Total synthesis of (+)-alexine by utilizing a highly stereoselective [3+2] annulation reaction of an TV-tosyl-α-amino aldehyde and a 1,3-bis(silyl)propene

Article abstract of DOI:10.1002/chem.200701776

A novel route towards the polyhydroxylated pyrrolizidine alkaloid (+)-alexine has been developed. A key step in this synthesis is a highly stereoselective [3+2] annulation reaction of N-Ts-α-amino aldehyde 7a (Ts=tosyl) and 1,3-bis(silyl)propene 8a for the construction of the polyhydroxylated pyrrolidine subunit of the target molecule. Previous synthetic strategies rely on carbohydrates that require several protecting-group manipulations, there-by making the total number of steps relatively high. The [3+2] annulation strategy compares favorably with carbohydrate-based syntheses and constitutes a highly efficient entry to polyhydroxylated alkaloids.

Full text of DOI:10.1002/chem.200701776

DOI: 10.1002/chem.200701776
Total Synthesis of (+)-Alexine by Utilizing a Highly Stereoselective [3+2]
Annulation Reaction of an N-Tosyl-a-Amino Aldehyde and a 1,3-
BisACHTREUNG(silyl)propene
Martina Dressel,[a] Per Restorp,[a] and Peter Somfai*[a, b]
Abstract: A novel route towards the
polyhydroxylated pyrrolizidine alkaloid
(+)-alexine has been developed. A key
step in this synthesis is a highly stereo-
selective [3+2] annulation reaction of
N-Ts-a-amino aldehyde 7a (Ts=tosyl)
pyrrolidine subunit of the target mole-
cule. Previous synthetic strategies rely
on carbohydrates that require several
protecting-group manipulations, there-
by making the total number of steps
relatively high. The [3+2] annulation
strategy compares favorably with car-
bohydrate-based syntheses and consti-
tutes a highly efficient entry to poly-
hydroxylated alkaloids.
Keywords: annulation · asymmetric
synthesis · natural products · nitro-
gen heterocycles · silanes
and 1,3-bisACHTREUNG(silyl)propene 8a for the
construction of the polyhydroxylated
Introduction
Polyhydroxylated pyrrolidine and pyrrolizidine alkaloids are
a class of naturally occurring compounds, primarily isolated
from plants throughout the world, that have attracted con-
siderable attention owing to their significant biological activ-
ity.[1] Many of these alkaloids exhibit diverse biological ac-
tivities, including powerful glycosidase inhibitory properties
and antiviral and antiretroviral activities, and are, therefore,
potential chemotherapeutic drug targets for HIV and cancer
therapy.[2] Noteworthy members of this important class of
compounds are (+)-alexine ((+)-1), (+)-australine ((+)-2),
(+)-casuarine ((+)-3), and hyacinthacine A1 (4), which are
all structurally related and differ only in relative stereo-
chemistry (compare 1 and 2) and the level of hydroxylation
(compare 3 and 4). Formally, compounds 1–4 can be derived
from the monocyclic glycosidase inhibitors 2,5-dideoxy-2,5-
imino-d-mannitol, DMDP (5) and 2,5-dideoxy-2,5-imino-d-
glucitol, DGDP (6).
Biological screenings of these compounds have demon-
strated that the substitution pattern and stereochemistry of
the hydroxy groups in the pyrrolizidine skeleton have a sig-
nificant impact on their biological activity.[2] Therefore, a
number of synthetic routes leading to natural as well as un-
natural isomers of pyrrolizidine alkaloids have been devel-
oped. Owing to the structural resemblance to sugars, syn-
thetic routes to alexine ((+)-1) and several of their structur-
ally related congeners have exploited the intrinsic chirality
and highly oxygenated architecture of carbohydrates as
starting materials.[3]
[a] Dr. M. Dressel, Dr. P. Restorp, Prof. P. Somfai
Organic Chemistry, KTH Chemical Science and Engineering
Royal Institute of Technology
Teknikringen 36, 10044 Stockholm (Sweden)
Fax : (+46)8-791-2333
E-mail: somfai@kth.se
Although the use of sugar-derived precursors minimizes
the need to introduce the requisite stereocenters and hy-
droxy moieties, several of these syntheses are impractical
owing to the large number of synthetic steps, the need for
extensive protecting group manipulations, and the apparent
lack of stereochemical flexibility. To meet the demands for
[b] Prof. P. Somfai
Institute of Technology
University of Tartu
Nooruse 1, 50411 Tartu (Estonia)
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FULL PAPER
higher synthetic efficiency, focused and divergent asymmet-
ric routes from achiral starting materials have been devel-
oped that, to date, mainly rely on stereoselective reductions
of pyrroles,[4] Sharpless asymmetric amino-hydroxylations[5]
and dihydroxylations,[6] ring-closing metathesis,[7] and
tandem [4+2]/ACHTREUNG[3+2] cycloaddition reactions of nitroal-
kenes.[8] Recently, a synthesis of polyhydroxylated pyrroli-
dine alkaloids based on asymmetric allylic alkylations of bu-
tadiene epoxide with amines was reported by Trost et al.[9]
The Lewis acid promoted addition of allylsilanes to alde-
hydes (Sakurai–Hosomi allylation) is an important method
[10]
ꢀ
for stereoselective C C bond formation. Allylsilanes can
also function as synthetic equivalents of 1,2- and 1,3-dipoles
in [3+2] annulation reactions with activated aldehydes,[11]
imines,[12] and chlorosulfonyl isocyanates.[13] These ap-
proaches have been well studied and provide efficient en-
tries to five-membered heterocyclic ring systems, mainly
functionalized 2-pyrrolidone (g-lactam)[13] and THF[11] sub-
units. In contrast, the corresponding [3+2] annulation reac-
tion to afford functionalized pyrrolidines has only received
scarce attention.[12,14] Recently, we reported that highly func-
tionalized pyrrolidines 9, containing four contiguous stereo-
centers can be prepared by a [3+2] annulation reaction of
Scheme 2. Retrosynthetic analysis of (+)-alexine ((+)-1).
duced by a substrate-controlled nucleophilic allylation or vi-
nylation of the corresponding aldehyde 11. The synthesis of
(+)-1 commenced with aldehyde 7a and silane 8a, which
smoothly underwent a highly stereoselective [3+2] annula-
tion reaction to afford pyrrolidine 9a as a single diastereo-
mer (Scheme 3).[15] Desilylation under acidic conditions then
protected a-amino aldehydes 7 and 1,3-bisACHTRE(UGN silyl)propenes 8
(Scheme 1).[15] The efficiency of the method was also dem-
Scheme 1. The stereoselective synthesis of functionalized pyrrolidines 9.
onstrated by a straightforward synthesis of DGDP (6). We
now wish to describe our efforts to apply this novel annula-
tion methodology to the synthesis of the polyhydroxylated
pyrrolizidine alkaloid (+)-alexine ((+)-1).
Scheme 3. Synthesis of aldehyde 11.
Results and Discussion
afforded diol 10 in an excellent yield. The synthesis then re-
quired a chemoselective oxidation of the primary hydroxy
group in 10, thus setting the stage for introducing the C7 ste-
reocenter. After screening several methods, it was found
that 2,2,6,6-tetramethylpiperidinyl-N-oxyl (TEMPO)/NaOCl
cleanly furnished aldehyde 11[18] in a quantitative yield with
no sign of oxidation of the secondary alcohol or aldehyde
epimerization.[17] At this point, the substrate-controlled dia-
stereoselective additions to aldehyde 11 were examined
(Scheme 4). It was envisioned that the correct C7 stereo-
chemistry required for (+)-1 could be installed by a Felkin–
Anh-controlled addition to 11 in which the (ꢀ)-sulfonamide
moiety acts as the large group and exerts the major stereodi-
recting effect.[19] Alternatively, a chelation-controlled nucle-
ophilic addition to a six-membered cyclic chelate, as previ-
Carbon–silicon bonds can be oxidized to carbon–oxygen
bonds with retention of configuration in which the reaction
requires proper selection of the substituents on the Si nu-
cleus.[16] With this in mind, it was reasoned that our recently
developed [3+2] annulation methodology would be an ideal
starting point for an expedient synthesis of (+)-alexine
((+)-1). Accordingly, we envisioned that pyrrolidine 9a,
which is readily available from aldehyde 7a[17] and silane 8a
by a [3+2] annulation reaction, would serve as an advanced
intermediate towards compound 1 (Scheme 2). Notably, four
of the stereocenters required for compound 1 are introduced
in this step with excellent selectivity. It was then reasoned
that the remaining C7 stereocenter of (+)-1 could be intro-
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3073

P. Somfai et al.
alcohol 15 in a 72% yield over two steps. Removal of the
tosyl group then gave amine 16 in excellent yield.
Different conditions were evaluated for the 5-exo-tet ring
closure of 16 into pyrrolizidine 17. It has recently been re-
ported that MsCl (MsCl=mesyl chloride) also effects this
cyclization in other similar systems, with the reaction pro-
ceeding by a selective mesylation of the primary hydroxy
group followed by ring closure.[4] However, treatment of 16
with MsCl at 08C only gave a complex mixture of products,
perhaps indicating that, for the present case, the mesylation
suffers from poor chemoselectively. Instead, the cyclization
could be accomplished by converting the primary hydroxy
moiety in 16 into the corresponding alkylbromide followed
by cyclization to afford the pyrrolizidine 17 in good yields.
Having synthesized 17, only two steps remained to com-
plete the synthesis of (+)-1: a stereospecific Tamao–Fleming
oxidation of the Me2PhSi groups and removal of the benzyl
ethers. It is known that the oxi-
Scheme 4. Allylation/vinylation of 11.
ously described for TiCl4-promoted additions of allylsilanes
to a-alkoxy aldehydes, is also expected to furnish the correct
C7 stereochemistry.[20] In this event, treatment of aldehyde
11 with vinylmagnesium bromide at ꢀ788C afforded pyrroli-
dine 12 in excellent yields but as an inseparable mixture of
C7 stereoisomers (Scheme 4 and Table 1, entry 1). Lowering
dation of dimethylphenylsilyl
moieties to the corresponding
alcohols can be accomplished in
a one-pot procedure by treat-
Table 1. Stereoselective allylation/vinylation of aldehyde 11.
Entry
Nu:
Lewis acid
T [8C]
dr[a] (Yield [%])[b]
Product
1[c]
2[c]
3[f]
4[g]
CH2=CHMgBr
CH2=CHMgBr
CH2=CHCH2TMS
CH2=CHCH2TMS
n/a[d]
n/a
TiCl4
ꢀ78
86:14 (90)
90:10 (85)
>95:5 (70)
>95:5 (56)
12[e]
12[e]
13
ꢀ100
ment with a suitable electro-
ꢀ78
phile (Br2 or Hg2+ ion) in
TiCl
2A
ꢀ78 to ꢀ50
13
AcOOH/AcOH.[16,23] Alterna-
[a] Determined by 1H NMR analysis of the crude reaction mixtures. [b] Yield of the isolated product after
flash chromatography. [c] Vinylmagnesium bromide (5 equiv) was added to a solution of aldehyde 11 in Et2O
at the indicated temperature. [d] n/a=non applicable. [e] Product not fully characterized. [f] Allyltrimethyl-
silane (3 equiv) was added to a solution of aldehyde 11 and TiCl4 (1.5 equiv) in CH2Cl2. [g] Allyltrimethyl-
tively, the oxidation can be per-
formed in a two-step sequence
by transforming the dimethyl-
phenylsilyl moieties into the
silane (3 equiv) was added to a solution of aldehyde 11 and TiCl2ACHTRE(UNG OiPr)2 (3 equiv) in CH2Cl2.
corresponding silylfluorides by
using BF3·AcOH or HBF4·OEt2
the reaction temperature to ꢀ1008C resulted in only a mar-
ginal improvement in the diastereoselectivity (Table 1,
entry 2). However, treatment of aldehyde 11 with allyltrime-
thylsilane and TiCl4 afforded pyrrolidine 13 in 70% yield as
a single detectable stereoisomer. The use of the less reactive
in CH2Cl2 or AcOH, followed by oxidation to the corre-
sponding alcohols by using H2O2. The latter protocol is re-
ported to be less prone to oxidize tertiary amines.[21] Initial
attempts to oxidize 17 by using Br2 (generated in situ from
KBr) in AcOOH/AcOH yielded a complex mixture of prod-
ucts with no sign of the formation of 18. Instead, we turned
our attention to the two-step procedures described above,
which have previously been successfully used for oxidation
of dimethylphenylsilyl moieties in the presence of tertiary
amines.[24] However, treatment of 17 with BF3·AcOH or
HBF4·OEt2 in CH2Cl2 or AcOH at ambient temperature
gave only starting material, whereas higher reaction temper-
atures resulted in the rapid decomposition of 17. Similarly,
Lewis acid analogue TiCl2ACHTRE(UNG OiPr)2 resulted in similar stereo-
selectivity but a somewhat diminished yield. Additionally,
the reaction temperature had to be increased to ꢀ508C to
ensure full conversion of 11 (Table 1, entry 4). Further at-
tempts to optimize this reaction by employing other mono-
dentate and chelating Lewis acids (BF3·OEt2 and MeAlCl2)
gave inferior results.
To complete the synthesis, the vinyl moiety in 13 must be
cleaved followed by insertion of the pyrrolizidine ring
system. Initially it was planned to perform this sequence
without protecting the secondary hydroxy groups in 13, the
argument being that sufficient chemoselectivity to perform
this should be inherent in the system. However, all attempts
to put this strategy into practice failed. Treating compound
13 with O3 or OsO4/NaIO4 only yielded complex mixtures
without any trace of the desired product.[21] As a result, the
alcohol moieties in 13 were protected as benzyl ethers,
which furnished pyrrolidine 14 in an excellent yield
(Scheme 4). The cleavage of the terminal olefin moiety in 14
by using a Lemieux–Johnson oxidation[22] was straightfor-
ward and the resultant aldehyde was reduced in situ to give
the use of HgACHTREU(GN OTf)2/AcOOH in TFA/CHCl3/AcOH (Tf=
trifluoromethanesulfonyl, TFA=trifluoroacetic acid), which
has been recently applied in the total synthesis of (+)-casu-
arine, only returned the starting material.[25] Interestingly, a
similar procedure with HgACHTRE(UNG OTf)2/AcOOH in AcOH at am-
bient temperature resulted in the chemoselective oxidation
of the primary silyl group. When the reaction time was pro-
longed, pyrrolizidine 18 and N-oxide 19 could be isolated in
satisfying yields. Hydrolysis of 18 gave alcohol 20, and final-
ly, treating compounds 19 and 20 to H2 and Pd/C gave (+)-1
in good yields (Scheme 5).
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Chem. Eur. J. 2008, 14, 3072 – 3077

Total Synthesis of (+)-Alexine
FULL PAPER
number of steps relatively high (20 steps with a 4% overall
yield[3a] and 26 steps with a 4% overall yield[3d]). Thus, it can
be seen that the [3+2] annulation strategy presented herein
compares favorably and constitutes a highly efficient entry
to polyhydroxylated alkaloids.
Experimental Section
General methods: All air- and moisture-sensitive reactions were carried
out in flame-dried flasks under nitrogen. The liquid reagents were trans-
ferred by using oven-dried syringes. THF and CH2Cl2 were dried by using
a glass-contour solvent-dispensing system. 1H and 13C NMR spectra were
recorded in CDCl3 or D2O by using the residual signal of CHCl3
(1H NM R d=7.26 ppm, 13C NM R d=77.0 ppm) or H2O (1H NM R d=
4.79 ppm) as the internal standard. Analytical TLC plates were visualized
by using UV light, phosphomolybdic acid/cerium sulfate, and/or Drag-
gendorff reagent.
(2S,3R,4R,5R)-4-[Dimethyl
ACHTRE(UGN phenyl)silyl]-5-{[dimethyl-
AHCTRE(UGN phenyl)silyl]methyl}-2-methyl-1-tosylpyrrolidin-3-(tert-butyldimethylsila-
noyl) (9a): MeAlCl2 (1m in hexanes, 6.98 mL) was added by using a sy-
ringe to a stirred solution of aldehyde 7a (2.08 g, 5.82 mmol) in CH2Cl2
(100 mL), which was cooled to ꢀ788C, followed by the addition of 8a
(1.98 g, 6.40 mmol). The resulting mixture was stirred at ꢀ788C for 2 h.
The reaction was quenched by the addition of a saturated aqueous solu-
tion of NH4Cl (10 mL) and extracted with CH2Cl2 (3”20 mL). The com-
bined organic phases were washed with brine (15 mL), dried over
MgSO4, filtered, and then evaporated to give a colorless oil. Flash chro-
matography (silica gel, pentane/EtOAc 5:1) of the residue yielded 9a as
a white solid (2.25 g, 58%). [a]2D5 =ꢀ3.4 (c=0.55, CH2Cl2); 1H NM R
(CDCl3, 500 MHz): d=7.56 (d, J=8.2 Hz, 2H), 7.45–7.23 (m, 12H), 3.99
(dd, J=10.1, 4.7 Hz, 1H), 3.87 (m, 2H), 3.80 (ddd, J=8.8, 5.9, 3.1 Hz,
1H), 3.52 (m, 1H), 3.45 (d, J=3.3 Hz, 1H), 2.42 (s, 3H), 1.69 (dd, J=
15.7, 8.8 Hz, 1H), 1.47 (t, J=5.7 Hz, 1H), 1.18 (dd, J=15.7, 3.1 Hz, 1H),
0.89 (s, 9H), 0.27 (s, 3H), 0.26 (s, 3H), 0.10 (s, 6H), 0.06 (s, 3H),
0.05 ppm (s, 3H); 13C NMR (CDCl3, 125 MHz): d=143.4, 139.2, 136.6,
135.4, 134.0, 133.9, 129.6, 129.3, 128.8, 127.9, 127.7, 127.6, 75.1, 64.1, 62.8,
60.3, 39.6, 26.7, 25.8, 21.5, 18.0, ꢀ1.5, ꢀ1.8, ꢀ4.0, ꢀ4.2, ꢀ5.4, ꢀ5.5 ppm;
IR (neat): n˜ =3490, 2950, 1350, 1160 cmꢀ1; MS (ESI): m/z (%): 690 (100)
[M+Na]+; HRMS (FAB): m/z calcd for C35H53NO4SSi3: 690.2895
[M+Na]+; found: 690.2899.
Scheme 5. The synthetic pathway towards (+)-alexine ((+)-1). py=pyri-
dine.
Conclusion
We have completed the first asymmetric, non-carbohydrate-
based total synthesis of the polyhydroxylated pyrrolizidine
alkaloid (+)-alexine ((+)-1) in twelve steps from the serine-
derived aldehyde 7a with an overall yield of 6%. The key
steps in the synthesis are a highly stereoselective [3+2] an-
nulation of N-Ts-a-amino aldehydes (Ts=tosyl) and 1,3-bis-
(2S,3R,4R,5R)-2-(Hydroxymethyl)-4-[dimethyl
ACHTRE(UNG phenyl)silyl]-5-
{[dimethyl(phenyl)silyl]methyl}-1-tosylpyrrolidin-3-ol (10): Pyrrolidine 9a
AHCTREUNG
(1.06 g, 1.58 mmol) was dissolved in AcOH/THF/H2O (3:1:1, 25 mL) and
stirred for 15 h at RT. The solvents were removed in vacuo. Flash chro-
matography (pentane/EtOAc 1:1) of the residue afforded pyrrolidine 10
as a colorless oil (840 mg, 96%). [a]2D5 =ꢀ23.4 (c=0.47 in CH2Cl2);
1H NMR (CDCl3, 500 MHz): d=7.61 (m, 2H), 7.51 (m, 2H), 7.39–7.19
(m, 8H), 7.52 (m, 2H), 3.97 (m, 1H), 3.84 (m, 3H), 3.42 (m, 1H), 2.55
(dd, J=7.1, 5.9 Hz, 1H), 2.44 (s, 3H), 2.38 (d, J=4.5 Hz, 1H), 1.76 (dd,
J=14.7, 8.7 Hz, 1H), 1.43 (t, J=5.3 Hz, 1H), 1.37 (dd, J=14.7, 3.3 Hz,
1H), 0.33 (s, 3H), 0.32 (s, 3H), 0.04 (s, 3H), ꢀ0.07 ppm (s, 3H);
13C NMR (CDCl3, 125 MHz): d=145.2, 140.6, 137.6, 136.1, 135.4, 135.3,
131.3, 131.1, 130.5, 129.6, 129.4, 129.2, 76.8, 65.3, 64.1, 61.9, 41.8, 28.8,
23.1, 0.04, ꢀ0.36, ꢀ2.0, ꢀ3.4 ppm; IR (neat): n˜ =3443, 2953, 2923, 1427,
1341, 1250, 1159, 1112, 1034, 815 cmꢀ1; HRMS (ESI): m/z: calcd for
C29H39NO4SSi2: 576.2031 [M+Na]+; found: 576.2028.
ACHTREUNG
a
Tamao oxidation of the dimethylphenylsilyl moieties. The
13C NMR data, melting point, and the optical rotation (160–
1618C, [a]2D0 =++39 (c=0.08 in H2O)) were in good agree-
ment with the published data for natural (+)-alexine (162–
1638C, [a]2D0 =+40 (c=0.25 in H2O)).[1a] However, all proton
signals in the 1H NMR spectrum were shifted d=0.2–
0.3 ppm downfield when compared with the data published
by Nash et al.[1a] Similar observations have been described
previously and have been ascribed to the particular pH
value of the NMR sample and the method used for its puri-
fication.[4d,7]
(2S,3R,4R,5R)-3-Hydroxy-4-[dimethyl
ACHTRE(UGN phenyl)silyl]-5-{[dimethyl-
AHCTRE(UGN phenyl)silyl]methyl}-1-tosylpyrrolidine-2-carbaldehyde (11): Pyrrolidine
10 (405 mg, 0.73 mmol) and 2,2,6,6-tetramethylpiperidinoxyl radical
(1.14 mg, 0.07 mmol) were dissolved in CH2Cl2 (20 mL). KBr (95.7 mg,
0.80 mmol) was dissolved in an aqueous solution of NaHCO3 (5% w/w,
40 mL) and added to the reaction mixture. The vigorously stirred two-
layer mixture was cooled to 08C and an aqueous solution of NaOCl
(496 mL, 0.80 mmol, 10% w/w) was slowly added. After complete conver-
sion of the alcohol (TLC control) the phases were separated and the
To date, two total syntheses of (+)-alexine have been de-
tailed in the literature,[3a,d] both of which rely on carbohy-
drates as the starting materials. As a result, several protect-
ing-group manipulations are required, which makes the total
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3075

P. Somfai et al.
aqueous phase was extracted with CH2Cl2 (3”10 mL). The combined or-
ganic phases were successively washed with an aqueous solution of
NaHCO3 (5% w/w, 10 mL) and brine (10 mL) and dried over MgSO4.
Filtration and evaporation of the solvents yielded a white solid (400 mg,
99%), which was used in the following allylation without further purifica-
tion. 1H NMR (CDCl3, 500 MHz): d=9.63 (d, J=3.0 Hz, 1H), 7.64–7.62
(m, 2H), 7.52 (m, 2H), 7.41–7.28 (m, 8H), 7.06–7.05 (m, 2H), 4.27 (dd,
J=5.4, 1.6 Hz, 1H), 3.94 (dt, J=10.7, 2.8 Hz, 1H), 3.64 (dd, J=5.4,
2.7 Hz, 1H), 2.44 (s, 3H), 1.87 (m, 1H), 1.69 (dd, J=14.7, 2.6 Hz, 1H),
1.43 (t, J=1.8 Hz, 1H), 1.37 (dd, J=14.7, 3.3 Hz, 1H), 0.29 (s, 3H), 0.28
(s, 3H), ꢀ0.1 (s, 3H), ꢀ0.3 ppm (s, 3H); 13C NMR (CDCl3, 125 MHz):
d=201.8, 144.2, 138.5, 135.6, 134.6, 134.0, 133.6, 133.6, 129.9, 129.7, 128.0,
128.0, 128.0, 76.8, 71.4, 60.8, 42.6, 28.0, 21.5, ꢀ1.6, ꢀ2.5, ꢀ3.9, ꢀ5.7 ppm.
diluted with H2O (15 mL) and extracted with Et2O (3”15 mL). The com-
bined organic phases were dried, filtered, and evaporated. The residue
was purified with flash chromatography (pentane/EtOAc 10:1) to afford
pyrrolidine 15 as a colorless crystalline solid (175 mg, 72%). M.p. 49–
508C; [a]2D5 =ꢀ4.0 (c=0.25 in CH2Cl2); 1H NMR (CDCl3, 500 MHz): d=
7.60 (d, J=8.3 Hz, 2H), 7.41–7.18 (m, 20H), 6.91 (d, J=8.0 Hz, 2H), 4.57
(d, J=11.2 Hz, 1H), 4.48 (d, J=11.2 Hz, 1H), 4.14 (d, J=12.1 Hz, 1H),
3.99–3.94 (m, 3H), 3.91–3.89 (m, 1H), 3.83–3.79 (m, 2H), 3.22 (dd, J=
7.8, 6.1 Hz, 1H), 2.42 (s, 3H), 2.14–2.09 (m, 1H), 1.96–1.91 (m, 1H), 1.46
(dd, J=7.8, 6.4 Hz, 1H), 1.15–1.10 (m, 1H), 1.06–1.02 (m, 1H), 0.35 (s,
3H), 0.28 (s, 3H), 0.06 (s, 3H), ꢀ0.06 ppm (s, 3H); 13C NMR (CDCl3,
125 MHz): d=143.4, 139.8, 138.3, 137.7, 136.8, 134.1, 133.8, 129.6, 129.4,
129.0, 128.7, 128.5, 128.3, 128.3, 128.2, 128.0, 128.0, 127.9, 127.9, 127.7,
127.7, 127.6, 127.5, 127.5, 81.1, 72.4, 71.4, 62.9, 60.4, 60.0, 59.1, 38.9, 33.9,
29.2, 21.6, 21.1, 14.2, ꢀ2.1, ꢀ3.2, ꢀ3.9, ꢀ4.6 ppm; IR (neat): n˜ =3484,
2954, 2876, 1349, 1248, 1164, 1112, 819, 735, 700 cmꢀ1; HRMS (ESI): m/z:
calcd for C45H55NO5SSi2: 778.3412 [M+H]+; found: 778.3416.
(2S,3R,4R,5R)-2-[(S)-1-Hydroxybut-3-enyl]-4-[dimethyl
ACHTRE(UNG phenyl)silyl]-5-
{[dimethyl(phenyl)silyl]methyl}-1-tosylpyrrolidin-3-ol (13): TiCl4 (42 mL,
ACHTREUNG
0.39 mmol) was added to a solution of 11 (160 mg, 0.3 mmol) in CH2Cl2
(8 mL) at ꢀ788C. Allyltrimethylsilane (140 mL, 0.9 mmol) was then
added and the resulting mixture was stirred at ꢀ788C for 1.5 h. The reac-
tion was quenched with a saturated solution of NH4Cl (10 mL) and ex-
tracted with CH2Cl2 (3”10 mL). The combined organic phases were
dried (MgSO4), filtered, and evaporated to give a yellowish oil. The resi-
due was then purified with flash chromatography (pentane/EtOAc 4:1)
to give pyrrolidine 13 as a colorless oil (115 mg, 70%). [a]2D5 =ꢀ19.5 (c=
0.19 in CH2Cl2); 1H NMR (CDCl3, 500 MHz): d=7.57 (m, 2H), 7.48 (m,
2H), 7.37 (m, 4H), 7.29 (m, 4H), 7.16 (m, 2H), 5.77 (tdd, J=17.3, 10.2,
7.0 Hz, 1H), 5.12 (m, 2H), 4.26 (m, 1H), 3.85 (m, 4H), 3.15 (t, J=5.2 Hz,
1H), 2.92 (d, J=3.5 Hz, 1H), 2.44 (m, 5H), 1.44 (m, 2H), 0.32 (s, 3H),
0.31 (s, 3H), ꢀ0.03 (s, 3H), ꢀ0.12 ppm (s, 3H); 13C NMR (CDCl3,
125 MHz): d=143.8, 139.2, 136.3, 134.7, 134.3, 133.9, 133.8, 129.9, 129.5,
128.9, 128.0, 127.8, 118.2, 75.1, 70.9, 65.0, 60.5, 41.3, 37.8, 29.0, 21.5, ꢀ1.8,
ꢀ2.4, ꢀ3.9, ꢀ4.5 ppm; IR (neat): n˜ =3420, 2954, 2904, 1427, 1347, 1250,
(S)-3-(Benzyloxy)-3-(2S,3R,4R,5R)-3-(benzyloxy)-4-[dimethyl-
ACHRTE(UNG phenyl)silyl]-5-({[dimethylACHTRE(UNG phenyl)silyl]methyl}pyrrolidin-2-yl)propan-1-
ol (16): A deep-green solution of sodium naphthalenide in dimethoxy-
ethane (2.5 mL) was added to a solution of 15 (120 mg, 0.15 mmol) in di-
methoxyethane (4 mL, freshly distilled over Na) at ꢀ608C until the
green color persisted and stirring was continued for 10 min. The reaction
was quenched with a saturated solution of NH4Cl (10 mL) and extracted
with Et2O (3”15 mL). The combined organic phases were dried, filtered,
and evaporated. Purification of the residue with flash chromatography
(pentane/EtOAc 1:1) afforded pyrrolidine 16 as a colorless oil (90 mg,
99%). [a]2D5 =+27.6 (c=1.5 in CH2Cl2); 1H NMR (CDCl3, 500 MHz): d=
7.38–7.13 (m, 20H), 4.53 (d, J=11.5 Hz, 1H), 4.36 (d, J=11.5 Hz, 1H),
4.22 (d, J=11.5 Hz, 1H), 4.02 (m, 2H), 3.73 (m, 2H), 3.49 (m, 1H), 3.08
(m, 1H), 2.56 (dd, J=9.3, 3.3 Hz, 1H), 1.91 (m, 2H), 1.28 (m, 2H), 0.97
(dd, J=15.1, 2.7 Hz, 1H), 0.88 (m, 1H), 0.78 (dd, J=15.1, 11.2 Hz, 1H),
0.32 (s, 3H), 0.31 (s, 3H), 0.29 (s, 3H), 0.25 ppm (s, 3H); 13C NM R
(CDCl3, 125 MHz): d=139.0, 138.8, 138.4, 137.1, 133.8, 133.5, 129.3,
128.8, 128.2, 127.9, 127.7, 127.4, 127.4, 127.4, 127.3, 82.8, 71.1, 69.7, 69.1,
58.3, 58.1, 44.1, 35.7, 26.0, ꢀ2.4, ꢀ2.8, ꢀ4.3, ꢀ4.5 ppm; IR (neat): 3067,
2925, 2856, 1455, 1264, 1112, 736, 701 cmꢀ1; HRMS (ESI): m/z: calcd for
C38H49NO3Si2: 624.3324 [M+H]+; found: 624.3314.
1162, 1112, 817 cmꢀ1
; HRMS (ESI): m/z: calcd for C32H43NO4SSi2:
616.2344 [M+Na]+; found: 616.2340.
(2S,3R,4R,5R)-3-(Benzyloxy)-2-[(S)-1-(benzyloxy)but-3-enyl]-4-
[dimethylACHTREUNG(phenyl)silyl]-5-{[dimethylCAHTRE(UGN phenyl)silyl]methyl}-1-tosylpyrroli-
dine (14): Potassium hexamethyldisilazide (KHMDS) (2.5 mL, 0.5m solu-
tion in PhMe) was added to a solution of 13 (250 mg, 0.42 mmol) and
BnBr (Bn=benzyl; 200 mL, 1.68 mmol) in THF (10 mL) at ꢀ788C and
the resulting mixture was stirred at ꢀ788C for 1 h and at 08C. The reac-
tion was quenched with a saturated solution of NH4Cl (10 mL) and ex-
tracted with Et2O (3”15 mL). The combined organic phases were dried,
filtered, and evaporated. Flash chromatography of the residue (pentane/
EtOAc 10:1) afforded pyrrolidine 14 as a colorless oil (260 mg, 85%).
(1R,2R,3R,7S,7aS)-1,7-Bis(benzyloxy)hexahydro-2-[dimethyl-
ACHRTENU(G phenyl)silyl]-3-{[dimethylAHCRTEU(GN phenyl)silyl]methyl}-1H-pyrrolizine (17): NEt3
(54 mL, 0.39 mmol), PPh3 (100 mg, 0.39 mmol), and CBr4 (127 mg,
0.39 mmol) were added to a solution of 16 (80 mg, 0.13 mmol) in CH2Cl2
(7 mL) and the solution was stirred at RT for 1 h. The reaction was
quenched by the addition of MeOH (2 mL) and the solvents were re-
moved in vacuo. Purification of the residue by flash chromatography
1
[a]2D5 =ꢀ6.1 (c=0.28 in CH2Cl2); H NMR (CDCl3, 500 MHz): d=7.56 (d,
J=8.2 Hz, 2H), 7.37–7.12 (m, 20H), 6.90 (d, J=6.5 Hz, 2H), 6.00 (m,
1H), 5.09 (d, J=17.1 Hz, 1H), 5.03 (d, J=10.1 Hz, 1H), 4.53 (d, J=
11.1 Hz, 1H), 4.42 (d, J=11.1 Hz, 1H), 4.24 (d, J=12.1 Hz, 1H), 3.92 (d,
J=12.1 Hz, 1H), 3.84 (m, 2H), 3.74 (dt, J=7.9, 3.5 Hz, 1H), 3.10 (dd, J=
9.3, 6.1 Hz, 1H), 2.68 (m, 1H), 2.52 (m, 1H), 2.38 (s, 3H), 1.44 (dd, J=
9.2, 7.4 Hz, 1H), 0.96 (m, 2H), 0.34 (s, 3H), 0.23 (s, 3H), 0.05 (s, 3H),
ꢀ0.16 ppm (s, 3H), 13C NMR (CDCl3, 125 MHz): d=143.3, 140.1, 138.7,
137.8, 136.9, 135.9, 134.0, 133.6, 129.6, 129.3, 128.5, 128.0, 127.8, 127.6,
127.5, 127.4, 127.2, 127.1, 116.8, 80.4, 78.1, 72.3, 71.5, 63.0, 58.5, 39.4, 37.3,
29.5, 21.5, ꢀ2.2, ꢀ3.3, ꢀ3.5, ꢀ4.9 ppm; IR (neat): n˜ =3067, 2954, 2925,
1640, 1349, 1264, 1164, 1112, 818, 756, 700 cmꢀ1; HRMS (ESI): m/z: calcd
for C46H55NO4SSi2: 796.3283 [M+Na]+; found: 796.3270.
(pentane/EtOAc 1:1) afforded 17 as a colorless oil (50 mg, 64%). [a]D25
=
1
+14.5 (c=0.5 in CH2Cl2); H NMR (CDCl3, 500 MHz): d=7.42 (m, 4H),
7.27 (m, 14H), 7.07 (m, 2H), 4.51 (d, J=11.8 Hz, 1H), 4.37 (d, J=
11.8 Hz, 1H), 4.32 (m, 1H), 4.12 (d, J=11.5 Hz, 1H), 4.04 (d, J=11.5 Hz,
1H), 3.82 (dd, J=5.6, 4.9 Hz, 1H), 3.13 (dd, J=5.6, 2.9 Hz, 1H), 3.03 (dt,
J=10.6, 3.0 Hz, 1H), 2.59 (m, 2H), 2.18 (m, 1H), 1.83 (m, 1H), 1.47 (dd,
J=9.6, 4.9 Hz, 1H), 1.32 (m, 1H), 0.89 (m, 1H), 0.31 (s, 3H), 0.28 (s,
3H), 0.27 (s, 3H), 0.26 ppm (s, 3H); 13C NMR (CDCl3, 125 MHz): d=
139.7, 138.6, 138.0, 133.9, 133.6, 129.1, 128.6, 128.3, 128.1, 127.8, 127.5,
127.4, 127.2, 127.1, 83.9, 78.1, 75.1, 71.6, 71.1, 58.8, 45.5, 40.5, 33.6, 19.7,
ꢀ2.3, ꢀ2.6, ꢀ3.6, ꢀ3.8 ppm; IR (neat): n˜ =2955, 2923, 2361, 1250, 1114,
835 cmꢀ1 HRMS (ESI): m/z: calcd for C38H47NO2Si2: 606.3218 [M+H]+;
found: 606.3199.
(S)-3-(Benzyloxy)-3-[(2S,3R,4R,5R)-3-(benzyloxy)-4-[dimethyl-
ACHTREUNG(phenyl)silyl]-5-({[dimethylACHTRE(UNG phenyl)silyl]methyl}pyrrolidin-2-yl)propan-1-
ol (15): Pyridine (55 mL, 0.64 mmol), NaIO4 (350 mg, 1.6 mmol), and
OsO4 (0.5 mL of a solution of 25 mg OsO4/mL in MeCN) were added to
a solution of 14 (250 mg, 0.32 mmol) in CH3CN/H2O (1:1, 10 mL) and
the solution was stirred for 3 h at RT. Et2O (10 mL) was added to the re-
action mixture and the phases were separated. The aqueous phase was
extracted with Et2O (3”10 mL) and the combined organic extracts were
washed with brine (10 mL), dried over MgSO4, filtered, and the solvent
removed in vacuo. The crude product was dissolved in MeOH (15 mL)
and the solution was cooled to 08C. NaBH4 was added and the stirring
was continued for 20 min. The solution was filtered through a Celite pad,
(1R,2R,3R,7S,7aS)-1,7-Bis(benzyloxy)hexahydro-3-(hydroxymethyl)-1H-
pyrrolizin-2-ol (20) and (1R,2R,3R,7S,7aS)-1,7-bis(benzyloxy)hexahydro-
3-(hydroxymethyl)-1H-pyrrolizin-2-ol-N-oxide (19): HgACHTRE(UNG OTf)2 (65.7 mg,
0.15 mmol) was added to a solution of 17 (23.3 mg, 38.0 mmol) in AcOH
(1.5 mL) at RT. The reaction mixture was stirred for 1 h before AcOOH
(4 mL, 32% solution in AcOH) was added. The solution was stirred at
RT for 5 d. EtOAc (10 mL) was added and the reaction mixture was
cooled to 08C. Saturated Na2S2O3 (10 mL) was added dropwise and the
aqueous phase was extracted with EtOAc (3”10 mL). The combined or-
ganic phases were washed with H2O (10 mL), saturated NaHCO3 (1m,
3076
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ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 3072 – 3077

Total Synthesis of (+)-Alexine
FULL PAPER
15 mL), and brine (10 mL), dried over Na2SO4, filtered, and the solvents
were removed in vacuo. The residue was purified by flash chromatogra-
phy (EtOAc+1% iPrNH2!EtOAc/MeOH 20:1+1% iPrNH2) to give
18 (6.4 mg, 41%) and 19 (3.0 mg, 21%) as colorless oils.
[2] For leading references to the biological activity of polyhydroxylated
alkaloids see: S. E. Denmark, A. R. Hurd, J. Org. Chem. 2000, 65,
2875–2886.
[3] a) G. W. J. Fleet, M. Haraldsson, R. J. Nash, L. E. Fellows, Tetrahe-
dron Lett. 1988, 29, 5441–5444; b) H. Yoda, F. Asai, K. Takabe, Syn-
lett 2000, 1001–1003; c) I. Izquierdo, M. T. Plaza, R. Robles, F.
Franco, Tetrahedron: Asymmetry 2001, 12, 2481–2487; d) H. Yoda,
H. Katoh, K. Takabe, Tetrahedron Lett. 2000, 41, 7661–7665.
[4] T. J. Donohoe, H. O. Sintim, J. Hollinshead, J. Org. Chem. 2005, 70,
7297–7304.
1
Compound 19: H NMR (CDCl3, 500 MHz): d=7.28–7.21 (m, 10H), 4.54
(s, 2H), 4.45 (d, J=11.7 Hz, 1H), 4.38 (d, J=11.7 Hz, 1H), 4.31–4.23 (m,
3H), 3.94 (dd, J=7.4, 4.4 Hz, 1H), 3.88 (dd, J=6.8, 4.4 Hz, 1H), 3.60 (t,
J=5.6 Hz, 1H), 3.08–3.04 (m, 1H), 2.92–2.87 (m, 1H), 2.80–2.76 (m,
1H), 2.18–2.12 (m, 1H), 2.02 (s, 3H), 1.93–1.86 ppm (m, 1H); 13C NM R
(CDCl3, 125 MHz): d=171.0, 138.2, 137.9, 137.6, 128.5, 128.4, 127.8,
127.7, 127.7, 127.6, 84.3, 78.4, 78.4, 72.4, 71.6, 71.3, 64.4, 62.7, 47.1, 33.4,
20.9 ppm.
[5] S. Singh, H. Han, Tetrahedron Lett. 2004, 45, 6349–6352.
[6] P. Somfai, P. Marchand, S. Torssell, U. M. Lindstrçm, Tetrahedron
2003, 59, 1293–1299.
Compound 20: Compound 18 (6.0 mg, 14.6 mmol) was dissolved in THF/
H2O (2 mL, 1:1) and LiOH (6.1 mg, 0.15 mmol) was added. The reaction
mixture was stirred for 15 min before removing the solvents in vacuo.
Flash chromatography of the residue afforded 20 as a colorless oil
(4.8 mg, 90%). [a]D25 =+32.5 (c=0.08 in CH2Cl2); 1H NMR (CDCl3,
500 MHz): d=7.34–7.21 (m, 10H), 4.64 (d, J=11.8 Hz, 1H), 4.56 (d, J=
11.8 Hz, 1H), 4.51 (d, J=11.7 Hz, 1H), 4.44 (d, J=11.7 Hz, 1H), 4.36–
4.32 (m, 1H), 4.17 (dd, J=6.5, 3.4 Hz, 1H), 3.91 (dd, J=6.3, 3.4 Hz, 1H),
3.87 (d, J=5.6 Hz, 2H), 3.86 (t, J=5.6 Hz, 1H), 3.09–3.05 (m, 1H), 2.93–
2.91 (m, 2H), 2.32–2.25 (m, 1H), 2.00–1.96 ppm (m, 1H); 13C NM R
(CDCl3, 125 MHz): d=138.1, 137.7, 128.7, 128.5, 128.4, 127.9, 127.8,
127.8, 127.7, 115.0, 83.8, 79.9, 76.4, 72.3, 72.2, 71.7, 97.6, 61.0, 46.5, 33.7;
IR (neat): n˜ =2953, 2920, 2364, 1250, 838 cmꢀ1; HRMS (ESI): m/z: calcd
for C22H27NO4: 370.2013 [M+H]+; found: 370.2004.
[7] a) J. D. White, P. Hrnciar, J. Org. Chem. 2000, 65, 9129–9142;
b) M. Y. Tang, S. G. Pyne, J. Org. Chem. 2003, 68, 7818–7824.
[8] S. E. Denmark, E. A. Martinborough, J. Am. Chem. Soc. 1999, 121,
3046–3056; see also reference [2].
[9] B. M. Trost, D. B. Horne, M. Woltering, Chem. Eur. J. 2006, 12,
6607–6620.
[10] L. Chabaud, P. James, Y. Landais, Eur. J. Org. Chem. 2004, 3173–
3199.
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Panek, M. Yang, J. Am. Chem. Soc. 1991, 113, 9868–9870; c) S. R.
Angle, N. A. El-Said, J. Am. Chem. Soc. 2002, 124, 3608–3613.
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[13] a) A. Romero, K. A. Woerpel, Org. Lett. 2006, 8, 2127–2130;
b) C. W. Roberson, K. A. Woerpel, J. Org. Chem. 1999, 64, 1434–
1435.
[14] S. Kiyooka, Y. Shiomi, H. Kira, Y. Kaneko, S. Tanimori, J. Org.
Chem. 1994, 59, 1958–1960.
[15] a) P. Restorp, A. Fischer, P. Somfai, J. Am. Chem. Soc. 2006, 128,
12646–12647; b) P. Restorp, M. Dressel, P. Somfai, Synthesis 2007,
1576–1583.
[16] G. R. Jones, Y. Landais, Tetrahedron 1996, 52, 7599–7662.
[17] J. Jurczak, D. Gryko, E. Kobrzycka, H. Gruza, P. Prokopowicz, Tet-
rahedron 1998, 54, 6051–6064.
[18] Oxidation of 11 by using Dess–Martin periodinane (DMP), pyridini-
um chlorochromate (PCC), or Swern conditions afforded aldehyde
12 in lower yields.
(+)-Alexine ((+)-1): Pd/C was added to
a mixture of 14 (2 mg,
4.86 mmol) and 15 (2 mg, 5.41 mmol) in EtOH (2 mL). The reaction mix-
ture was stirred under an atmosphere of H2 at RT for 16 h. The reaction
mixture was filtered over Celite and the solvent was removed in vacuo,
affording (+)-1 as a white solid (1.3 mg, 70%). M.p.=160–1618C; [a]D20
=
+39.0 (c=0.08 in H2O); 1H NM R (DO, 500 MHz): d=4.53–4.49 (m,
2
1H), 4.26 (t, J=7.6 Hz, 1H), 3.89–3.88 (m, 2H), 3.87–3.84 (m, 1H), 3.48
(t, J=6.6 Hz, 1H,), 3.12–3.07 (m, 2H), 3.03–2.98 (m, 1H), 2.28–2.23 (m,
1H), 1.86–1.78 ppm (m, 1H); 13C NM R (DO, 125 MHz, CH3CN as inter-
2
nal standard): d=76.3, 75.8, 71.5, 70.4, 65.6, 59.0, 46.8, 34.6 ppm; HRMS
(ESI): m/z: calcd for C8H15NO4: 190.1074 [M+H]+; found: 190.1073.
[19] a) R. S. Coleman, A. J. Carpenter, Tetrahedron Lett. 1992, 33, 1697–
1700; b) P. Restorp, P. Somfai, Org. Lett. 2005, 7, 893–895.
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b) D. A. Evans, B. D. Allison, M. G. Yang, C. E. Masse, J. Am.
Chem. Soc. 2001, 123, 10840–10852.
[21] Attempts with reductive workup did not improve the outcome.
[22] W. S. Yu, Y. Mei, Y. Kang, Z. M. Hua, Z. D. Jin, Org. Lett. 2004, 6,
3217–3219.
Acknowledgements
Financial support from the Royal Institute of Technology, the Swedish
Research Council and the Knut and Alice Wallenberg foundation is
gratefully acknowledged. M.D. thanks the Wenner-Gren foundation for a
scholarship.
[23] I. Fleming, R. Henning, D. C. Parker, H. E. Plaut, P. E. J. Sanderson,
J. Chem. Soc. Perkin Trans. 1 1995, 317–337.
[24] R. P. Polniaszek, L. W. Dillard, J. Org. Chem. 1992, 57, 4103–4110.
[25] See reference [2] and references therein.
[1] a) R. J. Nash, L. E. Fellows, J. V. Dring, G. W. J. Fleet, A. E.
Derome, T. A. Hamor, A. M. Scofield, D. J. Watkin, Tetrahedron
Lett. 1988, 29, 2487–2490; b) N. Asano, H. Kuroi, K. Ikeda, H.
Kizu, Y. Kameda, A. Kato, I. Adachi, A. A. Watson, R. J. Nash,
G. W. J. Fleet, Tetrahedron: Asymmetry 2000, 11, 1–8; c) J. R. Lid-
dell, Nat. Prod. Rep. 1999, 16, 499–507; d) J. R. Liddell, Nat. Prod.
Rep. 2000, 17, 455–462.
Received: November 12, 2007
Published online: January 31, 2008
Chem. Eur. J. 2008, 14, 3072 – 3077
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3077