Lipase-mediated synthesis of enantiomeric 2,5,6-trideoxy-2,5-iminohexitols

Article abstract of DOI:10.1016/j.tet.2008.03.089

Syntheses of 2,5,6-trideoxy-2,5-imino-d-alditol (2, 6-deoxy-DADP) and its enantiomer (3) from tri-orthogonally protected derivatives of DADP have been developed employing lipase-mediated kinetic desymmetrization and protecting group manipulations. Thus, and as an example, the starting DADP derivative (4) was transformed into a new symmetrical 2,5-bis(hydroxymethyl)pyrrolidine (6) by sequential N-protection and bis-O-desilylation. The lipase-mediated desymmetrization of 6 was best carried out under acetylation conditions to give (2R)-acetyloxymethyl derivative 7. The absolute configuration and ee of 7 were unambiguously established by chemical correlation with a homochiral sample. Compound 7 was straightforwardly transformed into the target 2,5,6-trideoxy-2,5-iminohexitol 3.

Full text of DOI:10.1016/j.tet.2008.03.089

Tetrahedron 64 (2008) 4993–4998
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Lipase-mediated synthesis of enantiomeric 2,5,6-trideoxy-
2,5-iminohexitolsq
*
*
´
Isidoro Izquierdo , Marıa T. Plaza, Juan A. Tamayo , Francisco Franco,
´
Fernando Sanchez-Cantalejo
Department of Medicinal and Organic Chemistry, Faculty of Pharmacy, University of Granada, 18071 Granada, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Syntheses of 2,5,6-trideoxy-2,5-imino-D-alditol (2, 6-deoxy-DADP) and its enantiomer (3) from tri-
Received 25 February 2008
Received in revised form 25 March 2008
Accepted 26 March 2008
orthogonally protected derivatives of DADP have been developed employing lipase-mediated kinetic
desymmetrization and protecting group manipulations. Thus, and as an example, the starting DADP
derivative (4) was transformed into a new symmetrical 2,5-bis(hydroxymethyl)pyrrolidine (6) by
sequential N-protection and bis-O-desilylation. The lipase-mediated desymmetrization of 6 was best
carried out under acetylation conditions to give (2R)-acetyloxymethyl derivative 7. The absolute con-
figuration and ee of 7 were unambiguously established by chemical correlation with a homochiral sample.
Compound 7 was straightforwardly transformed into the target 2,5,6-trideoxy-2,5-iminohexitol 3.
Ó 2008 Elsevier Ltd. All rights reserved.
Available online 29 March 2008
Dedicated to Professor Vicente Gotor on the
occasion of his 60th anniversary
1. Introduction
regioselective transesterification at the hydroxylmethyl groups on
the corresponding N-protected, bis-O-desilylated derivative 6,
Several 5-methylpyrrolidine-triols (1) of the type displayed in
obtained from pyrrolidine 4, was the methodology of choice in
order to obtain the required chirality. Although chemo-enzymatic
desymmetrizations have been described on different N-protected
acyclic11 and cyclic aminodiols,12 to the best of our knowledge, the
only example of this methodology applied to a pyrrolidinic skeleton
has been done by Donohoe et al.13 on a 2,5-bis(hydroxymethyl)-
D3-pyrroline. We described another approach of this method
performed on more complex pyrrolidines together with the use of
the resulting products in the enantiosynthesis of 2,5,6-trideoxy-
2,5-iminohexitols 2 and 3.
Figure 1 show potent inhibitory activity versus glycosidases in
general2 as well as a- -fucosidases3 in particular. They are also
L
rather weak a-[1,3]-fucosyl-transferase inhibitor with a potent
synergistic effect in the presence of GDP,4 and have been prepared
employing chemo-enzymatic2,5 and chemical methods.1,6
In the case of 2,5,6-trideoxy-2,5-imino-D-allitol (2, 6-deoxy-
DADP), only two chemical syntheses have been reported to date,
one by Defoin et al.,7 using a chiral 1,2-oxazines as starting material,
and a second by Ja¨ger and Palmer,8 where a nitrone approach was
the methodology of choice. To the best of our knowledge, no syn-
thesis for ent-2 (3) has been reported so far, and taking into
account the influence of the chirality of this type of compounds on
the specificity and inhibition potency,9 we considered that the
synthesis of 3 would be of interest for future enzymatic assays.
From a synthetic point of view, the symmetrical character of
(2R,3R,4S,5S)-3,4-dibenzyloxy-2,5-bis(tert-butyldiphenylsilyloxy-
methyl)pyrrolidine (4), recently prepared from the carbohydrate
OH
H
N
HO
OH
H
N
H
N
HO
OH
1
chiral pool (
starting material, suitable for further desymmetrization, to achieve
D
-fructose) by our group,10 makes it an appropriate
PGO
OPG
H
N
HO
6-Deoxy-DADP (2)
HO
Ent-2 (3)
Not described
OH
OH
the previously mentioned iminohexitol 3.
A lipase-mediated
BnO
OBn
4 (PG = TBDPS)
q
Part VII: Polyhydroxylated pyrrolidines. For Part VI, see Ref. 1.
* Corresponding authors. Tel.: þ34 958 249583; fax: þ34 958 243845 (I.I.); tel.:
þ34 958 243846; fax: þ34 958 243845 (J.A.T.).
Figure 1. General structure for 5-methylpyrrolidine-triols (1), the enantiomers of
6-deoxy-DADP (2 and 3), and an orthogonally protected derivative (4) of 2,5-dideoxy-
2,5-imino-D-allitol.
E-mail addresses: isidoro@ugr.es (I. Izquierdo), jtamayo@ugr.es (J.A. Tamayo).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.03.089

4994
I. Izquierdo et al. / Tetrahedron 64 (2008) 4993–4998
2. Results and discussion
chemoselective N-protection to the Cbz derivatives 15 and 16, re-
spectively. Compound 16 was subjected to chemo-enzymatic trans-
esterification causing its desymmetrization to 20-O-acetyl derivative
17 whose structure was determined by chemical correlation, after
O-silylation and subsequent O-deacetylation to pyrrolidine 19, pre-
viously reported by our group.9f Comparison of their respective
specificrotationindicateda97%eefordesymmetrizedpyrrolidine17.
According to Scheme 1, compound 4 was transformed into its
N-protected derivative 5 after reaction with di-tert-butyldicar-
bonate. Subsequently, bis-O-desilylation afforded (2R,3R,4S,
5S)-3,4-dibenzyloxy-N-tert-butyloxycarbonyl-2,5-bis(hydroxyl-
methyl)pyrrolidine (6), which was subjected to reaction with vinyl
acetate in the presence of ChirazymeÒ L-2, c.-f., C2, lyo from
Candida antarctica lipase-B, at room temperature (rt). The
chemo-enzymatic reaction caused desymmetrization yielding the
(2R,3R,4S,5S)-2-acetyloxymethyl-3,4-dibenzyloxy-N-tert-butyl-
Cbz
RO
OR1
O
OH
N
a
N3
BnO
15
+
CH2OH
OBn
oxycarbonyl-5-hydroxymethylpyrrolidine (7) isolated in an 81%
OBn
BnO
20
yield with a 94% ee, determined by its rotatory power14 [a]
(c 1) (see below).
ꢀ15
14
16 R = R1 = H
405
b
c
d
Cbz
N
17 R = Ac; R1 = H
18 R = Ac; R1 = PG
19 R = H; R1 = PG
HO
OH
R
N
R
N
R1O
OR2
R1O
OPG
b
PG = TBDPS
BnO
OBn
7
15
on 10
BnO
OBn
BnO
OBn
Scheme 3. Synthesis of partially protected DADP (19) from a derivative of 5-azido-5-
deoxy-D-fructose (14). Reagents and conditions: (a) (i) H2–Raney-Ni–MeOH, rt; (ii)
CbzCl–K2CO3–Me2CO, rt; (b) vinyl acetate–TBME–ChirazymeÒ L-2, c.-f., C2, lyo, rt; (c)
TBDPSCl–imidazole–DMF, rt; (d) MeOH–MeONa (cat.), rt.
4 R = H; R1 = R2 = PG
5 R = Boc; R1 = R2 = PG
6 R = Boc; R1 = R2 = H
7 R = Boc; R1 = Ac; R2 = H
8 R = R1 = H
a
b
c
a
d
9 R = Boc; R1 = H
10 R = Boc; R1 = Ac
To explain the formation of D-altro (minor) and D-allo (major)
PG = TBDPS
pyrrolidines, a proposed transition state is shown in Figure 2. The
intermediate 5-aminohexulose A, produced after the reduction of
N3 function in 14, reacts in a fast intramolecular process to give
D1-pyrroline intermediate B, which is finally hydrogenated in a
Scheme 1. Desymmetrization of 4 and absolute configuration assignment of pyrrolidine
7. Reagents and conditions: (a) (t-BuOCO)2O–TEA–DCM, rt; (b) TBAF$3H2O–THF, rt; (c)
vinyl acetate–TBME–ChirazymeÒ L-2, c.-f., C2, lyo, rt; (d) Ac2O–DMAP (cat.)–Py, rt.
The absolute configuration of desymmetrized pyrrolidine 7 was
easily established (Scheme 1 above) by chemical correlation
through conventional N-protection of pyrrolidine 8, previously
described by our group,10 as its N-Boc derivative (9) followed by
high stereoselective manner to the major D-allo diastereomer.
Comment merits the high stereoselectivity found in the
hydrogenation of D1-pyrroline intermediate, where compound
with the D-allo configuration was the major pyrrolidine isolated. Its
acetylation to 10. Final O-desilylation gave the homochiral 7, which
stereoselective formation can be explained if the hydrogen addition
takes place through the same a-face occupied by the substituent
next to the N]C bond, giving a product with trans-disposition for
the substituents at the C(2)–C(3) positions (see TS in Fig. 2). These
results are according to ours and other authors.5a,b,17
Transformation of the orthogonally protected pyrrolidine 19
was accomplished as for 7 (see Scheme 4 above). Thus, 19 was
subjected to OH/I interchange at C(5) to afford halogenated pyr-
rolidine 20 that was dehalogenated by catalytic hydrogenation, and
in this case also produces the loss of the N-Cbz protecting group
affording the 5-methylpyrrolidine 21. Straightforward total depro-
tection of 21 gave the expected 6-deoxy-DADP (2), which showed
analytical and spectroscopic data in total agreement with those
reported in the literature.7,8
20
showed an [a]
ꢀ16 (c 1).
405
Once the absolute configuration of pyrrolidine
7 was
established, we continue to the final synthesis of ent-6-deoxy-
DADP (3). According to the indications given in Scheme 2, reaction
of (2R,3R,4S,5S)-2-acetyloxymethyl-3,4-dibenzyloxy-N-tert-butyl-
oxycarbonyl-5-hydroxymethyl pyrrolidine (7) gave the corre-
sponding 5-iodomethyl derivative 11 under Garegg’s conditions.15
Catalytic hydrogenation of 11 with Raney-nickel16 caused dehalo-
genation9d concomitant with an O-deacetylation, probably due to
the weak-basic conditions affording the 5-methylpyrrolidine 12.
Final N- and O-deprotection yielded the proposed ent-6-deoxy-
DADP (3), whose spectroscopic data were in closed agreement with
those previously reported7,8 for its enantiomer 2.
Finally, we also investigated the influence of N-Boc protection
on the regioselectivity and enantioselectivity of the enzymatic
transesterification reaction. To compare with the previous results,
partially protected pyrrolidine 24, obtained from 23,18 was sub-
jected to the same transesterification conditions used for 6 (Scheme
5). The reaction afforded solely the monoacetylated pyrrolidine 25
whose structure was identical to that obtained by acetylation and
subsequent O-desilylation of the well known pyrrolidine 26.18
Boc
N
HO
RO
R1
H
N
c
a
7
RO
13 R = Bn
R = H
OR
BnO
OBn
11 R = Ac; R1 = I
12 R = R1 = H;
d
b
3
Scheme 2. Synthesis of ent-6-deoxy-DADP (3) from pyrrolidine 7. Reagents and con-
ditions: (a) I2–Ph3P–imidazole–THF, D; (b) H2 (balloon)–Raney-Ni–MeOH–TEA, rt; (c)
50% TFA–DCM, rt; (d) concd HCl (drops)/10% Pd–C–H2–MeOH, rt.
-Face
Unfavoured
H
N
H
HO
NH2
HO
OH
OH
D-Altro
(minor)
+
H
We were interested in two aspects of theabove syntheticstrategy.
One was the influence of pyrrolidine N-protection on the desym-
metrization process. The second was the possibility of using the 5-
O
H2
-H2O
H2
2
14
Cat.
Cat.
H
D-Allo
(major)
3
azido-5-deoxy-3,4-di-O-benzyl-D
-fructose (14)10 as precursor in the
BnO OBn
BnO OBn
A
synthesis of the symmetric pyrrolidine 16. Straightforward hydro-
genation of 14 would lead us to pyrrolidine 16 in one single step
shorting out the reaction sequence. As predicted, catalytic hydroge-
nation of 14 (see Scheme 3) afforded a mixture of 2,5-iminohexitols:
B
-Face
and Favoured
TS
Figure 2. Formation of pyrrolidines from 5-azido-5-deoxy-D-fructose derivative (14)
and transition state (TS) for catalytic hydrogenation of intermediate D1-pyrroline B.
D-altro (minor) and D-allo (major) that could be resolved after

I. Izquierdo et al. / Tetrahedron 64 (2008) 4993–4998
4995
4.32 mmol) and di-tert-butyl dicarbonate (706 mg, 3.24 mmol) at rt
for 12 h. TLC (Et2O–hexane, 1:1 v/v) then revealed the presence of
a faster-running compound. The reaction mixture was quenched by
the addition of MeOH (2 mL), and after 15 min was concentrated
and subjected to column chromatography (Et2O–hexane,1:3 v/v) to
afford pure 5 (1.95 g, 98%) as a white syrup. IR nmax/cmꢀ1 (neat):
3070 (aromatic), 1699 (CO, Boc) and 700 (aromatic); 1H NMR
(400 MHz): d 7.55–7.26 (m, 30H, 6Ph), 4.61 and 4.45 (2d, J¼12.5 Hz,
CH2Ph), 4.38 and 4.32 (2d, J¼11.7 Hz, CH2Ph), 4.15–3.72 (3m, 8H, H-
2,20a,20b,3,4,5,50a,50b),1.53 and 1.33 (2s, 9H, OCMe3, two rotamer),19
0.98 and 0.94 (2s, 18H, 2SiCMe3, two rotamers); 13C NMR (100 MHz,
inter alia): d 155.4 (CO, Boc), 79.9 (OCMe3), 76.9 and 75.5 (C-3,4, two
rotamers), 71.8 and 71.4 (CH2Ph, two rotamers), 63.0 and 62.9
(C-2,5, two rotamers), 61.9 (C-20,50), 28.5 (OCMe3), 27.1 (SiCMe3),
19.5 and 19.4 (SiCMe3, two rotamers). HRMS (LSIMS): m/z 942.4558
[MþþNa]. For C57H69NO6NaSi2 942.4561 (deviation þ0.3 ppm).
R1
N
R
OR2
d
a
19
2
on 22
BnO
OBn
20 R = I; R1 = Cbz; R2 = PG
21
b
c
R = R1 = H; R2 = PG
22 R = R1 = R2 = H
PG = TBDPS
Scheme 4. Synthesis of 6-deoxy-DADP (2) from 19. Reagents and conditions: (a)
I2–Ph3P–imidazole–THF, D; (b) H2–Raney-Ni–TEA–MeOH, rt; (c) TBAF$3H2O–THF, rt;
(d) concd HCl (drops)/10% Pd–C–H2–MeOH, rt.
Boc
N
Boc
N
OR1
RO
OR1
RO
PG = TBDPS
OBn
BnO
23 R = Bz; R1 = PG
24
OBn
BnO
4.1.2. (2R,3R,4S,5S)-3,4-Dibenzyloxy-N-tert-butyloxycarbonyl-2,5-
bis(hydroxymethyl)pyrrolidine (6)
26 R = H; R1 = PG
27 R = Ac; R1 = PG
25
a
b
c
d
R = R1 = H
25 R = Ac; R1 = H
To a stirred solution of 5 (1.9 g, 2.06 mmol) in THF (20 mL) was
added TBAF$3H2O (2 g, 6.3 mmol) and the mixture was kept at rt
for 6 h. TLC (Et2O–hexane, 1:1 v/v) then showed a new slower-
running compound. The mixture was concentrated to a residue that
was partitioned into Et2O and brine, the organic phase was sepa-
rated and concentrated to a residue that was subjected to column
chromatography (Et2O/Et2O–MeOH, 20:1 v/v) to afford pure 6
(900 mg, 98%) as a colourless syrup. IR nmax/cmꢀ1 (neat): 3400
(OH), 3064 and 3031 (aromatic), 1694 (CO, Boc), 737 and 698
(aromatic); 1H NMR (400 MHz): d 7.33–7.28 (m, 10H, 2Ph), 4.55 (br
s, 4H, 2CH2Ph), 4.13–3.50 (m, 8H, H-2,20a,20b,3,4,5,50a,50b), 1.45 (s,
9H, CMe3); 13C NMR (100 MHz, inter alia): d 156.2 (CO, Boc), 81.0
(OCMe3), 78.3 and 77.8 (C-3,4, two rotamers), 72.1 (2CH2Ph), 66.1
(C-20,50), 63.9 (C-2,5), 28.6 (CMe3). HRMS (LSIMS): m/z 466.2203
[MþþNa]. For C25H33NO6Na 466.2206 (deviation þ0.6 ppm).
Scheme 5. Chemo-enzymatic acetylation of a partially protected derivative of DALDP
(24) and structural elucidation of its monoacetylated product (25). Reagents and
conditions: (a) (i) TBAF$3H2O–THF, rt, (ii) MeONa (cat.)–MeOH, rt; (b) vinyl acetate–
TBME–ChirazymeÒ L-2, c.-f., C2, lyo, rt; (c) Ac2O–DMAP(cat.)–Py, rt; (d) TBAF$3H2O–
THF, rt.
3. Conclusions
Desymmetrization of partially protected symmetric tetrahy-
droxylated pyrrolidine alkaloids by enzymatic transesterification
seems to be an appropriated methodology for the synthesis of key
intermediates in the preparation of 2,5,6-trideoxy-2,5-iminohex-
itols. The nature of the N-protecting groups does not appear to play
an important role in the enzymatic process and the results show
that during the transesterification reaction, it is the left-hand side
hydroxymethyl group in 6, 16 and 24, which is always chosen for
the catalysis. Nevertheless, more experiments on other models are
required in order to confirm the scope of this methodology.
4.1.3. (2R,3R,4S,5S)-2-Acetyloxymethyl-3,4-dibenzyloxy-N-tert-
butyloxycarbonyl-5-hydroxymethylpyrrolidine (7)
To a gently stirred solution of 6 (500 mg, 1.13 mmol) and vinyl
acetate (520 mL, 5 equiv) in tert-butyl methyl ether (TBME, 10 mL)
was added ChirazymeÒ L-2, c.-f. C2. lyo (150 mg), and the mixture
maintained at rt. The reaction was monitored by TLC (Et2O) and
after 72 h revealed the absence of 6 and the presence of a faster-
running compound. The enzyme was removed by filtering,
thoroughly washed with ether, and the filtrate and washings
concentrated to a residue that was subjected to chromatography
(Et2O–hexane, 1:1 v/v) to give 7 (445 mg, 81%, ee 94%) as a colour-
4. Experimental
4.1. General
Solutions were dried over MgSO4 before concentration under
reduced pressure. The 1H and 13C NMR spectra were recorded with
Bruker AMX-300, AM-300, ARX-400 and AMX-500 spectrometers
for solutions in CDCl3 (internal Me4Si). Splitting patterns are desig-
nated as follows: s, singlet; d, doublet; t, triplet; q, quartet; quint,
quintet; m, multiplet and br, broad. IR spectra were recorded with
a Perkin–Elmer FT-IR Spectrum One instrument and mass spectra
were recorded with a Hewlett–Packard HP-5988-A and Fisons mod.
Platform II and VGAutospec-Q mass spectrometers. Optical rotations
were measured, unless otherwise stated, forsolutionsin CHCl3 (1 dm
tube) with a Jasco DIP-370 polarimeter. TLC was performed on pre-
coated silica gel 60 F254 alumnium sheets and detected byemploying
a mixture of 10% ammonium molybdate (w/v) in 10% aqueous sul-
furic acid containing 0.8% cerium sulfate (w/v) and heating. Column
chromatography wasperformed on silicagel (Merck, 7734). Thenon-
crystalline compounds were shown to be homogeneous by chro-
matographic methods and characterized by NMR and HRMS (LSIMS).
less syrup. [a]2D7 ꢀ7, [a] ꢀ15 (c 1); IR nmax/cmꢀ1 (neat): 3471 (OH),
27
405
3064 and 3031 (aromatic), 1745 (CO, Ac), 1697 (CO, Boc), 738 and
698 (aromatic); 1H NMR (400 MHz): d 7.33 (br s, 10H, 2Ph), 4.60–
3.40 (5m, 8H, H-2,20a,20b,3,4,5,50a,50b), 1.97 (s, 3H, Ac), 1.46 (s, 9H,
CMe3); 13C NMR (100 MHz, inter alia): d 170.5 (COMe), 156.6 (CO,
Boc), 81.6 (CMe3), 75.9 (C-3,4), 72.1 (2CH2Ph), 66.1, 64.7 and 62.9
(C-2050, two rotamers), 63.6 and 61.2 (C-2,5), 28.5 (CMe3), 21.0
(COMe). HRMS (LSIMS): m/z 508.2311 [MþþNa]. For C27H35NO7Na
508.2311 (deviation 0.0 ppm).
4.1.4. (2S,3S,4R,5R)-3,4-Dibenzyloxy-N-tert-butyloxycarbonyl-2-
tert-butyldiphenylsilyloxymethyl-5-hydroxymethylpyrrolidine (9)
An ice-water cooled and stirred solution of 810 (247 mg,
0.42 mmol) in anhydrous DCM (10 mL) was treated with TEA (118 mL,
0.85 mmol) and di-tert-butyl dicarbonate (140 mg, 0.64 mmol) at rt
for 24 h. TLC (Et2O) then revealed the presence of a faster-running
compound. The reaction mixture was quenched by the addition of
MeOH (0.5 mL), and after 15 min was concentrated and subjected to
column chromatography (Et2O–hexane, 1:1 v/v) to afford pure 9
(205 mg, 71%) as a colourless syrup. [a]2D5 þ11.4 (c 1); IR nmax/cmꢀ1
4.1.1. (2R,3R,4S,5S)-3,4-Dibenzyloxy-N-tert-butyloxycarbonyl-2,5-
bis(tert-butyldiphenylsilyloxymethyl)pyrrolidine (5)
A stirred solution of 410 (1.77 g, 2.16 mmol) in anhydrous
dichloromethane (DCM, 15 mL) was treated with TEA (0.6 mL,

4996
I. Izquierdo et al. / Tetrahedron 64 (2008) 4993–4998
(neat): 3441 (OH), 3070 and 3031 (aromatic), 1694 and 1674 (CO,
Boc), 740 and 700 (aromatic); 1H NMR (400 MHz): d 7.60–7.32 (2m,
20H, 4Ph), 4.53–3.57 (6m, 8H, H-2,20a,20b,3,4,5,50a,50b), 1.33 (s, 9H,
OCMe3), 1.03 (s, 9H, SiCMe3); 13C NMR (100 MHz, inter alia): d 156.8
(CO, Boc), 81.0 (OCMe3), 76.7 and 76.0 (C-3,4), 70.8 (CH2Ph), 65.4 and
63.1 (C-20,50), 64.4 and 63.9 (C-2,5), 27.3 (OCMe3), 25.9 (SiCMe3),19.4
(SiCMe3). HRMS (LSIMS): m/z 704.3386[MþþNa]. For C41H51NO6NaSi
704.3383 (deviation ꢀ0.3 ppm).
4.1.8. (2R,3R,4S,5S)-3,4-Dibenzyloxy-2-hydroxymethyl-5-
methylpyrrolidine (13)
Compound 12 (400 mg, 0.94 mmol) was dissolved in a 50%
solution of TFA–DCM (25 mL) and the mixture was stirred at rt
for 60 min. TLC (Et2O) then revealed a non-mobile compound. The
solvent was eliminated and the residue codistilled with toluene
to a new residue that was dissolved in DCM and washed with
aqueous 10% Na2CO3 and concentrated to a residue that was
subjected to column chromatography (Et2O–MeOH, 3:1 v/v) to
afford 13 (246 mg, 80%) as a white solid. Mp 93–94 ꢁC; [a]D25 –15.2
(c 1); IR nmax/cmꢀ1 (neat): 3243 (OH), 3065, 3031, 735 and 697
(aromatic); 1H NMR (300 MHz): d 7.37 (br s, 10H, 2 Ph), 4.66 and
4.57 (2d, 2H, J¼11.7 Hz, CH2Ph), 4.65 and 4.59 (2d, 2H, J¼11.7 Hz,
CH2Ph), 3.84 (t, 1H, J¼4.7 Hz, H-3 or 4), 3.62–3.41 (2m, 5H, H-
2,20a,20b,3 or 4,5), 2.53 (br s, 2H, OH and NH), 1.18 (d, 3H,
J5,Me¼6.2 Hz, Me-5); 13C NMR (75 MHz, inter alia): d 138.5, 138.4,
128.6, 128.2, 128.1 and 127.9 (2Bn), 84.0 and 78.8 (C-3,4), 72.2
(2CH2Ph), 62.8 (C-20), 62.7 and 56.3 (C-2,5), 20.6 (Me-5). HRMS
(LSIMS): m/z 350.1734. For C20H25NO3Na 350.1732 (deviation
ꢀ0.6 ppm). Anal. calcd for C20H25NO3: C 73.37, H 7.70, N 4.28;
found: C 73.46, H 7.56, N 4.45.
4.1.5. Synthesis of 7 from 9
Conventional acetylation of compound 9 (250 mg, 0.37 mmol)
in dry pyridine (5 mL) with acetic anhydride (0.5 mL, 5.3 mmol)
and DMAP (50 mg) afforded after usual work-up and column
chromatography (Et2O–hexane, 1:1 v/v) presumably (2R,3R,4S,5S)-
2-acetyloxymethyl-3,4-dibenzyloxy-N-tert-butyloxycarbonyl-5-
tert-butyldiphenylsilyloxymethylpyrrolidine (10, 215 mg, 81%) that
was not investigated but subjected to O-desilylation in THF (10 mL)
with TBAF$3H2O (110 mg, 0.35 mmol) at rt for 12 h. Work-up of the
reaction mixture as above gave after column chromatography (Et2O)
27
pure homochiral 7 (113 mg, 78%). [a]2D7 ꢀ8.8, [a]
ꢀ16 (c 1.0).
405
4.1.6. (2R,3R,4S,5R)-2-Acetyloxymethyl-3,4-dibenzyloxy-N-tert-
butyloxycarbonyl-5-iodomethylpyrrolidine (11)
4.1.9. (2R,3R,4S,5S)-3,4-Dihydroxy-2-hydroxymethyl-5-
To a solution of 7 (700 mg, 1.44 mmol) in dry THF (20 mL)
were added Ph3P (755 mg, 2.88 mmol), imidazole (392 mg,
5.76 mmol) and I2 (731 mg, 2.88 mmol) at rt. The mixture was
refluxed for 2 h. TLC (Et2O) showed not starting material and
the presence of a new compound. The solvent was evaporated,
the residue redissolved in ether, washed with aqueous 10% Na2S2O3
and brine and concentrated. Column chromatography (Et2O–
hexane, 1:3 v/v) of the residue gave 11 (690 mg, 82%) as a col-
ourless syrup. [a]D23 ꢀ9.3 (c, 1.2); IR nmax/cmꢀ1 (neat): 3064 and
3031 (aromatic), 1745 (CO, Ac), 1700 (CO, Boc), 738 and 699 (aro-
matic). 1H NMR (500 MHz): d 7.30–7.24 (m, 10H, 2Ph), 4.53–3.25
(6m, 12H, 2CH2Ph, H-2,20a,20b,3,4,5,50a,50b), 1.92 (s, 3H, Ac), 1.39
(s, 9H, CMe3); 13C NMR (125 MHz, inter alia): d 170.5 (COMe),
154.8 (CO, Boc), 81.2 (CMe3), 79.7, 78.3, 76.4 and 74.9 (C-3,4, two
rotamers), 72.0, 71.8 and 71.6 (2CH2Ph, two rotamers), 63.0 and
62.6 (C-20, two rotamers), 61.5, 60.9 and 60.3 (C-2,5, two rotam-
ers), 28.5 (CMe3), 21.1 (COMe), 10.8 and 8.6 (C-50, two rotamers).
HRMS (LSIMS): m/z 618.1323 [MþþNa]. For C27H34INO6Na 618.1329
(deviation þ0.9 ppm).
methylpyrrolidine (3, ent-6-deoxy-DADP)
A solution of 13 (205 mg, 0.63 mmol) in MeOH (10 mL) was
acidified with concd HCl (0,2 mL) and hydrogenated at 60 psi over
with 10% Pd–C (80 mg) for 24 h. The catalyst was filtered off and
washed with MeOH. The mixture was neutralized with Amberlite
IRA-400 (OHꢀ form) and concentrated to a residue that was
retained onto a column of DowexÒ 50Wx8 (200–400 mesh). The
column was thoroughly washed with MeOH (30 mL), water (30 mL)
and then with 1 N NH4OH (20 mL) to afford pure 3 (90 mg, 98%) as
colourless syrup; [a]2D7 þ1.9 (c 1.5, MeOH); 1H NMR (300 MHz,
MeOH-d4): d 3.87 0(dd, 1H, J2,3¼4.8, J3,4¼6.2 Hz, H-3), 3.68 (d, 2H,
0
0
J2,2 ¼4.4 Hz, H-2 ,2 ), 3.44 (t, 1H, J4,5¼7.0 Hz, H-4), 3.02 (q, 1H, H-2),
3.00 (quin, 1H, H-5), 1.24 (d, 3H, J5,Me¼6.6 Hz, Me-5); 13C NMR
(75 MHz, inter alia): d 77.7 (C-4), 72.3 (C-3), 65.9 (C-2), 61.6 (C-20),
58.3 (C-5), 17.1 (Me-5). MS (EI): m/z 116 (MþꢀCH2OH, 100%).
4.1.10. (2R,3R,4S,5S)-3,4-Dibenzyloxy-N-benzyloxycarbonyl-2,5-
bis(hydroxymethyl)pyrrolidine (16)
Compound 14 (1.5 g, 2.41 mmol) in MeOH (20 mL) was hydro-
genated at 60 psi over wet Raney-Ni (2 g) overnight. TLC (Et2O–
hexane, 1:1 v/v) then revealed the absence of starting material and
the presence of a non-mobile compound. When TLC was performed
with Et2O–MeOH 2:1 v/v, two compounds of similar mobility were
observed. The catalyst was filtered off, washed with MeOH and the
combined filtrate and washings were concentrated to a residue that
was dissolved in dry acetone (15 mL) and the resulting solution
treated with anhydrous K2CO3 (2.4 g) and benzyl chloroformate
(575 mL, 3.37 mmol) at rt with stirring for 12 h. TLC (Et2O–MeOH,
2:1 v/v) then showed the presence of two faster-running com-
pounds. The reaction mixture was filtered and concentrated to
4.1.7. (2R,3R,4S,5S)-3,4-Dibenzyloxy-N-tert-butyloxycarbonyl-2-
hydroxymethyl-5-methylpyrrolidine (12)
To a solution of compound 11 (650 mg, 1.09 mmol) in MeOH
(20 mL), triethylamine (TEA, 0.31 mL, 2.18 mmol) was added. The
mixture was hydrogenated (balloon) over wet Raney-nickel
(500 mg, Fluka) for 6 h. TLC (Et2O–hexane, 3:1 v/v) then revealed
the presence of a slower-running compound. The catalyst was fil-
tered off, washed with MeOH and the combined filtrate and
washings were concentrated to a residue that was dissolved in dry
methanol (10 mL). NaOMe–MeOH (2 N, 1 mL) was added and the
mixture was stirred for 2 h. TLC (Et2O–hexane, 3:1 v/v) then
showed a slower-running compound. The reaction mixture was
neutralized with AcOH and concentrated to a residue that was
subjected to column chromatography (Et2O–hexane, 1:2 v/v) to
afford syrup 12 (437 mg, 94%). [a]2D5 þ13 (c 1); IR nmax/cmꢀ1 (neat):
3437 (OH), 3064 and 3031 (aromatic), 1691 and 1669 (CO, Boc), 736
and 698 (aromatic); 1H NMR (300 MHz): d 7.37 (br s, 10H, 2Ph),
4.63–3.57 (3m, 8H, H-2,20a,20b,3,4,5,50a,50b), 1.50 (s, 9H, CMe3), 1.20
(d, 3H, J5,Me¼6.3 Hz, Me-5); 13C NMR (75 MHz, inter alia): d 157.2
(CO, Boc), 138.2, 128.7, 128.2 and 128.1 (2CH2Ph), 80.8 and 77.8
(CMe3, C-3,4), 72.1 (2CH2Ph), 65.8 (C-20), 63.9 and 57.8 (C-2,5), 28.7
(CMe3), 19.9 (Me-5). HRMS (LSIMS): m/z 450.2250 [MþþNa]. For
a
residue that was subjected to column chromatography
(Et2O–hexane, 5:1 v/v/Et2O/Et2O–MeOH, 20:1 v/v) to
afford first (2R,3R,4S,5R)-3,4-dibenzyloxy-N-benzyloxycarbonyl-
2,5-bis(hydroxymethyl)pyrrolidine (15, 90 mg, 8% from 14) as
24
a colourless syrup. [a]D24 ꢀ21, [a] ꢀ53 (c 0.8); IR nmax/cmꢀ1 (neat):
405
3430 (OH), 3032 (aromatic), 1701 (CO, Cbz), 739 and 699
(aromatic); 1H NMR (500 MHz): d 7.30–7.20 (m, 15H, 3Ph), 5.25–
3.30 (4m, 14H, 3CH2Ph and H-2,20a,20b,3,4,5,50a,50b, two rotamers);
13C NMR (125 MHz, inter alia): d 156.0 (CO, Cbz), 77.6, 76.5, and 76.1
(C-3,4, two rotamers), 72.5 and 72.3 (2CH2Ph), 67.8 (Cbz), 63.7, 62.8,
60.3 and 58.7 (C-2,5, two rotamers), 61.9, 61.2, 58.8þ and 58.5
(C-20,50, two rotamer). HRMS (LSIMS): m/z 500.2055 [M þNa]. For
C
25H33NO5Na 450.2256 (deviation þ1.4 ppm).
C28H31NO6Na 500.2049 (deviation ꢀ1.2 ppm).

I. Izquierdo et al. / Tetrahedron 64 (2008) 4993–4998
4997
Eluted second was 16 (760 mg, 66% from 14) as a colourless
syrup. IR nmax/cmꢀ1 (neat): 3411 (OH), 3064 and 3032 (aromatic),
1682 (CO, Cbz), 737 and 698 (aromatic); 1H NMR (500 MHz): d 7.27–
7.24 (m, 15H, 3Ph), 5.06 and 4.49 (2s, 6H, 3CH2Ph), 4.10–3.86 (m,
6H, H-20a,20b,3,4,50a,50b), 3.52 (br s, 2H, H-2,5); 13C NMR (125 MHz,
inter alia): d 156.5 (CO, Cbz), 78.2 and 77.9 (C-3,4, two rotamers),
72.2 (2CH2Ph), 67.7 (Cbz), 64.2 and 63.9 (C-2,5, two rotamers), 62.8
and 62.2 (C-20,50, two rotamers). HRMS (LSIMS): m/z 500.2045
[MþþNa]. For C28H31NO6Na 500.2049 (deviation þ0.8 ppm).
residue redissolved in DCM, washed with aqueous 10% Na2S2O3 and
brine and concentrated. Column chromatography (Et2O–hexane,
1:1 v/v) of the residue gave 20 (690 mg, 95%) as a colourless syrup.
[a]2D3 þ19 (c, 1); IR nmax/cmꢀ1 (neat): 3068 and 3031 (aromatic),
1709 (CO, Cbz), 739 and 699 (aromatic). HRMS (LSIMS): m/z
848.2242 [MþþNa]. For C44H48INO5NaSi 848.2244 (deviation
þ0.3 ppm).
4.1.15. (2S,3S,4R,5R)-3,4-Dibenzyloxy-2-tert-butyldiphenylsilyloxy-
methyl-5-methylpyrrolidine (21)
4.1.11. (2R,3R,4S,5S)-2-Acetyloxymethyl-3,4-dibenzyloxy-N-
benzyloxycarbonyl-5-hydroxymethylpyrrolidine (17)
To a solution of compound 20 (680 mg, 0.82 mmol) in MeOH
(15 mL), TEA (0.23 mL, 1.64 mmol) was added. The mixture was
hydrogenated at 60 psi over wet Raney-nickel (500 mg, Fluka) for
20 h. TLC (Et2O–hexane, 1:1 v/v) then revealed the presence of
a slower-running compound. The catalyst was filtered off, washed
with MeOH and the combined filtrate and washings were
concentrated to a residue that was subjected to column chroma-
tography (Et2O–hexane, 2:1 v/v) to afford colourless syrup 21
(400 mg, 86%). [a]D24 þ29.1 (c 1.4); IR nmax/cmꢀ1 (neat) 3360 (NH),
3069, 3030, 739 and 700 (aromatic); 1H NMR (300 MHz): d 7.68–
7.33 (2m, 10H, 2Ph), 4.66 and 4.55 (2d, 2H, J¼12.0 Hz, CH2Ph), 4.56
To a gently stirred solution of 16 (760 mg, 1.59 mmol) and vinyl
acetate (734 mL, 5 equiv) in TBME (15 mL) was added ChirazymeÒ
L-2, c.-f. C2. lyo (200 mg), and the mixture maintained at rt with
stirring. The reaction was monitored by TLC (Et2O) and after 18 h
revealed the absence of 16 and the presence of a faster-running
compound. The enzyme was removed by filtering, thoroughly
washed with ether and the filtrate and washings concentrated to
a residue that was subjected to chromatography (Et2O–hexane, 1:2
v/v/Et2O) to afford pure 17 (620 mg, 75%) as a colourless thick
28
syrup. [a]2D4 ꢀ8, [a]
ꢀ19.6 (c 1.1); IR nmax/cmꢀ1 (neat): 3467 (OH),
(s, 2H, CH2Ph), 3.88 (t, 1H, J¼4.7 Hz, H-3), 3.76 (dd, 1H, J2,2 a¼3.8 Hz,
0
405
J2 a,2 b¼10.6 Hz, H-20a), 3.71 (dd, 1H, J2,2 b¼4.1 Hz, H-20b), 3.41–3.33
(m, 3H, H-2,4,5), 1.66 (br s, 1H, NH), 1.23 (d, 3H, J5,Me¼5.9 Hz, Me-5),
1.08 (s, 9H, CMe3); 13C NMR (75 MHz, inter alia): d 84.6 (C-4), 78.6
(C-3), 72.2 and 71.9 (2 CH2Ph), 64.5 (C-20), 64.2 (C-2), 56.8 (C-5),
27.2 (CMe3), 19.7 (Me-5), 19.5 (CMe3). HRMS (LSIMS): m/z 566.3093
[MþþH]. For C36H44NO3 566.3090 (deviation ꢀ0.4 ppm).
0
0
0
3064 and 3032 (aromatic), 1743 (CO, Ac),1702 (CO, Cbz), 737 and
698 (aromatic); 1H NMR (400 MHz): d 7.36 (br s, 15H, 3Ph), 4.64–
4.52 (m, 4H, 2CH2Ph), 4.28–3.59 (m, 10H, CH2Ph, H-2,20a,20b,3,4,5,
50a,50b), 1.94 (br s, 3H, Ac). HRMS (LSIMS): m/z 542.2159 [MþþNa].
For C30H33NO7Na 542.2155 (deviation ꢀ0.9 ppm).
4.1.12. (2R,3R,4S,5S)-2-Acetyloxymethyl-3,4-dibenzyloxy-N-
benzyloxycarbonyl-5-tert-butyldiphenylsilyloxymethyl
pyrrolidine (18)
4.1.16. (2S,3S,4R,5R)-3,4-Dibenzyloxy-2-hydroxymethyl-5-
methylpyrrolidine (22)
Toa stirredsolution of17 (590 mg,1.13 mmol)in dryDMF(10 mL)
were added imidazole (165 mg, 2.43 mmol) and tert-butyl-
chlorodiphenylsilane (500 mL,1.9 mmol) and the mixture was left at
rt overnight. TLC (Et2O–hexane, 1:1 v/v) then showed a faster-run-
ning compound. MeOH (1 mL) was added and after 15 min the
reaction mixture was diluted with water (30 mL) and extracted with
ether (3ꢂ15 mL), then concentrated to a residue that was subjected
to chromatography (Et2O–hexane, 1:2 v/v/1:1 v/v) to afford 18
(710 mg, 82%) as a colourless syrup. [a]2D4 þ29 (c 1); IR nmax/cmꢀ1
(neat): 3069 and 3032 (aromatic), 1747 (CO, Ac), 1699 (CO, Cbz), 741
and 698 (aromatic); 1H NMR (400 MHz): d 7.61–7.29 (m, 25H, 5Ph),
5.20–3.60 (3m, 14H, 3CH2Ph, H-2,20a,20b,3,4,5,50a,50b, two rotam-
ers),1.82 and 1.74 (2br s, 3H, Ac, two rotamers),1.06 (br s, 9H, CMe3);
13C NMR (100 MHz, inter alia): d 170.5 (COMe), 155.7 (CO, Cbz), 77.1,
76.3, 76.0 and 75.3 (C-3,4, two rotamers), 71.9 (2CH2Ph), 67.4 and
62.1 (Cbz, C-20,50), 63.5, 63.0, 60.4 and 60.0 (C-2,5, two rotamers),
27.1 (CMe3), 20.7 (COMe), 19.5 (CMe3). HRMS (LSIMS): m/z 780.3339
[MþþNa]. For C46H51NO7NaSi 780.3333 (deviation ꢀ0.8 ppm).
To a stirred solution of 21 (370 mg, 0.65 mmol) in THF (15 mL)
was added TBAF$3H2O (310 mg, 0.98 mmol) and the mixture was
kept at rt for 16 h. TLC (Et2O) then showed a new compound of
lower mobility. The mixture was concentrated to a residue that was
subjected to column chromatography (Et2O/Et2O–MeOH, 10:1
v/v) to yield impure 22 that was retained onto a column of DowexÒ
50Wx8 (200–400 mesh). The column was thoroughly washed with
MeOH, water and then with 1 N NH4OH to afford pure 22 (200 mg,
93%) as a white solid. Mp 96–98 ꢁC; [a]D25 þ15.1 (c 1.1). The
spectroscopic data were identical to that of the above enantiomer
(ꢀ)-13.
4.1.17. (2S,3S,4R,5R)-3,4-Dihydroxy-2-hydroxymethyl-5-methyl-
pyrrolidine [2, (ꢀ)-6-deoxy-DADP]
A solution of 22 (190 mg, 0.58 mmol) in MeOH was acidified
with concd HCl and hydrogenated at 60 psi with 10% Pd–C (80 mg)
for 16 h. The catalyst was filtered off and washed with MeOH. The
mixture was neutralized with Amberlite IRA-400 (OHꢀ form), the
resin filtered off, washed with MeOH and the filtrate and washing
concentrated to a residue that was retained onto a column of
DowexÒ 50Wx8 (200–400 mesh). The column was thoroughly
washed with MeOH, water and then with 1 N NH4OH to afford pure
2 (72 mg, 85%) as colourless syrup. [a]3D0 ꢀ1.7 (c 1, MeOH) [lit.7 [a]2D0
ꢀ2 (c 1, MeOH), lit.8 [a]D20 ꢀ1 (c 1.5, MeOH)], which had analytical
and spectroscopic data in accordance to those previously
reported.7,8
4.1.13. (2S,3S,4R,5R)-3,4-Dibenzyloxy-N-benzyloxycarbonyl-2-tert-
butyldiphenylsilyloxymethyl-5-hydroxymethylpyrrolidine (19)
Conventional Zemplen deacetylation of 18 (695 mg, 0.91 mmol)
in anhydrous MeOH (15 mL) with 2 N MeONa (0.5 mL) for 12 h gave
after usual work-up and column chromatography (Et2O–hexane,
1:1 v/v/Et2O) pure 19 (576 mg, 86%, ee 97%) as a colourless syrup,
which had spectroscopic data in total agreement with those
previously reported.9f [a]D24 þ9.7 (c 1) [lit.9f [a]2D5 þ10 (c 1.8)].
4.1.18. (2R,3R,4S,5R)-3,4-Dibenzyloxy-N-tert-butyloxycarbonyl-
2,5-bis(hydroxymethyl)pyrrolidine (24)
4.1.14. (2S,3S,4R,5S)-3,4-Dibenzyloxy-N-benzyloxycarbonyl-2-tert-
butyldiphenylsilyloxymethyl-5-iodomethylpyrrolidine (20)
To a stirred solution of (2R,3R,4S,5R)-2-benzoyloxymethyl-3,4-
dibenzyloxy-N-tert-butyloxycarbonyl-5-tert-butyldiphenylsilyloxy-
methylpyrrolidine (23)18 (3.34 g, 4.26 mmol) in THF (20 mL) was
added TBAF$3H2O (2 g, 6.4 mmol) and the mixture was kept at rt
until disappearance of the starting material for 2 days. TLC (Et2O–
hexane,1:2 v/v) then showed two new slower-running compounds,
To a solution of 19 (630 mg, 0.88 mmol) in dry THF (15 mL) were
added Ph3P (482 mg, 1.76 mmol), imidazole (240 mg, 3.52 mmol)
and I2 (448 mg, 1.76 mmol) at rt. The mixture was refluxed for 2 h.
TLC (Et2O–hexane,1:1 v/v) then showed the end of the reaction and
the presence of a new compound. The solvent was evaporated, the

4998
I. Izquierdo et al. / Tetrahedron 64 (2008) 4993–4998
probably 24 and its 20-O-benzoyl derivative. MeONa solution in
MeOH (2 N, 2 mL) was added and the reaction monitored until only
24 was observed. The reaction mixture was neutralized with acetic
acid and concentrated to a residue that was subjected to column
chromatography (Et2O) to afford pure 24 (1.74 g, 92%) as a colour-
less syrup. [a]2D6 ꢀ42 (c 1.1); IR nmax/cmꢀ1 (neat): 3428 (OH), 3064
and 3032 (aromatic), 1694 (CO, Boc), 738 and 699 cmꢀ1 (aromatic);
1H NMR (400 MHz): d 7.40 (br s, 10H, 2Ph), 4.81–3.69 (2m, 12H,
2CH2Ph, H-2,20a,20b,3,4,5,50a,50b), 1.52 (s, 9H, CMe3); 13C NMR
(100 MHz, inter alia): d 155.8 (CO, Boc), 81.26 (CMe3), 79.1, 77.7 and
77.4 (C-3,4, two rotamers), 72.4 and 72.2 (2CH2Ph), 64.6 and 60.0
(C-2,5), 64.3, 62.7, 60.8 and 59.2 (C-20,50, two rotamers), 28.6
(CMe3). HRMS (LSIMS): m/z 466.2206 [MþþNa]. For C25H33NO6Na
466.2206 (deviation ꢀ0.1 ppm).
Acknowledgements
Major support for this project was provided by Ministerio de
´
Educacion y Ciencia of Spain (Project Ref. No. CTQ2006-14043).
´
Additional support was provided by Junta de Andalucıa (Group CVI-
´
´
250) and Fundacion Ramon Areces (Spain) for a grant (F.S.-C.).
Supplementary data
1H, 13C and DEPT NMR spectra of ent-6-deoxy-DADP (3) (two
pages). Supplementary data associated with this article can be
found in the online version, at doi:10.1016/j.tet.2008.03.089.
References and notes
´
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butyloxycarbonyl-5-hydroxymethylpyrrolidine (25)
thesis 2007. doi:10.1055/s-2008-1072566
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J.-L.; Solladie´, G. J. Org. Chem. 1998, 63, 8918–8921; (c) Yu, Ch.-Y.; Asano, N.;
Ikeda, K.; Wang, M.-X.; Butters, T. D.; Wormald, M. R.; Dwek, R. A.; Winters, A. L.;
Nash, R. J.; Fleet, G. W. J. Chem. Commun. 2004, 1936–1937; (d) Asano, N.; Ikeda,
K.; Yu, L.; Kato, A.; Takebayashi, K.; Adachi, I.; Kato, I.; Ouchi, H.; Takahatad, H.;
To a gently stirred solution of 24 (415 mg, 0.94 mmol) and vinyl
acetate (500 mL, 5 equiv) in TBME (15 mL) was added ChirazymeÒ
L-2, c.-f. C2. lyo (160 mg) and the mixture maintained at rt for 3 days.
The reactionwas monitoredbyTLC (Et2O) andafter72 hrevealed the
absence of 24 and the presence of a faster-running compound. The
enzyme was removed by filtering, thoroughly washed with ether
and the filtrate and washings concentrated to a residue that was
subjected to chromatography (Et2O–hexane, 1:1 v/v) to give 25
25
(315 mg, 69%) as a colourless syrup. [a]2D5 –26, [a]
n
–57 (c 1); IR
405
max/cmꢀ1 (neat): 3462 (OH), 3064 and 3031 (aromatic), 1746 (CO,
Ac), 1696 (CO, Boc), 738 and 699 (aromatic); 1H NMR (400 MHz):
d 7.39–7.29 (m, 10H, 2Ph), 4.80–3.82 (2m, 12H, 2CH2Ph, H-
2,20a,20b,3,4,5,50a,50b), 1.95 and 1.94 (2br s, 3H, Ac, two rotamers),
1.51 and 1.50 (2 s, 9H, CMe3, two rotamers); 13C NMR (100 MHz, inter
alia): d 170.5 and 170.4 (COMe, two rotamers), 155.0 and 154.2 (CO,
Boc, two rotamers), 81.3 and 81.2 (CMe3, two rotamers), 78.6, 77.2
and 76.6 (C-3,4, two rotamers), 72.8, 72.4 and 72.1 (2CH2Ph, two
rotamers), 63.2, 62.8, 61.2 and 59.3 (C-20,50, two rotamers), 61.1, 60.8
and 59.5 (C-2,5, two rotamers), 28.6 (CMe3), 20.9 (COMe). HRMS
(LSIMS): m/z 508.2316 [MþþNa]. For C27H35NO7Na 508.2311 (de-
viation ꢀ1 ppm).
4.1.20. (2R,3R,4S,5R)-2-Acetyloxymethyl-3,4-dibenzyloxy-N-tert-
butyloxycarbonyl-5-tert-butyldiphenylsilyloxymethyl-
pyrrolidine (27)
´
Fleet, G. W. J. Tetrahedron: Asymmetry 2005, 16, 223–229; (e) Bleriot, Y.; Gretzke,
Conventional acetylation of (2R,3S,4R,5R)-3,4-dibenzyloxy-
N-tert-butyloxycarbonyl-2-tert-butyldiphenylsilyloxymethylpyrro-
lidine18 (26, 300 mg, 0.44 mmol) in dry pyridine (5 mL) with acetic
anhydride (0.5 mL, 5.3 mmol) and DMAP (50 mg) afforded after
usual work-up and column chromatography (Et2O–hexane, 1:2 v/v)
pure 27 (270 mg, 85%). [a]2D8 þ18 (c 1.1); IR nmax/cmꢀ1 (neat): 3069
and 3031 (aromatic), 1746 (CO, Ac), 1698 (CO, Boc), 738 and 700
(aromatic); 1H NMR (300 MHz): d 7.80–7.30 (2m, 20H, 4Ph), 4.90–
3.75 (m, 12H, 2CH2Ph, H-2,20a,20b,3,4,5,50a,50b), 1.88 (s, 3H, Ac), 1.33
(s, 9H, OCMe3), 1.11 (s, 9H, SiCMe3); 13C NMR (75 MHz, inter alia):
d 170.6 (CO, Ac), 154.1 and 153.5 (CO, Boc, two rotamers), 80.5
(OCMe3), 80.7, 79.3, 77.8 and 77.1 (C-3,4, two rotamers), 72.7
(2CH2Ph), 63.6 and 62.4 (C-20,50), 60.4 (C-2,5), 28.5 (OCMe3), 27.2
(SiCMe3), 20.9 (COMe), 19.4 (SiCMe3). HRMS (LSIMS): m/z 746.3593
[MþþNa]. For C43H53NO7NaSi 746.3591 (deviation ꢀ2.6 ppm).
D.; Kru¨lle, T. M.; Butters, T. D.; Dwek, R. A.; Nash, R. J.; Asano, N.; Fleet, G. W. J.
Carbohydr. Res. 2005, 340, 2713–2718; (f) Izquierdo, I.; Plaza, M.-T.; Tamayo,
J. A.; Rodrı´guez, M.; Martos, A. Tetrahedron 2006, 62, 6006–6011.
10. (a) Izquierdo, I.; Plaza, M.-T.; Rodrı´guez, M.; Franco, F.; Martos, A. Tetrahedron
´
2005, 61, 11697–11704; (b) Izquierdo, I.; Plaza, M.-T.; Rodrıguez, M.; Franco, F.;
Martos, A. Tetrahedron 2006, 62, 1904.
11. (a) Takabe, K.; Iida, Y.; Hiyoshi, H.; Ono, M.; Hirose, Y.; Fukui, Y.; Yoda, H.; Mase, N.
Tetrahedron: Asymmetry 2000, 11, 4825–4829; (b) Tsuji, T.; Iio, Y.; Takemoto, T.;
Nishi, T. Tetrahedron: Asymmetry 2005,16, 3139–3142; (c) Nakamura, T.;Tsuji, T.;Iio,
Y.;Miyazaki, S.; Takemoto,T.;Nishi, T. Tetrahedron:Asymmetry2006,17, 2781–2792.
12. (a) Davoli, P.; Caselli, E.; Bucciarelli, M.; Forni, A.; Torre, G.; Prati, F. J. Chem. Soc.,
ˆ
Perkin Trans. 1 2002, 1948–1953; (b) Chenevert, R.; Jacques, F. Tetrahedron: Asym-
metry 2006,17,1017–1021; (c) Young Choi, J.; Borch, R. F. Org. Lett. 2007, 9, 215–218.
13. Donohoe, T. J.; Rigby, C. L.; Thomas, R. E.; Nieuwenhuys, W. F.; Bhatti, F. L.;
Cowley, A. R.; Bhalay, G.; Linney, I. D. J. Org. Chem. 2006, 71, 6298–6301.
14. Due to the higher specific rotation values at l¼405 nm, these were used for the
ee calculations.
15. Garegg, P. J.; Samuelsson, B. J. Chem. Soc., Chem. Commun. 1979, 978–980.
16. Hydrogenations were, in general, conducted under either neutral or weak-basic
conditions, in order to avoid partial O-debenzylations.
17. (a) Takayama, S.; Martin, R.; Wu, J.; Laslo, K.; Siuzdak, G.; Wong, C.-H. J. Am. Chem.
Soc. 1997, 119, 8146–8151; (b) Izquierdo, I.; Plaza, M.-T.; Robles, R.; Franco, F.
Carbohydr. Res. 2001, 330, 401–408; (c) Izquierdo, I.; Plaza, M.-T.; Franco, F. Tetra-
hedron: Asymmetry 2002,13,1581–1585; (d) Liu, J.; Numa, M. M. D.; Liu, H.; Huang,
S.-J.; Sears, P.; Shikhman, A. R.; Wong, C.-H. J. Org. Chem. 2004, 69, 6273–6283.
4.1.21. Synthesis of 25 from 27
To a stirred solution of 27 (230 mg, 0.32 mmol) in THF (10 mL)
was added TBAF$3H2O (130 mg, 0.41 mmol) and the mixture was
kept at rt for 14 h. TLC (Et2O–hexane, 1:2 v/v) then showed a new
slower-running compound. The reaction mixture was concentrated
´
18. Izquierdo, I.; Plaza, M.-T.; Tamayo, J. A.; Sanchez-Cantalejo, F. Eur. J. Org. Chem.
2007, 6078–6083.
19. Most of the compound bearing either N-Boc or N-Cbz protection showed
widening or duplication of some resonance signals in their 1H and 13C NMR
spectra.
and subjected to column chromatography (Et2O–hexane, 1:3/1:1
v/v) to afford pure 25 (127 mg, 82%). [a]2D6 ꢀ28, [a]
ꢀ59 (c 1.4).
26
405