Synthesis of a new 1,4-aminoalcohol and its use as catalyst in the enantioselective addition of organozinc to aldehydes

Article abstract of DOI:10.1016/j.tetasy.2006.04.010

The synthesis of a new enantiopure, conformationally constrained 1,4-aminoalcohol is reported, starting from commercially available reagents from the chiral pool. This 1,4-aminoalcohol was used as chiral ligand in the addition of Et₂Zn to aldehydes (best ee 98%) and in the synthesis of chiral propargylic alcohols (best ee 70%) by alkynylzinc species.

Full text of DOI:10.1016/j.tetasy.2006.04.010

Tetrahedron: Asymmetry 17 (2006) 1409–1414
Synthesis of a new 1,4-aminoalcohol and its use as catalyst
in the enantioselective addition of organozinc to aldehydes
Dina Scarpi,a,* Fabrizio Lo Galboa,ꢀ and Antonio Guarnaa,b
aDipartimento di Chimica Organica ‘U. Schiff ’, Synthesis and Study of Biologically Active Heterocycles (HeteroBioLab),
`
Universita degli Studi di Firenze, Via della Lastruccia 13, I-50019 Sesto Fiorentino, Italy
b
`
Laboratory of Design, Synthesis and Study of Biologically Active Heterocycles (HeteroBioLab), Universita degli Studi di Firenze,
Via della Lastruccia 13, I-50019 Sesto Fiorentino, Italy
Received 5 April 2006; accepted 19 April 2006
Available online 24 May 2006
Abstract—The synthesis of a new enantiopure, conformationally constrained 1,4-aminoalcohol is reported, starting from commercially
available reagents from the chiral pool. This 1,4-aminoalcohol was used as chiral ligand in the addition of Et2Zn to aldehydes (best ee
98%) and in the synthesis of chiral propargylic alcohols (best ee 70%) by alkynylzinc species.
ꢀ 2006 Elsevier Ltd. All rights reserved.
O
1. Introduction
O
N
O
R
N
O
The use of chiral ligands in asymmetric synthesis is a very
well-known tool in organic chemistry and there are many
examples of efficient catalysts, many of them commercially
available. In organozinc chemistry the chiral ligands mostly
belong to the class of 1,2-aminoalcohols,1 whereas 1,4-
aminoalcohols2 are rarely used maybe because of their
multi-step synthesis and, in order to guarantee good
enantioselectivities, because they require complicated rigid
structures that are less appealing than most simple and
commercially available 1,2-aminoalcohols. Therefore, an
efficient and easy-to-make chiral ligand, belonging to this
neglected class, seemed a challenging goal.
HO
HO
1
R = Et (A), i-Pr (B)
cHex (C), Bn (D) (ref. 3)
Chart 1. Structure of 1,4-aminoalcohols A–D and target N-methyl 1.
state model elaborated on the basis of the one proposed by
Noyori and Yamakawa.4 We therefore proposed that most
probably the N-methyl aminoalcohol 1 would have worked
better than all the other structures and decided to synthe-
sise it.
However, the synthetic strategy applied previously had the
inconvenience of the Fmoc protection–deprotection steps
that lower the yield and that did not follow the ‘atom-
economy’ principle. We elaborated a new synthesis that
affords the chiral ligand in only four steps, starting from
commercially available compounds from the chiral pool.
The synthesis can be easily extended to a multi-gram scale.
2. Results and discussion
We recently3 reported the synthesis of a few 1,4-aminoalco-
hols (Chart 1) and their application as chiral ligands in the
asymmetric addition of diethylzinc on aldehydes. In this
study, we verified that the less the N-substituent is hin-
dered, is the higher the enantioselectivity of the reaction.
This observation confirmed the hypothesis of the transition
The synthesis starts with the formation of an aluminium
amide5 by mixing (methylamino)acetaldehyde dimethyl
acetal 3 and AlMe3 (Scheme 1). This species reacts with
(ꢀ)-2,3-O-isopropylidene-D-erythronolactone
2 to give
*
Corresponding author. Tel.: +39 055 4573502; fax: +39 055 4573531;
e-mail: dina.scarpi@unifi.it
alcohol 4, formed in 93% yield that required no purification
for the next protection step. The corresponding acetate 5
(90% yield, prepared with Ac2O in dry pyridine) was heated
ꢀ Present address: ARPAT, Dipartimento Provinciale di Siena, Loc.
Ruffolo, 53100 Siena, Italy.
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.04.010

1410
D. Scarpi et al. / Tetrahedron: Asymmetry 17 (2006) 1409–1414
Table 1. Distribution of products obtained by diethylzinc addition on
aromatic and aliphatic aldehydes
O
O
O
Me OMe
N
Me OMe
N
O
a
9a
10a
eeb (%)
Configuration
of 9c
+
OMe
Entry
R1
H
OMe
(93%)
O
O
O
HO
3
4
2
1
2
3
4
5
6
7
8
9
10
11
12
13
14
C6H5
98
87
96
97
93
97
96
96
78d
99
94
94
97
42f
2
5
2
2
5
3
2
3
0
—
4
4
—
—
97
92
96
96
96
96
97
98
80
95
92e
88e
86
36e
S
S
S
S
S
S
S
S
S
S
S
S
S
S
(90%)
b
2-Cl–C6H4
3-Cl–C6H4
4-Cl–C6H4
2-Me–C6H4
3-Me–C6H4
4-Me–C6H4
3-MeO–C6H4
4-MeO–C6H4
4-MeS–C6H4
4-Biphenyl
2-Naphthyl
2-Thienyl
O
O
Me OMe
N
O
O
O
N
O
c
O
Me
N
O
OAc
Me
OAc
6 (48%)
OMe
O
AcO
5
7 (9%)
+
d (32%)
or
e (46%)
O
O
Me
N
CH3(CH2)5
1
HO
a Determined by GC.
b Determined by GC using b DEXTM 120 column.
Scheme 1. Reagents and conditions: (a) AlMe3 2.0 M in hexane
(1.1 equiv), DCM, 0 ꢁC ! rt, 18 h; (b) Ac2O, py, 0 ꢁC ! rt, 20 h; (c)
SiO2ÆH2SO4, toluene, reflux, 100; (d) BH3ÆSMe2, THF, reflux, 2 h, then
H2O (5 equiv), Amberlite IRA-743, rt, 12 h; (e) LiAlH4, THF, 55 ꢁC, 18 h,
then KOH 0.4 M, H2O, reflux, 300.
c Determined by the sign of the specific rotation.
d 1-Methoxy-4-propenylbenzene is formed during the reaction (22%).
e Determined by analysis of the corresponding Mosher ester 1H NMR
(400 MHz) spectrum.
f Isolated yield.
in refluxing toluene under acid catalysis of H2SO4 absorbed
on silica gel. Under these conditions, the C-7 stereocentre
of compound 6 partially racemised and the crude mixture
contained 6 and 7 in a 4:1 ratio. The two diastereoisomers
were easily separated by chromatography, and compound
6 was obtained in 48% yield after purification. The one
pot reduction and deprotection step was performed under
two different conditions in order to explore more methods
and increase the yield. Treatment of compound 6 with
BH3ÆSMe2 in dry THF under reflux was followed by the
quench with water and Amberlite IRA-7436 as boron scav-
enger.7 Product 1 was obtained in 32% yield after purifica-
tion. Alternatively, the same step was performed by
employing LiAlH4 in dry THF and heating the suspension
at 55 ꢁC for 18 h. After quenching the reaction by the addi-
tion of KOH 0.4 M and water, product 1 was recovered in
46% yield after purification. The overall yield of the synthe-
sis was 13–18% over four steps.
whereas with N-ethyl A at 20 mol % the ee was 90–95%.
In most cases a small amount of alcohol 10 also formed.
The substituent on the aromatic ring did not generally
influence the stereochemical outcome of the reaction, as
the chiral alcohols were obtained in 96–98% ee with the
exceptions represented by the cases of the 2-chlorobenz-
aldehyde (entry 2, ee 92%)—probably due to the steric
hindrance of the ortho position—and the 4-methoxybenzal-
dehyde (entry 9, ee 80%)—mainly because of the increased
competition of the noncatalysed reaction,9 that is probably
due to electronic effects of the substituent. In fact, the sub-
stitution of the methoxy group with a thiomethyl (entry 10)
improved the enantioselectivity to the average values (ee
95%); the same effect was obtained by the methoxy group
in the meta position (entry 8, ee 98%).
The ligand was also tested on a few more aromatic (entries
11 and 12) and heteroaromatic substrates (entry 13). In all
three cases, the enantioselectivity slightly decreased (ee
92%, 88%, 86%, entries 11, 12 and 13, respectively), but
not significantly.
Aminoalcohol 1 was then used as chiral ligand in the addi-
tion of Et2Zn to aldehydes. We applied the reaction condi-
tions that worked best with the N-ethyl ligand A3 (Chart 1)
but decreased the amount of ligand8 from 20 to 15 mol %
(Scheme 2). The results are reported in Table 1.
Unfortunately, performing the Et2Zn addition on an ali-
phatic aldehyde resulted in a poor enantioselectivity (entry
7, ee 36%). However, this result is consistent with some
analogous experiments reported in the literature for non-
aromatic aldehydes.10
OH
Et
9
O
1 (15% mol)
+
Et2Zn
+
R1
R1
OH
10
R1
H
toluene, r.t., 24 h
8
Scheme 2. Catalysed addition of Et2Zn to aldehydes.
Encouraged by these results, we decided to explore an
interesting reaction that has been very widely studied over
the last few years: the synthesis of chiral propargylic alco-
hols by addition of alkynylzinc species to aromatic and ali-
phatic aldehydes (Scheme 3).11
As hoped on the basis of our initial reasoning, the enantio-
selectivity increased with respect to the already reported
ligands belonging to the same class of compounds. Accord-
ing to the transition state model proposed in our previous
work,3 the Si face of the carbonyl group was always
attacked and therefore the (S)-alcohol was formed. The
ee range generally was 92–98% employing 1 at 15 mol %,
The organometallic reagent is usually prepared in situ by
mixing Et2Zn and the desired alkyne (in our case, phenyl-

D. Scarpi et al. / Tetrahedron: Asymmetry 17 (2006) 1409–1414
1411
O
OH
OH
H
H
OH
Et2Zn, L* (15% mol)
THF/hexane 2:1, 0 °C
R1
H
R1
Ph R1
Ph
13
+
Ph
H
R1
H
Ph
8
11
12
Scheme 3. Catalysed addition of alkynylzinc to aldehydes.
Chart 2. By-products of the synthesis of propargylic alcohols.
acetylene), in a stoichiometric ratio, in order to obtain the
corresponding ethyl-alkynylzinc reactant. Therefore, the
main problem can be the side reaction of the Et2Zn addi-
tion to the aldehydes to give alcohol 9 (and by-product
10) instead of propargylic alcohol 11. For this reason, the
use of a co-ordinating solvent11b–d or an additive11e
in the reaction mixture is advised, or even the change
of strategy by employing Zn(OTf)2 and a base (Et3N or
DIPEA).12 We decided to use the solvent mixture THF/
hexane ꢁ2:1 and study the reaction first on benzaldehyde.
The experiments are summarised in Table 2.
to manage experiment carried out over 6 h (entry 5).
We therefore applied these conditions (entry 5) to a few
more aldehydes and the results are reported in Table 3.
As already seen for the addition of Et2Zn to the aldehydes,
there is no significant influence of the substituents on the
aromatic ring on the enantioselectivity of the reaction
(entries 1–5): the ee range narrowed to 68–70% and
dropped, as expected, to 40–47% in the case of aliphatic
substrates (entries 8 and 9). The exceptions to this apparent
rule are represented by 4-methoxybenzaldehyde (entry 6)
that was recovered almost unreacted, and 4-nitrobenzalde-
hyde (entry 7) that reacted slower than all other substrates
and afforded the poorest ee (7%). As for the absolute con-
figuration of alcohol 11, this can easily be explained by the
same transition state model used in the former application:
also in this case, the Si face of the carbonyl group is
attacked and therefore the (R)-alcohol is formed.
Racemic propargylic alcohol 11 (28%) was formed through
the competitive noncatalysed reaction13 (entry 1), together
with alcohols 9 and 10 that derive from the Et2Zn addition
reaction, and alcohol 12 (Chart 2) that derives from a
carbozincation side reaction. The reaction catalysed by
N-methyl 1 (entry 2) afforded an increased amount of alco-
hol 11, but all by-products still formed. When the less effi-
cient ligand B was used (entry 3), alcohol 13 also formed.
Interestingly, in analogy with Et2Zn addition, the enantio-
selectivity of the reaction drastically decreased by increas-
ing the hindrance of the N-substituent of the ligand (ee
52%, entry 2, vs ee 8%, entry 3).
Table 3. Distribution of products obtained by phenylacetylene Et2Zn-
catalysed addition on aromatic and aliphatic aldehydes
Entry R1
9a
10a 11a eeb (%) Configuration
of 11b
In order to limit the amount and number of by-products,
the reaction was stopped after 6 h: by that time, the com-
petitive noncatalysed reaction could be neglected (only
4% conversion, entry 4) and no carbozincation occurred.
In the presence of chiral ligand 1, alcohol 11 was obtained
with higher ee (68%, entry 5) and the percentages of alco-
hols 9 and 10, the only by-products, did not increase signif-
icantly (12%, entry 5, vs 9%, entry 2). The use of a different
solvent (entry 6) resulted in a worse ee (33%) and in an in-
crease of the number of by-products (9, 10 and 13),
whereas the slow addition of the substrate to the organo-
zinc mixture (entry 7) did not significantly improve either
the yield (44%) or the ee (67%) with respect to the easier
1
2
3
4
5
6
7
8
9
C6H5
11
15
13
27 16
19
4
11
—
—
1
2
5
32 68
36 70
25 70
42 69
32 68
R
R
R
R
R
—
R
R
R
2-Cl–C6H4
3-Cl–C6H4
3-Me–C6H4
4-Me–C6H4
4-MeO–C6H4
4-NO2–C6H4
CH3(CH2)5
C(CH3)3
6
1
5
—
—
4
n.d.
25
7
15c 47
12c 40
a Determined by 1H NMR.
b Determined by analysis of the corresponding Mosher ester 1H NMR
(400 MHz) spectrum.
c Isolated yield.
Table 2. Distribution of products obtained by phenylacetylene Et2Zn-catalysed addition on benzaldehyde (R1 = Ph)
Entry
L* (a)
Time (h)
8b
9b
10b
11b
12b
13b
eec (%)
Configuration of 11c
1
2
3
4
None
1
Bd
20
20
20
6
6
6
44
29
0
96
56
53
45
5
6
3
2
3
3
—
1
28
50
58
3
32
15
44
21
12
19
—
0
—
0
17
—
0
—
52
8
—
68
33
67
—
R
R
None
1
—
R
5
1
1
1
11
19
8
6e
7f
2
3
0
0
11
0
R
24
R
a 15 mol %.
b Determined by 1H NMR.
c Determined by analysis of the corresponding Mosher ester 1H NMR (400 MHz) spectrum.
d Chart 1, R = i-Pr.
e DCM/hexane ꢁ 2.2:1 was used as a solvent.
f Slow addition of the aldehyde over 20 h.

1412
D. Scarpi et al. / Tetrahedron: Asymmetry 17 (2006) 1409–1414
27
3. Conclusion
Compound 4. Mp 65–66 ꢁC. ½aꢂD ¼ þ35:4 (c 0.76, CHCl3).
1H NMR (CDCl3) d (ppm) (3:1 mixture of two rotamers):
5.04 (d, J 6.2 Hz, 1H, minor rotamer), 4.99 (d, J 6.4 Hz,
1H, major rotamer), 4.55–4.32 (m, 2H), 3.84 (dd, J 13.4,
5.5 Hz, 1H, major rotamer), 3.75–3.48 (m, 2H+1H, minor
rotamer), 3.42 (s, 6H, minor rotamer), 3.38 (s, 6H,
major rotamer), 3.22 (dd, J 13.9, 4.7 Hz, 1H, major
rotamer), 3.14 (s, 3H, major rotamer), 3.03 (s, 3H, minor
rotamer), 1.57 (s, 3H, major rotamer), 1.55 (s, 3H,
minor rotamer), 1.40 (s, 3H, major rotamer), 1.33 (s, 3H,
minor rotamer). 13C NMR (CDCl3) d (ppm) (3:1 mixture
of two rotamers): 169.1 (s, minor rotamer), 168.3 (s, major
rotamer), 109.7 (s, major rotamer), 109.6 (s, minor rot-
amer), 103.4 (d, minor rotamer), 102.5 (d, major rotamer),
78.2 (d, minor rotamer), 77.3 (d, major rotamer), 74.8 (d,
minor rotamer), 74.6 (d, major rotamer), 62.3 (t, minor
rotamer), 61.9 (t, major rotamer), 55.5 (q, minor rotamer),
55.0 (q, minor rotamer), 54.8 (q, major rotamer), 54.5
(q, major rotamer), 52.1 (t, minor rotamer), 50.0 (t, major
rotamer), 36.7 (q, major rotamer), 35.5 (q, minor rotamer),
27.1 (q), 25.3 (q). MS m/z (%) 262 (M+ꢀCH3, 3), 185 (15),
75 (100). Anal. Calcd for C12H23NO6: C, 51.97; H, 8.36; N,
5.05. Found: C, 52.06; H, 9.00; N, 5.03.
In conclusion, in the present work a new chiral 1,4-amino-
alcohol was synthesised. The results obtained in the Et2Zn
addition to aromatic aldehydes confirm the influence of the
N-substituent of the ligand on the stereoselectivity of the
reactions. With this new conformationally constrained
1,4-aminoalcohol ee’s comparable to those obtained with
1,2-aminoalcohols are achieved. A second application, that
is, the synthesis of propargylic alcohols, proved less suc-
cessful both in yield and ee. However, to the best of our
knowledge, this is the first example of a 1,4-aminoalcohol
employed as a catalyst for the synthesis of chiral propargy-
lic alcohols. Furthermore, the narrow range of the enantio-
meric excesses obtained in both applications on the same
aromatic aldehydes (92–98% and 68–70%) seems to indi-
cate the maximum asymmetric induction obtainable by this
chiral rigid bicyclic system.
Further investigations employing ligand 1 in other cata-
lysed reactions are currently in progress.
4. Experimental
4.2. (4R,5R)-Acetic acid 5-[(2,2-dimethoxy-ethyl)-methyl-
carbamoyl]-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl ester 5
Melting points are uncorrected. Chromatographic separa-
tions were performed under pressure on silica gel by
flash-column techniques; Rf values refer to TLC carried
out on 25-mm silica gel plates (Merck F254), with the same
To a solution of 4 (4.2 g, 15.1 mmol) in dry pyridine
(20 mL), cooled at 0 ꢁC under nitrogen, was added acetic
anhydride (2.9 mL, 30.7 mmol). The reaction mixture was
allowed to warm to room temperature and stirred for
20 h. Then the solution was cooled to 0 ꢁC, quenched with
HCl (1 M, 20 mL), and diluted with DCM (50 mL). The
organic phase was washed with HCl (1 M, 2 · 20 mL)
and brine (20 mL), and then dried over Na2SO4. After fil-
tration and evaporation of the solvent, product 5 (4.34 g,
90%) was obtained without further purification as a colour-
less oil.
1
eluent as indicated for the column chromatography. H
NMR (200 MHz) and 13C NMR (50.33 MHz) spectra were
recorded with a Varian XL 200 instrument in CDCl3 solu-
tion. NMR spectra of Mosher esters were performed on a
Varian MercuryPlus 400 spectrometer operating at
1
400 MHz for H. Mass spectra were carried out by EI at
70 eV, unless otherwise stated, on Shimadzu GC/MS
QP5050 instruments. GC analyses were performed on a
HP5890 Series II instrument supported with a Supelco
b DEXTM 120, 30 m · 0.25 mm, 0.25 lm film column.
Microanalyses were carried out with a Perkin–Elmer
2400/2 elemental analyser. Optical rotations were deter-
mined with a JASCO DIP-370 instrument.
26
Compound 5. ½aꢂD ¼ þ23:6 (c 1.04, CHCl3). 1H NMR
(CDCl3) d (ppm) (3:1 mixture of two rotamers): 5.08 (d,
J 6.6 Hz, 1H, minor rotamer), 5.00 (d, J 7.0 Hz, 1H, major
rotamer), 4.62–4.44 (m, 2H), 4.23–4.03 (m, 2H), 3.53–3.27
(m, 2H), 3.40 (s, 6H), 3.12 (s, 3H, major rotamer), 3.00 (s,
3H, minor rotamer), 2.08 (s, 3H, major rotamer), 2.07
(s, 3H, minor rotamer), 1.61 (s, 3H, major rotamer), 1.59
(s, 3H, minor rotamer), 1.40 (s, 3H, major rotamer),
1.39 (s, 3H, minor rotamer). 13C NMR (CDCl3) d (ppm)
(3:1 mixture of two rotamers): 170.2 (s), 167.7 (s, minor
rotamer), 167.1 (s, major rotamer), 110.4 (s, major rota-
mer), 110.3 (s, minor rotamer), 103.2 (d, minor rotamer),
102.6 (d, major rotamer), 75.2 (d, minor rotamer), 74.5
(d, major rotamer), 74.0 (d, major rotamer), 73.8 (d, minor
rotamer), 63.5 (t, minor rotamer), 63.4 (t, major rotamer),
55.3 (q, minor rotamer), 55.2 (q, minor rotamer), 54.7
(q, major rotamer), 54.6 (q, major rotamer), 51.7 (t, minor
rotamer), 50.5 (t, major rotamer), 36.5 (q, major rota-
mer), 35.3 (q, minor rotamer), 27.1 (q), 25.3 (q), 20.7 (q).
MS m/z (%) 304 (M+ꢀCH3, 3), 115 (13), 75 (100). Anal.
Calcd for C14H25NO7: C, 52.65; H, 7.89; N, 4.39. Found:
C, 52.59; H, 8.17; N, 4.43.
Before use, Amberlite IRA-743 (Aldrich) was washed with
methanol (three times), dichloromethane (three times),
diethyl ether (three times) and dried to constant mass under
vacuum.
4.1. (4R,5R)-5-Hydroxymethyl-2,2-dimethyl-[1,3]dioxolane-
4-carboxylic acid (2,2-dimethoxy-ethyl)-methyl-amide 4
To a solution of 3 (2.3 mL, 17.9 mmol) in dry CH2Cl2
(64 mL), cooled at 0 ꢁC under nitrogen, was added AlMe3
(2 M in hexane, 8.96 mL, 17.9 mmol) and, after 30 min, 2
(2.58 g, 16.3 mmol). The reaction mixture was allowed to
warm to room temperature and after 18 h was cooled to
0 ꢁC and quenched with HCl (1 M, 40 mL). The aqueous
phase was extracted with CH2Cl2 (2 · 20 mL) and the com-
bined organic layers were dried over Na2SO4. After filtra-
tion and evaporation of the solvent, 4 was obtained
(4.2 g, 93%) as a white solid.

D. Scarpi et al. / Tetrahedron: Asymmetry 17 (2006) 1409–1414
1413
4.3. (1R,5R,7R)-Acetic acid 3-methyl-2-oxo-6,8-dioxa-3-
aza-bicyclo[3.2.1]oct-7-yl ester 6
were concentrated in vacuo to give the crude that was puri-
fied by chromatography (eluent: CH2Cl2–MeOH,
20:1 + 0.5% Et3N, Rf = 0.14) yielding 1 (255 mg, 46%) as
a colourless oil.
A solution of 5 (2.16 g, 6.78 mmol) in toluene (90 mL) was
quickly added, under nitrogen, to a refluxing suspension of
H2SO4/SiO2 (1.24 g) in toluene (250 mL). When 100 mL of
the solvent was distilled off (10 min), the hot solution was
filtered through a short pad of NaHCO3, and the pad was
washed with EtOAc (2 · 40 mL). The combined organic
phases were concentrated in vacuo and the crude contained
a mixture of 6 and 7. The compounds were separated by
chromatography (EtOAc–petroleum ether, 3:1 + 0.5%
Et3N) yielding 6 (0.70 g, 48%) as a pale yellow oil and 7
(0.26 g, 9%) as an orange solid.
22
Compound 1. ½aꢂD ¼ ꢀ91:2 (c 0.89, CHCl3). 1H NMR
(CDCl3) d (ppm): 7.13 (br s, 1H), 5.51 (s, 1H), 4.34–4.33
(m, 1H), 4.17–4.10 (m, 2H), 3.84 (d, J 11.7 Hz, 1H),
3.01–2.92 (m, 2H), 2.65–2.59 (m, 1H), 2.39 (d, J 11.0 Hz,
1H), 2.28 (s, 3H). 13C NMR (CDCl3) d (ppm): 98.6 (d),
78.1 (d), 74.3 (d), 58.8 (t), 57.8 (t), 54.4 (t), 43.5 (q). MS
m/z (%) 159 (M+, 28), 114 (49), 100 (17), 86 (47), 57
(100). Anal. Calcd for C7H13NO3Æ1/3H2O: C, 50.90; H,
8.14; N, 8.48. Found: C, 50.85; H, 8.48; N, 8.69.
28
1
Compound 6. Rf = 0.33. ½aꢂD ¼ ꢀ39:7 (c 0.63, CHCl3). H
NMR (CDCl3) d (ppm): 5.71 (d, J 2.6 Hz, 1H), 4.65 (d,
J 4.4 Hz, 1H), 4.33–4.24 (m, 2H), 4.06 (dd, J 12.8,
8.4 Hz, 1H), 3.49 (dd, J 12.0, 2.6 Hz, 1H), 3.18 (d, J
12.0 Hz, 1H), 2.92 (s, 3H), 2.09 (s, 3H). 13C NMR (CDCl3)
d (ppm): 169.9 (s), 164.7 (s), 96.6 (d), 77.2 (d), 75.3 (d), 62.1
(t), 54.1 (t), 32.0 (q), 20.4 (q). MS m/z (%) 216 (M++1, 5),
197 (17), 155 (30), 84 (100). Anal. Calcd for C9H13NO5:
C, 50.23; H, 6.09; N, 6.51. Found: C, 50.14; H, 6.30; N,
6.85.
4.5. General procedure for addition reaction of diethylzinc
to aldehydes
Diethylzinc (1.0 M solution in hexane, 1.5 mmol) was
added to a solution of ligand 1 (0.15 mmol) in anhydrous
toluene (1.5 mL). After 30 min, the aldehyde (1 mmol)
was added dropwise and the resulting mixture stirred for
24 h. The reaction was quenched by 1 M aqueous HCl
solution (5 mL) and the product extracted three times with
EtOAc. The combined organic phases were dried over
Na2SO4. After filtration and evaporation of the solvent,
the crude alcohol was obtained and directly analysed by
GC to determine product composition and ee. In the case
of chiral 3-nonanol, the ee and the absolute configuration
were determined by 1H NMR of the corresponding Mosher
ester.
24
Compound 7. Rf = 0.22. Mp 134–135 ꢁC. ½aꢂD ¼ ꢀ51:3 (c
0.92, CHCl3). 1H NMR (CDCl3) d (ppm): 5.37 (d, J
5.1 Hz, 1H), 4.85 (s, 1H), 4.49 (s, 1H), 4.15 (dd, J 13.2,
2.9 Hz, 1H), 3.94 (d, J 13.2 Hz, 1H), 3.79 (dd, J 13.6,
5.1 Hz, 1H), 3.38 (d, J 13.6 Hz, 1H), 3.03 (s, 3H), 2.18 (s,
3H). 13C NMR (CDCl3) d (ppm): 169.9 (s), 165.0 (s), 90.0
(d), 72.6 (d), 67.1 (d), 61.8 (t), 52.0 (t), 33.3 (q), 21.0 (q).
MS m/z (%) 215 (M+, 36), 142 (48), 71 (100). Anal. Calcd
for C9H13NO5: C, 50.23; H, 6.09; N, 6.51. Found: C,
50.55; H, 6.37; N, 6.52.
The chiral ligand can be recovered as follows: the aqueous
layer was neutralised with NaOH (s) until the pH was
8–9 (zinc hydroxides precipitate) and compound 1 was
extracted five times with CHCl3. The combined organic
phases were dried over Na2SO4 and, after filtration and
evaporation of the solvent, pure 1 was recovered (69%).
4.4. (1S,5R,7R)-(3-Methyl-6,8-dioxa-3-aza-bicyclo[3.2.1]-
oct-7-yl)-methanol 1
4.6. General procedure for alkynylation reactions
4.4.1. Method A. To
a suspension of 6 (423 mg,
1.97 mmol) in dry THF (20 mL), under nitrogen, was slowly
added a 10 M solution of BH3ÆSMe2 (590 lL). The reaction
mixture was refluxed for 2 h, cooled to rt and Amberlite
IRA-743 (4.2 g) was slowly added to the solution, immedi-
ately followed by H2O (532 lL, 29.5 mmol). The suspension
was stirred at rt for 12 h. The resin was then filtered off and
washed with Et2O (5 · 15 mL), and the combined organic
phases were concentrated in vacuo to give the crude that
was purified by chromatography (eluent: CH2Cl2–MeOH,
20:1 + 0.5% Et3N, Rf = 0.14) yielding 1 (100 mg, 32%) as
a colourless oil.
Diethylzinc (1.0 M solution in hexane, 1.05 mmol) was
added to a solution of ligand 1 (0.15 mmol) in anhydrous
THF (2.2 mL). After 1 h, phenylacetylene (1.05 mmol)
was added and after one more hour, the solution was
cooled at 0 ꢁC and the aldehyde (1 mmol) was added drop-
wise. After 6 h, the ice bath was removed and the reaction
quenched by saturated NH4Cl solution (5 mL) and the
product extracted three times with Et2O. The combined
organic phases were dried over Na2SO4 and after filtration
and evaporation of the solvent, the crude alcohol was puri-
fied by chromatography (eluent: EtOAc–petroleum ether,
1:6 + 0.5% Et3N; Rf = 0.20–0.32). The ee and the absolute
1
4.4.2. Method B. A solution of 6 (746 mg, 3.47 mmol) in
dry THF (13 mL) was added, under nitrogen, to a suspen-
sion of LiAlH4 (527 mg, 13.9 mmol) in dry THF (40 mL),
cooled at 0 ꢁC. The ice bath was removed and the mixture
was heated at 55 ꢁC. After 18 h, the mixture was cooled to
0 ꢁC, quenched with KOH (0.4 M, 3 mL) and water (2 mL)
and, after 50, refluxed for 300. The white salts were elimi-
nated by filtration on a short Celite pad that was washed
with EtOAc (3 · 15 mL). The combined organic phases
configuration were determined by H NMR of the corre-
sponding Mosher ester.
Acknowledgements
`
The authors thank Universita di Firenze for financial
support. Mr. Maurizio Passaponti and Mrs. Brunella
Innocenti are also acknowledged for their technical

1414
D. Scarpi et al. / Tetrahedron: Asymmetry 17 (2006) 1409–1414
6. Storer, R. I.; Takemoto, T.; Jackson, P. S.; Brown, D. S.;
Baxendale, I. R.; Ley, S. V. Chem. Eur. J. 2004, 10, 2529–
2547.
support. Ente Cassa di Risparmio di Firenze is acknow-
ledged for granting a 400 MHz NMR spectrometer.
7. The traditional use of TMEDA in the quenching step
decreased the product recovery; data not shown.
References
8. The ligand can be easily recovered as reported in the
Experimental section.
1. Pu, L.; Yu, H.-B. Chem. Rev. 2001, 101, 757–824.
9. This observation was already reported by Corey et al. See:
Corey, E. J.; Yuen, P.-W.; Hannon, F. J.; Wierda, D. A.
J. Org. Chem. 1990, 55, 784–786.
2. (a) Genov, M.; Dimitrov, V.; Ivanova, V. Tetrahedron:
Asymmetry 1997, 8, 3703–3706; (b) Genov, M.; Kostova, K.;
Dimitrov, V. Tetrahedron: Asymmetry 1997, 8, 1869–1876; (c)
10. (a) Kimura, K.; Sugiyama, E.; Ishizuka, T.; Kunieda, T.
Tetrahedron Lett. 1992, 33, 3147–3150; (b) Lawrence, C. F.;
Nayak, S. K.; Thijs, L.; Zwanenburg, B. Synlett 1999, 1571–
1572; (c) Shi, M.; Jiang, J.-K. Tetrahedron: Asymmetry 1999,
10, 1673–1679.
11. (a) Ishizaki, M.; Hoshino, O. Tetrahedron: Asymmetry 1994,
5, 1901–1904; (b) Sprout, C. M.; Seto, C. T. J. Org. Chem.
2003, 68, 7788–7794; (c) Watts, C. C.; Thoniyot, P.; Hiray-
ama, L. C.; Romano, T.; Singaram, B. Tetrahedron: Asym-
metry 2005, 16, 1829–1835; (d) Kang, Y.-F.; Liu, L.; Wang,
R.; Yan, W.-J.; Zhou, Y.-F. Tetrahedron: Asymmetry 2004,
15, 3155–3159; (e) Dahmen, S. Org. Lett. 2004, 6, 2113–2116.
12. (a) Pu, L. Tetrahedron 2003, 59, 9873–9886; (b) Anand, N.
K.; Carreira, E. M. J. Am. Chem. Soc. 2001, 123, 9687–9688;
(c) Jiang, B.; Chen, Z.; Xiong, W. Chem. Commun. 2002,
1524–1525; (d) Frantz, D. E.; Fa¨ssler, R.; Carreira, E. M. J.
Am. Chem. Soc. 2000, 122, 1806–1807.
Knollmuller, M.; Ferencic, M.; Ga¨rtner, P. Tetrahedron:
¨
Asymmetry 1999, 10, 3969–3975; (d) Hanyu, N.; Aoki, T.;
Mino, T.; Sakamoto, M.; Fujita, T. Tetrahedron: Asymmetry
2000, 11, 2971–2979; (e) Hanyu, N.; Aoki, T.; Mino, T.;
Sakamoto, M.; Fujita, T. Tetrahedron: Asymmetry 2000, 11,
4127–4136; (f) Hanyu, N.; Mino, T.; Sakamoto, M.; Fujita,
T. Tetrahedron Lett. 2000, 41, 4587–4590; (g) Martinez, A.
G.; Vilar, E. T.; Fraile, A. G.; de la Moya Cerero, S.; Maroto,
B. L. Tetrahedron: Asymmetry 2003, 14, 1959–1963; (h)
Martinez, A. G.; Vilar, E. T.; Fraile, A. G.; de la Moya
Cerero, S.; Maroto, B. L. Tetrahedron: Asymmetry 2004, 15,
753–756; (i) Martinez, A. G.; Vilar, E. T.; Fraile, A. G.; de la
Moya Cerero, S.; Maroto, B. L. Tetrahedron 2005, 61, 3055–
3064.
3. Scarpi, D.; Lo Galbo, F.; Occhiato, E. G.; Guarna, A.
Tetrahedron: Asymmetry 2004, 15, 1319–1324.
4. Yamakawa, M.; Noyori, R. J. Am. Chem. Soc. 1995, 117,
6327–6335.
5. (a) Basha, A.; Lipton, M.; Weinreb, S. M. Tetrahedron Lett.
1977, 48, 4171–4174; (b) Heitz, M.-P.; Overman, L. E. J. Org.
Chem. 1989, 54, 2591–2596.
13. Cozzi and co-workers reported a 30% of racemic alcohol
when carrying out the reaction with ZnMe2 at 0 ꢁC over 24 h.
See: Cozzi, P. G.; Rudolph, J.; Bolm, C.; Norrby, P.-O.;
Tomasini, C. J. Org. Chem. 2005, 70, 5733–5736.