Approach to a better understanding and modeling of (S)-dihydrofuran-2-yl, (S)-tetrahydrofuran-2-yl-, and furan-2-yl-β-dialkylaminoethanol ligands for enantioselective alkylation

Article abstract of DOI:10.1016/j.tetasy.2007.11.034

This paper outlines our efforts to study the influence of an oxygen atom adjacent to the stereogenic center of β-aminoalcohol derivatives used as ligands for catalysts in the asymmetric alkylation of aldehydes. Thirty-four enantiomerically pure (S)-dihydrofuran-2-yl, (S)-tetrahydrofuran-2-yl-, and furan-2-yl-β-dialkylamino alcohols have been prepared from 1,4:3,6-dianhydromannitol, 1,4:3,6-dianhydrosorbitol, and aminoacids, and then have been evaluated as ligands for the enantioselective addition of diethylzinc to benzaldehyde. Attention has been focused on the structural features governing the extent of chiral induction, the reaction rate, and the chemical yield of 1-phenyl-1-propanol which has been promoted by this wide collection of β-dialkylamino alcohols.

Full text of DOI:10.1016/j.tetasy.2007.11.034

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 18 (2007) 2923–2946
Approach to a better understanding and modeling of (S)-dihydrofuran-
2-yl, (S)-tetrahydrofuran-2-yl-, and furan-2-yl-b-dialkylaminoethanol
ligands for enantioselective alkylation
Claudio Paolucci* and Goffredo Rosini*
`
Dipartimento di Chimica Organica ‘A. Mangini’, Viale del Risorgimento n.4, Alma Mater Studiorum, Universita di Bologna, Bologna, Italy
Received 5 November 2007; accepted 29 November 2007
Abstract—This paper outlines our efforts to study the influence of an oxygen atom adjacent to the stereogenic center of b-aminoalcohol
derivatives used as ligands for catalysts in the asymmetric alkylation of aldehydes. Thirty-four enantiomerically pure (S)-dihydrofuran-2-
yl, (S)-tetrahydrofuran-2-yl-, and furan-2-yl-b-dialkylamino alcohols have been prepared from 1,4:3,6-dianhydromannitol, 1,4:3,6-dian-
hydrosorbitol, and aminoacids, and then have been evaluated as ligands for the enantioselective addition of diethylzinc to benzaldehyde.
Attention has been focused on the structural features governing the extent of chiral induction, the reaction rate, and the chemical yield of
1-phenyl-1-propanol which has been promoted by this wide collection of b-dialkylamino alcohols.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
NR2
OH
OH
NR2
O
OH
Chirality has a longstanding influence on the thinking of
chemists and the preparation of enantiomerically pure com-
pounds is a paramount task in synthesis. In 1984, Oguni and
Omi1 reported that the reaction of diethylzinc with benz-
aldehyde, catalyzed by a small amount of chiral 2-amino-
1-alcohols in toluene at room temperature, gave optically
active 1-phenyl-1-propanol (Fig. 1, A) almost quantitatively
in near 50% ee. Since then, the interest in the enantioselec-
tive addition of dialkylzinc reagents catalyzed by chiral
ligands has grown considerably.2–4 Moreover, it has been
found that stereocontrol is most easily achieved by selective
promotion or catalysis of comparably unreactive systems,
where racemic background reaction is slow.
∗
β
-aminoalcohol
EP ligands
∗
H
o
H
i
ZnEt2
o s
-Pr
CH3
o s
Ph
-Bu
A
t
Ph
β-aminoalcohol EP ligands
Figure 1.
alcohol derivatives has received a wide attention as a model
system for exploring asymmetric C–C bond formation.
Extensive mechanistic studies by Noyori et al. utilizing 3-
exo-dimethylaminoisoborneol (DAIB) as the amino alcohol
ligand have led to a good understanding of this complex
reaction.5 These pioneering studies revealed that ‘slight
structural changes sometimes have remarkable chemical
consequences. Organozinc complexes formed from b-
dialkylamino alcohols and dialkylzinc present a typical
example.6 This sentence clearly indicates how much any
difference, although slight, may be relevant and how little
we know about the parameters that influence the effective-
ness of a chiral non-racemic ligand in stereoinducing chiral-
ity catalyzing the reaction of dialkylzinc reagents with
aldehydes. Until now, several aspects have not been well
defined; how would an additional oxygen atom, adjacent
to the stereogenic center of b-amino alcohol derivatives,
influence the effectiveness as ligands in asymmetric
Carbon–carbon bond forming reactions lie at the heart of
organic synthesis and the dialkylzinc reaction with alde-
hydes allows access to chiral alcohols that are ubiquitous
in the structures of natural products and drug compounds.
Among the various types of chiral ligands explored in these
reactions, several b-dialkylamino alcohols have proven to
be especially efficient ligands and the enantioselective addi-
tion of organozinc reagents to aldehydes using chiral amino
*
Corresponding authors. Tel.: +39 051 2093634; fax: +39 051 2093630
(C.P.); tel.: +39 051 2093640; fax: +39 051 2093630 (G.R.); e-mail
addresses: paolucci@ms.fci.unibo.it; goffredo.rosini@unibo.it
0957-4166/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.11.034

2924
C. Paolucci, G. Rosini / Tetrahedron: Asymmetry 18 (2007) 2923–2946
alkylation reactions? What happens when the oxygen atom
belonging to a five-membered ring is bonded to the b-amino
alcohol residue through a proximal stereogenic carbon
atom? These, and other similar, interesting questions con-
vinced us to systematically explore the argument devising
well-focused experiments driven to collect data and pursue
answers for a better understand of the mechanistic principles
underlying catalysis in enantioselective alkylation reactions.
The key step of both processes is the alkyllithium-pro-
moted eliminative ring cleavage of halides derived from
1,4:3,6-dianhydrohexitols.10
The stereoselectivity of each step was very high and the
yields ranged from good to excellent. All these structures
have in common the absolute configuration of the stereo-
genic center of the dihydrofuran ring. The epimeric
(2R)- and (2S)-[(S)-2,5-dihydrofuran-2-yl]-2-(tosyloxy)ethyl
acetates, respectively, 4 and 7, were converted into (S)-2-
amino-2-[(S)-2,5-dihydrofuran-2-yl]ethanol 13 and into its
(2R)-epimer 14 following the procedure illustrated in
Scheme 2, based on sodium azide substitution with inver-
sion of configuration followed by alkaline hydrolysis and
reductive cleavage of the azido group. Therefore, com-
pounds 13 and 14 were used as versatile intermediates for
the preparation of the N,N-dialkylated derivatives 15–18
(Scheme 2) according to already known procedures.
Herein, we will outline our efforts to design a class of enan-
tiomerically pure dialkylaminoethanol ligands having some
structural and/or electronic modules, including five-mem-
bered rings containing oxygen, that have been varied in a sys-
tematic fashion to study the influence (reaction time, yield,
and enantiomeric excess) of each module in performing the
reaction of diethylzinc with benzaldehyde to obtain enantio-
merically enriched 1-phenyl-1-propanol. We assumed the
structure of 2-N,N-dialkylaminoethanol to be a molecular
scaffold and (S)-dihydrofuran-2-yl, (S)-tetrahydrofuran-2-
yl-, and furan-2-yl substituents on one of the two carbon
atoms of the base structure (Fig. 1). Therefore, we have
prepared and characterized several enantiomerically pure
(S)-dihydrofuran-2-yl, (S)-tetrahydrofuran-2-yl, and furan-2-
yl-b-dialkylaminoethanols starting from (3R,3aR,6R,6aR)-
hexahydrofuro[3,2-b]furan-3,6-diol (dianhydromannitol),
(3R,3aR,6S,6aR)-hexahydrofuro[3,2-b]furan-3,6-diol (dian-
hydrosorbitol),7 and aminoacids.
OTs
N3
N3
O
O
O
i
ii
iii
OAc
OAc
OH
4 (2R)
7 (2S)
9 (2S) 63%
11 (2S) 96%
10 (2R) 70%
12 (2R) 92%
NMe2
NMe2
OH
O
O
iv
or
OH
15 (77%)
NH2
The catalytic ability of each chiral ligand has been studied
in the asymmetric addition of diethylzinc addition to
benzaldehyde.
O
16 (80%)
OH
NBu2
NBu2
v
13 (2S) 84%
O
O
14 (2R) 85%
or
2. Results and discussion
OH
17 (61%)
OH
18 (67%)
2.1. Ligand synthesis. Preparation of EP (S)-dihydrofuran-2-
yl and (S)-tetrahydrofuran-2-yl-b-dialkylaminoethanols
Scheme 2. Reagents and conditions: (i) NaN3, DMF, 100 °C, 24 h; (ii)
15% NaOH aq, MeOH, 5 h; (iii) LiAlH4, THF; (iv) CH2O, HCO2H,
80 °C, 4 h; (v) n-BuI, K2CO3, MeCN, reflux, 30 h.
The preparation of building blocks 4 and 5 from dianhy-
dromannitol, and 7 and 8 from dianhydrosorbitol was per-
formed according to two modified procedures8,9 already
published and are summarized in Scheme 1.
Moreover, dihydrofuranyl derivatives 13 and 14 were con-
verted into the corresponding tetrahydrofurans 19 and 20
and then into the epimeric N,N-di(n-butyl) derivatives
(2S)-21 and (2R)-22 (Scheme 3).
OH
OPiv
i
O
O
dianhydromannitol
OTs
O
O
1
2a,b
I
I
NH2
NBu2
OH
NBu2
OH
OTs
O
O
O
O
O
i
ii
ii
iii
iv
O
O
or
13 or 14
OH
O
5
OTs
OAc
4
3a,b
19 (2S) 60%
20 (2R) 75%
I
21 (2S) 85%
22 (2R) 62%
OTs
iii
O
O
Scheme 3. Reagents and conditions: (i) 10% Pd(C), H2, MeOH/HCl concn
20:1; (ii) n-BuI, K2CO3, MeCN, reflux, 30 h.
dianhydrosorbitol
OAc
O
6a,b
7
I
O
O
iv
The oxiranes, (S)-2-[(S)-oxiran-2-yl]-2,5-dihydrofurane 5
and (S)-2-[(R)-oxiran-2-yl]-2,5-dihydrofurane 8, Scheme
1, were used as building blocks to prepare, respectively,
(S)-2-amino-1-[(S)-2,5-dihydrofuran-2-yl]ethanol 25 and
its epimer 26, which in turn were converted into the
epimeric N,N-dialkylated couples 27, 28 and 29, 30
8
Scheme 1. Reagents and conditions: (i) aq 15% NaOH, MeOH, rt to
40 °C, 90 min, 96%; (ii) TsCl, Py, 5 °C, 40 h, 97%; (iii) (a) BuLi, THF,
ꢀ75 °C; (b) AcCl, ꢀ75 °C to rt, 95% for 4, 90% for 7; (iv) NaOMe,
CH2Cl2/MeOH 15:1, 89% for 5, 93% for 8.

C. Paolucci, G. Rosini / Tetrahedron: Asymmetry 18 (2007) 2923–2946
2925
(Scheme 4). Clean reactions and satisfying yields of the
enantiomerically pure compounds made this approach very
effective.
OPiv
OPiv
ii, iii
OTBDS
OTBDS
iv
O
O
O
O
i
O
O
O
O
34
35
37
38
HO
Cl
OTBDS
vi
Cl
OTBDS
vii
OH
OH
OTBDS
viii
O
i
O
O
O
O
O
v
O
NH2
OH
OTs
N3
N3
39
40
41
42
23 (2S)
OH
24 (2R)
O
OH
OH
43 (R=n-Pr, 75%); 46 (R=n-Pent, 61%)
44 (R=n-Bu, 64%); 47 (R=n-Hex, 75%)
45 (R=i-Bu, 71%); 48 (R=-(CH2)4-, 51%)
ix
ii
O
O
O
O
or
or
NR2
43-48
NMe2
NMe2
iii
iv
OH
Scheme 6. Reagents and conditions: (i) Ph3P, CCl4, 50 °C, 20 h, 89%; (ii)
15% aq NaOH, MeOH, 50 °C, 2 h, 90% for 36; (iii) t-BuMe2SiCl, Im.,
DMF, 0 °C to rt, 3 h, 93%; (iv) t-BuOK, THF, rt to 50 °C, 3 h, 92%; (v)
PTSA (2.5 mol %), THF, rt to 45–50 °C, 35 min., 90%; (vi) TsCl, Et3N,
CH2Cl2, 4–5 °C, 24 h, 93%; (vii) NaN3, DMF, 95 °C, 16 h, 91%; (viii)
LiAlH4, THF, 83%; (ix) RI (2.1 equiv), K2CO3 (2.1 equiv), MeCN (1 mL/
mmol), 82 °C, 24–36 h.
27 (82%)
28 (73%)
O
NH2
OH
OH
25 (2S, 86%)
26 (2R, 82%)
NBu2
29 (68%)
NBu2
30 (66%)
Scheme 4. Reagents and conditions: (i) NaN3, MeOH–H2O, see lit.22; (ii)
LiAlH4, THF; (iii) CH2O, HCO2H, 80 °C, 4 h; (iv) n-BuI, K2CO3, MeCN,
reflux, 30 h.
terizes the 2-dihydro- and 2-tetrahydrofuranyl b-amino
ethanols already obtained. The efficiency of the process
can be ascribed to the driving force associated with the aro-
matization to a furan ring.
The same 2-dihydrofuranyl derivatives 25 and 26 were con-
verted into the corresponding (2S)- and (2R)-epimers of 2-
amino-1-[(S)-tetrahydrofuran-2-yl]ethanol by Pd-catalyzed
hydrogenation and then transformed into their N,N-di-
n-Bu derivatives 32 and 33 (Scheme 5).
A straightforward synthetic sequence allowed the conver-
sion of compound 39 into the hydroxyl-protected azide
41 and then into (R)-2-amino-1-(furan-2-yl)ethanol 42,11
which is the precursor of a collection of N,N-dialkylamino
derivatives 43–48. A similar approach was followed for the
preparation of ent-44 starting from the monoacetylated iso-
sorbite12 49 (Scheme 7). The eliminative ring opening was
performed on the protected intermediate 51 and gave ent-
39, which was efficiently converted into the desired ent-44
according to the procedure already used to prepare the
enantiomer 44.
OH
OH
O
O
ii
i
25
26
NH2
31 (67%)
NBu2
32 (74%)
OH
i, ii
O
OAc
OAc
OTBDS
O
O
ii
O
NBu2
33 (43%)
i
OTBDS
O
O
OH
O
HO
Cl
OH
Scheme 5. Reagents and conditions: (i) 10% Pd(C), H2, MeOH/HCl concn
20:1; (ii) n-BuI, K2CO3, MeCN, reflux, 30 h.
ent-39
49
50
O
51
iii
O
2.2. Preparation of EP furan-2-yl-b-dialkylaminoethanols
NBu2
ent-44
1,4:3,6-Dianhydrohexitols, dianhydromannitol, and dian-
hydrosorbitol, have been used as chiral sources for the
preparation of enantiomerically pure furanyl-2-yl-b-amino-
ethanols as well. The entire process to obtain (R)-2-amino-
(1-furan-2-yl)ethanol 42 from 1,4:3,6-dianhydromannitol
monopivalate 348 is shown in Scheme 6. After a straight-
forward conversion into the chlorine derivative 35 and
the replacement of the protecting group, an efficient and
clean base-induced 1,2-elimination of hydrogen chloride
gave the bicyclic dehydrohalogenated compound 38. This
key intermediate underwent cleavage of the condensed
tetrahydrofuran ring by an acid promoted 1,2-elimination
that gave the mono protected 2-furanyl ethandiol 39. This
step involved the loss of the stereogenic center that charac-
Scheme 7. Reagents and conditions: (i) SOCl2, Py, rt to 50 °C, 3 h, 97%;
(ii) (a) t-BuOK, THF, rt to 50 °C, 0.5 h; (b) TBDMSCl, rt, 0.5 h; (c) PTSA
(2.5 mol %), PhMe, rt to 50–55 °C, 72% overall; (iii) (a) TsCl, Et3N,
CH2Cl2, 4–5 °C, 24 h, 92% for ent-40; (b) NaN3, DMF, 95 °C, 16 h, 85%
for ent-41; (c) LiAlH4, THF, 82% for ent-42; (d) n-BuI (2.1 equiv), K2CO3
(2.1 equiv), MeCN, 82 °C, 24 h, 63% ent-44.
Unfortunately, the conversion of amino alcohol 42 into
(R)-2-(dimethylamino)-1-(furan-2-yl)ethanol 59 failed
under the classical conditions of an Escheweiler–Clarke
reaction.13 The dimethylamino derivative 59 was finally
obtained through conversion of compound 36 into (R)-2-
furanylethan-1,2-diol 5414 and therefore into the primary

2926
C. Paolucci, G. Rosini / Tetrahedron: Asymmetry 18 (2007) 2923–2946
O-Ts derivative 56. The pivaloyl ester 57 of the latter com-
pound underwent a clean substitution reaction with
dimethylamine in a sealed tube, to give the N,N-dimethyl-
amino derivative 59 after alkaline hydrolysis (Scheme 8).
2.3. Preparation of EP phenyl-b-dialkylamino alcohols and
other structures related to the structure of norephedrine
Over the course of our studies on the ability of tetrahydro-
furan-2-yl, dihydrofuran-2-yl, and furan-2-yl-b-dialkylami-
noethanol ligands to induce chirality through diethyl zinc
reaction with aldehydes, we required phenyl-b-dialkylami-
no alcohol derivatives to carry out comparative studies to
establish the influence of the furan ring in this type of
asymmetric catalysis. Our main goal was to reveal the par-
ticipation of the furan ring with its asymmetric conforma-
tions and the chelating attitude of its oxygen atom in
determining the preferential structures of transition states
with benzaldehyde and diethylzinc. Therefore, (R)-alaninol
66 and (S)-alaninol ent-66 were converted into the corre-
sponding N,N-dibutyl derivatives 67 and ent-67 by reaction
with n-butyl iodide, while the preparation of the N,N-di-
methyl derivatives 68 from (R)-66 was performed accord-
ing to the Escheweiler–Clarke reaction13 (Scheme 11).
TheN,N-dibutyl derivative 70 was obtained as previously
reported.16
OH
OH
OH
O
i, ii
O
iii
O
O
OH
O
O
OH
OTs
Cl
36
54
56
O
53
OPiv
OH
OPiv
O
O
v
iv
vi
NMe2
NMe2
OTs
57
58
59
Scheme 8. Reagents and conditions: (i) t-BuOK, THF, rt to 50 °C, 2 h; (ii)
PTSA (2.5 mol %), THF, rt to 45 °C, 35 min, 94% for 54; (iii) (a) Bu2SnO,
PhCH3, azeotr. distil.; (b) TsCl, CHCl3, 90% for 56; (iv) PivCl, Et3N,
CH2Cl2, 0 °C to rt, 14 h, 94%; (v) Me2NH (5.6 M in EtOH), 50 °C, sealed
tube, 24 h, 68%; (vi) 15% NaOH aq MeOH, rt 18 h, 92%.
The same procedure was used to prepare ent-59 starting
from compound 50, derived from monoacetylated isosor-
bite12 (Scheme 9).
NH2
NBu2
NBu2
i
OH
OH
OH
or
Ph
Ph
Ph
66 (R) or (S)
67
ent-67
OH
OH
OH
i
O
ii
iii
O
O
ii
50
OH
OH
O
OH
ent-54
NMe2
O
NMe2
OH
O
lit.16
Cl
64
ent-59
Ph
70
O
Ph
Ph
NBu2
65
68
69
Scheme 9. Reagents and conditions: (i) 15% aq NaOH, MeOH, rt to
50 °C, 94%; (ii) (a) t-BuOK, THF, rt to 50 °C, 4 h; (b) PTSA (2.5 mol %),
THF, rt to 50–55 °C, 80%; (iii) (a) Bu2SnO, PhCH3, azeotr. distil.; (b)
TsCl, CHCl3, 93% for ent-56; (c) PivCl, Et3N, CH2Cl2, 0 °C to rt, 14 h,
93% for ent-57; (d) Me2NH (5.6 M in EtOH), 50 °C, sealed tube, 24 h, 65%
for ent-58; (e) 15% NaOH aq. MeOH, rt 18 h, 93% for ent-59.
Scheme 11. Reagents and conditions: (i) n-BuI, K2CO3, MeCN, 83 °C,
24 h, 58%; (ii) From (R)-66: CH2O, HCO2H, 80 °C, 8 h, 85%.
We also examined some derivatives of norephedrine and
with the interesting results already obtained with these
compounds by Soai et al.,17 therefore we considered what
could be the behavior of a ligand having the same structure
with two well-defined stereogenic centers but with a furanyl
group instead of a phenyl one.
2-(Dibutylamino)-2-(furan-2-yl)ethanol enantiomers 63
and ent-63 were prepared from diols 54 and ent-54 accord-
ing to a well-established procedure15 and summarized in
Scheme 10.
We decided to prepare (1S,2S)-2-(dibutylamino)-1-(furan-
2-yl)propan-1-ol 73 and its syn-diastereoisomer according
to the procedure18 depicted in Scheme 12, and a small col-
lection of analogues with i-propyl 76, t-butyl 79, and phe-
nyl 80 groups instead of the methyl group typical for
ephedrine (Scheme 13).
O
N3
NH2
O
i
ii
iii
O
O
O
O
O
54
OH
OH
60
61
62
NBu2
NBu2
O
iv
v
ent-54
NH3+Cl-
NBu2
OH
OH
NBu2
ii
i
O
63
ent-63
anti/syn = 25:1
OH
O
Scheme 10. Reagents and conditions: (i) lit.15 (a) (MeO)2CO, KOH 60–
90 °C, 86%; (ii) NaN3, DMF, H2O, 120 °C, 10 h, 83%; (iii) H2/Lindlar
catalyst, MeOH, 87%; (iv) n-BuI, K2CO3, MeCN, 83 °C, 24 h, 74%; (v) (a)
lit.15 (MeO)2CO, KOH 60–90 °C, 75% for ent-60; (b) NaN3, DMF, H2O,
120 °C, 10 h, 85% for ent-61; (c) H2/Lindlar catalyst, MeOH, 93% ent-62;
(d) n-BuI, K2CO3, MeCN, 83 °C, 24 h, 61% for ent-63.
O
OH
73
71
72
Scheme 12. Reagents and conditions: (i) (a) n-BuI, K2CO3, THF/DMSO
4:1, reflux, 36 h, (b) LiAlH4, THF, 42% overall; (ii) (a) Swern oxidation;
(b) 2-lithiumfuran, 77%.

C. Paolucci, G. Rosini / Tetrahedron: Asymmetry 18 (2007) 2923–2946
2927
alcohol by reduction. From the results reported in Table
1 it is clear that besides the two adjacent stereogenic
centers, these (S)-dihydrofuran-2-yl, and (S)-tetrahydro-
furan-2-yl-b-dialkylamino alcohols show a modest enan-
tioselectivity. 2-(2,5-Dihydrofuran-2-yl)-2-aminoethanol
derivatives 15–18 catalyzed the formation of 1-phenyl-
1-propanol and the absolute configuration of the major
enantiomer was the same as the carbon atom of the ligand
bearing the dialkylated nitrogen. The isomeric 1-(2,5-
dihydrofuran-2-yl)-2-aminoethanol derivatives 27–30 with
the same (S)-dihydrofuran-2-yl group showed a different
enantioselectivity giving a scalemic mixture of 1-phenyl-1-
propanol where the major enantiomer was that with the
absolute configuration opposite to that of the carbon atom
of the ligands bearing the secondary hydroxyl group. A
reinforcing effect, albeit small, was observed for those epi-
mers of ligands with two opposite absolute configurations
(28 > 27, 30 > 29). The same trend was observed with
(S)-2-(dibutylamino)-2-[(S)-tetrahydrofuran-2-yl]ethanol 21
and its (R)-dibutylamino epimer 22, while the epimeric
2-amino-1-[(S)-tetrahydrofuran-2-yl]ethanol derivatives 32
and 33 showed more significant difference both in yield
and in asymmetric induction: matching for ligand 33 gave
(S)-1-phenylpropan-1-ol with 52% ee and mismatching
for ligand 32 generated the (R)-enantiomer with only 8%
ee. In every case, small changes were observed in ee with
the nature of the alkyl groups.
NH2
NBu2
OH
NBu2
i
ii
O
87%
66%
OH
OH
76
anti/syn = 12:1
74
75
NBu2
NBu2
NH2
ii
i
O
t-Bu
Ph
t-Bu
t-Bu
69%
79%
OH
79
OH
OH
anti/syn = 19:1
77
78
NBu2
NBu2
ii
O
Ph
67
60%
OH
OH
80
anti/syn = 15:1
Scheme 13. Reagents and conditions: (i) n-BuI, K2CO3, MeCN, 83 °C,
24 h; (ii) (a) Swern oxidation; (b) 2-lithiumfuran.
2.4. Asymmetric addition of Et2Zn to benzaldehyde. Reac-
tions with (S)-dihydrofuran-2-yl- and (S)-tetrahydrofuran-2-
yl-aminoethanol derivatives as ligands
To verify the effectiveness of the ligands prepared as de-
picted, we chose the reaction of diethylzinc with benzalde-
hyde as a standard reaction (Scheme 14).
2.5. Reactions with furan-2-yl-aminoethanol derivatives as
ligands
O
OH
β−aminoalcohol
EP ligands
ZnEt2
The reactions of diethylzinc with benzaldehyde carried out
in the presence of furan-2-yl-aminoethanol derivatives are
summarized in Table 2 and clearly indicate these ligands
work better than those depicted in Table 1.
A
Scheme 14.
The reactions were performed according to the reaction
conditions already established by Soai et al. for N,N-di-
alkylnorephedrines as ligands:17 treatment of the aldehyde
with diethylzinc (1 M solution in n-hexane) at 0 °C. The
progress of each reaction was monitored by chiral gas chro-
matography.19 The reactions were quenched with 10% HCl
and extracted with diethyl ether when the conversion of the
benzaldehyde was judged complete. The organic phase was
dried, the solvent evaporated, and the product purified by a
short silica gel column by flash chromatography.
As can be seen from Table 2, the addition of diethylzinc to
benzaldehyde in n-hexane at 0 °C in the presence of 6% of
ligands 59 and ent-59 was completed in only 2 h and led to
1-phenylpropan-1-ol in near 88% yield of isolated product
with 70–77% ee. It was shown that the enantioselectivity of
the reaction was very sensitive to the position of the hydrox-
yl group: better results were always observed with ligands
bearing the hydroxy group on the stereogenic center. For
example, when ligands 63 and ent-63 were employed, (S)-
1-phenylpropanol and (R)-1-phenylpropanol were, respec-
tively, obtained in high yield but with low ee values (21%
and 15% ee, Table 2, entries 9 and 10), while the corre-
sponding isomers 44 and ent-44 with the secondary hydro-
xyl group on stereogenic center, not only showed higher
catalytic activity, but also gave the product with better ee
values (73% and 72% ee, Table 2, entries 2 and 3).
The results of these reactions performed with (S)-dihydro-
furan-2-yl- and (S)-tetrahydrofuran-2-yl-aminoethanol
derivatives as ligands are summarized in Table 1.
Under the reaction conditions used, all ligands in Table 1
proved to be rather efficient as catalysts in the alkylation
reactions. Yields of 1-phenyl-1-propanol A are referred to
the isolated product and ranged from 38% to 93% from
reactions protracted until benzaldehyde was entirely con-
verted. In all the cases studied, besides the desired chiral
compound A, a small amount of benzyl alcohol was de-
tected as a by-product for the more sluggish reactions.5c,j
The comparative results of entry 7 (Table 1) show that
the yield of A was significantly increased by using more
ligand, allowing the conversion of benzaldehyde by alkyl-
ation to occur faster, minimizing the formation of benzyl
Similar results were also obtained with ligand 48 too (72%
ee, Table 2, entry 6). Whereas the (R)-2-amino-1-(furan-2-yl)-
ethanol derivatives (Table 2, entries 1, 2, and 5–7) catalyzed
the reaction to give (S)-1-phenylpropanol as the main
enantiomer,
(R)-2-di-n-butylamino-2-(furan-2-yl)ethanol
(Table 2, entry 10) gave mainly (R)-1-phenylpropanol
showing the same selectivity already observed for the (S)-
dihydrofuran-2-yl and (S)-tetrahydrofuran-2-yl analogues
(Table 1).

2928
C. Paolucci, G. Rosini / Tetrahedron: Asymmetry 18 (2007) 2923–2946
Table 1. Asymmetric addition of diethylzinc to benzaldehyde to obtain 1-phenyl-1-propanol A using (S)-dihydrofuran-2-yl and (S)-tetrahydrofuran-2-yl-
b-dialkylaminoethanol as ligands
Entrya
Ligands
Mol (%)
Time (h)
Yb (%)
eec (%)
Ad
NMe2
(S)
O
O
1
8.0
22
77
37
(S)
(S)
OH
15
NMe2
(S)
2
10.0
22
63
46
(R)
(R)
OH
16
NBu2
(S)
(S)
O
3
4
5
6
8.0
8.0
6.0
6.0
5.5
5.5
5
93
75
86
76
50
37
30
35
(S)
(R)
(S)
(R)
(S)
OH
17
NBu2
O
O
O
(R)
OH
18
NBu2
(S)
(S)
OH
21
NBu2
(S)
6
(R)
OH
22
OH
(S)
(S)
O
O
7
8
6.5
11.0
28
7
52
88
17
18
(R)
(R)
(S)
NMe2
27
OH
18.0
16
73
55
(S)
(R)
NMe2
28
OH
(S)
O
9
10
11
12
(S)
6.5
6.5
6.0
6.0
24
18
23
23
46
93
38
70
30
50
8
(R)
(S)
(R)
(S)
NBu2
29
OH
(S)
O
O
O
(R)
NBu2
30
OH
(S)
(S)
(S)
NBu2
32
OH
52
(R)
NBu2
33
a The molar ratio Et2Zn/benzaldehyde was 2.1:1. All the reactions were performed in n-hexane at 0 °C following the procedure developed by Soai et al.17
b Isolated yields.
c Determined by the observed rotations and confirmed by GC.19
d Absolute configuration of product A.

C. Paolucci, G. Rosini / Tetrahedron: Asymmetry 18 (2007) 2923–2946
2929
Table 2. Asymmetric addition of diethylzinc to benzaldehyde to obtain 1-phenyl-1-propanol (A) using furan-2-yl b-amino alcohols as ligands
Entrya
Ligands
Mol (%)
Time (h)
Yb (%)
eec (%)
Ad
OH
O
1
6.0
5
66
70
(S)
(S)
(R)
(R)
NPr2
43
OH
O
O
2
3
6.0
6.0
4
5
83
94
73
72
(R)
NBu2
44
OH
(S)
NBu2
ent-44
OH
O
O
4
6.0
24
62
5
(R)
(R)
N(i-Bu)2
45
OH
5
6
7
6.0
6.0
24
5
67
88
64
72
(S)
(S)
(R)
NHex2
47
OH
N
O
O
(R)
48
OH
6.0
10.0
2
2
85
92
76
77
(S)
(S)
(R)
NMe2
59
OH
O
8
(S)
6.0
2
73
75
(R)
NMe2
ent-59
NBu2
O
9
6.0
6.0
4
4
83
85
21
15
(S)
(R)
(S)
OH
63
NBu2
O
10
(R)
OH
ent-63
a The molar ratio of Et2Zn/benzaldehyde was 2.1:1. All the reactions were performed in n-hexane at 0 °C following the procedure developed by Soai et al.17
b Isolated yields.
c Determined by the observed rotations and confirmed by GC.19
d Absolute configuration of product A.
A maximum value of 76% ee was observed with dimethyl
derivative 59. When ligand 59, diethylzinc, and benzalde-
hyde were in a 1:1:1 ratio, no reaction was observed, while
the alkylation of benzaldehyde occurred in 40 min at 0 °C
giving (S)-1-phenylpropanol (79.3% ee) in high yield
(94%) with a 1:2.1:1 ratio of the reagents. Increasing the

2930
C. Paolucci, G. Rosini / Tetrahedron: Asymmetry 18 (2007) 2923–2946
Table 4. The effect of the solvent on the effectiveness of ligand 59
length of the n-alkyl groups of the ligands diminished the
rate of the reaction with only a slight effect on the enantio-
selectivity, while a loss of efficiency both in rate and in
enantioselectivity was observed working with the di-i-butyl
derivative 45.
O
OH
ZnEt2 (2,2 eq.), 6 mol% of 59
Ph
H
Ph
solvent, temperature
Entry
Solvent
T (°C)
Time (h)
ee (%)
Furthermore, the effects of the amount of the catalyst and
temperature on the asymmetric induction in the presence of
ligand 59 were examined. When increasing the amount of
chiral ligand 59 from 6 to 10 or 20 mol %, no significant
variation in product ee was observed (Table 3, entries 2–
4); reducing the amount to 2% was detrimental: the reac-
tion required 17 h to be complete and the enantioselectivity
dropped to 41% ee (Table 3, entry 1).
1
2
3
4
5
6
7
THF/n-hexane 1:4
THF/n-hexane 2:3
18
18
0
0
0
22
24
3
27
20
20
22
43
47
78
58
67
76
75
i-Pr2O/n-hexane 1:1
Furan/n-hexane 1:1
Toluene/n-hexane 1:1
t-BuOMe/n-hexane 1:1
t-BuOMe/n-hexane 1:8
0
0
Lowering the reaction temperature from 0 °C to ꢀ20 °C
led no an increase in selectivity while an increase to 30 °C
resulted in a small decrease in the ee value (Table 3, entries
5 and 6).
Table 5. The constancy of enantioselectivity of ligand 59 induced
alkylation reactions
O
OH
ZnEt2 (2,2 eq.), x mol% of 59
Ph
H
n-hexane, 0 °C
Ligand 59 (mol %)
Ph
Conversion %
Table 3. The influence of the amount of catalyst 59 and temperature on
the reaction rate and selectivity
Entry
ee (%)
1
2
3
4
5
6
7
6
6
6
4
4
4
4
30
50
100
13
20
33
74
75
74
73
77
77
76
O
OH
ZnEt2 (2,2 eq.), mol% of 59
n-hexane
Ph
H
Ph
Entry
Ligand 59 (mol %)
T (°C)
Time (h)
ee (%)
100
1
2
3
4
5
6
2
6
10
20
10
10
0
0
0
17
2
<2
1
2
1
41
76
77
78
77
70
0
an-2-yl)ethanol compounds were found to exhibit higher
enantioselectivities (up to 77% ee for ligand 59, Table 2)
than 2-dialkyamino-1-(2,5-dihydrofuran-2-yl)ethanol deriva-
tives (up to 55% ee for ligand 28 with anti-configuration,
Table 1) and the 2-dialkylamino-1-(2,5-tetrahydrofuran-2-
yl)ethanol derivatives (up to 52% ee for the ligand 33 with
anti-configuration, Table 1). The additional stereogenic
center of the 2-dihydrofuranyl and 2-tetrahydrofuranyl
ring, directly adjacent to the carbon bearing the hydroxyl
group, resulted in a detrimental effect on the enantioselec-
tivity of the ligands with syn-configuration. These results
appeared in contrast with the nucleophilicity of the oxygen
atoms of hydrogenated furan with respect to the less avail-
able oxygen of furan due to its aromaticity. In light of these
results our attention was focused on the role that the furan
ring plays and we attempted to give an answer to the ques-
tions: is the C-2 bonded furanyl group involved in effective
catalyst that controls the entire process? Does it work
better than the rotationally symmetric phenyl group? To
give an answer to these questions, ligands 67, 68, and 70
were prepared and tested (Table 6).
ꢀ20
30
All the results reported in Tables 1–3 were achieved using
n-hexane as a solvent. Next, the influence of the solvent
on the selectivity of ligand 59 was examined and Table 4
summarizes the results collected.
It is worth noting that iso-propyl ether (Table 4, entry 3) is
the only co-solvent that did not decrease the reaction rate
maintaining the same selectivity already observed for
ligand 59 in n-hexane. Tetrahydrofuran, furan, and toluene
had detrimental effects both on rate and selectivity (Table
4, entries 1, 2, 4, and 5), while t-BuOMe slowed down
the reaction without reduction of the selectivity (Table 4,
entries 6 and 7).
The selectivity induced by ligand 59 was constant during
the reaction, as shown by the results collected in Table 5
by monitoring the ee values of the product at different reac-
tion times.
It is worth noting the influence of the phenyl group, when
compared to the furanyl group, both on the reaction rate
and the effectiveness of the asymmetric induction. The dif-
ferent relationship between the absolute configuration of
these ligands and that induced in 1-phenylpropanol A is
due to the different group priority in the structure of
ligands. 2-(Dialkylamino)-2-phenylethanol 67, ent-67, and
68 as well as (S)-2-(dibutylamino)-1-phenylethanol 70
2.6. Reactions with phenyl-aminoethanol derivatives as
ligands
The results shown in Tables 1 and 2 indicated that 1-substi-
tuted-2-amino-1-ethanol derivatives were more effective
and enantioselective than the isomeric 2-substituted 2-ami-
no-1-ethanol derivatives. Moreover, 2-dialkylamino-1-(fur-

C. Paolucci, G. Rosini / Tetrahedron: Asymmetry 18 (2007) 2923–2946
2931
Table 6. The alkylation reaction performed with phenyl-aminoethanol Table 7. Alkylation reactions promoted by norephedrine like ligands
derivatives as ligands
Entrya
1
Ligands
OH
Time (h)
10
Yb (%)
75
eec (%)
70
Ad
O
OH
ZnEt2 (2,2 eq.),ligand
(S)
(R)
(S)
Ph
Entrya
H
Ph
n-hexane, 0 °C
O
NBu2
anti-73
Ligands
Mol
(%)
Time
(h)
Yb
(%)
eec
(%)
Ad
OH
(S)
NBu2
1
6.0
21
82
16
(S)
(R)
2
3
4
5
6
7
8
10
24
24
24
24
24
24
71
85
75
67
75
86
100
58
78
83
60
75
76
83
(S)
(R)
(S)
(R)
(S)
(S)
(R)
(R)
OH
OH
O
NBu2
Ph
67
syn-73
NBu2
OH
(S)
2
3
4
6.0
6.0
6.0
26
24
24
75
71
70
15
22
60
(R)
(S)
(S)
Ph
(S)
(S)
ent-67
O
NBu2
NMe2
anti-76
(R)
Ph
OH
68
OH
(S)
(R)
OH
(S)
Ph
O
NBu2
NBu2
syn-76
70
a The molar ratio of Et2Zn/benzaldehyde was 2.1:1. All the reactions were
performed in n-hexane at 0 °C following the procedure developed by
Soai et al.17
b Yields of isolated product.
c Determined by the observed rotations and confirmed by GC.19
d Absolute configuration of product A.
OH
(S)
(S)
t-Bu
t-Bu
Ph
O
NBu2
anti-79
OH
(S)
(R)
required over 20 h to complete the reaction against the 4 h
required for the corresponding furanyl substituted ligands
(Table 2, entries 3, 9, and 10). It is interesting to note that
the lower ee value observed with ligand 70 (60% ee in 24 h,
Table 6, entry 4) compared with the result of ligand 44
(73% ee in 4 h, Table 2, entry 2) under the same reaction
conditions.
O
NBu2
syn-79
OH
(R)
(R)
O
NBu2
anti-80
2.7. Reactions with 2-substituted 2-(dialkylamino)-1-(furan-
2-yl)ethanol ligands
OH
(R)
Ph
(S)
The investigations of Soai et al. established the effectiveness
of N,N-dialkylnorephedrines as ligands in the catalyzed
addition of dialkylzincs to aliphatic and aromatic alde-
hydes.17 Among them N,N-di-n-butylnorephedrine was
found to be the most effective catalyst. Inspired by these
outstanding achievements we prepared some derivatives
having the base structure of norephedrine but with a furan-
yl group instead of the phenyl group and a variety of
sidechains. Finally, we focused our attention on (1R,2S)-
2-(dibutylamino)-1-(furan-2-yl)-2-phenylethanol 80, a 2-
aminoethanol in which both the phenyl group and the furan-
yl group are present in well-established absolute configura-
tions. The results obtained with these ligands with two
adjacent stereogenic centers are shown in Table 7.
O
NBu2
syn-80
a The molar ratio of Et2Zn/benzaldehyde was 2.1:1. All the reactions were
performed in n-hexane at 0 °C following the procedure developed by
Soai et al.17
b Yields of isolated product.
c Determined by the observed rotations and confirmed by GC.19
d Absolute configuration of product A.
tative yield with 90% ee. (1R,2S)-2-(Dibutylamino)-1-(fur-
an-2-yl)propan-1-ol syn-73 showed lower effectiveness
both in yield (71%) and in induction power (58% ee). Better
results were obtained with ligand anti-73 (75% and 70% ee).
It is worth noting the great difference in reaction rate of
ligands anti-73 and syn-73 when compared with the other
ligands shown in Table 7 (10 h against 24 h). For these latter
ligands, the lower reactivity was accompanied by a major
inducing power (60–83% ee). In particular, their syn-isomer
In their pioneering paper, Soai et al.17 reported that
(1S,2R)-(ꢀ)-N,N-di-n-butylnorephedrine (DBNE), a syn-
diastereoisomer, catalyzed the addition of diethylzinc to
benzaldehyde and gave (S)-1-phenyl-1-propanol in quanti-

2932
C. Paolucci, G. Rosini / Tetrahedron: Asymmetry 18 (2007) 2923–2946
was more effective than the corresponding anti one; the
reverse observed for syn-73 and anti-73 ligands. The ligand
syn-80 showed the best performances in yield and ee.
ing syn-isomers. These latters showed the best induction
power with 83%, 75%, and 83% ee, respectively.
Extensive mechanistic studies by Noyori et al. utilizing (2S)-
3-exo-(dimethylamino)isoborneol (DAIB) as the amino
alcohol ligand for the alkylation of aldehydes with dialkyl-
zinc reagents have led to a good understanding of this com-
plex reaction. From the experimental results of the most
important and effective dialkylamino alcohol ligands, a
consistent empirical correlation between the absolute con-
figuration of ligand and product has been established and
the mechanism of the process has been studied by several
groups. More recently, several semiempirical TS
models20,4e have been developed for the enantioselective
chiral b-amino alcohol catalyzed additions of organozinc
reagents to benzaldehyde and general trends for varying
chiral b-amino alcohol ligands have been reproduced by
these models. It is likely that our findings will be useful
material for a detailed theoretical investigation of the selec-
tivity determining interactions for structures inside the class
of b-amino alcohol ligands we have prepared and tested.
3. Conclusions
In conclusion, we have developed a family of chiral ligands
including 34 enantiomerically pure (S)-dihydrofuran-2-yl,
(S)-tetrahydrofuran-2-yl, and furan-2-yl-b-dialkylamino-
ethanol derivatives, prepared from 1,4:3,6-dianhydro-
mannitol, 1,4:3,6-dianhydrosorbitol, and amino acids
through efficient and stereoselective synthetic schemes.
The molecular architecture of these ligands, built from
varying modules grafted in a controlled manner on a com-
mon chiral skeleton, allowed some variation of steric and/
or electronic characteristics, and has been used as a tool to
determine the influence of each module on the catalytic
properties. In this systematic study, we have employed a
well-established enantioselective process, the amino alco-
hol-promoted addition of diethylzinc to benzaldehyde.
Some important conclusions can be drawn from this study:
(a) all the dialkylamino alcohol ligands we have prepared
and tested accelerated the alkylation of benzaldehyde by
diethylzinc and revealed catalytic properties; (b) besides
the two adjacent stereogenic centers, all (S)-dihydrofuran-
2-yl and (S)-tetrahydrofuran-2-yl-b-dialkylamino alcohol
ligands revealed a modest enantioselectivity; (c) while the
2-(2,5-dihydrofuran-2-yl)-2-aminoethanol and 2-(tetrahy-
drofuran-2-yl)-2-aminoethanol derivatives induced prefer-
entially the formation of 1-phenylpropan-1-ol enantiomer
having the same absolute configuration of the carbon atom
bearing the secondary dialkylated nitrogen, 1-(2,5-dihydro-
furan-2-yl)-2-aminoethanol and 1-(2,5-tetrahydrofuran-2-
yl)-2-aminoethanol derivatives induced the formation of
1-phenylpropan-1-ol with the major enantiomer having
the opposite configuration with respect to that of the car-
bon atom of the ligand bearing the secondary hydroxyl
group; (d) with 1-(2,5-dihydrofuran-2-yl)-2-aminoethanol
derivatives, a significant reinforcing effect has been ob-
served when the two chiral centers of the ligands have
opposite absolute configurations; (e) the nature of alkyl
groups on the nitrogen atom of ligands did not influence
significantly the induction power; (f) better results have
been recorded with 2-dialkylamino-1-(furan-2-yl)-1-etha-
nol ligands while the induction power of the isomeric 2-
dialkylamino-2-(furan-2-yl)-1-ethanol derivatives was very
low; (g) for the best ligand in this series, compound 59,
we have investigated the effect of the catalyst amount on
the reaction rate and enantioselectivity, the influence of
temperature and of the solvent on the effectiveness; the
selectivity and the constancy of enantioselectivity during
the alkylation reaction promoted by ligand 59; (h) enanti-
omerically pure 2-dibutylamino-1-(furan-2-yl)-1-ethanol
was more effective as a ligand than 2-dibutylamino-1-phe-
nyl-1-ethanol, both in terms of reaction rate and in enanti-
oselectivity; (i) this beneficial effect of the furan-2-yl group
instead of the phenyl group was not observed with ligand
anti-73 when compared with the corresponding N,N-di-n-
butylnorephedrine developed by Soai et al.; (j) while anti-
73 was more effective than syn-73, the ligands anti-76,
anti-79, and anti-80 were less effective than the correspond-
4. Experimental
Melting points were obtained with a Buchi apparatus and
¨
are uncorrected. Yields are for isolated compounds. 1H
and 13C NMR spectra were recorded at 300 MHz and
75 MHz, respectively. Chemical shifts are in ppm down-
field of TMS. For optical rotation a Perkin Elmer 341
polarimeter was used. Bulb to bulb distillations were done
on a Buchi GRK-50 Kugelrohr; boiling points refer to air-
¨
bath temperatures and are uncorrected. All solvents and re-
agents were obtained from commercial sources and used
without further purification unless otherwise stated. Anhy-
drous solvents and reagents were obtained as follows: benz-
ene distilled over CaH2; DMSO distilled at 3 mm of
pressure over CaH2; THF was distilled over sodium
benzophenone.
4.1. (3R,3aR,6S,6aS) and (3R,3aR,6R,6aS)-6-iodohexa-
hydrofuro[3,2-b]furan-3-ols 2a and 2b
To a solution of isomeric esters 18 (17 g, 0.05 mol) dis-
solved in MeOH (50 mL), a 15% water solution of NaOH
(8 mL, 0.03 mol) was added. The reaction mixture was
warmed at 40 °C and stirred for 90 min. After solvent evap-
oration, under reduced pressure, the residue was dissolved
in CH2Cl2 (300 mL) and washed with H2O (15 mL, twice).
The water layer was extracted with CH2Cl2 (15 mL, twice),
and then the combined organic phases dried over MgSO4.
The residue, after solvent evaporation, was filtered through
a silica plug with petroleum ether/Et2O 1:3 to give 12.29 g
(96%) of 2a and 2b. A small sample was flash chromato-
graphed (petroleum ether/EtOAc 1:1) to isolate both the
isomers as pure compounds.
4.1.1. (3R,3aR,6S,6aS)-6-Iodohexahydrofuro[3,2-b]furan-3-
ol 2a. The first eluted was the major isomer 2a as a white
solid (Rf = 0.42, petroleum ether/EtOAc 2:3): mp 107–
22
108 °C (crystallized from n-hexane); ½aꢁD ¼ þ60:2 (c 1.32,
1
CHCl3); H NMR (CDCl3): d 4.85–4.78 (m, 2H), 4.38–

C. Paolucci, G. Rosini / Tetrahedron: Asymmetry 18 (2007) 2923–2946
2933
4.29 (m, 2H), 4.29–4.19 (m, 2H), 4.01 (dd, 1H, J = 9.3,
4.3. (R)-2-[(S)-2,5-Dihydrofuran-2-yl]-2-(tosyloxy)ethyl
acetate 4
6.3 Hz), 3.58 (dd, 1H, J = 9.3, 6.3 Hz), 2.65 [d, 1H,
J = 7.7 Hz (OH)]; 13C NMR (CDCl3): d 90.3, 81.6, 77.8,
74.4, 72.3, 26.3. IR (KBr) 3440 cmꢀ1; Anal. Calcd for
C6H9IO3: C, 28.15; H, 3.54; I, 49.56. Found: C, 28.23; H,
3.51; I, 49.26.
A mixture of 3a and 3b (9 g, 0.0219 mol) dissolved in THF
(190 mL) was reacted at ꢀ75 °C with BuLi (14.8 mL 1.6 M
in hexane, 0.0236 mol). After 30 min at ꢀ75 °C, the reac-
tion was quenched by the slow addition of AcCl (1.96 g,
0.025 mol) dissolved in THF (10 mL). After 30 min at
ꢀ75 °C, the reaction was left to warm spontaneously at
room temperature before being quenched with H2O
(2 mL). After solvent evaporation the residue was dissolved
in CH2Cl2 (100 mL) and, in succession, washed twice with
water (7 mL), dried over MgSO4, and the solvent distilled
under reduced pressure supporting the residue on silica
gel (12 g). From flash chromatography (Rf = 0.3, petro-
leum ether/EtOAc 7:3) acetate 4 (6.97 g, 95%) was ob-
4.1.2. (3R,3aR,6R,6aS)-6-Iodohexahydrofuro[3,2-b]furan-3-
ol 2b. The minor isomer 2b as a white solid (Rf = 0.3,
petroleum ether/EtOAc 2:3); mp 50–51 °C (crystallized
22
from i-propyl ether); ½aꢁD ¼ þ76:9 (c 1.15, CHCl3); 1H
NMR (CDCl3): d 4.55 (dd, 1H, J = 5.4, 4.3 Hz), 4.48–
4.41 (m, 1H), 4.43–4.35 (m, 1H), 4.28–4.21 (m, 1H), 4.11
(ddd, 1H, J = 11.0, 7.3, 4.3 Hz), 3.96 (dd, 1H, J = 9.6,
6.0 Hz), 3.81 (dd, 1H, J = 11.0, 8.2 Hz), 3.64 (dd, 1H,
J = 9.6, 6.0 Hz), 2.70 [br s, 1H (OH)]; 13C NMR (CDCl3):
d 82.4, 80.8, 75.8, 74.1, 72.9, 21.8; IR (KBr) 3492 cmꢀ1
;
tained as a white solid: mp 60–61 °C (crystallized from
20
MeOH); ½aꢁD ¼ ꢀ34:1 (c 1.05, CHCl3); 1H NMR (CDCl3):
Anal. Calcd for C6H9IO3: C, 28.15; H, 3.54; I, 49.56.
Found: C, 28.26; H, 3.55; I, 49.68.
d 7.80 (d, 2H, J = 8.3 Hz), 7.34 (d, 2H, J = 8.3 Hz), 6.02–
5.97 (m, 1H), 5.78–5.73 (m, 1H), 4.98–4.90 (m, 1H), 4.73
(ddd, 1H, J = 6.9, 4.7, 3.0 Hz), 4.59–4.43 (m, 2H), 4.30
(dd, 1H, J = 12.4, 3.0 Hz), 4.14 (dd, 1H, J = 12.4,
6.9 Hz), 2.44 (s, 3H), 1.92 (s, 3H); 13C NMR (CDCl3): d
170.4, 144.7, 134.1, 129.6, 129.5, 127.8, 124.7, 84.6, 80.8,
75.9, 62.2, 21.5, 20.5; IR (KBr) 1743 cmꢀ1; Anal. Calcd
for C15H18O6S: C, 55.20; H, 5.56; S, 9.82. Found: C,
55.03; H, 5.58; S, 9.81.
4.2. (3R,3aS,6S,6aS)- and (3R,3aS,6R,6aS)-6-iodohexa-
hydrofuro[3,2-b]furan-3-yl 4-methylbenzenesulfonates 3a
and 3b
To a solution of 2a and 2b (12 g, 0.0468 mol) in pyridine
(47 mL), TsCl (13.4 g, 0.070 mol) was added at 5 °C and
the reaction flask stored in the refrigerator. After 40 h,
the reaction mixture was slowly added to a well stirred
water-ice solution. The solid product was isolated by filtra-
4.4. (S)-2-[(S)-Oxiran-2-yl]-2,5-dihydrofuran 5
tion on a Buchner funnel, washed with water, and dried un-
¨
To
a
mechanically stirred solution of
4
(5.26 g,
der vacuum. Crystallization from MeOH gave 18.62 g
(97%) of 3a and 3b as a white solid. A small sample was
flash chromatographed to isolate both the isomers as pure
compounds.
16.11 mmol) in CH2Cl2/MeOH 15:1 (30 mL), a 4 M solu-
tion of NaOMe in MeOH (4.5 mL, 18 mmol) was slowly
added over 30 min and stirred at room temperature
for an additional 30 min. After filtration and solvent
evaporation, the residue was distilled at 85 °C, 20 mm, to
25
4.2.1. (3R,3aS,6S,6aS)-6-Iodohexahydrofuro[3,2-b]furan-3-
yl 4-methylbenzenesulfonate 3a. Isolated as a white solid
give epoxide 5 (1.62 g, 89%) as colorless oil: ½aꢁD
¼ ꢀ148:9 (c 1.3, CHCl3), {lit.8 bp 77 °C 16 mm,
29
1
½aꢁD ¼ ꢀ152:6 (c 2.56, CHCl3), H and 13C NMR spectra
(Rf = 0.48, petroleum ether/EtOAc 7:3); mp 109–111 °C
22
(crystallized from MeOH); ½aꢁD ¼ þ69:2 (c 1.51, CHCl3),
were identical to those previously reported}.
20
[lit.21 mp 109–110 °C, ½aꢁD ¼ 71; 1H NMR (CDCl3): d
7.82 (d, 2H, J = 8.4 Hz), 7.36 (d, 2H, J = 8.4 Hz), 4.93–
4.84 (m, 1H), 4.82–4.77 (m, 2H), 4.28 (dd, 1H, J = 3.5,
1.6 Hz), 4.20 (dd, 1H, J = 11.0, 3.5 Hz), 4.15 (dd, 1H,
J = 11.0, 1.6 Hz), 3.98 (dd, 1H, J = 9.6, 6.3 Hz), 3.74 (dd,
1H, J = 9.6, 6.9 Hz), 2.45 (s, 3H); 13C NMR (CDCl3): d
145.3, 133.0, 129.9, 128.0, 90.5, 80.1, 78.3, 78.1, 70.7,
25.5, 21.7; IR (KBr) 2979, 2941, 2874, 1355, 1190, and
4.5. (S)-2-[(S)-2,5-Dihydrofuran-2-yl]-2-(tosyloxy)ethyl
acetate 7
A mixture of 6a and 6b9 (26.5 g, 0.0646 mol) dissolved in
THF (600 mL) was reacted at ꢀ75 °C with BuLi
(28.5 mL 2.5 M in hexane, 0.071 mol). After 30 min at
ꢀ75 °C, the reaction was quenched by slow addition of
AcCl (5.04 mL, 0.071 mol) dissolved in THF (10 mL).
After 30 min at ꢀ75 °C, the reaction temperature was left
to rise to 0 °C spontaneously and quenched with water
(5 mL). The mixture was concentrated under reduced pres-
sure and the residue was taken up with a mixture of Et2O/
EtOAc 3:1 (300 mL). The organic solution was, in succes-
sion, washed with water (20 mL), 5% aqueous Na2S2O5
(10 mL), water (10 mL, twice), and brine. After being dried
over MgSO4, the solvents were distilled under reduced
pressure. The solid residue was crystallized two times: first
with 100 mL and then 50 mL of i-Pr2O to give 16.2 g of
acetate 7. From the crystallization solvents, by flash chro-
matography, were recovered 2.8 g of 7 (19 g overall,
90%): mp 64–65 °C (crystallized from i-Pr2O);
1177 cmꢀ1
.
4.2.2. (3R,3aS,6R,6aS)-6-Iodohexahydrofuro[3,2-b]furan-3-
yl 4-methylbenzenesulfonate 3b. Isolated as a white solid:
(Rf = 0.28, petroleum ether/EtOAc 7:3); mp 138–140 °C
22
(crystallized from MeOH); ½aꢁD ¼ þ99:9 (c 1.07, CHCl3),
20
1
{lit.21 mp 137–137.5 °C, ½aꢁD ¼ þ107}; H NMR (CDCl3):
d 7.82 (d, 2H, J = 8.3 Hz), 7.35 (d, 2H, J = 8.3 Hz), 4.96
(dd, 1H, J = 11.6, 6.1 Hz), 4.61–4.56 (m, 1H), 4.42–4.38
(m, 1H), 4.18–4.11 (m, 1H), 4.03 (ddd, 1H, J = 10.8, 7.3,
4.5 Hz), 3.90 (dd, 1H, J = 10.0, 6.1 Hz), 3.81–3.71 (m,
2H), 2.45 (s, 3H); 13C NMR (CDCl3): d 145.4, 133.2,
130.1, 128.0, 82.5, 79.5, 79.3, 76.1, 70.7, 21.8, 21.6; IR
(KBr) 2979, 2940, 2882, 1359, 1193, and 1178 cmꢀ1
.

2934
24
C. Paolucci, G. Rosini / Tetrahedron: Asymmetry 18 (2007) 2923–2946
1
½aꢁD ¼ ꢀ113:8 (c 1.05, CHCl3); H NMR (CDCl3): d 7.79
(d, 2H, J = 8.3 Hz), 7.34 (d, 2H, J = 8.3 Hz), 6.03–5.97
(m, 1H), 5.71–5.66 (m, 1H), 4.99–4.93 (m, 1H), 4.79–4.73
(m, 1H), 4.60–4.55 (m, 2H), 4.22 (dd, 1H, J = 12.3,
3.7, Hz), 4.14 (dd, 1H, J = 12.3, 7.7 Hz), 2.44 (s, 3H),
1.86 (s, 3H); 13C NMR (CDCl3): d 170.3, 144.7, 133.9,
129.8, 129.6, 127.9, 124.3, 84.4, 79.8, 75.9, 62.4, 21.5,
20.4; IR (KBr) 1740 cmꢀ1; Anal. Calcd for C15H18O6S:
C, 55.20; H, 5.56; S, 9.82. Found: C, 55.31; H, 5.57; S, 9.80.
added and stirred at room temperature for 5 h. After con-
centration, under reduced pressure, the residue was taken
up with CH2Cl2 (100 mL) and the water layer separated.
The organic phase was dried over MgSO4 and the crude,
after solvent distillation, purified by flash chromatography
(Rf = 0.23, petroleum ether/EtOAc 3:1) to give azido alco-
23
hol 11 (1.65 g, 96%) as a colorless oil: ½aꢁD ¼ ꢀ103:5 (c
1.29, CHCl3); 1H NMR (CDCl3): d 6.10–6.05 (m, 1H),
5.83–5.78 (m, 1H), 5.09–5.02 (m, 1H), 4.79–4.63 (m, 2H),
3.85 (dd, 1H, J = 11.5, 5.5 Hz), 3.81 (dd, 1H, J = 11.5,
6.0 Hz), 3.43–3.37 (m, 1H), 3.18 [br s, 1H (OH)]; 13C
NMR (CDCl3): d 128.9, 125.8, 86.3, 75.7, 65.4, 62.5; IR
(film) 3401, 2106 cmꢀ1; Anal. Calcd for C6H9N3O2: C,
46.45; H, 5.85; N, 27.08. Found: C, 46.52; H, 5.87; N,
27.16.
4.6. (S)-2-[(R)-Oxiran-2-yl]-2,5-dihydrofuran 8
Tosylate 7 (6.35 g, 19.46 mmol) was treated with NaOMe
in MeOH under the same conditions of the corresponding
isomer 4, distilled at 89 °C, 35 mm, to give epoxide 8
20
(2.03 g, 93%) as a colorless oil: ½aꢁD ¼ ꢀ174:5 (c 2.0,
29
CHCl3), {lit.9 bp 84 °C 40 mm, ½aꢁD ¼ ꢀ176:7 (c
4.10. (R)-2-Azido-2-[(S)-2,5-dihydrofuran-2-yl]ethanol 12
2.67, CHCl3)}, H1 and 13C NMR spectra were identical
to those previously reported.9
Acetate 10 (2.30 g, 0.0116 mol) was submitted to a sapon-
ification reaction under the same conditions as described
for the corresponding epimer 9. From flash chromato-
graphy (Rf = 0.25, petroleum ether/EtOAc 3:1) azido
4.7. (S)-2-Azido-2-[(S)-2,5-dihydrofuran-2-yl]ethyl acetate 9
A mixture of 4 (6.5 g, 0.020 mol) and NaN3 (2.6 g,
0.040 mol) in DMF (20 mL) was warmed at 100 °C under
N2. After 24 h, the reaction mixture was cooled to room
temperature, diluted with water (200 mL), and extracted
with Et2O (3 ꢂ 100 mL). The organic phase was first
washed with water (twice, 15 mL) then with brine
(30 mL) and finally dried over MgSO4. After solvent evap-
oration, under reduced pressure and purification by flash
chromatography (Rf = 0.32, petroleum ether/Et2O 3:2),
12 (1.66 g, 92%) was obtained as a colorless oil:
23
1
½aꢁD ¼ ꢀ81:5 (c 1.92, CHCl3); H NMR (CDCl3): d 6.10–
6.03 (m, 1H), 5.90–5.85 (m, 1H), 4.98–4.91 (m, 1H),
4.78–4.62 (m, 2H), 3.86–3.76 (m, 1H), 3.73–3.62 (m, 2H),
2.38 [br s, 1H (OH)]; 13C NMR (CDCl3): d 129.1, 125.9,
86.4, 75.6, 67.0, 62.3; IR (film) 3405 and 2112 cmꢀ1; Anal.
Calcd for C6H9N3O2: C, 46.45; H, 5.85; N, 27.08. Found:
C, 46.55; H, 5.84; N, 27.18.
azido acetate 9 (2.48 g, 63%) was obtained as colorless
4.11. (S)-2-Amino-2-[(S)-2,5-dihydrofuran-2-yl]ethanol 13
22
oil: ½aꢁD ¼ ꢀ119 (c 1.53, CHCl3); 1H NMR (CDCl3): d
6.12–6.07 (m, 1H), 5.80–5.75 (m, 1H), 5.02–4.95 (m, 1H),
4.78–4.62 (m, 2H), 4.29 (dd, 1H, J = 11.6, 4.9 Hz), 4.23
(dd, 1H, J = 11.6, 7.8 Hz), 3.62–3.55 (m, 1H), 2.11 (s,
3H); 13C NMR (CDCl3): d 170.5, 129.6, 125.3, 85.5, 75.8,
63.5, 62.8, 20.6; IR (film) 2110, 1746 cmꢀ1; Anal. Calcd
for C8H11N3O3: C, 48.73; H, 5.62; N, 21.31. Found: C,
48.62; H, 5.64; N, 21.28.
A solution of 11 (1.5 g, 9.66 mmol) in dry THF (96 mL)
was added dropwise under N2 to an LiAlH4 suspension
(0.368 g, 9.7 mmol) in dry THF (58 mL). The reaction mix-
ture was first stirred at room temperature for 1 h then
heated at solvent reflux. After 2 h, the reaction was cooled
at ꢀ10 °C and the excess hydride quenched with saturated
aqueous solution of NH4Cl (2.5 mL). After being warmed
to room temperature the reaction mixture was stirred until
a gray solid material was separated from the organic phase.
4.8. (R)-2-Azido-2-[(S)-2,5-dihydrofuran-2-yl]ethyl acetate
10
After filtration by Buchner the solid material was washed
¨
many times with CH2Cl2. The organic phase was dried
on MgSO4, and after solvent evaporation the residue was
Tosylate 7 (5.86 g, 0.018 mol) was left to react with NaN3
(2.34 g, 0.036 mol) in DMF (36 mL) as described above
for the corresponding epimer 4. From flash chromatogra-
bulb to bulb distilled to give 13 (1.05 g, 84%) as a hygro-
21
scopic white solid: ½aꢁD ¼ ꢀ120:1 (c 1.14, CHCl3); 1H
phy (Rf = 0.40, petroleum ether/Et2O 7:3) was recovered
NMR (CDCl3): d 6.05–5.99 (m, 1H), 5.81–5.76 (m, 1H),
4.87–4.80 (m, 1H), 4.72–4.58 (m, 2H), 3.64 (dd, 1H,
J = 10.9, 4.9 Hz), 3.55 (dd, 1H, J = 10.9, 6.9 Hz), 2.84
(ddd, 1H, J = 6.6, 4.9, 3.9 Hz), 2.55 [br s, 3H (OH and
NH2)]; 13C NMR (CDCl3): d 127.9, 126.8, 87.1, 75.4,
63.6, 55.9; IR (film) 3352, 3282, 2849 cmꢀ1; Anal. Calcd
for C6H11NO2: C, 55.80; H, 8.58; N, 10.84. Found: C,
55.67; H, 8.56; N, 10.87.
23
azido 10 (2.48 g, 70%) as a colorless oil: ½aꢁD ¼ ꢀ68:0 (c
1.0, CHCl3); 1H NMR (CDCl3): d 6.12–6.07 (m, 1H),
5.87–5.81 (m, 1H), 4.95–4.87 (m, 1H), 4.77–4.60 (m, 2H),
4.31 (dd, 1H, J = 11.6, 3.8 Hz), 4.08 (dd, 1H, J = 11.6,
7.7 Hz), 3.76 (ddd, 1H, J = 7.7, 4.8, 3.8 Hz), 2.10 (s, 3H);
13C NMR (CDCl3): d 170.2, 129.4, 125.0, 85.4, 75.5, 63.6,
63.1, 20.3; IR (film) 2112 and 1747 cmꢀ1. Anal. Calcd for
C8H11N3O3: C, 48.73; H, 5.62; N, 21.31. Found: C,
48.78; H, 5.63; N, 21.27.
4.12. (R)-2-Amino-2-[(S)-2,5-dihydrofuran-2-yl]ethanol 14
4.9. (S)-2-Azido-2-[(S)-2,5-dihydrofuran-2-yl]ethanol 11
Azido 12 was reduced under the same conditions as de-
scribed above for the corresponding epimer 11. Bulb to
To a solution of 9 (2.2 g, 11.1 mmol) in MeOH (11 mL), a
15% water solution of NaOH (3 mL, 11.2 mmol) was
bulb distillation gave 14 (0.60 g, 85%) as a hygroscopic
white solid: mp 56–59 °C; ½aꢁD ¼ ꢀ143:7 (c 1.32, CHCl3);
23

C. Paolucci, G. Rosini / Tetrahedron: Asymmetry 18 (2007) 2923–2946
2935
1H NMR (CDCl3): d 6.05–6.00 (m, 1H), 5.87–5.82 (m, 1H),
4.85–4.78 (m, 1H), 4.72–4.58 (m, 2H), 3.68 (dd, 1H,
J = 10.9, 4.4 Hz), 3.48 (dd, 1H, J = 10.9, 6.7 Hz), 3.00–
2.93 (m, 1H), 2.14 [br s, 3H (OH and NH2)]; 13C NMR
(CDCl3): d 128.3, 126.2, 88.0, 75.2, 63.1, 56.3; IR (KBr)
3473, 1851 cmꢀ1; Anal. Calcd for C6H11NO2: C, 55.80;
H, 8.58; N, 10.84. Found: C, 54.94; H, 8.55; N, 10.80.
127.6, 127.4, 85.0, 74.4, 65.3, 57.8, 50.4, 31.6, 20.4, 14.0;
IR (film) 3436, 2956, 2991, 2860 cmꢀ1; Anal. Calcd for
C14H27NO2: C, 69.66; H, 11.27; N, 5.80. Found: C,
69.45; H, 11.24; N, 5.79.
4.16. (R)-2-(Dibutylamino)-2-[(S)-2,5-dihydrofuran-2-yl]-
ethanol 18
4.13. (S)-2-[(S)-2,5-Dihydrofuran-2-yl]-2-(dimethylamino)-
ethanol 15
Amine 14 (0.208 g, 1.61 mmol) was alkylated with n-BuI
under the same conditions as described above for the cor-
responding epimer 13. Flash chromatography (Rf = 0.53,
A mixture of 13 (0.514 g, 3.98 mmol) 99% formic acid
(0.6 mL, 16 mmol) and 40% aqueous formaldehyde
(0.6 mL, 8 mmol) was heated at 80 °C for 4 h. After being
cooled to room temperature, the reaction mixture was basi-
fied with 30% aqueous NH4OH (1 mL) and concentrated
under reduced pressure. The residue was extracted with
CH2Cl2 (3 ꢂ 5 mL) and the organic phase dried over
K2CO3. The crude, after solvent evaporation, was bulb to
petroleum ether/EtOAc 3:2) and bulb to bulb distillation
24
gave 18 (0.258 g, 67%) as a colorless oil: ½aꢁD ¼ ꢀ35:5 (c
1.04, CHCl3); 1H NMR (CDCl3): d 5.93–5.88 (m, 1H),
5.85–5.80 (m, 1H), 5.07–4.99 (m, 1H), 4.68–4.54 (m, 2H),
3.58–3.52 (m, 2H), 3.13 [br s, 1H (OH)], 2.81–2.63 (m,
3H), 2.53–2.43 (m, 2H), 1.52–1.18 (m, 8H), 0.91 (t, 6H,
J = 7.1 Hz); 13C NMR (CDCl3): d 128.6, 126.7, 84.6,
75.6, 65.2, 58.0, 50.4, 31.5, 20.3, 14.0; IR (film)
3422 cmꢀ1; Anal. Calcd for C14H27NO2: C, 69.66; H,
11.27; N, 5.80. Found: C, 69.50; H, 11.28; N, 5.78.
bulb distilled to give 15 (0.484 g, 77%) as a colorless oil:
21
½aꢁD ¼ ꢀ114:8 (c 1.70, CHCl3); 1H NMR (CDCl3): d
5.98–5.93 (m, 1H), 5.79–5.74 (m, 1H), 4.99–4.91 (m, 1H),
4.71–4.55 (m, 2H), 3.45 (dd, 1H, J = 10.4, 5.5 Hz), 3.39
[br s, 1H (OH)], 3.38 (dd, 1H, J = 10.4, 9.3 Hz), 2.66
(ddd, 1H, J = 9.3, 6.8, 5.5 Hz), 2.47 (s, 6H); 13C NMR
(CDCl3): d 127.8, 127.4, 84.6, 74.5, 68.5, 58.0, 41.4; IR
(film) 3476 cmꢀ1; Anal. Calcd for C8H15NO2: C, 61.12;
H, 9.62; N, 8.91. Found: C, 61.24; H, 9.65; N, 8.92.
4.17. (S)-2-Amino-2-[(S)-tetrahydrofuran-2-yl]ethanol 19
Compound 13 (0.300 g, 2.76 mmol) dissolved in MeOH/
HCl concn 20:1 (10 mL) was added to a pre-hydrogenated
suspension of 10% Pd(0) on C (0.05 g) in MeOH (5 mL)
and hydrogenated (H2, 2 atm) for 8 h, then filtered on Cel-
ite. The filtrate was basified by 15% aqueous NaOH and
concentrated under reduced pressure. After bulb to bulb
distillation, the saturated amine 19 (0.217 g, 60%) was ob-
tained as a hygroscopic white solid: mp 57–60 °C;
4.14. (R)-2-[(S)-2,5-Dihydrofuran-2-yl]-2-(dimethylamino)-
ethanol 16
20
1
Amine 14 (0.450 g, 3.48 mmol) was dimethylated under the
same conditions as described above for the corresponding
epimer 13. Bulb to bulb distillation gave 16 (0.438 g,
½aꢁD ¼ þ2:6 (c 2.14, MeOH); H NMR (CDCl3): d 3.88–
3.69 (m, 3H), 3.61 (dd, 1H, J = 10.9, 4.0 Hz), 3.45 (dd,
1H, J = 10.9, 6.8 Hz), 2.80–2.72 (m, 1H), 2.71 [br s, 3H
(OH and NH2)], 2.02–1.82 (m, 3H), 1.70–1.58 (m, 1H);
13C NMR (CDCl3): d 80.4, 67.9, 64.1, 56.4, 28.2, 25.9; IR
(film) 3349, 2830 cmꢀ1; Anal. Calcd for C6H13NO2: C,
54.94; H, 9.99; N, 10.68. Found: C, 55.07; H, 10.02; N,
10.70.
21
1
80%) as a colorless oil: ½aꢁD ¼ ꢀ92:7 (c 1.56, CHCl3); H
NMR (CDCl3): d 5.96–5.91 (m, 1H), 5.83–5.77 (m, 1H),
5.14–5.06 (m, 1H), 4.68–4.54 (m, 2H), 3.64 (dd, 1H,
J = 11.0, 8.5 Hz), 3.55 (dd, 1H, J = 11.0, 5.1 Hz), 3.44 [br
s, 1H (OH)], 2.63 (ddd, 1H, J = 8.5, 5.1, 3.7 Hz), 2.42 (s,
6H); 13C NMR (CDCl3): d 128.2, 127.0, 83.1, 75.6, 68.3,
57.4, 41.3; IR (film) 3409 cmꢀ1
;
Anal. Calcd for
4.18. (R)-2-Amino-2-[(S)-tetrahydrofuran-2-yl]ethanol 20
C8H15NO2: C, 61.12; H, 9.62; N, 8.91. Found: C, 61.23;
H, 9.64; N, 8.93.
Dihydrofuran 14 (0.236 g, 1.83 mmol) was hydrogenated
under the same conditions as described above for the cor-
responding epimer 13. From flash chromatography and
bulb to bulb distillation, 20 (0.180 g, 75%) was obtained
4.15. (S)-2-(Dibutylamino)-2-[(S)-2,5-dihydrofuran-2-yl]-
ethanol 17
21
1
as a colorless oil: ½aꢁD ¼ ꢀ9:2 (c 0.88, CHCl3); H NMR
(CDCl3): d 3.89–3.80 (m, 1H), 3.79–3.64 (m, 3H), 3.49
(dd, 1H, J = 11.0, 6.6 Hz), 2.94–2.87 (m, 1H), 2.84 [br s,
3H (OH and NH2)], 2.03–1.84 (m, 3H), 1.77–1.65 (m,
1H); 13C NMR (CDCl3): d 80.7, 68.0, 63.9, 55.7, 27.6,
; Anal. Calcd for
C6H13NO2: C, 54.94; H, 9.99; N, 10.68. Found: C, 55.04;
H, 10.02; N, 10.71.
To a solution of 13 (0.517 g, 4 mmol) in acetonitrile (4 mL)
were added, in succession, K2CO3 dry (1.13 g, 8.2 mmol)
and n-BuI (1.5 g, 8.2 mmol). The reaction mixture was re-
fluxed for 30 h then cooled at room temperature and fil-
tered. The filtrate was concentrated under reduced
pressure, then the residue purified by flash chromatography
(Rf = 0.45, petroleum ether/EtOAc 2:3) to give, after bulb
25.6; IR (film) 3355, 2968 cmꢀ1
to bulb distillation, 17 (0.589 g, 61%) as a colorless oil:
19
½aꢁD ¼ ꢀ135:0 (c 1.14, CHCl3); 1H NMR (CDCl3): d
4.19. (S)-2-(Dibutylamino)-2-[(S)-tetrahydrofuran-2-yl]-
ethanol 21
5.96–5.91 (m, 1H), 5.76–5.71 (m, 1H), 4.98–4.89 (m, 1H),
4.68–4.54 (m, 2H), 3.41 [br s, 1H (OH)], 3.39 (dd, 1H,
J = 10.1, 5.5 Hz), 3.33–3.25 (m, 1H), 2.85 (ddd, 1H,
J = 10.5, 7.1, 5.5 Hz), 2.70–2.63 (m, 4H), 1.57–1.19 (m,
8H), 0.91 (t, 6H, J = 7.1 Hz); 13C NMR (CDCl3): d
Amine 19 (0.2 g, 1.5 mmol) alkylation, with n-BuI and
K2CO3, was performed as the corresponding dihydrofuran
13. After flash chromatography (Rf = 0.34 light petroleum/

2936
C. Paolucci, G. Rosini / Tetrahedron: Asymmetry 18 (2007) 2923–2946
EtOAc 2:3) and bulb to bulb distillation the alkylated
4.23. (S)-1-[(S)-2,5-Dihydrofuran-2-yl]-2-(dimethylamino)-
ethanol 27
amine 21 (0.311 g, 85%) was obtained as colorless oil:
20
1
½aꢁD ¼ ꢀ51:4 (c 2.54, CHCl3); H NMR (CDCl3): d 3.90–
3.78 (m, 2H), 3.77–3.68 (m, 1H), 3.70 [br s, 1H (OH)],
3.35 (dd, 1H, J = 10.0, 5.3 Hz), 3.18–3.09 (m, 1H), 2.82–
256 (m, 5H), 1.98–1.76 (m, 3H), 1.57–1.20 (m, 9H), 0.91
(t, 6H, J = 7.2 Hz); 13C NMR (CDCl3): d 78.2, 67.5,
65.4, 58.1, 50.6, 31.8, 29.8, 25.6, 20.5, 14.1; IR (film)
3435, 2956, 2861 cmꢀ1; Anal. Calcd for C14H29NO2: C,
69.09; H, 12.01; N, 5.75. Found: C, 68.96; H, 12.04; N,
5.73.
Amine 25 (0.467 g, 3.62 mmol) was methylated as de-
scribed for the corresponding regioisomer 13. Bulb to bulb
distillation gave dimethylamine 27 (0.466 g, 82%) as a col-
20
orless oil: ½aꢁD ¼ ꢀ146:9 (c 1.46, CHCl3); 1H NMR
(CDCl3): d 6.05–5.99 (m, 1H), 5.85–5.80 (m, 1H), 4.81–
4.74 (m, 1H), 4.74–4.59 (m, 2H), 3.71 (dt, 1H, J = 10.1,
3.7 Hz), 3.43 [br s, 1H (OH)], 2.53 (dd, 1H, J = 12.2,
10.1 Hz), 2.28 (s, 6H), 2.21 (dd, 1H, J = 12.2, 3.5 Hz);
13C NMR (CDCl3): d 128.2, 126.3, 87.5, 75.5, 69.3, 61.3,
45.5; IR (film) 3428, 2945, 2775, 1461 cmꢀ1; Anal. Calcd
for C8H15NO2: C, 61.12; H, 9.62; N, 8.91. Found: C,
60.19; H, 9.64; N, 9.94.
4.20. (R)-2-(Dibutylamino)-2-[(S)-tetrahydrofuran-2-yl]-
ethanol 22
Amine 20 (0.128 g, 0.976 mmol) was alkylated with n-BuI
under the same conditions as described above for the cor-
responding isomer 13. From flash chromatography
(Rf = 0.32 petroleum ether/EtOAc 3:2) and bulb to bulb
distillation, 22 (0.148 g, 62%) was obtained as a colorless
oil: ½aꢁD ¼ þ17:4 (c 1.93, CHCl3); H NMR (CDCl3): d
4.01–3.93 (m, 1H), 3.85–3.68 (m, 2H), 3.67 (dd, 1H,
J = 10.7, 6.3 Hz), 3.57 (dd, 1H, J = 10.7, 7.8 Hz), 3.21 [br
s, 1H (OH)], 2.73–2.55 (m, 3H), 2.50–2.39 (m, 2H), 2.10–
1.99 (m, 1H), 1.92–1.77 (m, 2H), 1.75–1.60 (m, 1H),
1.50–1.20 (m, 8H), 0.91 (t, 6H, J = 7.0 Hz); 13C NMR
(CDCl3): d 78.7, 68.2, 64.7, 59.2, 50.5, 31.6, 30.9, 25.5,
20.4, 14.0; IR (film) 3460, 2956, 2931, 2871 cmꢀ1; Anal.
Calcd for C14H29NO2: C, 69.09; H, 12.01; N, 5.75. Found:
C, 69.29; H, 12.02; N, 5.77.
4.24. (R)-1-[(S)-2,5-Dihydrofuran-2-yl]-2-(dimethylamino)-
ethanol 28
Alcohol 26 (0.299 g, 2.31 mmol) was dimethylated under
the same condition as described above for the correspond-
19
1
ing isomer 13. From bulb to bulb distillation 28 (0.264 g,
23
73%) was obtained as a colorless oil: ½aꢁD ¼ ꢀ83:0 (c
1.05, CHCl3); 1H NMR (CDCl3): d 6.01–5.97 (m, 1H),
5.94–5.90 (m, 1H), 4.77–4.70 (m, 1H), 4.71–4.59 (m, 2H),
3.64 (ddd, 1H, J = 9.7, 5.2, 3.6 Hz), 3.48 [br s, H, (OH)],
2.44 (dd, 1H, J = 12.3, 9.7 Hz), 2.35 (dd, 1H, J = 12.3,
3.6 Hz), 2.28 (s, 6H); 13C NMR (CDCl3): d 127.8, 126.8,
88.1, 75.7, 69.9, 61.5, 45.5; IR (film) 3418, 2947, 2855,
2778, 1462 cmꢀ1; Anal. Calcd for C8H15NO2: C, 61.12;
H, 9.62; N, 8.91. Found: C, 61.19; H, 9.65; N, 8.89.
4.25. (S)-2-(Dibutylamino)-1-[(S)-2,5-dihydrofuran-2-yl]-
ethanol 29
4.21. (S)-2-Amino-1-[(S)-2,5-dihydrofuran-2-yl]ethanol 25
Azide 2322 (2.79 g, 0.0180 mol) was reduced, with LiAlH4,
as described above for the corresponding regioisomer 9.
Amino 25 (0.226 g, 1.75 mmol) was alkylated with n-BuI as
described for the corresponding isomer 13. Bulb to bulb
distillation gave dibutylamine 29 (0.287 g, 68%) as a color-
Bulb to bulb distillation gave amino alcohol 25 (2 g,
20
86%) as a hygroscopic waxy material: ½aꢁD ¼ ꢀ129:5 (c
less oil (Rf = 0.2 petroleum ether/EtOAc 1:1):
24
1.07, CHCl3); 1H NMR (CDCl3): d 6.02–5.97 (m, 1H),
5.83–5.78 (m, 1H), 4.82–4.75 (m, 1H), 4.72–4.58 (m, 2H),
3.59–3.52 (m, 1H), 2.81 (dd, 1H, J = 12.8, 4.1 Hz), 2.74
(dd, 1H, J = 12.8, 7.7 Hz), 2.64 [br s, 3H (OH and
NH2)]; 13C NMR (CDCl3): d 128.0, 126.4, 88.0, 75.3,
73.8, 44.0; IR (film) 3360, 2857 cmꢀ1; Anal. Calcd for
C6H11NO2: C, 55.80; H, 8.58; N, 10.84. Found: C, 55.93;
H, 8.57; N, 10.83.
½aꢁD ¼ ꢀ148:8 (c 1.68, CHCl3); 1H NMR (CDCl3): d
6.04–5.99 (m, 1H), 5.86–5.80 (m, 1H), 4.82–4.75 (m, 1H),
4.74–4.58 (m, 2H), 3.64 (dt, 1H, J = 10.2, 4.0 Hz), 3.56
[br s, 1H (OH)], 2.60–2.47 (m, 3H), 2.46–2.35 (m, 3H),
1.50–1.20 (m, 8H), 0.91 (t, 6H, J = 7.2 Hz); 13C NMR
(CDCl3): d 128.1, 126.4, 87.5, 75.5, 68.9, 56.3, 53.9, 29.2,
20.5, 14.0; IR (film) 3447, 2957, 2932, 2861, 1467 cmꢀ1
;
Anal. Calcd for C14H27NO2: C, 69.66; H, 11.27; N, 5.80.
Found: C, 69.46; H, 11.30; N, 5.82.
4.22. (R)-2-Amino-1-[(S)-2,5-dihydrofuran-2-yl]ethanol 26
4.26. (R)-2-(Dibutylamino)-1-[(S)-2,5-dihydrofuran-2-yl]-
ethanol 30
Azido 2422 (3.20 g, 0.0296 mol) was reduced under the
same conditions as described above for its isomer 9. Bulb
Amine 26 (0.254 g, 1.97 mmol) was alkylated with n-BuI
under the same conditions as described above for the cor-
responding isomer 13. From flash chromatography
(Rf = 0.24, petroleum ether/EtOAc 1:1) and bulb to bulb
distillation, 30 (0.315 g, 66%) was obtained as a colorless
to bulb distillation gave 26 (2.18 g, 82%) as a waxy solid:
21
½aꢁD ¼ ꢀ133:6 (c 0.98, CHCl3); 1H NMR (CDCl3): d
6.02–5.97 (m, 1H), 5.93–5.87 (m, 1H), 4.78–4.71 (m, 1H),
4.71–4.57 (m, 2H), 3.54 (ddd, 1H, J = 7.90, 5.20, 3.5 Hz),
2.89 (dd, 1H, J = 12.8, 3.56 Hz), 2.72 (dd, 1H, J = 12.8,
7.9 Hz), 2.46 [br s, 3H (OH and NH2)]; 13C NMR (CDCl3):
d 127.9, 126.8, 87.9, 75.6, 74.3, 43.7; IR (KBr) 3462,
2875 cmꢀ1; Anal. Calcd for C6H11NO2: C, 55.80; H, 8.58;
N, 10.84. Found: C, 55.97; H, 8.55; N, 10.81.
22
1
oil: ½aꢁD ¼ ꢀ16:1 (c 1.72, CHCl3); H NMR (CDCl3): d
6.01–5.93 (m, 2H), 4.73–4.58 (m, 3H), 3.78 [br s, 1H
(OH)], 3.58–3.49 (m, 1H), 2.63–2.35 (m, 6H), 1.50–1.20
(m, 8H), 0.91 (t, 6H, J = 7.3 Hz); 13C NMR (CDCl3): d
127.5, 127.4, 88.3, 75.7, 69.6, 57.1, 54.0, 29.3, 20.5, 13.9;

C. Paolucci, G. Rosini / Tetrahedron: Asymmetry 18 (2007) 2923–2946
2937
IR (film) 3436, 2957, 2932, 2861, 1407 cmꢀ1; Anal. Calcd
for C14H27NO2: C, 69.66; H, 11.27; N, 5.80. Found: C,
69.53; H, 11.24; N, 5.78.
(22.87 g, 0.0872 mmol) was added in one portion at room
temperature under N2. The reaction mixture, after 2 h at
room temperature was warmed at 50 °C and stirred for
20 h. After the addition of petroleum ether (80 mL), the
4.27. (S)-2-Amino-1-[(S)-tetrahydrofuran-2-yl]ethanol 31
solid material was removed by filtration on Buchner funnel
¨
and the filtrate concentrated under reduced pressure. The
residue was taken up with petroleum ether (40 mL) and fil-
trated again to eliminate the last solid material. After sol-
vent evaporation the crude material was distilled at
Dihydrofuran 25 (0.187 g, 1.44 mmol) was hydrogenated
under the same conditions described for the corresponding
regioisomer 13. After bulb to bulb distillation, the satu-
rated amine 31 (0.127 g, 67%) was isolated as a colorless
135 °C/1 mm to give chloride 35 (9.646 g, 84%) as a color-
24
27
oil: ½aꢁD ¼ ꢀ1:7 (c 1.0, CHCl3); 1H NMR (CDCl3): d
less oil (Rf = 0.4, petroleum ether/Et2O 6:1): ½aꢁD ¼ þ96:6
1
3.90–3.73 (m, 3H), 3.50–3.43 (m, 1H), 3.04 [br s, 3H (OH
and NH2)], 2.85–2.68 (m, 2H), 2.00–1.82 (m, 3H), 1.78–
1.64 (m, 1H); 13C NMR (CDCl3): d 80.6, 74.1, 68.2, 44.6,
(c 1.20, CHCl3); H NMR (CDCl3): d 5.17–5.10 (m, 1H),
4.97–4.93 (m, 1H), 4.58 (dd, 1H, J = 4.5, 0.6 Hz), 4.36–
4.33 (m, 1H), 4.11–4.04 (m, 2H), 3.94 (dd, 1H, J = 10.0,
6.0 Hz), 3.82 (dd, 1H, J = 10.0, 4.9 Hz), 1.23 (s, 9H); 13C
NMR (CDCl3): d 177.7, 88.8, 80.4, 75.2, 73.4, 71.0, 60.5,
38.6, 27.0; IR (film) 2972, 2873, 1734 cmꢀ1. Anal. Calcd
for C11H17ClO4: C, 53.12; H, 6.89; Cl, 14.26. Found: C,
53.00; H, 6.90; Cl, 14.31.
27.7, 26.0; IR (film) 3468 cmꢀ1
; Anal. Calcd for
C6H13NO2: C, 54.94; H, 9.99; N, 10.68. Found: C, 54.80;
H, 10.02; N, 10.71.
4.28. (S)-2-(Dibutylamino)-1-[(S)-tetrahydrofuran-2-yl]-
ethanol 32
4.31. (3R,3aR,6S,6aS)-6-Chlorohexahydrofuro[3,2-b]furan-
3-ol 36
Amine 31 (0.148 g, 1.37 mmol) alkylation, with n-BuI and
K2CO3, was performed as for the corresponding isomer
13. After flash chromatography (Rf = 0.13 petroleum
ether/EtOAc 1:1) and bulb to bulb distillation the alkylated
amine 32 (0.248 g, 74%) was obtained as a colorless oil.
To a solution of 35 (9.20 g, 0.037 mol) in MeOH (35 mL),
15% aqueous NaOH (5 mL, 0.0187 mol) was added and the
resulting solution warmed at 50 °C. After 2 h, the reaction
mixture was cooled at room temperature and the solvent
distilled under reduced pressure. The residue was trans-
ferred into separator funnel with CH2Cl2 (100 mL) and
the aqueous layer separated. The organic phase was, in suc-
cession, dried over MgSO4, concentrated under reduced
pressure, and the residue supported on silica gel. From
flash chromatography (Rf = 0.26, petroleum ether/EtOAc
24
1
½aꢁD ¼ ꢀ55:4 (c 1.36, CHCl3). H NMR (CDCl3): d 3.94–
3.86 (m, 1H), 3.81–3.68 (m, 2H), 3.55 (ddd, 1H, J = 10.2,
4.8, 3.6 Hz), 3.57 [br s, 1H (OH)], 2.59–2.48 (m, 3H),
2.46–2.34 (m, 3H), 2.00–1.67 (m, 4H), 1.49–1.20 (m, 8H),
0.91 (t, 6H, J = 7.3 Hz).13C NMR (CDCl3): d 80.5, 69.4,
68.3, 57.2, 53.8, 29.2, 27.4, 25.8, 20.5, 14.0. IR (film)
3452, 2957, 2872, 1466 cmꢀ1
.
Anal. Calcd for
C14H29NO2: C, 69.09; H, 12.01; N, 5.75. Found: C,
68.89; H, 11.98; N, 5.74.
1:1) and distillation at 97 °C/1 mm, alcohol 36 (5.50 g,
27
90%) was obtained as a colorless oil. ½aꢁD ¼ þ56:6 (c 1.6,
20
CHCl3), [lit.23: ½aꢁ ¼ þ52 (c 1.0, CHCl3)]; 1H NMR spec-
D
4.29. (R)-2-(Dibutylamino)-1-[(S)-tetrahydrofuran-2-yl]-
ethanol 33
trum was identical to that previously reported;23 13C NMR
(CDCl3): d 88.5, 81.8, 75.9, 73.7, 72.2, 61.0.
Dihydrofuran 26 (0.285 g, 2.20 mmol) was hydrogenated
under the same conditions as described for the correspond-
ing isomer 13 and the resulting tetrahydrofuranylamine
was submitted to alkylation with n-BuI (0.830 g,
4.51 mmol) in refluxing acetonitrile (2.5 mL) in the pres-
ence of K2CO3 (0.623 g, 4.51 mmol) for 30 h. After the
usual work-up from flash chromatography (Rf = 0.2 petro-
leum ether/EtOAc 1:1) and bulb to bulb distillation 33
4.32. tert-Butyl((3R,3aS,6S,6aS)-6-chlorohexahydro-
furo[3,2-b]furan-3-yloxy)dimethylsilane 37
To a solution of 36 (5.2 g, 0.0316 mol) and t-BuMe2SiCl
(5.48 g, 0.0363 mol) in DMF (19 mL), imidazole (5.38 g,
0.079 mol) was added at 0 °C and under nitrogen. The
reaction was left at this temperature for 1 h, then 3 h at
room temperature before quenching by water addition
(80 mL). After extraction with Et2O (2 ꢂ 100 mL), the
organic phase was washed with water (15 mL), brine
(10 mL) and dried over MgSO4. The crude, after solvent
evaporation and flash chromatography (Rf = 0.35, petro-
leum ether/Et2O 19:1), gave 37 (8.19 g, 93%) as a colorless
(0.231 g, 43%) was obtained as
a
colorless oil:
23
1
½aꢁD ¼ þ68:0 (c 1.21, CHCl3); H NMR (CDCl3): d 3.90–
3.82 (m, 1H), 3.78–3.66 (m, 2H), 3.53 (ddd, 1H, J = 10.1,
6.2, 3.7 Hz), 3.42 [br s, 1H (OH)], 2.62–2.47 (m, 3H),
2.45–2.34 (m, 3H), 2.04–1.82 (m, 4H), 1.48–1.22 (m, 8H),
0.91 (t, 6H, J = 7.2 Hz); 13C NMR (CDCl3): d 81.5, 69.0,
68.4, 57.9, 54.0, 29.3, 27.8, 25.7, 20.5, 14.0; IR (film)
3436 cmꢀ1; Anal. Calcd for C14H29NO2: C, 69.09; H,
12.01; N, 5.75. Found: C, 69.01; H, 11.97; N, 5.73.
21
1
oil: ½aꢁD ¼ þ83:1 (c 1.30, CHCl3); H NMR (CDCl3): d
4.63–4.56 (m, 2H), 4.36–4.28 (m, 2H), 4.16 (dd, 1H,
J = 10.6, 3.6 Hz), 4.08 (d, 1H, J = 10.6 Hz), 3.81 (dd, 1H,
J = 8.6, 6.1 Hz), 3.56 (dd, 1H, J = 8.6, 7.1 Hz), 0.91 (s,
9H), 0.13 (s, 3H), 0.11 (s, 3H); 13C NMR (CDCl3): d
88.7, 81.8, 76.0, 73.8 72.8, 61.2, 25.8, 18.4, ꢀ4.8, ꢀ5.1;
4.30. (3R,3aR,6S,6aS)-6-Chlorohexahydrofuro[3,2-b]furan-
3-yl pivalate 35
IR (film): 2.954, 2930, 2858, 1472, 1461, and 1255 cmꢀ1
;
A flask equipped with a reflux condenser was charged with
Anal. Calcd for C12H23ClO3Si: C, 51.69; H, 8.31; Cl,
12.71, Si, 10.07. Found: C, 51.75; H, 8.29; Cl 12.74.
348 (10.06 g, 0.0437 mol) in CCl4 (44 mL) and Ph3P

2938
C. Paolucci, G. Rosini / Tetrahedron: Asymmetry 18 (2007) 2923–2946
4.33. tert-Butyldimethyl{(3R,3aS,6aR)-2,3,3a,6a-tetra-
hydrofuro[3,2-b]furan-3-yloxy}silane 38
ꢀ0.05 (s, 3H); 13C NMR (CDCl3): d 152.4, 144.8, 142.2,
132.9, 129.8, 127.9, 110.2, 107.7, 71.8, 66.7, 25.6, 21.6,
18.0, ꢀ5.17, ꢀ5.20; IR (film): 2955, 2930, 2887, 2856,
1519, 1366 cmꢀ1; Anal. Calcd for C19H28O5SSi: C, 57.54;
H, 7.12; S, 8.09; Si, 7.08. Found: C, 57.61; H, 7.13; S, 8.07.
To t-BuOK (36 mL 1 M in THF, 0.036 mol), a solution of
chloride 37 (5.56 g, 0.020 mol) in dry THF (7 mL) was
added at room temperature. The reaction was warmed at
50 °C for 3 h, then cooled to room temperature, and
quenched with water (0.5 mL). The reaction mixture was
diluted by petroleum ether (100 mL) and the solid material
4.36. (R)-[2-Azido-1-(furan-2-yl)ethoxy](tert-butyl)dimeth-
ylsilane 41
removed by filtration on a Buchner funnel. The crude, after
¨
solvent evaporation, was purified by flash chromatography
To a solution of 40 (3.49 g, 9.94 mmol) in DMF (20 mL),
NaN3 (0.969 g, 14.9 mmol) was added under a nitrogen
atmosphere. The reaction was heated at 95 °C for 16 h,
then cooled at room temperature and quenched by water
(200 mL) addition. The mixture was extracted with Et2O
(3 ꢂ 50 mL), and the combined ether solution washed with
water (10 mL), brine (10 mL), and dried over MgSO4.
After solvent evaporation at a reduced pressure, the crude
on Florisil (£ = 5, h = 6 cm, petroleum ether/Et2O 1:1) to
give unsaturated ether 38 (4.36 g, 92%) as a colorless oil:
21
½aꢁD ¼ þ66:3 (c 1.30, C6H6); 1H NMR (C6D6): d 6.57–
6.55 (m, 1H), 5.36 (dd, 1H, J = 6.4, 2.6 Hz), 5.05 (dt, 1H,
J = 2.5, 0.4 Hz), 4.48–4.42 (m, 1H), 4.31–4.22 (m, 1H),
4.01 (dd, 1H, J = 8.2, 6.4 Hz), 3.59 (dd, 1H, J = 9.6,
8.2 Hz), 1.18 (s, 9H), 0.30 (s, 3H), 0.24 (s, 3H); 13C
NMR (C6D6): d 152.1, 101.1, 85.3, 82.8, 75.0, 67.5, 26.6,
19.1, ꢀ4.0, ꢀ4.2; IR (film): 2955, 2930, 2859, and
1610 cmꢀ1; Anal. Calcd for C12H22O3Si: C, 59.46; H,
9.15; Si, 11.59. Found: C, 59.53; H, 9.13.
was flash chromatographed (Rf = 0.22, petroleum ether) to
22
give azide 41 (2.44 g, 91%) as a colorless oil: ½aꢁD ¼ þ89:6
(c 1.12, CHCl3); 1H NMR (CDCl3): d 7.41 (dd, 1H,
J = 1.8, 0.8 Hz), 6.38 (dd, 1H, J = 3.2, 1.8 Hz), 6.34–6.32
(m, 1H), 4.90 (dd, 1H, J = 7.4, 4.3 Hz), 3.55 (dd, 1H,
J = 12.5, 7.4 Hz), 3.42 (dd, 1H, J = 12.5, 4.3 Hz), 0.95 (s,
9H), 0.17 (s, 3H), 0.02 (s, 3H); 13C NMR (CDCl3): d
154.0, 142.0, 110.3, 107.3, 68.6, 56.1, 25.6, 18.1, ꢀ5.1,
ꢀ5.2; IR (film): 29.30, 2858, 2104 cmꢀ1; Anal. Calcd for
C12H21N3O2Si: C, 53.90; H, 7.92; N, 15.71; Si, 10.50.
Found: C, 53.83; H, 7.90; N, 15.67.
4.34. (R)-2-(tert-Butyldimethylsilyloxy)-2-(furan-2-yl)-
ethanol 39
To a solution of 38 (5.348 g, 0.022 mol) in dry THF
(60 mL) and under nitrogen, pyridinium p-toluensulfonate
(0.138 g, 2.5 mol %) was added, and the resulting solution
warmed at 45–50 °C. After 35 min, when PTSA was com-
pletely dissolved, the reaction was completed. NaHCO3
(0.146 g, 2 mmol) was added, and then after solvent evap-
oration and flash chromatography (Rf = 0.16, petroleum
ether/Et2O 85:15) purification, 39 (4.86 g, 90%) was iso-
4.37. (R)-2-Amino-1-(furan-2-yl)ethanol 42
To a suspension of LiAlH4 (0.656 g, 0.0172 mol) in dry THF
(20 mL), a solution of azido 41 (3.08 g, 0.0115 mol), dis-
solved in dry THF (90 mL), was added dropwise and under
nitrogen. The reaction was stirred before at room tempera-
ture for 2 h, then at reflux for 1 h. After cooling at ꢀ10 °C
the hydride excess was quenched with a 15% aqueous NaOH
(2.8 mL). The mixture was left to warm at room temperature
and stirred until a gray solid material was decanted from the
organic solvent. The solid material was removed by filtra-
22
1
lated as a colorless oil: ½aꢁD ¼ þ64:6 (c 1.26, CHCl3); H
NMR (CDCl3): d 7.36 (dd, 1H, J = 1.8, 0.9 Hz), 6.33
(dd, 1H, J = 3.2, 1.8 Hz), 6.27–6.25 (m, 1H), 4.79 (dd,
1H, J = 7.0, 4.5 Hz), 3.85–3.65 (m, 2H), 2.17 [br s, 1H
(OH)], 0.89 (s, 9H), 0.09 s, (3H), ꢀ0.04 (s, 3H); 13C
NMR (CDCl3): d 154.1, 141.9, 110.2, 107.2, 69.3, 65.9,
25.8, 18.2, ꢀ5.0, ꢀ5.2; IR (film): 3428, 2955, 2930, 2884,
2858 cmꢀ1; Anal. Calcd for C12H22O3Si: C, 59.46; H,
9.15; Si, 11.59. Found: C, 59.32; H, 9.17.
tion on a Buchner and washed many times with CH Cl .
¨
2
2
The combined organic phases were dried over MgSO4,
and after solvent evaporation the crude was bulb to bulb
distilled to give the amino alcohol 42 (1.22 g, 83%) as a
23
4.35. (R)-2-(tert-Butyldimethylsilyloxy)-2-(furan-2-yl)ethyl
4-methylbenzenesulfonate 40
white solid: mp 86–88 °C; ½aꢁD ¼ þ38:7 (c 1.1, CHCl3)
27
{lit. (S)-isomer mp 79 °C,24 ½aꢁD ¼ ꢀ40 (c 2, CH3
20
CN);24 ½aꢁD ¼ ꢀ32 (c 1, CHCl3)}.25 1H NMR spectrum
To a solution of 39 (2.59 g, 0.0107 mol) and Et3N (1.62 g,
0.016 mol) in CH2Cl2 (10.5 mL), TsCl (2.44 g,
0.0128 mol) was added in one portion and at 0 °C. After
24 h at 4–5 °C, the reaction was diluted by Et2O
(100 mL) addition, and in succession, washed with 2 M
HCl (10 mL), water (3 ꢂ 10 mL), and brine (10 mL). The
organic phase was dried over MgSO4, and after solvent
evaporation the residue was flash chromatographed
(Rf = 0.12, petroleum ether/Et2O 40:1) to give 40 (3.94 g,
agrees with those previously published.24–26 13C NMR
(CDCl3): d 155.4, 141.9, 110.1, 106.2, 68.1, 46.0.
4.38. General procedure for the preparation of 2-(dialkyl-
amino)-1-(furan-2-yl)ethanols 43–4817
Amino alcohol 42 (1 mmol) was alkylated with alkyl iodide
(2.10 mmol), K2CO3 (2.10 mmol) in refluxing CH3CN
(1 mL) for 24–36 h. It was then cooled at room tempera-
ture, filtered, and the filtrate was concentrated under
reduced pressure. The residue was purified by flash
21
1
93%) as a colorless oil: ½aꢁD ¼ þ46:5 (c 1.04, CHCl3); H
NMR (CDCl3): d 7.77–7.72 (m, 2H), 7.32–7.30 (m, 2H),
7.30 (dd, 1H, J = 1.8, 0.9 Hz), 6.29 (dd, 1H, J = 3.2,
1.8 Hz), 6.23–6.21 (m, 1H), 4.92 (dd, 1H, J = 7.5,
4.7 Hz), 4.18 (dd, 1H, J = 9.8, 4.7 Hz), 4.10 (dd, 1H,
J = 9.8, 7.5 Hz), 2.44 (s, 3H), 0.83 (s, 9H), 0.05 (s, 3H),
13C NMR does not agree with that previously reported by Demir et al.35
In particular the resonance at 96.7 ppm assigned to exo cyclic CHOH.

C. Paolucci, G. Rosini / Tetrahedron: Asymmetry 18 (2007) 2923–2946
2939
chromatography on silica gel to give, after bulb to bulb dis-
tillation, the desired dialkylated amino alcohol.
10.2 Hz), 2.64 (dd, 1H, J = 12.7, 3.8 Hz), 2.60–2.51 (m,
2H), 2.50–2.39 (m, 2H), 1.55–1.40 (m, 4H), 1.36–1.22 (m,
12H), 0.89 (t, 6H, J = 6.6 Hz); 13C NMR (CDCl3): d
154.9, 142.0, 110.1, 106.7, 63.4, 58.8, 54.1, 31.7, 27.07,
27.05, 22.6, 14.0; IR (film): 3420, 2955, 2929, 2858,
1467 cmꢀ1; Anal. Calcd for C18H33NO2: C, 73.17; H,
11.26; N, 4.74. Found: C, 73.40; H, 11.23; N, 4.75.
4.38.1. (R)-2-(Dipropylamino)-1-(furan-2-yl)ethanol 43.
Yield 75%; colorless oil: Rf = 0.5 in petroleum ether/
21
EtOAc 1:1; ½aꢁD ¼ þ95:3 (c 1.29, CHCl3); 1H NMR
(CDCl3): d 7.38 (dd, 1H, J = 1.8, 0.9 Hz), 6.33 (dd, 1H,
J = 3.2, 1.8 Hz), 6.30–6.28 (m, 1H), 4.66 (dd, 1H,
J = 10.2, 3.8 Hz), 3.84 [br s, 1H (OH)], 2.83 (dd, 1H,
J = 12.8, 10.2 Hz), 2.65 (dd, 1H, J = 12.8, 3.8 Hz), 2.59–
2.38 (m, 4H), 1.62–1.38 (m, 4H), 0.90 (t, 6H, J = 7.4 Hz);
13C NMR (CDCl3): d 154.8, 142.0, 110.0, 106.5, 63.4,
58.8, 56.0, 20.2, 11.6; IR (film): 3428 cmꢀ1; Anal. Calcd
for C12H21NO2: C, 68.21; H, 10.02; N, 6.63. Found: C,
68.08; H, 9.99; N, 6.64.
4.38.6. (R)-1-(Furan-2-yl)-2-(pyrrolidin-1-yl)ethanol 48.
Amino alcohol 42 (0.138 g, 1.09 mmol) was alkylated with
1,4-dibromobutane (0.257 g, 1.19 mmol), K2CO3 (0.323 g,
2.34 mmol) in refluxing acetonitrile (1.1 mL) and under
nitrogen. After 20 h, the reaction mixture was cooled to
room temperature, filtered, and the filtrate concentrated.
The residue was purified by flash chromatography
(Rf = 0.13 CH2Cl2/MeOH 9:1) on silica gel to give, after
bulb to bulb distillation the amino alcohol 48 (0.101 g,
4.38.2.
(R)-2-(Dibutylamino)-1-(furan-2-yl)ethanol
44.
19
1
Yield 64%; colorless oil: Rf = 0.3 in petroleum ether/
51%) as a colorless oil: ½aꢁD ¼ þ35:8 (c 0.6, CHCl3); H
NMR (CDCl3): d 7.38–7.36 (m, 1H), 6.34–6.32 (m, 1H),
6.31–6.28 (m, 1H), 4.78 (dd, 1H, J = 10.1, 3.5 Hz), 4.62
[br s, 1H (OH)], 3.10 (dd, 1H, J = 12.2, 10.2 Hz), 2.82–
2.70 (m, 2H), 2.62 (dd, 1H, J = 12.2, 3.5 Hz), 2.62–2.52
(m, 2H), 1.87–1.76 (m, 4H); 13C NMR (CDCl3): d 154.8,
142.0, 110.1, 106.5, 64.6, 60.0, 53.9, 23.5; IR (film): 344,
24
Et2O 3:2; ½aꢁ ¼ þ82:1 (c 1.07, CHCl3); 1H NMR
(CDCl3): d 7.3D7 (dd, 1H, J = 1.8, 0.9 Hz), 6.32 (dd, 1H,
J = 3.3, 1.8 Hz), 6.29–6.27 (m, 1H), 4.65 (dd, 1H, J =
10.1, 3.8 Hz), 3.98 [br s, 1H (OH)], 2.82 (dd, 1H,
J = 12.8, 10.1 Hz), 2.64 (dd, 1H, J = 12.8, 3.8 Hz), 2.63–
2.52 (m, 2H), 2.50–2.39 (m, 2H), 1.56–1.22 (m, 8H),
0.92 (t, 6H, J = 7.3 Hz); 13C NMR (CDCl3): d 154.8,
142.0, 110.0, 106.6, 63.4, 58.8, 53.8, 29.3, 20.5, 14.0; IR
2958, 2930, 2854, 1466 cmꢀ1
;
Anal. Calcd for
C10H15NO2: C, 66.27, H, 8.34; N, 7.73. Found: C, 66.08;
H, 8.36; N, 7.72.
(film): 3432, 2958, 2862 cmꢀ1
;
Anal. Calcd for
C14H25NO2: C, 70.25; H, 10.53; N, 5.85. Found: C,
70.41; H, 10.56; N, 5.84.
4.39. (3S,3aR,6S,6aS)-6-Chlorohexahydrofuro[3,2-b]furan-
3-yl acetate 50
4.38.3. (R)-2-(Di-iso-butylamino)-1-(furan-2-yl)ethanol 45.
Yield 71%; colorless oil: Rf = 0.3 in petroleum ether/Et2O
.
To a well-stirred solution of 4927 (7.76 g, 0.0412 mol) in
pyridine (8.6 mL), SOCl2 (3.46 mL, 0.0474 mol) was added
dropwise at 0 °C and under nitrogen, in accordance to the
Stross’ procedure.27 The temperature was left to rise at
room temperature and after 15 min heated at 100 °C;
during this time the reaction mixture became dark. After
1 h the reaction mixture was cooled at room temperature
then poured into water/ice (50 mL) and extracted with
Et2O (2 ꢂ 50 mL). The ether solution was washed with
water (10 mL), brine (10 mL), and dried over MgSO4.
After solvent evaporation the crude was purified by flash
22
17:3; ½aꢁD ¼ þ128:6 (c 1.2, CHCl3); 1H NMR (CDCl3):
d 7.36 (dd, 1H, J = 1.8, 0.9 Hz), 6.32 (dd, 1H, J = 3.2,
1.8 Hz), 6.29–6.27 (m, 1H), 4.67 (dd, 1H, J = 10.3,
3.6 Hz), 3.83 [br s, 1H (OH)], 2.84 (dd, 1H, J = 12.7,
10.3 Hz), 2.53 (dd, 1H, J = 12.7, 3.6 Hz), 2.23 (d, 4H,
J = 7.2 Hz), 1.90–1.70 (m, 2H), 0.95 (d, 6H, J = 6.5 Hz),
0.88 (d, 6H, J = 6.5 Hz); 13C NMR (CDCl3): d 154.6,
142.0, 110.1, 106.8, 64.0, 63.7, 60.3, 26.3, 21.1, 20.9; IR
(film): 3437 cmꢀ1; Anal. Calcd for C14H25NO2: C, 70.25;
H, 10.53; N, 5.85. Found: C, 70.11; H, 10.54; N, 5.87.
chromatography and bulb to bulb distilled to give chlo-
22
ride 50 (8.162 g, 96%) as a colorless oil: ½aꢁD ¼ þ87:0 (c
20
4.38.4. (R)-2-(Dipentylamino)-1-(furan-2-yl)ethanol 46.
23
Yield 61%; colorless oil: ½aꢁD ¼ þ78:4 (c 1.15, CHCl3);
1.36, CHCl3); {lit.: ½aꢁD ¼ þ79:5 (c 1.0, MeOH);27
20
1
1H NMR (CDCl3): d 7.37 (dd, 1H, J = 1.8, 0.8 Hz), 6.32
(dd, 1H, J = 3.2, 1.8 Hz), 6.29–6.27 (m, 1H), 4.65 (dd,
1H, J = 10.1, 3.7 Hz), 4.11 [br s, 1H (OH)], 2.82 (dd, 1H,
J = 12.7, 10.2 Hz), 2.64 (dd, 1H, J = 12.7, 3.8 Hz), 2.62–
2.51 (m, 2H), 2.50–2.39 (m, 2H), 1.58–1.18 (m, 12H),
0.90 (t, 6H, J = 7.0 Hz); 13C NMR (CDCl3): d 154.9,
142.0, 110.1, 106.6, 63.4, 58.8, 54.0, 29.6, 26.8, 22.6, 14.0;
IR (film): 3436, 2956, 2930, 2860, 1466 cmꢀ1; Anal. Calcd
for C16H29NO2: C, 71.86, H, 10.93; N, 5.24. Found: C,
72.02; H, 10.96; N, 5.23.
½aꢁD ¼ 99:0 (c 1.0, CHCl3)23}; H NMR and IR spectra
were identical to those previously reported.23 13C NMR
(CDCl3): d 169.72, 88.25, 84.96, 77.18, 74.74, 73.19,
60.32, 20.76.
4.40. (S)-2-(tert-Butyldimethylsilyloxy)-2-(furan-2-yl)
ethanol ent-39
To t-BuOK (53.1 mL 1 M in THF, 0.053 mol) a solution of
50 (4.11 g, 0.020 mol) in dry THF (3 mL) was added at
room temperature and under argon. The reaction was stir-
red for 30 min at room temperature, then heated to 50 °C
for 30 min. After cooling at room temperature a solid t-Bu-
Me2SiCl (3.3 g, 0.0219 mol) was added, in one portion, to
the basic reaction mixture (pH P 9 by universal paper).
The resulting reaction mixture was stirred at room temper-
ature for 30 min, then filtered through Florisil plug and
4.38.5. (R)-2-(Dihexylamino)-1-(furan-2-yl)ethanol 47.
Yield 75%; colorless oil: Rf = 0.3 in petroleum ether/Et2O
21
1
7:3; ½aꢁD ¼ þ71:0 (c 1.06, CHCl3); H NMR (CDCl3): d
7.38 (dd, 1H, J = 1.8, 0.8 Hz), 6.33 (dd, 1H, J = 3.2,
1.8 Hz), 6.30–6.27 (m, 1H), 4.65 (dd, 1H, J = 10.2,
3.7 Hz), 3.95 [br s, 1H (OH)], 2.82 (dd, 1H, J = 12.7,

2940
C. Paolucci, G. Rosini / Tetrahedron: Asymmetry 18 (2007) 2923–2946
washed with dry THF (the pH of filtered THF solution was
ꢃ7). After solvent evaporation,à the crude was dissolved in
PhCH3 (30 mL) and pyridinium p-toluensulfonate (0.120 g,
2.5 mol %) added. The resultant solution was gently
warmed at 50–55 °C and when the PTSA was completely
dissolved, 40–60 min, the reaction was completed. The
reaction mixture was cooled at room temperature, NaH-
CO3 (0.168 g, 2 mmol) added, and stirred for 15 min. After
solvent evaporation, the crude was purified by flash chro-
NMR, 13C NMR, and IR spectra were identical to the cor-
responding enantiomer 44.
4.45. (R)-1-(Furan-2-yl)ethane-1,2-diol 54
To
a solution of t-BuOK (104 mL 1 M in THF,
0.104 mmol), chlorohydrin 36 (8.2 g, 0.0493 mol) dissolved
in dry THF (15 mL) was added at room temperature, un-
der argon, and warmed at 50–55 °C. After 2 h, the reaction
mixture was cooled at room temperature, quenched with
water (10 mL), and stirred for 15 min. The organic phase
was separated and the aqueous one extracted with CH2Cl2.
The combined organic phases were dried before on K2CO3
and then filtered through a Florisil plug (£ = 2 cm,
h = 3 cm) and washed with THF (3 ꢂ 50 mL). After sol-
vent evaporation, under reduced pressure,§ the residue
was dissolved in dry THF (150 mL) and treated with pyrid-
inium p-toluensulfonate (PTSA, 0.3 g, 2.5 mol %). The
mixture was warmed at 45 °C and when PTSA was com-
pletely dissolved, after 40 min, the reaction was completed.
NaHCO3 (0.168 g, 2 mmol) was added and THF distilled
under reduced pressure. The crude after flash chromatogra-
phy– and after bulb to bulb distillation gave diol 54 (5.93 g,
94%) as a colorless oil (Rf = 0.2, petroleum ether/EtOAc
matography and bulb to bulb distilled to give the alcohol
22
ent-39 (3.47 g, 72%) as a colorless oil: ½aꢁD ¼ ꢀ62:2 (c
1
1.0, CHCl3); H NMR, 13C NMR, and IR spectra were
identical to the corresponding enantiomer 39.
4.41. (S)-2-(tert-Butyldimethylsilyloxy)-2-(furan-2-yl)ethyl
4-methylbenzenesulfonate ent-40
Alcohol ent-39 (2.74 g, 0.0113 mol) was esterified, with
TsCl, under the same conditions of the corresponding
enantiomer 39. The p-toluensulfonate ent-40 (4.137 g,
20
92%) was isolated as a colorless oil: ½aꢁD ¼ ꢀ42:1 (c 1.07,
1
CHCl3); H NMR, 13C NMR, and IR spectra were identi-
cal to the corresponding enantiomer 40.
24
24
2:3): ½aꢁD ¼ þ34:3 (c 1, CHCl3); {lit.14 ½aꢁD ¼ þ32:3 (c
4.42. (S)-[2-Azido-1-(furan-2-yl)ethoxy](tert-butyl)dimethyl-
silane ent-41
1
0.5, CHCl3) with an enantiomeric excess of 90% ee}; H
and 13C NMR spectra were identical to those previously
reported.14
Ester ent-40 (4.10 g, 0.0103 mol) was subjected to react
with NaN3 under the same condition of the corresponding
enantiomer 40 to give ent-41 (2.34 g, 85%) as a colorless oil.
4.46. (R)-2-(Furan-2-yl)-2-hydroxyethyl 4-methylbenzene-
sulfonate 56
21
1
½aꢁD ¼ ꢀ87:3 (c 1.06, CHCl3). H NMR, 13C NMR, and
IR spectra were identical to the corresponding enantiomer
41.
Following a published procedure29 a mixture of 54 (1.3 g,
0.0101 mol) and Bu2SnO (2.61 g, 0.0105 mol), in dry tolu-
ene (128 mL) and under nitrogen, was heated and the water
was removed by azeotropic distillation in a Dean–Stark
apparatus. After 2 h, the reaction mixture was cooled at
room temperature and the solvent removed under reduced
pressure. To the residue, dissolved in CHCl3 (40 mL, fil-
tered on neutral aluminum oxide), TsCl (2.0 g,
0.0105 mmol) was added in one portion. After 150 min at
room temperature, the solvent was distilled and the residue
supported on silica gel. From flash chromatography
(Rf = 0.3, petroleum ether/EtOAc 3:2), diol mono ester
4.43. (S)-2-Amino-1-(furan-2-yl)ethanol ent-42
Azido ent-41 (2.34 g, 8.75 mmol) was reduced under the
same conditions of the corresponding enantiomer 41 to give,
after bulb to bulb distillation, the amino alcohol ent-42
(0.912 g, 82%) as a hygroscopic white solid: mp 86–87 °C;
21
27
½aꢁD ¼ ꢀ38:6 (c 1.8, CHCl3), [lit. mp 79 °C,24 ½aꢁD ¼ ꢀ40
20
(c 2, CH3CN);24 ½aꢁD ¼ ꢀ32 (c 1, CHCl3)25]. 1H NMR, 13C
NMR, and IR spectra were identical to the corresponding
enantiomer 42.
56 (2.57 g, 90%) was obtained as
a colorless oil:
24
½aꢁD ¼ þ25:0 (c 1.0, CHCl3); 1H NMR spectrum was iden-
tical to that previously reported for the racemic mixture;30
13C NMR (CDCl3): d 151.4, 145.1, 142.6, 132.4, 129.9,
127.9, 110.4, 107.9, 71.4, 65.8, 21.6.
4.44. (S)-2-(Dibutylamino)-1-(furan-2-yl)ethanol ent-44
Amino alcohol ent-42 (0.190 g, 1.5 mmol) was alkylated
under the same conditions of the corresponding enantio-
mer 42 to give, after flash chromatography and bulb to
bulb distillation, the alkylated amine ent-44 (0.226 g,
§ A small sample was flash chromatographed to isolate (3R,3aR,6aR)-
21
1
63%) as a colorless oil: ½aꢁD ¼ ꢀ84:8 (c 1.0, CHCl3); H
24
2,3,3a,6a-tetrahydrofuro[3,2-b]furan-3-ol 53: ½aꢁD ¼ ꢀ75:1 (c 1.0, C6H6);
1H NMR (C6D6): d 6.15 (d, 1H, J = 2.6 Hz), 4.98 (dd, 1H, J = 6.4,
2.7 Hz), 4.80–4.77 (m, 1H), 4.22 (t, 1H, J = 6.0 Hz), 4.07–3.95 (m, 1H),
3.81 (dd, 1H, J = 8.7, 6.5 Hz), 3.08–3.01 (m, 1H), 2.44 [d, 1H,
J = 10.2 Hz (OH)]; 13C NMR (C6D6): d 150.2, 101.5, 84.1, 82.1, 73.0,
67.3.
à A small amount of crude was purified by flash chromatography to obtain
the intermediate enol ether tert-butyldimethyl{(3S,3aS,6aR)-2,3,3a,6a-
22
tetrahydrofuro[3,2-b]furan-3-yloxy}silane 51 as a colorless oil: ½aꢁD
¼
ꢀ2:8 (c 1.4, C6H6); 1H NMR (C6H6): d 6.16 (d, 1H, J = 2.6 Hz), 5.32–
5.28 (m, 1H), 4.85–4.82 (m, 1H), 4.55 (d, 1H, J = 6.5 Hz), 4.21–4.18 (m,
1H), 3.70 (dt, 1H, J = 9.8, 1.0 Hz), 3.41 (dd, 1H, J = 9.8, 3.1 Hz), 0.88 (s,
9H), ꢀ0.01 (s, 3H), ꢀ0.03 (s, 3H); 13C NMR (C6H6): d 149.9, 101.6, 90.7,
84.5, 78.3, 71.3, 26.6, 18.9, ꢀ4.10, ꢀ4.14; IR (film): 2965, 2931 2857, and
– Moreover the 1,4:2,5:3,6-trianhydro-D-mannitol 55 (0.128 g, 2%) was
23
isolated: mp = 67–68 °C; ½aꢁD ¼ 167:2 (c 1, CHCl3), [lit.;28 mp = 65–
23
67 °C; ½aꢁD ¼ 171:5 (c 2.8, CHCl3)]; 1H NMR (C6D6): d 4.32 (dd, 4H,
J = 12.8, 0.9 Hz,), 4.05 (dd, 2H, J = 8.4, 0.9 Hz), 3.61 (d, 2H,
1612 cmꢀ1
.
J = 8.4 Hz,); 13C NMR (C6D6): d 81.8, 77.1, 73.2.

C. Paolucci, G. Rosini / Tetrahedron: Asymmetry 18 (2007) 2923–2946
2941
4.47. (R)-1-(Furan-2-yl)-2-(tosyloxy)ethyl pivalate 57
4.50. (R)-4-(Furan-2-yl)-1,3-dioxolan-2-one 60
To alcohol 56 (2.57 g, 9.1 mmol) dissolved in CH2Cl2
(7 mL) were added at 0 °C Et3N (1.38 g, 13.6 mmol) and,
dropwise, trimethylacetyl chloride (1.43 g, 11.8 mmol) dis-
solved in CH2Cl2 (2 mL) over 10 min. After 2 h at 0 °C,
the reaction was left overnight at room temperature and
quenched with Et2O (70 mL) addition. The resulting solu-
tion was washed with 1 M HCl (10 mL), water
(3 ꢂ 10 mL), brine (5 mL), and dried over MgSO4. The res-
idue, after solvent evaporation, was supported on silica gel
and purified by flash chromatography (Rf = 0.24 in petro-
leum ether/Et2O 5:1) to give pivaloyl ester 57 (3.14 g, 94%)
Diol 54 (1.43 g, 0.0112 mol) was subjected to react with
dimethyl carbonate following the Zhou’s procedure.15
Carbonate 60 (1.48 g, 86%) was obtained as a colorless
21
oil: ½aꢁD ¼ ꢀ72:3 (c 0.8, EtOH) {corresponding (S)-enantio-
20
mer15 ½aꢁD ¼ þ63:4 (c 1.1, EtOH)}; 1H NMR and IR spec-
tra were identical to those previously reported;15 13C NMR
(CDCl3): d 154.4, 147.1, 144.6, 111.9, 110.8, 71.0, 67.3.
4.51. (S)-2-Azido-2-(furan-2-yl)ethanol 61
Carbonate 60 (0.880 g, 5.71 mmol) was reacted with NaN3
21
1
as a colorless oil: ½aꢁD ¼ þ60:8 (c 1.45, CHCl3); H NMR
(CDCl3): d 7.76 (d, 2H, J = 8.2 Hz), 7.37–7.31 (m, 3H),
6.36–6.33 (m, 1H), 6.32 (dd, 1H, J = 3.3, 1.8 Hz), 6.02
(dd, 1H, J = 7.7, 4.3 Hz), 4.42 (dd, 1H, J = 10.6, 7.7 Hz),
4.30 (dd, 1H, J = 10.6, 4.3 Hz), 2.44 (s, 3H), 1.16 (s, 9H);
13C NMR (CDCl3): d 177.4, 148.7, 145.4, 143.4, 133.1,
130.3, 128.2, 110.8, 110.0, 68.6, 66.1, 39.2, 27.3, 22.0; IR
following Zhou’s procedure.15 Azido alcohol 61 (0.725 g,
21
83%) was obtained as a colorless oil: ½aꢁD ¼ ꢀ128:8
(c 1.55, EtOH), {corresponding (R)-enantiomer lit.15
21
½aꢁD ¼ þ95:3 (c 1.3, EtOH)}; 1H NMR and IR spectra
were identical to those previously reported;15 13C NMR
(CDCl3): d 149.5, 143.2, 110.4, 108.8, 63.4, 60.4.
(film): 2975, 1738, 1599 cmꢀ1
;
Anal. Calcd for
4.52. (S)-2-Amino-2-(furan-2-yl)ethanol 62
C18H22O6S: C, 59.00, H, 6.05; S, 8.75. Found: C, 58.88,
H, 6.03; S, 8.78.
Azido alcohol 61 (0.217 g, 1.42 mmol) dissolved in MeOH
(8 mL) was added to a pre-hydrogenated suspension of
5 wt % Pd(0) on CaCO3 (75 mg,) poisoned with lead, and
hydrogenated (H2, 1 atm). After 6 h, the mixture was fil-
tered on Celite, after which the solvent was distilled under
reduced pressure, and the residue bulb to bulb distilled to
give the amino alcohol 62 (0.157 g, 87%) as a waxy solid:
4.48. (R)-2-(Dimethylamino)-1-(furan-2-yl)ethyl pivalate 58
In a sealed tube, 57 (1.34 g, 3.65 mmol) and Me2NH
(4.3 mL ꢄ5.6 M in EtOH) were warmed at 50 °C. After
24 h, the reaction was cooled at room temperature filtered
on paper and the solid washed with CH2Cl2 (2 ꢂ 5 mL).
The combined organic phases were filtered on a Florisil
plug (£ = 1 cm, h = 2 cm) washing with Et2O. The crude,
after solvent evaporation, was flash chromatographed
22
20
½aꢁD ¼ ꢀ11:8 (c 1.1, CHCl3); {lit.31 ½aꢁD ¼ ꢀ7:4 (c 0.8,
1
MeOH) for ee ꢃ 91%}; H and 13C NMR spectra were
identical to those previously reported.31
4.53. (S)-2-(Dibutylamino)-2-(furan-2-yl)ethanol 63
(Rf = 0.2, light petroleum/EtOAc 3:2) to give the dimethyl
22
amine 58 (0.598 g, 68%) as a colorless oil: ½aꢁD ¼ þ96:8 (c
Amino alcohol 62 (0.244 g, 1.92 mmol) was alkylated with
n-BuI under the same condition of the corresponding iso-
mer 42. After flash chromatography (Rf = 0.28, petroleum
ether/Et2O 5:1) and bulb to bulb distillation, the alkylated
amine 63 (0.340 g, 74%) was obtained as a colorless oil:
1.3, CHCl3); 1H NMR (CDCl3): d 7.38–7.36 (m, 1H), 6.34–
6.31 (m, 2H), 5.97 (dd, 1H, J = 7.1, 6.2 Hz), 2.84 (dd, 1H,
J = 13.1, 6.2 Hz), 2.77 (dd, 1H, J = 13.1, 7.1 Hz), 2.28 (s,
6H), 1.18 (s, 9H); 13C NMR (CDCl3): d 177.4, 152.1,
142.3, 110.2, 108.2, 66.4, 61.0, 45.8, 38.7, 27.0; IR (film):
25
1
½aꢁD ¼ ꢀ84:0 (c 1.02, CHCl3); H NMR (CDCl3): d 7.37
(dd, 1H, J = 1.9, 0.7 Hz), 6.32 (dd, 1H, J = 3.2, 1.9 Hz),
6.13–6.10 (m, 1H), 3.99 (dd, 1H, J = 10.8, 5.4 Hz), 3.75
(dd, 1H, J = 10.8, 10.3 Hz), 3.62 (dd, 1H, J = 10.3,
5.4 Hz), 3.15 [br s, 1H (OH)], 2.63–2.52 (m, 2H), 2.32–
2.22 (m, 2H), 1.50–1.18 (m, 8H), 0.92 (t, 6H, J = 7.3 Hz);
13C NMR (CDCl3): d 152.4, 141.9, 109.8, 107.8, 59.1,
58.6, 50.3, 30.9, 20.6, 14.1; IR (film): 3486 cmꢀ1; Anal.
Calcd for C14H25NO2: C, 70.25; H, 10.53; N, 5.85. Found:
C, 70.05; H, 10.50; N, 5.86.
2974, 2771, 1731, 1461 cmꢀ1
;
Anal. Calcd for
C13H21NO3: C, 65.25, H, 8.84; N, 5.85. Found: C, 65.40,
H, 8.83; N, 5.87.
4.49. (R)-2-(Dimethylamino)-1-(furan-2-yl)ethanol 59
To a solution of 58 (0.540 g, 2.25 mmol) in MeOH (2 mL) a
15% aqueous NaOH (0.6 mL, 2.25 mmol) was added. After
18 h the reaction was diluted with CH2Cl2 (10 mL) in a sep-
arator funnel. The separated organic phase was dried on
K2CO3 and the solvent distilled. After bulb to bulb distilla-
4.54. (3S,3aR,6S,6aS)-6-Chlorohexahydrofuro[3,2-b]furan-
3-ol 64
tion the amino alcohol 59 (0.321 g, 92%) was obtained as a
21
colorless oil: ½aꢁD ¼ þ44:4 (c 1.05, CHCl3); 1H NMR
(CDCl3): d 7.38 (dd, 1H, J = 1.8, 0.8 Hz), 6.34 (dd,
1H, J = 3.2, 1.8 Hz), 6.31–6.29 (m, 1H), 4.75 (dd, 1H,
J = 10.5, 3.5 Hz), 4.12 [br s, 1H (OH)], 2.85 (dd, 1H,
J = 12.3, 10.5 Hz), 2.48 (dd, 1H, J = 12.3, 3.5 Hz), 2.36
(s, 6H); 13C NMR (CDCl3): d 154.6, 142.1, 110.1, 106.8,
Acetate 50 (8.0 g, 0.0387 mol) was saponified as the corre-
sponding pivalate epimer 35. From flash chromatography
and bulb to bulb distillation, chlorohydrin 64 (6.21 g, 97%)
23
was isolated as a white solid: mp 61–62 °C; ½aꢁD
¼
23
þ43:9 (c 1.0, CHCl3), {lit.27 mp 68–69 °C; ½aꢁD ¼ þ60:0 (c
20
63.5, 63.3, 45.3; IR (film): 3391, 2948, 2827, 1463 cmꢀ1
;
1.0, MeOH); lit.23 mp 64.6–65.5 °C; ½aꢁD ¼ þ52:0 (c 0.5,
1
Anal. Calcd for C8H13NO2: C, 61.91, H, 8.44; N, 9.03.
Found: C, 62.04, H, 8.46; N, 9.05.
CHCl3)}; H, 13C NMR, and IR spectra were identical to
those previously reported.23

2942
C. Paolucci, G. Rosini / Tetrahedron: Asymmetry 18 (2007) 2923–2946
4.55. (S)-1-(Furan-2-yl)ethane-1,2-diol ent-54
4.59. (S)-2-(Dimethylamino)-1-(furan-2-yl)ethanol ent-59
To a solution of t-BuOK (30 mL 1 M in THF, 0.030 mmol)
a dry THF (4 mL) solution of chlorohydrin 64 (1.46 g,
0.010 mol) was added at room temperature under argon.
The reaction was warmed at 50–55 °C for 4 h, then cooled
at room temperature and quenched with water (1.5 mL).
The organic phase was separated and the aqueous one ex-
tracted with CH2Cl2. Combined organic phases were dried
before on K2CO3, then filtered through a Florisil plug
(£ = 3 cm, h = 3 cm) washed with Et2O/THF 4:1
(2 ꢂ 50 mL). The colorless and neutral filtrate was concen-
trated under reduced pressure to give the enol alcohol 65 as
hygroscopic white solid.k To a solution of enol alcohol 65,
in dry THF (30 mL), pyridinium p-toluensulfonate
(0.057 g, 2.5 mol %) was added and warmed at 50–55 °C.
After 60 min the reaction was cooled at room temperature
then NaHCO3 (0.084 g, 1 mmol) added and stirred for
15 min. The solution was concentrated under reduced pres-
sure and the residue purified by flash chromatography.
Pivalate ent-58 (0.450 g, 1.88 mmol) was saponified under
the same conditions as the corresponding enantiomer 58.
Bulb to bulb distillation gave amino alcohol ent-59
21
(0.271 g, 93%) as a colorless oil: ½aꢁD ¼ ꢀ54:3 (c 0.50,
1
CHCl3); H, 13C NMR, and IR spectra were identical to
the corresponding enantiomer 59.
4.60. (S)-4-(Furan-2-yl)-1,3-dioxolan-2-one ent-60
Diol ent-54 (1.58 g, 0.0136 mol) was esterified under the
same conditions as the corresponding enantiomer 54 (the
following the Zhou’s procedure15). The carbonate ent-60
22
(1.58 g, 75%) was obtained as colorless oil: ½aꢁD ¼ þ74:6
20
(c 1.2, EtOH); {lit.15 ½aꢁD ¼ þ63:4 (c 1.1, EtOH)}. 1H
NMR, 13C NMR, and IR spectra were identical to the
corresponding enantiomer 60.
4.61. (R)-2-Azido-2-(furan-2-yl)ethanol ent-61
From bulb to bulb distillation the diol ent-54 (1.035 g,
23
80%) was isolated as a colorless oil: ½aꢁD ¼ ꢀ35:4 (c 1.5,
Carbonate ent-60 (1.58 g, 0.0102 mol) was subjected to
reaction with NaN3 following Zhou’s procedure.15 The
azido alcohol ent-61 (1.36 g, 85%) was obtained as a color-
1
CHCl3); H NMR, 13C NMR, and IR spectra were identi-
cal to the corresponding enantiomer 54.
24
21
less oil. ½aꢁD ¼ þ135:3 (c 1.51, EtOH); {lit.15 ½aꢁD ¼ 95:3
(c 1.3, EtOH)}. H NMR, 13C NMR, and IR spectra were
1
4.56. (S)-2-(Furan-2-yl)-2-hydroxyethyl 4-methylbenzene-
sulfonate ent-56
identical to the corresponding enantiomer 61.
Diol ent-54 (1.05 g, 8.19 mmol) was esterified under the
same conditions of the corresponding enantiomer 54. Puri-
fication by flash chromatography gave ester ent-56 (2.15 g,
93%) as a colorless oil: ½aꢁD ¼ ꢀ24:6 (c 1.35, CHCl3); H
NMR, 13C NMR, and IR spectra were identical to the cor-
responding enantiomer 56.
4.62. (R)-2-Amino-2-(furan-2-yl)ethanol ent-62
21
Azido ent-61 (0.145 g, 0.947 mmol) was hydrogenated
under the same conditions as the corresponding enantio-
1
mer 61. Bulb to bulb distillation gave amino alcohol ent-
26
62 (0.113 g, 93%) as a waxy solid: ½aꢁD ¼ þ15:9 (c 2.41,
20
CHCl3); {lit.31 ½aꢁD ¼ þ7:8 (c 0.8, MeOH), ee ꢃ 96%};
4.57. (S)-1-(Furan-2-yl)-2-(tosyloxy)ethyl pivalate ent-57
1H NMR, 13C NMR, and IR spectra were identical to
the corresponding enantiomer 62.
Alcohol ent-56 (2.08 g, 7.37 mmol) was esterified under
the same conditions of the corresponding enantiomer 56.
4.63. (R)-2-(Dibutylamino)-2-(furan-2-yl)ethanol ent-63
Purification by flash chromatography gave diester ent-57
21
(2.15 g, 93%) as a colorless oil: ½aꢁD ¼ ꢀ59:6 (c 1.1,
1
CHCl3); H NMR, 13C NMR, and IR spectra were identi-
Amine ent-62 (0.168 g, 1.32 mmol) was alkylated under the
same conditions of the corresponding enantiomer 42. After
flash chromatography and bulb to bulb distillation the
alkylated amine ent-63 (0.193 g, 61%) was obtained as a
cal to the corresponding enantiomer 57.
4.58. (S)-2-(Dimethylamino)-1-(furan-2-yl)ethyl pivalate
ent-58
25
colorless oil: ½aꢁD ¼ þ83:9 (c 1.51 CHCl3). H NMR, 13C
NMR, and IR spectra were identical to the corresponding
enantiomer 63.
1
Toluensulfonate ent-57 (1.13 g, 3.08 mmol) was subjected
to reaction with Me2NH under the same conditions of
the corresponding enantiomer 57. After flash chromatogra-
4.64. (R)-2-(Dibutylamino)-2-phenylethanol 67
phy and bulb to bulb distillation, amine ent-58 (0.479 g,
21
(R)-(ꢀ)-2-Amino-2-phenyl-1-ethanol, (R)-66, (0.549 g,
4 mmol) was alkylated under the same condition of the cor-
responding furanyl 42 derived above to give, after flash
chromatography (petroleum ether/Et2O 3:2) and bulb to
65%) was obtained as a colorless oil: ½aꢁD ¼ ꢀ97:7 (c
1
1.10, CHCl3); H NMR, 13C NMR, and IR spectra were
identical to the corresponding enantiomer 58.
bulb distillation, the alkylated amine 67 (0.580 g, 58%) as
k (3S,3aR,6aR)-2,3,3a,6a-Tetrahydrofuro[3,2-b]furan-3-ol 65: (Rf = 0.17
petroleum ether/EtOAc 3:2); 1H NMR (CDCl3): d 6.40 (d, 1H,
J = 2.7 Hz), 5.38 (dd, 1H, J = 6.3, 2.6 Hz), 4.96–4.94 (m, 1H), 4.65 (d,
1H, J = 6.3 Hz), 4.17 (dd, 1H, J = 6.3, 2.7 Hz), 3.74 (d, 1H,
J = 10.3 Hz), 3.39 (dd, 1H, J = 10.3, 2.7 Hz), 2.85 (d, 1H, J = 6.2 Hz);
13C NMR (CDCl3): d 149.6, 99.7, 88.5, 83.7, 75.6, 69.8; IR (film):
24
colorless oil: ½aꢁD ¼ ꢀ64:4 (c 1.30, CHCl3); 1H NMR
(CDCl3): d 7.37–7.27 (m, 3H), 7.21–7.16 (m, 2H), 3.98–
3.87 (m, 2H), 3.66–3.56 (m, 1H), 3.24 [br s, 1H (OH)],
2.65–2.54 (m, 2H), 2.24–2.14 (m, 2H), 1.55–1.20 (m, 8H),
0.92 (t, 6H, J = 7.2 Hz); 13C NMR (CDCl3): d 136.5,
128.9, 128.1, 127.6, 64.6, 60.3, 49.4, 30.7, 20.6, 14.1; IR
3348 cmꢀ1
.

C. Paolucci, G. Rosini / Tetrahedron: Asymmetry 18 (2007) 2923–2946
2943
(film): 3390 cmꢀ1; Anal. Calcd for C16H27NO: C, 77.06; H,
10.91; N, 5.62. Found: C, 76.77; H, 10.93; N, 5.61.
of NH4Cl (5 mL). The mixture was left to warm at room
temperature and stirred until a gray solid material decanted
from the organic solvent. The solid material was removed
by filtration on a Buchner funnel and washed with CH Cl
¨
2
2
4.65. (S)-2-(Dibutylamino)-2-phenylethanol ent-67
(5 ꢂ 20 mL). The combined organic phases were dried over
K2CO3 and the solvent evaporated under reduced pressure.
From bulb to bulb distillation, amino alcohol 72 (1.89 g,
(S)-(ꢀ)-2-Amino-2-phenyl-1-ethanol, (S)-66, (0.548 g,
3.99 mmol) was alkylated under the same conditions of
the corresponding above enantiomer. Alkylated amine
42% overall) was obtained as
a
colorless oil:
24
1
½aꢁD ¼ þ112:3 (c 1.9, CHCl3); H NMR (CDCl3): d 3.52
[br s, 1H (OH)], 3.40–3.29 (m, 1H), 3.26–3.18 (m, 1H),
3.00–2.87 (m, 1H), 2.52–2.40 (m, 2H), 2.35–2.23 (m, 2H),
1.50–1.15 (m, 8H), 0.91 (t, 6H, J = 7.2 Hz), 0.85 (d, 3H,
J = 6.6 Hz); 13C NMR (CDCl3): d 62.6, 56.0, 48.7, 31.1,
20.5, 14.0, 9.0; IR (film): 3436, 2959, 2932, 2862,
1467 cmꢀ1. Anal. Calcd for C11H25NO: C, 70.53; H,
13.45; N, 7.48. Found: C, 70.68; H, 13.48; N, 7.49.
ent-67 (0.423 g, 43%) was isolated as a colorless oil:
22
½aꢁD ¼ 65:3 (c 1.10, CHCl3); 1H NMR, 13C NMR, and
IR spectra were identical to the corresponding enantiomer
67.
4.66. (R)-2-(Dimethylamino)-2-phenylethanol 68
A mixture of 66 (0.535 g, 3.9 mmol), formic acid (0.6 mL,
15.9 mmol), and 40% formaldehyde (0.6 mL, 8 mmol)
was heated at 80 °C for 8 h. Cooled at room temperature
the reaction mixture was basified with 30% aqueous
NH4OH (0.5 mL) and concentrated under reduced pres-
sure. The residue was extracted with CH2Cl2 (3 ꢂ 5 mL)
and the organic phase dried on MgSO4. The crude, after
solvent evaporation, was purified by flash chromato-
graphy (MeOH/CH2Cl2 1:20) and after bulb to bulb
4.69. (1S,2S)- and (1R,2S)-2-(dibutylamino)-1-(furan-2-
yl)propan-1-ol anti-73 and syn-73
To a solution of oxalyl chloride (1.40 g, 11 mmol) in
dichloromethane (25 mL), DMSO (1.87 g, 24 mmol) in
dichloromethane (5 mL) at ꢀ70 °C was added. The mixture
was stirred at ꢀ70 °C for 10 min, then a solution of the
amino alcohol 72 (1.89 g, 10 mmol) in dichloromethane
(5 mL) was added. The mixture was stirred at ꢀ70 °C for
15 min, then triethylamine (6.97 mL, 50 mmol) was added
and the reaction mixture allowed to warm to room temper-
ature. After 15 min at room temperature the reaction was
quenched with water (15 mL) addition. The organic layer
was separated and the aqueous one washed with dichloro-
methane (2 ꢂ 20 mL). The combined organic phases were
washed with water (2 ꢂ 8 mL), brine (8 mL), dried over
MgSO4, filtered, and concentrated under reduced pressure.
The crude aldehyde (1.9 g) was used in the next step with-
out purification. To furan (2.72 g, 40 mmol) in dry THF
(50 mL), BuLi (19 mL, 1.6 M in hexane, 30 mmol) was
added at ꢀ40 °C.18 The reaction mixture was warmed at
room temperature for 3 h, then cooled at ꢀ78 °C and a
solution of the above aldehyde in dry THF (3 mL), added.
After 3 h, the reaction was quenched, at ꢀ78 °C, with sat-
urated aqueous solution of NH4Cl (10 mL). The organic
layer was separated and the aqueous one washed with ether
(2 ꢂ 25 mL). The combined organic phases were dried over
MgSO4 and the solvents distilled under reduced pressure.
The crude was purified by flash chromatography (petro-
leum ether/EtOAc 4:1) to give syn-73 and anti-73 (1.88 g,
74%).
distillation gave 68 (0.548 g, 85%) as solid: mp 102–
24
103 °C; ½aꢁD ¼ ꢀ25:6 (c 1.20, CHCl3); {lit.32 mp
25
1
104–105 °C; ½aꢁD ¼ ꢀ30:8 (c 0.85, H2O)}; H NMR and
IR spectra coincided with those previously reported for
the racemic mixture;33 13C NMR (CDCl3): d 135.8, 128.9,
128.1, 127.8, 70.2, 61.4, 41.4.
4.67. (S)-2-(Dibutylamino)-1-phenylethanol 70
(S)-2-Phenyloxirane 69 (0.240 g, 2 mmol) was subjected to
reaction with lithium dibutylamide as described in the liter-
ature.16 The amino alcohol 70 (0.320 g, 64%) was isolated
22
1
as a colorless oil: ½aꢁD ¼ þ103:9 (c 1.05, CHCl3); H and
13C NMR spectra coincided with those previously reported
for the racemic mixture.16
4.68. (S)-2-(Dibutylamino)propan-1-ol 72
A mixture of L-alanine methyl ester hydrochloride 71
(3.3 g, 0.0238 mol), NaHCO3 (12 g, 0.142 mol), and n-BuI
(8.76 g, 0.0476 mol) in THF/DMSO 4:1 (64 mL) was
heated at reflux for 36 h. After cooling, the solid materials
were removed by filtration and the resulting filtrate concen-
trated under reduced pressure. The residue, diluted with
EtOAc (50 mL), was washed with water (5 mL) and dried
over MgSO4. After solvent evaporation, the crude product
was purified by flash chromatography (petroleum ether/
Et2O 9:1) to give N,N-dialkylated amines as a viscous oil
(2.4 g). To a suspension of LiAlH4 (0.415 g, 0.011 mol)
in dry THF (26 mL), the above N,N-dialkylated product,
in dry THF (60 mL), was added dropwise over 45 min at
20 °C. After 30 min at room temperature and 1 h at reflux,
the reaction mixture was cooled at ꢀ10 °C, then the excess
of the hydride quenched with a saturated aqueous solution
4.69.1. (1R,2S)-2-(Dibutylamino)-1-(furan-2-yl)propan-1-ol
syn-73. syn-73 (76 mg, 3%) as a colorless oil: (Rf = 0.33,
21
petroleum ether/EtOAc 9:1); ½aꢁD ¼ þ15:0 (c 0.4,
CHCl3); 1H NMR (CDCl3): d 7.38 (dd, 1H, J = 1.6,
0.8 Hz), 6.34–6.30 (m, 2H), 4.26 (d, 1H, J = 10.0 Hz),
3.06 (dq, 1H, J = 10.0, 6.7 Hz), 2.59–2.47 (m, 2H), 2.40–
2.29 (m, 2H), 1.60–1.20 (m, 9H), 0.94 (t, 6H, J = 7.4 Hz),
0.79 (d, 3H, J = 6.7 Hz); 13C NMR (CDCl3): d 154.5,
142.2, 110.1, 108.2, 67.9, 59.6, 49.4, 31.1, 20.6, 14.1, 8.7;
IR (film): 3370, 2959, 2929, 2873, 1466 cmꢀ1; Anal. Calcd
for C15H27NO2: C, 71.10; H, 10.74; N, 5.53. Found: C,
70.89; H, 10.71; N, 5.51.
As mixture of (S)-methyl and (S)-butyl 2-(dibutylamino)propanoate in a
4:1 ratio.

2944
C. Paolucci, G. Rosini / Tetrahedron: Asymmetry 18 (2007) 2923–2946
4.69.2. (1S,2S)-2-(Dibutylamino)-1-(furan-2-yl)propan-1-ol
anti-73. anti-73 (1.88 g, 74%) as colorless oil:
1.0, CHCl3); 1H NMR (CDCl3): d 7.39–7.37 (m, 1H),
6.33–6.30 (m, 2H), 5.34 [br s, 1H (OH)], 4.43 (d, 1H,
J = 9.8 Hz), 2.94 (dd, 1H, J = 4.8, 9.8 Hz), 2.73–2.62 (m,
2H), 2.60–2.50 (m, 2H), 1.92 (dhept, 1H, J = 6.9, 4.8 Hz),
1.62–1.23 (m, 8H), 0.94 (t, 6H, J = 7.2 Hz), 0.78 (d, 3H,
J = 6.9 Hz), 0.74 (d, 3H, J = 6.9 Hz); 13C NMR (CDCl3):
d 155.3, 141.6, 110.3, 108.5, 68.7, 64.0, 51.0, 31.9, 27.3,
23.0, 20.6, 19.4, 14.1; IR (film): 3340, 2958, 2931, 2873,
1468 cmꢀ1; Anal. Calcd for C17H31NO2: C, 72.55; H,
11.10; N, 4.98. Found: C, 72.38; H, 11.08; N, 4.98.
a
22
(Rf = 0.2, petroleum ether/EtOAc 9:1); ½aꢁD ¼ þ31:9 (c
1
1.22, CHCl3); H NMR (CDCl3): d 7.33 (dd, 1H, J = 1.7,
0.8 Hz), 6.31 (dd, 1H, J = 3.2, 1.7 Hz), 6.24–6.21 (m,
1H), 4.53 (d, 1H, J = 5.6 Hz), 4.32 [br s, 1H (OH)], 3.14–
3.04 (m, 1H), 2.34–2.19 (m, 4H), 1.50–1.12 (m, 8H), 1.03
(d, 3H, J = 7.0 Hz), 0.88 (t, 6H, J = 7.3 Hz); 13C NMR
(CDCl3): d 156.4, 141.2, 110.1, 106.3, 68.6, 59.5, 50.8,
31.0, 20.5, 14.1, 9.9; IR (film): 3345, 2958, 2932, 2974,
1466 cmꢀ1; Anal. Calcd for C15H27NO2: C, 71.10; H,
10.74; N, 5.53. Found: C, 70.94; H, 10.76; N, 5.53.
4.72. (S)-2-(Dibutylamino)-3,3-dimethylbutan-1-ol 78
Amino alcohol 7734 (1.12 g, 9.56 mmol) was alkylated un-
der the same conditions as described above for 74. From
flash chromatography (Rf = 0.2, in Et2O/petroleum ether
1:10) and distillation at 125 °C/3 mm the amino alcohol
4.70. (S)-2-(Dibutylamino)-3-methylbutan-1-ol 75
A mixture of amine alcohol 7434 (0.945 g, 9.13 mmol), n-
BuI (5.04 g, 27.4 mmol), K2CO3 (3.78 g, 27.4 mmol) in
MeCN (9.2 mL) was refluxed for 26 h. The reaction mix-
ture was cooled, diluted with CH2Cl2 (92 mL) and filtered.
The residue after solvent evaporation was dissolved in
Et2O (100 mL), washed with water (2 ꢂ 5 mL) brine, and
dried on K2CO3 dry. The solvent was evaporated, the res-
idue supported on silica gel and flash chromatographed
(Rf = 0.45, EtOAc/petroleum ether 1:5) to give, after distil-
lation at 110 °C/1 mm, amine 75 (1.72 g, 87%) as colorless
78 (1.74 g, 79%) was obtained as
a colorless oil:
23
1
½aꢁD ¼ þ35:2 (c 1.5, CHCl3); H NMR (CDCl3): d 3.56
(dd, 1H, J = 10.4, 4.6 Hz), 3.49–3.39 (m, 1H), 3.13 [br s,
1H (OH)], 2.83–2.63 (m, 4H), 2.57 (dd, 1H, J = 10.5,
4.6 Hz), 1.56–1.17 (m, 8H), 0.97 (s, 9H) 0.91 (t, 6H,
J = 7.1Hz); 13C NMR (CDCl3): d 70.9, 58.2, 52.2, 36.5,
33.3, 29.2, 20.5, 14.1; IR (film): 3401, 2957, 2872,
1467 cmꢀ1; Anal. Calcd for C14H31NO: C, 73.30; H,
13.62; N, 6.11. Found: C, 73.52; H, 13.59; N, 6.09.
23
1
oil: ½aꢁD ¼ 31:3 (c 1.1, CHCl3); H NMR (CDCl3): d 3.78
(br s, 1H), 3.55 (dd, 1H, J = 10.2, 5.2 Hz), 3.09 (t, 1H,
J = 10.2 Hz), 2.69–2.50 (m, 4H), 2.42 (ddd, 1H, J = 10.5,
9.1, 5.1 Hz), 1.82 (dhept, 1H, J = 9.1, 6.7 Hz), 1.56–1.20
(m, 8H), 1.00 (d, 3H, J = 6.7 Hz), 0.91 (t, 6H,
J = 7.1Hz), 0.83 (d, 3H, J = 6.7 Hz); 13C NMR (CDCl3):
d 68.6, 59.8, 51.4, 32.8, 28.6, 22.4, 20.5, 20.0, 14.0; IR
(film): 3436, 2957, 2931, 2873, 1467 cmꢀ1; Anal. Calcd
for C13H29NO: C, 70.50; H, 13.57; N, 6.50. Found: C,
70.71; H, 13.55; N, 6.51.
4.73. (1S,2S)- and (1R,2S)-2-(dibutylamino)-1-(furan-2-yl)-
3,3-dimethylbutan-1-ol anti-79 and syn-79
The amino alcohol 78 (1.50 g, 6.54 mmol) was first oxidized
and then added to a 1-lithiofuran solution under the same
conditions as described above for 72. From flash chro-
matography anti-79 ( Rf = 0.26, Et2O/petroleum ether
1:20) and syn-79 (Rf = 0.3, Et2O/petroleum ether 1:5) were
isolated as colorless oil.
4.71. (1S,2S)- and (1R,2S)-2-(dibutylamino)-1-(furan-2-yl)-
3-methylbutan-1-ol anti-76 and syn-76
4.73.1. (1S,2S)-2-(Dibutylamino)-1-(furan-2-yl)-3,3-dimeth-
23
ylbutan-1-ol anti-79. anti-79 (1.25 g, 64.7%): ½aꢁD ¼ ꢀ1:2
The amino alcohol 75 (1.59 g, 5.65 mmol) was first oxidized
and then added to a 1-lithiofuran solution under the same
conditions as described above for 72. From flash chro-
matography and bulb to bulb distillation, anti-76 (Rf =
0.2, Et2O/petroleum ether 1:20) and syn-76 (Rf = 0.3,
Et2O/petroleum ether 1:5) were isolated as colorless oils.
(c 2.9, CHCl3); 1H NMR (CDCl3): d 7.32 (dd, 1H,
J = 1.8, 0.9 Hz), 6.31 (dd, 1H, J = 3.2, 1.8 Hz), 6.21–6.19
(m, 1H), 4.82 (d, 1H, J = 5.9 Hz), 4.08 [br s, 1H (OH)],
2.82 (d, 1H, J = 5.9 Hz), 2.69–2.60 (m, 4H), 1.56–1.33
(m, 4H), 1.33–1.19 (m, 4H), 0.96 (s, 9H), 0.91 (t, 6H,
J = 7.1 Hz); 13C NMR (CDCl3): d 157.0, 140.6, 110.4,
106.8, 72.9, 65.9, 54.0 (br), 37.2, 33.0, 29.6, 20.5, 14.1; IR
(film): 3422, 2957, 2872, 1467 cmꢀ1; Anal. Calcd for
C18H33NO2: C, 73.17; H, 11.26; N, 4.74. Found: C,
72.99; H, 11.28; N, 4.75.
4.71.1. (1S,2S)-2-(Dibutylamino)-1-(furan-2-yl)-3-methyl-
21
butan-1-ol anti-76. anti-76 (0.975 g, 61%): ½aꢁD ¼ ꢀ25:1
(c 1.6, CHCl3); 1H NMR (CDCl3): d 7.32 (dd, 1H,
J = 1.8, 0.9 Hz), 6.30 (dd, 1H, J = 3.2, 1.8 Hz), 6.26–6.24
(m, 1H), 4.75 (br s, 1H), 4.71 (d, 1H, J = 5.0 Hz), 2.60–
2.45 (m, 3H), 2.33–2.21 (m, 2H), 2.05 (dhept, 1H,
J = 10.9, 6.5 Hz), 1.59–1.40 (m, 2H), 1.40–1.25 (m, 2H),
1.24–1.11 (m, 4H), 1.09 (d, 3H, J = 6.5 Hz), 1.01 (d, 3H,
J = 6.5 Hz), 0.87 (t, 6H, J = 7.1 Hz); 13C NMR (CDCl3):
d 156.6, 141.0, 110.0, 106.4, 73.1, 65.4, 53.6, 33.1, 28.2,
22.3, 21.0, 20.3, 14.0; IR (film): 3414, 2958, 2930, 2872,
1469 cmꢀ1; Anal. Calcd for C17H31NO2: C, 72.55; H,
11.10; N, 4.98. Found: C, 72.40; H, 11.07; N, 4.99.
4.73.2. (1R,2S)-2-(Dibutylamino)-1-(furan-2-yl)-3,3-dimeth-
24
ylbutan-1-ol syn-79. syn-76 (0.075 g, 5%): ½aꢁD ¼ þ40:6 (c
2.9, CHCl3); 1H NMR (CDCl3): d 7.38–7.37 (m, 1H), 6.33–
6.29 (m, 2H), 5.34 [br s, 1H (OH)], 4.52 (d, 1H, J = 9.7 Hz),
2.97 (d, 1H, J = 9.7 Hz), 2.89–2.71 (m, 4H), 1.68–1.50 (m,
2H), 1.50–1.38 (m, 2H), 1.38–1.24 (m, 4H), 0.94 (t, 6H,
J = 7.1 Hz), 0.81 (s, 9H); 13C NMR (CDCl3): d 155.0,
141.5, 110.3, 108.7, 72.8, 63.5, 52.4 (br), 36.8, 33.4, 29.3,
20.5, 14.0; IR (film): 3400, 2957, 2931, 2872, 1468 cmꢀ1
;
4.71.2. (1R,2S)-2-(Dibutylamino)-1-(furan-2-yl)-3-methyl-
butan-1-ol syn-76. syn-76 (0.075 g, 5%): ½aꢁD ¼ þ47:3 (c
Anal. Calcd for C18H33NO2: C, 73.17; H, 11.26; N, 4.74.
Found: C, 72.95; H, 11.29; N, 4.71.
21

C. Paolucci, G. Rosini / Tetrahedron: Asymmetry 18 (2007) 2923–2946
2945
Perkin Trans. 1 1998, 2547; (f) Yang, X.; Shen, J.; Da, C.;
Wang, R.; Choi, M. C. K.; Yang, L.; Wong, K. Tetrahedron:
Asymmetry 1999, 10, 133; (g) Wassmann, S.; Wilken, J.;
Martens, J. Tetrahedron: Asymmetry 1999, 10, 4437; (h) Sibi,
M. P.; Chen, J.-X.; Cook, G. R. Tetrahedron Lett. 1999, 40,
3301; (i) Lawrence, C. F.; Nayak, S. K.; Thijs, L.;
Zwanenburg, B. Synlett 1999, 1571; (j) Kossenjans, M.;
Soeberdt, M.; Wallbaum, S.; Harms, K.; Martens, J.; Aurich,
H. G. J. Chem. Soc., Perkin Trans. 1 1999, 2353; (k) Nugent,
W. A. Chem. Commun. 1999, 1369; (l) Paleo, M. R.; Cabeza,
I.; Sardina, F. J. J. Org. Chem. 2000, 65, 2108; (m) Reddy, K.
4.74. (1R,2R)- and (1S,2R)-2-(dibutylamino)-1-(furan-2-yl)-
2-phenylethanol anti-80 and syn-80
Amino alcohol 67 (1.43 g, 5.73 mmol) was first oxidized
and then added to a 1-lithiofuran solution under the same
conditions as described above for 72. From flash chro-
matography syn-80 (Rf = 0.4, Et2O/petroleum ether 1:20)
and anti-80 (Rf = 0.2, Et2O/petroleum ether 1:20) were
isolated.
`
`
S.; Sola, L.; Moyano, A.; Pericas, M. A.; Riera, A. Synthesis
2000, 1, 165; (n) Kawanami, Y.; Mitsuie, T.; Miki, M.;
Sakamoto, T.; Nishitani, K. Tetrahedron 2000, 56, 175; (n)
Dai, W.-M.; Zhu, H.-J.; Hao, X.-J. Tetrahedron: Asymmetry
2000, 11, 2315; (o) Harmata, M.; Kahraman, M. Tetra-
hedron: Asymmetry 2000, 11, 2875; (p) Ooi, T.; Saito, A.;
Maruoka, K. Chem. Lett. 2001, 1108; (q) Hu, Q.-S.; Sun, C.;
Monaghan, C. E. Tetrahedron Lett. 2001, 42, 7725; (r) Ohga,
T.; Umeda, S.; Kawanami, Y. Tetrahedron 2001, 57, 4825; (s)
Steiner, D.; Sethofer, S. G.; Goralsky, C. T.; Singaram, B.
Tetrahedron: Asymmetry 2002, 13, 1477; (t) Xu, Q.; Zhu, G.;
Pan, X.; Chan, A. S. C. Chirality 2002, 14, 716; (u) Sato, I.;
Kodaka, R.; Hosoi, K.; Soai, K. Tetrahedron: Asymmetry
2002, 13, 805; (v) Soperchi, S.; Giorgio, E.; Scafato, P.;
Rosini, C. Tetrahedron: Asymmetry 2002, 13, 1385; (w) Boyle,
G. A.; Govender, T.; Kruger, H. G.; Maguire, G. E. M.
Tetrahedron: Asymmetry 2004, 15, 2661; (y) Periasamy, M.;
Seenivasaperumal, M.; Rao, V. D. Tetrahedron: Asymmetry
2004, 15, 3847; (z) Sibi, M. P.; Stanley, L. M. Tetrahedron:
Asymmetry 2004, 15, 3353.
4.74.1. (1S,2R)-2-(Dibutylamino)-1-(furan-2-yl)-2-phenyl-
ethanol syn-80. syn-80 (0.068 g, 3.8%), white semisolid
24
1
material; ½aꢁD ¼ ꢀ13:0 (c 1.0, CHCl3); H NMR (CDCl3):
d 7.29–7.18 (m, 4H), 7.17–7.11 (m, 2H), 6.12 (dd, 1H,
J = 3.2, 1.8 Hz), 6.09–6.07 (m, 1H), 5.06 (d, 1H, J =
10.6 Hz), 5.02 [br s, 1H (OH)], 4.13 (d, 1H, J = 10.6 Hz),
2.69–2.60 (m, 2H), 2.21–2.11 (m, 2H), 1.61–1.22 (m, 8H),
0.95 (t, 6H, J = 7.3 Hz); 13C NMR (CDCl3): d 153.6,
142.0, 134.5, 129.4, 127.9, 127.6, 109.9, 108.5, 67.5, 64.5,
49.6, 30.7, 20.6, 14.1; IR (film): 3350, 2957, 2931, 2872,
1454 cmꢀ1; Anal. Calcd for C20H29NO2: C, 76.15; H,
9.27; N, 4.44. Found: C, 76.34; H, 9.25; N, 4.45.
4.74.2. (1R,2R)-2-(Dibutylamino)-1-(furan-2-yl)-2-phenyl-
ethanol anti-80. anti-80 (1.03 g, 56.9%), red light oil;
24
1
½aꢁD ¼ þ3:3 (c 1.4, CHCl3); H NMR (CDCl3): d 7.33–
719 (m, 6H), 6.23 (dd, 1H, J = 3.2, 1.8 Hz), 6.05–6.02 (m,
1H), 5.21 (d, 1H, J = 7.1 Hz), 4.07 (d, 1H, J = 7.1 Hz),
2.76 [br s, 1H (OH)], 2.57–2.46 (m, 2H), 2.36–2.25 (m,
2H), 1.44–1.28 (m, 4H), 1.27–1.06 (m, 4H), 0.85 (t, 6H,
J = 7.2 Hz); 13C NMR (CDCl3): d 154.8, 141.1, 136.8,
129.4, 127.9, 127.4, 110.1, 107.2, 68.9, 67.7, 50.1, 29.5,
4. For some recent papers, see: (a) Da, C.-s.; Ni, M.; Han, Z.-j.;
Yang, F.; Wang, R. J. Mol. Catal. A: Chem. 2006, 245, 1; (b)
Rocha Gonsalves, A. M. d’A.; Serra, M. E. S.; Murtinho, D.
J. Mol. Catal. A: Chem. 2006, 250, 104; (c) Unaleroglu, C.;
Ebru Aydin, A.; Demir, A. S. Tetrahedron: Asymmetry 2006,
20.4, 14.1; IR (film): 3422, 2954, 2921, 2862, 1457 cmꢀ1
;
`
17, 742; (d) Dave, R.; Andre Sasaki, N. Tetrahedron:
Anal. Calcd for C20H29NO2: C, 76.15; H, 9.27; N, 4.44.
Found: C, 76.30; H, 9.24; N, 4.45.
Asymmetry 2006, 17, 388; (e) Huang, J.; Ianni, J. C.;
Antoline, J. E.; Hsung, R. P.; Kozlowski, M. C. Org. Lett.
2006, 8, 1565.
5. (a) Kitamura, M.; Suga, S.; Kawai, K.; Noyori, R. J. Am.
Chem. Soc. 1986, 108, 6071; (b) Kitamura, M.; Okada, S.;
Suga, S.; Noyori, R. J. Am. Chem. Soc. 1989, 111, 4028; (c)
Noyori, R.; Suga, S.; Kawai, K.; Okada, S.; Kitamura, M.;
Oguni, N.; Hayashi, M.; Kaneko, T.; Matsuda, Y. J.
Organomet. Chem. 1990, 382, 19; (d) Kitamura, M.; Suga,
S.; Niwa, M.; Noyori, R.; Zhai, Z.-X.; Suga, S. J. Phys.
Chem. 1994, 98, 12776; (e) Kitamura, M.; Suga, S.; Niwa, M.;
Noyori, R. J. Am. Chem. Soc. 1995, 117, 4832; (f) Yama-
kawa, M.; Noyori, R. J. Am. Chem. Soc. 1995, 117, 6327; (g)
Kitamura, M.; Suga, S.; Oka, H.; Noyori, R. J. Am. Chem.
Soc. 1998, 120, 9800; (h) Kitamura, M.; Oka, H.; Noyori, R.
Tetrahedron 1999, 55, 3605; (i) Yamakawa, M.; Noyori, R.
Organometallics 1999, 18, 128; (j) Hodge, P.; Sung, D. W. L.;
Stratford, P. W. J. Chem. Soc., Perkin Trans. 1 1999, 2335.
6. Kitamura, M.; Yamakawa, M.; Oka, H.; Suga, S.; Noyori, R.
Chem. Eur. J. 1996, 2, 1173.
Acknowledgment
This research has been supported in part by Alma Mater
`
Studiorum, Universita di Bologna and MUR, Italy (PRIN
2005-Metodologie innovative per la sintesi di reagenti e di
prodotti enantiomericamente arricchiti).
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¨
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