Synthesis of (+)-febrifugine and a formal synthesis of (+)-halofuginone employing an organocatalytic direct vinylogous aldol reaction

Article abstract of DOI:10.1055/s-0033-1338706

The enantioselective organocatalytic direct vinylogous aldol reaction of γ-crotonolactone and a suitable aldehyde was utilized in the synthesis of a functionalized γ-butenolide. The γ-butenolide (aldol product) was stereoselectively converted into a 5-aminoalkyl butyrolactone, which isomerized to the key 2,3-disubstituted piperidinone, a common intermediate to (+)-febrifugine and (+)-halofuginone. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0033-1338706

PAPER
▌1863
paper
Synthesis of (+)-Febrifugine and a Formal Synthesis of (+)-Halofuginone
Employing an Organocatalytic Direct Vinylogous Aldol Reaction
Synthesis of (+)-Febrifugine
Sunil V. Pansare,* Eldho K. Paul
Department of Chemistry, Memorial University, St. John’s, NL, A1B 3X7, Canada
Fax +91(709)8643702; E-mail: spansare@mun.ca
Received: 19.02.2013; Accepted after revision: 14.04.2013
Dedicated to Professor Scott E. Denmark on the occasion of his 60th birthday
OH
N
O
R1
R2
N
O
Abstract: The enantioselective organocatalytic direct vinylogous
aldol reaction of γ-crotonolactone and a suitable aldehyde was uti-
lized in the synthesis of a functionalized γ-butenolide. The γ-bu-
tenolide (aldol product) was stereoselectively converted into a 5-
aminoalkyl butyrolactone, which isomerized to the key 2,3-disub-
stituted piperidinone, a common intermediate to (+)-febrifugine and
(+)-halofuginone.
OH
O
O
N
N
N
N
H
H
1: R1 = R2 = H 2: R1 = Br, R2 = Cl
3
Figure 1 (+)-Febrifugine (1), (+)-halofuginone (2) and isofebri-
fugine (3)
Key words: asymmetric catalysis, aldol reaction, stereoselective
synthesis, piperidines, total synthesis
with a suitable heterocycle. Retrosynthetically, the com-
mon precursor to 1 or 2 is a suitably protected piperidinyl
bromoketone3j such as A (Scheme 1), which derives from
the functionalized piperidinone B. The piperidinone B can
be obtained by isomerization9 of an aminoalkyl lactone
such as C. Ultimately, C derives from the functionalized
butenolide D, which leads us to the organocatalytic direct
vinylogous aldol reaction10 of crotonolactone and an ap-
propriate aldehyde. The vinylogous aldol reaction11 di-
rectly sets the absolute stereochemistry at C-3 in the
piperidine ring of the target. The stereochemistry at C-2 is
indirectly controlled by the aldol reaction and is achieved
by manipulation of the secondary alcohol stereocenter in
the aldol adduct (Scheme 1).
The prevalence of malaria in tropical regions and the need
for new medicines to combat malaria have resulted in a
persistent, and often challenging, search for new antima-
larial agents.1 In this context, febrifugine (1, Figure 1) and
halofuginone (2) have attracted considerable interest due
to their pronounced antimalarial activity.2 In solution, feb-
rifugine (1) is gradually converted to isofebrifugine (3)
which is less potent, but exhibits antimalarial activity sim-
ilar to febrifugine.2d The asymmetric synthesis of
febrifugine3 continues to be actively investigated and the
reported syntheses often showcase new methodology for
stereoselective construction of the 2,3-disubstituted piper-
idine ring in the targets. Only two asymmetric syntheses
of halofuginone3a,4 are reported. Febrifugine and halofugi-
none also have numerous other applications, which have
contributed to a continued interest in these alkaloids. No-
tably, in addition to its antimalarial properties, halofugi-
none is used as an antiprotozoal agent in poultry5 and also
as an antiangiogenic agent.6 It has been approved for the
treatment of scleroderma and is active against estrogen-
deficient osteoporosis in mice.7 Recently, the molecular
mechanism of action of febrifugine and halofuginone in
mice has been determined.8 These studies have highlight-
ed the importance of structural analogues of febrifugine in
the treatment of multiple sclerosis, scleroderma, and rheu-
matoid arthritis. Hence, an important consideration in de-
vising a synthesis of the title compounds is the flexibility
of the approach for making analogues of febrifugine.
OR2
OH
O
O
1 or 2
Br
O
N
N
O
H
CO2R1
B
amino lactone
isomerization
A
vinylogous aldol
NH2
∗
OH
O
O
O
O
∗
R
R
C
D
amination
Scheme 1
Our investigations began with the synthesis of 6 (Scheme
2). Initially, the direct vinylogous aldol reaction of com-
mercially available γ-crotonolactone and the aldehyde 412
was examined in the presence of selected cyclohexanedi-
amine, stilbenediamine, and cinchonidine derived
thioureas13 (5a, 5b, 5c) and cyclohexanediamine and stil-
benediamine derived squaramides14 (5d and 5e, Figure 2).
Accordingly, we decided to develop a synthesis of febri-
fugine (1) that would proceed through a precursor that
could also be converted into halofuginone and, potential-
ly, other heteroaryl-linked piperidines by simple coupling
SYNTHESIS 2013, 45, 1863–1869
Advanced online publication: 08.05.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1338706; Art ID: SS-2013-C0140-OP
© Georg Thieme Verlag Stuttgart · New York

1864
S. V. Pansare, E. K. Paul
PAPER
O
O
Table 1 Optimization of the Vinylogous Aldol Reaction of Crotono-
lactone and Aldehyde 4
O
O
H
4
OH
O
O
O
O
O
O
O
O
O
Ph
H
OH
O
O
O
Ph
4
Ar
N
H
N
H
O
O
5a–e, solvent, r.t.
6
N
O
dr = 8:1, er = 19:1
5e
O
(Ar = 3,5(CF3)2C6H3)
(74%)
6
1) H2, Pd/C
2) DMP
(80%)
Entrya Cat.b
Solvent
Time
(h)
Yield drc
eed (%)
(%)
(anti/syn) anti
O
OH
O
1
2
5a
5a
5a
5a
5a
5b
5b
5b
5c
5d
5d
5d
5d
5e
5e
5e
CH2Cl2
toluene
EtOAc
DMF
24
24
59
68
31
12
8
1.1:1
1:1
–55
–18
–58
–30
–62
–61
–
O
O
K-Selectride
O
O
O
THF, –78 °C
(70%)
O
O
7
3
24
1.1:1
1:1
'H–'
8
er = 19:1
dr = 16:1
O
4
24
H
O
R
O
5
CH2Cl2
CH2Cl2
EtOAc
toluene
CH2Cl2
CH2Cl2
CH2Cl2
EtOAc
toluene
EtOAc
CH2Cl2
toluene
144e
144
144
144
48
4.2:1
–
Scheme 2
6
2
7
0
–
8
0
–
–
S
Ph
S
N
Ar
O
Ph
Ar
9
13
31
16
20
39
18
74
27
1.5:1
1.9:1
2.2:1
1.6:1
1.5:1
2.4:1
8:1
–74
–90
–93
–88
–88
95
N
N
N
H
N
S
H
N
H
H
N
Ar
10
11
12
13
14
15
16
48
N
H
N
5a
5b
H
144e
48
N
5c
O
O
O
Ph
CF3
48
Ph
Ar
Ar
N
H
N
N
H
N
Ar =
120
192
120
H
N
H
N
CF3
91
5d
5e
2.9:1
90
Figure 2 Selected aminothiourea and aminosquaramide catalysts
a Crotonolactone used: 2 equiv.
Orienting experiments with the catalyst 5a suggested di- b Catalyst: 20 mol%.
c Based on 1H NMR of crude products.
chloromethane as a solvent for further studies based on
the yield and enantiomeric excess of 6 (Table 1, entries 1–
4). Although lowering the temperature (0 °C), increased
the diastereoselectivity and enantiomeric excess for 6, the
reaction was prohibitively slow (Table 1, entry 5, 8%
yield of 6). The stilbenediamine-derived aminothiourea
5b was ineffective as a catalyst and provided only a trace
of 6 in dichloromethane (entries 6–8). Catalyst 5c provid-
ed 6 in low yield and moderate enantiomeric excess (entry
9). Reactions with the aminosquaramide catalysts 5d and
5e were slower, but provided 6 with higher enantiomeric
excess (entries 10–16) than the aminothiourea catalysts
5a–c. For catalyst 5d, the use of dichloromethane as the
solvent provided the highest enantiomeric excess (entries
10–12), but the yield and diastereostelectivity for 6 re-
mained low. Further studies with the aminosquaramide
catalyst 5e14a in ethyl acetate provided 6 with good enan-
tiomeric excess (entry 14, 95%) but low diastereoselectiv-
ity and yield. In comparison, the reaction with 5e was
synthetically more useful when dichloromethane was
d Based on chiral HPLC analysis; negative ee values indicate forma-
tion of the enantiomer of 6.
e Reaction at 0 °C.
used as the solvent (entries 14–16). Thus the direct vinylo-
gous aldol reaction of γ-crotonolactone with the aldehyde
4 using 5e as the catalyst provided the butenolide 6 in
good yield and diastereoselectivity (entry 15, 74%, an-
ti/syn = 8:1) and excellent enantiomeric excess (er = 19:1
for the anti-diastereomer) when the reaction was conduct-
ed in dichloromethane15 (Scheme 2). Following the
planned synthetic strategy (Scheme 1), it may be noted
that the 2,3-trans substitution in the target piperidine can
be obtained only from the anti-diastereomer of the corre-
sponding amino butyrolactone (Scheme 1, C). Since our
approach to this amino lactone would involve an invertive
amination of the precursor alcohol, a switch of the aldol
product stereochemistry from the anti- to the syn-isomer
is required. For this, 6 was first hydrogenated and then
Mitsunobu inversion of the secondary alcohol was exam-
Synthesis 2013, 45, 1863–1869
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of (+)-Febrifugine
1865
ined under a variety of conditions. These attempts invari-
ably lead to complex mixtures and hence an alternate
strategy for alcohol inversion became necessary. Accord-
ingly, the alcohol was first oxidized to provide the keto-
lactone 7. Reduction of 7 with K-Selectride® gave syn-8
(70%) with good diastereoselectivity (syn/anti = 16:1,
presumably via the Felkin–Anh mode,16 Scheme 2).17
OBn
OBn
O
O
I2
acetone
(84%)
N
N
O
Cbz
Cbz
13
12
1) TMSOTf, DIPEA
then NBS
2) 4-OH-quinazoline
K2CO3
(47%, 2 steps)
The lactone 8 was readily converted into the azido lactone
9 (mesylation and azidation with inversion) with the re-
quired anti stereochemistry (anti/syn = 16:1). Reduction
of the azide (H2, Pd/C) generated a mixture of the corre-
sponding amino butyrolactone and the required piperi-
done 10, obtained from the intramolecular N-acylation of
the amino lactone. Notably, hydrogenation of 9 in the
presence K2CO3 significantly facilitated this rearrange-
ment to directly provide 10 (80% from 8) without any re-
sidual amino lactone. Reduction of the lactam in 10
provided the corresponding piperidine, which was isolat-
ed as a single diastereomer, presumably due to enrichment
of the trans-isomer during the reduction and isolation. N-
Protection of the piperidine provided 11, which was ben-
zylated to provide the key intermediate 12 (71% from 10,
Scheme 3).
OBn
N
N
6 M HCl
O
1
then K2CO3
(75%)
N
Cbz
O
14
Scheme 4
tion of a 2-aminoalkyl furanone to the 2,3-disubstituted
piperidine core of the target as the key steps. Since the
bromoketone obtained from 13 can be converted into (+)-
halofuginone by coupling with 7-bromo-6-chloro-4-hy-
droxyquinazoline,3a the present study also constitutes a
formal synthesis of (+)-halofuginone.
All commercially available reagents were used without purification.
All reactions requiring anhyd conditions were performed under an
atmosphere of dry N2 using oven-dried glassware. CH2Cl2 and THF
were distilled from CaH2 and sodium/benzophenone, respectively.
Commercial precoated silica gel plates were used for TLC. Silica
gel for column chromatography was 230–400 mesh. All melting
points are uncorrected. Optical rotations were measured at the sodi-
um D line on a digital polarimeter at r.t.
N3
OH
O
1) MsCl, Et3N
2) NaN3, DMF
O
O
O
O
O
O
O
8
9
H2, Pd/C
(80%, 3 steps)
K2CO3
OR
(S)-5-[(R)-1-Hydroxy-2-(2-methyl-1,3-dioxolan-2-yl)ethyl]fu-
ran-2(5H)-one (6)
O
OH
1) LAH, THF
O
A mixture of the catalyst 5e (20 mol%, 1.17 g), the aldehyde 4 (1.4
g, 10.75 mmol), and 2-(5H)-furanone (1.5 mL, 21.5 mmol) in
CH2Cl2 (10 mL) was stirred for 192 h at r.t. The mixture was diluted
with EtOAc (100 mL), filtered, and the filtrate was concentrated.
The residue was purified by flash chromatography (CH2Cl2–
EtOAc, 10:1) to provide 1.73 g (74%) of 6 as a pale yellow solid
N
O
2) CbzCl, Et3N
3) KH, BnBr
(71%, 3 steps)
O
N
O
Cbz
H
11: R = H
10
3)
12: R = Bn
Scheme 3
1
(anti/syn = 8:1 as determined by H NMR analysis of the crude
product); Rf = 0.30 (EtOAc–hexanes, 4:1); ee: 90% (anti).
With the piperidine 12 in hand, the final steps of the syn-
thesis were initiated (Scheme 4). The ketone in 12 was un-
masked by treatment of the ketal with iodine in acetone to
provide 13. Comparison of the spectral data of 13 with re-
ported values3a,i confirmed the trans orientation of the
substituents on the piperidine ring. This also confirms the
initial stereochemical assignments for 6. Bromination of
the ketone in 13 was achieved by the procedure reported
by Honda (TMSOTf, DBU then NBS)3i and the crude bro-
moketone was reacted with 4-hydrazoquinazoline to pro-
vide the protected febrifugine derivative 14. Deprotection
of 14 (aq 6 M HCl) and subsequent neutralization provid-
HPLC: Chiralpak AS-H, hexanes–propan-2-ol (92:8), 210 nm, anti-
6: tR = 42.4 min (minor), 76.7 min (major); syn-6: tR = 57.9 min (ma-
jor), 83.1 min (minor). In repeated runs anti-6 was obtained in 89–
93% ee.
IR (neat): 3467, 2988, 2889, 1795, 1748, 1378, 1163, 1104, 1034,
826 cm–1.
1H NMR (500 MHz, CDCl3): δ (anti) = 7.67–7.66 (dd, J = 5.8, 1.5
Hz, 1 H), 6.18–6.17 (dd, J = 5.8, 1.9 Hz, 1 H), 4.86–4.84 (dt, J = 7.0,
1.7 Hz, 1 H), 4.04–3.99 (m, 4 H), 3.90–3.86 (ddd, J = 10.1, 7.0, 2.0
Hz, 1 H), 3.83 (s, 1 H), 2.19–2.16 (dd, J = 14.6, 1.9 Hz, 1 H), 1.95–
1.89 (m, 1 H), 1.37 (s, 3 H); δ (syn) = 7.53–7.51 (dd, J = 5.7, 1.5 Hz,
1 H), 6.19 (part of dd, 1 H), 5.04–5.02 (m, 1 H), 4.28–4.25 (m, 1 H).
13C NMR (75 MHz, CDCl3): δ (anti) = 172.8, 154.9, 122.1, 110.0,
85.2, 69.6, 64.7, 64.3, 41.4, 24.1; δ (syn) = 172.9, 153.8, 122.7,
109.8, 84.9, 67.4, 64.8, 64.3, 40.1, 24.0.
23
ed (+)-febrifugine (1) ([α]D +17.7 (c 0.6, EtOH) {Lit.3a
[α]D25 +14.6 (c 1.0, EtOH), 86% ee}.
In conclusion, a stereoselective synthesis of (+)-febri-
fugine (1, 14 steps, 6.8% overall yield) was achieved by
employing an organocatalytic asymmetric direct vinylo-
gous aldol reaction of γ-crotonolactone and the isomeriza-
MS (APCI, +): m/z = 215.1 (M + 1).
HRMS (CI): m/z (M + H) calcd for C10H15O5: 215.0919; found:
215.0915.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1863–1869

1866
S. V. Pansare, E. K. Paul
PAPER
(S)-5-[(S)-1-Hydroxy-2-(2-methyl-1,3-dioxolan-2-yl)ethyl]dihy-
drofuran-2(3H)-one (7)
1.89–1.84 (dd, J = 14.8, 1.8 Hz, 1 H), 1.38 (s, 3 H); δ (anti) = 4.43–
4.40 (m, 1 H), 2.68–2.64 (m, 1 H), 1.88–1.85 (dd, J = 14.6, 2.0 Hz,
1 H), 1.37 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ (syn) = 177.9, 109.9, 82.4, 69.8, 64.8,
64.3, 40.8, 28.3, 24.1, 23.9; δ (anti) = 177.2, 110.0, 82.2, 69.1, 64.8,
40.9, 28.3, 24.2, 22.8.
Pd/C (10%, 340 mg) was added to a stirred solution of 6 (1.7 g, 7.93
mmol) in MeOH (80 mL). The mixture was stirred for 16 h at r.t.
under a balloon filled with H2 and then filtered through a pad of
Celite. The filter cake was washed with MeOH (2 × 30 mL) and the
combined filtrates were concentrated under reduced pressure to pro-
vide 1.7 g (99%) of (S)-dihydro-5-[(R)-1-hydroxy-2-(2-methyl-1,3-
dioxolan-2-yl)ethyl]furan-2(3H)-one as a white solid (anti/syn =
8:1); Rf = 0.30 (EtOAc–hexanes, 3:2).This was pure (1H NMR) and
was directly used in the next step.
MS (APCI, +): m/z = 217.1 (M + 1).
HRMS (CI): m/z (M + H) calcd for C10H17O5: 217.1076; found:
217.1072.
(S)-5-[(R)-1-Azido-2-(2-methyl-1,3-dioxolan-2-yl)ethyl]-dihy-
drofuran-2(3H)-one (9)
(S)-Dihydro-5-[(R)-1-hydroxy-2-(2-methyl-1,3-dioxolan-2-
yl)ethyl]furan-2(3H)-one
To a solution of 8 (600 mg, 2.77 mmol) in CH2Cl2 (10 mL) at 0 °C
under N2 was added Et3N (463 μL, 3.32 mmol) followed by MsCl
(259 μL, 3.32 mmol). The mixture was stirred for 1 h at 0 °C and
H2O (20 mL) was added at 0 °C. The mixture was extracted with
CH2Cl2 (2 × 20 mL). The combined organic layers were dried
(Na2SO4) and concentrated to provide 810 mg (99%) of the mesyl-
ate as a yellow oil. This was used immediately in the next step with-
out purification. NaN3 (822 mg, 12.6 mmol) was added to a solution
of the crude mesylate (744 mg, 2.53 mmol) in DMF (8 mL) and the
mixture was stirred at 80 °C for 96 h under N2. The mixture was
cooled to r.t. and EtOAc (30 mL) was added followed by H2O (30
mL). The resulting biphase was separated and the aqueous layer was
extracted with EtOAc (2 × 30 mL). The combined organic layers
were dried (Na2SO4), filtered, and concentrated to provide 610 mg
(quant) of 9 as a yellow oil (anti/syn = 16:1). This was pure (1H
NMR) and was directly used in the next step. An analytical sample
(anti/syn = 25:1) was obtained by flash column chromatography on
silica gel (hexanes–EtOAc, 7:3); Rf = 0.50 (EtOAc–hexanes, 3:2).
IR (neat): 3500, 2985, 2892, 1770, 1658, 1567, 1549, 1459, 1377,
1278, 1190, 1171, 1119, 1027, 996 cm–1.
1H NMR (500 MHz, CDCl3): δ (anti) = 4.37–4.32 (m, 1 H), 4.06–
3.99 (m, 5 H), 3.58 (br s, 1 H), 2.62–2.57 (ddd, J = 17.8, 9.4, 6.4 Hz,
1 H), 2.53–2.48 (m, 1 H), 2.28–2.23 (m, 1 H), 2.04–1.98 (dd, J =
14.6, 2.0 Hz, 1 H), 1.83–1.78 (dd, J = 14.6, 10.0 Hz, 1 H), 1.38 (s,
3 H); δ (syn) = 4.43–4.40 (m, 1 H), 2.68–2.64 (m, 1 H), 2.46–2.45
(m, 1 H), 2.11–2.04 (dd, J = 14.9, 10.5 Hz, 1 H), 1.88–1.85 (dd, J =
14.8, 1.8 Hz, 1 H), 1.37 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ (anti) = 177.2, 110.0, 82.3, 69.1,
64.8, 64.3, 40.9, 28.3, 24.2, 22.8; δ (syn) = 177.9, 109.9, 82.4, 69.8,
68.5, 64.8, 40.8, 28.3, 24.0, 23.9.
MS (APCI, +): m/z = 217.1 (M + 1).
HRMS (CI): m/z (M + H) calcd for C10H17O5: 217.1076; found:
217.1072.
To a solution of the above alcohol (900 mg, 4.16 mmol) in CH2Cl2
(30 mL) was added Dess–Martin periodinane (3.53 g, 8.32 mmol)
and the mixture was stirred at r.t. for 16 h. Sat. aq NaHCO3 (30 mL)
was added, the organic layer was separated and the aqueous layer
was extracted with CH2Cl2 (2 × 30 mL). The combined organic lay-
ers were washed with brine (30 mL), dried (Na2SO4), and concen-
trated. The residue was purified by flash chromatography (hexanes–
EtOAc, 1:1) to provide 714 mg (80%) of 7 as a pale yellow liquid;
Rf = 0.30 (EtOAc–hexanes, 1:1); [α]D23 +18.8 (c 0.92, CHCl3).
IR (neat): 2987, 2959, 2923, 2852, 2108, 1772, 1462, 1378, 1255,
1186, 1144, 1029, 948 cm–1.
1H NMR (500 MHz, CDCl3): δ (anti) = 4.56–4.52 (m, 1 H), 4.04–
3.96 (m, 4 H), 3.94–3.91 (m, 1 H), 2.66–2.60 (ddd, J = 17.9, 10.2,
5.5 Hz, 1 H), 2.55–2.48 (m, 1 H), 2.27–2.19 (m, 1 H), 2.15–2.07 (m,
1 H), 1.96–1.91 (dd, J = 14.9, 7.3 Hz, 1 H), 1.90–1.86 (dd, J = 14.9,
4.5 Hz, 1 H), 1.37 (s, 3 H); δ (syn) = 4.60–4.57 (m, 1 H), 3.58–3.54
(m, 1 H), 1.39 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ (anti) = 176.5, 108.1, 80.9, 64.7,
64.5, 60.5, 39.3, 28.2, 24.3, 22.2; δ (syn) = 176.4, 108.2, 81.8,
64.64, 64.61, 60.5, 39.2, 28.1, 24.5, 22.4.
7
IR (neat): 2996, 2893, 1769, 1718, 1373, 1252, 1153, 1043, 995,
947, 874 cm–1.
1H NMR (500 MHz, CDCl3): δ = 4.91–4.88 (m, 1 H), 3.99–3.95 (m,
4 H), 3.09 (d, J = 13.4 Hz, 1 H), 2.88 (d, J = 13.4 Hz, 1 H), 2.55–
2.45 (m, 3 H), 2.38–2.33 (m, 1 H), 1.44 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 205.0, 176.3, 108.0, 82.2, 64.8,
64.7, 47.5, 27.3, 24.7, 24.2.
MS (CI, +): m/z = 242.1 (M + 1).
HRMS (APCI, +): m/z calcd (M + H) for C10H16N3O4: 242.1141;
found: 242.1145.
(5S,6R)-5-Hydroxy-6-[(2-methyl-1,3-dioxolan-2-yl)methyl]pi-
peridin-2-one (10)
MS (APCI, +): m/z = 215.1 (M + 1).
To a stirred solution of the azide 9 (281 mg, 1.16 mmol) in MeOH
(5 mL) at r.t. was added K2CO3 (56 mg, 20%) followed by 10%
Pd/C (56 mg). The mixture was stirred for 16 h at r.t. under a bal-
loon filled with H2 and then filtered through a pad of Celite. The fil-
ter cake was washed with MeOH (2 × 20 mL) and the combined
filtrates were concentrated under reduced pressure to provide a yel-
low gum. This was purified by flash chromatography on silica gel
(CH2Cl2–MeOH, 19:1) to provide 200 mg (80%) of 10 as a white
solid (trans/cis = 17:1). The overall yield of 10 (from 8) is 80%; Rf
= 0.25 (CH2Cl2–MeOH, 4:1).
HRMS (CI): m/z calcd for C10H14O5: 214.0841; found: 214.0808.
(S)-5-[(S)-1-Hydroxy-2-(2-methyl-1,3-dioxolan-2-yl)ethyl)fu-
ran-2(5H)-one (8)
K-Selectride® (1.0 M soln in THF, 2.8 mL, 2.8 mmol) was added to
a stirred solution of the ketone 7 (400 mg, 1.86 mmol) in THF (2
mL) at –78 °C and the mixture was stirred at –78 °C for 1 h. Sat. aq
NH4Cl (15 mL) was added followed by EtOAc (20 mL). The organ-
ic layer was separated and the aqueous layer was extracted with
EtOAc (2 × 20 mL). The combined organic layers were dried
(Na2SO4), and concentrated. The residue was purified by flash chro-
matography (hexanes–EtOAc, 1:1) to provide 283 mg (70%) of 8 as
a colorless liquid (syn/anti = 16:1); Rf = 0.30 (EtOAc–hexanes, 3:2).
IR (neat): 3352, 3229, 1633, 1464, 1420, 1384, 1255, 1215, 1173,
1129, 1064, 1029, 988, 947, 902, 855 cm–1.
1H NMR (500 MHz, CDCl3): δ (trans) = 6.63 (br s, 1 H), 4.01–3.97
(m, 4 H), 3.56 (br t, J = 9.5 Hz, 1 H), 3.43–3.39 (m, 1 H), 2.86 (br
s, 1 H), 2.52–2.46 (ddd, J = 18.0, 6.2, 3.4 Hz, 1 H), 2.41–2.34 (ddd,
J = 17.9, 11.4, 6.4 Hz, 1 H), 2.33–2.30 (dd, J = 14.5, 2.1 Hz, 1 H),
2.08–2.03 (m, 1 H), 1.89–1.83 (m, 1 H), 1.75–1.70 (dd, J = 14.5, 9.8
Hz, 1 H), 1.35 (s, 3 H); δ (cis) = 6.47 (s, 1 H), 3.67–3.64 (m, 1 H),
2.01–1.99 (m, 1 H).
IR (neat): 3498, 2986, 2960, 2933, 2890, 1765, 1378, 1260, 1167,
1110, 1038, 913, 845 cm–1.
1H NMR (500 MHz, CDCl3): δ (syn) = 4.44–4.39 (m, 1 H), 4.02–
4.01 (m, 4 H), 4.00–3.95 (m, 1 H), 3.57 (br s, 1 H), 2.74–2.63 (m, 1
H), 2.50–2.39 (m, 1 H), 2.31–2.25 (m, 2 H), 2.15–2.02 (m, 1 H),
Synthesis 2013, 45, 1863–1869
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of (+)-Febrifugine
1867
13C NMR (75 MHz, CDCl3): δ (trans) = 170.9, 109.7, 68.9, 64.7,
64.3, 55.5, 41.8, 29.1, 29.0, 24.0; δ (cis) = 171.5, 109.4, 65.7, 64.6,
53.1, 40.5, 27.6, 25.8, 24.2.
at r.t. The mixture was stirred at r.t. for 2 h, cooled to 0 °C, and H2O
(5 mL) was added. The resulting mixture was extracted with EtOAc
(2 × 10 mL). The combined organic layers were dried (Na2SO4) and
concentrated. The residue was purified by flash chromatography on
silica gel (hexanes–EtOAc, 1:1) to give 87 mg (86%) of 12 as a col-
orless oil; Rf = 0.60 (EtOAc–hexanes, 1:1); [α]D –12.4 (c 0.48,
CHCl3).
MS (APCI, +): m/z = 216.1 (M + 1).
23
HRMS (CI): m/z (M + H) calcd for C10H18NO4: 216.1236; found:
216.1235.
IR (neat): 2930, 2881, 1692, 1423, 1351, 1255, 1200, 1157, 1090,
1045, 1025, 946 cm–1.
Benzyl (2R,3S)-3-Hydroxy-2-[(2-methyl-1,3-dioxolan-2-
yl)methyl]piperidine-1-carboxylate (11)
To a stirred suspension of LiAlH4 (101 mg, 2.66 mmol) in THF (5
mL) was added 10 (190 mg, 0.88 mmol) dissolved in THF (5 mL)
and the mixture was heated to reflux for 24 h. The mixture was
cooled to 0 °C, H2O (0.5 mL) was added slowly, and the mixture
was stirred for 20 min at r.t. Na2SO4 (1 g) was added to the mixture
and it was stirred for 10 min. The mixture was then filtered through
a pad of Celite. The filter cake was washed with EtOAc (3 × 20 mL)
and the combined filtrates were concentrated under reduced pres-
sure to provide 160 mg (90%) of (2R,3S)-2-[(2-methyl-1,3-dioxo-
lan-2-yl)methyl]piperidin-3-ol as a white solid; mp 108–111 °C;
Rf = 0.30 (CH2Cl2–MeOH, 4:1). This was exclusively the trans-dia-
stereomer (500 MHz 1H NMR) and was used in the next step with-
out purification.
1H NMR (500 MHz, CDCl3): δ (major rotamer) = 7.34–7.24 (m, 10
H), 5.11–5.07 (AB system, J = 12.4 Hz, 2 H), 4.69 (t, J = 5.6 Hz, 1
H), 4.54 (d, J = 12.2 Hz, 1 H), 4.43 (d, J = 12.2 Hz, 1 H), 4.18–4.15
(dd, J = 13.5, 3.5 Hz, 1 H), 3.91–3.82 (m, 3 H), 3.74–3.72 (m, 1 H),
3.50–3.46 (m, 1 H), 2.88–2.82 (td, J = 13.5, 2.9 Hz, 1 H), 2.04–1.82
(m, 3 H), 1.78–1.73 (m, 1 H), 1.70–1.62 (m, 2 H), 1.25 (s, 3 H); δ
(minor rotamer) = 5.19–5.14 (AB system, J = 12.6 Hz, 2 H), 4.88 (t,
J = 5.8 Hz, 1 H), 4.73 (d, J = 12.0 Hz, 1 H), 4.47 (d, J = 12.0 Hz, 1
H), 4.07–4.04 (dd, J = 13.4, 3.4 Hz, 1 H), 3.54–3.52 (m, 1 H), 2.92–
2.89 (td, J = 13.6, 2.8 Hz, 1 H), 1.36 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ (major rotamer) = 155.9, 138.9,
137.0, 128.3, 128.2 (2 C), 127.9, 127.7, 127.1, 109.1, 74.5, 69.8,
67.1, 64.5, 64.4, 49.8, 39.1, 38.4, 24.1, 24.0, 19.6; δ (minor rotamer)
= 155.7, 137.3, 128.4, 127.7, 127.6, 127.3, 109.2, 75.7, 70.1, 66.8,
64.6, 64.4, 48.9, 39.2, 38.0, 24.6, 24.0, 19.9.
(2R,3S)-2-[(2-Methyl-1,3-dioxolan-2-yl)methyl]piperidin-3-ol
IR (neat): 3316, 3122, 2928, 2862, 2824, 1439, 1374, 1252, 1117,
1086, 1036, 958 cm–1.
1H NMR (500 MHz, CDCl3): δ = 4.01–3.96 (m, 4 H), 3.22–3.18
(ddd, J = 13.1, 8.7, 4.4 Hz, 1 H), 2.96–2.92 (m, 1 H), 2.56–2.53 (td,
J = 11.8, 2.7 Hz, 1 H), 2.52–2.46 (ddd, J = 11.0, 7.3, 3.7 Hz, 1 H),
2.24–2.21 (dd, J = 14.8, 3.7 Hz, 1 H), 2.09–2.04 (m, 1 H), 1.74–1.69
(dd, J = 14.8, 7.2 Hz, 1 H), 1.68–1.66 (m, 1 H), 1.54–1.50 (m, 1 H),
1.38 (s, 3 H), 1.35–1.27 (m, 1 H).
MS (APCI, +): m/z = 426.2 (M + 1).
HRMS (CI): m/z (M + H) calcd for C25H32NO5: 426.2280; found:
426.2284.
Benzyl (2R,3S)-3-(Benzyloxy)-2-(2-oxopropyl)piperidine-1-car-
boxylate (13)
To a solution of 12 (64 mg, 0.15 mmol) in acetone (2 mL) was add-
ed a solution of I2 (1.0 mg, 7.8 × 10–2 mmol, 5 mol%) in acetone (1
mL) at r.t. The solution was stirred at r.t. for 30 min and then con-
centrated. The residue was dissolved in CH2Cl2 (10 mL) and aq 5%
Na2S2O3 (5 mL) was added. The biphase was stirred vigorously for
a few minutes and the organic layer was separated. The aqueous lay-
er was extracted with CH2Cl2 (2 × 10 mL). The combined organic
layers were dried (Na2SO4), filtered, and concentrated. The residue
was purified by flash chromatography on silica gel (hexanes–EtO-
Ac, 7:3) to provide 48 mg (84%) of 13 as a colorless oil; Rf = 0.25
13C NMR (75 MHz, CDCl3): δ = 110.1, 72.2, 64.6, 64.4, 59.9, 46.1,
42.2, 34.2, 25.4, 24.1.
MS (APCI, +): m/z = 202.1 (M + 1).
HRMS (CI): m/z (M – H) calcd for C10H18NO3: 200.1287; found:
200.1287. m/z (M + H) calcd for C10H20NO3: 202.1443; found:
202.1444.
To a solution of the above amino alcohol (160 mg, 0.79 mmol) in
CH2Cl2 (10 mL) were added benzyl chloroformate (113 μL, 0.79
mmol), and Et3N (133 μL, 0.95 mmol) at 0 °C. The solution was
stirred at r.t. for 16 h, H2O (10 mL) was added and the resulting mix-
ture was extracted with CH2Cl2 (2 × 20 mL). The combined organic
layers were dried (Na2SO4) and concentrated. Purification of the
residue by flash chromatography on silica gel (hexanes–EtOAc,
2:3) provided 243 mg (91%) of 11 as a colorless oil; Rf = 0.30
(EtOAc–hexanes, 3:2); [α]D23 –20.9 (c 0.38, CHCl3).
25
(hexanes–EtOAc, 7:3); [α]D23 –29.2 (c 1.0, CHCl3) {Lit.3a [α]D
–26.8 (c 1.0, CHCl3) with 86% ee3a}.
IR (neat): 2943, 2866, 1689, 1422, 1355, 1254, 1200, 1132, 1050,
959, 737, 697 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.32–7.25 (m, 10 H), 5.15–5.09
(AB system, J = 12.5 Hz, 2 H), 5.01 (br s, 1 H), 4.65 (br s, 1 H), 4.51
(d, J = 12.0 Hz, 1 H), 4.13 (br s, 1 H), 3.44 (br s, 1 H), 2.84 (br s, 1
H), 2.69–2.58 (m, 2 H), 2.11 (br s, 3 H), 1.94–1.85 (m, 2 H), 1.65–
1.59 (m, 1 H), 1.40 (br d, J = 11.8 Hz, 1 H).
13C NMR (75 MHz, CDCl3): δ = 205.9, 155.9, 138.6, 136.8, 128.4,
128.3, 127.9, 127.8, 127.5, 127.4, 73.3, 70.2, 67.2, 49.7, 43.7, 39.5,
30.0, 24.4, 19.5.
11
IR (neat): 3467, 2940, 2880, 1672, 1428, 1352, 1257, 1153, 1117,
1077, 1033, 983 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.38–7.28 (m, 5 H), 5.15 (s, 2 H),
4.49 (br s, 1 H), 4.07 (br s, 1 H), 3.90–3.88 (br m, 5 H), 2.89 (br m,
1 H), 1.98–1.83 (m, 2 H), 1.82–1.77 (dd, J = 14.6, 6.1 Hz, 1 H),
1.74–1.68 (m, 3 H), 1.45–1.35 (br m, 1 H), 1.32 (br s, 3 H).
HRMS (CI): m/z (M + H) calcd for C23H28NO4: 382.2018; found:
382.2021.
1
13C NMR (75 MHz, CDCl3): δ = 156.3, 136.9, 128.4, 127.9, 127.8,
109.0, 68.2, 67.2, 64.54, 64.50, 54.0, 39.1, 38.2, 25.7, 23.9, 19.1.
The H NMR and 13C NMR data are in agreement with reported
data.3a,i See the Supporting Information for a detailed comparison.
MS (APCI, +): m/z = 336.2 (M + 1).
(2R,3S)-3-Benzyloxy-2-[2-oxoquinazolin-3(4H)-yl)propyl]pi-
peridine-1-carbamic Acid Benzyl Ester (14)
HRMS (CI): m/z (M + H) calcd for C18H26NO5: 336.1811; found:
336.1813.
Bromination3i of 13 and coupling of the bromide with 4-hydroxy-
quinazoline according to the literature procedure3g provided 14
(47%) as a colorless liquid; Rf = 0.30 (EtOAc); [α]D23 –24.8 (c 1.7,
CHCl3) {Lit.3m [α]D25 –22.0 (c 1.0, CHCl3)}.
Benzyl (2R,3S)-3-(Benzyloxy)-2-[(2-methyl-1,3-dioxolan-2-
yl)methyl]piperidine-1-carboxylate (12)
To a solution of the carbamate 11 (80 mg, 0.24 mmol) in THF (3
mL) under N2 at r.t. was added KH (30% dispersion in mineral oil,
32 mg, 0.24 mmol) followed by benzyl bromide (29 μL, 0.24 mmol)
IR (neat): 1726, 1674, 1610, 1424, 1358, 1257, 1085, 1049, 910
cm–1.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1863–1869

1868
S. V. Pansare, E. K. Paul
PAPER
1H NMR (500 MHz, CDCl3): δ = 8.28–8.26 (dd, J = 8.0, 1.5 Hz, 1
H), 7.92 (br s, 1 H), 7.79–7.73 (m, 2 H), 7.52–7.49 (m, 1 H), 7.32–
7.26 (m, 10 H), 5.18–5.15 (d, J = 12.4 Hz, 1 H), 5.11–5.09 (d, J =
12.4 Hz, 1 H), 5.01–4.98 (m, 1 H), 4.94 (br s, 1 H), 4.65–4.63 (m, 1
H), 4.54–4.52 (br d, J = 11.9 Hz, 1 H), 4.06 (br s, 1 H), 3.52 (br s, 1
H), 2.97 (br s, 1 H), 2.88–2.83 (dd, J = 14.7, 8.7 Hz, 1 H), 2.80–2.76
(br dd, J = 14.7, 6.1 Hz, 1 H), 1.94–1.88 (br m, 2 H), 1.75 (br s, 1
H), 1.70–1.63 (m, 1 H), 1.45–1.43 (app br d, J = 12.5 Hz, 1 H).
13C NMR (75 MHz, CDCl3): δ = 200.0, 160.9, 156.2, 148.2, 146.5,
138.3, 136.5, 134.5, 128.5, 128.4, 128.0, 127.8, 127.7, 127.6, 127.5,
127.3, 126.7, 121.8, 73.7, 70.4, 67.4, 53.9, 50.6, 41.0, 39.6, 24.3,
19.4.
(3) Enantioselective syntheses of febrifugine: (a) McLaughlin,
N. P.; Evans, P. J. Org. Chem. 2010, 75, 518. (b) Wang, R.;
Fang, K.; Sun, B.; Xu, M.; Lin, G. Synlett 2009, 2301.
(c) Wijdeven, M. A.; van den Berg, R. J. F.; Wijtmans, R.;
Botman, P. N. M.; Blaauw, R. H.; Schoemaker, H. E.; van
Delft, F. L.; Rutjes, F. P. J. T. Org. Biomol. Chem. 2009, 7,
2976. (d) Liu, R.; Huang, W.; Ma, J.; Wei, B.; Lin, G.
Tetrahedron Lett. 2009, 50, 4046. (e) Ashoorzadeh, A.;
Archibald, G.; Caprio, V. Tetrahedron 2009, 65, 4671.
(f) Emmanuvel, L.; Kamble, D. A.; Sudalai, A.
Tetrahedron: Asymmetry 2009, 20, 84. (g) Sukemoto, S.;
Oshige, M.; Sato, M.; Mimura, K.; Nishioka, H.; Abe, H.;
Harayama, T.; Takeuchi, Y. Synthesis 2008, 3081. (h) Sieng,
B.; Ventura, O. L.; Bellosta, V.; Cossy, J. Synlett 2008,
1216. (i) Katoh, M.; Matsune, R.; Honda, T. Heterocycles
2006, 67, 189. (j) Huang, P.; Wei, B.; Ruan, Y. Synlett 2003,
1663. (k) Ooi, H.; Urushibara, A.; Esumi, T.; Iwabuchi, Y.;
Hatakeyama, S. Org. Lett. 2001, 3, 953. (l) Takeuchi, Y.;
Azuma, K.; Takakura, K.; Abe, H.; Kim, H.-S.; Wataya, Y.;
Harayama, T. Tetrahedron 2001, 57, 1213. (m) Taniguchi,
T.; Ogasawara, K. Org. Lett. 2000, 2, 3193. (n) Kobayashi,
S.; Ueno, M.; Suzuki, R.; Ishitani, H. Tetrahedron Lett.
1999, 40, 2175. (o) Okitsu, O.; Suzuki, R.; Kobayashi, S.
J. Org. Chem. 2001, 66, 809. (p) Kobayashi, S.; Ueno, M.;
Suzuki, R.; Ishitani, H.; Kim, H.-S.; Wataya, Y. J. Org.
Chem. 1999, 64, 6833.
MS (APCI, +): m/z = 526.2 (M + 1).
HRMS (EI+): m/z (M + H) calcd for C31H31N3O5: 525.2264; found:
525.2285.
Spectroscopic data (IR, 1H NMR, 13C NMR) and optical rotation for
14 are in agreement with the reported data.3a,m
3-{3-[(2R,3S)-3-Hydroxypiperidin-2-yl]-2-oxopropyl}quinazo-
lin-4(3H)-one [(+)-Febrifugine, 1]
Acid hydrolysis of 14 and purification of the crude product accord-
ing to the literature procedure3a provided (+)-1 (75%); amorphous
white solid; mp 133–136 °C; (Lit.3a mp 135–138 °C); Rf = 0.20
(CH2Cl2–MeOH–Et3N, 9.00:0.95:0.05); [α]D23 +17.7 (c 0.6, EtOH)
{Lit.3a [α]D25 +14.6 (c 1.0, EtOH)}.
IR (neat): 3306, 3052, 2926, 2851, 2687, 1726, 1669, 1607, 1468,
1361, 1325, 1078, 997 cm–1.
(4) Oalmann, C. J.; Richard, J.; Bockovich, N. Abstracts of
Papers, 232nd ACS National Meeting, San Francisco, USA,
Sept. 10–14, 2006; American Chemical Society:
1H NMR (300 MHz, CDCl3): δ = 8.27 (d, J = 7.9 Hz, 1 H), 7.91 (s,
1 H), 7.78–7.71 (m, 2 H), 7.54–7.48 (m, 1 H), 4.93–4.80 (AB sys-
tem, J = 17.5 Hz, 2 H), 3.30–3.26 (m, 1 H), 3.11 (dd, J = 16.0, 4.5
Hz, 1 H), 2.96 (d, J = 11.9 Hz, 1 H), 2.88–2.87 (m, 1 H), 2.64 (dd,
J = 16.1, 7.5 Hz, 1 H), 2.58 (dt, J = 12.2, 3.0 Hz, 1 H), 2.22 (br s, 2
H), 2.10–2.06 (m, 1 H), 1.74–1.70 (m, 1 H), 1.53–1.47 (m, 1 H),
1.38–1.30 (m, 1 H).
Washington DC; ORGN-71.
(5) Edgar, S. A.; Flanagan, C. Poultry Sci. 1979, 58, 1483.
(6) (a) Pines, M.; Vlodovsky, I.; Nagler, A. Drug Dev. Res.
2000, 50, 371. (b) De Jong, M. J. A.; Dumez, H.; Verweij, J.;
Yarkoni, S.; Snyder, D.; Lacombe, D.; Marréaud, S.;
Yamaguchi, T.; Punt, C. J. A.; van Oosterom, A. Eur. J.
Cancer 2006, 42, 1768.
13C NMR (75 MHz, CDCl3): δ = 202.7, 161.0, 148.2, 146.4, 134.5,
127.6, 127.4, 126.8, 121.8, 72.2, 60.2, 54.9, 46.0, 44.0, 34.5, 25.6.
(7) DeSelm, C. J.; Zou, W.; Teitelbaum, S. L. J. Cell. Biochem.
2012, 113, 3086.
The 1H NMR and 13C NMR data are in agreement with the reported
(8) Keller, T. L.; Zocco, D.; Sundrud, M. S.; Hendrick, M.;
Edenius, M.; Yum, J.; Kim, Y.-J.; Lee, H.-K.; Cortese, J. F.;
Wirth, D. F.; Dignam, J. D.; Rao, A.; Yeo, C.-Y.;
Mazitschek, R.; Whitman, M. Nat. Chem. Biol. 2012, 8, 311.
(9) For an early report, see: (a) Fleet, G. W. J.; Ramsden, N. G.;
Witty, D. R. Tetrahedron Lett. 1988, 29, 2871. Recent
reports: (b) Chavan, S. P.; Dumare, N. B.; Harale, K. R.;
Kalkote, U. R. Tetrahedron Lett. 2011, 52, 404.
data.3a,i See the Supporting Information for a detailed comparison.
Acknowledgment
Financial support from the Natural Sciences and Engineering Re-
search Council of Canada and the Canada Foundation for Innovati-
on is gratefully acknowledged.
(c) Emmanuvel, L.; Sudalai, A. Tetrahedron Lett. 2008, 49,
5736.
(10) Recent reviews on the vinylogous aldol reaction:
(a) Casiraghi, C.; Battistini, L.; Curti, C.; Rassu, G.; Zanardi,
F. Chem. Rev. 2011, 111, 3076. (b) Pansare, S. V.; Paul, E.
K. Chem. Eur. J. 2011, 17, 8770. (c) Bisai, V. Synthesis
2012, 44, 1453. Recent reports on the direct vinylogous aldol
reactions of crotonolactones: (d) Pansare, S. V.; Paul, E. K.
Chem. Commun. 2011, 47, 1027. (e) Yang, Y.; Zheng, K.;
Zhao, J.; Lin, L.; Liu, X.; Feng, X. J. Org. Chem. 2010, 75,
5382. (f) Ube, H.; Shimada, N.; Terada, M. Angew. Chem.
Int. Ed. 2010, 49, 1858. (g) Pansare, S. V.; Paul, E. K. Org.
Biomol. Chem. 2012, 10, 2119.
(11) Selected reports on the asymmetric vinylogous Mukaiyama
aldol reaction of silyloxyfurans: (a) Evans, D. A.;
Kozlowski, M. C.; Murry, J. A.; Burgey, C. S.; Campos, L.
R.; Connell, B. T.; Staples, R. J. J. Am. Chem. Soc. 1999,
121, 669. (b) Singh, R. P.; Foxman, B. M.; Deng, L. J. Am.
Chem. Soc. 2010, 132, 9558. (c) Zhu, N.; Ma, B.; Zhang, Y.;
Wang, W. Adv. Synth. Catal. 2010, 352, 1291. (d) Frings,
M.; Atodiresei, I.; Wang, V.; Runsink, J.; Raabe, G.; Bolm,
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
n
nfomartit
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Synthesis 2013, 45, 1863–1869
© Georg Thieme Verlag Stuttgart · New York

PAPER
C. Chem. Eur. J. 2010, 16, 4577. (e) Ferrié, L.; Figadére, B.
Synthesis of (+)-Febrifugine
1869
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(15) The stereochemical assignments for 6 were based on our
earlier studies of the organocatalytic vinylogous aldol
reaction of γ-crotonolactone in which aromatic aldehydes
provided the anti-aldol as the major product. For the anti and
syn assignments in the present study, the trend in chemical
shifts of the methine protons (CHO) in these aldol products
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Synthesis 2013, 45, 1863–1869