Polyhydroxylated pyrrolidines: synthesis from d-fructose of new tri-orthogonally protected 2,5-dideoxy-2,5-iminohexitols

Article abstract of DOI:10.1016/j.tet.2006.11.070

The readily available 3-O-benzyl-1,2-O-isopropylidene-β-d-fructopyranose (2) was transformed into its 5-O- (3) and 4-O-benzoyl (4) derivative. Compound 4 was straightforwardly transformed into 5-azido-4-O-benzoyl-3-O-benzyl-5-deoxy-1,2-O-isopropylidene-β-

Full text of DOI:10.1016/j.tet.2006.11.070

Tetrahedron 63 (2007) 1440–1447
Polyhydroxylated pyrrolidines: synthesis from D-fructose of new
tri-orthogonally protected 2,5-dideoxy-2,5-iminohexitols*
*
ꢀ
ꢀ
˜
Isidoro Izquierdo, Marıa T. Plaza and Victor Yanez
Department of Medicinal and Organic Chemistry, Faculty of Pharmacy, University of Granada, 18071 Granada, Spain
Received 23 October 2006; revised 17 November 2006; accepted 24 November 2006
Available online 18 December 2006
Abstract—The readily available 3-O-benzyl-1,2-O-isopropylidene-b-D-fructopyranose (2) was transformed into its 5-O- (3) and 4-O-benz-
oyl (4) derivative. Compound 4 was straightforwardly transformed into 5-azido-4-O-benzoyl-3-O-benzyl-5-deoxy-1,2-O-isopropylidene-b-
D-fructopyranose (7) via the corresponding 5-deoxy-5-iodo-a-L-sorbopyranose derivative 6. Cleavage of the acetonide in 7 to give 8, followed
by regioselective 1-O-silylation to 9 and subsequent catalytic hydrogenation gave a mixture of (2S,3R,4R,5R)- (10) and (2R,3R,4R,5R)-4-ben-
zoyloxy-3-benzyloxy-20-O-tert-butyldiphenylsilyl-2,5-bis(hydroxymethyl)pyrrolidine (12) that was resolved after chemoselective N-protec-
tion as their Cbz derivatives 11 and 1a, respectively. Stereochemistry of 11 and 1a could be determined after total deprotection of 11 to the well
known DGDP (13). Compound 2 was similarly transformed into the tri-orthogonally protected DGDP derivative 18.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
5-deoxy-1,2-O-isopropylidene-b-D-fructopyranose (7), start-
ing from the readily available D-fructose after appropriated
protection and functional groups interchange.
Figure 1 shows the retrosynthesis of different naturally oc-
curring hyacinthacines2 from tri-orthogonally protected de-
rivatives (1a and 1b) of 2,5-dideoxy-2,5-imino-D-mannitol
(DMDP), a polyhydroxylated pyrrolidinic alkaloid also
present in different natural sources.3 On the other hand,
our group has reported on a highly stereocontrolled synthesis
of 1b4 from the common sugar D-fructose and its use, as
source of chirality and functionalization, in the preparation
Thus, continuing with our efforts on this topic, we reported
herein a synthetic route for the requisite 1a and that of its
C(5) epimer (18) as well.
2g
2i
of protected derivatives of hyacinthacines A2 and A3 as
well. These pyrrolizidines could also be excellent intermedi-
ates for the preparation of the recently discovered hyacintha-
Inversion at C(1) Chain lengthening at C(5') and cyclization
OBz
OBz
OR
H
N
H
N
HO
5'
2b,5
1
1
OR1
cines A1
and A6,2c the latter not described so far, being
OBn
OBn
N
only necessary an inversion of the configuration at C(1)6 in
the former target molecules. For this purpose, it is necessary
the presence in such position of a functional group that could
be manipulated without affecting the other ones, in our case
the benzoyloxy was the group of choice.
Cbz
R
R
OTBDPS
OTBDPS
OTBDPS
R = H, Hyacinthacine A1 R = H, Hyacinthacine A2
R = Me, Hyacinthacine A6 R = Me, Hyacinthacine A3
1a R = Bz; R1 = Bn
1b R = R1 = Bn
R
OH
H
N
R1
OH
Extension of the above methodology would allow the syn-
thesis of many other hyacinthacines such as those displayed
in Figure 1.
R2
OH
R = R1 = H; R2 = Me, (5S)-Hyacinthacine A7
R = R1 = H, R2 = CH2OH, (5R)-Hyacinthacine B1
(5S)-Hyacinthacine B2
According to Figure 2, compound 1a could be synthesized
through the intermediate 5-azido-4-O-benzoyl-3-O-benzyl-
R = OH; R1 = H; R2 = Me, (5R,7R)-Hyacinthacine B3
(5R,7S)-Hyacinthacine B5
R = R1 = OH; R2 = Me, (5R,6R,7R)-Hyacinthacine C1
*
Part Vof the series. For Part IV, see Ref. 1.
* Corresponding author. Tel.: +34 958 249583; fax: +34 958 243845;
e-mail: isidoro@ugr.es
Figure 1. Retrosynthetic analysis and structures of several naturally occur-
ring hyacinthacines from tri-orthogonally protected derivatives of DMDP
(1a and 1b).
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.11.070

I. Izquierdo et al. / Tetrahedron 63 (2007) 1440–1447
1441
Introduction of the nitrogen function with
retention of the configuration at C(5)
to the expected structure. Treatment of 6 with lithium azide
in DMF effected SN2 substitution to yield 5-azido-4-O-benz-
oyl-3-O-benzyl-5-deoxy-1,2-O-isopropylidene-b-D-fructo-
pyranose (7). Cleavage of 1,2-O-isopropylidene group in 7
by treatment with 60% aq TFA afforded 5-azido-4-O-benz-
oyl-3-O-benzyl-5-deoxy-b-D-fructopyranose 8. Reaction
of 8 with tert-butyldiphenylchlorosilane catalyzed by imid-
azole (Im) took place mainly at the primary hydroxyl group
affording the corresponding 1-O-silylated derivative 9. Com-
pound 8 exists in a b-D-pyranose form, according to the
d value (98.41 ppm) for the C(2) resonance signal,10 in
a 2C5 conformation, with all bulkiest groups occupying equa-
torial positions, with H(3,4) and H(4,5) in trans-diaxial and
cis-axial–equatorial dispositions in accordance with the J3,4
and J4,5 values of 9.8 and 3.5 Hz, respectively, with the
anomeric effect operating at the same time.
OBz
OBn
OTBDPS
O
O
HO
Cbz
O
O
O
O
N
OBn
OBn
OBz
OBz
N3
OH
1a
7
4
D-Fructose
Figure 2. Retrosynthesis of partially protected pyrrolidine 1a from
D-fructose.
2. Results and discussion
2.1. Synthesis of tri-orthogonally protected DMDP
derivatives from D-fructose
OH
R1
O
OR
O
a
c
O
4
7
O
OBn
R
BzO
OBz
OBn
In order to synthesize the key intermediate 7, the protected
derivative of D-fructose, 4-O-benzoyl-3-O-benzyl-1,2-O-
isopropylidene-b-D-fructopyranose (4) was required, ac-
cording to the synthetic route outlined in Scheme 1. Thus,
the well known 3-O-benzyl-1,2-O-isopropylidene-b-D-fruc-
topyranose (2)7 was chosen as the starting material. In a first
attempt, we tried the low temperature regioselective benzoyl-
ation of compound 2 but on the contrary to previous results,8
the corresponding 5-O-benzoylated derivative (3) was the
main isolated (88% yield) product, whereas the requisite
4-O-regioisomer (4) was produced in a 12% yield.
N3
d
6 R = H; R1 = I
8 R = H
9 R = TBDPS
b
7 R = N3; R1 = H
Scheme 2. Synthesis of partially protected 5-azido-5-deoxy-D-fructose
derivatives. Reagents and conditions: (a) I2/Ph3P/Im/PhMe, 110 ꢁC; (b)
LiN3/DMF, 100 ꢁC; (c) 60% TFA/H2O, rt; (d) TBDPSCl/DMF/Im, rt.
Catalytic (Raney nickel) hydrogenation of 9 caused the re-
duction of 5-azido group to the corresponding 5-amino func-
tion, which internally condensed with the carbonyl group at
C(2) to produce a D1-pyrroline (A, not isolated but detected
by TLC), which is finally hydrogenated to the expected par-
tially O-protected pyrrolidines 10 (minor) and 12 (major).
Resolution of 10 and 12 could be achieved, after chemo-
selective N-protection as the Cbz derivatives 11 and 1a (in
anw1:2.2 ratio), respectively.
O
O
Ref. 8
D-Fructose
RO
R1O
O
OBn
2 R = R1 = H
a
c
3 R = Bz; R1 = H
4 R = H; R1 = Bz
The (S)-configuration of the new C(2) stereogenic centre in
11, and hence (R)-configuration in 12, could be easily deter-
mined through its total deprotection to the well known 2,5-
imino-2,5-dideoxy-D-glucitol (DGDP, 13)3a,11 (Scheme 3).
b
5 R = R1 = >Sn(n-Bu)2
Scheme 1. Synthesis of 3 and 4. Reagents and conditions: (a) BzCl/Py/
DCM/ꢀ65 ꢁC; (b) n-Bu2SnO/MeOH/D; (c) BzCl/TEA/dioxane, 0 ꢁC.
H
N
R
N
OH
HO
OTBDPS
HO
This result could be attributed to the change of the O(3) pro-
tecting group, benzyl instead of benzoyl,8 and not to the
change of the reaction conditions, since benzoylation of
the 3-O-benzoyl derivative under condition a of Scheme 1,
gave results similar to those previously reported.8c
c
HO
OH
BzO
OBn
10 R = H
11 R = Cbz
DGDP (13)
a
b
9
R
N
OTBDPS
HO
On the basis of the above results, an alternative approach was
essayed, consisting in the formation of the 4,5-O-stannylene
derivative (5) followed by its regioselective ring opening
at the equatorial position [O(4)] with benzoyl chloride in
dioxane at 0 ꢁC, resulting in the formation of the required
4-O-benzoyl derivative 4 (57% yield). Change of the ring
opening reaction conditions (DMF at ꢀ60 ꢁC) slightly low-
ered the yield of 4.
OBn
BzO
b
12 R = H
1a R = Cbz
Scheme 3. Synthesis and configurational assignment of pyrrolidines 10 and
12. Reagents and conditions: (a) H2/Raney Ni/MeOH, 70 psi, rt; (b) CbzCl/
K2CO3/Me2CO, rt; (c) (i) n-Bu4N+Fꢀ$3H2O/THF, rt; (ii) MeONa (cat.)/
MeOH, rt; (iii) HCl/H2/10% Pd/C, rt; (iv) Amberlite IR-400 (OHꢀ).
According to Scheme 2, the reaction of 4 under modified
Garegg’s conditions,9 caused the substitution of the hydroxyl
group at C(5), with concomitant inversion in configuration,
to afford the corresponding 5-deoxy-5-iodo-a-L-sorbo deriv-
ative6, whichhadanalyticalandspectroscopicdataaccording
The stereoselectivity resulted in the hydrogenation of A,
where 12 was the main isolated pyrrolidine, merits comment
(see Fig. 3). Thus, the formation of 12 would be in accor-
dance with our results4 and those of other authors,12 where

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I. Izquierdo et al. / Tetrahedron 63 (2007) 1440–1447
H
N
H
H
H
β-Face
β-Face
N
5
OTBDPS
OTBDPS
HO
HO
4
OBn
B
BzO
OBn
A
BzO
Figure 3.
Figure 5.
the preferential addition of hydrogen occurs at the b-face
giving a product with the C(2)–C(3)- and C(2)–C(4)-substit-
uent in a trans- and cis-disposition, respectively, whereas the
slight steric hindrance of the hydroxymethyl group at C(5)
and the incoming hydrogen molecule would account for
the formation of the minor compound 10, which is a result
of an a-addition.
Reaction of 14 with aq TFA caused the removal of 1,2-O-
isopropylidene group affording the free hexulose 15, pre-
sumably as the pyranosic a-anomer in the most stable C5
2
conformation, with all bulky groups in equatorial disposi-
tion, according to its 1H and 13C NMR spectra. Regioselec-
tive silylation at O(1) in 15 occurred after conventional
treatment with TBDPSCl giving 16 that was finally hydroge-
nated (Raney nickel) to afford in a highly stereoselective
manner a mixture of the expected tri-orthogonally protected
2,5-dideoxy-2,5-imino-D-glucitol (18) and its O(4)/O(50)
benzoyl group migration product 17 (see Scheme 4). The
chemical shift of H(4) in 18 [H(3) in 17], was crucial in order
to establish the position of the benzoyl group, thus whereas
the resonance signal for H(4) in 18 appeared as expected at
5.54 ppm, consequence of the deshielding effect of the gem-
inal benzoyloxy group, such resonance signal appeared at
4.13 ppm in 17 (not deshielding effect).
2.2. Synthesis of tri-orthogonally protected DGDP
derivatives from D-fructose
In accordance with the retrosynthesis displayed in Figure 4,
protected 2,5-imino-2,5-dideoxy-D-glucitol (DGDP) deriva-
tive (18) could be readily prepared from the intermediate 5-
azido-4-O-benzoyl-3-O-benzyl-5-deoxy-a-L-sorbopyranose
(14), which could be synthesized from 4 by introducing the
azido function at C(5) with a concomitant inversion in the
configuration.
The stereoselectivity found in the catalytic hydrogenation
of intermediate D1-pyrroline B was surprisingly high, with
the exclusive entry, in this case, of the hydrogen molecule
through the b-face (see Fig. 5), which is now favoured by
the a-disposition of the hydroxymethyl group at C(5). This
result was in agreement with other previously reported re-
sults by our group.11 On the other hand according to Figure 6,
the above benzoyl group migration would be due to the own
basic character of 18, that could act as the required B pro-
moter, and due to the cis disposition of the benzoyloxy
and hydroxymethyl groups, this is supported by the fact
that such benzoyl group migration was not observed in 1a,
where involved functional groups were in a trans disposition.
Introduction of the nitrogen function with
inversion in the configuration at C(5)
OBz
O
O
HO
O
O
OBn
O
N
O
OBn
H
N3
OBn
OBz
OTBDPS
OBz
14
OH
18
4
Figure 4. Retrosynthesis of pyrrolidine 18 from 4.
Reaction of 4 with diphenylphosphorylazide (DPPA)
under Mitsunobu’s conditions (see Scheme 4) gave 14.
The structure of 14 was established on the basis of its analyti-
cal and spectroscopic data. Thus, the IR spectrum contained
an absorption band (2105 cmꢀ1) for the azido function
at C(5), whereas the J3,4¼J4,5 value (9.6 Hz) clearly
indicated a trans-diaxial disposition for H(3,4,5) and, hence,
that an inversion in the configuration at that position had
took place.
The use of 18 as synthetic key intermediate for the prepara-
tion of the more complex polyhydroxylated pyrrolizidic
alkaloids requires its N-protection and in this context, com-
pound 18 was treated with CbzCl under reaction conditions
(MeOH/TEA) that assure such protection, but surprisingly
two products, the expected one (20, minor) and that from
the above mentioned O-benzoyl migration (19, major) could
be isolated from the reaction mixture (Scheme 5). The same
results were achieved when 17 was subjected to the same
procedure. Compounds 19 and 20 were convergently trans-
formed into 21. Any other N-protection (benzylation and
H
RO
OTBDPS
O
OR
OR1
a
N
d
N3
BzO
4
16
OBn
R1O
OBn
H
N
H
N
H
N
OTBDPS
OTBDPS
O
OTBDPS
14 R = R1 = >CMe2
15 R = R1 = H
17 R = Bz; R1 = H
+B
-
+BH
-B
b
c
O
18
17
O
18 R = H; R1 = Bz
-BH
Ph
-
16 R = H; R1 = TBDPS
OBn
OBn
O
Ph
O
O
OBn
Ph
-
O
O
O
Scheme 4. Synthesis of 17 and 18 from 4. Reagents and conditions: (a)
Ph3P/DIAD/DPPA/THF, 0 ꢁC/rt; (b) 70% TFA/H2O, rt; (c) TBDPSCl/
Im/DMF, rt; (d) Raney Ni/H2/MeOH, 60 psi.
Figure 6. Formation of 17 through an O(4)/O(50)-benzoyl group migra-
tion in 18.

I. Izquierdo et al. / Tetrahedron 63 (2007) 1440–1447
1443
allylation) of 18, even changing the reaction conditions,
always afforded similar results (see Section 4).
isopropylidene-b-D-fructopyranose7 (2, 3.1 g, 10 mmol)
and pyridine (2.42 mL, 30 mmol) in anhydrous dichloro-
methane (DCM, 20 mL) was added a solution of benzoyl
chloride (1.28 mL, 11 mmol) in the same solvent (10 mL)
dropwise. After 1 h, TLC (ether) showed the presence of
two faster-running compounds. The excess of acylating
agent was destroyed by the addition of methanol (1 mL)
and the reaction mixture was washed with 10% aq hydro-
chloric acid, water, aq 10% sodium hydrogen carbonate,
water and then concentrated. Column chromatography (1:2
ether/hexane) gave first pure 3 (3 g, 88%) as a colourless
syrup; [a]2D4 ꢀ137 (c 1.4); n (neat) 3481 (OH), 3064 and
3031 (aromatic), 1719 (CO, Bz), and 710 cmꢀ1 (aromatic).
1H NMR (300 MHz): d 8.07–8.05 and 7.62–7.29 (2m,
10H, 2Ph), 5.41 (m, 1H, H-5), 4.92 and 4.76 (2d, 2H,
J 11.4 Hz, CH2Ph), 4.31 (ddd, 1H, J3,4 9.8, J4,5 3.7, JOH,4
Cbz
N
RO
OTBDPS
R1O
OBn
19 R = Bz; R1 = H
20 R = H; R1 = Bz
21 R = R1 = Bz
b
Bn
N
All
N
a
RO
OTBDPS
RO
OTBDPS
c
d
18
R1O
OBn
R1O
OBn
22 R = Bz; R1 = H
23 R = H; R1 = Bz
24 R = Bz; R1 = H
25 R = H; R1 = Bz
5 Hz, H-4), 4.12 and 3.98 (2d, 2H, J1,1 8.7 Hz, H-1,10),
0
4.08 (dd, 1H, J5,6ax 1.3, J6ax,6eq 13.1 Hz, H-6ax), 3.87 (dd,
1H, J5,6eq 1.8 Hz, H-6eq), 3.78 (d, 1H, H-3), 2.31 (d, 1H,
OH-4), 1.49 and 1.45 (2s, 6H, CMe2). 13C NMR: d 166.52
(COPh), 137.81, 133.25, 129.86, 129.78, 128.47, 128.39,
127.97 and 127.91 (Ph), 112.09 (CMe2), 105.55 (C-2),
76.24, 72.78 and 70.47 (C-3,4,5), 75.14 (C-1), 71.85
(CH2Ph), 62.10 (C-6), 26.80 and 26.11 (CMe2). Anal. Calcd
for C23H26O7: C, 66.65; H, 6.32. Found: C, 66.86; H, 6.42.
Scheme 5. Orthogonal protection of polyhydroxylated pyrrolidine 18. Re-
agents and conditions: (a) CbzCl/TEA/MeOH, rt; (b) BzCl/DCM/TEA, rt;
(c) BnBr/DBU/acetonitrile, rt; (d) AllBr/K2CO3/Me2CO, rt.
3. Conclusions
D-Fructose is an appropriate chiral starting material for
the stereoselective synthesis of tri-orthogonally protected
polyhydroxylated pyrrolidine alkaloids. Thus, the highly
stereoselective hydrogenation of protected derivatives of
5-azido-5-deoxy-b-D-fructose and 5-azido-5-deoxy-a-L-sor-
bose, prepared from the above mentioned ketose, is an
excellent synthetic route to the target derivatives of 2,5-
dideoxy-2,5-imino-D-mannitol (DMDP, 1a) and its C(5)
epimer (DGDP, 18).
Second elution gave crystalline 4 (400 mg, 12%); mp 112 ꢁC
(from ether/hexane); [a]D24 ꢀ156 (c 1.4); n (KBr) 3525 (OH),
3063 and 3033 (aromatic), 1723 and 1697 (CO, Bz), 1384
1
and 1369 (CMe2), 711 and 696 cmꢀ1 (aromatic). H NMR
(300 MHz): d 8.07, 7.59 and 7.45 (3m, 5H, Bz), 7.23 (br s,
5H, PhCH2), 5.50 (dd, 1H, J3,4 10.1, J4,5 3.1 Hz, H-4),
4.83 and 4.62 (2d, 2H, J 11.4 Hz, CH2Ph), 4.28 (m, 1H,
H-5), 4.10 (dd, 1H, J5,6ax 0.8 Hz, H-6ax), 4.07 (d, 1H,
H-3), 4.00 and 3.96 (2d, 2H, J1,1 8.6 Hz, H-1,10), 3.76 (dd,
0
1H, J5,6eq 2, J6ax,6eq 12.7 Hz, H-6eq), 2.28 (d, 1H, J5,OH
3.2 Hz, OH-5), 1.50 and 1.40 (2s, 6H, CMe2). 13C NMR:
d 165.53 (COPh), 137.53, 133.36, 129.62, 128.53, 128.31
and 127.75 (Ph), 112.25 (CMe2), 105.79 (C-2), 75.21,
73.57 and 68.30 (C-3,4,5), 71.73 (C-1, CH2Ph), 63.77
(C-6), 26.89 and 26.00 (CMe2). Anal. Calcd for C23H26O7:
C, 66.65; H, 6.32. Found: C, 66.39; H, 6.13.
4. Experimental
4.1. General procedures
Melting points were determined with a Gallenkamp appara-
tus and are uncorrected. Solutions were dried over MgSO4
before concentration under reduced pressure. The H and
1
13C NMR spectra were recorded with Bruker AMX-300,
AM-300 and ARX-400 spectrometers for solutions in
CDCl3 (internal Me4Si). IR spectra were recorded with a
Perkin–Elmer 782 instrument and mass spectra with a Micro-
mass Mod. Platform II and Autospec-Q mass spectrometers.
Optical rotations were measured for solutions in CHCl3
(1-dm tube) with a Jasco DIP-370 polarimeter. TLC was per-
formed on precoated E. Merck silica gel 60 F254 aluminium
sheets with detection by charring with H2SO4 or employing
a mixture of 10% ammonium molybdate (w/v) in 10% aq
sulfuric acid containing 0.8% cerium sulfate (w/v) and heat-
ing. Column chromatography was performed on silica gel
(E. Merck, 7734). The noncrystalline compounds, for which
elemental analyses were not determined, were shown to be
homogeneous by chromatography and characterized by NMR
spectroscopy and FAB-HRMS with thioglycerol matrix.
Method b: to a solution of 2 (15.64 g, 50.4 mmol) in
anhydrous methanol (100 mL) was added dibutyltin oxide
(13.8 g, 55.4 mmol) and the suspension was heated for 7 h
under reflux, then concentrated to afford the 3,4-dibutylstan-
nylene derivative (5) as a solid foam that was dried under
vacuum over P2O5 overnight.
To a cooled (0 ꢁC) and stirred solution of 5 and TEA
(7.7 mL, 55.4 mmol) in anhydrous dioxane (150 mL) was
added a solution of benzoyl chloride (6.4 mL, 55.4 mmol)
in the same solvent (30 mL) dropwise. The reaction mixture
was left to reach room temperature and stirred for additional
4 h. TLC (ether) then revealed the presence of two new com-
pounds of higher mobility. Methanol (4 mL) was added and
after 30 min the mixture was concentrated to a residue that
was dissolved in DCM (100 mL) and washed with brine.
The organic phase was concentrated and the residue was
subjected to flash chromatography (1:1/2:1, ether/hexane)
to afford first pure 3 (8.71 g, 38%). Second elution gave 4
(13.1 g, 57%).
4.1.1. 5-O-Benzoyl-(3) and 4-O-benzoyl-3-O-benzyl-1,2-
O-isopropylidene-b-D-fructopyranose (4). Method a: to a
stirred and cooled (ꢀ65 ꢁC) solution of 3-O-benzyl-1,2-O-

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I. Izquierdo et al. / Tetrahedron 63 (2007) 1440–1447
4.1.2. 4-O-Benzoyl-3-O-benzyl-5-deoxy-5-iodo-1,2-O-iso-
propylidene-a-L-sorbopyranose (6). To a solution of tri-
phenylphosphine (3.2 g, 12.4 mmol), Im (1.8 g, 24.8 mmol)
and iodine (3.1 g, 12.4 mmol) in dry toluene (60 mL) was
added 4 (2.54 g, 6.2 mmol) and the mixture was heated at
110 ꢁC for 2 h. TLC (3:2, ether/hexane) then revealed
a faster-running compound. The reaction mixture was
cooled, washed with 10% aq sodium thiosulfate, brine and
then concentrated. Column chromatography (1:1, DCM/
3H, H-5,6ax,6eq), 3.78 (d, 1H, H-3), 3.60 and 3.56 (2d,
2H, J1,1 11.4 Hz, H-1,10) and 2.08 (br s, 2H, 2OH). 13C
NMR (inter alia): d 165.95 (COPh), 98.41 (C-2), 75.88
(CH2Ph), 74.12 (C-4), 73.55 (C-3), 65.84 (C-1), 61.58
(C-6) and 60.74 (C-5). Anal. Calcd for C20H21N3O6: C,
60.14; H, 5.30; N, 10.52. Found: C, 59.75; H, 5.41; N, 10.24.
0
4.1.5. 5-Azido-4-O-benzoyl-3-O-benzyl-1-O-tert-butyldi-
phenylsilyl-5-deoxy-b-D-fructopyranose (9). To a stirred
solution of 8 (3.4 g, 8.5 mmol) in dry DMF (40 mL) were
added Im (630 mg, 9.3 mmol) and tert-butylchlorodiphenyl-
silane (2.2 mL, 8.5 mmol) and the mixture was left at room
temperature for 72 h. TLC (1:1 ether/hexane) then showed
a faster-running compound. The reaction mixture was di-
luted with ether (150 mL) and washed with brine, water
and then concentrated to a residue that was subjected to
chromatography (1:2, ether/hexane/ether) to afford 9
(3.6 g, 78%) as a colourless syrup; [a]2D5 ꢀ23 (c 1);
n (neat) 3476 (OH), 3070 and 3032 (aromatic), 2102 (N3),
1725 (CO, Bz) and 709 cmꢀ1 (aromatic). 1H NMR
(400 MHz, inter alia): d 5.73 (dd, 1H, J3,4 10.0, J4,5
3.6 Hz, H-4), 4.72 and 4.53 (2d, 2H, J 11.2 Hz, CH2Ph),
4.27–4.24 (m, 2H, H-5,6ax), 4.08 (d, 1H, J6ax,6eq 10.4 Hz,
hexane) afforded crystalline 6 (2.66 g, 82%); mp 171–
ꢀ25.5 (c 1);
26
405
173 ꢁC (from ether); [a]2D6 ꢀ18.3, [a]
n (KBr) 3089, 3064 and 3032 (aromatic), 1729 (CO, Bz),
1386 and 1373 (CMe2), 752 and 706 cmꢀ1 (aromatic). H
1
NMR (400 MHz): d 8.09, 7.60 and 7.48 (3m, 5H, Bz),
7.21–7.13 (m, 5H, CH2Ph), 5.83 (t, 1H, J3,4¼J4,5¼10.0 Hz,
H-4), 4.63 and 4.47 (2d, 2H, J 11.6 Hz, CH2Ph), 4.22–4.13
0
(m, 2H, H-6ax,6eq), 3.93 and 3.86 (2d, 2H, J1,1 8.4 Hz,
H-1,10), 3.93–3.90 (m, 1H, H-5), 3.61 (d, 1H, H-3), 1.52
and 1.41 (2s, 6H, CMe2). 13C NMR (inter alia): d 165.26
(COPh), 113.05 (CMe2), 105.78 (C-2), 78.78 (C-3,4),
75.35 and 71.78 (C-1 and CH2Ph), 65.80 (C-6), 27.31 and
26.16 (CMe2), and 23.53 (C-5). Anal. Calcd for
C23H25IO6: C, 52.68; H, 4.81. Found: C, 52.81; H, 4.98.
0
H-6eq), 3.81 (d, 1H, H-3), 3.71 and 3.63 (2d, 2H, J1,1
4.1.3. 5-Azido-4-O-benzoyl-3-O-benzyl-5-deoxy-1,2-O-
isopropylidene-b-D-fructopyranose (7). A stirred solution
of 6 (2.33 g, 4.4 mmol) and lithium azide (640 mg,
13.2 mmol) in dry DMF (50 mL) was heated at 100 ꢁC for
24 h. TLC (4:1, DCM/hexane) then revealed a slightly
slower-running compound. The mixture was concentrated
to a residue that was dissolved in ether (40 mL), washed
with brine and concentrated. Column chromatography
(2:1/3:1, DCM/hexane) of the residue afforded crystalline
7 (1.1 g, 56%); mp 64–66 ꢁC (from DCM/ether); [a]2D7 ꢀ57
(c 1.1); n (neat) 3090, 3064 and 3033 (aromatic), 2108 (N3),
1721 (CO, Bz), 1386 and 1373 (CMe2), 752 and 707 cmꢀ1
(aromatic). 1H NMR (300 MHz): d 8.09 (br d, 2H, Hortho),
7.60 (t, 1H, Hpara), 7.47 (t, 2H, Hmeta), 7.34 (br s, 5H,
CH2Ph), 5.63 (dd, 1H, J3,4 10, J4,5 3.8 Hz, H-4), 4.84 and
4.64 (2d, 2H, J 12.1 Hz, CH2Ph), 4.24 (m, 1H, H-5), 4.14
(dd, 1H, J5,6ax 1.5, J6ax,6eq 12.7 Hz, H-6ax), 4.02 (d, 1H,
10.0 Hz, H-1,10), 3.57 (br s, 1H, OH) and 1.01 (s, 9H,
CMe3). HRMS (LSIMS): m/z 660.2507 [M++Na]; calcd
for C36H39N3O6NaSi: 660.2506 (deviation ꢀ0.2 ppm).
Starting material (0.5 g) was also recovered.
4.1.6. Catalytic hydrogenation of 9. Compound 9 (3.6 g,
5.6 mmol) in MeOH (30 mL) was hydrogenated at 70 psi
over wet Raney nickel (3 g, Fluka) for 24 h. TLC (ether)
then revealed the presence of two slower-running com-
pounds. The catalyst was filtered off, washed with MeOH
and the combined filtrate and washings were concentrated
to a residue that was subjected to column chromatography
(1:1, ether/hexane) to afford an unresolvable mixture
(2.64 g, 86%) of (2S,3R,4R,5R)- (10) and (2R,3R,4R,5R)-
4-benzoyloxy-3-benzyloxy-20-O-tert-butyldiphenylsilyl-2,5-
bis(hydroxymethyl)pyrrolidine (12) as a syrup that was
chemoselectively N-protected as follows.
H-3), 3.98 and 3.94 (2d, 2H, J1,1 8.7 Hz, H-1,10), 3.75 (dd,
0
1H, J5,6eq 1.7 Hz, H-6eq), 1.49 and 1.40 (2s, 6H, CMe2).
13C NMR (inter alia): d 165.75 (COPh), 112.61 (CMe2),
105.83 (C-2), 75.55 (CH2Ph), 74.36 (C-4), 73.93 (C-3),
71.84 (C-1), 61.80 (C-6), 60.76 (C-5), 27.00 and 26.07
(CMe2). Anal. Calcd for C23H25N3O6: C, 62.86; H, 5.73;
N, 9.56. Found: C, 62.61; H, 5.96; N, 9.41.
4.1.7. (2S,3R,4R,5R)- (11) and (2R,3R,4R,5R)-4-benzoyl-
oxy-3-benzyloxy-N-benzyloxycarbonyl-20-O-tert-butyldi-
phenylsilyl-2,5-bis(hydroxymethyl)pyrrolidine (1a). To
a well stirred solution of 10 and 12 (2.64 g, 4.44 mmol) in
dry acetone (40 mL), anhydrous potassium carbonate
(1.8 g) and a solution of benzyl chloroformate (0.9 mL,
6.3 mmol) in the same solvent (10 mL) were added and
the mixture was kept at room temperature overnight. TLC
(3:1 ether/hexane) then revealed the presence of two
faster-running compounds. The mixture was filtered and
the solid was thoroughly washed with acetone and the filtrate
and washings were concentrated to a residue that was sub-
jected to chromatography (1:2 ether/hexane) to give first
11 as colourless syrup (714 mg, 22%); [a]2D9 ꢀ27 (c 1);
n (neat) 3442 (OH), 3069 and 3032 (aromatic), 1706 (C]O,
Bz and Cbz), 709 and 701 cmꢀ1 (aromatic). 1H NMR
(300 MHz, inter alia): d 8.10–7.20 (m, 25H, 5Ph), 5.78 (br
t, 1H, J3,4¼J4,5¼4.9 Hz, H-4), 5.13 and 5.08–4.98 (d and
br d, 2H, J 12.2 Hz, CH2Ph), 4.66 (s, 2H, Cbz), 4.35 (t,
1H, J 7.0 Hz, H-3), 4.19–3.85 (m, 6H, H-2,20a,20b,5,50a,50b)
and 1.08 (s, 9H, CMe3). 13C NMR (inter alia): d 166.04
4.1.4. 5-Azido-4-O-benzoyl-3-O-benzyl-5-deoxy-b-D-
fructopyranose (8). A solution of 7 (4.13 g, 9.4 mmol) in
60% aq TFA (10 mL) was kept at room temperature for
2 h. TLC (3:1, ether/hexane) then revealed a slower-running
compound. The mixture was concentrated and the residue
was dissolved in DCM and washed with 10% aq sodium hy-
drogen carbonate and water. Removal of the solvent gave
crystalline 8 that was recrystallized from ether/hexane to
yield pure 8 (3 g, 80%); mp 54–56 ꢁC; [a]D29 ꢀ22 (c 1);
n (KBr): 3456 (OH), 3064 and 3033 (aromatic), 2106 (N3),
1
1723 (CO, Bz), 739 and 712 cmꢀ1 (aromatic). H NMR
(400 MHz): d 8.09, 7.63 and 7.48 (3m, 5H, Bz), 7.25–7.22
(m, 5H, CH2Ph), 5.70 (dd, 1H, J3,4 9.8, J4,5 3.5 Hz, H-4),
4.79 and 4.67 (2d, 2H, J 11.0 Hz, CH2Ph), 4.24–4.16 (m,

I. Izquierdo et al. / Tetrahedron 63 (2007) 1440–1447
1445
(COPh), 80.13 and 77.31 (C-3,4), 73.03 (CH2Ph), 67.72
(CH2Ph, Cbz), 64.90 and 60.47 (C-2,5), 64.75 and 61.35
(C-20,50), 26.99 (CMe3) and 19.21 (CMe3). HRMS (LSIMS):
m/z 752.3016 [M++Na]; calcd for C44H47NO7NaSi:
752.3020 (deviation +0.5 ppm).
165.35 (COPh), 137.09, 133.34, 129.73, 129.45, 128.49,
128.30, 127.84 and 127.79 (Ph), 112.77 (CMe2), 104.98
(C-2), 76.76 and 74.61 (C-3,4), 75.01 (C-1), 71.43
(CH2Ph), 60.84 (C-6), 60.12 (C-5), 26.99 and 25.87
(CMe2). Anal. Calcd for C23H25N3O6: C, 62.86; H, 5.73;
N, 9.56. Found: C, 63.18; H, 5.40; N, 9.57.
Second elution gave syrupy 1a (1.51 g, 47%); [a]2D9 ꢀ21 (c
1); n (neat) 3453 (OH), 3069 and 3033 (aromatic), 1722
(CO, Bz), 1706 (CO, Cbz), 709 and 700 cmꢀ1 (aromatic).
1H NMR (300 MHz): d 7.95–7.12 (m, 25H, 5Ph), 5.53–
4.72 (3m, 5H, two rotamers), 4.49–3.58 (4m, 7H, two ro-
tamers), 1.05 and 0.95 (2s, 9H, CMe3 for two rotamers).
13C NMR (inter alia): d 165.49 (COPh), 155.52 (Cbz), 82.01
and 78.86 (C-3,4), 71.94 (CH2Ph), 67.49 (Cbz), 66.96 and
65.75 (C-2,5), 63.33 and 62.14 (C-20,50), 26.78 (CMe3) and
19.18 (CMe3). HRMS (LSIMS): m/z 752.3014 [M++Na];
calcd for C44H47NO7NaSi: 752.3020 (deviation +0.8 ppm).
4.1.10. 5-Azido-4-O-benzoyl-3-O-benzyl-5-deoxy-a-L-
sorbopyranose (15). A solution of 14 (9.1 g, 20.7 mmol)
in 70% aq TFA (50 mL) was kept at room temperature for
2.5 h. TLC (ether) then revealed a slower-running com-
pound. The mixture was diluted with water and the white
precipitate was filtered, washed with water and air dried to
give pure crystalline 15 (8.11 g, 98%); mp 150–151 ꢁC;
[a]2D6 ꢀ30 (c 1.1); n (KBr) 3505 and 3488 (OH), 3088 (aro-
matic), 2109 (N3), 1716 (CO, Bz), 707 and 698 cmꢀ1 (aro-
matic). 1H NMR (300 MHz): d 8.07, 7.61 and 7.48 (3m, 5H,
Bz), 7.18 (m, 5H, CH2Ph), 5.72 (t, 1H, J3,4¼J4,5¼9.7 Hz,
H-4), 4.64 and 4.58 (2d, 2H, J 11.0 Hz, CH2Ph), 3.90 (t,
1H, J5,6ax¼J6ax,6eq¼11.2 Hz, H-6ax), 3.84 (dd, 1H, J5,6eq
5.8 Hz, H-6eq), 3.81 (d, 1H, H-3), 3.71 (dt, 1H, H-5), 3.59
A mixture of 11 and 1a (738 mg) was also obtained.
4.1.8. (2R,3R,4R,5S)-3,4-Dihydroxy-2,5-bis(hydroxy-
methyl)pyrrolidine (DGDP, 13). To a stirred solution of
11 (330 mg, 0.45 mmol) in THF (10 mL) was added
TBAF$3H2O (200 mg, 0.63 mmol) and the mixture was
left at room temperature for 4 h. TLC (ether) then revealed
a new compound of lower mobility. The mixture was con-
centrated and the residue was dissolved in ether and washed
with brine, water and then concentrated. Column chromato-
graphy of the residue (1:1 ether/hexane/ether) afforded the
corresponding desilylated compound (200 mg, 90%) that
was not investigated but used in the next step.
and 3.53 (2d, 2H, J1,1 11.6 Hz, H-1,10), 3.47 (br s, OH).
0
13C NMR: 165.65 (COPh), 136.79, 133.53, 129.89,
129.47, 128.63, 128.53, 128.45 and 128.27 (Ph), 97.83
(C-2), 76.78 and 74.05 (C-3,4), 75.31 and 65.53 (C-1,
CH2Ph), 60.66 (C-6) and 60.07 (C-5). Anal. Calcd for
C20H21N3O6: C, 60.14; H, 5.30; N, 10.52. Found: C,
60.05; H, 5.68; N, 10.29.
4.1.11. 5-Azido-4-O-benzoyl-3-O-benzyl-1-O-tert-butyl-
diphenylsilyl-5-deoxy-a-L-sorbopyranose(16).Toastirred
solution of 15 (8.35 g, 20.9 mmol) in dry DMF (30 mL)
were added Im (1.50 g, 22 mmol) and tert-butylchlorodiphe-
nylsilane (5.63 mL, 22 mmol) and the mixture was left at
room temperature overnight. TLC (ether) then showed a
faster-running compound. The reaction mixture was diluted
with ether (150 mL) and washed with brine, water and then
concentrated to a residue that was subjected to chromato-
graphy (2:5 ether/hexane) to afford 16 (10.3 g, 77%) as a col-
ourless syrup; [a]2D2 ꢀ15.5 (c 1); n (neat) 3522 (OH), 3051
(aromatic), 2108 (N3), 1730 (CO, Bz) and 709 cmꢀ1 (aro-
matic). 1H NMR (300 MHz, inter alia): d 5.76 (t, 1H,
J3,4¼J4,5¼9.7 Hz, H-4), 4.59 and 4.47 (2d, 2H, J 11.0 Hz,
CH2Ph), 3.92 (t, 1H, J5,6ax¼J6ax,6eq¼11.2 Hz, H-6ax), 3.85
Conventional Zemplen debenzoylation of the above com-
pound in anhydrous methanol (10 mL) with 0.4 M MeONa
in methanol (0.7 mL) gave the related trihydroxypyrrolidine
(TLC evidence) that was fully deprotected by hydrogenation
(balloon) over 10% Pd/C (100 mg) in acid medium (HCl) for
2 days at room temperature. Neutralization (Amberlite IRA-
400, OHꢀ form) of the hydrogenated mixture and column
chromatography afforded the title compound 13 (60 mg,
89%), which had optical and spectroscopic data identical
to those previously reported.11
4.1.9. 5-Azido-4-O-benzoyl-3-O-benzyl-5-deoxy-1,2-O-
isopropylidene-a-L-sorbopyranose (14). To a cooled
(0 ꢁC) and stirred solution of 4 (3.75 g, 9 mmol) in dry
THF (50 mL) were consecutively added triphenylphosphine
(2.63 g, 10.1 mmol), a solution of DIAD (2 mL, 9.9 mmol)
in the same solvent (10 mL) dropwise and after 10 min
DPPA (2.6 mL, 12 mmol). The mixture was allowed to reach
room temperature and then left overnight. TLC (2:1 ether/
hexane) then revealed a new faster-running compound.
The mixture was concentrated, supported on silica gel and
then subjected to chromatography (4:1 DCM/hexane) to af-
ford pure crystalline 14 (3.53 g, 89%); mp 114–115 ꢁC
(from ether/hexane); [a]2D3 ꢀ69 (c 1); n (KBr) 3065 and
3033 (aromatic), 2105 (N3), 1729 (CO, Bz), 1385 and
1373 (CMe2), 710 and 701 cmꢀ1 (aromatic). 1H NMR
(300 MHz): d 8.08, 7.54 and 7.47 (3m, 5H, Bz), 7.21–7.13
(m, 5H, CH2Ph), 5.70 (t, 1H, J3,4¼J4,5¼9.6 Hz, H-4), 4.68
and 4.52 (2d, 2H, J 11.3 Hz, CH2Ph), 3.96 and 3.88 (2d,
0
(dd, 1H, J5,6eq 5.8 Hz, H-6eq), 3.76 and 3.60 (2d, 2H, J1,1
10.3 Hz, H-1,10), 3.72 (d, 1H, H-3), 3.68 (dt, 1H, H-5), and
1.10 (s, 9H, CMe3). 13C NMR (inter alia): d 98.08 (C-2),
77.21 and 74.18 (C-3,4), 75.25 (CH2Ph), 66.00 (C-6),
60.58 (C-1), 60.29 (C-5), 26.95 (CMe3) and 19.39 (CMe3).
HRMS (LSIMS): m/z 660.2509 [M++Na]; calcd for
C36H39N3O6NaSi: 660.2506 (deviation ꢀ0.5 ppm).
4.1.12. Catalytic hydrogenation of 16. Compound 16
(6.4 g, 10 mmol) in MeOH (50 mL) was hydrogenated at
60 psi over wet Raney nickel (7.8 g, Fluka) for 24 h. TLC
(20:1 ether/methanol) then revealed the presence of two
slower-running compounds. The catalyst was filtered off,
washed with MeOH, and the combined filtrate and washings
were concentrated to a residue that was subjected to column
chromatography (ether/20:1 ether/methanol) to afford first
syrupy (2S,3R,4R,5R)-20-O-benzoyl-4-benzyloxy-50-O-tert-
butyldiphenylsilyl-3-hydroxy-2,5-bis(hydroxymethyl)pyr-
rolidine (17, 500 mg, 8.4%); [a]2D6 +19 (c 1.5); n (neat) 3379
2H, J1,1 8.7 Hz, H-1,10), 3.86–3.65 (m, 3H, H-5,6ax,6eq),
0
3.62 (d, 1H, H-3), 1.50 and 1.40 (2s, 6H, CMe2). 13C NMR:

1446
I. Izquierdo et al. / Tetrahedron 63 (2007) 1440–1447
and 3273 (OH, NH), 3064 (aromatic), 1724 (CO, Bz), 739
and 704 cmꢀ1 (aromatic). 1H NMR (300 MHz): d 8.10–7.23
HRMS (LSIMS): m/z 856.2918 [M++Na]; calcd for
C51H51NO8NaSi: 856.2917 (deviation ꢀ0.1 ppm).
0
0
0
(3m, 20H, 4Ph), 4.65 (dd, 1H, J2,2 a 6.6, J2 a,2 b 11.1 Hz,
H-20a), 4.59 and 4.52 (2d, 2H, J 11.9 Hz, CH2Ph), 4.46
(dd, 1H, J2,2 b 6.5 Hz, H-20b), 4.13 (d, 1H, J2,3 3.3 Hz,
4.1.14. N-Benzylation of 18. To a stirred solution of 18
(780 mg, 1.3 mmol) in dry acetonitrile (10 mL), DBU
(0.8 mL, 5.2 mmol) and benzyl bromide (0.5 mL,
3.9 mmol) were added and the mixture was left at room tem-
perature for 4 days. TLC (2:1, ether/hexane) then showed the
presence of two less polar compounds. The reaction mixture
was concentrated and the residue was subjected to column
chromatography (1:2/1:1 ether/hexane) to yield first
(2S,3R,4R,5R)-20-O-benzoyl-N-benzyl-4-benzyloxy-50-O-
tert-butyldiphenylsilyl-3-hydroxy-2,5-bis(hydroxymethyl)-
pyrrolidine (22, 460 mg, 52%) as a colourless syrup; [a]D23
+27 (c 1); n (neat) 3444 (OH), 3068 and 3025 (aromatic),
1719 (CO, Bz) and 704 cmꢀ1 (aromatic). 1H NMR
(400 MHz): d 8.06–8.03, 7.66–7.55 and 7.46–7.20 (3m,
0
0
H-3), 3.88 (d, 1H, J4,5 2.3 Hz, H-4), 3.73 (dd, 1H, J5,5 a
3.9, J5 a,5 b 10.5 Hz, H-50a), 3.68 (dd, 1H, J5,5 b 3.6 Hz,
H-50b), 3.62 (dt, 1H, H-2), 3.34 (q, 1H, H-5), and 1.05 (s,
9H, CMe3). 13C NMR (inter alia): d 166.80 (COPh), 87.36
and 74.81 (C-3,4), 71.82 (CH2Ph), 65.56 and 64.09
(C-20,50), 65.01 and 60.69 (C-2,5), 26.92 (CMe3) and 19.24
(CMe3). HRMS (LSIMS): m/z 618.2653 [M++Na]; calcd
for C36H41NO5NaSi: 618.2652 (deviation ꢀ0.1 ppm).
0
0
0
Second elution gave syrupy (2R,3R,4R,5S)-4-benzoyloxy-
3-benzyloxy-20-O-tert-butyldiphenylsilyl-2,5-bis(hydroxy-
26
405
methyl)pyrrolidine (18, 2.57 g, 43%); [a]2D5 ꢀ9; [a] ꢀ35
25H, 5Ph), 4.65 (dd, 1H, J2,2 a 8.0, J2 a,2 b 11.0 Hz, H-20a),
0
0
0
(c 1.6); n (neat) 3593 and 3500 (OH, NH), 3063 (aromatic),
1
1721 (CO, Bz), 709 and 700 cmꢀ1 (aromatic). H NMR
4.57 (dd, 1H, J2,2 b 6.0 Hz, H-20b), 4.60 and 4.54 (2d, 2H, J
0
(300 MHz): d 8.10–7.25 (3m, 20H, 4Ph), 5.54 (dd, 1H, J3,4
1.8, J4,5 4.2 Hz, H-4), 4.78 and 4.60 (2d, 2H, J 11.8 Hz,
CH2Ph), 4.12 (dd, 1H, J2,3 4.8 Hz, H-3), 3.88 (dd, 1H,
12.0 Hz, OCH2Ph), 4.21 (dd, 1H, J3,4 10.3, J2,3 3.6 Hz,
H-3), 4.08 and 3.80 (2d, 2H, J 14.1 Hz, NCH2Ph), 3.98 (br
s, 1H, OH), 3.96 (d, 1H, H-4), 3.62 (m, 1H, H-2), 3.43 (dd,
J2,2 a 5.2, J2 a,2 b 10.4 Hz, H-20a), 3.80 (dd, 1H, J2,2 b
4.8 Hz, H-20b), 3.77–3.67 (m, 3H, H-5,50a,50b), 3.37 (q,
1H, H-2), 2.90 (br s, 2H, NH, OH) and 1.05 (s, 9H,
CMe3). 13C NMR (inter alia): d 166.0 (COPh), 85.07 and
79.27 (C-3,4), 72.22 (CH2Ph), 64.82 and 61.61 (C-2,5),
64.22 and 60.82 (C-20,50), 26.82 (CMe3) and 19.21
(CMe3). HRMS (LSIMS): m/z 618.2652 [M++Na]; calcd
for C36H41NO5NaSi: 618.2652 (deviation 0.0 ppm).
1H, J5,5 a 2.7, J5 a,5 b 10.5 Hz, H-50a), 3.36 (dd, 1H, J5,5 b
3.8 Hz, H-50b), 3.09 (br t, 1H, H-5) and 1.06 (s, 9H, CMe3).
13C NMR (inter alia): d 166.68 (COPh), 85.69 (C-4), 74.10
(C-3), 71.69 (C-5), 71.25 (OCH2Ph), 66.10 (C-2), 65.03
(C-50), 63.30 (C-20), 58.26 (NCH2Ph), 26.88 (CMe3) and
19.16 (CMe3). HRMS (LSIMS): m/z 708.3122 [M++Na];
calcd for C43H47NO5NaSi: 708.3121 (deviation ꢀ0.2 ppm).
0
0
0
0
0
0
0
0
Second elution gave (2R,3R,4R,5S)-4-benzoyloxy-N-benzyl-
3-benzyloxy-20-O-tert-butyldiphenylsilyl-4-hydroxy-2,5-
bis(hydroxymethyl)pyrrolidine (23, 87 mg, 10%) as a
colourless syrup; [a]D24 ꢀ30 (c 1); n (neat) 3460 (OH),
3067 and 3028 (aromatic), 1719 (CO, Bz), 736 and
4.1.13. N-Benzyloxycarbonylation of 18. To a cooled
(0 ꢁC) and stirred solution of 18 (1.87 g, 3.1 mmol) in anhy-
drous MeOH (20 mL) and TEA (1.4 mL, 10.8 mmol) was
added benzyl chloroformate (560 mL, 3.9 mmol) and the
mixture was allowed to reach room temperature. TLC (3:1
ether/hexane) then showed the presence of a faster-running
compound. The solvent was eliminated and the residue was
partitioned in DCM/water, the organic phase was concen-
trated to yield an unresolvable mixture of 19 and 20 (1.9 g,
84%) (1H NMR evidence) that was used in the next step.
1
708 cmꢀ1 (aromatic). H NMR (400 MHz): d 8.04–8.01,
7.63–7.58 and 7.46–7.20 (3m, 25H, 5Ph), 5.57 (dd, 1H,
J3,4 4.3, J4,5 6.3 Hz, H-4), 4.74 and 4.66 (2d, 2H, J
11.7 Hz, OCH2Ph), 4.43 (t, 1H, J2,3 4.3 Hz, H-3), 3.92 and
0
3.88 (2d, 2H, J 13.6 Hz, NCH2Ph), 3.73 (dd, 1H, J2,2 a 6.4,
0
J2 a,2 b 10.6 Hz, H-20a), 3.60 (dd, 1H, J2,2 b 4.1 Hz, H-20b),
0
0
3.55 (dt, 1H, J5,5 a 2.1 Hz, H-5), 3.50 (dd, 1H, H-50a),
0
3.34 (dd, 1H, J5,5 b 5.8, J5a,5 b 11.4 Hz, H-50b), 3.21 (dt,
1H, H-2) and 1.06 (s, 9H, CMe3). 13C NMR (inter alia):
d 166.51 (COPh), 82.05 (C-3), 78.30 (C-4), 72.12
(OCH2Ph), 69.02 and 65.13 (C-2,5), 63.33 and 59.20 (C-
20,50), 58.52 (NCH2Ph), 26.89 (CMe3) and 19.21 (CMe3).
HRMS (LSIMS): m/z 708.3121 [M++Na]; calcd for
C43H47NO5-NaSi: 708.3121 (deviation 0.0 ppm).
0
0
When compound 17 was treated as above the same mixture
was obtained.
To a stirred solution of the above mixture (19 and 20, 3.31 g,
4.5 mmol) and TEA (2.5 mL, 18 mmol) in anhydrous DCM
(30 mL) was added dropwise benzoyl chloride (1.6 mL,
13.6 mmol) and the mixture was left at room temperature
for 12 h. TLC (2:1 ether/hexane) then showed a faster-
running compound. Conventional work-up and column
chromatography afforded (2S,3R,4R,5R)-20-O-benzoyl-3-
benzoyloxy-4-benzyloxy-N-benzyloxycarbonyl-50-O-tert-
butyldiphenylsilyl-2,5-bis(hydroxymethyl)pyrrolidine (21,
3.5 g, 93%) as a colourless syrup; [a]2D4 +11 (c 1); n (neat)
3065 and 3028 (aromatic), 1731 (CO, Bz), 1704 (CO,
4.1.15. N-Allylation of 18. To a solution of 18 (2.53 g,
4.25 mmol) in dry acetone (30 mL), anhydrous K2CO3
(2.9 g) and allyl bromide (1.3 mL, 15 mmol) were added and
the mixture sonicated for 30 min and then stirred at room
temperature for 24 h. TLC (ether) then showed the presence
of two less polar compounds. The reaction mixture was fil-
tered and the solid was washed with acetone. Removal of
the solvent gave a residue that was partitioned into DCM/
water, the organic phase was separated and concentrated.
Column chromatography (1:3 ether/hexane) of the residue
yielded first (2S,3R,4R,5R)-N-allyl-20-O-benzoyl-4-benzyl-
oxy-50-O-tert-butyldiphenylsilyl-3-hydroxy-2,5-bis(hydroxy-
methyl)pyrrolidine (24, 1.84 g, 68%) as a colourless syrup;
1
Cbz), 745 and 711 cmꢀ1 (aromatic). H NMR (300 MHz):
d 7.86–7.12 (3m, 30H, 6Ph), 5.78 (br s, 1H, H-3), 5.08
(br s, 2H, H-20a,20b), 4.80–3.72 (4m, 9H, 2CH2Ph,
H-2,4,5,50a,50b) and 1.05 (s, 9H, CMe3). 13C NMR
(inter alia): d 165.85 and 165.42 (2COPh), 155.53 (CO,
Cbz), 72.08 (2CH2Ph), 67.47 (C-20,50), 64.63, 64.57, 62.40
and 62.17 (C-2,3,4,5), 26.89 (CMe3) and 19.25 (CMe3).

I. Izquierdo et al. / Tetrahedron 63 (2007) 1440–1447
1447
[a]2D7 +22 (c 1.1); n (neat) 3460 (OH), 3068 (aromatic), 1724
(CO, Bz), 740 and 710 cmꢀ1 (aromatic). 1H NMR
(300 MHz): d 8.06–7.25 (m, 20H, 4 Ph), 5.84 (dddd, 1H,
CH2–CH]CH2), 5.13 (br dd, 1H, Jtrans 17.1, Jgem 1.6 Hz,
H-trans), 5.04 (br dd, 1H, Jcis 10.2 Hz, H-cis), 4.65–4.55
(m, 4H, CH2Ph, H-20a,20b), 4.18 (dd, 1H, J3,4 10.4, J2,3
3.6 Hz, H-3), 3.98 (br s, 1H, OH), 3.92 (d, 1H, H-4), 3.64
95; (b) Asano, N.; Kuroi, H.; Ikeda, K.; Kizu, H.; Kameda,
Y.; Kato, A.; Adachi, I.; Watson, A. A.; Nash, R. J.; Fleet,
G. W. J. Tetrahedron: Asymmetry 2000, 11, 1; (c) Yamashita,
T.; Yasuda, K.; Kizu, H.; Kameda, Y.; Watson, A. A.; Nash,
R. J.; Fleet, G. W. J.; Asano, N. J. Nat. Prod. 2002, 65, 1875;
(d) Kato, A.; Kano, E.; Adachi, I.; Molyneux, R. J.; Watson,
A. A.; Nash, R. J.; Fleet, G. W. J.; Wormald, M. R.; Kizu, H.;
Ikeda, K.; Asano, N. Tetrahedron: Asymmetry 2003, 14, 325;
For the synthesis of (+)-hyacinthacines A2, see: (e) Rambaud,
L.; Compain, P.; Martin, O. R. Tetrahedron: Asymmetry
2001, 12, 1807; (f) Cardona, F.; Faggi, E.; Liguori, F.;
Cacciarini, M.; Goti, A. Tetrahedron Lett. 2003, 44, 2315; (g)
Izquierdo, I.; Plaza, M.-T.; Franco, F. Tetrahedron:
(dd, 1H, J5,5 a 3.8, J5 a,5 b 10.5 Hz, H-50a), 3.57 (dd, 1H,
0
0
0
J5,5 b 2.7 Hz, H-50b), 3.46 and 3.31 (2br dd, 2H, Jgem
0
0
0
14.7 Hz, CH2–CH]CH2), 3.39 (ddd, 1H, J2,2 a 5.6, J2,2 b
7.1 Hz, H-2), 3.09 (br t, 1H, H-5) and 1.06 (s, 9H, CMe3).
13C NMR (inter alia): d 166.70 (COPh), 117.92 (CH2–
CH]CH2), 85.77 and 74.06 (C-3,4), 71.32 (CH2Ph),
70.29 and 64.71 (C-2,5), 64.79 and 63.20 (C-20,5),
55.57 (CH2–CH]CH2), 26.76 (CMe3) and 19.09 (CMe3).
HRMS (LSIMS): m/z 658.2963 [M++Na]; calcd for
C39H45NO5NaSi: 658.2965 (deviation +0.2 ppm).
ꢀ
Asymmetry 2003, 14, 3933; (h) Desvergnes, S.; Py, S.; Vallee,
Y. J. Org. Chem. 2005, 70, 1459; For the synthesis of (+)-
hyacinthacine A3, see: (i) Izquierdo, I.; Plaza, M.-T.; Franco,
F. Tetrahedron: Asymmetry 2002, 13, 1581.
3. For recent isolations of DMDP and DGDP, see: (a) Asano, N.;
Yamauchi, T.; Kagamifuchi, K.; Shimizu, N.; Takahashi, S.;
Takatsuka, H.; Ikeda, K.; Kizu, H.; Chuakul, W.; Kettawan,
A.; Okamoto, T. J. Nat. Prod. 2005, 68, 1238; (b) Ueda, H.;
Kawanishi, K.; Ayala, F.; Moriyasu, M. Nat. Med. 2004, 58,
85; For a review on DMDP, see: (c) Wrodnigg, T.-M.
Monatsh. Chem. 2002, 133, 393.
4. (a) Izquierdo, I.; Plaza, M.-T.; Franco, F. Tetrahedron:
Asymmetry 2002, 13, 1503; (b) Izquierdo, I.; Plaza, M.-T.;
Tamayo, J. A. J. Carbohydr. Chem. 2006, 25, 281.
5. For an approach to (+)-hyacinthacine A1, see: Toyao, A.;
Tamura, O.; Takagi, H.; Ishibashi, H. Synlett 2003, 35; For total
synthesis, see: Chabaud, L.; Landais, Y.; Renaud, P. Org. Lett.
2005, 7, 2587; For (ꢂ)-hyacinthacine A1, see: Donohoe, T. J.;
Sintim, H. O.; Hollinshead, J. J. Org. Chem. 2005, 70, 7297.
6. Zhao, Z.; Song, L.; Mariano, P. M. Tetrahedron 2005, 61, 8888.
7. Izquierdo, I.; Plaza, M.-T. An. Quim. 1990, 36, 554.
Second elution gave (2R,3R,4R,5S)-N-allyl-4-benzoyloxy-
3-benzyloxy-20-O-tert-butyldiphenylsilyl-2,5-bis(hydroxy-
methyl)pyrrolidine (25, 350 mg, 13%) as a colourless syrup;
[a]2D5 ꢀ43 (c 1); n (neat) 3471 (OH), 3067 (aromatic), 1721
(CO, Bz), 741 and 704 cmꢀ1 (aromatic). 1H NMR
(300 MHz): d 8.05–7.23 (m, 20H, 4Ph), 5.84 (dddd, 1H,
CH2–CH]CH2), 5.52 (dd, 1H, J3,4 4.2, J4,5 5.9 Hz, H-4),
5.18 (br dd, 1H, Jtrans 17.1, Jgem 1.6 Hz, H-trans), 5.11 (br
dd, 1H, Jcis 10.2 Hz, H-cis), 4.73 and 4.66 (2d, 2H, J
11.8 Hz, CH2Ph), 4.36 (t, 1H, J2,3 4.3 Hz, H-3), 3.75 (dd,
1H, J5,5 a 4.6, J5 a,5 b 10.6 Hz, H-50a), 3.71 (dd, 1H, J5,5 b
6.1 Hz, H-50b), 3.58–3.44 (m, 3H, H-20a,20b,5), 3.40–3.25
(m, 2H, CH2–CH]CH2), 3.11 (br q, 1H, H-2), 3.01 (br s,
1H, OH) and 1.05 (s, 9H, CMe3). 13C NMR (inter alia):
d 166.50 (COPh), 118.26 (CH2–CH]CH2), 82.27 and
78.46 (C-3,4), 72.13 (CH2Ph), 68.28 and 64.27 (C-2,5),
63.68 and 59.23 (C-20,50), 56.30 (CH2–CH]CH2), 26.93
(CMe3) and 19.25 (CMe3). HRMS (LSIMS): m/z 658.2965
[M++Na]; calcd for C39H45NO5NaSi: 658.2965 (deviation
0.0 ppm).
0
0
0
0
ꢀ
8. (a) Garcia-Moreno, I. M.; Rodrıguez-Lucena, D.; Ortiz Mellet,
C.; Garcia Fernandez, J. M. J. Org. Chem. 2004, 69, 3578; (b)
€
Tatibouet, A.; Lefoix, M.; Nadolny, J.; Martin, O. R.; Rollin, P.;
Yang, J.; Holman, G. D. Carbohydr. Res. 2001, 333, 327; (c)
Lichtenthaler, F. W.; Doleschal, W.; Hahn, S. Liebigs Ann.
Chem. 1985, 2454.
9. Garegg, P. J.; Samuelsson, B. J. Chem. Soc., Perkin Trans. 1
1980, 2866.
Acknowledgements
10. Angyal, S. J.; Bethell, G. S. Aust. J. Chem. 1976, 29, 1249.
11. Izquierdo, I.; Plaza, M.-T.; Robles, R.; Franco, F. Carbohydr.
Res. 2001, 330, 401.
ꢀ
The authors are deeply grateful to Junta de Andalucıa
(Group CVI-250) and University of Granada (Project
Ref. No. 30.PP.00.7900) for financial support.
12. (a) Liu, K. K.-C.; Kajimoto, T.; Chen, L.; Zhong, Z.; Ichikawa,
Y.; Wong, C.-H. J. Org. Chem. 1991, 56, 6280; (b) Kajimoto,
T.; Chen, L.; Liu, K. K.-C.; Wong, C.-H. J. Am. Chem. Soc.
1991, 113, 6678; (c) Wang, Y.-F.; Dumas, D. P.; Wong, C.-H.
Tetrahedron Lett. 1993, 34, 403; (d) Takayama, S.; Martin,
R.; Wu, J.; Laslo, K.; Siuzdak, G.; Wong, C.-H. J. Am.
Chem. Soc. 1997, 119, 8146; (e) Espelt, L.; Parella, T.;
References and notes
ꢀ
1. Izquierdo, I.; Plaza, M.-T.; Rodrıguez, M.; Tamayo, J.-A.;
Martos, A. Tetrahedron 2006, 62, 2693.
2. (a) Kato, A.; Adachi, I.; Miyauchi, M.; Ikeda, K.; Komae, T.;
Kizu, H.; Kameda, Y.; Watson, A. A.; Nash, R. J.; Wormald,
M. R.; Fleet, G. W. J.; Asano, N. Carbohydr. Res. 1999, 316,
ꢀ
Bujons, J.; Solans, C.; Joglar, J.; Delgado, A.; Clapes, P.
Chem.—Eur. J. 2003, 9, 4887.