separable â-hydroxy ester 9d and â-ketoester 10d . The
overall yield for 9d from 5d was about 52% (Scheme 4).
In a similar manner, except for Pd/C-catalyzed hydro-
genation, â-hydroxy ester 9e was obtained from the
mixture of 6e and 7e.
After the success in obtaining the reduction products
8, 9d , and 9e diastereoselectively, the next problem was
assignment of the stereochemistry of two new stereogenic
centers. We planned to solve this problem by further
conversion of these products. As shown in Scheme 5,
treatment of 8a with tetrabutylammonium fluoride fol-
lowed by hydrolysis of the ester moiety with aqueous
sodium hydroxide provided the corresponding â-hydroxy
acid 11a . Compound 11a gave fine crystals which allowed
us to determine its structure by X-ray analysis. As
outlined in Figure 1, the X-ray studies of 11a clearly
indicated that the 4-hydroxy and 5-carboxylate groups
are cis to each other and both trans to the n-propyl group.

6012 J . Org. Chem., Vol. 65, No. 19, 2000
Ma and Sun
Sch em e 7
Sch em e 8
lowed by trapping the generated anion with the aldehyde
18 provided the coupling product, which was converted
to the corresponding â-benzoyloxy sulfones and then
subjected to sodium amalgam reduction to provide diene
1
19. By H NMR it was found that the purity for 19 is
expected, the hydrogenation of 13 catalyzed by Raney-
Ni delivered the piperidine 15 in which the three sub-
stituents at the 2-, 4-, and 5-positions are all cis to each
other. This structure was assigned by its NOESY spec-
trum in which marked NOEs between 2-H and 4-H, 4-H
and 5-H, and 5-H and 2-H were observed.
about 90%, which implied that other minor isomers of
diene were also formed during the J ulia olefination.
Finally, the cyclic carbamate 19 was transformed into
pseudodistomins B triacetate 20 by following deprotection
and protection steps: (1) hydrolysis with aqueous NaOH;
(2) protecting the free hydroxy and amino groups with
acetyl group; (3) removal of the Boc group with saturated
methanolic HCl; (4) acylation of the free amine with
acetic anhydride. The spectral data of 20 were the same
With â-hydroxy esters 9d in hand, we developed a new
route for synthesizing pseudodistomins B triacetate as
shown in Scheme 7. First, we planned to convert the ester
moiety of 9d to the corresponding amino moiety by means
of Curtius rearrangement. Accordingly, selective protec-
tion of the primary hydroxy group in 9d with tert-
butyldiphenylsilyl chloride (TPS-Cl) provided 16. After
hydrolysis of the ester 16 with aqueous NaOH, the
resultant acid was treated with diphenylphosphoryl azide
(DPPA) to form a carboxyl azide.13 This intermediate was
subjected to Curtius rearrangement to afford a cyclic
carbamate, which was transformed to 17 by removing the
TPS protecting group with n-Bu4NF. Next, the alcohol
17 was converted into the corresponding aldehyde via a
Dess-Martin oxidation, which was treated with tri-
phenylarsonium salt of bromoacetaldehyde under the
action of K2CO3 to deliver a formyl-olefination product
18.14 Now we decided to employ J ulia olefination to
introduce the desired trans,trans-diene moiety.15 Thus,
treatment of n-pentyl phenyl sulfone with n-BuLi fol-
1
for those reported except for some small peaks in the H
NMR spectra displayed by some minor isomers (the ratio
of 20 to minor isomers is about 6/1 as detected by 1H
NMR). The overall yield for this synthetic protocol is
about 6.6% from â-amino ester 4d .
The â-hydroxy acid 9e is obviously a suitable interme-
diate for the total synthesis of pseudodistomin F. Our
efforts to this goal are shown in Scheme 8. After
transformation of 9e to the cyclic carbamate 21 according
to the procedure from 9d to 17, we tried to use J ulia
olefination to introduce the desired side chain. Accord-
ingly, through its mesylate, the alcohol 21 was converted
into the corresponding phenyl sulfide, which was oxidized
to phenyl sulfone 22 with MCPBA. Next, coupling of 22
with aldehyde 2312c followed by J ulia olefination provided
tetraene 24 in 52% yield. Finally, deprotection of 24 with
aqueous KOH and subsequent HCl/MeOH gave 1f in 70%
yield. Its spectral data were identical with those re-
ported.10d In this case only one isomer was observed in
1H NMR, which implied that the purity of our synthetic
pseudodistomin F was over 97%. To the best of our
(13) Shioiri, T.; Ninomiya, K.; Yamada, S. J . Am. Chem. Soc. 1972,
94, 6203.
(14) Huang, Y.; Shi, L.; Yang, J . Tetrahedron Lett. 1985, 26, 6447.
(15) Kocienski, P. J .; Lythgoe, B.; Waterhouse, I. J . Chem. Soc.,
Perkin Trans. 1 1980, 1045, and references therein.

General Route to 2,4,5-Trisubstituted Piperidines
J . Org. Chem., Vol. 65, No. 19, 2000 6013
triethylamine. The mixture was stirred at room temperature
for 6 h before it was partitioned between CH2Cl2 and brine.
The organic phase was dried over Na2SO4 and concentrated,
and the residue was chromatographed to give the correspond-
ing silyl ether, which was dissolved in 100 mL of methanol.
After this solution was added 1 g of 10% Pd/C, the mixture
was stirred under hydrogen for 10 h, and then the catalyst
was filtered off. To the filtrate was added methyl acrylate (5
mL, 55 mmol) in a dropwise manner. The solution was stirred
at room temperature for 48 h, and then the solvent was
evaporated. After the residue was dissolved in 100 mL of 1,4-
dioxane, di-tert-butyl dicarbonate (12 g, 55 mmol) and NaHCO3
(5.7 g, 68 mmol) were added. The resultant mixture was stirred
at 30 °C for 5 h and then concentrated in vacuo. The residue
was partitioned between 50 mL of water and 100 mL of ethyl
acetate. The organic phase was separated, and the aqueous
phase was extracted with ethyl acetate. The combined organic
phase was washed with brine and dried over Na2SO4. After
the solvent was evaporated, the residue was chromatographed
to give 15.5 g (80%) of 5e: [R]25D -11.1 (c 1.2, CHCl3); IR (neat)
knowledge, the present result is the first total synthesis
of pseudodistomin F. It is notable that if the â-hydroxy
acid 15 was used as the starting material we could also
synthesize pseudodistomin C by employing the same
reaction sequence mentioned above.
In conclusion, we have developed a method to synthe-
size the chiral 2,4,5-trisubstituted piperidines starting
from enantiopure â-amino esters. The key step for this
synthetic method is the diastereoselective hydrogenation
of enol ether intermediates. Varying the N-substituents
at the 1-position of enol ethers could change the stereo-
chemistry of hydrogenation products. The importance of
this method was demonstrated by its capability for
synthesis of pseudodistomin B triacetate and the first
total synthesis of pseudodistomin F. The further applica-
tion of this method to synthesize other biologically
important alkaloids and the procedure improvement are
in progress.
2956, 2932, 1742, 1697 cm-1 1H NMR (300 MHz, CDCl3) δ
;
4.11 (m, 1H), 3.80 (m, 1H), 3.66 (s, 7H), 3.48 (m, 2H), 2.72 (m,
1H), 2.63 (m, 3H), 1.44 (s, 9H), 0.87 (s, 9H), 0.35 (s, 6H); MS
m/z 434 (M+ + H+). Anal. Calcd for C20H39NO7Si: C: 55.40,
H: 9.06, N: 3.23. Found: C: 55.60, H: 9.49, N: 3.16.
Exp er im en ta l Section
Gen er a l P r oced u r e for P r ep a r in g Diester s 5 fr om
â-Am in o Ester s 4. To a solution of â-amino ester 4 (10 mmol)
in methanol (30 mL) was added 10% Pd/C (1 mmol). After the
mixture was stirred under hydrogen for 10 h, the catalyst was
filtered off. To the filtrate was added methyl acrylate (12
mmol) in a dropwise manner before the solution was stirred
at room temperature for 24-48 h. After the solvent was
evaporated and the residue was dissolved in 1,4-dioxane, di-
tert-butyl dicarbonate (12 mmol) and NaHCO3 (15 mmol) were
added. The mixture was stirred at 30 °C for 5 h, and then the
solvent was removed in vacuo. The residue was partitioned
between water and ethyl acetate. The organic phase was
separated, and the aqueous phase was extracted with ethyl
acetate for three times. The combined organic phase was
washed with brine and dried over Na2SO4. After removal of
solvent, the residue was chromatographed to give the product.
(R)-3-[N-(ter t-Bu tyloxyca r bon yl)-N-(2-ca r bom eth oxy-
eth yl)]a m in oh exa n oic a cid m eth yl ester 5a : 71% yield;
(3S,4R,6R)-4-ter t-Bu tyld im eth ylsiloxy-6-p r op ylp ip er i-
d in e-1,3-d ica r boxylic Acid 1-ter t-Bu t yl E st er 3-Met h yl
Ester 8a . To a solution of 5a (6.0 g, 18 mmol) in 50 mL of
benzene were added sodium (0.5 g, 22 mmol) in small pieces
and 0.2 mL of methanol. After the reaction mixture was stirred
under N2 at room temperature for 48 h, saturated aqueous
NH4Cl was added to quench the reaction. The organic phase
was separated, and the aqueous phase was extracted with
ethyl acetate for three times, the combined organic phase was
washed with brine and dried over Na2SO4. The solvent was
evaporated, and the residue was chromatographed to give the
crude Dieckmann condensation products, which were dissolved
in CH2Cl2. To this solution were added tert-butyldimethylsilyl
chloride (3.0 g, 20 mmol), 70 mg of DMAP, and 3 mL of
triethylamine. After the mixture was stirred at room temper-
ature for 24 h, it was partitioned between CH2Cl2 and brine.
The organic layer was concentrated, and the residue was
chromatographed to give the corresponding silyl ethers 6 and
7. This mixture was dissolved in ethyl acetate, and then 1.0 g
of Raney-Ni (50% slurry in water) was added. After the
mixture was stirred under hydrogen (80 atm) at 80 °C for 24
h, the catalyst was filtered off, and the filtrate was concen-
trated followed by chromatography to give 3.7 g (49%) of 8a :
[R]25 +7.0 (c 2.5, CHCl3); IR (neat) 2956, 2932, 1725, 1680
D
cm-1; 1H NMR (300 MHz, CDCl3) δ 4.21 (m, 1H), 3.66 (s, 6H),
3.45 (m, 2H), 2.58 (m, 3H), 2.47 (m, 1H), 1.60 (m, 2H), 1.46 (s,
9H), 1.42 (m, 2H), 0.90 (t, J ) 6.8 Hz, 3H); MS m/z 331 (M+).
(R)-3-[N-(ter t-Bu tyloxyca r bon yl)-N-(2-ca r bom eth oxy-
eth yl)]a m in oocta d eca n oic a cid m eth yl ester 5b: 64%
yield; [R]15 -1.6 (c 8.0, CHCl3); IR (neat) 2926, 2855, 1743,
[R]15 +3.7 (c 1.07, CHCl3); IR (neat) 2937, 2860, 1745, 1697
D
D
1696 cm-1; 1H NMR (300 MHz, CDCl3) δ 4.22 (m, 1H), 3.67 (s,
6H), 3.45 (m, 2H), 2.59 (m, 3H), 2.48 (m, 1H), 1.59 (m, 2H),
1.46 (s, 9H), 1.25 (br s, 26H), 0.88 (t, J ) 6.5 Hz, 3H); MS m/z
500 (M+ + H+); HRMS found m/z 499.3856, C28H53NO6 requires
499.3873.
cm-1; 1H NMR (300 MHz, CDCl3) δ 4.34 (m, 1H), 4.20 (m, 1H),
4.11 (m, 1H), 3.63 (s, 3H), 3.05 (dd, J ) 14.4, 3.8 Hz, 1H), 2.70
(m, 1H), 2.23 (m, 1H), 1.65 (m, 2H), 1.55 (m, 1H), 1.44 (s, 9H),
1.28 (m, 2H), 0.89 (t, J ) 7.4 Hz, 3H), 0.84 (s, 9H), 0.04 (s,
6H); MS m/z 416 (M+ + H+). Anal. Calcd for C21H41NO5Si: C:
60.68, H: 9.94, N: 3.37. Found: C: 60.96, H: 10.30, N: 3.45.
(3S,4R,6R)-4-ter t-Bu t yld im et h ylsiloxy-6-p en t a d ecyl-
p ip er id in e-1,3-d ica r b oxylic Acid 1-ter t-Bu t yl E st er 3-
Meth yl Ester 8b. Following the procedure for preparation of
8a from 5a , 8b was obtained from 5b in 59% overall yield:
(R)-3-[N-(ter t-Bu tyloxyca r bon yl)-N-(2-ca r bom eth oxy-
eth yl)]a m in o-4-p h en ylbu tyr ic a cid m eth yl ester 5c: 67%
yield; [R]18 +34.0 (c 18.8, CHCl3); IR (neat) 2976, 1739, 1693
D
cm-1; 1H NMR (300 MHz, CDCl3) δ 7.20 (m, 5H), 4.05 (m, 1H),
3.55 (s, 6H), 3.19 (m, 2H), 2.77 (m, 3H), 2.55(m, 2H), 2.20 (m,
1H), 1.34 (s, 9H); MS m/z 379 (M+); HRMS found m/z 379.1996,
[R]15 +3.1 (c 1.04, CHCl3); IR (neat) 2928, 2856, 1747, 1699
D
cm-1; 1H NMR (300 MHz, CDCl3) δ 4.30 (m, 1H), 4.20 (m, 1H),
4.10 (m, 1H), 3.63 (s, 3H), 3.05 (dd, J ) 14.5, 3.9 Hz, 1H), 2.70
(m, 1H), 2.23 (m, 1H), 1.65 (m, 1H), 1.55 (m, 2H), 1.44 (s, 9H),
1.24 (m, 26H), 0.91 (t, J ) 6.4 Hz, 3H), 0.84 (s, 9H), 0.03 (s,
6H); MS m/z 584 (M+ + H+); HRMS found m/z 526.3901 (M+
- t-Bu), C29H56NO5Si requires 526.3927.
C
20H29NO6 requires 379.1986.
(R)-9-P h en ylm eth oxy-3-[N-(ter t-bu tyloxyca r bon yl)-N-
(2-ca r bom eth oxyeth yl)]a m in on on a n oic a cid m eth yl es-
ter 5d : 63% yield; [R]22 -1.1 (c 3.97, CHCl3); IR (neat) 2934,
D
2859, 1740, 1693 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.32 (m,
5H), 4.46 (s, 2H), 4.23 (m, 1H), 3.66 (s, 6H), 3.45 (t, J ) 6.6
Hz, 2H), 3.41 (m, 2H), 2.60 (m, 3H), 2.45 (m, 1H), 1.60 (m,
4H), 1.45 (br s, 9H), 1.32 (m, 6H); MS m/z 480 (M+ + H+).
Anal. Calcd for C26H41NO7 requires C: 65.11, H: 8.62, N: 2.92.
Found: C: 65.08, H: 8.77, N: 2.72.
(3S,4R,6R)-4-ter t-Bu tyld im eth ylsiloxy-6-p h en ylm eth -
ylp ip er id in e-1,3-d ica r boxylic Acid 1-ter t-Bu tyl Ester 3-
Meth yl Ester 8c. Following the procedure for preparation of
8a from 5a , 8c was obtained from 5c in 44% overall yield:
(S)-4-ter t-Bu tyld im eth ylsiloxy-3-[N-(ter t-bu tyloxyca r -
bon yl)-N-(2-car bom eth oxyeth yl)]am in obu tyr ic Acid Meth -
yl Ester 5e. To a stirring solution of 3 (12 g, 45 mmol) in 30
mL of CH2Cl2 were added DMAP (50 mg, 0.41 mmol), tert-
butyldimethylsilyl chloride (8 g, 54 mmol), and 10 mL of
[R]18 +24.9 (c 0.5, CHCl3); IR (neat) 2953, 2858, 1744, 1697
D
1
cm-1; H NMR (300 MHz, CDCl3) δ 7.2 (m, 5H), 4.5 (m, 1H),
4.23 (m, 2H), 3.62 (s, 3H), 3.22 (dd, J ) 14.5, 4.0 Hz, 1H), 2.92
(dd, J ) 13.3, 7.6 Hz, 1H), 2.76 (m, 2H), 2.12 (m, 1H), 1.58 (m,
1H), 1.33 (s, 9H), 0.8 (s, 9H), 0.05 (s, 6H); MS m/z 464 (M+
+

6014 J . Org. Chem., Vol. 65, No. 19, 2000
Ma and Sun
H+); HRMS found m/z 406.2054 (M+ - t-Bu), C21H32NO5Si
requires 406.2049.
(m, 1H), 2.98 (dd, J ) 14.1, 3.2 Hz, 1H), 2.88 (br s, 1H), 2.01
(m, 1H), 1.80 (m, 1H), 1.62 (m, 2H), 1.44 (br s, 9H), 1.30 (m,
2H), 0.91 (t, J ) 8.2 Hz, 3H); MS m/z 287 (M+). Anal. Calcd
for C14H25NO5: C: 58.54, H: 8.71, N: 4.88. Found: C: 58.34,
H: 8.88, N: 4.75.
(3S,4R,6R)-4-H yd r oxy-6-(6-h yd r oxyh exyl)p ip er id in e-
1,3-d ica r boxylic Acid 1-ter t-Bu tyl Ester 3-Meth yl Ester
9d . To a solution of 5d (10 g, 21 mmol) in 100 mL of benzene
were added sodium (0.58 g, 25 mmol) in small pieces and 0.2
mL of methanol. The mixture was stirred under N2 at room
temperature for 48 h before 30 mL of saturated aqueous NH4Cl
was added to quench the reaction. The organic phase was
separated, and the aqueous phase was extracted with ethyl
acetate. The combined organic phase was washed with brine
and dried over Na2SO4. The solvent was evaporated, and the
residue was chromatographed to give the corresponding Dieck-
mann condensation products. The crude products were dis-
solved in 30 mL of CH2Cl2, and then tert-butyldimethylsilyl
chloride (3.5 g, 23 mmol), 30 mg DMAP, and 5 mL of
triethylamine were added. The reaction mixture was stirred
at room temperature for 24 h before it was partitioned between
200 mL of CH2Cl2 and 50 mL of brine. The organic layer was
dried and concentrated, and the residue was allowed to pass
through a short column of silica gel to give a mixture of 6d
and 7d . This mixture was dissolved in 100 mL of ethyl acetate,
and then 1 g of 10% Pd/C was added. After this suspension
solution was stirred under hydrogen (30 atm) at 50 °C for 24
h, the catalyst was filtered off. To the filtrate was added 2 g
of Raney-Ni (50% slurry in water) before the mixture was
stirred under hydrogen (80 atm) at 80 °C for 24 h. The catalyst
was filtered off, and the filtrate was concentrated. The residue
was dissolved in 50 mL of methanol. To this solution was
added TsOH (5 g, 29 mmol) before the solution was stirred at
room temperature for 1 h. After the solvent was removed, the
(S)-4-ter t-Bu t yld im et h ylsiloxy-3-[N-(p h en ylm et h oxy-
ca r bon yl)-N-(2-ca r bom eth oxyeth yl)]a m in obu tyr ic Acid
Meth yl Ester 12. To a stirring solution of 4 (1.2 g, 4.5 mmol)
in 5 mL of CH2Cl2 were added 20 mg of DMAP, tert-
butyldimethylsilyl chloride (0.8 g, 5.3 mmol), and 1 mL of
triethylamine. After the mixture was stirred at room temper-
ature for 6 h, it was partitioned between 30 mL of CH2Cl2 and
10 mL of brine. The organic phase was dried and evaporated,
and the residue was chromatographed to give the correspond-
ing silyl ether. This silyl ether was dissolved in 10 mL of
methanol, and then 100 mg of 10% Pd/C was added. After the
mixture was stirred under H2 for 10 h, the catalyst was filtered
off. The filtrate was added methyl acrylate (0.5 mL, 5.5 mmol)
in a dropwise manner. The resultant solution was stirred at
room temperature for 48 h before the solvent was evaporated.
The residue was dissolved in 5 mL of 1,4-dioxane, and then
benzyl chloroformate (1.0 g, 5.9 mmol) and NaHCO3 (0.6 g, 7
mmol) were added. After the mixture was stirred at 30 °C for
5 h, the solvent was removed in vacuo. The residue was diluted
with 10 mL of water and 20 mL of ethyl acetate. The organic
phase was separated, and the aqueous phase was extracted
with ethyl acetate. The combined organic phase was washed
with brine, dried over Na2SO4, and concentrated. The residue
was chromatographed to afford 1.6 g (76%) of 12: [R]20D -10.2
(c 4.3, CHCl3); IR (neat) 2955, 2858, 1741, 1702 cm-1; 1H NMR
(300 MHz, CDCl3) δ 7.47 (m, 5H), 5.28 (s, 2H), 4.10 (m, 1H),
4.01 (m, 1H), 3.83 (s, 6H), 3.81 (m, 3H), 2.98 (m, 1H), 2.81 (m,
3H), 1.03 (s, 9H), 0.18 (s, 6H); MS m/z 467 (M+); HRMS found
m/z 467.2331, C23H37NO7Si requires 467.2323.
residue was chromatographed to give 3.9 g (52%) of 9d : [R]22
D
-17.3 (c 1.44, CHCl3); IR (neat) 3422, 2933, 2860, 1739, 1693,
1
1671 cm-1; H NMR (300 MHz, CDCl3) δ 4.53 (brs, 1H), 4.32
(m, 1H), 3.95 (m, 1H), 3.71 (s, 3H), 3.62 (t, J ) 6.5 Hz, 2H),
3.33 (m, 1H), 2.95 (dt, J ) 14.3, 3.6 Hz, 1H), 2.84 (br s, 1H),
1.95 (ddd, J ) 12.4, 12.4, 6.1 Hz, 1H), 1.79 (m, 1H), 1.60 (m,
4H), 1.42 (br s, 9H), 1.32 (m, 6H); MS m/z 360 (M+ + H+).
Anal. Calcd for C18H33NO6: C: 58.76, H: 9.57, N: 4.03.
Found: C: 58.91, H: 9.34, N: 3.59.
(3S,4R,6S)-4-Hyd r oxy-6-h yd r oxym eth ylp ip er id in e-1,3-
d ica r boxylic Acid 1-ter t-Bu tyl Ester 3-Meth yl Ester 9e.
Following the procedure for preparing 6d and 7d from 5d , the
mixture of 6e and 7e was obtained from 5e, and it was
dissolved in 100 mL of ethyl acetate. To this solution was
added 2 g of Raney-Ni (50% slurry in water) before the mixture
was stirred under H2 (80 atm) at 80 °C for 24 h. The catalyst
was filtered off, and the filtrate was concentrated. The residue
was dissolved in 50 mL of methanol before TsOH was added.
After the solution was stirred at room temperature for 1 h,
the solvent was removed under reduced pressure. The residue
(3R,4S,6S)-4-ter t-Bu t yld im et h ylsiloxy-6-ter t-b u t yld i-
m eth ylsiloxym eth ylp ip er id in e-3-ca r boxylic Acid Meth yl
Ester 15. To a solution of 12 (0.8 g, 1.7 mmol) in 10 mL of dry
benzene were added sodium (70 mg, 3 mmol) in small pieces
and 0.05 mL of methanol. After the mixture was stirred under
N2 at room temperature for 48 h, 5 mL of saturated aqueous
NH4Cl was added to quench the reaction. The organic phase
was separated, and the aqueous phase was extracted with
ethyl acetate. After the combined organic phase was washed
with brine and dried over Na2SO4, the solvent was evaporated,
and the residue was chromatographed to provide the crude
Dieckmann condensation products. This mixture was dissolved
in 3 mL of CH2Cl2, and then tert-butyldimethylsilyl chloride
(300 mg, 2 mmol), DMAP (20 mg, 0.16 mmol), and 0.3 mL of
triethylamine were added. After the reaction solution was
stirred at room temperature for 24 h, it was partitioned
between 20 mL of CH2Cl2 and 10 mL of brine. The organic
layer was concentrated, and the residue was chromatographed
to give the corresponding silyl ethers. They were dissolved in
10 mL of methanol, and then 100 mg of 10% Pd/C was added.
The mixture was stirred under H2 at room temperature for 5
h before the catalyst was filtered off. The filtrate was concen-
trated and chromatographed to give crude 13, which was
dissolved in 15 mL of ethyl acetate. After this solution was
added to 100 mg of Raney-Ni (50% slurry in water), the
mixture was stirred under H2 (40 atm) at 40 °C for 12 h. The
catalyst was filtered off, and the filtrate was concentrated
followed by chromatography to give 0.35 g (49% overall yield
was chromatographed to afford 9e in 42% overall yield: [R]21
D
-64.0 (c 0.58, CHCl3); IR (neat) 3452, 2978, 1732, 1670 cm-1
;
1H NMR (300 MHz, CDCl3) δ 4.23 (m, 2H), 4.15 (m, 1H), 3.76
(s, 3H), 3.73 (m, 1H), 3.40 (dd, J ) 14.0, 3.5 Hz, 1H), 3.28 (dm,
J ) 8.3 Hz, 1H), 2.79 (dd, J ) 8.6, 4.3 Hz, 1H), 2.68 (br s, 1H),
1.93 (m, 2H), 1.47 (s, 9H); MS m/z 290 (M+ + H+). Anal. Calcd
for C13H23NO6: C: 53.96, H: 8.01, N: 4.79. Found: C: 53.96,
H: 7.96, N: 4.77.
(3S,4R,6R)-4-H yd r oxy-6-p r op ylp ip er id in e-1,3-d ica r -
bolylic Acid 1-ter t-Bu tyl Ester 11a . To a solution of 8a (0.5
g, 1.2 mmol) in 5 mL of THF were added TBAF (0.9 g, 3.4
mmol) and 0.01 mL of HOAc. After the solution was stirred
at room temperature for 24 h, the solvent was removed in
vacuo, and the residue was chromatographed to give the
corresponding alcohol. This alcohol was dissolved in 3 mL of
methanol, and then 3 mL of 10% aqueous NaOH was added.
The mixture was stirred at room temperature for 3 h before
methanol was evaporated. The residue was acidified to pH )
4 by adding 3 N HCl and then extracted with ethyl acetate.
The combined organic phase was dried and concentrated to
give crude product, which was recrystallized to give 286 mg
(87%) of 11a as a fine crystals: [R]20D -10.9 (c 0.6, CHCl3); IR
(neat) 3317, 2920, 1741, 1651 cm-1; 1H NMR (300 MHz, CDCl3)
δ 6.5 (br s, 1H), 4.57 (dm, J ) 14.1 Hz, 1H), 4.35 (m, 1H), 4.05
from 12) of 15: [R]22 -47.6 (c 0.82, CHCl3); 1H NMR (300
D
MHz, CDCl3) δ 3.99 (m, 1H), 3.75 (dd, J ) 9.8, 5.6 Hz, 1H),
3.65 (s, 3H), 3.53 (dd, J ) 9.8, 4.8 Hz, 1H), 3.26 (dd, J ) 13.5,
3.5 Hz, 1H), 2.76 (dd, J ) 13.5, 3.7 Hz, 1H), 2.69 (m, 1H), 2.66
(m, 1H), 1.95 (s, 1H), 1.74 (m, 2H), 0.90 (s, 9H), 0.86 (s, 9H),
0.59 (s, 6H), 0.49 (s, 6H); MS m/z 417 (M+); HRMS found m/z
417.2727; C20H43NSi2O4 requires 417.2723.
(3S,4R,6R)-(4-H yd r oxy-6-(6-ter t-b u t yld ip h en ylsiloxy-
h exyl)p ip er id in e-1,3-d ica r boxylic Acid 1-ter t-Bu tyl Ester
3-Meth yl Ester 16. To a stirring solution of 9d (1.1 g, 3 mmol)
in 3 mL of CH2Cl2 were added tert-butyldiphenylsilyl chloride
(900 mg, 3.3 mmol) 20 mg of DMAP, and 0.5 mL of triethyl-
amine. The resultant solution was stirred at room temperature

General Route to 2,4,5-Trisubstituted Piperidines
J . Org. Chem., Vol. 65, No. 19, 2000 6015
for 6 h before it was partitioned between 20 mL of CH2Cl2 and
10 mL of brine. The organic phase was separated, dried, and
concentrated, and the residue was chromatographed to give
graphed to give the corresponding ester. This ester was
dissolved in 1 mL of methanol and 0.5 mL of ethyl acetate,
and the solution was cooled to -25 °C. To this solution was
added 0.42 g of 6% sodium amalgam. The mixture was stirred
at this temperature for 1 h before the liquid was decanted into
water. The residue was washed with ethyl acetate for three
times, and the aqueous phase was extracted with ethyl acetate.
The combined organic phase was washed with brine and dried
over Na2SO4. After the solvent was evaporated, the residue
was chromatographed to give 31.7 mg (69%) of 19: [R]22D -47.6
1.55 g (85%) of 16. [R]15 -16.5 (c 3.2, CHCl3); IR (neat) 3460,
D
2933, 2859, 1740, 1695 cm-1
;
1H NMR (300 MHz, CDCl3) δ
7.65 (m, 4H), 7.39 (m, 6H), 4.55 (m, 1H), 4.32 (m, 1H), 3.95
(m, 1H), 3.72 (s, 3H), 3.63 (t, J ) 6.4 Hz, 2H), 3.43 (dm, J )
10.8 Hz, 1H), 2.95 (dd, J ) 13.2, 3.4 Hz, 1H), 2.83 (br s, 1H),
1.97 (m, 1H), 1.72 (m, 1H), 1.55 (m, 4H), 1.42 (s, 9H), 1.30 (m,
6H), 1.05 (s, 9H); MS m/z 498 (M+ - Boc + 2H+). Anal. Cacld
for C34H51NO6Si: C: 68.31, H: 8.60, N: 2.34. Found: C: 68.44,
H: 8.75, N: 2.00.
(c 0.82, CHCl3); IR (neat) 3300, 2932, 2859, 1749, 1674 cm-1
;
1H NMR (300 MHz, CDCl3) δ 5.95 (m, 2H), 5.50 (m, 3H), 4.92
(m, 1H), 4.10 (m, 2H), 3.95 (m, 1H), 2.88 (m, 1H), 2.21 (m,
1H), 2.02 (m, 4H), 1.84 (m, 1H), 1.44 (m, 2H), 1.39 (br s, 9H),
1.26 (m, 10H), 0.86 (t, J ) 6.4 Hz, 3H); MS m/z 420 (M+),
HRMS found m/z 420.3008 (M+); C24H40N2O4 requires 420.3028.
P seu d od istom in B Tr ia ceta te 20. To a solution of 19 (15
mg, 0.036 mmol) in 1 mL of methanol was added 1 mL of 10%
aqueous NaOH. The resultant mixture was refluxed for 3 h
before it was extracted with CH2Cl2. The combined organic
phase was dried and evaporated, and the residue was dissolved
in 2 mL of CH2Cl2. To this stirring solution were added 1 mg
of DMAP, 50 µL of Ac2O, and 50 µL of triethylamine. The
stirring was continued for 3 h, and then the solvent was
evaporated. The residue was chromatographed to give the
crude acylation product. This product was dissolved in 1 mL
of ethyl acetate, and then 1 mL of saturated methanolic HCl
was added. After the solution was stirred at room temperature
for 30 min, 3 mL of 20% aqueous K2CO3 was added to quench
the reaction. The resultant mixture was extracted with CH2Cl2,
and the combined organic phase was dried and concentrated.
The residue was dissolved in 1 mL of CH2Cl2 before 1 mg of
DMAP, 50 µL of Ac2O, and 50 µL of triethylamine were added.
The stirring was continued for 2 h, and then the solvent was
evaporated. The residue was chromatographed to give 10 mg
(3S ,4R ,6R )-6-(6-H y d r o x y h e x y l)-2-o x o h e x a h y d r o -
oxa zlolo[4,5-c]p ip er id in e-5-ca r boxylic Acid ter t-Bu tyl
Ester 17. To a solution of 16 (1.2 g, 2 mmol) in 3 mL of
methanol was added 3 mL of 10% NaOH solution. After the
mixture was stirred at room temperature for 6 h, methanol
was removed in vacuo. The residue was acidified to pH ) 4 by
adding 3 N HCl, and then the aqueous phase was extracted
with ethyl acetate. The combined organic phase was dried over
Na2SO4 and concentrated. After the residue was dissolved in
15 mL of dry benzene, DPPA (0.66 g, 2.4 mmol) and 1 mL of
triethylamine were added. The solution was heated at reflux
for 16 h, and then solvent was evaporated. The residue was
chromatographed to give the corresponding oxazolidinone,
which was dissolved in 5 mL of THF. After this solution was
added TBAF (0.65 g, 2.5 mmol), it was stirred at room
temperature for 6 h. The solvent was evaporated, and the
residue was chromatographed to provide 467 mg (68%) of 17:
[R]22D -63.8 (c 1.02, CHCl3); IR (neat) 3298, 2935, 2856, 1748,
1733, 1698 cm-1; 1H NMR (300 MHz, CDCl3) δ 5.22 (br s, 1H),
4.91 (m, 1H), 4.04 (m, 2H), 3.95 (m, 1H), 3.64 (t, J ) 6.5 Hz,
2H), 2.87 (m, 2H), 2.27 (m, 1H), 1.56 (m, 3H), 1.45 (s, 9H),
1.33 (m, 8H); MS m/z 342 (M+), HRMS found m/z 342.2122
(M+), C17H30N2O5 requires 342.2090.
(3S,4R,6R)-2-Oxo-6-(8-oxooct-6-en yl)h exah ydr ooxazlolo-
[4,5-c]p ip er id in e-5-ca r boxylic Acid ter t-Bu tyl Ester 18.
To a solution of 17 (220 mg, 0.64 mmol) in 5 mL of CH2Cl2
was added Dess-Martin oxidant (330 mg, 0.78 mmol). The
solution was stirred at room temperature for 2 h before it was
filtered through silica gel. The filtrate was concentrated, and
the residue was chromatographed to give the corresponding
aldehyde, which was dissolved in 3.5 mL of dry ethyl ether
and 1.5 mL of dry THF. To this solution was added triphenyl-
arsonium salt of bromoacetaldehyde (338 mg, 0.96 mmol),
K2CO3 (106 mg, 0.77 mmol), and 30 µL of water. The resultant
mixture was stirred at room temperature for 20 h, and then
it was filtered through silica gel. The filtrate was concentrated,
(69%) of 20: [R]22 35.7 (c 1.0, CHCl3); 1H NMR (300 MHz,
D
CDCl3) δ 5.95 (m, 2H), 5.50 (m, 2H), 5.15 (br s, 1H), 4.92 (br
s, 3/4H), 4.61 (m, 1/4H), 4.51 (br s, 1/4H), 4.37 (br s, 3/4H),
4.01 (br s, 1/4H), 3.96 (m, 3/4H), 3.29 (m, 3/4H), 2.93 (m, 1/4H),
2.14 (br s, 2H), 2.04 (br s, 13H), 1.74 (m, 2H), 1.55 (m, 2H),
1.30 (br s, 10H), 0.89 (t, J ) 6.5 Hz, 3H); MS m/z 420 (M+).
(3S,4R,6S)-6-Hyd r oxym eth yl-2-oxoh exa h yd r ooxa zlolo-
[4,5-c]p ip er id in e-5-ca r boxylic Acid ter t-Bu tyl Ester 21.
To a stirring solution of 9e (1.2 g, 4.1 mmol) in 3 mL of CH2Cl2
were added tert-butyldiphenyl chloride (1.2 g, 4.4 mmol), 20
mg of DMAP, and 0.5 mL of triethylamine. The resultant
solution was stirred at room temperature for 6 h, and then it
was partitioned between 20 mL of CH2Cl2 and 10 mL of brine.
The organic phase was dried and concentrated, the residue
was chromatographed to give the corresponding silyl ether.
This silyl ether was dissolved in 3 mL of methanol, and then
3 mL of 10% aqueous NaOH was added. The mixture was
stirred at room temperature for 6 h before methanol was
removed in vacuo. The residue was added 3 N HCl to adjust
pH to 4, and then it was extracted with ethyl acetate. The
combined organic phase was dried over Na2SO4 and concen-
trated. The residue was dissolved in 15 mL of dry benzene,
and then DPPA (1.2 g, 4.4 mmol) and 1.5 mL of triethylamine
were added. After the resultant solution was heated at reflux
for 16 h, the cooled solution was concentrated, and the residue
was chromatographed to give the corresponding oxazolidinone,
which was dissolved in 3 mL of THF. After TBAF (1.2 g, 4.6
mmol) was added to this solution, it was stirred at room
temperature for 6 h. The solvent was evaporated, and the
residual oil was chromatographed to provide 0.59 g (52%) of
21: [R]21D -111.4 (c 0.92, CH3OH); IR (neat) 3456, 3298, 2970,
and the residue was chromatographed to give 172 mg (73%)
1
of unsaturated aldehyde 18: [R]22 -56.8 (c 1.0, CHCl3); H
D
NMR (300 MHz, CDCl3) δ 9.52 (d, J ) 7.8 Hz, 1H), 6.85 (dd,
J ) 15.6, 6.8 Hz, 1H), 6.12 (dd, J ) 15.6, 7.8 Hz, 1H), 5.60 (m,
1H), 4.92 (m, 1H), 4.1 (m, 2H), 3.95 (m, 1H), 2.88 (m, 1H), 2.33
(m, 3H), 1.61 (m, 3H), 1.44 (s, 9H), 1.32 (br s, 6H); MS m/z
366 (M+), HRMS found m/z 311.1634 (M+ - t-Bu + 2H+),
C
15H23N2O5 requires 311.1661.
(3S ,4R ,6R )-2-O x o -6-t r id e c a -6,8-d ie n y lh e x a h y d r o -
oxa zlolo[4,5-c]p ip er id in e-5-ca r boxylic Acid ter t-Bu tyl
Ester 19. A solution of n-pentyl phenyl sulfone (52 mg, 0.24
mmol) in 1 mL of dry THF was cooled to -78 °C, and then
n-BuLi (2 M solution in hexane, 0.24 mmol) was added. The
reaction mixture was stirred at this temperature for 2 h before
a solution of 18 (40 mg, 0.11 mmol) in 0.5 mL of dry THF was
added. The stirring was continued for another 1 h, and then 1
mL of saturated aqueous NH4Cl was added at -78 °C to
quench the reaction. After the mixture was warmed to room
temperature, the organic layer was separated, and the aqueous
layer was extracted with CH2Cl2. The combined organic layers
were washed with brine and dried over Na2SO4, the solvent
was evaporated, and the residue was chromatographed to give
the corresponding alcohol. This alcohol was dissolved in 1 mL
of dry CH2Cl2, and then benzoyl chloride (15.5 mg, 0.11 mmol),
1 mg of DMAP, and 20 mL of triethylamine were added. After
the solution was stirred at room temperature for 3 h, the
solvent was removed in vacuo, and the residue was chromato-
1
1744, 1671 cm-1; H NMR (300 MHz, CDCl3) δ 5.45 (m, 1H),
5.05 (m, 1H), 4.13 (m, 2H), 4.04 (m, 1H), 3.91 (m, 1H), 3.62
(m, 1H), 3.10 (m, 1H), 2.20 (m, 1H), 2.03 (m, 1H), 1.51 (br s,
9H); MS m/z 272 (M+); HRMS found m/z 272.1374, C12H20N2O5
requires 272.1376.
(3S ,4R ,6S )-6-Be n ze n e su lfon ylm e t h yl-2-oxoh e xa h y-
d r ooxa zlolo[4,5-c]p ip er id in e-5-ca r boxylic Acid ter t-Bu -
tyl Ester 22. To a stirring solution of 21 (110 mg, 0.4 mmol)
in 3 mL of CH2Cl2 were added MsCl (58 mg, 0.5 mmol), 2 mg

6016 J . Org. Chem., Vol. 65, No. 19, 2000
Ma and Sun
of DMAP, and 0.1 mL of triethylamine. The resulting solution
was stirred at room temperature for 6 h before it was
partitioned between 15 mL of CH2Cl2 and 5 mL of brine. The
organic phase was separated, dried, and concentrated, and
then the residue was chromatographed to give the correspond-
ing mesylate. After this product was dissolved in 3 mL of 1,4-
dioxane, NaHCO3 (50 mg, 0.6 mmol) and thiophenol (66 mg,
0.6 mmol) were added. The resulting mixture was stirred at
room temperature for 24 h before it was filtered through silica
gel. The filtrate was concentrated, and the residue was
chromatographed to give the corresponding thiol ether, which
was dissolved in 3 mL of dry CH2Cl2. To this solution was
added MCPBA (60%, 287 mg, 1 mmol). After the mixture was
stirred at room temperature for 3 h, 5 mL of 10% aqueous
K2CO3 was added. The stirring was continued for 10 min, and
then the organic phase was separated, and the aqueous phase
was extracted with CH2Cl2. After the combined organic phase
was dried over Na2SO4 and concentrated in vacuo, the residue
was chromatographed to give 133 mg (87%) of 22: [R]15D -69.2
(c 0.4, CH3OH); 1H NMR (300 MHz, CDCl3) δ 7.87 (m, 2H),
7.61 (m, 3H), 5.1 (s, 1H), 4.97 (m, 1H), 4.37 (m, 1H), 4.02 (m,
1H), 3.99 (m, 1H), 3.40 (m, 2H), 3.07 (m, 1H), 2.60 (m, 1H),
2.15 (m, 1H), 1.29 (br s, 9H); MS m/z 396 (M+); HRMS found
m/z 396.1369, C18H24SN2O6 requires 396.1383.
(3S,4R,6S)-2-Oxo-6-pen tadeca-1,3,8,10-tetr aen ylh exah y-
d r ooxa zolo[4,5-c]p ip er id in e-5-ca r boxylic Acid ter t-Bu tyl
Ester 24. A solution of 22 (85 mg, 0.21 mmol) in 3 mL of DME
was cooled to -78 °C. To this stirring solution was added
n-BuLi (2 M solution in hexane, 0.21 mmol). After the solution
was stirred at this temperature for 2 h, a solution of aldehyde
23 (108 mg, 0.53 mmol) in 1 mL of DME was added in a
dropwise manner. The stirring was continued for 30 min before
saturated aqueous NH4Cl was added to quench the reaction.
The organic phase was separated, the aqueous layer was
extracted with CH2Cl2, and the combined organic phase was
washed with brine and dried. After the solvent was evaporated,
the residue was chromatographed to give the corresponding
coupling products. This mixture was dissolved in 1 mL of
CH2Cl2, and then at 0 °C benzoyl chloride (33 mg, 0.23 mmol),
3 mg of DMAP, and 50 mL of triethylamine were added with
stirring. The ice bath was removed, and the stirring was
continued for 3 h. After the mixture was filtered through silica
gel, the filtrate was concentrated, and then the residue was
dissolved in 1 mL of methanol and 0.5 mL of ethyl acetate.
The resultant solution was cooled to -25 °C, and then 0.8 g of
6% sodium amalgam was added. After the mixture was stirred
at this temperature for 1 h, the liquid was decanted into water,
and the residue was washed with ethyl acetate for three times.
The aqueous phase was extracted with ethyl acetate. The
combined organic phase was washed with brine and dried over
Na2SO4. After the solvent was evaporated, the residue was
chromatographed to give 48 mg (52%) of 24. [R]11 +10.1 (c
D
1.5, CHCl3); 1H NMR (300 MHz, CDCl3) 6.09 (m, 4H), 5.65 (m,
5H), 4.99 (m, 1H), 4.60 (m, 1H), 4.08 (m, 2H), 3.08 (m, 1H),
2.45 (m, 1H), 2.23 (m, 6H), 1.71 (m, 1H), 1.48 (br s, 9H), 1.55-
1.35 (m, 6H), 0.95 (t, J ) 6.8 Hz, 3H); MS m/z 444 (M+); HRMS
found m/z 444.2982, C26H40N2O4 requires 444.2976.
P seu d od istom in F. To a solution of 24 (10 mg, 0.023 mmol)
in 1 mL of methanol was added 1 mL of 30% aqueous KOH.
After the resultant mixture was refluxed for 3 h, it was
extracted with CH2Cl2. The combined organic phase was dried
and concentrated. The residue was dissolved in 1 mL of ethyl
acetate, and then 1 mL of saturated methanolic HCl was
added. After the resultant solution was stirred at room
temperature for 30 min, 3 mL of 20% aqueous K2CO3 was
added to quench the reaction. The mixture was extracted with
CH2Cl2, and the combined organic phase was dried and
concentrated. The residue was chromatographed to afford 5
mg (70%) of 1f: [R]11 -12.6 (c 0.2, CH3OH); 1H NMR (300
D
MHz, CD3OD) δ 6.17 (dm, J ) 14.6 Hz, 1H), 6.05 (dm, J )
14.6 Hz, 1H), 6.00 (dm, J ) 14.6 Hz, 2H), 5.67 (dm, J ) 14.6
Hz, 1H), 5.55 (dm, J ) 14.6 Hz, 3H), 3.95 (m, 1H), 3.45 (m,
1H), 2.73 (m, 3H), 2.06 (m, 6H), 1.85 (m, 2H), 1.48 (m, 3H),
1.36 (m, 4H), 0.92 (t, J ) 7.0 Hz, 3H); MS m/z 318 (M+).
Ack n ow led gm en t. The authors are grateful to the
Chinese Academy of Sciences, National Natural Science
Foundation of China (grants 29725205 and 29972049),
and Qiu Shi Science & Technologies Foundation for
their financial support.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
compounds 5b, 5c, 8b, 12, 15, 17-19, 21, 22, and 24. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O000447Q