A highly flexible route to 1,2,3,4,5,6-hexahydro-5-hydroxypyrimidin-2-ones as potential HIV protease inhibitors

Article abstract of DOI:10.3987/COM-03-S(P)51

The first asymmetric synthesis of potential HIV protease inhibitors of type II, III and IV is described. Key step of the synthesis is an auxiliary based stereoselective alkylation by means of the (R)-1-amino-2-methoxymethylpyrrolidine (RAMP)- / (S)-1-amino-2-methoxymethylpyrrolidine (SAMP)-hydrazone method starting from a readily available key building block, pyrimidin-2,5-dione (6). The synthesis is short and highly versatile in the choice of the substitution pattern as well as the absolute configuration of the alkylated 1,2,3,4,5,6-Hexahydro-5-hydroxypyrimidin-2-ones.

Full text of DOI:10.3987/COM-03-S(P)51

HETEROCYCLES, Vol. 62, 2004, pp. 559 - 581
Received, 11th August, 2003, Accepted, 11th November, 2003, Published online, 17th November, 2003
A HIGHLY FLEXIBLE ROUTE
TO 1,2,3,4,5,6-HEXAHYDRO-5-
HYDROXYPYRIMIDIN-2-ONES AS POTENTIAL HIV PROTEASE
INHIBITORS
Dieter Enders,* Lars Wortmann, Gerhard Raabe, and Barbara Dücker
Institut für Organische Chemie der RWTH Aachen, Professor-Pirlet-Strasse 1,
52074 Aachen, Germany; Fax: +49(241)8092127, E-mail: Enders@RWTH-
Aachen.de
Abstract - The first asymmetric synthesis of potential HIV protease inhibitors of
type II, III and IV is described. Key step of the synthesis is an auxiliary based
stereoselective alkylation by means of the (R)-1-amino-2-methoxymethyl-
pyrrolidine (RAMP)- / (S)-1-amino-2-methoxymethylpyrrolidine (SAMP)-
hydrazone method starting from a readily available key building block, pyrimidin-
2,5-dione (6). The synthesis is short and highly versatile in the choice of the
substitution pattern as well as the absolute configuration of the alkylated
1,2,3,4,5,6-Hexahydro-5-hydroxypyrimidin-2-ones.
Introduction
HIV-1 infects millions of people worldwide to cause the lethal disease Accquired Immune Deficiency
Syndrome (AIDS).1, 2 An asymptomatic period precedes AIDS in which the immune system becomes
progressively compromised and unable to fight opportunistic infections and certain cancers. To inhibit
HIV-1 replication and slow down the destruction of the immune system, current therapies utilize a
combination of protease and reverse transcriptase inhibitors.
The HIV protease belongs to the class of aspartate proteases, which cleaves the gag- and gagpol
polyproteins (encoded by the pol- gene of the virus) into structural and functional proteins, which in turn
are required for function of the mature virus.3 Currently several FDA approved HIV protease inhibitors4
are on the market, such as Saquinavir5 (Hofmann-La Roche), Nelfinavir6 (Agouron), Amprenavir7 (Glaxo
Wellcome), Indinavir8 (Merck Research), Ritonavir9 (Abbott) and Lopinavir10 (Abbott). While
suppression of viral replication through combination therapy delays progression to AIDS the HI virus

rapidly develops resistance against new drug molecules. Therefore there is an ongoing need for new
chemical entities in this area.11
All HIV protease inhibitors of the first generation contained typical peptidomimetic structure elements.
Coworkers of the Merck Dupont company could demonstrate that not only the acyclic molecules depicted
in Scheme 1 were excellent HIV protease inhibitors but also their corresponding cyclic analogues of type
I if all stereogenic centers were inverted at the same time.12, 13
O
R
N
R
N
R1
R1
R2
R1
R1
N
N
2
R2
R2
R
HO
OH
HO
Type I
OH
Acyclic
Inhibitor
Scheme 1
According to the C2-symmetry of the HIV protease active site type I inhibitors retain the same symmetry.
It was shown that the trans diaxial position of both substituents R2 was not only the preferred
conformation of the free molecule but also crucial for good enzyme inhibition.
O
O
O
R1
R1
R2
R1
R1
R2
R1
R1
R2
N
N
N
N
N
N
R2
2
R
OH
OH
OH
Type IV
Type II
Type III
Scheme 2
Investigation of the influence of different ring sizes resulted in HIV protease inhibitors of type II, III and
IV (Scheme 2).14 As expected in the six membered ring case the residues R2 cannot be arranged in a trans
diaxial manner and therefore are responsible for the low affinity to the HIV protease. However it was
possible to nearly retain potency by simply introducing an additional methylene group on one of the two
R2 groups (type IV inhibitors). This additional CH2 group functions as a joint to turn R2 into a
pseudoaxial position.

Retrosynthesis: Our retrosynthetic plan was to synthesize inhibitors of type II, III and IV using one
mutual key building block as starting material (Scheme 3).
O
1
R
R1
R2
O
N
N
R1
R1
R2
3
R
N
N
O
N
N
3
R
R1
R1
R2
N
N
N
O
OH
R1
R1
Type III and IV
N
N
MeO
A
N
O
O
R1
R1
R2
N
N
MeO
B
C
OH
Type II
Scheme 3
It was desired that our synthesis should be short, efficient and allow a high flexibility in the choice of the
residues R1 and R2 as well as free choice of the absolute configuration. Based on our investigations in the
area of asymmetric alkylations of dioxanones15, 16 we considered the RAMP-/SAMP-hydrazone method17
to suit well for a stereoselective alkylation of ketone C leading after removal of the auxiliary and
subsequent reduction of the ketone to compounds of type II, III or IV.
Results and Discussion
OH
NH2
0°C, reflux,
neat, 59%
Ph
Ph
NH HN
1
2
O
3
+
Cl
Scheme 4
The synthesis of the achiral key building block (6)18 starts from readily available materials such as a
primary amine and epichlorohydrine (2) (Scheme 4). With the choice of 1 as primary amine residue R1

is determined. Diamino alcohol (3) could be easily synthesized in one step and purified by
recrystallization of the corresponding hydrochloride salt.
The cyclization of 3 with a phosgene equivalent provided mixtures of the thermodynamically controlled
product (4) and the kinetically controlled product (5) (Scheme 5) in favor of the latter.
OH
OH
O
N
O
Ph
see Table 1
and /
or
Ph
Ph
N
N
Ph
Ph
NH HN
O
Ph
NH
3
O
O
DMP, 79%
4
5
Ph
Ph
N
N
6
Scheme 5
Several reaction conditions were applied in order to reverse the selectivity towards the desired six
memberd urea (4), some of which are depicted in Table 1. According to the literature no solution of
similar cyclization problems are described.19 In our case only bis(4-nitrophenyl) carbonate as phosgene
equivalent provided the desired urea (4) as single isomer in excellent yield. The purification of 4 is simple
and does not require a chromatography. Basic extraction removes the 4-nitrophenol by-product and
crystallization of the crude mixture gives rise to the alcohol (4) which is available in multigram quantities.
Table 1
Reaction Conditions
Triphosgene, K2CO3, CH2Cl2, 0°C
Diphosgene, K2CO3, toluene, 0°C
CDI, CH2Cl2, 0°C
Compounds detected
4 + 5
4 + 5
4 + 5
Diphenyl carbonate, CH2Cl2, reflux
Bis(4-Nitrophenyl) carbonate, CH2Cl2, reflux
No reaction
Only 4

Subsequent oxidation of 4 with the Dess-Martin periodinane finishes the synthesis of our key building
block (6) (Scheme 5).
By simply stirring dione (6) with RAMP or SAMP, the corresponding chiral hydrazones (7) could be
obtained in excellent yield (Scheme 6). By choice of the alkyl halide as electrophile in the auxiliary
directed aza-enolate alkylation, the residue R2 is introduced.
LiTMP,
O
SAMP or
RAMP,
CH2Cl2
THF,
-78°C,
R1X
N
N
N
N
N
N
OMe
R2
OMe
Ph
Ph
N
N
93%
Ph
Ph
N
Ph
Ph
N
O
O
O
DDO, acetone,
or aq. CuCl2
8a-e
6
7
44-59 %
(2 steps)
O
R2
OH
LiAlH4,
ether,
76-84%
R2
Ph
Ph
N
N
Ph
Ph
N
N
O
O
de = > 96%
ee = 76 - > 96%
10a-e
9a-e
Scheme 6
X-Ray structure analysis20 of the allylated (Z)-configured SAMP-hydrazone (8c) confirmed the
configuration at the newly formed stereogenic center, with the sense of asymmetric induction assenting to
our SAMP/RAMP alkylation model (Figure 1).
O
N
N
N
N
O
Figure 1

Without further purification the alkylated hydrazones (8a-e) were directly cleaved to the corresponding
ketones (9a-e). The numerous reagents suitable for recovery of carbonyl compounds from
dialkylhydrazones were reviewed recently.21 The best overall yields were obtained when according to a
hydrazone cleavage method published by Curci dimethyldioxirane (DDO) in acetone solution was used.22
Slightly lower yield of ketones (9a-e) were obtained when an aqueous CuCl2 was used. After column
chromatography on silica gel, the alkylated ketones (9a-e) were reduced with LiAlH4 to the desired cis-
configured alcohols (10a-e) representing the desired potential HIV protease inhibitors of type II. The
relative configuration was confirmed by an X-Ray structure analysis23, 24 of alcohol (10c) (Figure 2).
O
N
N
O
Figure 2
1
The diastereomeric excess of the LiAlH4-reduction to the cis-alcohols (10a-e) was determined by H-
1
NMR spectroscopy (Table 2). The enantiomeric excess of the alcohols (10a-e) was determined by H-
NMR spectrometry using Pirkle alcohol as shift reagent.
Table 2
10
R2
Me
de [%] ee [%]
10a
10b
10c
10d
10e
≥ 96
≥ 96
≥ 96
≥ 96
≥ 96
76
≥ 96
80
76
86
n-Bu
Allyl
PhCH2
PhCH2CH2
The synthesis of inhibitors of types III and IV was carried out in a similar manner as the synthesis of
type II inhibitors.25 The monoalkylated hydrazones (8a-e) were subjected to a second alkylation to give
rise to hydrazones (11a-e) (Scheme 7). The diastereomeric excess of the second alkylation could not be
determined on this step as one abtains a mixture of the (E)- and the (Z)-configured hydrazone (11a-e).
Attempts to alkylate 7 directly with two equivalents of base and electrophile failed and gave complex

mixtures of products. In case of the double alkylated hydrazones (11a-e) ozonolysis worked out as the
best method to recover the ketones (12a-e).
LiTMP,
SAMP or
RAMP,
CH2Cl2
O
THF,
-78°C,
R1X
N
N
N
N
N
N
OMe
Ph
OMe
Ph
R2
Ph
Ph
N
N
93%
Ph
Ph
N
N
O
O
O
8a-e
6
7
LiTMP,
THF,
O3,
CH2Cl2,
-78°C
O
N
R3
R2
-78°C,
N
O
R2X
OMe
Ph
R3
R2
Ph
Ph
N
N
39-47 %
(3 steps)
Ph
N
N
O
de = 80 - > 96%
ee = 76 - > 96%
12a-e
11a-e
Scheme 7
Table 3
12
R2
R3
i-Pr
Electrophile
Yield over
de
ee
3 steps [%] [%] [%]
12a
12b
12c
i-Pr
n-Bu
Bn
i-PrI
n-BuI
43
39
40
47
34
>96 86
>96 >96
>96 76
>96 86
n-Bu
Bn
BnBr
12d PhCH2CH2 PhCH2CH2
12e
Bn
PhCH2CH2I
PhCH2CH2 BnBr/PhCH2CH2I
80
76
The diastereomeric excess (de) of 12 was determined by 1H-NMR spectrum and lies in the range of 80- >
1
96 % (Table 3). The enantiomeric excess (ee) was determined by H-NMR-shift experiments with (-)-
Pirkle alcohol.
Because no new stereogenic center is formed the C2-symmetrical ketones (12a-d) could be transformed
into their corresponding alcohols (13a-d) using standard sodium borohydride reduction (Scheme 8) and
thus completing the synthesis of potential type III HIV protease inhibitors.

OH
O
O
O
R
R
NaBH4,
MeOH
R
R
Ph
Ph
N
N
Ph
Ph
N
N
71-91%
12a-d
13a-d
Scheme 8
The reduction of the unsymmetrical ketones such as 12e (Scheme 9) leads to a new stereogenic center. As
the benzyl and the phenylethyl residues in 12e have similar bulk it was ambitious to find an appropriate
reduction reagent leading to high diastereoselection.
OH
OH
O
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Table 3
+
Ph
N
N
Ph
N
N
Ph
N
N
O
O
O
12e
14
15
The reagents which were examined for the diastereoselective reduction of 12e leading to the two
diastereomeric alcohols (14 and 15) are listed in Table 4.
Table 4
Reaction conditions
Diastereomeric
Ratio 14 : 15
1 : 2
LiAlH4, Ether, 0 °C26
NaBH4, MeOH, 0 °C27
1 : 2
only 15
1 : 8.7
1.5 : 1
1.6 : 1
(L)-Selectride, THF, -78 °C to rt28
Superhydride, THF, Ether, -78 °C to rt29
Catecholborane, Ether, -78 °C to rt30
BH3-SMe2, THF, Ether, rt31
The best diastereomeric excess was observed with (L)-Selectride as reduction agent in favour of
diasteomer (15). An inversion of selectivity was observed with borane reagents, however the
diastereomeric ratio was not very high. The relative stereochemistry could be elaborated by comparison
with literature data.32 Thus, the asymmetric synthesis of inhibitors of type IV was completed.
Conclusion
The first asymmetric synthesis of potential HIV protease inhibitors of types II, III and IV is described.
Key step of the synthesis is an auxiliary based stereoselective alkylation by means of the RAMP- /SAMP-

hydrazone method starting from a readily available key building block (6). The synthesis is short and
highly versatile in the choice of the substitution pattern as well as the absolute configuration of products.
EXPERIMENTAL
Synthesis of Diamino alcohol (3):
Benzylamine (1) (120 mL, 1.1 mol) was cooled to 0 °C and epichlorohydrine 2 (20 mL, 0.31 mol) were
added. The reaction was stirred for 5 h at 0 °C and then refluxed for 4 h. After cooling the reaction a
colorless solid precipitated. Aqueous NaOH (1 M) was added until the precipitate disappeared. After
extraction with CH2Cl2 the solvent and benzylamine were removed by destillation. The mixture was
dissolved in EtOH, then crystallised as the hydrochloride salt by addition of conc. HCl (aq) and
recrystallised from EtOH. The colorless solid was stirred with NaOH (2 M), extracted with ether, dried
over MgSO4 and evaporated. 3 was isolated in 59 % yield (175.2 g) as yellow oil wich solidified after
standing (mp = 45 °C).1H NMR (300 MHz, CDCl3) (δ, ppm) 2.53 (3H, br s), 2.58 (2H, dd, 2J = 12.1, 3J =
2
3
13
8.0) 2.69 (2H, dd, J = 12.1, J = 3.7, 3.76 (4H, d, J = 3.0), 3.78 (1H, m), 7.30 (10H, m); C NMR (75
MHz, CDCl3) (δ, ppm) 53.1, 53.9 68.6, 127.2, 128.2, 128.5, 140.1; IR (KBr) (cm-1) 3306, 3107, 3085,
3062, 3027, 2905, 2831, 1603, 1585, 1547, 1495, 1453, 1384, 1357, 1199, 1117, 1074, 1029, 1003, 972,
908, 868, 826, 738, 699, 601, 470; MS (EI, 70 eV, 80°C) m/z 150 (10.2 %), 146 (13.6 %), 145 (39.0 %),
134 (7.5 %), 121 (2.2 %), 120 (21.7 %), 119 (5.2 %), 107 (7.9 %), 106 (17.4 %), 92 (100 %), 65 (7.9%);
MS (CI, 70 eV) m/z 273 (2.0 %), 272 (20.1 %), 271 (100 %), 270 (1.3 %), 269 (2.7 %), 145 (3.6 %).
Anal. Calcd for C17H22N2O: C, 75.52; H, 8.20; N, 10.36. Found: C, 75.19, H, 8.43; N, 10.28.
Synthesis of the Alcohol (4):
Bis(4-nitrophenyl) carbonate (10 g, 32.87 mmol) and diamino alcohol (3) (15 g, 55.56 mmol) were
refluxed in CH2Cl2 (2.5 L) for 24 h. The reaction mixture was washed once with sat. citric acid and five
times with NaOH (2M). After evaporation the product was recrystallised from ether and CH2Cl2. 4 was
isolated in 85 % yield (8.3 g) as a colorless solid. mp=115°C. 1H NMR (300 MHz, CDCl3) (δ, ppm) 2.24
(1H, s), 3.15 (2H, dd, 2J = 11.8, 3J =4.0), 3.34 (2H, dd, 2J = 11.8, 3J = 3.4), 4.03 (1H, m), 4.53 (2H, d, J =
14.8), 4.67 (2H, d, J = 14.8), 7.30 (10H, m); 13C NMR (75 MHz, CDCl3) (δ, ppm) 51.7, 51.8, 62.0, 127.5,
128.1, 128.7, 138.1, 155.9; IR (KBr) (cm-1) 3316, 3084, 3062, 3023, 2915, 2856, 1619, 1603, 1583, 1528,
1496, 1471, 1453, 1444, 1422, 1396, 1363, 1329, 1314, 1297, 1259, 1228, 1219, 1200, 1181, 1112, 1078,
1056, 1030, 981, 958, 840, 764, 748, 729, 698, 658, 621, 606, 554, 532, 476, 453; MS (EI, 70 eV, 100°C)
m/z 297 (7.0 %), 295 (42.9 %), 294 (1.8 %), 204 (17.6 %), 144 (4.6 %), 132 (11.3 %), 120 (9.4 %), 118
(12.0 %), 106 (6.1 %), 105 (5.7 %), 104 (11.4 %), 92 (8.4 %), 91 (100 %), 90 (2.5 %), 89 (3.4 %), 77 (5.4

%)65 (9.9 %). MS (CI, 70 eV) m/z 299 (3.0 %), 298 (25.0 %), 297 (65 %), 296 (100 %). Anal. Calcd for
C18H20N2O2: C, 72.95; H, 6.80; N, 9.45. Found: C, 72.64, H, 6.63; N, 9.36.
Synthesis of the Ketone (6):
Alcohol (4) (11.5 g, 38.85 mmol) and the freshly prepared Dess-Martin reagent (24.7 g, 58.28 mmol, 1.5
eq) were stirred overnight in CH2Cl2 (100 mL) saturated with water (TLC-control). The reaction was
quenched by addition of saturated NaHCO3 (aq.) and Na2S2O3 (aq.) and stirred until the precipitate
completely dissolved. After extraction with CH2Cl2, drying over MgSO4 and evaporation the crude
product was filtered through a short column of silica (ether : pentane 1 : 1). Ketone (6) was isolated as a
1
yellow oil in 79% (9.0 g), which crystallized after some time. mp = 73 °C. H NMR (300 MHz, CDCl3)
(δ, ppm) 3.69 (4H, s), 4.59 (4H, s), 7.30 (10H, m); 13C NMR (75 MHz, CDCl3) (δ, ppm) 51.8, 55.6,
128.4, 129.0, 129.4, 137.2, 158.7, 202.0; IR (KBr) (cm-1) 3086, 3063, 3030, 3005, 2919, 2864, 1743,
1651, 1585, 1495, 1454, 1437, 1408, 1358, 1289, 1230, 1178, 1155, 1079, 1030, 961, 911, 883, 733, 702,
649, 608, 489, 456; MS (EI, 70 eV, 70°C) m/z 296 (1.7 %), 295 (13.2 %), 294 (80.1 %), 293 (3.1 %), 276
(2.4 %), 275 (7.2 %), 203 (13.6 %), 189 (4.1 %), 176 (3.7 %), 175 (38.6 %), 132 (18.2 %), 118 (12.8 %),
106 (12.9 %), 104 (7.5 %), 92 (8.1 %), 91 (100 %), 65 (15.4 %). MS (CI, 70 eV) m/z 296 (14.4 %), 295
(100 %), 294 (1.1 %). Anal. Calcd for C18H18N2O2: C, 73.45; H, 6.16; N, 9.52. Found: C, 72.64, H, 5.90;
N, 9.39.
Synthesis of the Hydrazone (7):
Ketone (6) (9 g, 30.61 mmol) and SAMP or RAMP (4.48 mL, 33.67 mmol, 1.1 eq.) were dissolved in
CH2Cl2 (150 mL) and stirred for 5 h at rt with molecular sieves (3 Å) (2 g). After filtration and
evaporation of the solvent the crude product was filtered through a short column of silica (ether). 7 was
1
isolated in 93% yield (11.6 g) as a yellow oil. H NMR (300 MHz, CDCl3) (δ, ppm) 1.59 (1H, m), 1.76
(2H, m), 1.93 (1H, m), 2.36 (1H, q, J = 7.97), 2.94 (1H, m), 3.18 (2H, m), 3.27 (3H, s), 3.30 (1H, m), 3.77
(1H, d, J = 17.85), 3.80 (2H, s), 4.06 (1H, d, J = 17.31), 4.43 (1H, d, J = 15.11), 4.57 (1H, d, J = 14.83),
13
4.67 (1H, d, J = 14.83), 4.78 (1H, d, J = 15.11), 7.33 (10H, m); C NMR (75 MHz, CDCl3) (δ, ppm)
23.2, 27.2, 48.0, 50.9, 51.9, 52.0, 55.3, 59.7, 67.3, 75.8, 128.0, 128.0, 128.7, 128.9, 129.1, 129.2, 138.0,
138.1, 154.8, 158.6; IR (neat) (cm-1) 3086, 3063, 3029, 2973, 2923, 2875, 2243, 1645, 1586, 1497, 1454,
1428, 1384, 1358, 1304, 1239, 1202, 1179, 1107, 1078, 1030, 1002, 962, 911, 733, 703, 646, 610; MS
(EI, 70 eV, 90°C) m/z 406 (11.8 %), 362 (5.3 %), 361 (28.3 %), 293 (6.3 %), 292 (13.2 %), 291 (6.1 %),
251 (6.1 %), 200 (9.3 %), 175 (9.9 %), 159 (9.4 %), 132 (8.6 %), 128 (6.4 %), 118 (4.4 %), 114 (5.1 %),
92 (7.3 %), 91 (100 %), 70 (11.2 %), 65 (4.9 %). High Resol. MS Calcd for C24H30N4O2: 406.236876.
Found: 406.236794.

General procedure I for the synthesis of the alkylated hydrazones (8a-e) (1-3 mmol-scale):
TMP (1.3 eq.) was dissolved in dry THF (20 mL) in a pre-dried Schlenk-flask under argon and nBuLi-
solution (1.2 eq. of a 1.6 M solution in hexane) was added. The pale yellow solution was stirred for 10
min at rt and then cooled to –78 °C. A solution of the hydrazone (7) (1eq., -78 °C) in THF (20 mL) was
added slowly via a double ended needle. After stirring for 10 min at –78 °C a solution of the electrophile
in THF (5 mL) was added with a syringe pump (5 mL / h), stirred for a further 2 more h at –78 °C and
then quenched with sat. NH4Cl. After extraction with ether and drying over MgSO4 the solvent was
removed. The crude hydrazones were used directly in the following hydrazone cleavage reactions.
General procedure II for the synthesis of the alkylated ketones (9a-e) (Method A):
The alkylated hydrazones (8a-e) were dissolved in acetone (20 mL) and water (5 mL). A 0.1 M solution
of dimethyldioxirane (5 eq.) in acetone were added and stirred overnight (TLC-control). After addition of
water, the reaction mixture was extracted with ether and dried over MgSO4 and the solvent was removed.
The product was purified by chromatography on silica (ether : pentane 1:3) to afford the ketones (9a-e) in
44-59% yield.
General procedure III for the synthesis of the alkylated ketones (9a-e) (Method B):
The alkylated hydrazones (8a-e) were dissolved in THF (5 mL) and water (1 mL). CuCl2(5 eq.) was
added and stirred overnight (TLC-control). After addition of water, the reaction mixture was extracted
with ether, dried over MgSO4 and the solvent removed. The product was purified by chromatography on
silica (ether : pentane 1:3).
Ketone (9a) was prepared according to the general precedures I-III. Yields over two steps: Method A:
1
53 %; Method B: 50%. H NMR (300 MHz, CDCl3) (δ, ppm) 1.18 (3H, d, J = 7.05), 3.62 (3H, m), 4.08
(1H, d, J = 15.11), 4.38 (1H, d, J = 14.77), 4.67 (1H, d, J = 14.77), 5.02 (1H, d, J = 15.11), 7.24 (10H,
13
m); C NMR (75 MHz, CDCl3) (δ, ppm) 15.6, 49.0, 51.1, 53.9, 60.0, 127.8, 127.9, 128.2, 128.5, 128.9,
128.9, 136.8, 137.4, 157.6, 203.8; IR (neat) (cm-1) 3086, 3063, 3030, 2977, 2927, 2869, 1741, 1713,
1656, 1605, 1586, 1495, 1479, 1452, 1417, 1358, 1332, 1262, 1232, 1178, 1155, 1079, 1029, 1003, 974,
912, 734, 702, 649, 607, 457; MS (EI, 70 eV, 150°C) m/z 309 (10.9 %), 308 (50.11 %), 281 (5.3 %), 280
(30.5 %), 275 (8.1 %), 265 (20 %), 189 (32.5 %), 149 (6.1 %), 146 (4.5 %), 132 (15.4 %), 120 (10.9 %),
118 (12.0 %), 106 (15.9 %), 104 (8.3 %), 92 (10.2 %), 91 (100 %), 70 (4.9 %), 65 (10.1 %), 57 (6.1 %),
56 (5.7 %), 55 (5.1 %); MS (CI, 70 eV) m/z 310 (19.8 %), 309 (100 %), 308 (5.0 %), 283 (10.7 %), 282
(4.1 %), 281 (20.8 %), 269 (8.1 %). Anal. Calcd for C19H20N2O2: C, 74.03; H, 6.49; N, 9.09. Found: C,
73.81, H, 6.51; N, 9.33.

Ketone (9b) was prepared according to the general precedures I-III. Yields over two steps: Method A:
59 %; Method B: 52 %. 1H NMR (300 MHz, CDCl3) (δ, ppm) 0.84 (3H, m), 1.22 (4H, m), 1.68 (2H, m),
3.58 (1H, dd, 3J = 6.38, 3J = 3.70), 3.68 (2H, d, J = 8.39), 4.09 (1H, d, J = 15.11), 4.40 (1H, d, J = 14.77),
4.77 (1H, d, J = 5.19 (1H, d, J = 15.11), 7.30 (10H, m); 13C NMR (75 MHz, CDCl3) (δ, ppm) 14.4, 23.0,
27.6, 30.7, 50.2, 51.5, 54.6, 64.9, 128.3, 128.4, 128.7, 129.1, 129.4, 129.4, 137.4, 138.0, 158.1, 203.5; IR
(solution in CDCl3) (cm-1) 3087, 3064, 3031, 3008, 2958, 2932, 2872, 1740, 1714, 1651, 1606, 1586,
1495, 1479, 1453, 1382, 1358, 1304, 1263, 1230, 1177, 1157, 1114, 1079, 1030, 1003, 968, 821, 754,
702, 666, 644, 613, 567, 492, 457; MS (EI, 70 eV, 120°C) m/z 351 (10.6 %), 350 (39.6 %), 294 (10.6 %),
293 (4.4 %), 266 (12.3 %), 265 (60.8 %), 231 (7.1 %), 203 (7.5 %), 132 (10.4 %), 106 (9.4 %), 92
(8.8 %), 91 (100 %), 65 (10.6 %); MS (CI, 70 eV) m/z 352 (24.4 %), 351 (100 %), 350 (7.5 %), 297
(7.4 %), 295 (18.5 %), 281 (9.7 %), 270 (8.1 %), 269 (44.8 %), 176 (9.2 %), 136 (19.3 %), 120 (6.4 %).
Anal. Calcd for C22H26N2O2: C, 75.43; H, 7.43; N, 8.00. Found: C, 75.87, H, 7.35; N, 8.01.
Ketone (9c) was prepared according to the general precedures I-III. Yields over two steps: Method A:
1
44 %; Method B: 46 %. H NMR (300 MHz, CDCl3) (δ, ppm) 2.42 (2H, t, J = 6.72), 3.58 (1H, d, J =
18.80), 3.66 (1H, m), 3.68 (1H, d, J = 18.00), 4.13 (1H, d, J = 15.11), 4.38 (1H, d, J = 14.77), 4.67 (1H, d,
13
J = 14.44), 4.98 (2H, m), 5.15 (1H, d, J = 15.11), 5.60 (1H, m), 7.28 (10H, m); C NMR (75 MHz,
CDCl3) (δ, ppm) 35.5, 49.7, 51.1, 54.3, 64.3, 119.6, 127.8, 127.9, 128.2, 128.6, 128.8, 128.9, 131.8,
136.8, 137.5, 157.3, 202.1; IR (solution in CDCl3) (cm-1) 3310, 3064, 3031, 3006, 2978, 2925, 2858,
1739, 1713, 1651, 1606, 1586, 1495, 1479, 1453, 1419, 1385, 1358, 1335, 1287, 1231, 1178, 1156, 1113,
1078, 1030, 995, 923, 821, 751, 734, 702, 648, 620, 608, 488, 456; MS (EI, 70 eV, 70°C) m/z 334
(5.2 %), 294 (9.1 %), 293 (46.6 %), 92 (9.3 %), 91 (100 %), 65 (9.0 %); MS (CI, 70 eV) m/z 337 (5.1 %),
336 (22.7 %), 335 (100 %), 334 (3.2 %), 321 (7.8 %), 269 (9.7 %). High Resol. MS Calcd for
C21H22N2O2: 334.168128. Found: 334.168271.
Ketone (9d) was prepared according to the general precedures I-III. Yields over two steps: Method A:
1
57 %; Method B: 51 %. H NMR (300 MHz, CDCl3) (δ, ppm) 2.87 (2H, d, J = 6.32), 3.34 (1H, d, J =
18.97), 3.52 (1H, dd, 2J = 18.96, 3J = 0.82), 3.64 (1H, d, J = 15.11), 3.74 (1H, t, J = 6.05), 4.21 (1H, d, J
= 14.84), 4.25 (1H, d, J = 14.85), 5.08 (1H, d, J = 15.12), 6.95-7.22 (15H); 13C NMR (75 MHz, CDCl3)
(δ, ppm) 37.0, 49.7, 51.0, 54.2, 65.6, 127.5, 127.9, 127.9, 128.3, 128.5, 128.7, 128.9, 129.0, 129.6, 135.7,
136.8, 137.2, 157.2, 202.5; IR (solution in CDCl3) (cm-1) 3311, 3108, 3087, 3063, 3030, 3006, 2929,
2870, 1740, 1712, 1651, 1606, 1586, 1495, 1479, 1454, 1384, 1359, 1257, 1230, 1181, 1157, 1079, 1030,
1004, 962, 911, 735, 701, 674, 648, 620, 607, 569, 508, 490; MS (EI, 70 eV, 130°C) m/z 384 (5.5 %), 293

(14.1 %), 92 (7.7 %), 91 (100 %), 74 (31.5 %), 65 (9.8 %), 59 (29.6 %), 45 (19.6 %); MS (CI, 70 eV) m/z
386 (17.5 %), 385 (63.4 %), 384 (5.4 %), 371 (6.5 %), 295 (4.9 %), 270 (4.4 %), 269 (25.3 %), 210
(14.9 %), 192 (11.4 %), 190 (10.4 %), 137 (13.3 %), 136 (100 %), 133 (4.1 %), 117 (43.3 %), 107
(6.1 %). Anal. Calcd for C25H24N2O2: C, 78.10; H, 6.29; N, 7.28. Found: C, 78.12, H, 6.51; N, 7.28.
Keton (9e) was prepared according to the general precedures I-III. Yields ober two steps: Method A:
56 %; Method B: 56 %. 1H NMR (300 MHz, CDCl3) (δ, ppm) 1.86 (2H, m), 2.35 (1H, m), 2.49 (1H, m),
3.47 (1H, m), 3.54 (2H, d, J = 7.05), 3.93 (1H, d, J = 15.11), 4.30 (1H, d, J = 14.77), 4.58 (1H, d, J =
13
14.77), 4.95 (1H, d, J = 14.77), 7.10 (15H, m); C NMR (75 MHz, CDCl3) (δ, ppm) 31.1, 31.9, 49.6,
51.1, 54.1, 63.4, 126.5, 127.8, 127.9, 128.2, 128.3, 128.6, 128.7, 128.9, 128.9, 136.8, 137.2, 140.2, 157.6,
202.7; IR (solution in CDCl3) (cm-1) 3086, 3062, 3029, 2928, 2864, 1737, 1713, 1651, 1586, 1495, 1480,
1453, 1384, 1358, 1231, 1180, 1156, 1077, 1030, 1003, 959, 909, 820, 751, 701, 667, 607, 566, 490, 457;
MS (EI, 70 eV, 90°C) m/z 399 (3.2 %), 398 (10.3 %), 294 (15.4 %), 280 (6.9 %), 266 (5.8 %), 265
(27.9 %), 203 (10.3 %), 175 (4.7 %), 106 (5.9 %), 92 (8.9 %), 91 (100 %), 65 (9.1 %); MS (CI, 70 eV)
m/z 401 (5.1 %), 400 (26.7 %), 399 (100 %), 398 (6.3 %), 397 (4.1 %), 385 (6.9 %), 301 (5.6 %). Anal.
Calcd for C26H26N2O2: C, 78.39; H, 6.53; N, 7.04. Found: C, 77.85, H, 6.34; N, 7.10.
General procedure IV for the synthesis of the alkylated alcohols (10a-e):
A solution of ketone 9a-e in THF (10 mL) was added to a suspension of LiAlH4 (3 eq.) in dry ether (10
mL) at 0 °C. The reaction mixture was stirred for 1 h (TLC-control) at 0°C and then quenched with sat.
NH4Cl, filtered and washed with CH2Cl2, dried over MgSO4 and the solvent removed. The pure alcohols
(10a-e) were obtained after column chromatography on silica (ether:pentane 1:1) in 76-84% yield. The de
of the reduction was in all cases ≥ 96 % (1H-NMR spectrum). The enantioselectivities were determined
with (-)-Pirkle-1H-NMR-shift experiments (ee = 76 %).
Alcohol (10a) was prepared according to the general precedure IV. Yield: 76 %. The de of the reduction
was ≥ 96 % (1H-NMR spectrum). The enantioselectivities were determined with (-)-Pirkle-1H-NMR-shift
1
experiments: ee = 76 %. H NMR (300 MHz, CDCl3) (δ, ppm) 1.05 (3H, d, J = 6.6), 2.12 (s, 1H), 3.06
2
3
2
(1H, dd, J = 11.55, J = 8.52), 3.11 (1H, ddd, J = 11.27, 3J = 5.22, 4J = 0.82), 3.29 (1H, m), 3.91 (1H,
m), 3.94 (1H, d, J = 15.39),, 4.46 (1H, d, J = 14.85), 4.53 (1H, d, J = 14.85), 5.13 (1H, d, J = 15.40), 7.22
13
(10H, m); C NMR (75 MHz, CDCl3) (δ, ppm) 13.0, 48.2, 49.0, 51.7, 53.6, 64.9, 127.3, 127.4, 127.8,
128.0, 128.6, 128.7, 138.1, 138.8, 155.7; IR (neat) (cm-1) 3314, 3108, 3086, 3065, 3030, 3005, 2956,
2930, 2873, 2859, 2245, 1949, 1604, 1505, 1468, 1453, 1381, 1354, 1305, 1254, 1215, 1160, 1126, 1093,
1077, 1050, 1030, 1002, 967, 910, 810, 734, 759, 701, 674, 648, 606, 565, 511, 487, 457; MS (CI, 70 eV)

m/z 311 (2.1 %), 310 (100 %), 309 (2.0 %). Anal. Calcd for C19H22N2O2: C, 73.55; H, 7.10; N, 9.03.
Found: C, 73.60, H, 7.37 N, 9.05.
Alcohol (10b) was prepared according to the general precedure IV. Yield: 80 %. The de of the reduction
was ≥ 96 % (1H-NMR spectrum). The enantioselectivities were determined with (-)-Pirkle-1H-NMR-shift
1
experiments: ee ≥ 96 %. H NMR (300 MHz, CDCl3) (δ, ppm) 0.80 (3H, t, J = 7.14), 1.23 (2H, m), 1.39
2
3
(1H, m), 1.55 (1H, m), 2.16 (1H, d, J = 4.67), 3.02 (1H, dd, J = 11.54, J = 8.79), 3.10 (2H, m), 3.84
(1H, d, 2J = 15.38), 3.86 (1H, m), 4.42 (1H, d, J = 14.83), 4.53 (1H, d, J = 14.84), 5.29 (1H, d, J = 15.38),
13
7.23 (10H, m); C NMR (75 MHz, CDCl3) (δ, ppm) 14.5, 23.6, 28.8, 29.6, 49.3, 50.8, 52.1, 58.5, 65.0,
127.8, 127.9, 128.3, 128.6, 129.2, 129.2, 138.5, 139.3, 156.3; IR (neat) (cm-1) 3649, 3629, 3349, 3108,
3087, 3064, 3029, 3004, 2961, 2930, 2872, 2860, 2607, 2369, 2345, 1948, 1803, 1715, 1676, 1607, 1505,
1466, 1453, 1383, 1356, 1258, 1218, 1141, 1091, 1030, 968, 930, 873, 805, 759, 702, 667, 607, 563, 510,
492, 456; MS (EI, 70 eV, 80°C) m/z 353 (7.6 %), 352 (38.7 %), 295 (13.6 %), 261 (6.2 %), 205 (7.7 %),
132 (8.1 %), 120 (15.5 %), 92 (7.5 %), 91 (100 %), 74 (10.6 %), 65 (8.4 %), 59 (11.6 %); MS (CI, 70 eV)
m/z 355 (2.9 %), 353 (100 %), 351 (2.9 %), 149 (25.7 %), 75 (29.3 %). Anal. Calcd for C22H28N2O2: C,
75.00; H, 7.95; N, 7.95. Found: C, 74.77, H, 8.13 N, 7.81.
Alcohol (10c) was prepared according to the general precedure IV. Yield: 79 %. The de of the reduction
was ≥ 96 % (1H-NMR spectrum). The enantioselectivities were determined with (-)-Pirkle-1H-NMR-shift
1
experiments: ee = 80 %. H NMR (300 MHz, CDCl3) (δ, ppm) 1.90 (1H, s), 2.29 (1H, m), 2.43 (1H, m),
2
3
2
3
3.13 (1H, dd, J = 11.41, J = 8.73), 3.23 (1H, dd, J = 12.43, J = 5.71), 3.32 (1H, m), 3.90 (1H, d, J =
15.44), 3.99 (1H, m), 4.52 (1H, d, 14.77), 4.66 (1H, d, J = 14.77), 5.09 (2H, m), 5.34 (2H, d, J = 15.44),
13
5.82 (1H, m), 7.30 (10H, m); C NMR (75 MHz, CDCl3) (δ, ppm) 33.2, 48.8, 49.9, 51.7, 57.8, 64.7,
118.2, 127.3, 127.5, 127.8, 128.2, 128.7, 128.7, 135.1, 138.0, 138.6, 155.7; IR (neat) (cm-1) 3298, 3087,
3064, 3030, 2974, 2930, 1714, 1682, 1651, 1607, 1556, 1505, 1453, 1383, 1359, 1317, 1250, 1180, 1163,
1132, 1079, 1030, 1002, 959, 916, 879, 840, 819, 807, 751, 702, 667, 605, 565, 507, 457; MS (EI, 70 eV,
80°C) m/z 336 (6.2 %), 296 (7.5 %), 295 (24.5 %), 120 (21.8 %), 92 (13.8 %), 91 (100 %), 90 (21.4 %),
73 (5.4 %), 65 (9.7 %), 61 (5.6 %), 57 (5.0 %), 45 (9.8 %); MS (CI, 70 eV) m/z 339 (33.8 %), 337
(100 %). Anal. Calcd for C21H24N2O2: C, 74.97; H, 7.19; N, 8.33. Found: C, 74.45, H, 7.03 N, 8.21.
Alcohol (10d) was prepared according to the general precedure IV. Yield: 84 %. The de of the reduction
was ≥ 96 % (1H-NMR spectrum). The enantioselectivities were determined with (-)-Pirkle-1H-NMR-shift
1
experiments: ee = 76 %. H NMR (300 MHz, CDCl3) (δ, ppm) 2.34 (1H, s), 2.68 (1H, dd, 2J = 13.19, 3J
2
3
= 8.52), 2.98 (1H, dd, J = 13.19, J = 5.50), 3.16 (2H, m), 3.21 (1H, d, J = 15.40), 3.42 (1H, m), 3.89

(1H, m), 4.48 (1H, d, J = 14.85), 4.69 (1H, d, J = 14.85), 5.19 (1H, d, J = 15.40), 7.20-7.35 (15H, m); 13C
NMR (75 MHz, CDCl3) (δ, ppm) 34.5, 48.7, 49.9, 51.8, 59.9, 64.2, 115.4, 120.6, 126.7, 127.3, 127.6,
127.9, 128.1, 128.6, 129.5, 137.8, 138.2, 138.4, 155.7; IR (solution in CHCl3) (cm-1) 3294, 3064, 3028,
2926, 1707, 1607, 1510, 1469, 1453, 1389, 1358, 1296, 1250, 1217, 1179, 1140, 1093, 1076, 1053, 1029,
1001, 973, 913, 807, 754, 702, 668, 633, 607, 549, 507, 458 ; MS (EI, 70 eV, 80°C) m/z 296 (13.2 %),
295 (61.8 %), 120 (26.5 %), 92 (8.3 %), 91 (100 %), 65 (7.1 %); MS (CI, 70 eV) m/z 388 (28.5 %), 387
(100 %). Anal. Calcd for C25H26N2O2: C, 77.72; H, 6.74; N, 7.25. Found: C, 77.22; H, 6.67; N, 7.32.
Alcohol (10e) was prepared according to the general precedure IV. Yield: 83 %. The de of the reduction
was ≥ 96 % (1H-NMR spectrum). The enantioselectivities were determined with (-)-Pirkle-1H-NMR-shift
1
experiments: ee 86 %. H NMR (300 MHz, CDCl3) (δ, ppm) 1.78 (1H, m), 2.02 (1H, m), 2.34 (1H, s),
2.70 (2H, t), 3.09-3.28 (3H, m), 3.87 (1H, d, J = 15.44), 3.97 (1H, m), 4.49 (1H, d, J = 15.11), 4.59 (1H,
13
d, J = 14.77), 5.33 (1H, d, J = 15.11), 7.25 (15H, m); C NMR (75 MHz, CDCl3) (δ, ppm) 30.3, 33.0,
48.6, 50.4, 51.7, 57.3, 64.5, 126.2, 127.3, 127.5, 128.0, 128.1, 128.4, 128.6, 128.7, 128.7, 138.0, 138.6,
141.5, 155.8; IR (solution in CHCl3) (cm-1) 3342, 3106, 3085, 3063, 3027, 3007, 2925, 2861, 1708, 1673,
1607, 1506, 1467, 1453, 1357, 1250, 1219, 1180, 1156, 1095, 1077, 1030, 1011, 958, 910, 809, 755, 701,
667, 608, 563, 510, 457; MS (EI, 70 eV, 80°C) m/z 401 (10.1 %), 400 (32.5 %), 296 (10.7 %), 295
(8.0 %), 279 (9.5 %), 265 (8.1 %), 206 (5.6 %), 205 (42.3 %), 132 (10.5 %), 92 (9.1 %), 91 (100 %), 65
(7.3 %); MS (CI, 70 eV) m/z 403 (5.4 %), 402 (28.6 %), 401 (100 %), 400 (6.4 %), 399 (5.8 %), 295
(6.6 %), 281 (11.1 %), 275 (5.1 %), 270 (5.2 %), 269 (17.7 %), 268 (52.4 %), 255 (15.9 %), 242 (6.9 %),
241 (33.8 %), 240 (47.1 %), 224 (9.0 %), 190 (7.4 %), 136 (10.4 %), 132 (6.1 %). Anal. Calcd for
C26H28N2O2: C, 78.00; H, 7.00; N, 7.00. Found: C, 77.45; H, 7.11; N, 7.08.
General procedure V for the synthesis of the double alkylated hydrazones (11a-e) (1-3 mmol-scale):
The crude monoalkylated hydrazones (8a-e) (prepared according to general procedure I) were directly
used for the second alkylation. TMP (1.3 eq.) was dissolved in dry THF (20 mL) in a pre-dried Schlenk-
flask under argon and nBuLi-solution (1.2 eq. of a 1.6 M solution in hexane) was added. The pale yellow
solution was stirred for 10 min at rt and then cooled to –78 °C. A solution of the hydrazones (8a-e) (1eq.,
-78 °C) in THF (20 mL) was added slowly via a double ended needle. After stirring for 10 min at -78 °C a
solution of the electrophile in THF (5 mL) was added, stirred for a further 3 more h at -78 °C and then
quenched with NH4Cl (aq). After extraction with ether (3x) and drying over MgSO4 the solvent was
removed. The crude hydrazones were used directly in the following hydrazone cleavage reaction (general
procedure VI).

General procedure VI for the synthesis of the double alkylated ketones (12a-e) (1-3 mmol scale):
Ozone was bubbled through a solution of hydrazone (11a-e) (1 eq.) in CH2Cl2 (250 mL) at –78°C with a
flow of 75 L/h until a blue or green color is observed, then for 1 min air was bubbled through the reaction
mixture until the color disappeared again. The solvent was removed under reduced pressure and the crude
products were purified by column chromatography on silica gel (ether : pentane 1:1).
Ketone (12a) was prepared according to the general precedures V and VI. Yield over three steps: 43 %.
1
The de of the second alkylation was ≥ 96 % (1H-NMR spectrum). H NMR (300 MHz, CDCl3) (δ, ppm)
0.77 (3H, d, J = 7.05), 0.93 (3H, d, J = 6.72), 2.06 (1H, m), 3.30 (1H, d, J = 5.71), 3.90 (1H, d, J = 14.43),
5.28 (1H, d, J = 14.77), 7.30 (5H, m); 13C NMR (75 MHz, CDCl3) (δ, ppm) 18.7, 19.5, 31.6, 50.7, 68.9,
127.9, 128.7, 129.2, 136.9, 157.2, 204.7; IR (neat) (cm-1) 3031, 2964, 2933, 2875, 2248, 1728, 1646,
1495, 1471, 1453, 1389, 1370, 1348, 1317, 1236, 1148, 1111, 1077, 1030, 910, 734, 702, 648; MS (EI, 70
eV, 80°C) m/z 380 (15.3 %), 338 (15.5 %), 337 (65.2 %), 181 (6.7 %), 162 (27.0 %), 120 (20.5 %), 92
(8.0 %), 91 (100 %). Anal. Calcd for C24H30N2O2: C, 76.19; H, 7.94; N, 7.41. Found: C, 75.80; H, 7.88;
N, 7.58.
Ketone (12b) was prepared according to the general precedures V and VI. Yield over three steps: 39 %.
1
The de of the second alkylation was ≥ 96 % (1H-NMR spectrum). H NMR (300 MHz, CDCl3) (δ, ppm)
13
0.8-1.8 (9H, m), 3.54 (1H, m), 3.92 (1H, d, J = 14.77), 5.28 (1H, d, J = 14.78), 7.30 (5H, m); C NMR
(75 MHz, CDCl3) (δ, ppm) 13.9, 22.6, 27.0, 30.4, 49.2, 63.1, 127.9, 128.8, 128.8, 137.2, 157.3, 205.1; IR
(neat) (cm-1) 3315, 3086, 3063, 3029, 3006, 2957, 2929, 2860, 1739, 1712, 1656, 1586, 1495, 1477,
1453, 1383, 1357, 1303, 1263, 1229, 1177, 1156, 1111, 1078, 1029, 968, 755, 702, 666; MS (EI, 70 eV,
80°C) m/z 407 (17.3 %), 406 (60.1 %), 350 (20.5 %), 349 (17.7 %), 322 (21.2 %), 321 (100 %), 315
(10.6 %), 259 (16.0 %), 244 (5.6 %), 176 (5.6 %), 106 (5.4 %), 92 (7.2 %), 91 (96.4 %); Anal. Calcd for
C26H34N2O2: C, 76.85; H, 8.37; N, 6.90. Found: C, 76.51; H, 8.17; N, 7.21.
Ketone (12c) was prepared according to the general precedures V and VI. Yield over three steps: 40 %.
1
The de of the second alkylation was ≥ 96 % (1H-NMR spectrum). H NMR (300 MHz, CDCl3) (δ, ppm)
2.90 (2H, m), 3.68 (1H, d, J = 14.77), 3.72 (1H, m), 4.98 (1H, d, J = 14.77), 7.18 (4H, m), 7.28 (6H, m);
13C NMR (75 MHz, CDCl3) (δ, ppm) 37.1, 49.6, 63.9, 127.4, 128.0, 128.9, 129.0, 129.3, 129.8, 136.0,
137.0, 156.9, 203.3; IR (neat) (cm-1) 3088, 3066, 3019, 2928, 2855, 1739, 1711, 1650, 1604, 1496, 1470,
1454, 1359, 1216, 1080, 1030, 757, 701, 669; MS (EI, 70 eV, 80°C) m/z 474 (3.8 %), 384 (18.3 %), 383
(64.7 %), 266 (21.1 %), 92 (7.1 %), 91 (100 %). Anal. Calcd for C32H30N2O2: C, 81.01; H, 6.33; N, 5.91.
Found: C, 81.47; H, 6.23; N, 5.78.

Ketone (12d) was prepared according to the general precedures V and VI. Yield over three steps: 47 %.
1
The de of the second alkylation was ≥ 96 % (1H-NMR spectrum). H NMR (300 MHz, CDCl3) (δ, ppm)
1.97 (2H, m), 2.38 (1H, m), 2.56 (1H, m), 3.60 (1H, m), 3.87 (1H, d, J = 14.56), 5.20 (1H, d, J = 14.56),
13
7.10-7.33 (10H, m); C NMR (75 MHz, CDCl3) (δ, ppm) 31.1, 32.5, 49.5, 62.3, 126.6, 127.1, 128.1,
128.6, 128.8, 128.9, 137.1, 140.5, 157.0, 204.7; IR (neat) (cm-1) 3084, 3061, 3027, 3003, 2926, 2861,
1734, 1658, 1602, 1584, 1495, 1453, 1384, 1356, 1303, 1278, 1236, 1170, 1119, 1078, 1030, 919, 751,
699, 619, 518, 499, 482; MS (EI, 70 eV, 80°C) m/z 503 (6.1 %), 502 (16.2 %), 399 (12.4 %), 398
(43.7 %), 397 (12.0 %), 370 (8.8 %), 369 (32.5 %), 307 (19.4 %), 295 (5.6 %), 294 (17.1 %), 293
(14.6 %), 203 (14.2 %), 149 (6.7 %), 132 (11.6 %), 105 (7.6 %), 92 (8.1 %), 91 (100 %), 57 (8.0 %).
Anal. Calcd for C34H34N2O2: C, 81.27; H, 6.77; N, 5.58. Found: C, 81.66; H, 6.53; N, 5.31.
Ketone (12e) was prepared according to the general precedures V and VI. Yield over three steps: 34 %.
1
The de of the second alkylation was ≥ 96 % (1H-NMR spectrum). H NMR (300 MHz, CDCl3) (δ, ppm)
1.88 (2H, m), 2.30 (1H, m), 2.48 (1H, m), 2.98 (2H, m), 3.44 (1H, m), 3.63 (1H, d, J = 14.83), 3.84 (1H,
13
m), 3.86 (1H, d, J = 14.56), 4.79 (1H, d, J = 14.83), 5.25 (1H, d, J = 14.56), 7.13-7.35 (20H, m); C
NMR (75 MHz, CDCl3) (δ, ppm) 31.1, 32.6, 37.5, 49.6, 49.8, 62.4, 64.6, 126.2, 126.5, 127.3, 127.5,
127.9, 128.7, 128.9, 129.0, 129.0, 129.1, 129.9, 129.9, 136.0, 137.0, 137.1, 140.5, 157.1, 204.2; IR (neat)
(cm-1) 3086, 3063, 3029, 2929, 2863, 2247, 1736, 1648, 1604, 1585, 1495, 1470, 1453, 1384, 1358, 1230,
1179, 1157, 1079, 1030, 910, 733, 701, 648; MS (EI, 70 eV, 80°C) m/z 309 (7.6 %), 118 (31.9 %), 92
(8.5 %), 91 (100 %). Anal. Calcd for C33H32N2O2: C, 81.15; H, 6.56; N, 5.74. Found: C, 80.41; H, 6.44,
N, 5.82.
General procedure VII for the synthesis of the symmetrical double alkylated alcohols (13a-d) (1-3 mmol
scale):
NaBH4 (3 eq.) was added in small portions to a solution of the ketones (12a-d) (1 eq.) in MeOH (10 mL)
and at 0°C. The reaction mixture was stirred for another 2 h at 0 °C, quenched with sat. aq. NH4Cl and
extracted with ether (3x). The combined organic layers were dried over MgSO4, the solvent was removed
under reduced pressure and the crude product was purified by column chromatography on silica gel
(ether : pentane 1:1).
1
Alcohol (13a) was prepared according to the general precedure VII. Yield: 71 %. H NMR (300 MHz,
CDCl3) (δ, ppm) 0.77 (3H, d, J = 6.59), 0.95 (3H, d, J = 7.14), 1.01 (3H, d, J = 6.87), 1.04 (3H, d, J =
6.87), 1.60 (1H, m), 1.88 (1H, s), 2.19 (1H, m), 2.79 (1H, dd, J = 9.06, J = 3.84) 2.86 (1H, dd, J = 5.77, J

= 4.39), 3.67 (1H, d, J = 14.56), 3.74 (1H, d, J = 15.11), 3.91 (1H, m), 5.55 (1H, d, J = 14.56), 5.60 (1H,
d, J = 15.10), 7.30 (10H, m); 13C NMR (75 MHz, CDCl3) (δ, ppm) 18.5, 19.1, 20.4, 28.1, 31.4, 47.7, 52.2,
58.4, 66.4, 66.6, 127.6, 128.0, 128.5, 128.6, 128.8, 129.2, 137.9, 138.9, 157.0; IR (neat) (cm-1) 3356,
3108, 3087, 3064, 3030, 2960, 2930, 2874, 1711, 1614, 1453, 1389, 1358, 1312, 1242, 1178, 1125, 1076,
1065, 1030, 1003, 966, 951, 911, 841, 820, 797, 734, 702, 633, 619, 606, 562, 542, 513, 455; MS (EI, 70
eV, 80°C) m/z 381 (5.0 %), 380 (17.8 %), 338 (16.6 %), 337 (69.7 %), 181 (7.4 %), 162 (29.3 %), 149
(5.3 %), 120 (22.4 %), 92 (8.3 %), 91 (100 %), 70 (8.3 %), 61 (6.5 %), 57 (6.3 %), 55 (5.8 %), 45 (6.1 %).
Anal. Calcd for C24H32N2O2: C, 75.79; H, 8.42; N, 7.37. Found: C, 75.31; H, 8.23; N, 7.51.
1
Alcohol (13b) was prepared according to the general precedure VII. Yield: 85 %. H NMR (300 MHz,
CDCl3) (δ, ppm) 0.86 (6H, m), 1.07-1.40 (8H, m), 1.56 (4H, m), 1.77 (1H, s), 3.13 (2H, m), 3.68 (1H, m),
3.87 (1H, d, J = 14.48), 4.01 (1H, d, J = 15.66), 5.34 (1H, d, J = 14.56), 5.40 (1H, d, J = 15.38), 7.30
(10H, m); 13C NMR (75 MHz, CDCl3) (δ, ppm) 14.3, 14.3, 23.1, 23.2, 27.4, 28.3, 28.4, 31.3, 48.1, 50.1,
55.2, 59.2, 65.8, 127.3, 127.8, 127.9, 128.6, 128.7, 129.0, 138.5, 138.9, 156.4; IR (neat) (cm-1) 3348,
3108, 3087, 3064, 3029, 3003, 2957, 2931, 2871, 2861, 1605, 1494, 1453, 1382, 1356, 1304, 1247, 1218,
1169, 1120, 1103, 1076, 1030, 966, 808, 756, 701, 665, 647, 619, 605, 512; MS (EI, 70 eV, 80°C) m/z
409 (14.7 %), 408 (52.7 %), 352 (10.8 %), 351 (34.5 %), 318 (9.8 %), 317 (44.6 %), 181 (5.2 %), 177
(6.0 %), 176 (42.0 %), 132 (7.4 %), 120 (11.7 %), 106 (6.6 %), 92 (8.1 %), 91 (100 %). Anal. Calcd for
C26H36N2O2: C, 76.47; H, 8.82; N, 6.68. Found: C, 76.01; H, 9.12; N, 6.88.
1
Alcohol (13c) was prepared according to the general precedure VII. Yield: 82 %. H NMR (300 MHz,
CDCl3) (δ, ppm) 2.00 (1H, s), 3.43 (1H, dd, J = 13.74, J = 7.97), 2.73 (2H, m), 2.91 (1H, dd, J = 12.64, J
= 5.50), 3.18 (1H, m), 3.25 (1H, m), 3.34 (1H, m), 3.70 (1H, d, J = 14.55), 3.86 (1H, d, J = 15.66), 5.27
13
(1H, d, J = 14.83), 5.42 (1H, d, J = 15.38), 6.74 (2H, m), 6.87 (2H, m), 7.05-7.30 (18 H, m); C NMR
(75 MHz, CDCl3) (δ, ppm) 34.4, 38.2, 48.0, 50.1, 56.9, 60.7, 64.3, 126.7, 126.9, 127.0, 127.6, 128.0,
128.7, 128.8, 128.9, 129.1, 129.2, 129.3, 129.5, 136.8, 137.8, 138.3, 138.6, 156.2; IR (neat) (cm-1) 3343,
3086, 3063, 3027, 3006, 2928, 2871, 1706, 1670, 1604, 1537, 1495, 1453, 1383, 1357, 1247, 1217, 1182,
1156, 1096, 1074, 1043, 1030, 1004, 974, 755, 702, 667, 609, 505; MS (EI, 70 eV, 80°C) m/z 386 (18.0
%), 385 (74.3 %), 210 (11.7 %), 182 (26.7 %), 155 (6.7 %), 120 (14.2 %), 92 (8.0 %), 91 (100 %), 65 (5.2
%), 57 (6.0 %), 55 (5.1 %); MS (CI, 70 eV) m/z 478 (30.4 %), 477 (90.0 %), 391 (12.3 %), 385 (9.2 %),
371 (10.1 %), 281 (5.2 %), 280 (9.0 %), 254 (5.1 %), 253 (6.5 %), 235 (7.5 %), 226 (30.0 %), 223 (6.8
%), 198 (40.5 %), 190 (24.0 %), 182 (12.8 %), 181 (93.9 %), 165 (22.7 %), 164 (18.8 %), 163 (100 %),
157 (8.1 %), 147 (14.4 %), 146 (5.8 %), 145 (10.6 %), 137 (6.1 %), 136 (10.8 %), 133 (12.7 %), 132 (9.0

%), 108 (56.0 %), 107 (34.1 %), 106 (14.6 %), 92 (8.2 %), 91 (25.4 %). Anal. Calcd for C32H32N2O2: C,
80.67; H, 6.72; N, 5.88. Found: C, 80.12, H, 6.81; N, 5.99.
1
Alcohol (13d) was prepared according to the general precedure VII. Yield: 91 %. H NMR (300 MHz,
CDCl3) (δ, ppm) 1.45-2.00 (4H, m), 2.43 (3H, m), 2.69 (1H, m), 3.12 (1H, m), 3.20 (1H, m), 3.78 (1H,
m), 3.84 (1H, d, J = 14.56), 3.98 (1H, d, J = 15.38), 5.32 (1H, d, J = 14.84), 5.46 (1H, d, J = 15.39), 7.00
13
(4H, m), 7.25 (16H, m); C NMR (75 MHz, CDCl3) (δ, ppm) 29.6, 31.6, 32.0, 33.1, 48.0, 50.1, 54.2,
58.6, 65.4, 126.3, 126.5, 127.5, 127.9, 128.1, 128.4, 128.5, 128.5, 128.7, 128.7, 128.8, 129.1, 138.1,
138.6, 141.0, 141.1, 156.8; IR (solution in CHCl3) (cm-1) 3345, 3085, 3063, 3026, 2927, 2860, 1603,
1495, 1453, 1384, 1357, 1245, 1217, 1179, 1156, 1077, 1030, 1002, 757, 700, 667; MS (EI, 70 eV, 80°C)
m/z 505 (13.8 %), 504 (30.6 %), 503 (7.1 %), 414 (11.9 %), 413 (43.2 %), 400 (9.8 %), 399 (11.6 %), 296
(12.0 %), 295 (6.8 %), 279 (5.7 %), 224 (14.6 %), 205 (19.5 %), 120 (8.8 %), 92 (8.7 %), 91 (100 %).
Anal. Calcd for C34H36N2O2: C, 80.95; H, 7.14; N, 5.56. Found: C, 80.61; H, 7.34; N, 5.28.
Synthesis of alcohol (14):
To a solution of ketone (12e) (100 mg, 0.2 mmol) in ether (10 mL) at –78 °C was added a solution of
BH3-SMe2 in THF (1M, 0.61 mL). The reaction mixture was allowed to warm to ambient temperature
overnight and quenched with saturated aqueous NH4Cl solution. After extraction with ether (3 x) the
collected organic phases were dried over MgSO4. The solvent was removed and the crude product was
analyzed by 1H-NMR spectroscopy indicating an 1.6 : 1 mixture of the diastereomers (14) and (15). Both
diasteomers could be seperated by flash chromatography on silica gel (ether : pentane 1:1). Yield of the
diasteromeric mixture: 74 %. The enantioselectivity was determined with (-)-Pirkle-1H-NMR-shift
experiments: ee = 76 %. Analytical data for the major isomer (14): 1H NMR (300 MHz, CDCl3) (δ, ppm)
1.61 (1H, m), 1.63 (1H, s), 1.87 (1H, m), 2.41 (2H, t, J = 8.24), 2.82 (1H, dd, J = 12.63, J = 9.34), 2.96
(1H, dd, J = 12.61, J = 5.46), 3.17 (1H, m), 3.33 (1H, m), 3.41 (1H, m), 3.84 (1H, d, J = 14.83), 3.90 (1H,
13
d, J = 15.38), 5.40 (1H, d, J = 14.56), 5.47 (1H, d, J = 15.39), 7.00 (4H, m), 7.15-7.35 (16H, m); C
NMR (75 MHz, CDCl3) (δ, ppm) 31.4, 33.8, 34.5, 48.3, 50.2, 57.3, 58.3, 65.0, 126.4, 126.8, 127.6, 127.9,
128.1, 128.4, 128.7, 128.8, 128.8, 128.9, 129.1, 129.4, 137.9, 138.2, 138.6, 140.9, 157.0; IR (solution in
CHCl3) (cm-1) 3342, 3086, 3063, 3027, 2929, 2867, 1603, 1494, 1484, 1453, 1357, 1245, 1217, 1180,
1157, 1094, 1077, 1030, 756, 701, 668; MS (EI, 70 eV, 80°C) m/z 490 (23.1 %), 400 (23.1 %), 399
(77.6 %), 225 (5.2 %), 224 (30.1 %), 120 (18.4 %), 92 (8.2 %), 91 (100 %). Anal. Calcd for C33H34N2O2:
C, 80.82; H, 6.94; N, 5.71. Found: C, 80.51; H, 7.33; N, 5.63.

Synthesis of alcohol (15):
To a solution of ketone (12e) (100 mg, 0.2 mmol) in ether (10 mL) at –78 °C was added a solution of
(L)-Selectride in THF (1M, 0.61 mL). The reaction mixture was allowed to warm to ambient temperature
overnight and quenched with saturated aqueous NH4Cl solution. After an aqueous solution of H2O2 (30%)
and NaOH (1 M) was added the reaction mixture was stirred for 5 more min. After extraction with ether
(3 x) the collected organic phases were dried over MgSO4. The solvent was removed and the crude
1
product was analyzed by H-NMR spectroscopy indicating 15 as the only diastereoisomer. The crude
product was purified by flash chromatography on silica gel (ether : pentane 1:1). Yield: 89 %. The
enantioselectivity was determined with (-)-Pirkle-1H-NMR-shift experiments: ee = 76 %. Analytical data
for 15: 1H NMR (300 MHz, CDCl3) (δ, ppm) 1.62 (1H, s), 1.95 (1H, m), 2.04 (1H, m), 2.38 (1H, m), 2.45
(1H, dd, J = 14.01, J = 8.27), 2.64 (1H, m), 2.79 (1H, dd, J = 13.73, J = 5.77), 3.22 (1H, m), 3.41 (1H,
m), 3.62 (1H, m), 3.81 (1H, d, J = 14.56), 4.00 (1H, d, J = 15.39), 5.29 (1H, d, J = 11.54), 5.47 (1H, d, J
13
= 15.38), 6.89 (2H, d), 6.98 (2H, d), 7.26 (16H, m); C-NMR (75 MHz, CDCl3) (δ, ppm) 29.7, 31.9,
37.9, 47.9, 50.3, 54.1, 60.8, 65.2, 126.2, 127.1, 127.5, 128.0, 128.1, 128.4, 128.7, 128.8, 128.8, 129.0,
129.1, 129.2, 136.9, 138.1, 138.6, 141.0, 156.2; IR (neat) (cm-1) 3338, 3085, 3062, 3027, 3003, 2928,
2861, 1604, 1495, 1453, 1384, 1358, 1246, 1030, 990, 969, 910, 733, 701, 647, 608; MS (EI, 70 eV,
80°C) m/z 490 (5.1 %), 400 (25.6 %), 399 (97.8 %), 295 (23.5 %), 224 (18.3 %), 181 (6.4 %), 120
(15.8 %), 92 (8.0 %), 91 (100 %). Anal. Calcd for C33H34N2O2: C, 80.82; H, 6.94; N, 5.71. Found: C,
80.41; H, 6.99; N, 5.51.
REFERENCES AND NOTES
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G. V. De Lucca, S. Erickson-Viitanen, and P. Y. S. Lam, Drug Discovery Today, 1997, 2, 6.
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Cordova, J. Med. Chem., 1997, 40, 1707; d) G. V. De Lucca, T. U. Kim, J. Liang, B. Cordova,
and R. M. Klabe, J. Med. Chem., 1998, 41, 2411; e) D. Enders, U. Jegelka, and B. Dücker, Angew.
Chem., Int. Ed. Engl., 1993, 32, 423; f) L. Bernardi, B. F. Bonini, G. Dessole, M. Fochi, M.
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14
15
16
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D. Enders, U. Jegelka, and B. Dücker, Angew. Chem., 1993, 105, 423; Angw. Chem., Int. Ed.
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18
19
D. Enders, L. Wortmann, B. Dücker, and G. Raabe, Helv. Chim. Acta, 1999, 82, 1195.
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20
Crystal structure analysis of 8c. CCDC 116037. Crystals were obtained from CH2Cl2. 8c
(C27H34O2N4, Mcalc=446.6, crystal size ca. 0.3 × 0.3 × 0.3 mm) crystallizes in orthorhombic space
group P 2 2 2 (no. 19), a=7.7066(5), b=10.5628(6), c=30.780(2) Å, Z=4, V=2505.6 Å3,
1 1 1
Dcalc=1.184 gcm-3. Enraf-Nonius CAD4-diffractometer, CuK radiation (graphit monochromator,
α
λ=1.54179Å). The structure was solved by means of direct methods (GENSIN, GENTAN as
implemented in Xtal 3.4.[19]. Some of the hydrogen atoms could be located, the others were
calculated. All parameters were kept constant in the refinement. The allyl group is disordered, in
that C7 and C6 occur in two components (0.75:0.25), which could be refined isotropically with
constant occupation numbers. 2552 observed reflections (I > 2σ(I)) in the final full-matrix least
squares refinement of 296 parameters, terminating at R=0.064, Rw=0.040 (w=σ-2) and residual
electron density of -0.29/+0.29 eÅ-3.
21
22
D. Enders, L. Wortmann, and R. Peters, Acc. Chem. Res., 2000, 33, 157.
a) A. Altamura, R. Curci, and J. O. Edwards, J. Org. Chem., 1993, 58, 7289; b) Encyclopedia of
Reagents for Organic Synthesis, Vol 2, (Hrsg.: L. A. Paquette), John Wiley & Sons, 1995, S. 2061.
Crystal structure analysis of 10c. CCDC 116038. Crystals were obtained from CH2Cl2 / ether. 10c
(C21H24O2N2, Mcalc=336.4, crystal size ca. 0.3 × 0.3 × 0.3 mm) crystallizes in orthorhombic space
23
group P 2
2
2 (no. 19), a=7.1682(7), b=12.019(2), c=21.592(3) Å, Z=4, V=1860.3 Å3,
1
1 1
Dcalc=1.201gcm-3. Enraf-Nonius CAD4-diffractometer, CuK radiation (graphit-monochromator,
α
λ=1.54179Å). Direct methods (GENSIN, GENTAN from Xtal 3.4.[19] were used to solve the
structure. Some of the hydrogen atoms could be located, the others were calculated. Hydrogen
parameters were not refined. Final full-matrix least squares refinement of 226 parameters (1745
observed reflections (I>2σ(I)) converged at R=0.061, Rw=0.062 (w=(σ(F)2 +0.0004·F2)-1) and a
final residual electron density of -0.29/+0.37 eÅ-3.
24
S. R. Hall, G. S. D. King, J. M. Stewart (Ed.), Xtal 2.4 User´s Manual. University of Western
Australia, Leuven, and Maryland. Lamb, Perth, 1995.
25
26
27
D. Enders and L. Wortmann, Heterocycles, 2002, 58, 293.
H. C. Brown, J. Am. Chem. Soc., 1947, 69, 1197.
S. W. Chaikin and H. C. Brown, J. Am. Chem. Soc., 1949, 71, 122.

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1997, 7, 495.
32