Asymmetric Syntheses of (-)-8-epi-Swainsonine Triacetate and (+)-1,2-Di-epi-swainsonine. Carbonyl Addition Thwarted by an Unprecedented Aza-Pinacol Rearrangement

Article abstract of DOI:10.1021/jo000527u

Indolizidines (-)-8-epi-swainsonine triacetate and (+)-1,2-di-epi-swainsonine were synthesized from the O'Donnell Schiff base ester 1 derived from D-serine. Reductive-alkenylation of 1 with ⁱBu₅-Al₂H/H₂C=CHMgBr followed by substrate-directed dihydroxylation of the pendant allylic group with OsO₄, reduction of imine, and cyclization with Ph₃P/CCl₄ gave the polyhydroxylated pyrrolidines 8a and 8b as advanced intermediates. Efficient protecting group manipulations converted pyrrolidines 8a and 8b to their corresponding partially protected analogues 10a and 10b, which upon Swern oxidation and diastereoselective Keck-type allylation with BF₃·Et₂O afforded the required three-carbon homologues (10a, >20:1 de; 10b, 3.5:1 de). Use of the chelating Lewis acid MgBr₂ instead of BF₃·Et₂O with 10a led to a novel aza-pinacol rearrangement and allylation at the α-carbon to yield amino alcohol 17, which is similar to a hydride migration in the biosynthetic pathway of indolizidine alkaloids. Subsequent hydroboration, cyclization, and deprotection furnished (-)-8-epi-swainsonine triacetate 15a and (+)-1,2-di-epi-swainsonine 16b in good overall yields (6.3% for 1 → 15a, 13 steps, and 4.0% for 1 → 16b, 14 steps).

Full text of DOI:10.1021/jo000527u

J . Org. Chem. 2000, 65, 5693-5706
5693
Asym m etr ic Syn th eses of (-)-8-epi-Sw a in son in e Tr ia ceta te a n d
(+)-1,2-Di-epi-sw a in son in e. Ca r bon yl Ad d ition Th w a r ted by a n
Un p r eced en ted Aza -P in a col Rea r r a n gem en t
Hossein Razavi and Robin Polt*
Department of Chemistry, The University of Arizona, Tucson, Arizona 85721
polt@u.arizona.edu
Received April 10, 2000
Indolizidines (-)-8-epi-swainsonine triacetate and (+)-1,2-di-epi-swainsonine were synthesized from
i
the O’Donnell Schiff base ester 1 derived from D-serine. Reductive-alkenylation of 1 with Bu5-
Al2H/H2CdCHMgBr followed by substrate-directed dihydroxylation of the pendant allylic group
with OsO4, reduction of imine, and cyclization with Ph3P/CCl4 gave the polyhydroxylated pyrrolidines
8a and 8b as advanced intermediates. Efficient protecting group manipulations converted
pyrrolidines 8a and 8b to their corresponding partially protected analogues 10a and 10b, which
upon Swern oxidation and diastereoselective Keck-type allylation with BF3‚Et2O afforded the
required three-carbon homologues (10a , >20:1 de; 10b, 3.5:1 de). Use of the chelating Lewis acid
MgBr2 instead of BF3‚Et2O with 10a led to a novel aza-pinacol rearrangement and allylation at
the R-carbon to yield amino alcohol 17, which is similar to a hydride migration in the biosynthetic
pathway of indolizidine alkaloids. Subsequent hydroboration, cyclization, and deprotection furnished
(-)-8-epi-swainsonine triacetate 15a and (+)-1,2-di-epi-swainsonine 16b in good overall yields (6.3%
for 1 f 15a , 13 steps, and 4.0% for 1 f 16b, 14 steps).
In tr od u ction
immunological disorders.10 Thus, the efficient chemical
synthesis of swainsonine and various analogues has
become increasingly important for structure-activity
relationship (SAR) and for clinical studies.
Polyhydroxylated indolizidine alkaloids were initially
recognized for their toxic effects on biological organisms.
The toxicological focus on indolizidines has since ex-
panded to their use as glycosidase inhibitors1-4 and their
application as tools for the study of glycobiology.5 Swain-
sonine, castanospermine, and slaframine (Figure 1)
represent a class of glycosidase inhibitors that can be
regarded as conformationally constrained bicyclic “aza-
sugars” or “nitrogen-in-the-ring” sugar analogues,6 which
may be useful in the treatment of cancer,7,8 HIV,9 and
Swainsonine is the active agent responsible for the
toxicity of plants indigenous to Australia and North
America11 that include Swainsona (Darling pea), As-
tragalus lentiginosus (locoweed), and Oxytropis,12 and the
ubiquitous mold Rhizoctonia leguminicola,13 where it can
also poison diverse human populations.14 The biogenesis
of swainsonine starts with L-lysine, and the early stages
of biosynthesis are identical in several other indolizidine
alkaloids (e.g., slaframine). (Figure 2) Although enoliza-
tion of the 1-ketoindolizidine intermediate can occur,
hydride migration from the 8a f 1 position appears to
be responsible for the biological reduction of the ketone
during biosynthesis. Interestingly, a similar Lewis acid-
promoted hydride shift has been observed during these
studies (vide infra).
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10.1021/jo000527u CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/10/2000

5694 J . Org. Chem., Vol. 65, No. 18, 2000
Razavi and Polt
F igu r e 1. Major indolizidine alkaloids.
F igu r e 3. Enantiodivergent approach allows for the synthesis
of various indolizidines from common intermediates and
starting materials.
of simple â-amino alcohols (sphingosines) from their
corresponding amino acids in a stereoselective fashion.20
This method has since been extended to the synthesis of
sphingosine analogues,21 and heterocycles such as N-
methyl-D-fucosamine, deoxyfuconojirimycin, and imi-
nolyxitols.22
F igu r e 2. Biosynthesis of swainsonine.
In principle, all the stereoisomers of swainsonine can
be accessed by an enantiodivergent modification of this
amino acid-based approach (Figure 3): (1) Starting with
D- vs L-serine inverts the enantiomeric series; (2) the
reductive-alkenylation methodology can furnish either
the threo- or erythro-â-amino alcohols from the fully
protected serine Schiff base; (3) substrate-directed cis-
vs trans-diol formation could alter the hydroxyl config-
uration in the pyrrolidine ring; and (4) chelation-
controlled vs Felkin-Ahn addition of the allyl moiety
could, in principle, invert the hydroxyl configuration in
the piperidine ring.
Syn th esis of th e P yr r olid in e Segm en t. Construc-
tion of the aza-furanose skeleton required the addition
of a vinyl group to D-serine in a manner that would afford
the enantiomerically pure threo â-amino alcohol (syn or
like product) in good yield.23 To this end, we relied on
the reductive-alkenylation methodology which has previ-
ously worked well with more-substituted sp2-hybridized
carbanions.
acid15 and D-tartaric acid16 have been used as sources of
chirality. The fact that the four contiguous chiral centers
of swainsonine resemble those of manno- and gluco-
sugars has led to the utilization of these carbohydrates
as starting materials for a large number of syntheses.17
However, the preexisting chiral centers can limit the
scope of carbohydrate-based methods. In addition, the
need for orthogonal protection of the hydroxyl groups
confines these methods to arduous and redundant se-
quences of protecting group manipulations that reduces
the efficiency and lengthens this approach. In light of
these limitations, the need for non-carbohydrate-based
syntheses has become more apparent, and a few asym-
metric syntheses, starting from achiral substrates, have
been published.18 In view of the fact that the biosynthetic
pathway to swainsonine begins with L-lysine, it is
surprising to note that very few approaches to the total
synthesis of this compound from an amino acid precursor
have been reported.19
The starting material 1, conveniently prepared from
D-serine,21,24 was treated sequentially with i-Bu5Al2H (1:1
mixture of i-Bu2AlH and i-Bu3Al in hexanes) and vinyl-
magnesium bromide in THF/CH2Cl2 at -78 °C. This
provided a chromatographically separable mixture25 of
diastereomers (2a :2b, 1.7:1) in 76% yield (Scheme 1). We
attribute the lack of stereoselectivity to the presence of
THF in the reaction mixture, which destroys the five-
membered chelation template that is essential for threo-
selectivity.20 In fact, the reductive alkenylation method-
ology has been shown to be threo-selective (∼8:1) when
the carbanion is prepared in Et2O, and extremely selec-
As part of a program directed at efficient chemical
syntheses of enantiomerically pure glycosidase inhibitors
such as (-)-swainsonine, we have synthesized (-)-8-epi-
swainsonine and (+)-1,2-di-epi-swainsonine from D-
serine. Previous communications describe the synthesis
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(21) Mitchell, S. A.; Oates, B. D.; Razavi, H.; Polt, R. J . Org. Chem.
1998, 63, 8837.
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D.; Polt, R. Synlett 1995, 552. (c) Razavi, H.; Polt, R. Tetrahedron Lett.
1998, 39, 3371.
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Uyehara, T.; Yamamoto, Y. J . Org. Chem. 1991, 56, 4370-4382. (b)
Angle, S. R.; Henry, R. M. J . Org. Chem. 1997, 62, 8549-8555. (c)
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Soc. 1999, 121, 9088-9095. (e) Coleman, R. S.; Carpenter, A. J .
Tetrahedron Lett. 1992, 33, 1697-700.
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9 in Amino Acid Derivatives: A Practical
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Synthesis of (-)-8-epi-Swainsonine Triacetate
J . Org. Chem., Vol. 65, No. 18, 2000 5695
Sch em e 1a
Sch em e 2a
a
Reagents: (i) (CH3)3CCOCl/pyridine/DMAP, (ii) K2OsO2(OH)4/
K3Fe(CN)6/tBuOH/H2O/base (see table).
a
Reagents: (i) iBu5Al2H, (ii) H2CdCHMgBr/THF/-78 °C f rt,
(iii) NaHCO3 workup.
Sch em e 3a
tive (>20:1) in noncoordinating solvents such as toluene
or hexanes.26 The threo product 2a and the erythro
product 2b exist as a mixture of oxazolidine-imine
tautomers. In each case, the oxazolidine is the major
species. Based on the integration of the proton spectra,
the ratio of the oxazolidine to the open chain imine was
estimated to be ∼14:1 for 2a and ∼2:1 for 2b in CDCl3.
Subsequently, the threo-hydroxy Schiff base (oxazoli-
dine) 2a was protected as the corresponding pivalate, and
the substrate-directed osmylation27 of compound 3a with
a catalytic amount of K2OsO2(OH)4 and K3Fe(CN)6 as a
reoxidant proceeded cleanly in accordance with the
Stork-Kishi28 rule to afford the desired diol 4a in 70%
yield (10:1 ratio). A reduction in yield (60%) and the
diastereomeric ratio (7:1) was observed when K2CO3 was
solely used in the reaction (pH 12). These results have
been attributed to the base-catalyzed migration of the
pivalate from its original location to the newly created
hydroxyl groups that are less sterically demanding. This
migration was significantly suppressed when the aqueous
layer was buffered to pH 10 using a 1:1 mixture of K2-
CO3 and NaHCO3 (Scheme 2).
a
Reagents: (i) NaCNBH3/AcOH, CH3CN 4 Å mol sieves, (ii)
Next, the imine 4a was reduced with NaH3BCN to
provide the amino diol 5a , which was cyclized with CCl4/
PPh3 to give an inseparable mixture of pyrrolidines 6a
and 6a ′.29 Hydrolysis of the pivaloyl groups of 6a and 6a ′
under basic conditions (Bu4NOH, H2O, dioxane) was
complicated by the premature removal of the tert-bu-
tyldimethylsilyl protecting group. The desired transfor-
mation was achieved using a modified Zemple`n transes-
terification procedure (1 equiv of NaOMe, anhydrous
MeOH),30 which provided the silyl-protected pyrrolidine
8a in quantitative yield (Scheme 3).
Ph3P/CCl4/Et3N/DMF, (iii) NaOMe/MeOH, (iv) LiBH4/THF reflux.
reduction of the imine under conditions that also removed
the pivaloyl group. The simultaneous reduction of Schiff
bases and esters was feasible with LiAlH4; however this
reagent can remove silyl ethers, presumably due to the
presence of AlH3.31 The less-reactive LiBH4 effected the
desired tandem reduction in 84% overall yield.32 Cycliza-
tion of the amino triol 7a was then achieved with CCl4/
PPh3 as before to give the trihydroxylated pyrrolidine 8a
in much higher yield. A single crystal X-ray analysis of
compound 8a confirmed the absolute configuration (Fig-
ure 4).
Efforts were made to reduce the number of synthetic
transformations and purifications required by combining
two or more steps into one. One such expedient was the
The hydroxyl groups on the pyrrolidine ring were
protected as an acetonide, giving a degree of rigidity to
the substrate, which would allow better stereochemical
control of the ensuing allylation reaction. After initial
(26) Polt, R.; Sames, D.; Chruma, J . J . Org. Chem. 1999, 64, 6147.
(27) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem.
Rev. 1994, 94, 2483.
(28) (a) Cha, J . K.; Christ, W. J .; Kishi, Y. Tetrahedron Lett. 1983,
24, 3943. (b) Christ, W. J .; Cha, J . K.; Kishi, Y. Tetrahedron Lett. 1983,
24, 3947. (c) Stork, G.; Kahn, M. Tetrahedron Lett. 1983, 24, 3951.
(29) Chen, Y.; Vogel, P. Tetrahedron Lett. 1992, 33, 4917.
(30) Szurmai, Z.; Kerekgyarto, J .; Harangi, J .; Liptak, A. Carbohydr.
Res. 1987, 164, 313.
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Chem. 1992, 57, 1179.
(32) Soai, K.; Ookawa, A. J . Org. Chem. 1986, 51, 4000.

5696 J . Org. Chem., Vol. 65, No. 18, 2000
Razavi and Polt
Sch em e 5a
F igu r e 4. Single-Crystal X-ray Structure of Aza-D-lyxitol, 8a .
Sch em e 4a
a
Reagents: (i) (CH3)3CCOCl/pyridine/DMAP, (ii) K2OsO2(OH)4/
K3Fe(CN)6/tBuOH/H2O/base (see table).
amines to OsO4 and their ability to direct and accelerate
osmylation reactions has been documented,37 but the
stereochemical influence of the imine nitrogen was
expected to be minor.26 Thus, the erythro-amino alcohol
2b was converted to the corresponding pivalate 3b and
reacted with K2OsO2(OH)4/K3Fe(CN)6 and CH3SO2NH2
(Scheme 5).
a
Reagents: (i) (CH3)2C(OCH3)2/cat. CSA/CH2Cl2 reflux, (ii)
nBu4NF/THF, (iii) (CH3)2C(OCH3)2/1.45 equiv of CSA/CH2Cl2
reflux/72 h.
These experiments indicate that osmylation of com-
pounds 3a and 3b proceed with the predicted stereo-
chemical results. That is, the approach of OsO4 is
primarily dictated by the configuration at the oxygen-
bearing allylic center, and the chirality at the nitrogen-
bearing homoallylic carbon has a negligible effect on the
stereochemical outcome of the reaction. Once again, the
use of additives had a profound effect on the yield and
the selectivity of the osmylation reaction. As expected,
the use of a 1:1 mixture of K2CO3 and NaHCO3 (pH 10)
instead of K2CO3 (pH 12) resulted in a marked improve-
ment in the reaction yield (from 60% to 71%), which was
identical to the results obtained from the dihydroxylation
of the diastereomer 3a . However, unlike the earlier
studies, a lower ratio (5.4:1) was observed at pH 10, which
seemed inconsistent with the earlier result. Interestingly,
the 13C NMR spectrum of the major product showed that
4b existed entirely as the 1,3-oxazine. It appears that
the migration of the pivalate did not occur with the major
product 4b because the hydroxyl group adjacent to the
pivalate was immediately protected upon its formation.
But, migration of this type did occur in the diastereomeric
product 4b′ (e.g., 4b′ f 4b′′). Buffering of the aqueous
layer to pH 10 suppressed the migration of the pivalate
and enhanced the isolated yield of the minor product 4b′,
which resulted in a lower observed ratio.
screening of various methods for ketal formation,33 the
diol portion of 8a was protected with the aid of 2,2-
dimethoxypropane and CSA to provide acetonide 9a .34
The pendent silyl group was cleaved with TBAF under
standard conditions to yield pyrrolidine 10a (Scheme
4).22c,35
During acetonide formation, the silyl protecting group
was removed to some extent, and desilylated compound
10a was obtained as a minor product. Armed with this
knowledge, it was possible to optimize the reaction
conditions (1.45 equiv of CSA, refluxing CH2Cl2, 72 h) to
effect tandem acetonide formation-desilylation to afford
the desired product 10a in 81% yield in one step (Scheme
4).
In a parallel sequence of reactions, the erythro-amino
alcohol 2b was converted to the corresponding pyrrolidine
8b. This sequence provided the biologically interesting
aza-sugar 1,4-dideoxy-1,4-imino-D-ribitol.36 The interest
in this erythro-series of compounds stemmed primarily
from the desire to understand the factors that control the
stereochemical outcome of the dihydroxylation reactions
of allylic alcohols bearing a homoallylic amine. A second-
ary interest in the erythro-series was to examine the
stereochemical influence on the allylation reaction ex-
erted by the acetonide orientation versus the configura-
tion of the R-amino aldehyde bearing the bulky N-ben-
zhydryl group (vide infra). The complexation of tertiary
Subsequently, compound 4b was reduced with NaC-
NBH3 under acidic conditions, and the resulting amino
tetrol 5b was cyclized to give a mixture of pyrrolidines
6b and 6b′ in 84% yield. Since chromatographic separa-
tion of 6b/6b′ was difficult, the mixture was treated with
NaOMe (1 equiv) in MeOH, which removed the pivaloyl
ester to give the dihydroxylated pyrrolidine 8b in quan-
titative yield (Scheme 6).
(33) (a) Evans, M. E.; Parrish, F. W.; Long, L. Carbohydr. Res. 1967,
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Synthesis of (-)-8-epi-Swainsonine Triacetate
J . Org. Chem., Vol. 65, No. 18, 2000 5697
Sch em e 6a
F igu r e 5. Dioxolane ring cis to the aldehyde moiety prevents
normal Felkin-Ahn stereocontrol.
Keck-type39 allylation. The only concern was the stereo-
chemical outcome of the reaction. We were confident that
the stereocontrol at this stage of the construction was
attainable, in part because of the preliminary molecular
modeling that had indicated a strong inherent steric bias
due to the presence of the N-benzhydryl protecting group.
Added assurance was provided by literature precedent
describing the stereoselective allylation of amino alde-
hydes,40 as well as the X-ray structure (Figure 4) of the
protected alcohol 8a that indicated the N-benzhydryl
group would project out to mask one face of the carbonyl.
Thus, Swern oxidation of hydroxy pyrrolidine 10a
under standard conditions furnished the corresponding
aldehyde,41 which was immediately used in the next step
without purification due to the well-documented configu-
rational instability of R-amino aldehydes.42 In an attempt
to synthesize the homoallylic alcohol 11a , nBu3SnCH2-
CHdCH2 and BF3‚OEt2 was added to the unpurified
amino aldehyde. To our delight, the reaction proceeded
at -78 °C to give one stereoisomer in 80% yield (>20:1
diastereomeric ratio). In addition, allylation of the pro-
tected aza-lyxose from 10a with Sn(CH2CHdCH2)4 (0.3
equiv) in MeOH proceeded at room temperature to afford
compound 11a exclusively (Scheme 5).43 Reaction with
Me3SiCH2CHdCH2 under the same conditions (BF3‚OEt2,
-78 °C, 2 h) afforded a much lower (8%) yield of 11a . A
similar lack of reactivity for the allylation of a protected
amino aldehyde with Me3SiCH2CHdCH2 in the presence
BF3‚OEt2 was reported by Ganem et al. in their synthesis
of (+)-castanospermine.44
a
Reagents: (i) NaCNBH3/AcOH, CH3CN 4 Å mol sieves, (ii)
Ph3P/CCl4/Et3N/DMF, (iii) 1 equiv of NaOMe/MeOH, (iv) LiBH4/
THF reflux, (v) (CH3)2C(OCH3)2/1.45 equiv of CSA/CH2Cl2 reflux/
72 h.
Alternatively, amino alcohol 4b was subjected to
LiBH4, which effected reduction of the imine, followed
by treatment of the reaction mixture with MeOH to
remove the pivalate in 82% yield. However, contrary to
earlier results from the reduction of 4a with LiBH4,
reduction of the imine 4b proceeded very slowly and was
completed only after 4 days at reflux. The resistance of
4b toward reduction with LiBH4 further illustrates that
this compound does not exist as an imine. Cyclization of
the newly generated secondary amine to the terminal
carbon provided the protected 1,4-dideoxy-1,4-imino-D-
ribitol 8b in good yield.
The hydroxyl groups of compound 8b were protected
as an acetonide. Once again, diol protection and silyl
ether hydrolysis proceeded in tandem under mild acidic
conditions (1.45 equiv of CSA). This transformation
furnished the desired partially protected pyrrolidine 10b,
but more importantly it proved that the two hydroxyl
groups on the periphery of the pyrrolidine were posi-
tioned on the same face of the ring. Thus, assignment of
the stereochemical outcome based on rational mechanis-
tic considerations of the earlier transformations was
correct.
According to the Felkin-Ahn model, nucleophilic ad-
ditions to aldehydes bearing R-heteroatoms proceed
principally via two reactive conformers.45 The normal
application of the Felkin-Ahn model led us to conclude
that the homoallylic alcohol would have the (R) config-
uration (Figure 5). However, the configuration at the
Alk yla tion of th e P yr r olid in e Rin g. It was envis-
aged that stereoselective addition of an allylic nucleophile
to an aldehyde would ultimately give the indolizidine
carbon skeleton. The subsequent functional group trans-
formation, protecting group manipulation, and cyclization
would afford the desired indolizidine alkaloid.
(39) Keck, G. E.; Castellino, S. J . J . Am. Chem. Soc. 1986, 108, 3847.
(40) Marshall, J . A.; Seletsky, B. M.; Coan, P. S. J . Org. Chem. 1994,
59, 5139.
(41) Mancuso, A. J .; Huang, S. L.; Swern, D. J . Org. Chem. 1978,
43, 2480.
(42) J urczak, J .; Golebiowski, A. Chem. Rev. 1989, 89, 149.
(43) (a) Cokley, T. M.; Harvey, P. J .; Marshall, R. L.; McCluskey,
A.; Young, D. J . J . Org. Chem. 1997, 62, 1961. (b) Yasuda, M.;
Fujibayashi, T.; Baba, A. J . Org. Chem. 1998, 63, 6401.
(44) Hamana, H.; Ikota, N.; Ganem, B. J . Org. Chem. 1987, 52, 5492.
(45) (a) Cherest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968,
2199. (b) Ahn, N. T.; Eisenstein, O. Nouv. J . Chim. 1977, 1, 61.
An efficient method for construction of the requisite
three-carbon adduct is the Hosomi-Sakurai38 or the
(38) Hosomi, A.; Sakurai, H. Tetrahedron Lett. 1976, 1295.

5698 J . Org. Chem., Vol. 65, No. 18, 2000
Razavi and Polt
Ch a r t 1. Rotom er En er gies for th e Am in o Ald eh yd es Der ived fr om 10a a n d 10b
homoallylic center was shown to be (S) based on the
correlation of the C-8 configuration of the triacetoxy
indolizidine with that of triacetoxy 8-epi-swainsonine
(vide infra). These results indicated that A was the
preferred conformer. Other methods, including nBu3-
SnCH2CHdCH2/TiCl4 and BrMgCH2CHdCH2 also failed
to provide the elusive chelation-controlled aldehyde ad-
dition product. It appeared that B was the higher energy
conformer due to the dipole-dipole and/or steric interac-
tion between the carbonyl and the dioxolane groups. In
theory, this interaction was avoided in conformer A, and
the higher energy associated with the approach of the
nucleophile along this pathway was still lower than the
energy associated with conformer B.
To confirm this hypothesis, molecular mechanics cal-
culations46 (MM2) were undertaken to examine the
conformational preferences of the epimeric aldehydes
derived from alcohols 10a and 10b. The minimum energy
calculated for the “cis” aldehyde derived from alcohol 10a
was 27.3 and 25.4 kcal/mol for the corresponding “trans”
isomer derived from 10b (vide infra). After minimization
and “bump testing” to ensure that the conformations were
at true global minima, a dihedral driving routine was
used to rotate each carbonyl in 10° increments, and the
compounds were minimized again with the OdC-C-N
angle constrained to this angle. To facilitate conforma-
tional comparison, the global minima were both set to
zero, and the energy differences were plotted as a function
of dihedral angle for each rotomer. The results are
illustrated in Chart 1. While it is not possible to speculate
about the population of the rotomer states displayed, it
is clear that the preferred dihedral angles for the two
aldehydes are quite different, and that the observed
energy minima support the transition state suggested in
Figure 5 for the “cis” case. Furthermore, this suggested
F igu r e 6. Dioxolane ring trans to the aldehyde moiety allows
normal Felkin-Ahn stereocontrol.
that the epimeric “trans” case should react via a normal
Felkin-Ahn transition state (Figure 6, vide infra).
Aza -P in a col Rea r r a n gem en t. Remarkably, allyla-
n
tion of the aldehyde derived from 10a with Bu3SnCH2-
CHdCH2 in the presence of MgBr2‚OEt2 at -23 °C,
expected to provide the chelation-controlled homoallylic
alcohol, instead afforded the R-allylation product 17 as
the only isolable product (64%). Apparently, â-chelation
of the substrate induced a [1,2]-hydride shift to afford
the corresponding cyclic iminium ion,47 which was at-
tacked by the nucleophile from the least-hindered face
(opposite to the isopropylidene group) to furnish 17
(Scheme 8). The Mg ion, in addition to aligning the two
(46) Calculations were performed on a Macintosh G4, using Chem-
3D Pro, available from CambridgeSoft Corp., http://www.camsoft.com.
(47) For a related mechanism, see: Deng, W.; Overman, L. E. J .
Am. Chem. Soc. 1994, 116, 11241-11250.

Synthesis of (-)-8-epi-Swainsonine Triacetate
J . Org. Chem., Vol. 65, No. 18, 2000 5699
Sch em e 7a
Sch em e 9a
a
Reagents: (i) (ClCO)2,/DMSO/Et3N/CH2Cl2/-60 °C f rt, (ii)
(see table).
Sch em e 8a
a
Reagents: (i) TBDMS-OTfl/2,6-lutidine/CH2Cl2/0 °C, (ii) 9-BBN/
THF/rt, (iii) H2O2/EtOH/NaOH, (iv) MeSO2Cl/Et3N/CH2Cl2, (v) H2/
Pd-C/MeOH, (vi) CF3COOH/H2O, (vii) Ac2O/DMAP/pyridine.
Sch em e 10a
a
Reagents: (i) (ClCO)2,/DMSO/Et3N/CH2Cl2/-60 °C f rt, (ii)
a
Reagents: (i) (ClCO)2,/DMSO/Et3N/CH2Cl2/-60 °C f rt, (ii)
H2CdCHCH2SnBu3/BF3‚Et2O/CH2Cl2/-78 °C.
H2CdCHCH2SnBu3/MgBr2‚Et2O/CH2Cl2/-20 °C.
synthesis of 1,2-di-epi-swainsonine. On the basis of the
MM2 calculations described above, we reasoned that the
dipole-dipole and/or steric interactions between the
carbonyl and the acetonide groups, which previously
thwarted the desired stereochemical outcome of the
allylation, would be minimized, since the dioxolane group
resided on the opposite face of the pyrrolidine ring. On
the basis of the steric inaccessibility of the reactive
conformer A in the Felkin-Ahn transition state, it was
expected that the reaction would proceed through the
alternate conformer B to give homoallylic alcohol 11b as
the major product (Figure 6). In fact, Swern oxidation of
compound 10b followed by the allylation of the resulting
aldehyde afforded a mixture of homoallylic alcohols in
3.5:1 diastereomeric ratio (Scheme 10).
oxygens of the â-chelate, polarizes the carbonyl group,
which is then perfectly aligned with the migrating
hydride, probably assisted by the nitrogen lone pair.7
P ip er id in e Rin g F or m a tion . Elaboration of the
epimeric Keck product proceeded as expected. Alcohol
11a was protected as the t-butyldimethylsilyl ether
(96%),48 and hydroboration/oxidation49 of the resulting
silyl ether 12a with 9-BBN provided the corresponding
1° alcohol 13a in 73% yield (Scheme 9).
Compound 13a was converted to its corresponding
mesylate 14a under standard conditions,50 and hydro-
genolysis of the N-benzhydryl group proceeded with the
concomitant piperidine ring formation. The product was
then globally deprotected under acidic conditions, and the
resulting indolizidine was acetylated in situ to facilitate
isolation and characterization (64% yield from 13a )
(Scheme 9). Product 15a exhibited physical properties
identical to those reported in the literature for 8-epi-
To confirm the configuration at the homoallylic center,
the piperidine portion of the indolizidine alkaloid was
constructed so that axial/equatorial coupling constants
could be observed in the piperidine ring. The homoallylic
alcohol 11b was converted to the triacetate 15b as before
in excellent overall yield (63%; six transformations)
(Scheme 11). The final deprotection with NaOMe/MeOH
afforded (+)-1,2-di-epi-swainsonine 16b.
swainsonine triacetate {mp 77-78 °C, [R]22 -19.3° (c
D
0.73, CHCl3); lit.51 mp 79-80 °C, [R]19 -17.1° (c 0.35,
D
CHCl3); lit.52 [R]25 -17.4° (c 0.80, CHCl3)}.
D
The Keck-type allylation, featured prominently in the
synthesis of 8-epimer above, was also utilized in the
To our knowledge, (+)-1,2-di-epi-swainsonine has not
previously been synthesized. Thus, the identity of in-
dolizidine 16b was unequivocally established based on
the comparison of its physical and spectral data to those
from its enantiomer. The spectral data (1H and 13C) and
melting point for synthetic (+)-1,2-di-epi-swainsonine
were in good agreement with previously published data
(48) Corey, E. J .; Cho, H.; Rucker, C.; Hua, D. H. Tetrahedron Lett.
1981, 22, 3455.
(49) (a) Brown, H. C.; Narasimhan, S.; Choi, Y. M. Synthesis 1981,
441. (b) Burgess, K.; Ohlmeyer, M. J . J . Org. Chem. 1991, 56, 1027.
(50) Furst, A.; Koller, F. Helv. Chim. Acta 1947, 30, 1454.
(51) Tadano, K.-I.; Iimura, Y.; Hotta, Y.; Fukabori, C.; Suami, T.
Bull. Chem. Soc. J pn. 1986, 59, 3885.
(52) Blanco, M. J .; Sardina, F. J . J . Org. Chem. 1996, 61, 4748.

5700 J . Org. Chem., Vol. 65, No. 18, 2000
Razavi and Polt
Sch em e 11a
F igu r e 7. Diaxial coupling constants confirm the configura-
tion of 1,2-di-epi-swainsonine.
yield; 3.5:1 dr for 10b f 11b). Both the dioxolane and
the benzhydryl protecting groups can control the stereo-
chemical outcome of the allylation reaction due to dipole-
dipole and steric interactions. For the system studied,
the Lewis acid induced â-chelation allowed 1,2-hydride
migration to compete effectively with allylation of the
aldehyde group, resulting in an aza-pinacol-type rear-
rangement. Obviously, favorable orbital overlap between
the carbonyl, the hydride, and the amine lone pair must
have been achieved to permit this rearrangement, but it
is much less clear if dipole-dipole interactions due to the
acetonide oxygens play a role in the rearrangement. This
novel reaction may have synthetic utility for the synthe-
sis of sterically hindered â-amino alcohols.
In conclusion, the attractive feature of the synthetic
method offered is the stereocontrolled introduction of
functional groups in stepwise fashion. This approach
offers greater flexibility in manipulating orthogonal
protection schemes than carbohydrate-based approaches
and lends itself well to the syntheses of swainsonine
epimers.
a
Reagents: (i) TBDMS-OTfl/2,6-lutidine/CH2Cl2/0 °C, (ii) 9-BBN/
THF/rt, (iii) H2O2/EtOH/NaOH, (iv) MeOSO2Cl/Et3N/CH2Cl2, (v)
H2/Pd-C/MeOH, (vi) CF3COOH/H2O, (vii) Ac2O/DMAP/pyridine,
(viii) cat. NaOMe/MeOH.
for (-)-8,8a-di-epi-swainsonine. In addition, the observed
optical rotation for 16b was comparable in magnitude
and opposite in sign to the literature values for (-)-8,-
8a-di-epi-swainsonine {(+)-1,2-di-epi-swainsonine: mp
127-128 °C, [R]25 +16.1° (c 1.23, MeOH); (-)-8,8a-di-
D
epi-swainsonine: lit.53 mp 130-131 °C, [R]22 -21.2° (c
D
Exp er im en ta l Section
0.78, MeOH); lit.54 mp 129-130 °C, [R]D -18.7° (c 0.55,
Gen er a l Meth od s. 1H NMR spectra were measured at 250
or 500 MHz, and were referenced with internal TMS (0.0 ppm).
The attached proton test (APT) 13C spectra were performed
at 62.9 MHz and were referenced with CDCl3. COSY and
HETCOR spectra were performed at 300 and 75.4 MHz,
respectively. IR spectra were recorded in a KBr pellet, neat,
or as CHCl3 solutions. Melting points are uncorrected. Optical
rotations were taken at the NaD-line. Thin-layer chromato-
graphic analyses were performed on silica gel TLC plates (UV,
250 µm), and visualization was accomplished using 10%
phosphomolybdic acid in EtOH or ninhydrin in a 3% HOAc/
n-BuOH solution. Flash chromatography was performed on
silica gel 60 (230-400 mesh) as described by Still et al.56
Unless stated otherwise, all reactions were carried out in
flame-dried glassware under dry argon atmosphere. Pyridine
and Et3N were dried and distilled over KOH. Solvents were
dried and purified in the following fashion: toluene was
distilled from sodium; Et2O and THF were distilled from
potassium benzophenone ketyl; CH2Cl2 was distilled from
P2O5. DMSO was distilled over CaH2 under reduced pressure.
DMF was dried and distilled from BaO. All other reagents and
solvents were used without further purification.
(2R,3R)-N-Dip h en ylm eth ylen e-1-O-ter t-bu tyld im eth yl-
silyl-2-a m in o-4-p en ten e-1,3-d iol (2a ), (2R,3S)-N-Dip h en -
ylm eth ylen e-1-O-ter t-bu tyld im eth ylsilyl-2-a m in o-4-p en -
ten e-1,3-d iol (2b). To a solution of Schiff base ester 1 (8.00
g, 20.1 mmol) in 200 mL of dry CH2Cl2 was added i-Bu5Al2H
(20.1 mmol, 40.2 mL of 0.5 M 1:1 mixture of DIBAL:TRIBAL
in hexanes) over two h via syringe pump at -78 °C, and the
yellow solution was stirred for 1 h. Next, vinylmagnesium
bromide (60.4 mmol, 60.4 mL 1.0 M solution in THF) was
added to the reaction mixture in a dropwise fashion over 90
min while maintaining the internal temperature of the reac-
tion below -70 °C. The resulting bright orange solution was
allowed to warm to rt gradually. After 10 h, the reaction
MeOH); lit.55 mp 134-135 °C, [R]29 -13.2° (c 0.27,
D
MeOH)}. Furthermore, the 1H NMR analysis of the
indolizidine 16b indicated 8.6 and 7.5 Hz coupling
constants for proton 8a (Figure 7), characteristic of fused
six-membered ring axial-axial protons.
Con clu sion s
Syntheses of (-)-8-epi-swainsonine triacetate 15a and
(+)-1,2-di-epi-swainsonine 16b from D-serine have been
achieved in 6.3% and 4.0% overall yields, respectively.
Both the threo and erythro amino alcohols were synthe-
sized from the O’Donnell’s Schiff base of D-serine 1 in
good yields (44% and 31%, respectively) and without any
detectable racemization of the original chiral center.
Substrate-directed dihydroxylation of the resultant threo
and erythro products proceeded with good selectivity (10:1
at pH 10; 7:1 at pH 12 for 3a ; 5.4:1 at pH 10; 7.8:1 at pH
12 for 3b). The osmylation was primarily directed by the
oxygen-bearing allylic center, and the yield of osmylation
was enhanced at lower pH regardless of the substrate
(70% at pH 10; 60% at pH 12 for 3a , 71% at pH 10; 60%
at pH 12 for 3b). In addition, hydroxyl protecting group
manipulations, typically achieved in a stepwise manner,
were accomplished in tandem with great efficiency (81%
for 8a f 10a , 95% for 8b f 10b). The Keck-type
allylation of pyrrolidines 10a and 10b in the presence of
BF3‚OEt2 proceeded with high yields and moderate to
high selectivities (80% yield; >20:1 dr for 10a f 11a , 77%
(53) Tadano, K-i.; Morita, M.; Hotta, Y.; Ogawa, S.; Winchester,
B.; Cenci di Bello, I. J . Org. Chem. 1988, 53, 5209.
(54) Keck, G. E.; Romer, D. R. J . Org. Chem. 1993, 58, 6083.
(55) Oishi, T.; Iwakuma, T.; Hirama, M.; Ito, S. Synlett 1995, 404.
(56) Still, W. C.; Khan, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923.

Synthesis of (-)-8-epi-Swainsonine Triacetate
J . Org. Chem., Vol. 65, No. 18, 2000 5701
Ta ble 1. 1H NMR Da ta for Ser in e Der ived Acyclic Th r eo
Ta ble 3. 1H NMR Da ta for Ser in e-Der ived Acyclic
P r od u cts (250 MHz, CDCl3)
Er yth r o P r od u cts (250 MHz, CDCl3)
2a a
3a
4a
7a
2ba
3b
4b
7b
Chemical Shift (ppm), Multiplicity
Chemical Shift (ppm), Multiplicity
H-1
H-1′
H-2
H-3
H-4
H-5
H-5′
Ph2CH
5.30 ddd
5.16 ddd
5.74 ddd
5.21 ddd
5.14 ddd
5.75 ddd
5.41 dt
3.62 dd
3.44 dd
3.65 dd
3.56 dd
H-1
H-1′
H-2
H-3
H-4
H-5
H-5′
Ph2CH
5.26 ddd
5.17 ddd
6.06 ddd
5.25 ddd
5.22 ddd
5.91 ddd
5.42 dddd
3.70 dd
3.55 dd
3.61 ddd
3.76
3.76
3.62 dd
3.65
2.75 ddd
3.89 dd
3.86 dd
d
d
3.90
4.94 dd
3.94
m
3.81
3.81
m
m
4.40
t
4.38
3.37
t
m
4.99
3.04
t
d
t
3.01 dt
3.71 dd
3.92 dd
3.81
3.74
3.74
m
m
m
-
m
2.90 dt
3.73 dd
4.04 dd
3.84
3.77
3.77
m
m
m
-
3.83 dd
3.83 dd
3.78 dd
3.71 dd
3.73 dd
3.64 dd
-
-
-
-
-
5.02
s
-
-
-
-
-
4.98
s
Coupling Constants (J H,H, Hz)
Coupling Constants (J H,H, Hz)
J 1,1′
J 1,2
J 1′,2
J 1,3
J 1′,3
J 2,3
J 3,4
J 4,5
J 4,5′
J 5,5′
1.7
17.2
10.2
0.7
0.6
7.9
8.0
1.4
3.1
1.4
17.3
10.6
1.4
1.2
6.2
5.5
-
12.0
3.0
3.9
-
11.3
4.3
4.7
-
-
-
2.8
3.6
4.0
J 1,1′
J 1,2
J 1′,2
J 1,3
J 1′,3
J 2,3
J 3,4
J 4,5
J 4,5′
J 5,5′
1.7
17.2
10.3
1.2
0.9
7.5
7.7
4.9
3.1
10.5
1.2
17.3
10.5
1.2
1.0
6.7
3.9
-
12.5
2.0
4.3
-
-3.5
3.5
-
-
8.3
7.0
2.6
3.9
10.4
-
-
8.9
3.8
5.1
7.2
10.0
9.9
10.0
2.3
2.2
10.0
-
-
-
10.6
-
10.6
a
a
This compound exists as a mixture of two tautomers. The
resonances for the major tautomer (the oxazolidine) are reported
in this table.
This compound exists as a mixture of two tautomers. The
resonances for the major tautomer (the oxazolidine) are reported
in this table.
Ta ble 2. 13C NMR Da ta for Ser in e-Der ived Acyclic Th r eo
Ta ble 4. 13C NMR Da ta for Ser in e Der ived Acyclic
P r od u cts (62.9 MHz, CDCl3)
Er yth r o P r od u cts (62.9 MHz, CDCl3)
chemical shift (ppm)
chemical shift (ppm)
2a a
3a
4a
7a
carbon no.
2ba
3b
4b
7b
carbon no.
C-1
C-2
C-3
C-4
C-5
Ph2CH
116.9
136.3
79.6
62.1
60.4
-
117.6
134.1
75.2
66.2
64.1
-
62.4
64.9
73.4
54.1
61.0
-
63.8
74.3
69.1
59.4
58.5
64.0
C-1
C-2
C-3
C-4
C-5
Ph2CH
117.3
138.0
81.0
65.2
59.4
-
117.3
134.5
74.5
66.3
64.1
-
62.9
70.8
71.7
64.5
62.6
-
64.1
73.5
72.4
56.3
62.5
64.0
a
a
This compound exists as a mixture of two tautomers. The
resonances for the major tautomer (the oxazolidine) are reported
in this table.
This compound exists as a mixture of two tautomers. The
resonances for the major tautomer (the oxazolidine) are reported
in this table.
8.90 mmol) and DMAP (109 mg, 0.890 mmol) in dry pyridine
(36 mL) at 0 °C over 30 min via syringe pump. The resulting
mixture was warmed to rt, and the reaction progress was
monitored by TLC. After 60 h, the reaction mixture was cooled
to 0 °C and poured into a cold saturated NaHCO3, and the
resulting mixture was extracted with CH2Cl2. The organic
layers were pooled, dried over anhydrous K2CO3, filtered
through Celite, and concentrated in vacuo. The residue was
chromatographed (5% EtOAc/hexanes) to provide 3.93 g of 3a
as a colorless oil (92%). Data for 3a : 1H NMR (Table 1); 13C
mixture was cooled to -10 °C and quenched with saturated
NaHCO3. The mixture was poured into ice-cold saturated
NaHCO3, and the phases were separated. The aqueous layer
was extracted with CH2Cl2, and the combined organic layers
were dried over anhydrous K2CO3, filtered, and concentrated
in vacuo. The resulting golden brown oil was purified by flash
chromatography (3% f 5% EtOAc/hexanes gradient) to afford
3.52 g of the amino alcohol 2a and 2.49 g of the diastereomeric
product 2b as colorless oils (76%). Data for 2a : 1H NMR (Table
1); 13C NMR (Table 2); [R]28 -88.6° (c 4.75, CHCl3); IR (neat)
D
NMR (Table 2); [R]28 +12.8° (c 6.16, CHCl3); IR (neat) 3065,
3307, 3056, 2952, 1663, 1447 cm-1; HRMS (FAB) calcd for
D
2952, 1732, 1637, 1464 cm-1; HRMS (FAB) calcd for C29H42
-
C
24H34NO2Si (MH+) 396.2359, found 396.2350. Data for 2b:
NO3Si (MH+) 480.2934, found 480.2941.
1H NMR (Table 3); 13C NMR (Table 4); [R]26 -60.7° (c 4.01,
D
CHCl3); IR (neat) 3480, 3307, 3065, 2952, 1628, 1455 cm-1
;
(2R,3S)-N-Dip h en ylm eth ylen e-1-O-ter t-bu tyld im eth yl-
silyl-3-O-tr im eth yla cetyl-2-a m in o-4-p en ten e-1,3-d iol (3b).
Prepared from allylic alcohol 2b (527 mg, 1.33 mmol), accord-
ing to the procedure used for the synthesis of 3a , to afford 3b
as a pale yellow oil (576 mg, 90% yield). Data for 3b: 1H NMR
HRMS (FAB) calcd for C24H34NO2Si (MH+) 396.2359, found
396.2361.
(2R,3R)-N-Dip h en ylm eth ylen e-1-O-ter t-bu tyld im eth yl-
silyl-3-O-tr im eth yla cetyl-2-a m in o-4-p en ten e-1,3-d iol (3a ).
Trimethylacetyl chloride (6.58 mL, 53.4 mmol) was added to
a solution of Schiff base-protected amino alcohol 2a (3.52 g,
(Table 3); 13C NMR (Table 4); [R]30 -37.5° (c 0.505, CHCl3);
D
IR (neat) 3079, 2957, 1737, 1632, 1477 cm-1; HRMS (FAB)

5702 J . Org. Chem., Vol. 65, No. 18, 2000
Razavi and Polt
Ta ble 5. 1H NMR Da ta for D-Im in olyxitol P r od u cts (250
MHz, CDCl3)
calcd for C29H42NO3Si (MH+) 480.2934, found 480.2930.
(2R ,3S ,4R )-N -Dip h e n ylm e t h yle n e -5-O-t er t -b u t yld i-
methylsilyl-3-O-trimethylacetyl-4-aminopentane-1,2,3,5-tetrol
(4a ). The dihydroxylation was performed according to the
procedure described by Sharpless et al.57 A solution of allylic
pivalate 3a (3.93 g, 8.18 mmol) in t-BuOH (40 mL) was added
to a stirred solution K2CO3 (3.39 g, 24.6 mmol), NaHCO3 (2.06
g, 24.6 mmol), K3Fe(CN)6 (8.08 g, 24.6 mmol), potassium
osmate dihydrate (90.5 mg, 0.246 mmol), and methanesulfona-
mide (778 mg, 8.18 mmol) in H2O, and the resulting bright
yellow biphasic mixture was stirred vigorously at rt for 12 h.
The reaction mixture turned dark brown over time, and the
periodic TLC analysis indicated that the reaction was proceed-
ing very slowly. Thus, additional K2CO3 (3.39 g, 24.6 mmol),
NaHCO3 (2.06 g, 24.6 mmol K3Fe(CN)6 (8.08 g, 24.6 mmol),
and potassium osmate dihydrate (30.2 mg, 0.0818 mmol) was
added to the reaction mixture, and the vigorous stirring was
continued for an additional 24 h. The reaction was quenched
with Na2SO3 (12.4 g, 98.2 mmol), and the resulting dark green
solution was stirred for 45 min. The phases were separated,
and the aqueous layer was extracted with CHCl3. The com-
bined organic layers were dried over MgSO4, filtered, and
concentrated in vacuo. Flash chromatography (20% f 30%
EtOAc/Hexanes gradient) afforded 2.91 g of 4a as a colorless
viscous oil (70%, 10:1 diastereomeric ratio based on 1H NMR
of the crude reaction mixture). Data for 4a : 1H NMR (Table
8a
9a
10a
Chemical Shift (ppm), Multiplicity
H-1
H-1′
H-2
H-3
H-4
H-5
H-5′
Ph2CH
2.50
3.03
3.96
4.26
3.09
3.33
3.51
4.74
dd
d
t
dd
bs
dd
dd
s
2.50
3.53
4.01
4.28
3.08
3.02
3.11
4.76
dd
d
t
dd
m
dd
dd
s
2.06
3.13
4.50
4.64
2.44
3.75
3.88
5.04
dd
d
dd
t
ddd
dd
dd
s
Coupling Constants (J H,H, Hz)
J 1,1′
J 1,2
J 1′,2
J 2,3
J 3,4
J 4,5
J 4,5′
J 5,5′
10.8
3.7
0
4.8
8.7
4.0
1.3
10.4
11.2
4.1
0
5.0
8.8
4.0
1.6
11.3
11.0
4.4
0
6.4
5.0
3.3
6.4
11.7
1); 13C NMR (Table 2); [R]25 -29.9° (c 1.47, CHCl3); IR (neat)
D
Ta ble 6. 13C NMR Da ta for D-Im in olyxitol P r od u cts (62.9
MHz, CDCl3)
3437, 3056, 2961, 1724, 1620, 1464 cm-1; HRMS (FAB) calcd
for C29H44NO5Si (MH+) 514.2989, found 514.2980.
(4R,5R,6S)-4-(ter t-Bu t yld im et h ylsiloxym et h yl)-6-h y-
dr oxym eth yl-5-tr im eth ylacetoxy-2,2-diph en yltetr ah ydr o-
1,3-oxa zin e (4b). Prepared from pivalate 3b (576 mg, 1.20
mmol), according to the procedure used for the synthesis of
4a , to give 4b as a colorless oil (437 mg, 71%, 5.4:1 diastereo-
meric ratio based on 1H NMR of the crude reaction mixture).
chemical shift (ppm)
Data for 4b: 1H NMR (Table 3); 13C NMR (Table 4); [R]20
D
carbon no.
8a
9a
10a
-52.6° (c 1.08, CHCl3); IR (neat) 3437, 3065, 2961, 1724, 1456,
1265, 1152 cm-1; HRMS (FAB) calcd for C29H44NO5Si (MH+)
514.2989, found 514.2969.
C-1
C-2
C-3
C-4
C-5
Ph2CH
56.3
70.8
73.4
62.2
61.6
72.4
56.3
70.5
73.1
62.8
59.0
72.6
53.8
77.3
81.4
64.5
60.3
66.3
(2R,3S,4R)-N-Dip h en ylm eth yl-5-O-ter t-bu tyld im eth yl-
silyl-4-a m in op en ta n e-1,2,3,5-tetr ol (7a ). LiBH4 (472 mg,
21.7 mmol) was added to a solution of diol 4a (2.78 g, 5.42
mmol) in THF (20 mL). The flask was equipped with a reflux
condenser, the resulting mixture was brought to a gentle
reflux, and MeOH (880 µL, 21.7 mmol) was added via syringe
pump over 2 h. The resulting mixture was refluxed for an
additional 8 h, cooled to 0 °C, and quenched by careful addition
of H2O. The mixture was partitioned between saturated
aqueous NaHCO3 and CH2Cl2, and the phases were separated.
The aqueous layer was extracted with CH2Cl2, and the
combined organic layers were dried over MgSO4, filtered, and
concentrated to give a colorless oil. The residue was chromato-
graphed (50% f 70% EtOAc/hexanes gradient) to provide 1.96
g of 7a as a white solid (84%). Data for 7a : 1H NMR (Table
chromatography (50% EtOAc/hexanes) to give 302 mg of 7b
as an oil (82%). Data for 7b: 1H NMR (Table 3); 13C NMR
(Table 4); [R]25D -63.4° (c 1.32, CHCl3); IR (CHCl3) 3411, 3065,
3056, 2918, 2857, 1464, 1256, 1118, 1066 cm-1; HRMS (FAB)
calcd for C24H38NO4Si (MH+) 432.2570, found 432.2582.
5-O-t er t -Bu t yld im e t h ylsilyl-N -d ip h e n ylm e t h yl-1,4-
d id eoxy-1,4-im in o-D-lyxitol (8a ). Ph3P (2.38 g, 9.07 mmol),
CCl4 (880 µL, 9.07 mmol), and Et3N (1.26 mL, 9.07 mmol) were
sequentially added to a solution of aminotetrol 7a (1.96 g, 4.53
mmol) in anhydrous DMF (15 mL) under argon, and the
resulting mixture was stirred in the dark at rt for 17 h. Next,
the reaction mixture was quenched by a dropwise addition of
anhydrous MeOH (10 mL). The mixture was stirred for 30 min,
concentrated in vacuo, and passed through a plug of silica gel.
The filtrate was concentrated, and the resulting residue was
chromatographed (25% EtOAc/hexanes) to afford 1.70 g of 8a
as a white crystalline solid (90%). A small sample was
recrystallized from CH2Cl2/pentane to give an analytically pure
sample. Data for 8a : 1H NMR (Table 5); 13C NMR (Table 6);
mp 80-81 °C; [R]31D +44.4° (c 0.570, CHCl3); IR (CHCl3) 3681,
3616, 3006, 2974, 1518, 1420 cm-1; HRMS (FAB) calcd for
1); 13C NMR (Table 2); mp 99-100 °C; [R]29 -53.0° (c 6.04,
D
CHCl3); IR (CHCl3) 3681, 3616, 3470, 3006, 2974, 1518, 1412
cm-1; HRMS (FAB) calcd for C24H38NO4Si (MH+) 432.2570,
found 432.2562.
(2S,3R,4R)-N-Dip h en ylm eth yl-5-O-ter t-bu tyld im eth yl-
silyl-4-a m in op en ta n e-1,2,3,5-tetr ol (7b). A solution of diol
4b (437 mg, 0.850 mmol) in THF (5 mL) was treated with
LiBH4 (74 mg, 3.40 mmol). The resulting mixture was refluxed,
and the reaction progress was monitored by TLC. After 4 days,
the reduction of imine was deemed complete. Next, MeOH (140
µL, 3.40 mmol) was added in a dropwise manner, and the
resulting mixture was refluxed for an additional 8 h. The
reaction mixture was cooled to 0 °C, quenched with H2O, and
partitioned between saturated NaHCO3 and CH2Cl2. The
aqueous layer was extracted with CH2Cl2, and the combined
organic layers were dried over MgSO4, filtered, and concen-
trated to give a colorless oil. The residue was purified by flash
C
24H36NO3Si (MH+) 414.2464, found 414.2453.
5-O-t er t -Bu t yld im e t h ylsilyl-N -d ip h e n ylm e t h yl-1,4-
d id eoxy-1,4-im in o-D-r ibitol (8b). Aminopolyol 7b (270 mg,
0.626 mmol) was cyclized according to the procedure used for
the synthesis of 8a , to afford 8b as an oil (208 mg, 80%). Data
for 8b: 1H NMR (Table 9); 13C NMR (Table 10); [R]26 +56.0°
D
(c 0.600, CHCl3); IR (CHCl3) 3394, 3065, 3048, 2918, 2857,
1447, 1256, 1100 cm-1; HRMS (FAB) calcd for C24H36NO3Si
(MH+) 414.2464, found 414.2454.
(57) Gobel, T.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl. 1993,
32, 1329.

Synthesis of (-)-8-epi-Swainsonine Triacetate
J . Org. Chem., Vol. 65, No. 18, 2000 5703
Ta ble 7. 1H NMR Da ta for Im in o-L-gu lo-octitol P r od u cts
(250 MHz, CDCl3)
Ta ble 9. 1H NMR Da ta for D-Im in or ibitol P r od u cts (500
MHz, CDCl3)
8b
10b
11a
12a
13a
1.83
Chemical Shift (ppm), Multiplicity
Chemical Shift (ppm), Multiplicity
H-1
H-1′
H-2
H-3
H-4
H-5
H-5′
Ph2CH
3.17
2.57
4.16
4.07
2.94
3.26
3.03
4.84
dd
dd
q
3.03
2.99
4.70
4.52
3.33
3.36
3.32
5.29
dd
dd
ddd
dd
dd
dd
dd
s
H-1
H-1′
H-2
H-3
H-4
H-5
H-6
H-6′
H-7
H-8
2.22
3.03
4.44
4.56
2.65
4.03
2.37
2.65
5.84
5.11
5.11
5.45
dd
dd
dt
dd
m
ddd
dt
m
1.78
3.04
4.34
4.48
2.40
4.32
2.50
2.65
5.98
5.02
5.01
5.76
dd
d
dd
dd
dd
m
ddt
ddd
dddd
d
dd
d
3.07
4.37
4.50
2.43
4.32
1.69
2.03
1.69
3.62
3.62
5.65
dd
dd
dd
m
m
m
m
t
t
dt
dd
dd
s
dddd
d
d
Coupling Constants (J H,H, Hz)
J 1,1′
J 1,2
J 1′,2
J 2,3
J 3,4
J 4,5
J 4,5′
J 5,5′
11.3
5.0
3.8
4.9
4.9
8.5
4.3
9.8
12.9
4.7
2.0
6.2
0
8.9
5.5
12.8
H-8′
Ph2CH
d
s
t
s
s
Coupling Constants (J H,H, Hz)
J 1,1′
J 1,2
J 1′,2
J 2,3
J 3,4
J 4,5
J 5,6
J 5,6′
J 6,6′
J 6,7
J 6′,7
J 7,8
J 7,8′
J 8,8′
11.7
4.9
1.5
5.4
6.5
3.1
8.6
6.5
14.4
8.6
6.2
9.7
17.9
0
11.2
4.5
0
6.4
4.8
7.6
1.7
5.2
15.0
3.7
11.2
4.5
0
6.4
4.7
7.4
Ta ble 10. 13C NMR Da ta for D-Im in or ibitol P r od u cts
(62.9 MHz, CDCl3)
-
-
-
-
-
8.6
10.8
-16.2
0
6.1
-
-
chemical shift (ppm)
carbon no.
8b
10b
Ta ble 8. 13C NMR Da ta for Im in o-L-gu lo-octitol P r od u cts
(62.9 MHz, CDCl3)
C-1
C-2
C-3
C-4
C-5
Ph2CH
57.8
70.6
77.0
67.0
66.1
74.3
55.7
80.7
83.6
66.4
59.9
70.9
mg, 0.403 mmol), according to the procedure used for the
chemical shift (ppm)
synthesis of 10a , to afford 10b as a colorless oil (130 mg, 95%).
carbon no.
11a
12a
13a
Data for 10b: 1H NMR (Table 9); 13C NMR (Table 10); [R]27
D
C-1
C-2
C-3
C-4
C-5
C-6
C-7
C-8
52.7
77.8
80.5
66.5
69.9
39.4
135.7
117.6
66.0
52.5
76.8
80.1
65.1
73.0
39.1
136.2
116.5
63.5
52.8
76.8
80.5
65.5
73.0
30.1
28.7
63.4
64.0
+62.77° (c 0.150, CHCl3); IR (neat) 3446, 3065, 3022, 2987,
1490, 1455, 1386 cm-1; HRMS (FAB) calcd for C21H26NO3
(MH+) 340.1913, found 340.1916.
2,3-O-Isop r op ylid en e-N-d ip h en ylm eth yl-1,4,6,7,8-p en -
ta d eoxy-1,4-im in o-L-gu lo-oct-7-en itol (11a ). Meth od A: A
mixture of oxalyl chloride (60 µL, 0.682 mmol) in CH2Cl2 (800
µL) was cooled to -60 °C under anhydrous conditions, treated
with DMSO (97 µL, 1.36 mmol), and stirred for 10 min. Next,
a solution of alcohol 10a (210 mg, 0.620 mmol) in CH2Cl2 (1.6
mL) was added dropwise via syringe. After 30 min, Et3N (432
µL, 3.01 mmol) was added; the reaction was allowed to warm
to rt at which time it was quenched with H2O and extracted
with CH2Cl2. The combined organic layers were washed with
NH4Cl, saturated NaHCO3, and brine. After drying over
MgSO4, the solution was concentrated at 0 °C in the dark and
used in the next step without purification. The solution of
crude aldehyde and tributylallyl tin (211 µL, 0.682 mmol) in
CH2Cl2 (1.8 mL) was treated with 4 Å molecular sieves and
cooled to -78 °C. Next, BF3‚OEt2 (105 µL, 0.806 mmol) was
added dropwise, and the mixture was stirred for 2 h. Subse-
quently, a mixture of pentane/ether (1:1, 20 mL) was added,
and the reaction was quenched at -78 °C with saturated
NaHCO3. The resulting mixture was vigorously stirred at rt
for 3 h and extracted with ether. The organic layers were dried
over MgSO4, filtered, and concentrated to give a yellow oil
which was flash chromatographed (5% f 10% EtOAc/hexanes
gradient) to afford 189 mg of 11a as a colorless oil (80%, >20:1
diastereomeric ratio).
Ph2CH
2,3-O-Isop r op ylid en e-N-d ip h en ylm eth yl-1,4-d id eoxy-
1,4-im in o-D-lyxitol (10a ). Camphorsulfonic acid (621 mg, 2.03
mmol) and 2,2-dimethoxypropane (1.13 mL, 9.21 mmol) were
added to a solution of pyrrolidine 8a (762 mg, 1.84 mmol) in
CH2Cl2 (30 mL), the resulting mixture was brought to a gentle
reflux, and the reaction progress was monitored by TLC. After
72 h, the reaction mixture was poured into aqueous saturated
NaHCO3, and the phases were separated. The aqueous layer
was extracted with CH2Cl2, and the combined organic layers
were dried over MgSO4, filtered through a pad of Celite, and
concentrated in vacuo. The residue was chromatographed (5%
f 25% EtOAc/hexanes gradient) to afford 504.7 mg of 10a as
a colorless oil (81%). Data for 10a : 1H NMR (Table 5); 13C NMR
(Table 6); [R]24 -44.7° (c 2.06, CHCl3); IR (neat) 3437, 3056,
D
3022, 3013, 2926, 1499, 1447, 1369 cm-1; HRMS (FAB) calcd
for C21H26NO3 (MH+) 340.1913, found 340.1909.
2,3-O-Isop r op ylid en e-N-d ip h en ylm eth yl-1,4-d id eoxy-
1,4-im in o-D-r ibitol (10b). Prepared from pyrrolidine 8b (167

5704 J . Org. Chem., Vol. 65, No. 18, 2000
Razavi and Polt
Ta ble 11. 1H NMR Da ta for Im in o-D-a llo-octitol P r od u cts
(500 MHz, CDCl3)
Ta ble 12. 13C NMR Da ta for Im in o-D-a llo-octitol
P r od u cts (62.9 MHz, CDCl3)
11b
12b
13b
3.09
chemical shift (ppm)
Chemical Shift (ppm), Multiplicity
carbon no.
11b
12b
13b
H-1
H-1′
H-2
H-3
H-4
H-5
H-6
H-6′
H-7
H-8
3.15
2.78
4.65
4.76
3.06
3.63
2.15
2.14
5.60
5.04
5.05
5.12
dd
dd
dt
dd
dd
ddd
m
m
dddd
d
3.09
2.88
4.64
4.81
3.27
3.84
2.14
2.05
4.98
4.64
4.74
5.09
dd
dd
ddd
d
d
ddd
dt
dd
d
t
d
d
ddd
m
m
m
t
C-1
C-2
C-3
C-4
C-5
C-6
C-7
C-8
56.4
79.8
80.9
69.5
68.8
38.5
134.4
117.9
69.8
57.4
81.7
81.8
68.6
72.9
40.3
133.4
116.8
71.8
57.4
81.7
81.8
68.9
72.6
31.6
28.2
62.2
71.7
2.91
4.66
4.81
3.24
3.79
1.38
1.38
0.83
3.24
3.24
5.09
m
dddd
dd
ddd
s
Ph2CH
H-8′
Ph2CH
d
s
t
s
mg, 1.05 mmol) and 2,6-lutidine (305 µL, 2.62 mmol) in CH2-
Cl2 (20 mL) was cooled to -5 °C and treated with t-BuMe2-
Si-SO2CF3 (289 µL, 1.26 mmol). After 30 min at 0 °C, the
reaction mixture was quenched with aqueous saturated NaH-
CO3, phases were separated, and the aqueous layer was
extracted with CH2Cl2. The combined organic layers were dried
over MgSO4, filtered, and concentrated in vacuo. The crude
reaction product was chromatographed (2% EtOAc/hexanes)
to give 498 mg of 12a as an oil (96%). Data for 12a : 1H NMR
Coupling Constants (J H,H, Hz)
J 1,1′
J 1,2
J 1′,2
J 2,3
J 3,4
J 4,5
J 5,6
J 5,6′
J 6,6′
J 6,7
J 6′,7
J 7,8
J 7,8′
J 8,8′
11.4
5.4
2.9
6.4
1.8
3.0
5.8
8.2
-
7.1
6.8
10.2
17.2
0
11.8
5.0
1.0
6.2
0
1.5
9.6
4.0
14.2
7.6
6.5
10.2
17.1
3.2
11.7
0
4.9
6.2
0
1.0
9.5
2.7
(Table 7); 13C NMR (Table 8); [R]25 -63.0° (c 0.540, CHCl3);
D
-
IR (neat) 3061, 3024, 2931, 2851, 1641, 1597, 1492, 1443, 1375
cm-1; HRMS (FAB) calcd for C30H44NO3Si (MH+) 494.3090,
found 494.3076.
-
-
-
-
0
5-O-ter t-Bu t yld im et h ylsilyl-2,3-O-isop r op ylid en e-N-
d ip h en ylm et h yl-1,4,6,7,8-p en t a d eoxy-1,4-im in o-D-a llo-
oct-7-en itol (12b). Prepared from homoallylic alcohol 11b
(105 mg, 0.276 mmol), according to the procedure used for the
synthesis of 12a , to give 12b as a colorless oil (123 mg, 90%).
Meth od B: A solution of oxalyl chloride (13 µL, 0.142 mmol)
in CH2Cl2 (160 µL) was cooled to -70 °C treated with DMSO
(20 µL, 0.283 mmol) and stirred for 5 min. Alcohol 10a (43.7
mg, 0.129 mmol) in CH2Cl2 (340 µL) was added to the reaction
mixture in a dropwise manner, and the resulting solution was
stirred for 30 min. Next, Et3N (90 µL, 0.644 mmol) was added
at -70 °C, and the mixture was allowed to warm to rt. The
reaction was quenched with H2O and extracted with CH2Cl2.
The combined organic layers were sequentially washed with
NH4Cl, saturated NaHCO3, and brine, dried over MgSO4,
concentrated at 0 °C in the dark, and used without further
purification.
Data for 12b: 1H NMR (Table 11); 13C NMR (Table 12); [R]25
D
+19.4° (c 0.720, CHCl3); IR (neat) 3091, 3082, 2926, 2857, 1646,
1602, 1447, 1377, 1248, 1118 cm-1; HRMS (FAB) calcd for
C
30H44NO3Si (MH+) 494.3090, found 494.3085.
5-O-(ter t-Bu tyld im eth ylsilyl)-2,3-O-isop r op ylid en e-N-
d ip h en ylm eth yl-1,4,6,7-tetr a d eoxy-1,4-im in o-L-gu lo-octi-
tol (13a ). A solution of compound 12a (76.2 mg, 0.154 mmol)
in anhydrous THF (1.2 mL) was treated with 9-BBN (0.232
mmol, 463 µL of a 0.5 M solution in THF) and stirred at RT
for 20 h. Next, the reaction was cooled to 0 °C and quenched
with EtOH (1 mL). The resulting mixture was sequentially
treated with NaOH (0.232 mmol, 77.0 µL, 3 M) and H2O2
(0.232 mmol, 23.0 µL, 30% solution). After stirring at rt for 3
h, the reaction mixture was diluted with CH2Cl2 and washed
with brine. The aqueous layer was back-extracted with CH2-
Cl2, and the combined organic layers were washed with
saturated NH4Cl, aqueous saturated NaHCO3, and brine.
Subsequently, the organic layer was dried over MgSO4, filtered
through a pad of Celite, and concentrated. Chromatography
(20% EtOAc/hexanes) afforded 57.2 mg of 13a (73%). Data for
The crude aldehyde was dissolved in MeOH (130 µL) and
treated with Sn(CH2CHdCH2)4 (9 µL, 0.039 mmol). The
resulting mixture was stirred at rt, and the reaction progress
was monitored by TLC. After 4 days, ether (5 mL) and aqueous
KF (1 mL saturated KF; 4 mL H2O) were added, and the
mixture was vigorously stirred at rt for 20 min. Phases were
separated, and the aqueous layer was extracted with ether.
Organic layers were pooled, extracted with NaHCO3, dried
over MgSO4, filtered, and concentrated to give a yellow oil
which was purified on silica gel (10% EtOAc/hexanes) to afford
32.1 mg of 11a as an oil (66%, .20:1 diastereomeric ratio).
13a : 1H NMR (Table 7); 13C NMR (Table 8); [R]22 -91.1° (c
0.640, CHCl3); IR (neat) 3432, 3065, 3021, 2933, 2855, 1597,
1457, 1378 cm-1; HRMS (FAB) calcd for C30H46NO4Si (MH+)
512.3196, found 512.3196.
D
Data for 11a : 1H NMR (Table 7); 13C NMR (Table 8); [R]27
-76.9° (c 1.08, CHCl3); IR (neat) 3567, 3468, 3061, 2974, 2931,
1641, 1591, 1492 cm-1; HRMS (FAB) calcd for C24H30NO3
(MH+) 380.2226, found 380.2222.
D
5-O-(ter t-Bu tyld im eth ylsilyl)-2,3-O-isop r op ylid en e-N-
d ip h en ylm eth yl-1,4,6,7-tetr a d eoxy-1,4-im in o-D-a llo-octi-
tol (13b). Prepared from compound 12b (120 mg, 0.243 mmol),
according to the procedure used for the synthesis of 13a , to
furnish 13b as an oil (94 mg, 76%). Data for 13b: 1H NMR
2,3-O-Isop r op ylid en e-N-d ip h en ylm eth yl-1,4,6,7,8-p en -
ta d eoxy-1,4-im in o-D-a llo-oct-7-en itol (11b). Prepared from
alcohol 10b (128 mg, 0.376 mmol), according to procedure A,
to give 11b as a colorless oil (110 mg, 77%, 3.5:1 diastereomeric
ratio). Data for 11b: 1H NMR (Table 11); 13C NMR (Table 12);
[R]30D +6.71° (c 0.830, CHCl3); IR (neat) 3446, 3074, 3030, 2987,
(Table 11); 13C NMR (Table 12); [R]28 -3.30° (c 1.01, CHCl3);
D
IR (neat) 3437, 3065, 3030, 2952, 2849, 1455, 1386, 1248, 1049
cm-1; HRMS (FAB) calcd for C30H46NO4Si (MH+) 512.3196,
found 512.3190.
2926, 1455, 1386, 1109 cm-1; HRMS (FAB) calcd for C24H30
NO3 (MH+) 380.2226, found 380.2216.
-
5-O-ter t-Bu t yld im et h ylsilyl-2,3-O-isop r op ylid en e-N-
d ip h en ylm et h yl-1,4,6,7,8-p en t a d eoxy-1,4-im in o-L-gu lo-
oct-7-en itol (12a ). A solution of homoallylic alcohol 11a (398
(1S,2R,8S,8a R)-1,2,8-Tr ia cetoxyin d olizid in e [(-)-8-epi-
sw a in son in e tr ia ceta te] (15a ). A solution of alcohol 13a (321
mg, 0.626 mmol) in CH2Cl2 (30 mL) was cooled to -5 °C and

Synthesis of (-)-8-epi-Swainsonine Triacetate
J . Org. Chem., Vol. 65, No. 18, 2000 5705
Ta ble 13. 1H NMR Da ta for In d olizid in e P r od u cts (500
MHz, CDCl3)
Ta ble 14. 13C NMR Da ta for In d olizid in e P r od u cts (62.9
MHz, CDCl3)
15a
15b
16b
3.94
chemical shift (ppm)
Chemical Shift (ppm), Multiplicity
carbon no.
15a
15b
16b
H-1
5.40
5.26
3.27
2.43
2.10
3.22
1.54
2.00
1.46
1.90
5.36
2.26
t
5.01
5.20
3.57
2.33
2.10
2.93
1.63
1.72
1.29
2.10
4.69
2.29
t
t
C-1
C-2
C-3
C-5
C-6
C-7
C-8
C-8a
71.9
69.8
59.1
53.2
19.6
29.6
66.1
66.6
73.9
68.4
58.5
51.2
23.6
30.1
72.9
67.4
75.9
69.3
61.6
53.3
25.3
34.9
73.4
74.2
H-2
dt
dd
dd
m
ddd
dd
dd
m
4.20
3.41
2.27
2.13
2.93
1.54
1.78
1.34
2.06
3.54
1.99
q
H-3
dd
dd
t
br,d
m
br,d
dq
m
dt
t
H-3′
H-5ax
H-5eq
H-6ax
H-6eq
H-7ax
H-7eq
H-8
m
br,d
dddt
m
m
m
ddd
t
m
m
m
m
mp 132-134 °C, [R]23D +61.1° (c 2.11, CHCl3); IR (CHCl3) 2952,
2926, 2857, 1750, 1395, 1239, 1109 cm-1; HRMS (FAB) calcd
for C14H22NO6 (MH+) 300.1447, found 300.1449.
br,t
dd
H-8a
Coupling Constants (J H,H, Hz)
(1R,2S,8R,8a R)-1,2,8-Tr ih yd r oxyin d olizid in e [(+)-1,2-
d i-epi-sw a in son in e] (16b). A solution of compound 15b (34
mg, 0.114 mmol) in anhydrous MeOH (1 mL) was treated with
NaOMe/MeOH at rt until the solution remained basic, and the
reaction progress was monitored by TLC. Upon completion,
the reaction mixture was applied to a short column of SiO2
and eluted with 20% MeOH/CH2Cl2 to give 19.4 mg of 16b as
a white crystalline solid (98%). Data for 16b: 1H NMR (Table
13); 13C NMR (Table 14); mp 127-128 °C, [R]25D +16.1° (c 1.23,
MeOH); HRMS (FAB) calcd for C8H16NO3 (MH+) 174.1130,
found 174.1134.
J 1,2
6.5
5.8
1.8
6.8
11.2
-
7.7
7.7
6.9
5.7
10.0
10.7
-
7.5
7.5
7.4
6.4
9.8
J 1,8a
J 2,3
J 2,3′
J 3,3′
J 5ax,5eq
J 5ax,6eq
J 5ax,6ax
J 6ax,5eq
J 6eq,5eq
J 6ax,6eq
J 6ax,7eq
J 6ax,7ax
J 6eq,7eq
J 6eq,7ax
J 7eq,7ax
J 7ax,8
10.2
1.2
11.1
-
-
-
-
-
-
-
-
-
-
13.6
-
13.8
-
-
-
-
-
-
4-C-Allyl-2,3-O-isop r op ylid en e-N-d ip h en ylm eth yl-1,4-
d id eoxy-1,4-im in o-D-lyxitol (17). Swern oxidation was per-
formed on alcohol 10a (139 mg, 0.411 mmol) as prescribed in
procedure A. Next, the crude aldehyde was treated with 4A
activated molecular sieves (150 mg, powder) and MgBr2‚OEt2
(212 mg, 0.822 mmol) in CH2Cl2 (6 mL) at -20 °C. The
resulting mixture was stirred at -20 °C for 30 min, Bu3SnCH2-
CHdCH2 (140 µL, 0.452 mmol) was added, and the reaction
mixture was stored at -23 °C. After 20 h, ether (10 mL) and
aqueous KF (1 mL saturated KF; 4 mL H2O) were added, and
the mixture was vigorously stirred at rt for 30 min. Phases
were separated, and the aqueous layer was extracted with
ether. Organic layers were pooled, extracted with NaHCO3 (5
mL), dried over MgSO4, filtered, and concentrated. The residue
was purified on silica gel (10% EtOAc/hexanes) to afford 99.6
mg of 17 as an oil (64%, >20:1 dr). Data for 17: 1H NMR
(CDCl3, 250 MHz) δ 7.15-7.40 (10H, m, Ar), 5.50-5.66 (1H,
dddd, J ) 17.8, 10.3, 7.6, 7.3 Hz, CH)CH2), 5.24 (1H, s,
Ph2CH), 4.9-5.0 (2H, m, CdCH2), 4.58 (1H, s, H-C(3)), 4.57
(1H, d, J ) 2.0 Hz, H-C(2)), 3.61-3.78 (2H, ddd, J ) 11.8, 7.0,
5.7 Hz, H-C(5)), 3.14 (1H, d, J ) 10.8 Hz, H-C(1)), 2.83 (1H,
dt, J ) 10.8, 2.0 Hz, H-C(1)), 2.71 (1H, dd, J ) 7.0, 5.7 Hz,
O-H), 2.25 (1H, dd, J ) 14.1, 7.7 Hz, CH-CdC), 2.10 (1H, dd,
J ) 14.1, 7.3 Hz, CH-CdC), 1.62 (3H, s, Me), 1.31 (3H, s, Me);
13C NMR (CDCl3, 62.9 MHz) δ 143.1 (Ar), 142.1 (Ar), 134.0
(CHdCH2), 129.6 (Ar), 128.2 (Ar), 128.1 (Ar), 127.9 (Ar), 126.9
(Ar), 126.6 (Ar), 118.1 (C)CH2), 111.1 (-O-C-O-), 85.0 (C3),
77.5 (C2), 68.5 (C4), 65.7 (C5), 62.8 (Ph2C), 52.7 (C1), 36.7
(CH2-CdC), 26.2 (CH3), 24.3 (CH3); HRMS (FAB) calcd for
-
-
-
-
3.7
12.4
9.9
4.2
8.6
-
-
-
11.0
4.6
9.2
J 7eq,8
J 8,8a
-
1.3
sequentially treated with Et3N (131 µL, 0.939 mmol) and CH3-
SO2Cl (73 µL, 0.939 mmol). After 30 min, the reaction was
quenched with saturated NaHCO3. Next, the organic layer was
washed with aqueous saturated NH4Cl and brine, dried over
MgSO4, filtered, and concentrated in vacuo. The crude reaction
mixture was used in the next step without purification.
The crude mesylate 14a was azeotroped with EtOAc and
dissolved in MeOH (30 mL). The flask was purged with argon
and charged with Pd-C (200 mg, 10%). Subsequently, the
reaction vessel was evacuated and charged with H2 gas three
times. The suspension was stirred under an atmosphere of H2
gas (rubber balloon) for 20 h. Next, the reaction was quenched
with 2 mL of CH2Cl2, filtered through a pad of Celite, and
concentrated to give a yellow oil. The crude indolizidine was
dissolved in a mixture of H2O (5 mL) and TFA (5 mL) and
stored at rt. After 72 h, the mixture was concentrated in vacuo
at rt, and the resulting residue was azeotroped with toluene
to give a waxy solid.
The crude reaction mixture was dissolved in dry pyridine
(5 mL) and treated with DMAP (8 mg, 63 µmol). Next, the
reaction was cooled to 0 °C, and Ac2O (540 µL, 5.67 mmol) was
added in a dropwise fashion. The reaction mixture was stirred
at rt for 14 h, concentrated, dissolved in CH2Cl2, and extracted
with saturated NaHCO3. Subsequently, the organic layer was
dried over MgSO4, filtered, and concentrated in vacuo. The
residue was flashed chromatographed to give 120 mg of 15a
as a off-white solid (64%). Data for 15a : 1H NMR (Table 13);
C
24H30NO3 (MH+) 380.2226, found 380.2231.
Ack n ow led gm en t. We gratefully acknowledge the
Arizona Disease Control Research Commission, the
National Science Foundation (CHE-9526909), and the
U.S. Army for financial support. H.R. thanks the
University of Arizona Graduate College for a Dean’s
Fellowship. Full spectral characterization of compound
16b was performed by Mr. Michael M. Palian to whom
we are indebted. Additionally, we thank Dr. Michael
Carducci of the University of Arizona Molecular Struc-
ture Laboratory, and Dr. Charles Campana of Bruker
Analytical X-ray Systems, for the X-ray structure de-
13C NMR (Table 14); mp 77-78 °C, [R]22 -19.3° (c 0.730,
D
CHCl3); IR (CHCl3) 2935, 2857, 1741, 1377, 1248, 1109 cm-1
;
HRMS (FAB) calcd for C14H22NO6 (MH+) 300.1447, found
300.1458.
(1R,2S,8R,8a R)-1,2,8-Tr ia cetoxyin d olizid in e [(+)-1,2-
d i-epi-sw a in son in e tr ia ceta te] (15b). Prepared from alcohol
13b (93.4 mg, 0.183 mmol), according to the procedure used
for the synthesis of 15a , to give 15b as a white solid (34.4 mg,
63%). Data for 15b: 1H NMR (Table 13); 13C NMR (Table 14);

5706 J . Org. Chem., Vol. 65, No. 18, 2000
Razavi and Polt
10b, 12a , 12b, 15b, 16b, and 17. A complete X-ray structure
report is available for compound 8a . This material is available
free of charge via the Internet at http://pubs.acs.org.
termination of 8a , and Prof. Michael P. Doyle for use of
analytical equipment.
Su p p or tin g In for m a tion Ava ila ble: Proton and carbon
NMR spectra are available for compounds 2a , 2b, 7a , 7b, 10a ,
J O000527U