Studies toward the synthesis of (+)-palustrine: The first asymmetric synthesis of (-)-methyl palustramate

Article abstract of DOI:10.1021/jo980749g

The stereoselective synthesis of (-)-methyl palustramate, a possible intermediate for the synthesis of (+)-palustrine, is described. The key step of the synthesis is a conformationally restricted Claisen rearrangement to afford the highly functionalized 1-benzylpipecolic ester 10. In addition, a new procedure for debenzylation of 1-benzylpiperidines (Li, NH₂CH₂)₂, Et₃N, THF) was used to remove the benzyl protecting group where traditional methods failed.

Full text of DOI:10.1021/jo980749g

7490
J . Org. Chem. 1998, 63, 7490-7497
Stu d ies tow a r d th e Syn th esis of (+)-P a lu str in e: Th e F ir st
Asym m etr ic Syn th esis of (-)-Meth yl P a lu str a m a te
Steven R. Angle* and Robert M. Henry
Department of Chemistry, University of CaliforniasRiverside, Riverside, California 92521-0403
Received April 21, 1998
The stereoselective synthesis of (-)-methyl palustramate, a possible intermediate for the synthesis
of (+)-palustrine, is described. The key step of the synthesis is a conformationally restricted Claisen
rearrangement to afford the highly functionalized 1-benzylpipecolic ester 10. In addition, a new
procedure for debenzylation of 1-benzylpiperidines (Li, (NH2CH2)2, Et3N, THF) was used to remove
the benzyl protecting group where traditional methods failed.
Palustrine, a piperidine alkaloid, is a toxic component
of the horsetail plant Equisetum paluster L., found in the
moist meadows of Europe.1 If ingested, the horsetail
plant has deleterious effects on grazing animals, par-
ticularly cows. The major biological effects of this
alkaloid are a loss of appetite, weight loss, and decreased
milk secretion.2
Palustrine was isolated by Eugster and co-workers in
1948.1 The structure was tentatively assigned with the
alkene at the C(15)-C(16) position, rather than at the
C(14)-C(15) position, on the basis of spectroscopic data.3
The correct position of the alkene became apparent when
Natsume4 and Wasserman5 independently reported the
racemic synthesis of the ∆C(15)-C(16) alkene isomer,
which was not identical with the natural product. Hy-
drogenation of natural palustrine and the synthetic
∆C(15)-C(16) alkene isomer afforded the structurally
identical product dihydropalustrine, indicative of the
isomeric nature of the alkene in the two compounds.4,5
Natsume and Ogawa then confirmed the structure with
the synthesis of (()-palustrine.6
To date there has been a single synthesis of (-)-methyl
dihydropalustramate (4),7 a degradation product of
palustrine.3c Compound 4 has been reported to be a
possible intermediate for the synthesis of dihydropalus-
trine.8 We viewed the previously unknown (-)-methyl
palustramate (3) as a possible intermediate for the
synthesis of palustrine and as a compound that might
be easily prepared via our conformationally restricted
Claisen rearrangement methodology.8,9
A key part of our analysis relied on the ready avail-
ability of the known L-homoserine lactone 5 (Scheme 1).
We hoped the lactone would be compatible with the
DIBAl-H-Grignard addition to esters of R-amino acids
that had proven successful in our previous work.9 In
addition, the lactone would, in effect, be a protecting
group for the latent primary alcohol.
Lactone 5,10 prepared from L-methionine, was treated
sequentially9 with DIBAl-H and freshly prepared vinyl-
magnesium chloride11 to afford the amino alcohol 6 as
an 11:1 mixture of diastereomers (1H NMR) in 71% yield
(Scheme 1).12 Reduction of the benzamide with lithium
aluminum hydride afforded benzylamine 7 in 89% yield.
This material was then recrystallized to afford 7 as a 32:1
mixture of diastereomers in 76% yield from 6. Alkylation
of the amine with phenyl R-bromoacetate,13 followed by
stirring at room temperature for 66 h, led to selective
lactonization onto the secondary alcohol, affording the
six-membered-ring lactone 8 in 71% yield. Treatment of
(1) For the isolation see: Karrer, Von P.; Eugster, C. Helv. Chim.
Acta 1948, 31, 1062-1066.
(2) Eugster, C. H. Heterocycles 1976, 4, 51-105.
(3) (a) Eugster, C. H.; Walchli, P. C. Helv. Chim. Acta 1978, 61, 885-
898. (b) Eugster, C. H.; Ruedi, P. Helv. Chim. Acta 1978, 61, 899-
904. (c) Eugster, C. H.; Walchli, P. C.; Trueb, W.; Green, C. L.; Mayer,
C. Helv. Chim. Acta 1978, 61, 905-920. (d) Eugster, C. H.; Walchli, P.
C.; Muller, G. M. Helv. Chim. Acta 1978, 61, 921-927. (e) Eugster, C.
H.; Schaer-Walchli, M. Helv. Chim. Acta 1978, 61, 928-935.
(4) (a) Natsume, M.; Ogawa, M.; Yoda, I.; Shiro, M. Chem. Pharm.
Bull. 1984, 32, 812-814.
(9) (a) Angle, S. R.; Henry, R. M. J . Org. Chem. 1997, 62, 8549-
8552. (b) Angle, S. R.; Breitenbucher, J . G.; Arnaiz, D. O. J . Org. Chem.
1992, 57, 5947-5955. For the DIBAl-H-Grignard reaction see: (c)
Ibuka, T.; Habashita, H.; Otaka, A.; Fujii, N.; Oguchi, Y.; Uyehara,
T.; Yamamoto, Y. J . Org. Chem. 1991, 56, 4370-4382.
(10) (a) Natelson, S.; Natelson, E. A. Microchem. J . 1989, 40, 226-
232. (b) Seela, F., Cramer, F.; Chem. Ber. 1976, 109, 82-89.
(11) Commercial vinylmagnesium chloride was inferior to freshly
prepared reagent: Ramsden, H. E.; Leebrick, J . R.; Sanders, D.;
Rosenberg, S. D.; Miller, E. H.; Walburn, J . J .; Balint, A. E.; Cserr, R.
J . Org. Chem. 1957, 22, 1602-1607.
(5) Wasserman, H. H.; Leadbetter, M. R.; Kopka, I. E. Tetrahedron
Lett. 1984, 25, 2391-2394.
(6) Natsume, M.; Ogawa, M. Chem. Pharm. Bull. 1984, 32, 3789-
3791.
(7) Muraoka, O.; Zheng, B.-Z.; Okumura, K.; Tanabe, G.; Momose,
T.; Eugster, C. H. J . Chem. Soc., Perkin Trans. 1 1996, 1567-1576.
(8) For leading references to synthesis approaches to palustrine and
palustramic acid see: (a) Hirai, Y.; Watanabe, J .; Nozaki, T.; Yokoya-
ma, H.; Yamaguchi, S. J . Org. Chem. 1997, 62, 776-777. (b) Nader,
B.; Bailey, T. R.; Franck, R. W.; Weinreb, S. M. J . Am. Chem. Soc.
1981, 103, 7573-7580.
(12) Ratios of diastereomers were determined by integration of 1H
NMR spectra; see the Supporting Information for details.
(13) Dellaria, J . F., J r.; Santarsiero, B. D. J . Org. Chem. 1989, 54,
3916-3926.
S0022-3263(98)00749-X CCC: $15.00 © 1998 American Chemical Society
Published on Web 10/01/1998

Asymmetric Synthesis of (-)-Methyl Palustramate
J . Org. Chem., Vol. 63, No. 21, 1998 7491
Sch em e 1a
Sch em e 3
the undesired diastereomer.16 While this route afforded
primarily the incorrect diastereomer 14, it did serve the
desired purpose of providing samples of both diastereo-
mers to allow their stereochemical assignment.16
a
Legend: (a) DIBAL-H; H2OdCHMgCl, 71%; (b) LiAlH4, 89%;
(c) BrCH2CO2Ph, EtN(i-Pr)2, 71%; (d) (i-Pr)3SiOTf, Et3N, 96%.
Sch em e 2a
The stereochemistry of 13 and 14 was assigned by
conversion to cyclic carbamates that were similar to
compounds of known relative stereochemistry. Hydro-
genation/hydrogenolysis of 13 and 14 followed by treat-
ment with carbonyldiimidazole afforded cyclic carbam-
ates 15 and 16. The Ha-Hb coupling constants for the
two diastereomers (see Scheme 3 for a/b labels) were
extremely close and not diagnostic. However, the chemi-
cal shift of hydrogens Ha differed by over 0.35 ppm for
the two diastereomers. Comparison of the chemical shifts
of these hydrogens with those for similar compounds of
known relative stereochemistry, 17 and 18, showed a
strong correlation and allowed the assignment of the
relative stereochemistry in 13 and 14.8b
a
Legend: (a) DIBAL-H 79%; (b) Swern oxidation; (c) EtMgBr,
70% from 11.
We hoped to exploit the high preference for addition
to the aldehyde carbonyl by reversing the order of the
reduction and ethyl addition steps. This strategy re-
quired conversion of silyl ester 10 to an ethyl ketone
followed by reduction. Direct conversion of the TIPS
ester to the ketone failed; ester 10 was inert to excess
ethyl Grignard and alkyllithium reagents. Thus, the
hindered TIPS ester was converted to a Weinreb amide,17
as outlined below (Scheme 4). Hydrolysis of silyl ester
10 with potassium carbonate in ethanol/THF/water (3:
1:1) afforded the carboxylic acid, which was treated with
carbonyldiimidazole to give the acyl imidazole. This
activated ester was then treated with additional imid-
azole (3 equiv) and methoxymethylamine hydrochloride
(4 equiv, room temperature, 12 h) to afford Weinreb
amide 19 in 76% overall yield from lactone 8. Treatment
of 19 with excess ethylmagnesium bromide gave ketone
20, which was immediately reduced with lithium boro-
hydride16 in CH3OH to afford alcohols 13 and 14 in 81%
yield and a 32:1 ratio, respectively.
lactone 8 with 2.1 equiv of TIPS-OTf effected formation
of the silyl ketene acetal as well as protection of the
primary alcohol to afford 9 (1H NMR analysis). The silyl
ketene acetal 9 was not isolated; simply stirring the above
reaction mixture at room temperature afforded pipecolic
ester 10 in 96% yield. This material was used without
purification in subsequent reactions but could be purified
by flash chromatography to afford analytically pure silyl
ester 10 in 75-96% yield.
We next addressed homologation about the silyl ester
and introduction of the secondary alcohol in the correct
relative orientation to the existing stereocenters. Relying
on the easy access to the corresponding aldehyde,9a we
reduced 10 with DIBAl-H to afford the corresponding
primary alcohol 11 in 79% yield (Scheme 2). Swern
oxidation14 afforded aldehyde 12, which was immediately
treated with excess ethylmagnesium bromide to afford
alcohols 13 and 14 in an unoptimized yield of 70% and a
1:24 ratio (13:14, based on isolated yields).15 As we had
predicted on the basis of Felkin-Ahn addition to the
aldehyde, the major diastereomer turned out to be 14,
The completion of the synthesis of (-)-methyl palus-
tramate was accomplished via the route shown in Scheme
5. Protection of the secondary alcohol 13 as the MOM
ether followed by treatment of the resulting ether 21,
(14) Mancuso, A. J .; Huang, S.-L.; Swern, D. J . Org. Chem. 1978,
43, 2480-2482.
(15) The stereochemistry of 13 and 14 was tentatively assigned by
correlation with similar compounds reported in the literature, as shown
in the text. The ultimate proof of the assignment was provided by
correlation of the spectral data for 4 with those in the literature; see
the Supporting Information for details.
(16) Natsume, M.; Ogawa, M. Chem. Pharm. Bull. 1982, 30, 3442-
3445.
(17) Weinreb, S. M.; Lipton, M. F.; Basha, A. Org. Synth. 1980, 59,
49-53.

7492 J . Org. Chem., Vol. 63, No. 21, 1998
Angle and Henry
Sch em e 4a
a solvent mixture of ethylenediamine, triethylamine, and
THF (1:10:5) afforded 22 in 71% yield. This reaction was
carried out at room temperature (2.3 h) and completely
avoided the use of liquid ammonia. If the percentage of
ethylenediamine was increased, reduction of the alkene
was competitive with debenzylation. This dissolving-
metal reduction, which appears to be quite general for
2,6-disubstituted-1-benzylpiperidines, offers an attractive
alternative to traditional procedures which involve liquid
ammonia as the solvent. A similar procedure for the
debenzylation of amides was recently reported by Garst
and co-workers.22
Attempts to oxidize silyl ether 22 or the corresponding
alcohol with J ones reagent to the carboxylic acid afforded
products in poor yield and low purity. Even when the
amine was pretreated with sulfuric acid, many of the
problems appeared to result from the presence of this
functionality. Accordingly, amine 22 was protected as
the TROC carbamate23 and the TIPS ether was removed
by treatment with HF-pyridine to afford alcohol 23 in
91% overall yield (Scheme 5). Oxidation of primary
alcohol 23 with PDC in DMF24 afforded the acid, which
was esterified by sequential treatment with carbonyldi-
imidazole and methanol to afford 24 in 55% yield from
primary amine 22. Completion of the synthesis required
only removal of the protecting groups. Reductive cleav-
age of the TROC carbamate23 with zinc afforded the
secondary amine. Removal of the MOM ether using
Kim’s transketylization conditions25 with butanethiol and
magnesium bromide afforded (-)-methyl palustramate
(3) in 56% yield from 24. The structure of 3 was proven
by hydrogenation to (-)-methyl dihydropalustramate (4)
and comparison of the spectral data and optical rotation
of 4 with those reported in the literature.3,7,12
a
Legend: (a) K2CO3, EtOH/THF/H2O 3:1:1; (b) CDI, H2NCH3-
(OCH3)Cl, 79%; (c) EtMgBr, THF; (d) LiBH4, 81% from 15.
Sch em e 5a
The first asymmetric synthesis of (-)-methyl palus-
tramate has been achieved using a conformationally
restricted Claisen rearrangement and a novel debenzyl-
ation reaction as the key steps. The application of the
methodology to the synthesis of (+)-palustrine is cur-
rently under investigation.
a
Legend: (a) CH3OCH2Br, Et3N, 83%; (b) Li, (NH2CH2)2, Et3N,
THF, 71%; (c) Cl3CH2COC(O)Cl, pyridine, 93%; (d) HF-pyridine,
98%; (e) PDC, DMF, 85%; (f) CDI; CH3OH, 70%; (g) Zn, 74%; (h)
BuSH, MgBr2, 76%.
under standard dissolving-metal conditions with so-
dium18 or lithium19 in ammonia, resulted in poor yields
of secondary amine 22 (Scheme 5). Using 2-20 equiv of
sodium or lithium afforded mainly starting material, and
employing a large excess of metal (100-2000 equiv)
resulted in poor mass recovery (<50%) and the products
isolated were apparently derived from Birch reduction
(1H NMR analysis), with negligible cleavage of the benzyl
group. A survey of classic conditions18-20 to effect this
transformation failed to afford 22 in acceptable yield.
Hydrogenolysis conditions were not acceptable due to the
presence of the alkene in the piperidine ring, and
chloroformate dealkylation reactions failed to afford any
of the desired products. Benkeser and co-workers inves-
tigated dissolving-metal reductions and found that the
reducing ability of the system was attenuated by addition
of ethylenediamine.21 After some experimentation, we
found that treatment of 21 with lithium (50 equiv) using
Exp er im en ta l Section
r-L-Ben zam ido-γ-bu tyr olacton e (5).26 L-Methionine (30.0
g, 0.201 mol) was added to a solution of H2O (120 mL),
2-propanol (120 mL), and glacial acetic acid (48 mL). The
solution was stirred until homogeneous; then bromoacetic acid
(28.0 g, 0.202 mol; caution! this compound is highly toxic and
a severe irritant) was added and the reaction mixture refluxed
for 2 h. The reaction mixture was then cooled to room
temperature and concentrated to a viscous orange oil.
solution of 2-propanol and toluene (1:1, v/v, 100 mL) was
added, and the reaction mixture was stirred until homoge-
A
(21) (a) Benkeser, R. A.; Robinson, R. E.; Landesman, H. J . Am.
Chem. Soc. 1952, 74, 5699-5701. (b) Benkeser, R. A.; Robinson, R. E.;
Sauve, D. M.; Thomas, O. W. J . Am. Chem. Soc. 1955, 77, 3230-3233.
(22) Garst, M. E.; Dolby, L. J .; Esfandiari, S.; Chamberlain, N. C.;
Fedoruk, N. Abstracts of Papers, 213th National Meeting of the
American Chemical Society, San Francisco, CA, April 13-17 1997,
American Chemical Society: Washington, DC, 1997; ORG-290.
(23) (a) Carson, J . F. Synthesis 1981, 268-270. (b) Windholz, T. B.;
J ohnston, D. B. R. Tetrahedron Lett. 1967, 2555-2557.
(24) Corey, E. J .; Schmidt, G. Tetrahedron Lett. 1979, 5, 399-402.
(25) Kim, S.; Kee, I. S.; Park, Y. H.; Park, J . H. SYNLETT, 1991,
183-184.
(26) General information: Capillary GC was carried out using an
FID detector on a 25 m HP-102 (methyl silicone) column. The following
standard GC parameters were used: flow rate 60 mL/min; injector
temperature 200 °C; detector temperature 280 °C; temperature
program 40-280 °C at 8 °C/min; initial time 1 min.
(18) Vigneaud, V. D.; Behrens, K. O. J . Biol. Chem. 1937, 117, 27-
36.
(19) Smith, H. Organic Reactions in Liquid Ammonia; Interscience
Publishers: New York, 1963; Vol. 2, Part 2.
(20) (a) Calcium metal in reductions: Benkeser, R. A.; Belmonte,
F. G.; Kang, J . J . Org. Chem. 1983, 48, 2796-2802. (b) Pandey, G.;
Rani, K. S. Tetrahedron Lett. 1984, 29, 4157-4158. (c) Kaiser, E. M.
Synthesis 1972, 391-415.

Asymmetric Synthesis of (-)-Methyl Palustramate
J . Org. Chem., Vol. 63, No. 21, 1998 7493
neous. Concentration (90 °C, bath temperature) afforded an
orange oil. A solution of dioxane (80 mL) and concentrated
HCl (40 mL) was then added to the orange oil, and the
resulting solution was heated to 50 °C for 10 min. The heating
bath was then removed, the mixture was stirred for 12 h, and
the reaction flask was then placed in an ice bath for 4 h
without stirring to precipitate an orange solid. The orange
solid was then filtered and rinsed with cold 2-propanol (50 mL,
-78 °C) until the rinsings were colorless. The resulting white
solid was then dried (0.5 mmHg) to afford the product,
homoserine lactone hydrobromide (21 g, 57%): mp 229-231
(5.0 g, 0.13 mol) in THF (225 mL) at 0 °C. The resulting
suspension was warmed to room temperature, heated to reflux
for 4 h, and then cooled to 0 °C. H2O (5 mL), 15% NaOH (5
mL), and H2O (15 mL) were sequentially added, and the
resulting suspension was warmed to room temperature and
stirred overnight. Filtration through Celite, followed by
concentration, afforded the crude product (6.5 g) as a yellow
oil. Flash chromatography (silica gel, 4.5:3.0:2.5:0.4 ethyl
acetate/hexanes/2-propanol/triethylamine) afforded 7 (∼11:1
1
ratio of diastereomers, H NMR) (6.20 g, 89%) as a clear oil.
This oil was then crystallized by the addition of ether (20 mL,
-50 °C, 1 week). Filtration afforded the diastereomerically
enriched 7 as colorless crystals (5.3 g, 76%; ∼30:1; 3S,4S and
3S,4R) as determined by 1H NMR integration of CHOH signals
at δ 4.18 (major, 3R,4S) and 4.41 (minor, 3R,4R): mp 56-57
°C; 1H NMR (300 MHz, CDCl3) δ 7.40 (m, 5H), 5.84 (ddd, J )
17.1, 10.3, 6.8 Hz, 1H), 5.31 (d, J ) 17.1 Hz, 1H), 5.20 (d, J )
10.3 Hz, 1H), 4.14 (t, J ) 6.4 Hz, 1H), 3.89-3.74 (m, 4H), 3.53
(bs, 3H), 2.83 (dt, J ) 6.5, 4.1 Hz, 1H), 1.91-1.83 (m, 1H),
1.63-1.55 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 139.6, 138.4,
128.5, 128.2, 127.2, 117.2, 73.7, 61.3, 61.1, 51.4, 31.0; IR (neat)
3353-3303 (br), 2928, 2865, 1455 cm-1; MS (CI, NH3) m/z 222
1
°C (lit.10a mp 234-236 °C); H NMR (300 MHz, DMSO-d6) δ
8.79 (bs, 3H), 4.30 (m, 3H), 2.50-2.46 (m, 1H), 2.32-2.18 (m,
1H); 13C NMR (75 MHz, DMSO-d6) δ 173.2, 66.2, 47.7, 27.0;
IR (KBr) 2300-4000 (br), 1774 cm-1; [R]D25 ) -24.4° (c )
0.087, H2O), lit.10a [R]D25 ) -26.5° (c ) 0.130, H2O). Homo-
serine lactone hydrobromide (10.0 g, 54.9 mmol) was added
to H2O and CH2Cl2 (1:1, v/v, 120 mL), and this mixture was
then cooled to 0 °C. K2CO3 (23.0 g, 165 mmol) was then added
and the resulting mixture stirred for 5 min. Benzoyl chloride
(7.0 mL, 61 mmol) was added dropwise, and the resulting
mixture was warmed to room temperature and stirred for 20
h. The reaction mixture was then diluted with ethyl acetate
(100 mL) and the aqueous layer extracted with ethyl acetate
(4 × 60 mL) followed by CHCl3 (4 × 60 mL). The combined
organic extracts were then dried (Na2SO4) and concentrated
to afford the crude product as a yellow solid. The crude
product was then rinsed with ethyl acetate (-78 °C) until the
rinsings were colorless and the solid was white. The solid was
then dried (0.5 mmHg) for 1 h to yield the product 5 (10.0 g,
89%): mp 145-147 °C (lit.10b mp 140-141 °C);1H NMR (300
MHz, CDCl3) δ 7.78 (m, 2H), 7.49 (m, 1H), 7.39 (m, 2H), 7.09
(br d, J ) 5.2 Hz, 1H), 4.80 (m, 1H), 4.49 (dt, J ) 10.0, 0.9 Hz,
1H), 4.32 (m, 1H), 2.87 (m, 1H), 2.29 (dq, J ) 20.4, 8.9 Hz,
1H); 13C NMR (75 MHz, CDCl3) δ 175.9, 167.7, 132.9, 132.0,
(MH+, 100), 164 (42), 106 (11), 91 (39); HRMS calcd for C13H20
-
NO2 (MH+) 222.1494, found 222.1492; [R]2D5 ) -20.8° (c )
0.048, CHCl3); GC major tR ) 28.33.
(5S,6S)-6-Eth en yl-5-(h yd r oxyeth yl)-4-(p h en ylm eth yl)-
3,4,5,6-tetr a h yd r o-2H-1,4-oxa zin -2-on e (8). Solid phenyl
R-bromoacetate (892 mg, 4.14 mmol) was dissolved in CH3CN
(13 mL) and this solution then added via cannula over 30 min
to a stirred solution of benzylamine 7 (865 mg, 3.92 mmol)
and diisopropylethylamine (3.5 mL, 20 mmol) in CH3CN (13
mL) at 0 °C. The resulting solution was slowly warmed to
room temperature and stirred for 66 h. The solution was then
concentrated using a rotary evaporator, followed by high
vacuum (0.3 mmHg) for 30 min. Addition of ethyl acetate (30
mL) with continuous stirring resulted in the precipitation of
amine salts. Washing of the precipitate with ethyl acetate (5
× 30 mL), followed by concentration of the ethyl acetate
washings, afforded the crude product as a gold oil. Flash
chromatography (silica gel, 25:75 hexanes/ethyl acetate) af-
forded lactone 8 (0.731 g, 71%) as a clear oil: 1H NMR (300
MHz, CDCl3) δ 7.31 (m, 5H), 5.92 (ddd, J ) 17.1, 10.3, 6.8 Hz,
1H), 5.40 (d, J ) 17.1 Hz, 1H), 5.35 (d, J ) 10.7 Hz, 1H), 4.70
(t, J ) 7.2 Hz, 1H), 3.77 (m, 2H), 3.73 (s, 2H), 3.38 (AB q, J )
17.4 Hz, ∆v ) 30.6 Hz, 2H), 2.99 (m, 2H), 1.85-1.67 (m, 2H);
13C NMR (75 MHz, CDCl3) δ 168.9, 136.5, 134.0, 129.1, 128.6,
127.8, 119.7, 81.5, 60.2, 59.1, 58.4, 49.8, 29.5; IR (neat) 3487-
3387 (br), 2937, 1736 cm-1; MS (CI, NH3) m/z 262 (MH+, 100),
172 (11), 120 (7), 106 (9), 91 (21); HRMS calcd for C15H20NO3
(MH+) 262.1443, found 262.1440; [R]2D5 ) -85.0° (c ) 0.0456,
CHCl3); GC major tR ) 74.12 min.
(2S,6S)-1-(P h en ylm eth yl)-6-[[(tr iisopr opylsilyl)oxy]car -
bon yl]-2-[2-[(tr iisop r op ylsilyl)oxy]eth yl]-1,2,5,6-tetr a h y-
d r op yr id in e (10). Triisopropylsilyl triflate (2.2 mL, 8.3
mmol) was added to a stirred solution of lactone 8 (1.03 g, 3.93
mmol) and triethylamine (2.7 mL, 20 mmol) in benzene (35
mL) at 5 °C. The resulting suspension was stirred for 4 h at
room temperature and then concentrated to 3 mL. Im-
mediately following partial concentration, filtration (silica gel,
95:5:0.5 hexanes/ethyl acetate/triethylamine) afforded the
crude pipecolic ester 10 (2.17 g, 96%) as a light yellow oil that
was used without further purification. Flash chromatography
of a similar sample afforded an analytical sample as a colorless
oil: 1H NMR (300 MHz, CDCl3) δ 7.41 (d, J ) 7.0 Hz, 2H),
7.26 (m, 3H), 5.81-5.73 (m, 2H), 4.00 (m, 2H), 3.87-3.80 (m,
1H), 3.74-3.65 (m, 1H), 3.49 (m, 2H), 2.46-2.35 (dm, J ) 16.4
Hz, 1H), 2.33-2.25 (dm, J ) 16.0 Hz, 1H), 2.00-1.90 (m, 1H),
1.74-1.62 (m, 1H), 1.28 (m, 3H), 1.08-1.02 (m, 39H); 13C NMR
(75 MHz, CDCl3) δ 174.2, 139.1, 129.9, 128.8, 128.1, 126.8,
122.6, 60.7, 58.2, 57.5, 55.0, 36.7, 25.9, 18.1, 17.9, 12.0, 12.0;
IR (neat) 2944, 2867, 1718 cm-1; MS (FAB+, ether, NBA/PEG)
m/z 574 (MH+, 21), 530 (9), 372 (100), 370 (21), 328 (15), 172
(31), 170 (55); HRMS calcd for C33H60NO3Si2 (MH+) 574.4112,
found 574.4134; [R]D25 ) -8.27° (c ) 0.114, CHCl3).
128.6, 127.1, 66.2, 49.6, 30.3; IR (CCl4) 1786, 1677 cm-1
;
[R]D25 ) -28.6° (c ) 0.0198, EtOH abs) lit.10b [R]2D0 ) -29.6° (c
) 1.2, ethanol).
(3S,4S)-3-[(P h en ylcar bon yl)am in o]-5-h exen e-1,4-diol (6).
A solution of DIBAl-H (1.8 mL, 9.9 mmol) in hexanes (0.4 mL)
was added dropwise over 10 min to a mechanically stirred
solution of lactone 5 (1.01 g, 4.93 mmol) in CH2Cl2 (45 mL) at
-78 °C. The rate of addition was adjusted as needed to
maintain a temperature of <-75 °C. The resulting solution
was stirred for 20 min. Vinylmagnesium chloride (9.5 mL of
a 1.55 M solution in THF, 14.8 mmol) was then added slowly,
again continuously adjusting the rate of addition to maintain
a temperature of <-75 °C. Immediately after the addition
was complete, the reaction flask was placed in a 0 °C ice bath,
slowly warmed to room temperature, and stirred for 13 h. The
mixture was then slowly poured into stirred 1 N HCl (50 mL)
at 0 °C and stirred for 10 min. The aqueous layer was then
extracted with ether (2 × 50 mL) and CHCl3 (5 × 40 mL), and
the combined organic extracts were dried (K2CO3) and con-
centrated to afford 1.33 g of crude product as a yellow oil. Flash
chromatography (silica gel, 5.5:3.5:1 ethyl acetate/hexanes/2-
propanol) afforded diol 6 (0.824 g, 71%; 11:1 mixture of
1
diastereomers, determined by H NMR integration of NH’s at
δ 6.76 major (3S,4S) and δ 6.91 minor (3S,4R)) as a white
solid: mp 68-70 °C; 1H NMR (300 MHz, CDCl3, major
diastereomer) δ 7.77 (d, J ) 7.8 Hz, 2H), 7.47 (m, 3H), 6.76
(br d, J ) 7.6 Hz, 1H), 5.94 (ddd, J ) 16.1, 10.0, 4.2 Hz, 1H),
5.37 (d, J ) 16.2 Hz, 1H), 5.21 (d, J ) 10.4 Hz, 1H), 4.43 (m,
2H), 3.84 (bs, 1H), 3.80-3.60 (m, 2H), 3.11 (bs, 1H), 2.04-
1.95 (m, 1H), 1.87-1.79 (m, 1H); 13C NMR (75 MHz, CDCl3) δ
168.8, 138.1, 133.8, 131.8, 128.6, 127.0, 116.3, 74.1, 58.6, 50.8,
35.5; IR (neat) 3421-3284 (br), 2955, 2882, 1637, 1537 cm-1
;
MS (CI, NH3) m/z 236 (MH+, 100), 218 (4), 178 (9), 122 (13),
105 (26), 74 (11); HRMS calcd for C13H18NO3 (MH+) 236.1287,
found 236.1283; [R]2D5 ) -38.6° (c ) 0.0825, CHCl3); GC major
tR ) 41.16 min, minor tR ) 41.47 min.
(3S,4S)-3-(Ben zyla m in o)-5-h exen e-1,4-d iol (7). A solu-
tion of benzamide 6 (7.44 g, 31.7 mmol) in THF (75 mL) was
added dropwise to a suspension of lithium aluminum hydride

7494 J . Org. Chem., Vol. 63, No. 21, 1998
Angle and Henry
(2S,6S)-6-(Hyd r oxym eth yl)-1-(p h en ylm eth yl)-2-[2-[(tr i-
isop r op ylsilyl)oxy]eth yl]-1,2,5,6-tetr a h yd r op yr id in e (11).
TIPS ester 10 (244 mg, 0.449 mmol) was dissolved in CH2Cl2
(20 mL), and the solution was then cooled to 0 °C. DIBAl-H
(0.179 mL, 0.915 mmol) was slowly added to the reaction
mixture. After the addition was complete, the cooling bath
was removed and the reaction mixture was warmed to room
temperature and stirred for 20 min. The reaction mixture was
then recooled to 0 °C and poured into a stirred 0 °C solution
of pH 7.5 phosphate buffer (25 mL). The resulting solution
was stirred for 10 min at room temperature; then the aqueous
layer was extracted with ether (4 × 25 mL). The combined
organic extracts were washed with H2O (25 mL) and brine (25
mL) and dried (K2CO3) to afford the crude material (244 mg)
as a yellow oil. Flash chromatography (silica gel, 80:20
hexanes/ethyl acetate) afforded alcohol 11 (135 mg, 79%) as a
light yellow oil: 1H NMR (500 MHz, CDCl3) δ 7.33 (m, 3H),
7.24 (m, 2H), 5.77 (m, 1H), 5.71 (dm, J ) 11.0 Hz, 1H), 3.84
(AB q, J ) 13.6 Hz, ∆v ) 10.0 Hz, 2H), 3.72 (m, 2H), 3.44 (t,
J ) 10.3 Hz, 1H), 3.34 (m, 2H), 3.04 (ddd, J ) 12.2, 8.1, 2.2
Hz, 1H), 2.95-2.75 (vbr s, 1H), 2.33 (d sextet, J ) 17.9, 2.4
Hz, 1H), 1.77-1.62 (m, 3H), 1.02 (m, 21H); 13C NMR (75 MHz,
CDCl3) δ 140.0, 128.8, 128.4, 127.2, 122.6, 62.8, 60.8, 60.4, 55.6,
54.1, 39.8, 21.7, 18.1, 12.0; IR (neat) 3600-3200, 2942, 2891,
1463 cm -1; [R]D25 ) +41.1° (c ) 0.0233, CH2Cl2).
(1′S,2S,6S)-6-(1′-H yd r oxyp r op yl)-1-(p h en ylm et h yl)-2-
[2-[(t r iisop r op ylsilyl)oxy]et h yl]-1,2,5,6-t et r a h yd r op yr i-
d in e (13). Red u ction of Keton e 20 w ith LiBH4. Crude
ketone 20 (from 0.779 g, 1.69 mmol of amide 19) was im-
mediately dissolved in methanol (12.5 mL) and the solution
cooled to 0 °C. LiBH4 (1.8 mL of a 2.0 M solution in THF, 3.6
mmol) was then added, the cooling bath was removed, and the
mixture was stirred at room temperature for 12 h. The
reaction mixture was then concentrated, diluted with CH2Cl2
(30 mL), and poured into saturated aqueous NaHCO3 (30 mL).
The resulting mixture was stirred for 15 min. Extraction of
the aqueous layer with CH2Cl2 (3 × 30 mL), followed by
washing of the combined organic extracts with H2O (75 mL)
and drying (K2CO3), afforded the crude material (597 mg) as
a yellow oil. Flash chromatography (silica gel, 90:10 hexanes/
ethyl acetate) afforded 13 (567 mg, Rf 0.42, clear oil) and 14
(17.6 mg, Rf 0.24, clear oil) in a 32:1 ratio and an 81% combined
yield: 1H NMR (13 major diastereomer, 300 MHz, CDCl3) δ
7.35-7.22 (m, 5H), 5.75 (s, 2H), 4.21 (s, 1H), 3.87-3.77 (AB q,
J ) 13.4 Hz, ∆v ) 10.3 Hz, 2H), 3.70 (t, J ) 5.8 Hz, 2H), 3.42
(m, 1H), 3.35 (m, 1H), 2.64 (dt, J ) 7.8, 1.4 Hz, 1H), 2.33-
2.24 (m, 1H), 1.90-1.72 (m, 2H), 1.69-1.49 (m, 2H), 1.16 (m,
1H), 1.00 (s, 21H), 0.93 (t, J ) 7.3 Hz, 3H); 13C NMR (13 major
diastereomer, 75 MHz, CDCl3) δ 139.7, 129.2, 128.9, 128.4,
127.2, 122.5, 70.4, 60.6, 60.0, 54.0, 39.6, 27.2, 19.9, 18.0, 11.9,
10.0; IR (neat) 3380, 2942, 2924, 1463 cm-1; MS (CI, NH3) m/z
432 (MH+, 46), 372 (38), 247 (76), 148 (20), 91 (100); HRMS
calcd for C26H46NO2Si (MH+) 432.3298, found 432.3289:
[R]2D5 ) +36.4° (c ) 0.0213, CHCl3); GC tR ) 44.57 min.
30.2 mmol) in ether (100 mL). The reaction mixture was kept
in the cooling bath and slowly warmed to room temperature
over 16 h. The reaction mixture was then poured into 1 N
HCl (50 mL) at 0 °C, the cooling bath was removed, and the
resulting mixture was stirred at room temperature for 15 min.
The pH of the resulting solution was then adjusted to 10 (pH
paper) with solid Na2CO3 (60 g). The aqueous layer was
extracted with ether (3 × 50 mL) and CHCl3 (3 × 50 mL). The
combined organic extracts were then washed with H2O (200
mL) and brine (200 mL), dried (K2CO3), and concentrated to
afford the crude material (790 mg) as a yellow oil. Flash
chromatography (silica gel, 90:10 hexanes/ethyl acetate) af-
forded 14 (undesired diastereomer, 497 mg, 67%; a single
diastereomer by 1H and 13C NMR, GC tR ) 45.23 min; Rf 0.24;
90:10 hexanes/ethyl acetate) as a colorless oil. A second
column (silica gel, 95:5 hexanes/ethyl acetate) of the less polar
material from above afforded 13 (desired diastereomer, 21 mg,
2.8%; a single diastereomer by 1H and 13C NMR, GC, tR ) 44.57
min; Rf 0.31; 95:5 hexanes/ethyl acetate) as a colorless oil.
Major diastereomer 14: 1H NMR (500 MHz, CDCl3) δ 7.32 (m,
3H) 7.23 (m, 2H), 5.85 (m, 1H), 5.78 (dm, J ) 5.8 Hz, 1H),
3.82 (m, 2H), 3.68 (m, 3H), 3.40 (m, 1H), 2.64 (dt, J ) 7.6, 5.0
Hz, 1H), 2.18 (dm, J ) 14.8 Hz, 1H), 2.04 (dm, J ) 17.0 Hz,
1H), 1.74 (m, 1H) 1.59 (m, 2H), 1.38 (m, 1H), 1.02 (m, 21H),
0.91 (t, J ) 7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 140.2,
129.5, 128.6, 128.3, 126.9, 124.3, 71.7, 60.6, 60.4, 58.7, 55.9,
39.9, 26.0, 21.1, 18.0, 12.0, 10.5; IR (neat) 3600-3200 (br),
2943, 2865, 1463 cm-1; [R]D25 ) +26.5° (c ) 0.0099, CHCl3);
MS (CI, NH3) m/z 432 (MH+, 100), 372 (47), 172 (10), 91 (2);
HRMS calcd for C26H46NO2Si (MH+) 432.3298, found 432.3305.
(1S,5R,9S)-1-Eth yl-4,5,6,7,8,9-h exah ydr o-3-oxo-5-[2-[(tr i-
isop r op ylsilyl)oxy]eth yl]-3H-oxa zolo[3,4-a ]p yr id in e (15).
The benzyl-protected amine 13 (56.6 mg, 0.131 mmol) was
dissolved in absolute ethanol (1 mL) and hydrogenated using
a Parr hydrogenator (35 psi of H2, 30 mg of Pd(OH)2) for 90
min at 50 °C. The reaction mixture was then cooled to room
temperature and diluted with CHCl3 (5 mL). The Pd(OH)2 was
then filtered from the reaction mixture and rinsed with CHCl3
(4 × 10 mL). The combined organic rinsings were dried
(K2CO3) and then concentrated to afford (1′S,2S,6R)-2-
(1-h ydr oxypr opyl)-6-[2-[(t r iisopr opylsilyl)oxy]et h yl]pip-
eridine (42.8 mg, 96%) as a light yellow oil: 1H NMR (300
MHz, CDCl3) δ 3.78 (m, 2H), 3.19 (dt, J ) 3.4, 7.7 Hz, 1H),
2.67 (m, 1H), 2.40 (tm, J ) 9.0 Hz, 1H), 1.82 (dm, J ) 13.1
Hz, 1H), 1.70-1.50 (m, 5H), 1.43-1.21 (m, 3H), 1.05 (m, 24
H), 0.97 (t, J ) 7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 75.8,
60.9, 60.8, 54.1, 40.2, 32.8, 29.0, 26.6, 24.6, 18.0, 12.0, 10.0;
IR (neat) 3500-3000 (br), 2940, 2866, 1463 cm -1; MS (CI,
NH3) m/z 344 (MH+, 100), 284 (23), 58 (23); HRMS calcd for
C
19H42NO2Si (MH+) 344.2985, found 344.2984; [R]2D5 ) -8.5°
(c ) 0.0192, CH2Cl2). Carbonyldiimidazole (12 mg, 0.07 mmol)
was carefully added to a solution of the above amino alcohol
(15.4 mg, 0.045 mmol) in CH3CN (0.15 mL) at 0 °C. The
resulting solution was stirred and gradually warmed (while
in cooling bath) to room temperature over 10 h. The reaction
mixture was then concentrated to afford 21.4 mg of crude
product. Flash chromatography (silica gel, 85:15 ethyl acetate/
hexanes) afforded cyclic carbamate 15 (6.8 mg, 40%, unopti-
mized) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 3.84
(m, 3H), 3.35 (m, 1H), 3.18 (apparent dt, J ) 11.6, 4.2 Hz,
1H), 2.77 (dm, J ) 5.0 Hz, 1H), 1.98-1.78 (m, 2H), 1.78-1.56
(m, 4H), 1.54-1.30 (m, 3H), 1.04 (bs, 21H), 0.99 (t, J ) 7.4
(1′R,2S,6S)-6-(1′-Hyd r oxyp r op yl)-1-(p h en ylm et h yl)-2-
[2-[(t r iisop r op ylsilyl)oxy]et h yl]-1,2,5,6-t et r a h yd r op yr i-
d in e (14). Rea ction of Ald eh yd e 11 w ith Eth yl Gr ign a r d .
A solution of dimethyl sulfoxide (1.22 mL, 15.1 mmol) in
CH2Cl2 (5 mL) was slowly added to a stirred solution of oxalyl
chloride (0.75 mL, 8.6 mmol) in CH2Cl2 (5 mL) at -62 °C
(CHCl3/CO2) over 5 min. A solution of 11 (692 mg, 1.72 mmol)
in CH2Cl2 (25 mL) was added to the reaction mixture, and the
resulting solution was stirred for 20 min at -62 °C. Triethyl-
amine (3.2 mL, 22.6 mmol) in CH2Cl2 (10 mL) was then added,
and the reaction mixture was stirred for 15 min at -62 °C
and then slowly warmed to room temperature over 75 min.
The reaction mixture was then poured into stirred pH 7
phosphate buffer (50 mL). The aqueous layer was extracted
with ether (4 × 40 mL), and the combined organic extracts
were washed with H2O (40 mL) and brine (40 mL) and dried
(K2CO3), and concentrated. The resulting aldehyde 12 (dark
yellow oil) was then immediately diluted with dry ether (10
mL) and added dropwise to a stirred -78 °C solution of
ethylmagnesium bromide (13.1 mL of a 2.3 M solution in THF,
1
Hz, 3H); H NMR (300 MHz, C6D6) δ 3.94 (m, 1H), 3.82 (m,
1H), 3.32 (dt, J ) 7.3, 5.1 Hz, 1H), 3.15 (m, 1H), 3.03 (m, 1H),
2.54 (dt, J ) 11.0, 4.4 Hz, 1H), 1.87 (m, 1H), 1.31 (m, 3H),
1.78-0.78 (m, 26 H), 0.67 (t, J ) 7.4 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 155.8, 80.3, 62.2, 60.4, 54.0, 34.7, 31.4, 30.6,
26.8, 23.8, 18.1, 12.0, 9.2; IR (neat) 2941, 2866, 1750, 1458 cm
-1; MS (CI, NH3) m/z 370 (MH+, 100), 326 (36); HRMS calcd
for C20H40NO3Si (MH+) 370.2778, found 370.2778; [R]2D5
-32.0° (c ) 0.0083, CH2Cl2).
)
(1R,5R,9S)-1-Eth yl-4,5,6,7,8,9-h exah ydr o-3-oxo-5-[2-[(tr i-
isop r op ylsilyl)oxy]eth yl]-3H-oxa zolo[3,4-a ]p yr id in e (16).
A suspension of benzyl-protected amine 14 (68.4 mg, 0.158

Asymmetric Synthesis of (-)-Methyl Palustramate
J . Org. Chem., Vol. 63, No. 21, 1998 7495
mmol), Pd/C (60 mg), and anhydrous K2CO3 (41 mg) in ether
was stirred for 2 h. The solids were removed by filtration and
rinsed with CHCl3 (5 × 5 mL), and the combined rinsings were
concentrated. The above process was repeated one additional
time. The benzyl-protected amine was then diluted with
absolute ethanol (1.2 mL) and hydrogenated using a Parr
hydrogenator (35 psi of H2, 34 mg of Pd(OH)2) for 90 min at
50 °C. The reaction mixture was then cooled, anhydrous
K2CO3 (20 mg) was added, followed by CHCl3 (5 mL). The
solids were then removed by filtration and rinsed with CHCl3
(4 × 10 mL). The combined organic rinsings were dried
(K2CO3) and concentrated to afford the crude product as a light
yellow oil. Flash chromatography (silica gel, 60:40 ethyl
acetate/hexanes) afforded (1′R,2S,6R)-2-(1′-hydroxypropyl)-6-
[2-[(triisopropylsilyl)oxy]ethyl]piperidine (46.6 mg, 86%) as a
colorless oil: 1H NMR (300 MHz, CDCl3) δ 3.82 (m, 4H), 3.58
(m, 1H), 2.90 (m, 1H), 2.72 (m, 1H), 1.86-1.17 (m, 10H), 1.05
(m, 21H), 0.96 (t, J ) 7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3)
δ 74.6, 61.2, 60.6, 55.9, 38.7, 31.6, 25.6, 23.8, 23.4, 18.0, 11.9,
10.6; IR (neat) 3382-3354 (br), 2940, 1462 cm-1; MS (CI, CH4)
g, 16.3 mmol) and N,O-dimethylhydroxylamine hydrochloride
(2.12 g, 21.7 mmol) were added sequentially. The mixture was
stirred at room temperature for 12 h and then poured into a
stirred solution of ether/pH 6 buffer (1:1, v/v, 30 mL). The
aqueous layer was extracted with ether (3 × 40 mL), and then
the combined organic extracts were washed with H2O (50 mL)
and brine (50 mL), dried (Na2SO4), and concentrated to afford
crude product 19 (2.82 g) as a light yellow oil. Flash chroma-
tography (silica gel, 75:25:3 hexanes/ethyl acetate/triethy-
lamine) afforded product 19 (1.38 g, 76% from lactone 8) as a
clear oil: 1H NMR (300 MHz, CDCl3) δ 7.35 (d, J ) 6.9 Hz,
2H), 7.25 (m, 3H), 5.86 (bd, J ) 8.8 Hz, 1H), 5.71 (d, J ) 9.8
Hz, 1H), 3.85 (bs, 3H), 3.68 (m, 2H), 3.56 (bs, 3H), 3.58-3.45
(bm, 1H), 3.13 (bs, 3H), 2.45-2.30 (bs, 1H), 2.19 (dd, J ) 15.1,
2.2 Hz, 1H), 1.82 (m, 1H), 1.64 (m, 1H), 1.01 (bs, 21H); 13C
NMR (75 MHz, CDCl3) δ 140 (br), 129.1, 128.5, 128.0, 126.8,
123.4, 61 (br), 60.6, 57.3, 56.1, 37.4, 33 (br), 24 (br), 18.0, 17.7,
12.3, 12.0; IR (neat) 2958, 1672, 1463 cm-1; [R]D25 ) +28.6° (c
) 0.0180, CH2Cl2).
(2S,6S)-1-(P h en ylm eth yl)-6-(1-oxop r op yl)-2-[2-[(tr iiso-
pr opylsilyl)oxy]eth yl]-1,2,5,6-tetr ah ydr opyr idin e (20). Eth-
ylmagnesium bromide (5.6 mL of a 2.13 M solution in THF,
11.8 mmol) was slowly added to a solution of amide 19 (0.779
g, 1.69 mmol) in THF (13 mL) at 0 °C. The resulting solution
was carefully maintained at 0 °C and stirred for 6 h. The
reaction mixture was then poured into pH 7 buffer (20 mL) at
0 °C and the aqueous phase extracted with CH2Cl2 (3 × 20
mL). The combined organic extracts were then washed with
H2O (50 mL), dried (Na2SO4), and concentrated to afford the
unstable ketone 20 as a yellow oil, which was immediately
used in the next step. An analytical sample was obtained by
concentration of a similar reaction mixture to afford 20 as a
yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.40 (m, 2H), 7.29
(m, 3H), 5.87 (dm, J ) 10.3 Hz, 1H), 5.64 (dm, J ) 10.3 Hz,
1H), 3.86 (s, 2H), 3.84-3.65 (m, 2H), 3.38-3.32 (m, 2H), 2.94-
2.80 (dq, J ) 17.6, 7.4 Hz, 1H), 2.41-2.32 (m, 1H), 2.30-2.24
(q, J ) 7.3 Hz, 1H), 2.14-2.04 (dm, 1H), 1.62-1.41 (m, 2H),
1.02 (bs, 21H), 0.93 (t, J ) 7.3 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 212.9, 139.4, 129.1, 128.3, 127.2, 123.4, 62.6, 60.5,
55.5, 38.3, 32.1, 19.5, 18.0, 12.0, 8.0; IR (neat) 2866, 1719, 1462
cm-1; [R]2D5 ) +15.1° (c ) 0.0351, CH2Cl2).
m/z 344 (MH+, 53), 300 (33), 284 (100); HRMS calcd for C19H42
-
NO2Si (MH+) 344.2985, found 344.2999; [R]25 ) -8.1° (c )
0.036, CHCl3). Carbonyldiimidazole (16 mg, D0.16 mmol) was
carefully added to a solution of the above amino alcohol (35
mg, 0.10 mmol) in CH3CN (0.2 mL) at 0 °C. The resulting
solution was stirred and slowly warmed to room temperature
over 10 h. The reaction mixture was then concentrated to
afford crude product. Flash chromatography (silica gel, 15:
85 ethyl acetate/hexanes) afforded the cyclic carbamate 16 (23
mg, 61%, unoptimized) as a colorless oil: 1H NMR (500 MHz,
CDCl3) δ 4.25 (dt, J ) 8.7, 6.1 Hz, 1H), 3.80 (m, 2H), 3.43 (m,
2H), 2.68 (m, 1H), 1.97 (m, 1H), 1.86-1.79 (ddd, J ) 8.6, 5.4,
2.6 Hz, 1H), 1.76-1.69 (m, 1H), 1.66 (dd, J ) 13.4, 2.9 Hz,
1H, CH), 1.59-1.36 (m, 5H), 1.08-1.03 (21H), 1.01 (t, J ) 7.4
Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 156.3, 77.9, 61.2, 60.2,
54.4, 34.9, 30.8, 24.3, 24.0, 21.7, 18.0, 12.0, 10.2; 1H NMR (300
MHz, C6D6) δ 3.92 (m, 1H), 3.80 (m, 1H), 3.73 (partially
obscured dt, J ) 8.5, 6.0 Hz, 1H), 3.21 (m, 1H), 2.97 (apparent
octet, J ) 4.6 Hz, 1H), 2.71 (m, 1H), 1.86 (ddd, J ) 8.5, 5.2,
2.1 Hz, 1H), 1.45-0.8 (m, 29 H), 0.65 (t, J ) 7.4 Hz, 3H); IR
(neat) 2941, 2866, 1754 cm-1; MS (CI, CH4) m/z 370 (MH+,
14), 327 (24), 326 (100), 196 (38); HRMS calcd for C20H40NO3-
Si (MH+) 370.2778, found 370.2793; [R]2D5 ) -36.1° (c )
0.0160, CH2Cl2).
(1′S,2S,6S)-6-[1′-(Meth oxym eth oxy)p r op yl]-1-(p h en yl-
m eth yl)-2-[2-[(tr iisopr opylsilyl)oxy]eth yl]-1,2,5,6-tetr ah y-
d r op yr id in e (21). Bromomethyl methyl ether (0.40 mL, 4.9
mmol) was added dropwise to a 0 °C solution of the secondary
alcohol 13 (1.33 g, 3.08 mmol) and N,N-diisopropylethylamine
(1.2 mL, 6.6 mmol) in CH2Cl2 (10 mL). The mixture was then
warmed to room temperature and stirred for 4 h. An ad-
ditional portion of bromomethyl methyl ether (0.26 mL, 3.2
mmol) was then subsequently added and the mixture stirred
for an additional 3 h. The reaction mixture was then diluted
with CH2Cl2 (10 mL) and poured into a stirred solution of
saturated aqueous NaHCO3 (10 mL). The aqueous layer was
extracted with CH2Cl2 (3 × 25 mL); then the combined organic
extracts were washed with H2O (35 mL), dried (Na2SO4), and
concentrated to afford the crude product (1.51 g) as a dark
oil. Flash chromatography (silica gel, 9:1:0.2 hexanes/ethyl
acetate/triethylamine) afforded the MOM ether 21 as a color-
less oil (1.21 g, 83%): 1H NMR (300 MHz, CDCl3) δ 7.38 (m,
2H), 7.25 (m, 3H), 5.84 (m, 1H), 5.73 (dm, J ) 9.9 Hz, 1H),
4.57 (AB q, J ) 6.8 Hz, ∆v ) 19.0 Hz, 2H), 3.82 (partially
obscured AB q, J ) 15.4 Hz, ∆v ) 31.4 Hz, 2H), 3.72 (m, 2H),
3.56 (m, 1H), 3.36 (partially obscured bs, 1H), 3.36 (s, 3H),
2.95 (m, 1H), 2.08 (m, 2H), 1.86 (m, 1H), 1.65 (m, 2H), 1.28
(m, 1H), 1.03 (s, 21H), 0.68 (t, J ) 7.3 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 141.2, 129.7, 128.4, 128.0, 126.5, 124.6, 96.6,
81.3, 60.8, 60.4, 57.8, 57.5, 55.6, 38.6, 23.4, 23.3, 18.0, 12.0,
10.2; IR (neat) 2942, 2866, 1457 cm-1; MS (CI, NH3) m/z 476
(MH+, 100), 372 (31), 359 (15), 299 (17), 91 (22); HRMS calcd
(2S,6S)-6-[[(Meth oxym eth yl)a m in o]ca r bon yl]-1-(p h en -
ylmethyl)-2-[2-[(2-triisopropylsilyl)oxy]ethyl]-1,2,5,6-tetrahy-
d r op yr id in e (19). Crude pipecolic ester 10 from above (2.17
g, 3.79 mmol) was dissolved in absolute ethanol (15 mL), THF
(5 mL), and H2O (5 mL). Solid K2CO3 (10 g) was then added
and the resulting suspension stirred at room temperature for
5 h. The solids were then rinsed with EtOH and the combined
organic rinsings concentrated. The resulting oil was then
diluted with CH2Cl2 (20 mL) and poured into stirred pH 7
buffer/CH2Cl2 (1:1, v/v, 100 mL). The aqueous layer was then
extracted with CH2Cl2 (5 × 100 mL). The combined organic
extracts were dried (Na2SO4) and then concentrated to yield
the crude product (2S,6S)-1-(phenylmethyl)-2-[2-[(triisopro-
pylsilyl)oxy]ethyl]-1,2,5,6-tetrahydropyridine-6-carboxylic acid
(2.27 g) as a yellow oil (containing silanol) that was used
without further purification: 1H NMR (300 MHz, CDCl3) δ 7.45
(m, 2H), 7.33 (m, 3H), 6.75-6.45 (bs, 1H), 5.94 (m, 1H), 5.76
(dm, J ) 10.1 Hz, 1H), 4.18 (AB q, J ) 13.5 Hz, ∆v ) 67.6 Hz,
2H), 3.86 (m, 1H), 3.75 (m, 2H), 3.56 (t, J ) 6.0 Hz, 1H), 2.68
(dm, J ) 17.7 Hz, 1H), 2.42 (dm, J ) 17.6 Hz, 1H), 2.07 (m,
1H), 1.86 (m, 1H), 1.04 (m, 21H); 13C NMR (75 MHz, CDCl3)
δ 174.2, 139.2, 129.9, 128.8, 128.1, 126.8, 122.6, 60.7, 58.2, 57.6,
55.0, 36.7, 25.8, 18.0, 17.9, 12.0, 12.0; IR (neat) 3600-2400
(br), 2866, 1653 cm-1; MS (DCI, NH3) m/z 418 (MH+, 100), 216
(50), 148 (55), 131 (18); HRMS calcd for C24H40NO3Si (MH+)
418.2777, found 418.2776; [R]2D5 ) +21.6° (c ) 0.0231, CH2-
Cl2). Carbonyldiimidazole (2.64 g, 16.3 mmol) was carefully
added to a stirred solution of the above crude acid (2.27 g, 5.44
mmol) in CH2Cl2 (40 mL) at 0 °C. The resulting solution was
stirred for 1 h at room temperature, and then imidazole (1.11
for C28H50NO3Si (MH+) 476.3560, found 476.3562; [R]2D5
+16.8° (c ) 0.0498, CHCl3).
)
(1′S,2S,6S)-6-[1′-(Met h oxym et h oxy)p r op yl]-2-[2-[(t r i-
isop r op ylsilyl)oxy]eth yl]-1,2,5,6-tetr a h yd r op yr id in e (22).
Lithium (0.875 g, 127 mmol) was added to a stirred, room-

7496 J . Org. Chem., Vol. 63, No. 21, 1998
Angle and Henry
temperature solution of benzyl-protected amine 21 (1.21 g, 2.54
mmol) and triethylamine (20 mL) in THF (10 mL). Ethylene-
diamine (2.0 mL) was then added dropwise. After 140 min,
the dark brown solution was cooled in an ice bath to 0 °C. The
reaction mixture was then carefully quenched with saturated
aqueous NH4Cl (30 mL), followed by dilution with H2O (30
mL) and CHCl3 (30 mL). After it was stirred for 10 min at
room temperature, the mixture was basified with Na2CO3 (3
g) until a pH of 10 was achieved (pH paper). The aqueous
layer was then extracted with CHCl3 (5 × 50 mL). The
combined organic extracts were dried (K2CO3) and concen-
trated to yield the crude product (1.07 g) as a light yellow oil.
Flash chromatography (silica gel, gradient 90:10 to 65:35
hexanes/ethyl acetate) afforded 22 as a colorless oil (698 mg,
71%): 1H NMR (300 MHz, CDCl3) δ 5.71 (m, 1H), 5.62 (dm, J
) 10.0 Hz, 1H), 4.70 (AB q, J ) 6.7 Hz, ∆v ) 5.9 Hz, 2H), 3.83
(t, J ) 5.9 Hz, 2H), 3.57 (bm, 1H), 3.40 (partially obscured m,
1H), 3.40 (s, 3H), 2.87 (m, 1H), 2.15-1.85 (bs, 3H), 1.80-1.58
(m, 3H), 1.55-1.41 (m, 1H), 1.06 (s, 21H), 0.92 (t, J ) 7.4 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ 131.2, 124.5, 96.5, 82.9, 60.4,
55.8, 55.1, 52.0, 39.4, 28.5, 22.9, 18.4, 12.0, 8.6; IR (neat) 2942,
2866, 1464 cm-1; MS (CI, NH3) m/z 386 (MH+, 100), 282 (18),
108 (4); HRMS calcd for C21H44NO3Si (MH+) 386.3084, found
386.3090; [R]D25 ) -13.2° (c ) 0.0093, CH2Cl2).
(1′S,2S,6S)-2-(2-Hydr oxyeth yl)-6-[1′-(m eth oxym eth oxy)-
propyl]-1-[[(2′′,2′′,2′′-trichloroethyl)oxy]carbonyl]-1,2,5,6-tetrahy-
d r op yr id in e (23). Amine 23 (698 mg, 1.81 mmol) was
dissolved in pyridine (15 mL) and the resulting solution cooled
to 0 °C. TROC-Cl (1.24 mL, 9.03 mmol) was added, and the
mixture was stirred at room temperature for 4.25 h. The
mixture was then poured into a stirred solution of ether and
saturated aqueous Na2CO3 (1:1, v/v, 25 mL). The aqueous
layer was then extracted with CHCl3 (3 × 30 mL), and the
combined organic extracts were washed with H2O (100 mL),
dried (K2CO3), and concentrated to afford the crude material
(1.63 g) as a dark oil. Flash chromatography (silica gel, 90:10
hexanes/ethyl acetate) afforded the product (1′S,2S,6S)-6-
[1′-(methoxymethoxy)propyl]-1-[[(2′′,2′′,2′′-trichloroethyl)-
oxy]carbonyl]-2-[2-[(triisopropylsilyl)oxy]ethyl]-1,2,5,6-tetra-
hydropyridine (945 mg, 93%) as a clear oil: 1H NMR (300 MHz,
CDCl3) δ 5.88 (dt, J ) 10.4, 2.9 Hz, 1H), 5.72 (bm, 1H), 4.90-
4.67 (m, 2H), 4.64 (s, 2H), 4.57 (t, J ) 7.2 Hz, 1H), 4.46 (m,
1H), 3.88 (m, 2H), 3.60 (dt, J ) 12.2, 4.6 Hz, 1H), 3.52 (s, 3H),
2.39 (bd, J ) 15.3 Hz, 1H), 2.12 (dd, J ) 17.3, 6.0 Hz, 2H),
1.93-1.73 (bm, 2H), 1.48 (m, 1H), 1.05 (s, 21H), 0.95 (t, J )
7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3) mixture of rotational
isomers δ 154.4, 127.8 (br), 121.0, 96.7, 95.9, 80.7 (br), 75.3,
62.1, 56.0, 51.3, 50.8, 39.0, 25.2, 24.4, 18.1, 12.1, 9.1 (br); IR
(neat) 2943, 2867, 1711, 1034 cm-1; MS (CI, NH3) m/z 562
(MH+, 100), 560 (MH+, 96), 528 (21), 520 (19), 518 (54), 516
(52), 458 (17), 256 (18); HRMS calcd for C24H45NO5SiCl3 (MH+)
560.2133, found 560.2116; [R]2D5 ) +27.1° (c ) 0.0379, CHCl3).
The above TIPS ether (945 mg, 1.68 mmol) was dissolved in
THF (6.0 mL) and cooled to 0 °C. HF-pyridine (1.6 mL of a
solution containing ∼30% HF and ∼70% pyridine, Aldrich
Chemical Co.) was added dropwise and the mixture stirred at
room temperature for 3 h. The mixture was then diluted with
CH2Cl2 and poured into a stirred solution of saturated aqueous
Na2CO3 and CH2Cl2 (1:1, v/v, 20 mL) at 0 °C. The aqueous
layer was extracted with CH2Cl2 (4 × 40 mL), and then the
combined organic extracts were washed with H2O (75 mL),
dried (K2CO3), and concentrated to afford crude material (676
mg) as a light yellow oil. Flash chromatography (silica gel,
50:50 hexanes/ethyl acetate) afforded alcohol 23 (663 mg, 98%)
as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 5.75 (m, 1H),
5.67 (m, 1H), 4.82 (partially obscured AB q, J ) 11.8 Hz, ∆v
) 63.1 Hz, 2H), 4.62 (m, 4H), 3.78-3.58 (m, 4H), 3.36 (s, 3H),
2.39 (dm, J ) 17.6 Hz, 1H), 2.10 (dd, J ) 17.6, 5.7 Hz, 1H),
1.95-1.65 (m, 3H), 1.55-1.42 (m, 1H), 0.95 (t, J ) 7.4 Hz, 3H);
13C NMR (125 MHz, CDCl3, 45 °C) δ 155.7, 127.9, 121.6, 96.6,
95.6, 79.5, 75.3, 58.8, 56.1, 50.6, 49.3, 38.6, 25.2, 24.2, 7.6; IR
(neat) 3650-3180 (br), 2951, 2885, 1708 cm-1; MS (CI, NH3)
m/z 406 (MH+, 91), 404 (MH+, 100), 374 (62), 372 (70), 192
(22), 120 (27); HRMS calcd for C15H25NO5Cl3 (MH+) 404.0798,
found 404.0788; [R]D25 ) +40.1° (c ) 0.0352, CH2Cl2).
(1′S ,2S ,6S )-2-{(Ca r b om e t h oxy)m e t h yl]-6-[1′-(m e t h -
oxym eth oxy)p r op yl]-1-[[(2′′,2′′,2′′-tr ich lor oeth yl)oxy]ca r -
bon yl]-1,2,5,6-tetr a h yd r op yr id in e (24). Primary alcohol 23
(113 mg, 0.278 mmol) was dissolved in DMF (1.5 mL) at room
temperature. Pyridinium dichromate (PDC; 523 mg, 1.39
mmol) was then added, and the mixture was stirred for 30 h
and then concentrated. NaHSO3 (1 g), pH 7 buffer, and CH2Cl2
(1:2, v/v, 30 mL) were sequentially added, and the mixture
was stirred for 10 min. The aqueous layer was then extracted
with CH2Cl2 (4 × 25 mL), and the combined organic extracts
were dried (Na2SO4). Filtration of the solids through Celite,
followed by concentration, afforded crude (1′S,2S,6S)-2-(car-
boxymethyl)-6-[1′-(methoxymethoxy)propyl]-1-[[(2′′,2′′,2′′-trichlo-
roethyl)oxy]carbonyl]-1,2,5,6-tetrahydropyridine (997 mg, 85%)
as a yellow oil that was used without further purification: 1H
NMR (300 MHz, CDCl3, mixture of rotational isomers) δ
10.00-8.00 (vb, 1H), 5.78 (bm, 2H), 4.88 (bm, 3H), 4.62 (m,
3H), 3.53 (m, 1H), 3.36 (s, 3H), 3.00 (m, 1H), 2.86 (m, 1H),
2.42 (m, 1H), 2.14 (dd, J ) 17.2, 3.5 Hz, 1H), 1.65 (m, 1H),
1.46 (m, 1H), 0.95 (m, 3H); 13C NMR (75 MHz, CDCl3, mixture
of rotational isomers) δ 176.5, 154.3, 125.9, 125.1, 122.8, 122.6,
122.4, 96.2, 96.0, 95.4, 81.6, 80.1, 75.1, 56.1, 50.2, 49.9, 48.8,
48.3, 39.5, 38.7, 25.7, 25.5, 24.3, 9.0, 8.1; IR (neat) 3400-2900
(br), 2942, 1708 cm-1; [R]D25 ) +61.9° (c ) 0.0163, CH2Cl2).
Carbonyldiimidazole (CDI; 841 mg, 5.18 mmol) was carefully
added to a stirred solution of the above crude acid (435 mg,
1.04 mmol) in CH2Cl2 (5 mL) at 0 °C. The solution was
warmed to room temperature and stirred for 2 h. Imidazole
(141 mg, 2.07 mmol) and methanol (0.84 mL, 21 mmol) were
then added sequentially. The mixture was then stirred at
room temperature for 19 h, concentrated, and dried in vacuo
(0.3 mmHg, 1 h). The solid residue was diluted with ethyl
acetate (10 mL) and then poured into a stirred solution of ethyl
acetate and pH 7 buffer (1:1, v/v, 30 mL) at room temperature.
The aqueous layer was extracted with ethyl acetate (3 × 15
mL), and the combined organic extracts were washed with H2O
(40 mL), dried (K2CO3), and concentrated to afford the crude
product (525 mg) as a yellow oil. Flash chromatography (silica
gel, 85:15 hexanes/ethyl acetate) afforded ester 20 (315 mg,
70%) as a colorless oil: 1H NMR (300 MHz, CDCl3, mixture of
rotational isomers) δ 5.83-5.69 (m, 2H), 4.99-4.72 (m, 2H),
4.62 (apparent q, J ) 7.0 Hz, 2H), 4.62 (obscured m, 2H), 3.69
(s, 3H), 3.53 (m, 1H), 3.36 (s, 3H), 3.01-2.50 (m, 2H), 2.51-
2.08 (m, 2H), 1.85-1.60 (m, 1H), 1.55-1.40 (m, 1H), 0.95 (t, J
) 7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3, mixture of rotational
isomers) δ 171.6, 154.2, 126.1, 125.3, 122.4, 96.4, 96.3, 81.4,
80.1, 75.1, 56.1, 51.5, 50.2, 50.0, 49.0, 48.5, 39.6, 38.6, 25.7,
24.3, 8.9, 8.1; IR (neat) 2952, 1738, 1711 cm-1; MS (DCI, NH3)
m/z 434 (MH+, 20), 432 (MH+, 21) 402 (100), 400 (99), 258 (33),
256 (16), 254 (14); HRMS calcd for C16H25NO6Cl3 (MH+)
432.0748, found 432.0734; [R]2D5 ) +69.0° (c ) 0.0148, CH2Cl2).
(-)-Meth yl P a lu str a m a te (3). Zinc (300 mg, excess) and
aqueous KH2PO4 (0.1 mL, 1 M solution) were added to a stirred
solution of 24 (41.6 mg, 0.097 mmol) in THF (0.20 mL). The
reaction mixture was then stirred for 15 h at room tempera-
ture. It was then diluted with CHCl3 and saturated aqueous
Na2CO3 (1:1, v/v, 5 mL). The aqueous layer was extracted with
CHCl3 (4 × 10 mL), and the combined organic extracts were
washed with H2O (30 mL), dried (K2CO3), and concentrated
to afford the crude product (37.2 mg) as a light yellow oil. Flash
chromatography (neutral alumina, 96:4 hexanes/ethyl acetate)
afforded (1′S,2S,6S)-2-[(carbomethoxy)methyl]-6-[(1′-meth-
oxymethoxy)propyl]-1,2,5,6-tetrahydropyridine (18.3 mg, 74%)
as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 5.78 (m, 1H),
5.51 (dm, J ) 9.9 Hz, 1H), 4.70 (AB q, J ) 6.7 Hz, ∆v ) 11.0
Hz, 2H), 3.81 (bm, 1H), 3.68 (s, 3H), 3.41 (s, 3H), 3.37 (partially
obscured m, 1H), 2.89 (m, 1H), 2.47 (m, 2H), 1.91 (m, 3H), 1.73
(m, 1H), 1.50 (m, 1H), 0.93 (t, J ) 7.4 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 172.4, 129.3, 125.9, 96.5, 82.5, 55.9, 54.8, 51.5,
51.4, 40.9, 28.3, 22.9, 8.6; IR (neat) 2933, 1738, 1438 cm-1
MS (DCI, NH3) m/z 258 (MH+, 100), 154 (38), 80 (35); HRMS
calcd for C13H24NO4 (MH+) 258.1705, found 258.1704; [R]2D5
;
)

Asymmetric Synthesis of (-)-Methyl Palustramate
J . Org. Chem., Vol. 63, No. 21, 1998 7497
-26.6° (c ) 0.0044, CH2Cl2). MgBr2 (55 mg, 0.30 mmol) and
butanethiol (0.27 mL, 0.23 mmol) were sequentially added to
a solution of the above amine (17.2 mg, 0.067 mmol) in ether
(0.5 mL). The reaction mixture was stirred for 39 h at room
temperature and then diluted with ether (3 mL) and saturated
aqueous Na2CO3 (3 mL). It was then extracted with CHCl3
(4 × 5 mL), and the combined organic extracts were dried
(K2CO3) and concentrated to afford the crude material (24.9
mg) as a yellow oil. Flash chromatography (neutral alumina,
80:20 hexanes/ethyl acetate) afforded (-)-methyl palustramate
(3; 11 mg, 76%) as a colorless oil: 1H NMR (500 MHz, CDCl3)
δ 5.81 (m, 1H), 5.60 (dt, J ) 9.3, 2.0 Hz, 1H), 3.76 (bs, 1H),
3.68 (s, 3H), 3.25 (dt, J ) 3.3, 8.1 Hz, 1H), 2.96 (bs, 1H), 2.68
(ddd, J ) 11.6, 8.0, 4.2 Hz, 1H), 2.50 (dd, J ) 15.7, 5.4 Hz,
1H), 2.44 (dd, J ) 15.7, 8.3 Hz, 1H), 2.03-1.93 (dm, J ) 18.3
Hz, 1H), 1.90-1.68 (m, 2H), 1.66-1.57 (dp, J ) 7.6, 3.3 Hz,
1H), 1.43-1.35 (sept, J ) 7.4 Hz, 1H), 0.99 (t, J ) 7.9 Hz,
3H); 13C NMR (125 MHz, CDCl3) δ 172.3, 129.8, 126.3, 75.6,
57.3, 51.6, 51.4, 40.5, 28.0, 26.0, 9.7; 1H NMR (500 MHz, C6D6)
δ 5.58 (m, 1H), 5.42 (m, 1H), 3.68 (m, 1H), 3.29 (s, 3H), 3.06
(dt, J ) 8.0, 3.2 Hz, 1H), 2.52 (dd, J ) 14.5, 7.7 Hz, 1H), 2.28
(dd, J ) 15.7, 7.7 Hz, 1H), 2.18 (dd, J ) 15.7, 5.0 Hz, 1H),
1.61 (m, 2H), 1.37 (d sextet, J ) 7.6, 3.2 Hz, 1H), 1.24 (septet,
J ) 7.3 Hz, 1H), 0.96 (t, J ) 7.3 Hz, 3H); 13C NMR (125 MHz,
C6D6) δ 171.8, 130.2, 126.4, 75.6, 57.7, 51.8, 50.9, 40.8, 28.3,
26.5, 9.9; IR (neat) 3315, 3309, 2959 1734 cm-1; MS (CI, NH3)
m/z 214 (MH+, 100), 154 (22), 140 (8), 80 (26); HRMS calcd
OH) afforded an analytical sample of (-)-methyl dihydropalus-
tramate (4) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ
3.68 (s, 3H, OCH3), 3.26 (dt, J ) 3.7, 10.2 Hz, 1H), 2.97 (m,
1H), 2.52 (m, 1H), 2.44 (d, J ) 6.6 Hz, 2H), 2.20-1.70 (partially
obscured vb, 2H), 1.85 (dt, J ) 13.2, 3.1 Hz, 2H), 1.65 (bd, J )
14.0 Hz, 1H), 1.61-1.50 (m, 1H), 1.51-1.30 (m, 2H), 1.27-
1.06 (dp, J ) 12.0, 3.4 Hz, 2H), 0.98 (t, J ) 7.4 Hz, 3H); 13C
NMR (125 MHz, CDCl3) δ 172.7, 75.8, 60.5, 53.1, 51.5, 41.5,
32.2, 28.4, 26.6, 24.2, 9.9; 1H NMR (300 MHz, C6D6) δ 3.25 (s,
3H), 3.08 (dt, J ) 8.5, 3.6 Hz, 1H), 2.74 (m, 1H), 2.95-2.18
(dd, J ) 15.8, 8.2 Hz, 1H), 2.23 (obscured m, 1H), 2.16-2.08
(dd, J ) 15.7, 5.1 Hz, 1H), 1.55-0.75 (m, 10H), 0.96 (t, J )
7.3 Hz, 3H); 13C NMR (75 MHz, C6D6) δ 172.3, 75.6, 61.1, 53.3,
51.0, 41.5, 32.4, 28.8, 27.1, 24.6, 10.4; IR (neat) 3700-3050
(br), 2933, 1736 cm-1; MS (CI, NH3) m/z 216 (MH+, 100), 198
(6), 156 (27); HRMS calcd for C11H22NO3 (MH+) 216.1600,
found 216.1598; [R]D25 ) -26.4° (c ) 0.0014, CH3OH); lit.7
[R]D16 ) -22.1° (c ) 0.8 mg/mL, CH3OH); lit.3d [R]2D2 ) -23° (c
) 2.45 mg/mL, CH3OH).
Ack n ow led gm en t . We thank Drs. J ames Guy
Breitenbucher and J ames P. Boyce for early work on
this project. Acknowledgment is made to the National
Science Foundation (Grant No. 9528266) and for an A.
P. Sloan Foundation Research Fellowship (to S.R.A.;
1993-1997).
for C11H20NO3 (MH+) 214.1443, found 214.1445; [R]25 ) -18.2°
D
(c ) 0.0044, CH2Cl2).
(-)-Meth yl Dih yd r op a lu str a m a te (4). (-)-Methyl palus-
tramate (3; 10 mg, 0.046 mmol) was added to CD3OD (0.7 mL)
and the reaction mixture hydrogenated using a Parr hydro-
genator (16 psi of H2, 5 mg of Pd(OH)2) for 35 min. The
reaction mixture was then diluted with CH2Cl2 (2 mL), and
K2CO3 (15 mg) was added. The solids were rinsed with CH2Cl2
(6 × 5 mL) and the combined organic rinsings concentrated
to afford crude material (4.5 mg, 45%; unoptimized) as a light
yellow oil. Flash chromatography (silica gel, 9:1 CHCl3/CH3-
Su p p or tin g In for m a tion Ava ila ble: Figures giving NMR
spectra and a tabular comparison of spectral data for our
synthetic 4 with those in the literature (59 pages). This
material is contained in many libraries on microfiche, im-
mediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
J O980749G