A tetracarbonyl Paal-Knorr approach to semicorrins

Article abstract of DOI:10.3987/COM-08-S(F)54

A semicorrin model system was prepared via a novel twofold Paal-Knorr type cyclization of a tetracarbonyl precursor which was obtained from an aldol reaction between virtually identical partners, readily available from one and the same precursor.

Full text of DOI:10.3987/COM-08-S(F)54

HETEROCYCLES, Vol. 77, No. 2, 2009
873
HETEROCYCLES, Vol. 77, No. 2, 2009, pp. 873 - 886. © The Japan Institute of Heterocyclic Chemistry
Received, 22nd July, 2008, Accepted, 12th September, 2008, Published online, 18th September, 2008
DOI: 10.3987/COM-08-S(F)54
A TETRACARBONYL PAAL-KNORR APPROACH TO SEMICORRINS
Anna Innitzer and Johann Mulzer*
Institute of Organic Chemistry, University of Vienna, Waehringerstrasse 38,
A-1090 Wien, Austria. johann.mulzer@univie.ac.at
Abstract –A semicorrin model system was prepared via a novel twofold Paal-
Knorr type cyclization of a tetracarbonyl precursor which was obtained from an
aldol reaction between virtually identical partners, readily available from one and
the same precursor.
INTRODUCTION
The syntheses of cobyric acid (1) by Woodward and Eschenmoser are true milestones in organic
synthesis.1 Despite extensive efforts1h,2 no further synthesis has been accomplished over the last thirty
years. In previous work we have developed a synthesis of the A-B-fragment 2 from monomers 3 and 4.2h
In continuation of this research we have been aiming for an approach to such semicorrinoids without
taking recourse to the venerable Eschenmoser sulfide contraction.3 More specifically, we opted for the
incorporation of two nitrogen atoms into a tetra-carbonyl precursor in the last step. This double Paal-
Knorr approach is new and was therefore tried on the stripped model system 5 (Scheme 1).
H2NOC
CONH2
PGO
PGO
B
A
CONH2
H2NOC
H2NOC
N
N
A
B
N
HN
PGO
TrO
NC Co OH
H
OPG
O
2
N
N
D
C
sulfide
contraction
CONH2
COOH
TrO
HN
cobyric Acid (1)
S
B
A
NH
TrO
OTr
NC
O
3
4
6
4
Paal-Knorr
6
4
A
9
B
O
O
O
O
N
HN
1
9
1
O
OH
5
6
Model System
Scheme 1. Previous Retrosynthetic Disconnection2h and New Plan

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HETEROCYCLES, Vol. 77, No. 2, 2009
RESULTS AND DISCUSSION
Two different approaches to the tetracarbonyl precursor 6 were initiated. For instance, 6 was accessed via
a global oxidation of tetra-olefin 7, which we thought to prepare from fragments 8 and 9. As outlined in
Scheme 2, either fragment might be employed as an organometallic species (8b, 9a) or as an electrophile
(8a, 9b) in transition-meta-mediated cross couplings. Several attempts were undertaken to achieve such a
transformation, however, none was successful. Therefore, instead of the intermolecular coupling of the
fragments, we used a Claisen rearrangement reaction, thus making the CC-bond formation by an
intramolecular process. After extensive experimentation, the rearrangement of ester 10 to acid 11 could
be achieved albeit in low yield. Moreover, the conversion of the carboxyl function into an exo-methylene
group turned out to be rather messy. Therefore, we dropped the idea of the tetra-olefin precursor and
turned to compound 12, which was an obvious candidate for an aldol reaction between 13 and 14. One
major advantage of this approach lies in the possibility to capitalize on symmetry as the fragments 13 and
14 have identical carbon skeletons, though with different oxidation levels.
6
4
O
O
O
O
9
1
OH
6
oxidation
CO2H
11
7
cross
coupling
Claisen
rearrangement
O
X
Y
O
8a X = OTf
8b X = SnMe3
9a Y = [M]Br
9b Y = Br
10
aldol
O
O
6
O
OH
O
O
OPG
OPG
O
13
O
12
14
Scheme 2. Retrosynthetic Considerations.
The synthesis of ketone 14 started with a Johnson-Claisen rearrangement4 of allylic alcohol 15.5 The
crude ester was reduced to alcohol 16, which was obtained in 77 % yield over 2 steps. After protecting the
primary alcohol as a pivaloate (17a) or as a TBDPS ether (17b), oxidation with ruthenium (III) chloride
and sodium periodate6 led to methyl ketones 14a and 14b (Scheme 3).

HETEROCYCLES, Vol. 77, No. 2, 2009
875
PivCl,
pyridine,
DMAP
OPiv
DCM, rt
95%
1) CH3CH2C(OEt)3,
propionic acid,
140°C
2) LAH, Et2O, rt
OH
17a
OH
77%
( 2 steps)
15
16
TBDPSCl,
NEt3
OTBDPS
DCM, rt
95%
17b
RuCl3,
NaIO4
OPG
OPG
CCl4/CH3CN/H2O
0 °C - rt
O
17a PG = Piv
17b PG = TBDPS
14a PG = Piv, 85%
14b PG = TBDPS, 70%
Scheme 3. Synthesis of Ketones 14a and 14b.
For the synthesis of aldehyde 13, the carbonyl group in 14a was ketalized and the pivaloyl group was
removed with DIBAL-H to give alcohol 19. The ketalization failed with the TBDPS-ether 14b, which
decomposed under acidic conditions. Oxidation of 19 with Dess-Martin periodinane (DMP) furnished
aldehyde 13 in an overall yield of 63 % from ketone 14a (Scheme 4).
ethylene glycol,
CSA,
OPiv
DIBAL-H,
benzene, reflux
THF -78 °C
14a
O
quant.
70%
O
18
DMP,
NaHCO3,
DCM, rt
OH
O
O
O
O
90%
O
19
13
Scheme 4. Synthesis of Aldehyde 13.
For the aldol reaction, ketone 14b was deprotonated with 1.5 equivalents of LDA and treated with
aldehyde 13 to give aldol adduct 20 in 70% yield. The subsequent deprotection of the silyl group was
accomplished with TBAF in THF at room temperature and led to hemiketal 21. Other deprotection
conditions such as HF·pyridine in THF or ammonium fluoride in MeOH resulted in the elimination of the
6-hydroxy group. For the oxidation of 21 to the labile ketolactone 22, best results were obtained using 10
mol% tetrapropylammonium perruthenate (TPAP) and 10 equivalents of N-methylmorpholine N-oxide

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HETEROCYCLES, Vol. 77, No. 2, 2009
monohydrate (NMO·H2O) as a cooxidant in DCM at 0 °C.7 Under these conditions water was eliminated
to give enol lactone 23 directly. A number of other oxidation protocols (e.g. Dess-Martin periodinane or
chromium reagents) led to decomposition. Next, the deprotection of the ketal function was investigated
under acidic conditions (e.g. p-toluenesulfonic acid, 0.1 M HCl, AcOH), which, however, failed to give
any defined product (Scheme 5).
6
O
LDA, THF,
- 78 °C
OH
O
O
O
O
1
70 %
OTBDPS
O
OTBDPS
14b
O
20
13
TBAF
THF, rt
85 %
TPAP,
NMO.H2O,
DCM, 0 °C - rt
HO
O
HO
O
O
O
OH
O
55%
O
O
O
21
22
- H2O
HCl, rt or
pTSOH or
PPTS
O
O
O
O
O
O
O
O
O
24
23
Scheme 5. Synthesis of Enol Lactone 23.
Therefore, we decided to incorporate nitrogen into the ring B prior to ketal removal. Thus, lactone 23 was
treated with ammonia followed by azeotropic removal of water to give pyrrolidinone 25. Deprotection of
the ketal group of 25 with acid failed. However, on heating 23 in acetic acid containing excess
ammonium acetate (Scheme 6), 1,4-diketone 26 was obtained in good yield.
1) NH3, DCM, rt
2) toluene, Δ
B
O
HN
O
O
90%
O
25
23
NH4OAc,
AcOH,110 °C
B
O
HN
9
75%
O
O
26
Scheme 6. Formation of pyrrolidinone 25 and 1,4-diketone 26.

HETEROCYCLES, Vol. 77, No. 2, 2009
877
With 1,4-diketone 26 in hand the missing nitrogen was inserted into the A-ring with ammonia in ethanol
1
at room temperature. The reaction was monitored by H-NMR. After 16 h approximately 30% of the
starting material was consumed and after additional 80 h 60% conversion was achieved. By thorough 1H-
NMR analysis the product was identified as semicorrin 27 (Scheme 7). Based on similar results by
Stevens8 and Eschenmoser,9 we reason that 1,2-elimination of water from adduct 28 could have generated
semicorrin 5. Then, a [1,5] hydrogen shift leads to tautomer 27, which could also have been formed from
28 via 1,4-elimination of water. In a related case, Stevens et al have observed8 that the equilibrium
between tautomers such as 27 and 5 is fully established, however, with inevitable epimerization at C-7.
Nevertheless, epimerization is also observed in Eschenmoser’s sulfide contraction,1e-g whereas,
regrettably, this problem was not addressed in Jacobi’s model studies.2c-g
NH3,
EtOH, rt
O
HN
N
HN
27
60%
conversion
O
O
O
26
NH3
[1,5] H-shift
7
1,2 elimination
N
HN
1
N
HN
OH
O
O
5
28
Scheme 7. Synthesis of semicorrin 27.
In conclusion, we have developed a twofold Paal-Knorr approach towards a semicorrin model system.
Extension of this simple methodology to the synthesis of A-B-semicorrin 2 is ongoing and will be
reported in due course.
EXPERIMENTAL
General
All reactions were carried out in flame-dried glassware under argon atmosphere. Solvents were purified
by distillation over the agents indicated: Dichloromethane (DCM) (P4O10), Et2O (Na), THF (Na), MeOH
(Mg). NEt3, diisopropylamine and TMSCl were distilled over CaH2 prior to use. Pivaloyl chloride was
purified by distillation prior to use. All commercially available compounds (Aldrich, FLUKA, Acros)
were used without further purification. Monitoring of the reactions was carried out by thin layer
chromatography (TLC) with E. Merck silica gel 60-F254 plates. Flash column chromatography was

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performed with Merck silica gel (0.04-0.63 μm, 240-400 mesh) with ethyl acetate and hexane mixtures as
eluent. NMR spectra were recorded on a Bruker Avance DRX 400 spectrometer. NMR spectra were
measured in CDCl3 or C6D6 solution and are referenced to 1H, δ = 7.26; 13C, δ = 77.16 (CHCl3) and 1H, δ
1
= 7.15; 13C, δ = 128.62 (C6H6) respectively. All H and 13C shifts are given in ppm (s = singlet; d =
doublet; t = triplet; q = quadruplet; m = multiplet; bs = broad signal). Coupling constants J are given in
Hz. Proton and carbon assignment was confirmed, when possible, by correlated spectroscopy (COSY,
HSQC, HMBC). Stereochemical assignment was confirmed by NOESY experiments. IR spectra were
recorded as thin films on a silicon disc on a Perkin-Elmer 1600 FT-IR spectrometer. Mass spectra were
measured on a Micromass, trio 200 Fisions Instrument. High resolution mass spectra (HRMS) were
performed with a Finnigan MAT 8230 with a resolution of 10000.
Starting Materials: 2,3-Dimethylbut-2-en-1-ol (15) was synthesized according to a previously published
procedure.5
Synthesis of 2,3,3,4-tetramethylpent-4-en-1-ol (16)
A three neck round bottom flask equipped with a distillation apparatus was charged with 2,3-dimethylbut-
2-en-1-ol (15) (17.3 g, 172 mmol, 1.00 eq), triethyl orthopropionate (745 mL, 3.75 mol, 22.0 eq) and
propionic acid (1.00 mL, cat.). The resulting mixture was stirred at 140 °C for 2 h. After being cooled
down to rt, 0.10 M HCl (200 mL) was added and the layers separated. The aqueous layer was extracted
two times with Et2O and the combined organic layer was washed sucessively with 0.10 M HCl, sat. aq.
NaHCO3 solution, water and brine. After drying over MgSO4 and filtration, the solvent was removed in
vacuo. Due to difficulties when subjected to distillation, the crude product was used directly in the next
step. LAH (7.00 g, 184 mmol, 1.07 eq) was suspended in Et2O (60 mL) and the crude ester, dissolved in
Et2O (160 mL), was added with stirring at such a rate that refluxing of the reaction mixture was
maintained. After completion of the addition, the reaction mixture was stirred for additional 2 h at rt. The
suspension was diluted with Et2O (200 mL) and cooled down to 0 °C. H2O (7 mL) was added cautiously,
followed by 1 M NaOH (40 mL). After being stirred for 15 min vigorously at rt, the resulting mixture was
filtered and the solvent was removed in vacuo. The crude product was purified by distillation at a reduced
pressure to yield 18.8 g of alcohol 16 as a colorless oil (77% over 2 steps).
Mr = 142.24, C9H18O. bp 80 °C, 0.1 mbar. 1H NMR (400 MHz, CDCl3): δ 4.76 (m, 2H), 3.68 (dd, 1H, J
= 10.7, 4.7 Hz), 3.28 (m, 1H), 1.81 (m, 1H), 1.75 (s, 3H), 1.00 (s, 3H), 0.98 (s, 3H), 0.89 (d, 3H, J = 6.9
Hz). 13C NMR (101 MHz, CDCl3): δ 153.4 (C), 109.9 (CH2), 65.8 (CH2), 41.5 (CH), 40.6 (C), 24.8
(CH3), 22.7 (CH3), 19.6 (CH3), 12.5 (CH3). IR νmax 3346, 3091, 2970, 1635, 1455, 1376, 1362 cm-1. MS
(EI, 70 eV, 30 °C): m/z: 142, 127, 109, 97, 83, 69, 55. HRMS (70 eV, 30 °C): m/z calcd for C9H18O:
142.1354, found: 142.1358.

HETEROCYCLES, Vol. 77, No. 2, 2009
879
Synthesis of 2,2-dimethylpropionic acid 2,3,3,4-tetramethylpent-4-enyl ester (17a)
Pivaloyl chloride (3.80 mL, 30.9 mmol, 1.10 eq) was dissolved in DCM (60 mL) and treated with
pyridine (2.72 mL, 33.7 mmol, 1.20 eq) with stirring at 0 °C. A solution of alcohol 16 (4.00 g, 28.1 mmol,
1.00 eq) and DMAP (cat.) in DCM (20 mL) was added slowly by a syringe. The resulting mixture was
stirred at rt until completion (TLC). Sat. aq. NH4Cl solution was added and the layers were separated. The
aqueous layer was extracted three times with DCM and the combined organic layer was washed
successively with 1 M HCl, sat. aq. NaHCO3 solution and brine. After drying over MgSO4, filtration and
removal of the solvent in vacuo, the crude product was purified by column chromatography
(hexane/EtOAc = 10:1) to yield 17a (6.00 g, 95%) as a colorless oil.
Mr = 226.36, C14H26O. Rf = 0.6 (Hex/EE = 10:1). 1H NMR (400 MHz, CDCl3): δ 4.75 (m, 2H), 4.11 (dd,
1H, J = 10.8, 4.0 Hz), 3.72 (dd, 1H, J = 10.8, 8.9 Hz), 1.93 (m. 1H), 1.73 (s, 3H), 1.19 (s, 9H), 1.03 (s,
3H), 1.00 (s, 3H), 0.87 (d, 3H, J = 6.8 Hz). 13C NMR (101 MHz, CDCl3): δ 178.8 (C), 152.0 (C), 111.2
(CH2), 67.3 (CH2), 40.7 (C), 38.9 (C), 38.1 (C), 27.4 (CH3, 3C), 24.2 (CH3), 23.3 (CH3), 19.5 (CH3), 12.6
(CH3). IR νmax 3091, 2972, 1731, 1636, 1481, 1460, 1398, 1378 cm-1. MS (EI, 70 eV, 30 °C): m/z: 226,
143, 124, 109, 83, 69, 57. HRMS (70 eV, 30 °C): m/z calcd for C14H26O: 226.1933, found: 226.1929.
Synthesis of 2,2-dimethylpropionic acid 2,3,3-trimethyl-4-oxo-pentyl ester (14a)
17a (6.00 g, 26.5 mmol, 1.00 eq) was dissolved in a mixture of CCl4 (40 mL), MeCN (40 mL) and water
(60 mL) and cooled to 0 °C. NaIO4 (22.0 g, 106 mmol, 4.00 eq) and RuCl3 (550 mg, 2.66 mmol, 0.10 eq)
were added with stirring and the resulting mixture was stirred at rt until completion (TLC). After dilution
with DCM and water, the layers were separated and the aqueous layer was extracted three times with
DCM. After drying over MgSO4, filtration and concentration under a reduced pressure, the residue was
taken up in Et2O and filtered through Celite®. The solvent was removed in vacuo and the crude product
was purified by column chromatography (pentane/Et2O = 10:1) to yield 14a (5.14 g, 85%) as colorless oil.
Mr = 228.33, C13H24O3, Rf = 0.35 (pentane/Et2O = 10:1). 1H NMR (400 MHz, CDCl3): δ 4.03 (m, 1H),
3.79 (m, 1H), 2.25 (m, 1H), 2.15 (s, 3H), 1.18 (s, 9H), 1.09 (s, 3H), 1.07 (s, 3H), 0.89 (d, 3H, J = 6.9 Hz).
13C NMR (101 MHz, CDCl3): δ 213.1 (C), 178.7 (C), 66.6 (CH2), 49.7 (C), 39.0 (C), 38.3 (CH), 27.3
(CH3, 3 C), 25.5 (CH3), 21.8 (CH3), 20.9 (CH3), 12.7 (CH3). IR νmax 2975, 1729, 1480, 1394, 1366 cm-1.
MS (EI, 70 eV, 30 °C): m/z: 228, 185, 126, 111, 83, 69, 57. HRMS (70 eV, 30 °C): m/z calcd for
C13H24O3: 228.1725, found: 228.1713.
Synthesis of 2,2-dimethylpropionic acid 2,3-dimethyl-3-(2-methyl-1,3-dioxolan-2-yl)butyl ester (18)
14a (5.00 g, 21.9 mmol, 1.00 eq), ethylene glycol (6.10 mL, 109 mmol, 5.00 eq) and CSA (cat.) in
benzene (150 mL) were heated with stirring on a Dean-Stark trap at 110 °C for 4 h (TLC). After being

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HETEROCYCLES, Vol. 77, No. 2, 2009
cooled down to rt, the reaction mixture was diluted with Et2O and treated with sat. aq. NaHCO3 solution.
The layers were separated and the aqueous layer was extracted three times with Et2O. The combined
organic layer was washed with brine and dried over MgSO4. After removal of the solvent in vacuo, the
crude product was purified by column chromatography (hexane/EtOAc = 10:1) to yield 18 (4.20 g, 70%)
as a colorless oil.
Mr = 272.38, C15H28O4. Rf = 0.56 (hexane/EtOAc = 5:1). 1H NMR (400 MHz, C6D6): δ 4.82 (dd, 1H, J =
11.0, 3.7 Hz), 3.93 (dd, 1H, J = 11.0, 9.5 Hz), 3.40 (m, 4H), 1.98 (m, 1H), 1.2 (m, 12H), 1.05 (d, 3H, J =
6.8 Hz), 0.99 (s, 3H), 0.92 (s, 3H). 13C NMR (101 MHz, C6D6): δ 178.4 (C), 114.9 (C), 68.5 (CH2), 65.4
(CH2), 64.8 (CH2), 44.7 (C), 39.4 (C), 39.2 (CH), 28.0 (CH3, 3C), 22.8 (CH3), 19.9 (CH3), 18.8 (CH3),
13.9 (CH3). IR νmax 2976, 2881, 1727, 1480, 1399, 1377, 1156 cm-1. MS (EI, 70 eV, 30 °C): m/z: 257,
171, 109, 87. HRMS (70 eV, 30 °C): m/z calcd for C14H25O4 (M - CH3): 257.1753, found: 257.1761.
Synthesis of 2,3-dimethyl-3-(2-methyl-1,3-dioxolan-2-yl)butan-1-ol (19)
To a solution of 18 (4.20 g, 15.4 mmol, 1.00 eq) in DCM (100 mL) was added DIBAL-H (1.20 M in
toluene, 28.5 mL, 33.9 mmol, 2.20 eq) with stirring at -78 °C. The resulting solution was stirred for 1 h
(TLC) and then allowed to warm to rt. H2O and 2 M NaOH solution were added and the layers were
separated. The aqueous layer was extracted three times with DCM and the combined organic layer was
washed with brine, dried over MgSO4 and filtered. The solvent was removed in vacuo to yield alcohol 19
(2.90 g, quant.) as a colorless oil.
Mr = 188.26, C10H20O3. Rf = 0.17 (Hex/EE = 5:1). 1H NMR (400 MHz, C6D6): δ 3.83 (m, 1H), 3.46 (m,
1H), 3.34 (m, 4H), 2.57 (bs, 1H), 1.75 (m, 1H), 1.22 (s, 3H), 0.99 (s, 3H), 0.91 (d, 3H, J = 7.0 Hz), 0.89 (s,
3H). 13C NMR (101 MHz, C6D6): δ 114.5 (C), 65.9 (CH2), 65.1 (CH2), 64.3 (CH2), 44.4 (C), 42.3 (CH),
24.1 (CH3), 19.9 (CH3), 17.2 (CH3), 14.2 (CH3). IR νmax 3417, 2982, 1455, 1374, 1221, 1158 cm-1. MS
(EI, 70 eV, 30 °C): m/z: 173, 158, 143, 127, 111, 99, 87, 69, 55. HRMS (70 eV, 30 °C): m/z calcd for
C9H17O3 (M – CH3): 173.1178, found: 173.1175.
Synthesis of 2,3-dimethyl-3-(2-methyl-1,3-dioxolan-2-yl)butyraldehyde (13)
To a solution of alcohol alcohol 19 (1.10 g, 5.84 mmol, 1.00 eq) in DCM (60 mL) was added NaHCO3
(2.45 g, 29.2 mmol, 5.00 eq) at 0°C. The resulting suspension was treated with stirring with DMP (3.22 g,
7.59 mmol, 1.30 eq) and stirring was continued at 0°C until completion (TLC). Et2O was added and the
suspension was treated with sat. aq. NaHCO3 and sat. aq. Na2S2O3 solution. After being vigorously stirred
for 30 min at rt, the layers were separated and the aqueous layer was extracted three times with Et2O. The
combined organic layer was washed successively with sat. aq. NaHCO3 solution, water and brine, dried
over MgSO4, filtered and concentrated in vacuo. The crude material was purified by column

HETEROCYCLES, Vol. 77, No. 2, 2009
881
chromatography (pentane/Et2O = 5:1) to yield 980 mg of 13 (90%) as a colorless oil.
Mr = 186.25, C10H18O3. Rf = 0.40 (hexane/EtOAc = 5:1). 1H NMR (400 MHz, C6D6): δ 9.61 (d, 1H, J =
4.8 Hz), 3.43 (m, 4H), 2.34 (dq, 1H, J = 7.3, 4.8 Hz), 1.05 (s, 3H), 0.91 (s, 3H), 0.85 (s, 3H), 0.81 (d, 3H,
J = 7.3 Hz). 13C NMR (101 MHz, C6D6): δ 201.9 (CH), 114.6 (C), 65.6 (CH2), 64.4 (CH2), 51.2 (CH),
45.7 (C), 23.6 (CH3), 19.9 (CH3), 18.9 (CH3), 10.7 (CH3). IR νmax 2973, 1770, 1461, 1384, 1097 cm-1.
Synthesis of tert-butyldiphenyl(2,3,3,4-tetramethylpent-4-enyloxy)silane (17b)
To a solution of alcohol 16 (2.00 g, 14.1 mmol, 1.00 eq) in DCM (50 mL) were added NEt3 (5.10 mL,
36.6 mmol, 2.60 eq), TBDPSCl (4.80 mL, 18.3 mmol, 1.30 eq) and DMAP (cat.) at rt. The resulting
suspension was stirred for 18 h (TLC). Sat. aq. NH4Cl solution was added and the layers were separated.
The aqueous layer was extracted two times with DCM and the combined organic layer was washed with
brine, dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by column
chromatography (hexane/EtOAc = 10:1) to yield 17b (5.10 g, 96%) as a colorless oil.
Mr = 380.64, C25H36OSi. Rf = 0.82 (hexane/ EtOAc = 5:1). 1H NMR (400 MHz, CDCl3): δ 7.67 (m, 4H),
7.39 (m, 6H), 4.65(m, 2H), 3.69 (m, 1H), 3.37 (m,1H), 1.79 (m, 1H), 1.61 (s, 3H), 1.06 (s, 9H), 0.96 (d,
3H, J = 6.8 Hz), 0.93 (s, 3H), 0.91 (s, 3H). 13C NMR (101 MHz, CDCl3): δ 152.8 (C), 135.8 (CH, 4C),
134.3 (C, 2C), 129.6 (CH, 2C), 127.7 (CH, 4C), 109.6 (CH2), 65.9 (CH2), 41.4 (CH), 40.7 (C), 27.1 (CH3,
3C), 24.2 (CH3), 23.6 (CH3), 19.4 (C), 19.4 (CH3), 12.9 (CH3). IR νmax 3071, 3050, 2965, 2858, 1635,
1589, 1472, 1390, 1376, 1159, 1111, 739, 700 cm-1. MS (EI, 70 eV, 30 °C): m/z: 323, 280, 241, 223, 183,
141, 84. HRMS (70 eV, 30 °C): m/z calcd for C21H27OSi (M – t-Bu): 323.1831, found: 323.1829.
Synthesis of 5-(tert-butyldiphenylsilanyloxy)-3,3,4-trimethylpentan-2-one (14b)
17b (5.10 g, 13.4 mmol, 1.00 eq) was dissolved in a mixture of CCl4 (20 mL), MeCN (20 mL) and water
(30 mL) and cooled to 0°C. NaIO4 (11.5 g, 53.6 mmol, 4.00 eq) and RuCl3 (278 mg, 1.34 mmol, 0.10 eq)
were added with stirring and the resulting mixture was stirred at rt until completion (TLC). After dilution
with DCM and water, the layers were separated and the aqueous layer was extracted three times with
DCM. After drying the organic layer over MgSO4, filtration and concentration under a reduced pressure,
the residue was taken up in Et2O and filtered through Celite®. The solvent was removed in vacuo and the
crude product was purified by column chromatography (hexane/EtOAc = 10:1) to yield 14b (3.60 g,
70%) as a colorless oil.
Mr = 382.61, C24H34O2Si. Rf = 0.42 (hexane/EtOAc = 10:1). 1H NMR (400 MHz, CDCl3): δ 7.66 (m,
4H), 7.40 (m, 6H), 3.53 (dd, 1H, J = 10.2, 5.8 Hz), 3.41 (dd, 1H, J = 10.2, 7.3 Hz), 2.14 (m, 1H), 2.05 (s,
3H), 1.05 (s, 9H), 1.01 (s, 3H), 0.99 (s, 3H), 0.89 (d, 3H, J = 6.9 Hz). 13C NMR (101 MHz, CDCl3): δ
213.8 (C), 135.9 (CH, 4C), 133.9 (C, 2C), 130.3 (CH, 2C), 128.0 (CH, 4C), 66.4 (CH2), 49.7 (C), 42.0

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(CH), 27.1 (CH3, 3C), 25.4 (CH3), 22.4 (CH3), 20.4 (CH3), 19.3 (C), 12.4 (CH3). IR νmax 3049, 2962,
1704, 1589, 1471, 1427, 1187, 1111, 741, 702 cm-1. MS (EI, 70 eV, 30 °C): m/z: 323, 280, 241, 223, 183,
141, 84. HRMS (70 eV, 30 °C): m/z calcd for C20H25O2Si (M – t-Bu) : 325.1624, found: 325.1631.
Synthesis of 1-(tert-butyldiphenylsilanyloxy)-6-hydroxy-2,3,3,7,8-pentamethyl-8-(2-methyl-1,3-
dioxolan-2-yl)nonan-4-one (20)
To a solution of freshly prepared LDA (0.39 M, 10.0 mL, 3.92 mmol, 1.50 eq) in THF (8 mL) was added
slowly ketone (14b) (1.00 g, 2.61 mmol, 1.00 eq) in THF (8 mL) with stirring at -78 °C. Stirring of the
slightly yellow solution was continued for additional 30 min. Then aldehyde 13 (730 mg, 3.92 mmol,
1.50 eq) in THF (6 mL) was added at once. The solution was kept at -78 °C for 2 ½ h (TLC) and then
quenched by the addition of MeOH and solid NH4Cl. The mixture was allowed to warm up and diluted
with Et2O. Water was added and the layers were separated. The aqueous layer was extracted three times
with Et2O and the combined organic layer was washed with water and brine, dried over MgSO4, filtered
and concentrated in vacuo. The crude product was purified by column chromatography (hexane/EtOAc =
10:1) to yield 20 (1.04 g, 70%) as a colorless oil.
Mr = 568.86, C34H52O5Si. Rf = 0.40 (hexane/EtOAc = 5:1). d.e. ~ 5:4 (determined by 1H NMR)
major diastereomer:
1H NMR (400 MHz, CDCl3): δ 7.65 (m, 4H), 7.39 (m, 6H), 4.65 (m, 1H), 3.92 (m, 4H), 3.54 (dd, 1H, J
= 10.2, 5.4 Hz), 3.41 (m, 1H), 2.95 (d, 1H, J = 3.7 Hz), 2.72 (dd, 1H, J = 19.3, 8.5 Hz), 2.38 (dd, 1H, J =
17.3, 4.3 Hz), 2.13 (m, 1H), 1.43 (m, 1H), 1.04 (s, 9H), 1.00 (m, 18H), 0.89 (m, 3H). 13C NMR (101
MHz, CDCl3): δ 215.1 (C), 135.8 (CH, 4C), 133.7 (C, 2C), 129.8 (CH, 2C), 127.8 (CH, 4C), 114.8 (C),
67.4 (CH), 66.0 (CH2), 64.9 (CH2), 64.5 (CH2), 49.7 (C), 45.1 (C), 43.9 (CH), 43.1 (CH2), 41.2 (CH),
27.0 (CH3, 3C), 23.6 (CH3), 21.6 (CH3), 21.1 (CH3), 20.7 (CH3), 20.1 (CH3), 19.3 (C), 12.5 (CH3), 9.1
(CH3).
minor diastereomer :
1H NMR (400 MHz, C6D6): δ 7.65 (m, 4H), 7.39 (m, 6H), 4.65 (m, 1H), 3.92 (m, 4H), 3.60 (dd, 1H, J =
10.1, 5.2 Hz), 3.41 (m, 1H), 3.03 (d, 1H, J = 3.5 Hz), 2.76 (dd, 1H, J = 17.2, 8.7 Hz), 2.26 (dd, 1H, J =
17.2, 3.7 Hz), 2.13 (m, 1H), 1.43 (m, 1H), 1.04 (s, 9H), 1.00 (m, 18H), 0.89 (m, 3H). 13C NMR (101
MHz, CDCl3): δ 215.8 (C), 135.7 (CH, 4C), 133.7 (C, 2C), 129.8 (CH, 2C), 127.8 (CH, 4C), 114.8 (C),
67.6 (CH), 65.9 (CH2), 64.9 (CH2), 64.5 (CH2), 49.8 (C), 45.1 (C), 43.6 (CH), 43.1 (CH2), 41.2 (CH),
27.0 (CH3, 3C), 23.4 (CH3), 21.3 (CH3), 21.1 (CH3), 20.6 (CH3), 20.1 (CH3), 19.3 (C), 12.7 (CH3), 9.0
(CH3).
IR νmax 3518, 3071, 2973, 2884, 1698, 1589, 1471, 1427, 1112, 741, 703 cm-1. MS (EI, 70 eV, 30 °C):
m/z: 553, 511, 449, 325, 239, 199, 125, 87, 55. HRMS (70 eV, 30 °C): m/z calcd for C33H49O5Si (M –

HETEROCYCLES, Vol. 77, No. 2, 2009
883
CH3): 553.3349, found: 553.3338.
Synthesis of 5-[3,4-dimethyl-4-(2-methyl-1,3-dioxolan-2-yl)-2-oxopent-(Z)-ylidene]-3,4,4-trimethyl-
dihydrofuran-2-one (23)
To a solution of 20 (1.00 g, 1.76 mmol, 1.00 eq) in THF (21 mL) was added TBAF (1 M in THF, 2.64
mL, 2.64 mmol, 1.50 eq) at rt. The resulting yellow solution was stirred for 1 h (TLC) and then diluted
with Et2O (50 mL). The organic layer was washed successively with sat. aq. NH4Cl solution. water and
brine, dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by column
chromatography (hexane/EtOAc = 4:1) to yield 21 (491 mg, 85%) as a colorless oil. A solution of 21
(34.0 mg, 0.10 mmol, 1.00 eq) in DCM (1.5 mL) was cooled with stirring to 0 °C. Then, TPAP (4.00 mg,
0.01 mmol, 0.10 eq) and NMO.H2O (270 mg, 2.00 mmol, 20.0 eq) were added, the resulting green
mixture was stirred for 30 min at 0 °C and additionally for 30 min at rt (TLC). After dilution with Et2O,
filtration over SiO2 (pretreated with NEt3) yielded 23 (18.0 mg, 55%) as a colorless oil.
Mr = 324.41, C18H28O5. Rf = 0.40 (hexane/EtOAc = 2:1). Mixture of diastereomers, due to overlap of
signals, the ratio could not be determined by NMR. 1H NMR (400 MHz, CDCl3): δ 5.38 (m, 1H), 3.89
(m, 4H), 3.22 (m, 1H), 2.52 (m, 1H), 1.31 (s, 3H), 1.27 (m, 3H), 1.20 (m, 3H), 1.15 (s, 3H), 1.10 (m, 3H),
1.03 (s, 3H), 1.01 (s, 3H). 13C NMR (101 MHz, CDCl3): δ 202.4 (C), 175.0 (C), 166.1 (C), 114.3 (C),
104.5 (CH), 64.9 (CH2), 64.6 (CH2), 48.3 (CH), 45.5 (C), 44.2 (CH), 43.7 (C), 25.3 (CH3), 23.7 (CH3),
21.2 (CH3), 20.3 (CH3), 19.4 (CH3), 13.6 (CH3), 9.1 (CH3). IR νmax 2978, 2882, 1817, 1679, 1652, 1468,
1374, 1159 cm-1. MS (EI, 70 eV, 30 °C): m/z: 324, 309, 249, 167, 87, 69, 55. HRMS (70 eV, 30 °C): m/z
calcd for C18H28O5: 324.1937, found: 324.1926.
Synthesis of 5-[3,4-dimethyl-4-(2-methyl-1,3-dioxolan-2-yl)-2-oxopent-(Z)-ylidene]-3,4,4-trimethyl-
pyrrolidin-2-one (25)
23 (10.0 mg, 0.03 mmol, 1.00 eq) was dissolved in DCM (1.00 mL) and treated with NH3 (2M in EtOH,
0.30 mmol, 0.15 mL, 10.0 eq) and stirred at rt overnight. After evaporation of the solvent in vacuo, the
residue was dissolved in toluene (5 mL). A micro distillation apparatus was attached and the toluene was
distilled off under heating at 140 °C. Drying under a reduced pressure yielded 25 (8.70 mg, 90%) as a
yellow oil.
Mr = 323.43, C18H29NO4. Rf = 0.46 (hexane/EtOAc = 2:1). Mixture of diastereomers, due to overlap of
signals, the ratio could not be determined by NMR. 1H NMR (400 MHz, CDCl3): δ 10.65 (bs, 1H), 5.39
(bs, 1H), 3.89 (m, 4H), 2.75 (dq, 1H, J = 7.1, 2.2 Hz), 2.35 (dq, 1H, J = 7.5, 1.7 Hz), 1.28 (d, 3H, J = 1.7
Hz), 1.27 (bs, 3H), 1.15 (d, 3H, J = 7.5 Hz), 1.13 (d, 3H, J = 2.2 Hz), 1.10 (d, 3H, J = 7.1 Hz), 1.06 (bs,
3H), 1.01 (bs, 3H). 13C NMR (101 MHz, CDCl3): δ 205.1 (C), 179.2 (C), 165.5 (C), 114.3 (C), 97.8

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HETEROCYCLES, Vol. 77, No. 2, 2009
(CH), 64.7 (CH2), 64.4 (CH2), 50.0 (CH), 45.8 (CH), 45.2 (C), 42.7 (C), 26.9 (CH3), 24.6 (CH3), 20.9
(CH3), 20.7 (CH3), 19.4 (CH3), 14.0 (CH3), 9.9 (CH3). IR νmax 3294, 2974, 1745, 1660, 1586, 1456, 1375,
1333, 1160 cm-1. MS (EI, 70 eV, 30 °C): m/z: 323, 280, 261, 246, 220, 205, 195, 185, 166. HRMS (70
eV, 30 °C): m/z calcd for C18H29NO4: 323.2097, found: 323.2088.
Synthesis of 3,4,4-trimethyl-1-[3,3,4-trimethyl-5-oxopyrrolidin-(2Z)-ylidene]hexane-2,5-dione (26)
23 (32 mg, 0.10 mmol, 1.00 eq) was added to a suspension of ammonium acetate (154 mg, 2.00 mmol,
20.0 eq) in AcOH (2.00 mL) and H2O (0.50 mL) and heated at 110 °C for 2 h. After being cooled down to
rt, sat. aq. NaHCO3 solution was added cautiously under stirring at 0 °C. Ethyl acetate was added and the
layers were separated. The aqueous layer was extracted three times with ethyl acetate, the combined
organic layer was washed with H2O and brine, dried over MgSO4, filtered and concentrated in vacuo.
Purification by column chromatography (hexane/EtOAc = 2:1) yielded 26 (21 mg, 75%) as a yellow oil.
Mr = 279.37, C16H25NO3. Rf = 0.40 (hexane/EtOAc = 2:1). Mixture of diastereomers, due to overlap of
signals, the ratio could not be determined by NMR. 1H NMR (400 MHz, CDCl3): δ 10.59 (bs, 1H), 5.46
(s, 1H), 3.04 (dq, 1H, J = 7.4, 2.3 Hz), 2.28 (d, 1H, J = 7.4 Hz), 2.19 (s, 3H), 1.29 (s, 3H), 1.21 (s, 3H),
1.16 (s, 3H), 1.14 (s, 3H), 1.11 (s, 3H), 1.10 (s, 3H). 13C NMR (101 MHz, CDCl3): δ 213.2 (C), 202.9
(C), 179.0 (C), 166.9 (C), 96.3 (CH), 51.9 (C), 49.0 (CH), 45.7 (CH), 42.5 (C), 26.8 (CH3), 25.8 (CH3),
24.5 (CH3), 24.2 (CH3), 23.3 (CH3), 21.3 (CH3), 9.7 (CH3). IR νmax 3294, 2925, 1727, 1664, 1581, 1465,
1380 cm-1. MS (EI, 70 eV, 30 °C): m/z: 279, 230, 187, 122. HRMS (70 eV, 30 °C): m/z calcd for
C16H25NO3: 279.1834, found: 279.1841.
Synthesis of 3,4,4-trimethyl-5-[1-(3,4,4,5-tetramethyl-3,4-dihydro-2H-pyrrol-2-yl)meth-(Z)-ylidene]-
pyrrolidin-2-one (27)
26 (5 mg, 0.02 mmol, 1.00 eq) was dissolved in EtOH (0.4 mL), treated with NH3 (2M in EtOH, 0.20
mmol, 0.10 mL, 10 eq) and stirred at rt. For monitoring of the reaction, the solvent was evaporated, the
1
residue was dried under a reduced pressure and a H NMR spectra were recorded. After 96 h, 60%
conversion of the starting material was achieved according to the 1H NMR spectra.
Mr = 260.37, C16H24N2O. Rf = 0.20 (hexane/EtOAc = 2:1). Mixture of diastereomers, due to overlap of
signals, the ratio could not be determined by NMR. 1H NMR (400 MHz, CDCl3): δ 10.36 (bs, 1H), 5.18
(s, 1H), 2.35 (d, 1H, J = 7.5 Hz), 2.12 (s, 3H), 1.79 (s, 3H), 1.31 (s, 3H), 1.16 (s, 3H), 1.14 (s, 3H), 1.03 (s,
6H). 13C NMR (101 MHz, CDCl3): δ 185.7 (C), 177.9 (C), 149.5 (C), 143.3 (C), 133.0 (C), 90.6 (CH),
56.1 (C), 47.1 (CH), 42.1 (C), 27.3 (CH3), 24.5 (CH3), 21.2 (CH3), 21.1 (CH3), 15.4 (CH3), 10.1 (CH3),
8.9 (CH3). IR νmax 3295, 2926, 1730, 1660, 1458 cm-1. MS (EI, 70 eV, 30 °C): m/z: 260, 245, 166, 147,
97, 70. HRMS (70 eV, 30 °C): m/z calcd for C16H24N2O: 260.1889, found: 260.1881.

HETEROCYCLES, Vol. 77, No. 2, 2009
885
ACKNOWLEDGEMENTS
This paper is dedicated to Professor Emeritus Keiichiro Fukumoto on the occasion of his 75th
birthday.
We thank Susanne Felsinger, Lothar Brecker and Hanspeter Kählig for NMR analysis, and Peter
Unteregger and Eberhard Lorbeer for recording the MS.
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