Practical racemic and asymmetric formal total syntheses of the homocamptothecin derivative and anticancer agent diflomotecan via tertiary homoallylic alcohols as masked aldol equivalents

Article abstract of DOI:10.3987/COM-06-S(K)10

An efficient and scalable racemic as well as an asymmetric approach to the key building block for the synthesis of homocamptothecin and derivatives thereof such as the potent anticancer agent diflomotecan (4) are described. In the asymmetric route, the pyridone ring was assembled applying straightforward carbonyl chemistry. The selective generation of the quaternary stereocenter was accomplished by self reproduction of chiral information starting from (S)-2-hydroxybutyric acid (22) utilizing an allyl moiety to act as a masked carbonyl group. The optically pure DE building block (7) (er > 99.95 : 0.05) was obtained in 9.0% overall yield over 10 steps (two chromatographic purifications). The asymmetric "de novo pyridone approach" has the potential to serve as the basis for a technical synthesis of diflomotecan.

Full text of DOI:10.3987/COM-06-S(K)10

HETEROCYCLES, Vol. 72, 2007
255
HETEROCYCLES, Vol. 72, 2007, pp. 255 - 273. © The Japan Institute of Heterocyclic Chemistry
Received, 6th October, 2006, Accepted, 16th November, 2006, Published online, 17th November, 2006. COM-06-S(K)10
PRACTICAL RACEMIC AND ASYMMETRIC FORMAL TOTAL
SYNTHESES OF THE HOMOCAMPTOTHECIN DERIVATIVE AND
ANTICANCER AGENT DIFLOMOTECAN VIA TERTIARY
HOMOALLYLIC ALCOHOLS AS MASKED ALDOL EQUIVALENTS
René Peters,*†§ Christian Diolez,‡ Alain Rolland,‡ Eric Manginot,# and Marc
Veyrat#
(†) F. Hoffmann-La Roche Ltd, Pharmaceuticals Division, Safety & Technical
Sciences, Synthesis and Process Research, Grenzacherstr. 124, CH-4070 Basel,
Switzerland
(‡) Ipsen, 5 avenue du Canada, F-91966 Les Ulis, France
(#) Expansia, route d’Avignon, F-30390 Aramon, France
(§) Current address: ETH Zürich, Laboratory of Organic Chemistry,
Wolfgang-Pauli-Str. 10, Hönggerberg HCI E 111, CH-8093 Zürich, Switzerland
E-mail: peters@org.chem.ethz.ch
Abstract – An efficient and scalable racemic as well as an asymmetric approach
to the key building block for the synthesis of homocamptothecin and derivatives
thereof such as the potent anticancer agent diflomotecan (4) are described. In the
asymmetric route, the pyridone ring was assembled applying straightforward
carbonyl chemistry. The selective generation of the quaternary stereocenter was
accomplished by self reproduction of chiral information starting from
(S)-2-hydroxybutyric acid (22) utilizing an allyl moiety to act as a masked
carbonyl group. The optically pure DE building block (7) (er > 99.95 : 0.05) was
obtained in 9.0% overall yield over 10 steps (two chromatographic purifications).
The asymmetric "de novo pyridone approach" has the potential to serve as the
basis for a technical synthesis of diflomotecan.

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INTRODUCTION
Almost five decades after its first isolation from the Chinese tree Camptotheca accuminata by Wani and
Wall,1 the alkaloid camptothecin (CPT, 1) still serves as a very attractive lead structure for the
development of new anticancer drugs due to its potent antiproliferative activity.2 The structure of the
pentacyclic system, which was published in 1966 eight years after the isolation of CPT,3 contains a highly
electrophilic α-hydroxy-δ-lactone ring (ring E), which rapidly hydrolyzes in basic and neutral media
leading to the open chain carboxylate form 2 (Scheme 1), which is biologically almost inactive.
O
O
N
C
D
A
E
B
O
N
Et
OH
CPT (1)
OH−
O
OH
O
N
C
A
D
B
O
N
Et
OH
2
Scheme 1. Hydrolysis of CPT leading to biologically almost inactive 2.
This equilibrium is shifted toward the carboxylate form in human plasma thus explaining the lower
efficacy of most CPT analogues in clinical trials compared to the very promising results measured with
Xenograft models.4 In order to suppress this unwanted hydrolysis, a novel CPT analogue, the so called
homocamptothecin (hCPT, 3, Figure 1), entailing a seven membered β-hydroxy-ε-lactone ring has been
developed by the Ipsen scientists Bigg, Lavergne et al.5 Prior to their investigations, it was generally
accepted that an α-hydroxy-δ-lactone is an indispensable structural feature for the anticancer activity of
CPT derivatives. However, hCPT retains the TOPO I mediated activity and at the same time displays
enhanced stability against hydrolysis. hCPT thus provided an excellent template for the preparation of
new TOPO I inhibitors with high cytotoxicity toward solid tumor cell lines. The most promising hCPT
derivative so far is diflomotecan (4) bearing two fluorine atoms at ring A.

HETEROCYCLES, Vol. 72, 2007
257
O
O
N
O
N
Et
OH
hCPT (3)
O
F
F
O
N
O
N
Et
OH
diflomotecan (4)
Figure 1. hCPT (3) and its currently most active derivative diflomotecan (4).
The convergent Ipsen discovery chemistry synthesis utilized a coupling of DE fragment (7) with AB
quinoline derivatives (6) via a Mitsunobu alkylation of the pyridone N atom followed by a Heck
cyclization to build up ring C of the pentacycle (Scheme 2).5 This strategy was previously developed by
Comins et al. for the total synthesis of (S)-CPT (1).6 Due to its convergent character and the robustness of
the final two steps we decided to maintain this concept for the production of kilogram amounts of 4 for
clinical trials.
alkylation
O
Y
O
N
A
X
C
B
D
E
O
N
Et
OH
Heck coupling
5
O
Y
O
HN
OH
+
D
E
X
A
O
B
N
Cl
Et
OH
6
7
Scheme 2. Coupling strategy of DE fragment (7) with AB quinoline derivatives (6).
In a previous paper, we have presented two practical approaches to the DE fragment (7) highlighting the
development of stoichiometric asymmetric acetate aldol additions to pyridinyl ketones.7 In this paper, we
disclose a racemic and an asymmetric route toward 7, which both rely on the formation of homoallylic

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HETEROCYCLES, Vol. 72, 2007
tertiary alcohols acting as masked aldol equivalents, since the oxidative cleavage of the homoallylic C=C
double bond furnishes the aldol structural subunit.
RESULTS AND DISCUSSION
Racemic Allyl Addition Approach
The nicotinic amide derivative (10) was prepared over two steps starting from 2-chloronicotinic acid (8)
by acid chloride formation followed by reaction in the same pot with diethylamine yielding 9 (Scheme 3).
SOCl2, then
t-BuLi, TMEDA,
HNEt2, DCM,
0 °C
NaOMe,
MeOH
OMe
Cl
NEt2
O
THF, −78 °C,
then 11
Cl
NEt2
O
CO2H
N
N
N
O
75%
(2 steps)
66%
N
10
8
9
11
O
allylMgBr,
THF, −78 °C,
then HCl
OMe
OMe
OMe
NEt2
O
O3, HOAc/
H2O, 0 °C
LiAlH4,
THF
N
OH
OH
N
N
O
O
O
69%
84%
(2 steps)
Et
13
Et
14
Et
12
0.1 TEMPO,
NaOCl, toluene/
acetone/H2O, 0 °C
OMe
Et
O
OMe
DME, HBr,
50 °C
O
O
O
O
N
HN
N
O
OH
64%
(2 steps)
Et
Et
OH
16
OH
OH
15
(rac)-7
overall yield:
18% (8 steps)
Scheme 3. Racemic allyl addition approach.
Subsequent nucleophilic displacement of the 2-chloro substituent by a methoxy group using NaOMe
provided 10. Ortho-Lithiation of the pyridine-4-position of 10 was accomplished by slow addition of a
solution of 10 to a THF solution of tert.-BuLi / TMEDA at −78 °C. The carbanion thus formed was
trapped by morpholine amide (11), which was prepared from propionyl chloride using standard
conditions.8 Metalation of 10 was accompanied by intermolecular attack of the generated lithiated species
at the amide functionality of 10 resulting in formation of a bispyridinyl ketone as side product, which

HETEROCYCLES, Vol. 72, 2007
259
became the main product, when the base was added to a solution of 10. After recrystallization ketone (12)
was subjected to a nucleophilic allyl Grignard addition, which proceeded smoothly providing the
corresponding tertiary alcohol leading to γ-lactone (13) during acidic workup with aqueous HCl. The
γ-lactone moiety of 13 was then reduced by LiAlH4 providing diol (14), which was directly used in an
ozonolysis without protection of the free hydroxyl groups. The oxidative cleavage of the C=C double
bond proceeded much cleaner in aqueous acetic acid than in dichloromethane and provided 7-membered
lactol (15) in the form of two diastereomers (dr 5 : 1). Lactol (15) was subsequently smoothly oxidized by
NaOCl and catalytic amounts of TEMPO furnishing lactone (16). Methyl ether cleavage with aqueous
HBr in DME finally provided (rac)-7 in 18% overall yield (over 8 steps).
After this racemic proof of concept for the allyl approach, a stereoselective version was sought-after.
Several enantiomerically pure analogues of 10 were synthesized bearing either a chiral tertiary amide
moiety (17a-f) or an oxazoline ring (17g,h) at the pyridine 3-position (Scheme 4). However, none of these
derivatives allowed for highly efficient acylation of the pyridine 4-position in acceptable yields via
ortho-metalation due to low conversion and decomposition. The best result was obtained using SMP
amide (17a), resulting in ca. 40-50% conversion to 18a (ca. 10% dimerization) with 1.6 equiv. tert-BuLi /
TMEDA at −78 °C. Since replacement of tert.-BuLi by a safer base and variation of the reaction
conditions did not lead to higher yields, this approach was abandoned in favor of the 'de novo' approach
described below.
OMe
OMe
Y
O
OMe
Y
1. base
2. 11
M
N
N
X
O
N
X
O
Et
(R)-13
Et
17
18
Ph
Ph
O
O
O
OMe
Y
MeO
=
O
N
N
N
N
X
Ph
O
O
O
O
a
b
d
c
O
Bn
OBn
O
BnO
N
N
N
N
O
O
O
O
g
h
e
f
Scheme 4. Planned asymmetric allyl additions to ketones (18).

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HETEROCYCLES, Vol. 72, 2007
Asymmetric Synthesis of 7: de Novo Pyridone Approach
All existing approaches reported so far for the synthesis of DE-fragment (7) started from commercially
available pyridine building blocks, which were regioselectively functionalized in the 3- or 4-position by
lithiation reactions.5,7,9 In a conceptually different approach toward 7, we present herein the construction
of the pyridone ring via straightforward carbonyl chemistry. The retrosynthetic analysis depicted in
Scheme 5 is based on our previously reported practical formal total synthesis of (S)-CPT.10 The
quaternary stereocenter was introduced by self reproduction of chiral information11,12 starting from
commercially available optically pure (S)-hydroxybutyric acid (22) (Scheme 6).13 This concept finally
gave access to lactone intermediate [(R)-13], the optically active complement of 13 used in the racemic
"allyl addition approach" described above (Scheme 3).
asymmetric
γ-lactone
reduction
allylation
O
ε-lactone
O
O
O
O
O
O
formation
O
HN
HN
OH
OH
HN
EtO
Et
OH
O
O
O
HO
oxidative
C=C bond
cleavage
Et
Et
Et
Et
OH
20
22
21
19
7
Knoevenagel
condensation /
lactonization
pyridone
formation
Scheme 5. Retrosynthetic analysis of 7.
Chiral acetal (23) was prepared according to literature in high yield with the kinetically favored cis
diastereomer (dr = 92.7 : 7.3, 1H-NMR) being preferentially formed (Scheme 6).14,15 Deprotonation of 23
with LDA at low temperature and subsequent trapping of the enolate with allylbromide provided the
known acetal (24) (dr > 95 : 5, er = 92.0 : 8.0).14 MeLi addition to the lactone group and subsequent
aqueous HCl workup furnished α-hydroxy ketone (25), which was then exposed to a tandem
Knoevenagel condensation / lactonization with diethylmalonate. The resulting γ-lactone (21) was
subsequently purified by column chromatography. The strategy of our de novo pyridone formation is
based on the pronounced activation of the lactone β-methyl group in 21. In fact, 21 can be regarded as a
vinylogous malonate thus allowing easy dienolate formation with bases like sodium ethoxide. The
deprotonated species can be trapped by triazine as HCN equivalent16 and furnished pyridone (20) as
crystalline material.

HETEROCYCLES, Vol. 72, 2007
261
pivaldehyde,
PTSA, H2SO4,
O
O
O
LDA, THF, −95 °C,
MeLi, THF,
−78 °C
O
Et
pentane, ∆
then allyl bromide
OH
Et
O
O
Et
OH
22
HO
O
O
70%
87%
89%
Et
dr > 95 : 5
er = 92 : 8
dr = 93 : 7
25
23
24
O
O
OMe
N
O
O
O
Me3O+BF4 ,
DCM
-
LiAlH4,
THF
diethyl malonate,
Cs2CO3, EtOH
triazine,
NaH, EtOH
EtO
HN
O
O
O
column
chromatography
er = 89 : 11
59% (2 steps)
crystallization
Et
Et
(R)-13
Et
21
20
TEMPO,
NaOCl,
toluene/
acetone/
H2O, 0 °C
O
DME,
HBr,
50 °C
OMe
OH
OMe
Et
OMe
Et
O3, HOAc/
H2O, 0 °C
O
O
O
HN
N
N
N
O
OH
OH
O
44%
(4 steps)
er = 89 : 11
64%
Et
Et
(R)-14
crystallization
OH
OH
OH
column
(R)-15
7
(R)-16
chromatography
overall yield:
9.0% (10 steps)
er > 99.95 : 0.05
Scheme 6. De novo pyridone approach.
All attempts to reduce lactone (20) to the corresponding diol were unsuccessful, since the reduction
stopped at the lactol stage with Al-based hydride reagents such as LiAlH4, Red-Al or AlH3 possibly due
to the formation of stable Al chelate complexes. Boron derived reducing agents like NaBH4,
Na[HB(OAc)3], superhydride or K-selectride resulted mainly in decomposition of 20. Complex (26) was
identified by GC-MS as the main product of LiAlH4 reductions after aqueous workup with HCl (Figure
2).
Cl
Al
O
O
N
O
Et
26
Figure 2. Main product of the LiAlH4 reduction of 20.

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HETEROCYCLES, Vol. 72, 2007
Attempts to further reduce (26) e.g. by Meerwein-Ponndorf reduction failed as well. Consequently, we
chose to protect the pyridone oxygen. Silyl protection (TMS, TBS, TIPS) was ineffective, since the
silyloxy pyridines were found to be too labile. Therefore, we chose a methyl protecting group which led
to the optically active pyridine intermediate [(R)-13]. The regioselectivity problem for the methylation
−
(N- versus O-alkylation) was solved by using Meerwein’s salt (Me3O+BF4 ). In contrast, methyl iodide in
combination with Ag2CO3 as base or dimethylsulfate resulted in preferential N-alkylation, which was also
observed when bases like proton sponge or 2,6-di-tert.-butylpyridine were employed in combination with
Meerwein’s salt. After a solvent screening (dichloromethane, dichloroethane, acetone, THF)
dichloromethane was selected as solvent of choice (er of (R)-13: 88.5 : 11.5 as determined by chiral GC).
The subsequent reduction, ozonolysis, TEMPO oxidation (er of (R)-16: 88.5 : 11.5 as determined by
chiral HPLC) and methyl ether cleavage reactions paralleled the racemic allyl addition approach shown in
Scheme 3 (yield: 27% over 5 steps (20 Æ 7), average yield per step: 77%). Gratifyingly, the er was
significantly increased in the final step due to preferential crystallization of the (R)-7 out of the reaction
mixture. The key building block (7) was obtained in optically pure form as determined by chiral HPLC.
The yield of the final step highly depends on the er of [(R)-16], since the mother liquid contains the
almost racemic product. Therefore, starting material (R)-16 with an er of 88.5 : 11.5 (ee = 77%) could, in
principal, lead to a maximum yield of 100 − (2 * 11.5) = 77% for optically pure material. No purification
was required for intermediates [(R)-13], [(R)-14] and [(R)-15], while (R)-16 was purified by column
chromatography.17 Enantiomerically pure pyridone (7) was thus prepared in 9.0% overall yield over 10
steps.
Summary
In summary, we have described both an efficient racemic and an asymmetric approach to DE ring
fragment (7), which is the required key building block for the synthesis of homocamptothecin and
derivatives thereof such as the potent anticancer agent diflomotecan (4). Especially the asymmetric "de
novo pyridone approach" has the potential to serve as the basis for a technical synthesis of diflomotecan.
The pyridone ring was assembled applying straightforward carbonyl chemistry and the selective
generation of the quaternary stereocenter was accomplished by self reproduction of chiral information
starting from (S)-2-hydroxybutyric acid (22) by introducing an allyl group serving as a masked carbonyl
group. The optically pure DE building block 7 (er > 99.95 : 0.05) was obtained in 9.0% overall yield over
10 steps (two chromatographies).
EXPERIMENTAL

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263
General Methods. Unless otherwise noted, solvents and reagents were used as received from commercial
suppliers. All reactions were carried out under argon atmosphere. Thin-layer chromatography (TLC) was
performed on silica gel 60 F254 plates, 0.25 mm. Qualitative HPLC was performed with UV detection at a
wavelength of 210 nm using Chromolith Performance columns (100 x 4.6 mm) with gradient eluent
H2O/MeCN containing 10% of a phosphate buffer at pH 3.0. 1H NMR are given in ppm (δ) and coupling
constants J are reported in Hz. Peaks in IR spectra are reported in cm−1. Low resolution electron impact
mass spectra (EI-MS) were obtained at an ionization voltage of 70 eV. Data are reported in the form of m/z
(intensity relative to base = 100).
Synthesis of 2-chloro-N,N-diethylnicotinamide (9)
Thionylchloride (99%, 15.0 mL, 204.0 mmol, 1.31 equiv) and DMF (1.0 mL, 13.0 mmol, 0.08 equiv) were
added to a stirred solution of 2-chloronicotinic acid (8, 98%, 25.0 g, 155.5 mmol) in acetonitrile (250 mL).
The mixture was heated to reflux and monitored by HPLC (sample preparation: 5 µL of the reaction
mixture were added to 0.2 mL MeOH). After 5.5 h, the reaction mixture was cooled to room temperature
and all volatiles were removed in a rotary evaporator (40 °C/10 mbar). The residual oil was dissolved in
dichloromethane (250 mL) and the solution was cooled to 0 °C. Diethylamine (48.5 mL, 466.5 mmol, 3.0
equiv) was added and the solution was allowed to slowly warm up to room temperature overnight. Aqueous
HCl (65 mL, 1.0 M) was added in order to adjust pH 8 and the phases were separated. The aqueous phase
was extracted with dichloromethane (2 x 50 mL). The combined organic phases were washed with brine
(200 mL), dried over sodium sulfate (15 g, 30 min) and filtered. The filter cake was washed with
dichloromethane (30 mL). After removal of solvent in a rotary evaporator (40 °C/8 mbar), the crude
product (36.78 g, 107% by weight) was obtained as a dark green oil. 1H NMR (300 MHz, CDCl3): δ 8.43
(dd, 1H, J = 4.8 Hz, J = 2.0 Hz), 7.63 (dd, 1H, J = 7.5 Hz, J = 1.9 Hz), 7.30 (dd, 1H, J = 7.5 Hz, J = 4.7 Hz),
3.80 (m, 1H), 3.38 (m, 1H), 3.17 (m, 2H), 1.28 (t, 3H, J = 7.1 Hz), 1.09 (t, 3H, J = 7.1 Hz) ppm.
Synthesis of N,N-diethyl-2-methoxynicotinamide (10)
9 (37.10 g, 174.4 mmol) dissolved in methanol (38 mL) was added to a stirred solution of NaOMe (272.5
mL, 3.2 M in MeOH, 872.0 mmol, 5.0 equiv) at room temperature. The solution was heated to 90 °C (oil
bath temperature) and the reaction was monitored by HPLC. After 6 h 40 min, the mixture was cooled to
room temperature and quenched by addition of saturated aqueous NH4Cl (250 mL) and water (300 mL).
The product was extracted with ethyl acetate (3 x 200 mL) and the combined organic phases were washed
with brine (400 mL), dried over sodium sulfate (40 g, 30 min) and filtered. The filter cake was washed with
ethyl acetate (80 mL). After removal of solvent in a rotary evaporator (40 °C/10 mbar), the crude product
(31.26 g, 86% by weight) was obtained as a brown oil. Purification was achieved by crystallization. The
crude product was dissolved in diisopropylether (193 mL) and isopropanol (12.5 mL) at reflux temperature.
After hot filtration from undissolved material, heptane (230 mL) was added at room temperature and the

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HETEROCYCLES, Vol. 72, 2007
resulting suspension was allowed to stand at 5 °C. After 3 days, the precipitate was collected by filtration
and washed with heptane (20 mL) furnishing product (10) (25.60 g, 12.29 mmol, 70% by weight (75% over
2 steps from 8)) as a dark brown solid. mp 88 °C; 1H NMR (300 MHz, CDCl3): δ 8.18 (dd, 1H, J = 4.9 Hz,
J = 2.0 Hz), 7.52 (dd, 1H, J = 7.2 Hz, J = 1.9 Hz), 6.92 (dd, 1H, J = 7.3 Hz, J = 5.0 Hz), 3.96 (s, 3H), 3.56 (q,
2H, J = 7.1 Hz), 3.14 (q, 2H, J = 7.1 Hz), 1.25 (t, 3H, J = 7.1 Hz), 1.06 (t, 3H, J = 7.1 Hz) ppm; 13C NMR
(100 MHz, CDCl3): δ 167.1, 159.5, 147.4, 136.5, 121.1, 116.7, 53.6, 42.9, 39.1, 14.0, 12.8 ppm; IR (Nujol)
2924, 1627, 1579, 1463, 1404, 1304, 1258, 1189, 814 cm−1; MS (ESI) m/z 209.2 (MH+); HRMS (ESI POS)
calcd for C11H17N2O2 (MH+) 209.1290, found 209.1290; Anal. Calcd for C11H16N2O2: C, 63.44; H, 7.74; N,
13.45. Found: C, 63.28; H, 7.57; N, 13.45.
Synthesis of N,N-diethyl-2-methoxy-4-propionylnicotinamide (12)
A solution of TMEDA (99.5%, 11.7 mL, 76.8 mmol, 1.6 equiv) and tert.-butyllithium (51.2 mL, 1.5 M in
pentane, 76.8 mmol, 1.6 equiv) in THF (150 mL at −78 °C) was treated dropwise over 20 min with a
solution of 10 (10.0 g, 48.0 mmol) in THF (50 mL). After 1 h 45 min, a solution of 11 (12.38 g, 86.4 mmol,
1.8 equiv) in THF (25 mL) was added within 20 min and stirring was continued for 2 h at −78 °C. The
reaction was then quenched by addition of saturated aqueous NH4Cl (250 mL). After dilution with toluene
(500 mL) and water (250 mL), the phases were separated and the organic phase was washed with brine (300
mL), dried over Na2SO4 (20 g, 30 min) and filtered. The filter cake was washed with toluene (40 mL). After
evaporation of solvent in a rotary evaporator (50 °C/10 mbar), a yellow solid was obtained (13.38 g, 105%
by weight). The crude product was dissolved in TBME (13 mL) and heptane (65 mL) was subsequently
added. The resulting suspension was allowed to stand at 5 °C. After 3 days, the precipitate was collected by
filtration and washed with heptane (20 mL) furnishing product (12) (8.37 g, 31.66 mmol, 66% by weight) as
orange crystals. mp 92 °C; 1H NMR (300 MHz, CDCl3): δ 8.26 (d, 1H, J = 5.2 Hz), 7.09 (d, 1H, J = 5.3 Hz),
3.97 (s, 3H), 3.68 (m, 1H), 3.47 (m, 1H), 3.13 (q, 2H, J = 7.2 Hz), 2.89 (m, 2H), 1.27 (t, 3H, J = 7.1 Hz),
1.16 (t, 3H, J = 7.3 Hz), 1.08 (t, 3H, J = 7.2 Hz) ppm; 13C NMR (100 MHz, CDCl3): δ 202.0, 166.0, 160.5,
147.5, 145.4, 119,1, 113.4, 54.1, 42.9, 38.7, 34.4, 13.3, 12.2, 7.6 ppm; IR (Nujol) 2924, 1702, 1629, 1582,
1558, 1453, 1379, 1311, 1286, 1069, 1018, 836 cm−1; MS (ESI) m/z 265.2 (MH+); HRMS (ESI POS) calcd
for C14H21N2O3 (MH+) 265.1552, found 265.1553; Anal. Calcd for C14H20N2O3: C, 63.62; H, 7.63; N, 10.60.
Found: C, 63.56; H, 7.53; N, 10.58.
Synthesis of 1-allyl-1-ethyl-4-methoxy-1H-furo[3,4-c]pyridin-3-one (13)
A solution of 12 (5.0 g, 18.9 mmol) in THF (25 mL) was added at −78 °C to a stirred solution of allyl
magnesium bromide (28.4 mL, 1 M in Et2O, 28.4 mmol, 1.50 equiv) in THF (100 mL). After 2 h at −78 °C,
aqueous 1 M HCl (165 mL, 165.0 mmol, 8.7 equiv) was added and stirring was continued for 18 h at room
temperature. The pH was then adjusted to 5 by addition of potassium dihydrogen phosphate. The resulting
suspension was extracted with ethyl acetate (2 x 150 mL) and the combined organic phases were washed

HETEROCYCLES, Vol. 72, 2007
265
with brine (300 mL), dried over Na2SO4 (20 g, 30 min) and filtered. The solid was washed with ethyl
acetate (40 mL). After evaporation of solvent in a rotary evaporator (40 °C/10 mbar), the crude product
1
(4.59 g, 19.7 mmol, 104% by weight) was obtained as a beige solid. mp 89 °C; H NMR (300 MHz,
CDCl3): δ 8.37 (d, 1H, J = 5.3 Hz), 6.87 (d, 1H, J = 5.3 Hz), 5.53 (m, 1H), 5.08 (br. d, 1H, J = 0.9 Hz), 5.03
(dm, 1H, J = 5.5 Hz), 4.13 (s, 3H), 2.71 (ddt, 1H, J = 14.1 Hz, J = 7.5 Hz, J = 1.1 Hz), 2.60 (ddt, 1H, J = 14.2
Hz, J = 7.0 Hz, J = 1.1 Hz), 2.10 (dq, 1H, J = 14.5 Hz, J = 7.3 Hz), 1.89 (dq, 1H, J = 14.5 Hz, J = 7.5 Hz),
13
0.76 (t, 3H, J = 7.5 Hz) ppm; C NMR (100 MHz, CDCl3): δ 166.2, 163.9, 160.6, 151.4, 129.2, 119.6,
108.9, 108.4, 87.5, 53.3, 41.4, 29.6, 6.4 ppm; IR (ATR-FTIR) 2969, 1758, 1642, 1607, 1592, 1474, 1409,
1329, 1239, 1134, 1020, 920 cm−1; MS (EI) m/z (rel. intensity) 234 (0.4), 192 (100); HRMS (ESI POS)
calcd for C13H16NO3 (MH+) 234.1130, found 234.1127; Anal. Calcd for C13H15NO3: C, 66.94; H, 6.48; N,
6.00. Found: C, 66.66; H, 6.58; N, 5.83.
Synthesis of 3-(3-hydroxymethyl-2-methoxy-pyridin-4-yl)-hex-5-en-3-ol (14)
A solution of lithium aluminum hydride (4.46 mL, 1 M in THF, 4.46 mmol, 0.52 equiv) was added at
−78 °C to a stirred solution of 13 (2.0 g, 8.57 mmol) in THF (40 mL). After 10 min, the cooling bath was
replaced by an ice bath. After 90 min at 0 °C, stirring was continued at room temperature. The reaction was
monitored by HPLC. After 2 h 30 min, the reduction was quenched at 0 °C by addition of aqueous 0.5 M
HCl (40 mL). Stirring was continued for 15 min and the mixture was extracted with dichloromethane (5 x
80 mL). The combined organic phases were dried over Na2SO4 (20 g, 30 min) and filtered. The solid was
washed with dichloromethane (40 mL). After evaporation of solvent in a rotary evaporator (40 °C/10 mbar),
the crude product (2.15 g, 105% by weight) was obtained as a yellow oil, which was purified by column
chromatography with heptane / ethyl acetate (3 : 2) yielding product (14) (1.65 g, 6.94 mmol, 81% by
weight (84% over 2 steps from 13)) as white crystals. mp 88 °C; 1H NMR (300 MHz, CDCl3): δ 7.96 (d, 1H,
J = 5.5 Hz), 6.71 (d, 1H, J = 5.4 Hz), 5.58 (m, 1H), 5.09 (m, 1H), 5.05 (m, 1H), 4.90 (dd, 1H, J = 11.9 Hz,
J = 6.6 Hz), 4.84 (dd, 1H, J = 12.1 Hz, J = 6.3 Hz), 3.91 (s, 3H), 2.90 (br. s, 1H), 2.78 (br., 1H), 2.68 (ddt,
1H, J = 13.9 Hz, J = 7.1 Hz, J = 1.1 Hz), 2.48 (ddt, 1H, J = 13.9 Hz, J = 7.9 Hz, J = 1.1 Hz), 1.91 (dq, 1H,
J = 14.1 Hz, J = 7.4 Hz), 1.78 (dq, 1H, J = 14.3 Hz, J = 7.3 Hz), 0.75 (t, 3H, J = 7.5 Hz) ppm; 13C NMR (100
MHz, CDCl3): δ 163.4, 154.5, 145.3, 132.8, 121.3, 120.2, 116.0, 78.5, 56.7, 53.8, 47.2, 35.3, 8.0 ppm; IR
(ATR-FTIR) 3216, 2972, 1765, 1643, 1592, 1553, 1445, 1380, 1305, 1275, 1058, 978, 826 cm−1; MS (EI)
m/z (rel. intensity) 196 (3), 190 (8), 178 (100); HRMS (ESI POS) calcd for C13H20NO3 (MH+) 238.1443,
found 238.1440; Anal. Calcd for C13H19NO3: C, 65.80; H, 8.07; N, 5.90. Found: C, 65.80; H, 8.22; N, 5.71.
Synthesis of 5-ethyl-1-methoxy-5,6,7,9-tetrahydro-8-oxa-2-aza-benzocycloheptene-5,7-diol (15)
A stirred solution of 14 (1.23 g, 5.18 mmol) in acetic acid (27 mL) and water (3 mL) was cooled to 0 °C. O3
was bubbled through the solution (150 L/h) until after 5.5 min a blue color appeared. Subsequently, argon
was bubbled through the solution for 10 min and the volume was reduced to ca. 4 mL in a rotary evaporator

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(40 °C/10 mbar). Dichloromethane (50 mL) was added and the mixture was cooled to 0 °C before addition
of dimethylsulfide (99%, 3.84 mL, 51.8 mmol, 10.0 equiv). Stirring was continued overnight and the
mixture was allowed to slowly warm up to room temperature. pH-7 buffer (20 mL) was added and pH 5 was
adjusted by addition of potassium dihydrogen phosphate. After phase separation, the aqueous phase was
extracted with dichloromethane (3 x 30 mL) and subsequently with dichloromethane / ethanol (4 : 1, 3 x 30
mL). The combined organic phases were dried over Na2SO4 (10 g, 30 min) and filtered. The solid was
washed with chloroform / ethanol (4 : 1, 20 mL). After evaporation of solvent in a rotary evaporator
(40 °C/10 mbar), the crude product (0.85 g, 69% by weight, dr = 5 : 1) was obtained as a yellow semisolid.
An analytical sample (white semisolid) was obtained by column chromatography with heptane / ethyl
acetate (1 : 1). 1H NMR (300 MHz, CDCl3): major diastereomer: δ 8.03 (d, 1H, J = 5.4 Hz), 7.15 (d, 1H, J
= 5.5 Hz), 5.41 (dd, 1H, J = 7.3 Hz, J = 6.0 Hz), 5.05 (d, 1H, J = 16.4 Hz), 4.86 (d, 1H, J = 16.4 Hz), 3.94 (s,
3H), 3.4 (br. s, 1H), 2.71 (br. s, 1H), 2.41 (m, 1H), 2.39 (m, 1H), 1.91 (m, 2H), 1.03 (t, 3H, J = 7.5 Hz) ppm;
minor diastereomer: δ 8.06 (d, 1H, J = 5.5 Hz), 7.02 (d, 1H, J = 5.6 Hz), 5.55 (m, 1H), 5.05 (d, 1H, J = 16.4
Hz), 4.94 (d, 1H, J = 16.6 Hz), 3.95 (s, 3H), 3.4 (br. s, 1H), 2.76 (br. s, 1H), 2.41 (m, 1H), 2.39 (m, 1H), 1.91
(m, 2H), 0.82 (t, 3H, J = 7.5 Hz) ppm; 13C NMR (100 MHz, CDCl3): major diastereomer: δ 161.0, 157.5,
145.2, 120.0, 116.5, 93.0, 74.8, 57.3, 54.2, 43.9, 33.9, 8.5 ppm; minor diastereomer: δ 161.9, 153.5, 145.8,
122.6, 115.8, 94.0, 74.7, 57.4, 54.3, 43.0, 35.4, 9.2 ppm; IR (ATR-FTIR) 3367, 2948, 1595, 1561, 1359,
1263, 1122, 1027, 986, 838 cm−1; MS (EI) m/z (rel. intensity) 239 (20), 221 (76), 192 (100), 177 (89), 164
(91); HRMS (ESI POS) calcd for C12H18NO4 (MH+) 240.1236, found 240.1237; Anal. Calcd for
C12H17NO4: C, 60.24; H, 7.16; N, 5.85. Found: C, 60.42; H, 7.32; N, 5.77.
Synthesis of 5-ethyl-5-hydroxy-1-methoxy-5,9-dihydro-6H-8-oxa-2-aza-benzocyclohepten-7-one (16)
2,2,6,6-Tetramethylpiperidin-1-oxy radical (TEMPO, 96%, 17.6 mg, 0.11 mmol, 0.1 equiv) was added to a
stirred solution of 15 (258.7 mg, 1.08 mmol) in acetone (2.6 mL) and toluene (7.8 mL). After cooling to
0 °C, a mixture of saturated aqueous NaHCO3 / aqueous 10% NaOCl (10 : 7, 3.0 mL) was added while
vigorously stirring the biphasic system. After 1 h, additional saturated aqueous NaHCO3 / aqueous 10%
NaOCl (10 : 7, 3.0 mL) was added. After 90 min, water (20 mL) was added and the mixture was extracted
with dichloromethane (3 x 30 mL). The combined organic phases were dried over Na2SO4 (10 g, 30 min)
and filtered. The solid was washed with dichloromethane (20 mL). After evaporation of solvent in a rotary
evaporator (40 °C/10 mbar), the crude product (268.6 mg, 105% by weight) was obtained as an orange oil.
An analytical sample (white solid) was obtained by column chromatography with heptane / ethyl acetate
(1 : 1). mp 118 °C. 1H NMR (300 MHz, CDCl3): δ 8.16 (d, 1H, J = 5.4 Hz), 7.13 (d, 1H, J = 5.7 Hz), 5.52 (d,
1H, J = 15.0 Hz), 5.25 (d, 1H, J = 15.1 Hz), 3.97 (s, 3H), 3.44 (d, 1H, J = 13.6 Hz), 3.07 (d, 1H, J = 13.5 Hz),
13
2.43 (br. s, 1H), 1.92 (q, 2H, J = 7.4 Hz), 0.90 (t, 3H, J = 7.5 Hz) ppm; C NMR (100 MHz, CDCl3): δ
171.7, 160.7, 153.8, 147.1, 116.0, 115.7, 73.7, 61.9, 54.1, 42.9, 37.3, 8.3 ppm; IR (film) 3336, 2972, 1729,

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1599, 1566, 1456, 1371, 1285, 1266, 1141, 1047, 1024, 837 cm−1; MS (ESI) m/z 238.1 (MH+); HRMS (ESI
POS) calcd for C12H16NO4 (MH+) 238.1079, found 238.1078; Anal. Calcd for C12H15NO4: C, 60.75; H,
6.37; N, 5.90. Found: C, 60.56; H, 6.49; N, 5.78.
Synthesis of (rac)-5-ethyl-5-hydroxy-2,5,6,9-tetrahydro-8-oxa-2-aza-benzocycloheptene ((rac)-7)
Aqueous HBr (48%) (77 µL, 0.69 mmol, 1.05 equiv) was added to a stirred solution of 16 (155 mg, 0.65
mmol) in 1,2-dimethoxyethane (1.55 mL). After 6 h at room temperature, the solution was heated to 50 °C.
The reaction was monitored by HPLC. After 17 h 30 min at 50 °C, the reaction mixture was allowed to
stand at 5 °C for 48 h. The precipitate was then filtered and subsequently washed with heptane (0.2 mL).
After evaporation of residual solvent in a rotary evaporator (40 °C/10 mbar), the product (88.7 mg, 61%
1
by weight (64% over 2 steps)) was obtained as a white powder. mp > 210 °C (decomp.); H NMR (300
MHz, DMSO): δ 11.67 (br. s, 1H), 7.34 (d, 1H, 7.2 Hz), 6.33 (d, 1H, 7.2 Hz), 5.72 (br. S, 1H), 5.34 (d, 1H,
J = 15.1 Hz), 5.21 (d, 1H, J = 15.1 Hz), 3.32 (d, 1H, J = 13.5 Hz), 2.98 (d, 1H, J = 13.7 Hz), 1.68 (m, 2H),
0.80 (t, 3H, J = 7.5 Hz) ppm. The other analytical data are in accordance with those for 7 described in Ref
[7].
Synthesis of 1-morpholin-4-yl-propan-1-one (11)
Propionyl chloride (98%, 18.9 mL, 200.2 mmol) was rapidly added at 0 °C to a solution of morpholine
(99%, 18.3 mL, 208.2 mmol, 1.04 equiv) in dichloromethane (200 mL) containing 32.3 mL triethylamine
(232.2 mmol, 1.16 equiv). After complete addition, the mixture was stirred for 1 h at 0 °C and 2.5 h at room
temperature. The solution was subsequently washed with saturated aqueous NH4Cl (200 mL), saturated
aqueous NaHCO3 (200 mL) and brine (200 mL). The organic phase was dried over sodium sulfate (20 g, 30
min) and filtered. The filter cake was washed with dichloromethane (40 mL). After evaporation of solvent
in a rotary evaporator (50 °C/5 mbar), product (11) was obtained as a yellow liquid (23.70 g, 165.5 mmol,
83% by weight). 1H NMR (300 MHz, CDCl3): δ 3.67 (m, 4H), 3.64 (m, 2H), 3.46 (m, 2H), 2.33 (q, 2H, J =
7.4 Hz), 1.16 (t, 3H, J = 7.3 Hz) ppm.
Synthesis of (2S,5S)-2-tert.-butyl-5-ethyl-[1,3]dioxolan-4-one (23)
p-Toluenesulfonic acid monohydrate (99%, 309.8 mg, 1.61 mmol, 0.018 equiv) and sulfuric acid (9.8 µL,
0.19 mmol, 0.002 equiv) were added to a suspension of 9.80 g (S)-2-hydroxybutyric acid (22, 97%, 91.3
mmol) and 20.6 mL pivaldehyde (97%, 1.98 equiv, 180.8 mmol) in 400 mL pentane. The mixture was
heated vigorously to reflux overnight (oil bath temperature 55 °C). After cooling down to room temperature,
the mixture was washed with water (2 x 300 mL). The organic phase was dried over sodium sulfate (20 g,
30 min) and filtered. The filter cake was washed with pentane (40 mL). After evaporation of solvent in a
rotary evaporator (50 °C/5 mbar), product (23) was obtained as a colorless liquid (13.96 g, 81.1 mmol, 89%
by weight, dr (cis/trans) = 92.7 : 7.3 (1H-NMR)). 1H NMR (300 MHz, CDCl3): cis-isomer: δ 5.12 (d, 1H, J
= 1.1 Hz), 4.22 (m, 1H), 1.93 (m, 1H), 1.80 (m, 1H), 1.03 (t, 3H, J = 7.4 Hz), 0.97 (s, 9H) ppm.

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trans-isomer: δ 5.27 (d, 1H, J = 1.5 Hz), 4.32 (m, 1H), 1.93 (m, 1H), 1.80 (m, 1H), 1.03 (t, 1H, J = 7.4 Hz),
0.95 (s, 9H) ppm. Analytical data are in accordance with literature data.14
Synthesis of (2S,5R)-5-allyl-2-butyl-5-ethyl-[1,3]dioxolan-4-one (24)
n-Butyllithium (56.8 mL, 85.1 mmol, 1.05 equiv) was added at 0 °C to a solution of diisopropylamine (12.6
mL, 89.2 mmol, 1.1 equiv) in THF (420 mL). After 30 min at 0 °C, the solution was cooled to −95 °C. A
solution of 23 (13.96 g, 81.1 mmol) in THF (42 mL) was added dropwise over 30 min. The resulting yellow
solution was kept for additional 2 h at −95 °C. Subsequently, a solution of allylbromide (99%, 10.4 mL,
121.6 mmol, 1.5 equiv) in THF (35 mL) was added dropwise over 10 min. The reaction mixture was
allowed to slowly warm to room temperature overnight and was then poured into saturated aqueous NH4Cl
(750 mL). The mixture was extracted with TBME (3 x 500 mL). The combined organic phases were dried
over sodium sulfate (30 g, 30 min) and then filtered. The filter cake was washed with TBME (60 mL). After
evaporation of solvent in a rotary evaporator (50 °C/5 mbar), product (24) was obtained as a yellow oil
(14.98 g, 70.6 mmol, 87% by weight, dr > 95 : 5 (1H-NMR), er = 92.0 : 8.0 (chiral GC: carrier gas: H2, 90
kPa (split ratio 1/20), column: BGB-172, 30 m * 0.25 mm, temperature: 70 – 3 − 200 °C, injector
temperature: 200 °C, detector temperature: 210 °C, retention time: 21.74 min (S)-24, 22.31 min (R)-24)).1H
NMR (300 MHz, CDCl3): cis-isomer: δ 5.82 (m, 1H), 5.20 (br. s, 1H), 5.19 (m, 2H), 2.48 (m, 2H), 1.81 (m,
2H), 0.97 (t, 3H, J = 7.4 Hz), 0.96 (s, 9H) ppm. The analytical data are in accordance with literature data.14
Synthesis of (R)-3-ethyl-3-hydroxy-hex-5-en-2-one (25)
Methyllithium (15.6 mL, 1.6 M in Et2O, 99%, 24.7 mmol, 1.05 equiv) was added dropwise over 7.5 min to
a solution of 24 (5.0 g, 23.6 mmol) in THF (135 mL) at −78 °C. The reaction was monitored by TLC. After
2 h 40 min at −78 °C, additional methyllithium (15.0 mL, 23.8 mmol, 1.01 equiv) was added dropwise over
7.5 min. After additional 2 h at −78 °C, aqueous HCl (1.0 M, 135 mL) was added and the cooling bath was
subsequently removed. The resulting mixture was allowed to stir at room temperature overnight and was
then extracted with dichloromethane (3 x 200 mL). The combined organic phases were dried over 20 g
sodium sulfate (30 min) and then filtered. The filter cake was washed with dichloromethane (40 mL). After
evaporation of the solvent in a rotary evaporator (50 °C/5 mbar), crude product was obtained as a light
yellow liquid (3.58 g, 107% by weight), which was purified by high vacuum Kugelrohr distillation (bp
80 °C at 0.030 mbar) furnishing product (25) (2.36 g, 16.6 mmol, 70% by weight) as colorless liquid. An
analytical sample (colorless liquid) was obtained by column chromatography with pentane / diethyl ether
(1 : 1). [α]D20 (c = 0.9939 g/dL, MeOH) = −23.5; 1H NMR (300 MHz, CDCl3): δ 5.72 (m, 1H), 5.12 (dd, 1H,
J = 7.2 Hz, J = 1.3 Hz), 5.07 (br. s, 1H), 3.83 (s, 1H), 2.47 (m, 2H, J = 12.3 Hz, J = 6.4 Hz), 2.17 (s, 3H),
1.77 (q, 2H, J = 7.5 Hz), 0.82 (t, 3H, J = 7.3 Hz) ppm; 13C NMR (100 MHz, CDCl3): δ 211.5, 132.3, 118.5,
81.9, 43.0, 31.2, 24.2, 7.4 ppm; IR (ATR-FTIR) 3478, 2967, 1707, 1641, 1357, 1153, 1000, 918 cm−1; MS

HETEROCYCLES, Vol. 72, 2007
269
(EI) m/z (rel. intensity) 99 (15), 57 (100), 43 (62); Anal. Calcd for C8H14O2: C, 67.57; H, 9.92. Found: C,
67.61; H, 10.22.
Synthesis of (R)-5-allyl-5-ethyl-4-methyl-2-oxo-2,5-dihydro-furan-3-carboxylic acid ethyl ester (21)
Cs2CO3 (99.5%, 10.68 g, 32.63 mmol, 2.5 equiv) was added at room temperature to a solution of 25 (1.86 g,
13.05 mmol) and diethylmalonate (97%, 6.13 mL, 39.15 mmol, 3.0 equiv) in ethanol (62 mL). The reaction
was monitored by HPLC. After 26 h 20 min, the brown suspension was cooled to 0 °C and aqueous HCl
(130 mL, 0.5 M, 65.5 mmol, 5.0 equiv) was added dropwise over 30 min. Ethanol (45 mL) was
subsequently removed in a rotary evaporator (50 °C/5 mbar) and subsequently, ethyl acetate (50 mL) was
added. The organic phase was washed with brine (50 mL), and was after that dried over sodium sulfate (5 g,
30 min) and next filtered. The filter cake was washed with ethyl acetate (10 mL). After evaporation of
solvent in a rotary evaporator (50 °C/5 mbar), crude product was obtained as a yellow liquid (4.40 g, 142%
by weight), which was purified by column chromatography with heptane / ethyl acetate (7 : 3) yielding
product (21) (3.30 g, 13.84 mmol, 106% by weight) as yellow oil. [α]D20 (c = 0.6496 g/dL, MeOH) = −21.2;
1H NMR (300 MHz, CDCl3): δ 5.55 (m, 1H), 5.14 (m, 1H, J = 7.2 Hz, J = 1.3 Hz), 5.09 (m, 1H), 4.33 (q, 2H,
J = 7.1 Hz), 2.66 (ddt, 1H, J = 14.5 Hz, J = 6.8 Hz, J = 1.3 Hz), 2.40 (ddt, 1H, J = 14.5 Hz, J = 7.5 Hz, J =
1.0 Hz), 2.25 (s, 3H), 1.98 (dq, 1H, J = 14.6 Hz, J = 7.4 Hz), 1.72 (dq, 1H, J = 14.5 Hz, J = 7.3 Hz), 1.36 (t,
3H, J = 7.1 Hz), 0.77 (t, 3H, J = 7.3 Hz) ppm; 13C NMR (100 MHz, CDCl3): δ 178.1, 167.7, 161.4, 129.8,
120.7, 120.2, 89.7, 61.3, 40.5, 28.9, 14.2, 13.4, 7.0 ppm; IR (ATR-FTIR) 2978, 1765, 1714, 1651, 1316,
1238, 1044, 967 cm−1; MS (EI) m/z (rel. intensity) 239 (20), 197 (89), 151 (100); HRMS (ESI POS) calcd
for C13H18O4Na (MNa+) 261.1103, found 261.1104; Anal. Calcd for C13H18O4: C, 65.53; H, 7.61. Found: C,
65.84; H, 7.88.
Synthesis of (R)-1-allyl-1-ethyl-1H,5H-furo[3,4-c]pyridine-3,4-dione (20)
Sodium ethoxide (1.10 g, 15.31 mmol, 1.1 equiv) was added at 0 °C to a solution of 21 (3.32 g, 13.92 mmol)
in ethanol (33 mL). 11 min later, a solution of s-1,3,5-triazine (1.28 g, 15.31 mmol, 1.1 equiv) in ethanol (25
mL) was added and the ice bath was removed. The reaction was monitored by HPLC. After 22 h 20 min,
additional sodium ethoxide (199.4 mg, 2.78 mmol, 0.2 equiv) was added. After 3 h, the reaction was
quenched by addition of saturated aqueous NH4Cl (100 mL). The mixture was extracted with
dichloromethane (3 x 75 mL). The combined organic phases were dried over sodium sulfate (15 g, 30 min)
and next filtered. The filter cake was washed with dichloromethane (30 mL). After evaporation of solvent
in a rotary evaporator (40 °C/29 mbar), the crude product was obtained as red oil (2.05 g, 67% by weight),
which was dissolved in ethyl acetate (12 mL) under reflux (oil bath temperature 100 °C). Heptane (5 mL)
was subsequently added and the resulting mixture was allowed to slowly cool down to room temperature
overnight. The precipitate was collected by filtration and washed with heptane (1 mL) furnishing product
(20) (1.70 g, 7.73 mmol, 56% by weight (59% over 2 steps)) as red solid. [α]D20 (c = 0.6496 g/dL, MeOH) =

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−25.0; mp 137 °C. 1H NMR (300 MHz, CDCl3): δ 13.0 (br. s, 1H), 7.93 (d, 1H, J = 6.6 Hz), 6.33 (d, 1H, J
= 6.4 Hz), 5.57 (m, 1H), 5.12 (s, 1H), 5.08 (dm, 1H, J = 6.6 Hz), 2.72 (dd, 1H, J = 14.3 Hz, J = 7.6 Hz), 2.57
(dd, 1H, J = 14.3 Hz, J = 7.1 Hz), 2.10 (dq, 1H, J = 14.5 Hz, J = 7.3 Hz), 1.87 (dq, 1H, J = 14.5 Hz, J = 7.2
Hz), 0.81 (t, 3H, J = 7.3 Hz) ppm; 13C NMR (100 MHz, CDCl3): δ 170.7, 167.7, 160.1, 143.2, 129.8, 120.9,
114.1, 100.3, 88.0, 41.9, 30.2, 7.3 ppm; IR (ATR-FTIR) 3360 (br), 2921, 1758, 1715, 1660, 1614, 1563,
1189, 1157, 968, 826, 814, 724 cm−1; MS (EI) m/z (rel. intensity) 219 (2), 178 (100); HRMS (ESI POS)
calcd for C12H13NO3Na (MNa+) 242.0793, found 242.0793; Anal. Calcd for C12H13NO3: C, 65.74; H, 5.98;
N, 6.39. Found: C, 65.65; H, 5.97; N, 6.44.
Synthesis of (R)-1-allyl-1-ethyl-4-methoxy-1H-furo[3,4-c]pyridin-3-one ((R)-13))
Trimethyloxonium tetrafluoroborate (95%, 1.06 g, 6.77 mmol, 1.1 equiv) was added to a solution of 20
(1.35 g, 6.16 mmol) in dichloromethane (40 mL). The reaction was monitored by HPLC. After 6 h 25 min,
additional trimethyloxonium tetrafluoroborate (958.8 mg, 6.16 mmol, 0.9 equiv) was added portion wise
over the next 19 h. After 28 h, the reaction was quenched by addition of brine (20 mL). The mixture was
extracted with dichloromethane (20 mL). The organic phase was dried over sodium sulfate (2 g, 30 min)
and filtered. The filter cake was washed with dichloromethane (4 mL). After evaporation of the solvent in a
rotary evaporator (40 °C/10 mbar), the crude product was obtained as a brown solid (1.35 g, 94% by weight,
er = 88.5 : 11.5 (chiral GC: carrier gas: H2, 120 kPa (split ratio 1/20), column: BGB-172, 30 m * 0.25 mm,
temperature: 100 – 2 − 200 °C, injector temperature: 200 °C, detector temperature: 220 °C, retention time:
45.71 min (S)-13, 46.36 min (R)-13)). An analytical sample (white crystals) was obtained by column
chromatography with heptane / ethyl acetate (7 : 3). [α]D20 (c = 0.9885 g/dL, CHCl3) = −8.1 (corrected for
ee = 100%); mp: 87 °C. The other analytical data are in accordance with the racemate (13).
Synthesis of (R)-3-(3-hydroxymethyl-2-methoxy-pyridin-4-yl)-hex-5-en-3-ol ((R)-14)
According to the preparation of (rac)-14 described above, (R)-13 (660.0 mg, 2.83 mmol) was treated with
lithium aluminum hydride (1.75 mL, 1.75 mmol, 0.62 equiv) yielding the crude product (622.6 mg, 93% by
weight) as a brown oil, which was used without further purification in the next step. An analytical sample
(white crystals) was obtained by column chromatography with heptane / ethyl acetate (3 : 2). [α]D20 (c =
0.9957 g/dL, CHCl3) = 13.4; mp: 83 °C. The other analytical data are in accordance with the racemate (14).
Synthesis of (R)-5-ethyl-1-methoxy-5,6,7,9-tetrahydro-8-oxa-2-aza-benzocycloheptene-5,7-diol
((R)-15)
According to the preparation of (rac)-15 described above, (R)-14 (618.3 mg, 2.61 mmol) was treated with
O3 furnishing the crude product (673.0 mg, 108% by weight, dr = 5 : 1) as a yellow waxy solid. An
analytical sample (white semisolid) was obtained by column chromatography with heptane / ethyl acetate
(2 : 1). [α]D20 (c = 0.5879 g/dL, CHCl3) = −69.1. The other analytical data are in accordance with the
racemate (15).

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Synthesis of (R)-5-ethyl-5-hydroxy-1-methoxy-5,9-dihydro-6H-8-oxa-2-aza-benzocyclohepten-7-one
((R)-16)
According to the preparation of (rac)-16 described above, (R)-15 (657.3 mg, 2.75 mmol) was treated with
2,2,6,6-tetramethylpiperidin-1-oxy radical (TEMPO, 44.7 mg, 0.32 mmol, 0.1 equiv) and saturated
aqueous NaHCO3 / aqueous 10% NaOCl (10 : 7, 7.9 mL) furnishing the crude product (535.8 mg, 82% by
weight) as a yellow-brown oil (er = 88.5 : 11.5 (chiral HPLC sample preparation: ethanol solution, column:
chiralpak-ADH, 250 x 4.6, temperature: 25 °C, mobile phase: 90% heptane, 10% ethanol / trifluoroacetic
acid (99 : 1), flow: 0.8 mL/min, injection volume: 5 µL, detection: UV 275 nm, retention time: 35.49 min
(R)-16, 45.43 min (S)-16)), which was purified by column chromatography with heptane / ethyl acetate (1 :
1). Product (R)-16 (285.5 mg, 1.21 mmol, 44% by weight, 42% over 4 steps) was obtained as a white
powder. An analytical sample (white crystals) was obtained by column chromatography with heptane /
ethyl acetate (1 : 1). [α]D20 (c = 0.9884 g/dL, CHCl3) = +23.2; mp 103 °C. The other analytical data are in
accordance with the racemate (16).
Synthesis of (R)-5-ethyl-5-hydroxy-2,5,6,9-tetrahydro-8-oxa-2-aza-benzocycloheptene (7)
According to the preparation of (rac)-7 described above, (R)-16 (286.0 mg, 1.21 mmol) was treated with
aqueous HBr (48%, 284 µL, 2.53 mmol, 2.1 equiv) yielding product 7 (171.9 mg, 64% by weight, 0.77
mmol, er > 99.95 : 0.05 (chiral HPLC: sample preparation: ethanol solution, column: chiralcel-ODH, 250 x
4.6, temperature: 25 °C, mobile phase: 75% heptane, 25% ethanol / trifluoroacetic acid (99 : 1), flow: 0.8
mL/min, injection volume: 5 µL, detection: UV 308 nm, retention time: 9.68 min (S)-7, 13.28 min (R)-7))
as a white powder. [α]D20 (c = 0.178 g/dL, DMSO-d6) = +137.7; mp > 270 °C (decomp.); 1H NMR (300
MHz, DMSO): δ 11.67 (br. s, 1H), 7.34 (d, 1H, 7.2 Hz), 6.33 (d, 1H, 7.2 Hz), 5.72 (br. S, 1H), 5.34 (d, 1H,
J = 15.1 Hz), 5.21 (d, 1H, J = 15.1 Hz), 3.32 (d, 1H, J = 13.5 Hz), 2.98 (d, 1H, J = 13.7 Hz), 1.68 (m, 2H),
0.80 (t, 3H, J = 7.5Hz) ppm. The other analytical data are in accordance with those for 7 described in Ref
[7].
ACKNOWLEDGEMENTS
We thank Dr. Martin Karpf for valuable discussions. Mrs. Sévérine Baumgartner and Mr. Thomas Naber
are acknowledged for skillful experimental work. We also thank the members of the analytical services of
F. Hoffmann-La Roche Ltd, Basel, especially the mass spectroscopy group of Dr. Andreas Stämpfli, for
efficiently and persistently providing the physical data of all compounds described.

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