Asymmetric synthesis of (-)-swainsonine

Article abstract of DOI:10.1021/jo802800d

(Chemical Equation Presented) We report a new asymmetric synthetic method for (-)-swainsonine utilizing a chiral oxazoline precursor. The key features in this strategy are the diastereoselective oxazoline formation reaction catalyzed by palladium(0), dias

Full text of DOI:10.1021/jo802800d

Asymmetric Synthesis of (-)-Swainsonine
Yong-Shou Tian,† Jae-Eun Joo,† Bae-Soo Kong,†
Van-Thoai Pham,† Kee-Young Lee,‡ and Won-Hun Ham*,†
FIGURE 1. The structure of (-)-swainsonine.
College of Pharmacy, Sung Kyun Kwan UniVersity,
Suwon 440-746, Korea, and Yonsung Fine Chemicals Co.,
Ltd., 129-9 Suchon-ri, Jangan-myeon, Hwaseong-si,
Gyeonggi-do 445-944, Korea
SCHEME 1. Palladium-Catalyzed Oxazoline Formation
whham@skku.edu
ReceiVed January 19, 2009
(Scheme 1).7 We have also been exploring the utility of
enantiopure oxazoline as a chiral building block for the
stereocontrolled synthesis of natural products.8 As part of this
program, we have developed a novel strategy for stereoselective
synthesis of (-)-swainsonine. Herein we describe the novel
asymmetric synthesis of (-)-swainsonine utilizing an oxazoline
as a chiral building block.
As shown in Scheme 2, our retrosynthetic analysis suggested
that (-)-swainsonine (1) could be synthesized by mesylation,
hydrogenolysis, and deprotection of 2. Also, it was anticipated
that 3 could be converted to 2 in two steps (mesylation and
cyclization).
We report a new asymmetric synthetic method for (-)-
swainsonine utilizing a chiral oxazoline precursor. The key
features in this strategy are the diastereoselective oxazoline
formation reaction catalyzed by palladium(0), diasteroselec-
tive dihydroxylation, and the stereocontrolled allylation
reaction with TiCl4.
We focused our initial efforts upon the enantioselective
synthesis of the primary alcohol 3, hypothesizing that it would
be accessible via the protection and oxidation of the anti-amino
alcohol 4.
The primary alcohol 5 would be converted to the aldehyde,
which would then be employed in diastereoselective anti-amino
alcohol formation by using TiCl4-mediated allyltrimethylsilane
addition. The primary alcohol 5 could be synthesized by
diastereoselective dihydroxylation of the syn-amino alcohol 6,
(-)-Swainsonine was first isolated from the fungus Rhizoc-
tonia leguminicola in 19731 and later found in several plants
and fungi.2 (-)-Swainsonine (1, Figure 1) exhibits lysosomal
R-mannosidase and mannosidase II inhibitory properties3 and
has been tested as a treatment for cancer, HIV, and im-
munological disorders.4 (-)-Swainsonine was the first glyco-
protein processing inhibitor to be selected for clinical testing
as an anticancer drug, reaching phase II clinical trials.5 A number
of synthetic approaches have been reported due to its novel
indolizidine structure and its promising biological activity.6
Over the past several years, we have been investigating the
stereoselective intramolecular cyclization of homoallyl benza-
mide through a π-allylpalladium complex catalyzed by Pd(0)
(6) For a review of swainsonine syntheses, see: (a) Nemr, A. E. Tetrahedron
2000, 56, 8579. (b) Pyne, S. G. Curr. Org. Synth. 2005, 2, 39. For more recent
syntheses, see: (c) Martin, R.; Murruzzu, C.; Pericas, M. A.; Riera, A. J. Org.
Chem. 2005, 70, 2325. (d) Kadlecikova, K.; Dalla, V.; Marchalin, S.; Decroix,
B.; Baran, P. Tetrahedron 2005, 61, 4743. (e) Tinarelli, A.; Paolucci, C. J. Org.
Chem. 2006, 71, 6630. (f) Pyne, S. G.; Au, C. W. G. J. Org. Chem. 2006, 71,
7097. (g) Ceccon, J.; Greene, A. E.; Poisson, J. F. Org. Lett. 2006, 8, 4739. (h)
Guo, H.; O’Doherty, G. A. Org. Lett. 2006, 8, 1609. (i) Dechamps, I.; Pardo,
D. G.; Cossy, J. ArkiVoc 2007, 5, 38. (j) Dechamps, I.; Pardo, D. G.; Cossy, J.
Tetrahedron 2007, 63, 9082. (k) Guo, H.; O’Doherty, G. A. Tetrahedron 2008,
64, 304. (l) Sharma, P. K.; Shah, R. N.; Carver, J. P. Org. Process Res. DeV.
2008, 12, 831. (m) Shi, G. F.; Li, J. Q.; Jiang, X. P.; Cheng, Y. Tetrahedron
2008, 64, 5005.
† Sung Kyun Kwan University.
‡ Yonsung Fine Chemicals Co., Ltd.
(1) (a) Guengerich, F. P.; DiMari, S. J.; Broquist, H. P. J. Am. Chem. Soc.
1973, 95, 2055. (b) Schneider, M. J.; Ungemach, F. S.; Broquist, H. P.; Harris,
T. M. Tetrahedron 1983, 39, 29.
(2) (a) Colegate, S. M.; Dorling, P. R.; Huxtable, C. R. Aust. J. Chem. 1979,
32, 2257. (b) Ermayanti, T. M.; McComb, J. A.; O’Brien, P. A. Phytochemistry
1994, 36, 313. (c) Tamerler, C.; Kesharaz, T. Biotechnol. Lett. 1999, 21, 501.
(3) (a) Liao, Y. F.; Lal, A.; Moreman, K. W. J. Biol. Chem. 1996, 271, 28348.
(b) Elbein, A. D.; Solf, R.; Dorling, P. R.; Vosbeck, K. Proc. Natl. Acad. Sci.
U.S.A. 1981, 78, 7393. (c) Kaushal, G. P.; Szumilo, T.; Pastuszak, I.; Elbein,
A. D. Biochemistry 1990, 29, 2168. (d) Pastuszak, I.; Kaushal, G. P.; Wall, K. A.;
Pan, Y. T.; Sturm, A.; Elbein, A. D. Glycobiology 1990, 1, 71.
(4) (a) Goss, P. E.; Baker, M. A.; Carver, J. P.; Dennis, J. W. Clin. Cancer
Res. 1995, 1, 935. (b) Goss, P. E.; Reid, C. L.; Bailey, D.; Dennis, J. W. Clin.
Cancer Res. 1997, 3, 1077. (c) Dennis, J. W. Cancer Res. 1986, 46, 5131. (d)
White, S. L.; Schweitzer, K.; Humphries, M. J.; Olden, K. Biochem. Biophys.
Res. Commun. 1988, 150, 615.
(7) (a) Lee, K. Y.; Kim, Y. H.; Park, M. S.; Ham, W. H. Tetrahedron Lett.
1998, 39, 8129. (b) Lee, K. Y.; Kim, Y. H.; Park, M. S.; Oh, C. Y.; Ham, W. H.
J. Org. Chem. 1999, 64, 9450. (c) Joo, J. E.; Lee, K. Y.; Pham, V. T.; Tian,
Y. S.; Ham, W. H. Org. Lett. 2007, 9, 3627.
(8) (a) Lee, K. Y.; Kim, Y. H.; Oh, C. Y.; Ham, W. H. Org. Lett. 2000, 2,
4041. (b) Lee, K. Y.; Oh, C. Y.; Ham, W. H. Org. Lett. 2002, 4, 4403. (c) Lee,
K. Y.; Oh, C. Y.; Kim, Y. H.; Joo, J. E.; Ham, W. H. Tetrahedron. Lett. 2002,
43, 9361. (d) Lee, Y. S.; Shin, Y. H.; Kim, Y. H.; Lee, K. Y.; Oh, C. Y.; Pyun,
S. J.; Park, H. J.; Jeong, J. H.; Ham, W. H. Tetrahedron: Asymmetry 2003, 14,
87. (e) Pyun, S. J.; Lee, K. Y.; Oh, C. Y.; Ham, W. H. Heterocycles 2004, 62,
333. (f) Pyun, S. J.; Lee, K. Y.; Oh, C. Y.; Joo, J. E.; Cheon, S. H.; Ham, W. H.
Tetrahedron 2005, 61, 1413. (g) Tian, Y. S.; Joo, J. E.; Pham, V. T.; Lee, K. Y.;
Ham, W. H. Arch. Pharm. Res. 2007, 30, 167. (h) Pham, V. T.; Joo, J. E.; Tian,
Y. S.; Chung, Y. S.; Lee, K. Y.; Oh, C. Y.; Ham, W. H. Tetrahedron: Asymmetry
2008, 19, 318.
(5) (a) Klein, J.-L. D.; Roberts, J. D.; George, M. D.; Kurtzberg, J.; Breton,
P.; Chermann, J.-C.; Olden, K. Br. J. Cancer 1999, 80, 87–95. (b) Shaheen, P.;
Stadler, W.; Elson, P.; Knox, J.; Winquist, E.; Bukowski, R. InVest. New Drugs
2005, 23, 577.
3962 J. Org. Chem. 2009, 74, 3962–3965
10.1021/jo802800d CCC: $40.75 2009 American Chemical Society
Published on Web 04/10/2009

TABLE 1. Diastereoselective Dihydroxylation of 6
SCHEME 2. Retrosynthetic Analysis
entry
solvent
workup
yielda (%)
ratiob
1
2
3
4
CH2Cl2/H2O
acetone/H2O
CH2Cl2/H2O
acetone/H2O
15% Na2S2O3
15% Na2S2O3
sat. Na2SO3
sat. Na2SO3
91
91
89
89
8a/8b ) 4:1
8a/8b ) 9:1
8c/8d ) 4:1
8c/8d ) 9:1
a Yields refer to the isolated and mixture products. b Ratio was
determined by H NMR analysis of the crude mixture after workup.
1
SCHEME 3
TABLE 2. Diastereoselective Allylation Reaction
entry
molar equiv of TiC14
dra (anti 4:syn 4′)
yieldb (%)
1
2
3
4
5
6
7
0.8
1.0
1.2
1.5
1.8
2.0
2.2
1:2
4:1
8:1
15:1
7:1
5:1
45
63
62
83
70
65
43
which could be synthesized by ring cleavage of trans-oxazoline
7 under Schotten-Baumann conditions. The trans-oxazoline 7
was made from D-serine according to known procedures.8e
Oxazoline could then be utilized to set the vicinal amino alcohol
stereochemistry of (-)-swainsonine.
3:1
a
1
Ratio was determined by H NMR on the basis of the ratio of 9 and
9′. b Yields refer to the isolated and mixture products.
at -78 °C to give adduct anti-amino alcohol 4 with low
diastereoselectivity (4:1 mixture of anti/syn isomer; entry 2,
Table 2).12
The yield and the diastereoselectivity were improved to 83%
and 15:1 when the amount of TiCl4 was increased to 1.5 equiv
(entries 2, 3, and 4). When excess TiCl4 (1.8, 2.0, and 2.2 equiv)
was employed, the yields and diastereomeric ratios decreased
(entries 5, 6, and 7).
Through extensive examination of various experimental
conditions, we established that the reaction of 1.0 equiv of
aldehyde and 1.5 equiv of TiCl4 with 1.5 equiv of allyltri-
methylsilane formed anti-amino alcohol 4 with 15:1 diastereo-
selectivity in 83% yield after silica gel chromatography.
On the basis of the results of the above experiments, the
quantity of TiCl4 is clearly an important factor in controlling
the course of the reaction. In the case of entry 4, it is interesting
to note that high anti selectivity (15:1) was obtained in the
reaction with 1.5 equiv of TiCl4.
This stereoselectivity apparently arises from the ꢀ-chelated
conformer (A), which is characteristic of an aldehyde with
ꢀ-alkoxy groups;12a in such cases, ꢀ-chelation (A) is more
effective than R-chelation (B) (Figure 2).
The synthesis of 1 commenced with trans-oxazoline 7 as
shown in Scheme 3. The trans-oxazoline 7 was treated with
benzyl chloroformate in the presence of aqueous sodium
bicarbonate,9 affording the carbamate 6 in 96% yield. In the
next step, diastereoselective dihydroxylation of 6 was attempted
with a catalytic amount of osmium tetraoxide in the presence
of 1.5 equiv of N-methylmorpholine N-oxide as the reoxidant
(OsO4/NMO).10 As expected, the approach of the oxidant took
place from the least hindered site to give 8a as the predominant
product. The selectivity was dramatically improved through
solvent selection; use of acetone/H2O (10/1) resulted in a 9:1
mixture of the diastereoisomers 8a and 8b in 91% yield.
Interestingly, treatment of the reaction mixture with sat.
aqueous Na2SO3 caused the benzoyl group of 8a and 8b to
migrate to the primary alcohol position. The minor product 8d
was easily separated by silica gel chromatography. The results
are summarized in Table 1.
Oxidation of alcohol 5 with Dess-Martin periodinane11 gave
the corresponding aldehyde, which was subsequently reacted
with allyltrimethylsilane in the presence of 1.0 equiv of TiCl4
(9) (a) Kouklovsky, C.; Pouilhes, A.; Langlois, Y. J. Am. Chem. Soc. 1990,
112, 6672. (b) Pyun, S. J.; Lee, K. Y.; Oh, C. Y.; Ham, W. H. Heterocycles
2004, 62, 333.
(10) (a) Noriki, K.; Shigeru, N. Bull. Chem. Soc. Jpn. 2006, 79, 468. (b)
Cha, J. K.; Christ, W. J.; Kishi, Y. Tetrahedron Lett. 1983, 24, 3943. For a
recent review, see: (c) Cha, J. K.; Kim, N. S. Chem. ReV. 1995, 95, 1761. (d)
VanRheenen, V.; Cha, D. Y.; Hartley, W. M. Organic Syntheses; Wiley & Sons:
New York, 1988; Collect. Vol. VI, p 342.
A mixture of anti-4 and syn-4′ could not the separated by
chromatography. To verify the stereochemical outcome of the
(12) (a) Jurczak, J.; Prokopowicz, P. Tetrahedron. Lett. 1998, 39, 9835. (b)
Marshall, J. A.; Seletsky, B. M.; Coan, P. S. J. Org. Chem. 1999, 59, 5139. (c)
Kiyooka, S.; Nakano, M.; Shiota, F.; Fujiyama, R. J. Org. Chem. 1989, 54,
5409.
(11) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
J. Org. Chem. Vol. 74, No. 10, 2009 3963

SCHEME 4
FIGURE 2. ꢀ-Chelation (A) and R-Chelation (B) Conformer.
SCHEME 5
FIGURE 3. J values between 4-H and 5-H in 4,5-disubstituted
oxazolidin-2-ones.
newly generated stereocenter, these isomers were converted to
the corresponding 4,5-disubstituted oxazolidin-2-ones under
basic conditions (NaH and then NaOH). Mixtures of cis-9/trans-
9′ were readily separable by chromatography (Figure 3).
The anti/syn stereochemistry of 4 and 4′ was assigned on
the basis of the stereochemistry of the corresponding 4,5-
disubstituted oxazolidin-2-ones.
The coupling constants between 4-H and 5-H of the deriva-
tives are known to be cis > trans.12c,13 The J value (J4,5 ) 8.0
Hz) observed in the major isomer clearly indicates that this
compound possesses the assigned cis structure.
The protection of the resulting alcohol 4 by TBSOTf and
subsequent oxidation of the alkene with borane-methyl sulfide
gave the corresponding alcohol 3 in 70% yield (Scheme 4).
Hydrolysis of the benzoyl group with 2N NaOH and
subsequent mesylation of the corresponding diol gave 10 in 77%
yield. With the precursor in hand, we predicted that cyclization
would lead to the desired transformation, but exposure of 10 to
several reagents [Pd(OH)2, Pd-C, etc.] proceeded sluggishly
under various conditions (K2CO3 or NaOH in MeOH).14a
After the mesylation of 3, exposure of the corresponding
mesylate at room temperature to NaH and then to 2 N NaOH
led to intramolecular cyclization and then benzoate hydrolysis
providing 2 in 76% yield (Scheme 5).14b,15
identical with those of synthetic (-)-swainsonine, and the
physical properties of 1 {mp 140-142 °C, [R]25D -82.6 (c 1.03,
MeOH)} showed good agreement with those reported.6g
In conclusion, the potent mannosidase inhibitor (-)-swain-
sonine (1) was synthesized from trans-oxazoline 7 as a chiral
building block. The net result was synthesis from a linear
sequence of 13 steps from the oxazoline 7 in 18% overall yield.
Our approach features the use of trans-oxazoline to install
the stereocenters at C1 and C8a and makes use of diastereose-
lective dihydroxylation to utilize the stereocenter at C2. TiCl4-
promoted allylsilane addition adjusted the stereochemistry at
C8 and provided the allyl group, which could be converted to
the appropriate alcohol for ring construction. The key features
in this strategy are the diastereoselective oxazoline formation
reaction catalyzed by palladium(0), diastereoselective dihy-
droxylation, and the stereocontrolled allylation reaction with
TiCl4.
Experimental Section
Mesylation of 2 (MeSO2Cl, Et3N, 0 °C) gave mesylate in
excellent yield (95%). Hydrogenolysis of a EtOH/AcOH solu-
tion of mesylate (70 psi of H2 gas) afforded the protected (-)-
swainsonine (12). Finally, acidic hydrolysis of the protection
groups afforded (-)-swainsonine (1) in 82% yield after Dowex-
50WX8-100 (H+ form) ion-exchange chromatography. The
spectroscopic (1H and 13C NMR) data for synthetic 1 were
(2S,3R)-Benzyl 3-(tert-Butyldimethylsilyloxy)-2-((4S,5R)-5-
(hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)piperidine-1-
carboxylate (2). A solution of the homoallylic alcohol 3 (1.30 g,
2.16 mmol) and triethylamine (0.66 mL, 4.75 mmol) in dry CH2Cl2
(70 mL) was treated with methanesulfonyl chloride (0.35 mL, 4.54
mmol) at 0 °C under an argon atmosphere. The reaction mixture
was stirred for 1 h (from 0 °C to rt) and diluted with diethyl ether.
The organic layer was separated and washed with water and brine.
After drying (Na2SO4) and concentration in vacuo, the residue was
purified over silica gel to give a pure mesylated product. A solution
of the mesylated product (1.38 g, 2.03 mmol) in THF (200 mL) at
0 °C was treated with NaH (60% dispersion in oil, 0.24 g, 6.09
mmol, 3.0 equiv) in several portions over 15 min. After 3 h, the
reaction mixture was quenched by the addition of saturated aqueous
NaHCO3 (50 mL) and the aqueous layer was extracted with EtOAc
(4 × 100 mL) and concentrated. The residue was dissolved in
MeOH (10 mL) and then stirred with 2 N NaOH (10 mL) at rt for
2 h and concentrated. The residue was extracted with EtOAc (4 ×
50 mL). The combined organic layer was dried (Na2SO4) and
concentrated in vacuo. The residue was purified over silica gel
chromatography (ethyl acetate/hexane ) 2:1) to give 2 (0.94 g,
(13) (a) Fujikawa, S.; Inui, T.; Shiba, T. Bull. Chem. Soc. Jpn. 1973, 43,
3308. (b) Garigipati, R. S.; Freyer, A. J.; Whittle, R. R.; Weireb, S. M. J. Am.
Chem. Soc. 1984, 106, 7861. (c) Kano, S.; Yokomatsu, T.; Iwasawa, H.; Shibuya,
S. Tetrahedron Lett. 1987, 28, 6331.
(14) (a) Adger, B.; Dyer, U.; Hutton, G.; Woods, M. Tetrahedron Lett. 1996,
37, 6399–6402, 35. (b) Boger, D. L.; McKie, J. A.; Nishi, T.; Ogiku, T. J. Am.
Chem. Soc. 1997, 119, 311–325.
(15) After the mesylation of 3, the reaction mixture was treated with NaH
to afford a 85:15 mixture of 2 and 11 in 76% yield. 11 was reacted with NaOH
to afford 2 in 99% yield.
.
90%) as a colorless oil: [R]25 +33.46 (c 1.0, CHCl3); IR (neat)
D
3964 J. Org. Chem. Vol. 74, No. 10, 2009

1
2930, 1687, 1526, 1461, 1258, 1041 cm-1. Rotamer: H NMR
J ) 4.5, 10.7 Hz, 1H), 3.12 (d, J ) 10.5 Hz, 1H), 3.80 (ddd, J )
4.7, 8.8, 10.7 Hz, 1H), 4.55 (dd, J ) 4.5, 6.0 Hz, 1H), 4.61 (dd, J
) 4.5, 6.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ -4.7, -4.3,
18.3, 24.3, 24.9, 26.1, 26.2, 34.4, 52.0, 60.7, 68.0, 74.2, 78.1, 79.4,
110.9; HRMS calcd for C17H33NO3Si (M + 1) 328.2308, found
328.2310.
(500 MHz, CDCl3) δ 0.02 (s, 3 × 0.55H), 0.04 (s, 3 × 0.55H),
0.06 (s, 3 × 0.45H), 0.09 (s, 3 × 0.45H), 0.86 (s, 9 × 0.55H),
0.88 (s, 9 × 0.45H), 1.36 (br, 3H), 1.40 (br, 3 × 0.55H), 1.46 (br,
3 × 0.45H), 1.67-1.77 (m, 2H), 1.83-2.06 (m, 2H), 2.91-2.97
(m, 0.55H), 3.19-3.25 (m, 0.45H), 3.57-3.64 (m, 1H), 3.68-3.76
(m, 1.55H), 3.80-3.82 (m, 0.45H), 4.05-4.08 (m, 0.45H), 4.11-
4.14 (m, 0.55H), 4.19-4.23 (m, 1H), 4.32-4.37 (m, 0.55H),
4.35-4.40 (m, 1H), 4.48-4.53 (m, 0.45H), 5.00-5.03 (d, J ) 12.5
Hz, 0.55H), 5.14-5.16 (d, J ) 12.5 Hz, 0.45H), 5.18-5.21 (d, J
) 12.5 Hz, 0.45H), 5.26-5.29 (d, J ) 12.5 Hz, 0.55H), 7.28-7.37
(m, 5H); 13C NMR (125 MHz, CDCl3) δ -4.7, -4.4, 19.1, 19.2,
25.7, 25.8, 25.9, 28.3, 39.4, 56.3, 61.7, 66.0, 67.1, 73.3, 75.1, 108.5,
127.8, 127.9, 128.0, 128.5, 128.6, 137.3, 156.7; HRMS calcd for
C25H41NO6Si (M + 1)480.2781, found 480.2780.
(1S,2R,8R,8aR)-Octahydroindolizine-1,2,8-triol ((-)-Swain-
sonine (1)). To a solution of 12 (251 mg, 0.77 mmol) in THF
(8 mL) was added 6 N HCl (8 mL), and the mixture was stirred at
rt for 12 h. The mixture was concentrated in vacuo to dryness, and
the resulting crude product was applied to ion-exchange chroma-
tography (Dowex 50WX8-100, H+ form, 100-200 mesh) eluting
with aqueous ammonium hydroxide solution (0.6 M). Removal of
water in vacuo provided 1 (110 mg, 83%) as a white solid: mp
140-142 °C; [R]25 -82.6 (c 0.5, MeOH); IR (neat) 3853, 3741,
D
(3aR,9R,9aS,9bS)-9-(tert-Butyldimethylsilyloxy)-2,2-dimethyl-
octahydro-[1,3]dioxolo[4,5-a]indolizine (12). A solution of the
homoallylic alcohol 2 (808 mg, 1.68 mmol) and triethylamine (0.52
mL, 3.70 mmol) in dry CH2Cl2 (56 mL) was treated with
methanesulfonyl chloride (0.27 mL, 3.54 mmol) at 0 °C under an
argon atmosphere. The reaction mixture was stirred for 1 h (from
0 °C to rt) and diluted with diethyl ether. The organic layer was
separated and washed with water and brine. After drying (anhydrous
sodium sulfate) and concentration in vacuo, the residue was purified
over silica gel to give a pure mesylated product. To a solution of
the above mesylated product (932 mg, 1.67 mmol) in EtOH/AcOH
(8 mL, v/v ) 9:1) was added Pd(OH)2/C (100 mg) and the mixture
was shaked on a parr apparatus under hydrogen at a 70 psi pressure
for 3 days at room temperature. The catalyst was filtered off through
a short pad of Celite and concentrated under reduced pressure. The
resulting crude product was purified by using silica gel flash
chromatography eluting with 10% MeOH/CHCl3 to give protected
swainsonine 12 (530 mg, 96%) as a colorless oil: [R]25D +15.92 (c
1.0, CHCl3); IR (neat) 3420, 2937, 1651, 1462, 1379, 1197, 840,
777 cm-1; 1H NMR (500 MHz, CDCl3) δ 0.09 (s, 3H), 0.09-0.11
(m, 3H), 0.90 (s, 9H), 1.17-1.29 (m, 1H), 1.30 (s, 3H), 1.49 (s,
3H), 1.58-1.64 (m, 3H), 1.82 (dd, J ) 4.0, 5.5 Hz, 1H), 1.95 (dd,
J ) 4.0, 12.0 Hz, 1H), 2.08 (dd, J ) 4.5, 10.5 Hz, 1H), 2.96 (dt,
2927, 1688, 1526, 676 cm-1;1H NMR (500 MHz, D2O) δ 1.19
(dddd, J ) 4.5, 11.5, 13.0, 13.5 Hz, 1H), 1.46 (qt, J ) 4.5, 13.5
Hz, 1H), 1.68 (ddd, J ) 2.5, 4.5, 14.5 Hz, 1H), 1.95 (dd, J ) 4.0,
9.0 Hz, 1H), 1.99 (dd, J ) 3.5, 12.5 Hz, 1H), 2.01 (dq, J ) 3.5,
14.5 Hz, 1H), 2.57 (dd, J ) 8.0, 11.5 Hz, 1H), 2.87 (dd, J ) 2.5,
11.0 Hz, 1H), 2.86-2.92 (m, 1H), 3.75 (ddd, J ) 4.5, 9.5, 11.0
Hz, 1H), 4.21 (dd, J ) 4.0, 6.0 Hz, 1H), 4.31 (ddd, J ) 2.5, 6.0,
8.0 Hz, 1H); 13C NMR (125 MHz, D2O) δ 23.0, 32.3, 51.5, 60.5,
66.2, 68.9, 69.5, 72.7; HRMS calcd for C8H16NO3 (M + 1)
174.1130, found 174.1132.
Acknowledgment. This work was financially supported by
the Yonsung Fine Chemicals Co., Ltd., and the Seoul R & BD
program (10541).
Supporting Information Available: Full spectral details and
1
assignments and copies of the H and 13C NMR spectra of
compounds 7, 6, 8c, 8d, 8a, 8b, 5, 4, 9, 9′, 3, 2, 11, 12, 1, and
precursors of 5, 3, and 10. This material is available free of
charge via the Internet at http://pubs.acs.org.
JO802800D
J. Org. Chem. Vol. 74, No. 10, 2009 3965