Formal synthesis of TMC-69-6H via a one-pot enantioselective domino proline-mediated aldol/olefin homologation procedure

Article abstract of DOI:10.1016/j.tet.2011.11.025

Enantioselective synthesis of TMC-69-6H was accomplished from readily accessible pyridone derivative via a domino proline-mediated aldol reaction/olefin homologation, followed by tandem ring-closing and cross metathesis.

Full text of DOI:10.1016/j.tet.2011.11.025

Tetrahedron 68 (2012) 433e439
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Formal synthesis of TMC-69-6H via a one-pot enantioselective domino
proline-mediated aldol/olefin homologation procedure
*
ꢀ
Sophie Vuong, Nicolas Brondel, Christophe Len, Sebastien Papot, Brigitte Renoux
ꢁ
ꢀ
ꢀ
ꢀ
Laboratoire “Synthese et Reactivite des Substances Naturelles”, Universite de Poitiers, UMR-CNRS 6514, 4 rue Michel Brunet, BP 633, 86022 Poitiers, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Enantioselective synthesis of TMC-69-6H was accomplished from readily accessible pyridone derivative
via a domino proline-mediated aldol reaction/olefin homologation, followed by tandem ring-closing and
cross metathesis.
Received 13 September 2011
Received in revised form 4 November 2011
Accepted 8 November 2011
Available online 13 November 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Proline
Aldolization
Tebbe
Crotylation
Enantioselectivity
1. Introduction
OH
O
Recently, 4-hydroxy-2-pyridone-containing alkaloids have
emerged as attractive targets in medicinal chemistry. Numerous
derivatives of this family exhibit a wide range of biological effects
including antibacterial, antifungal, and cytotoxic activities.1 In 2001,
the Kohno group reported the isolation and structural de-
termination of a new antibiotic,2 TMC-69 1, from the fermenta-
tion broth of a mitosporic fungus, Chrysosporium sp. TC 1068
(Scheme 1). This pyridone showed promising antiproliferative ac-
tivities in vitro against various tumor cell lines. However, TMC-69
was found labile in solid state as well as in solution therefore
limiting its use as an anticancer drug. Under such circumstances,
much more attention has been paid to the hydrogenated analogue
TMC-69-6H 2, which presents significant improved stability
in vivo.3 When evaluated in mice transplanted with either B16
melanoma or P388 leukemia, compound 2 induced significant
prolongation of survival time demonstrating its potential as a new
antitumor agent. Interestingly, TMC-69-6H exhibits inhibitor ac-
tivity against Cdc25 A and B phosphatases, key regulators of the cell
cycle progression and mitogenic signaling pathways. These phos-
phatases are overexpressed in many human tumors and constitute
suitable targets for drug discovery.
N
OH
O
O
1
TMC-69
OH
O
N
OH
2
TMC-69-6H
Scheme 1.
In 2003, Furstner reported the first total synthesis of both (17R)
and (17S) isomers of 2 through an elegant and versatile strategy.4
Rather than being potent inhibitors of Cdc25A and B, Furstner
€
found TMC-69-6H and analogues to inhibit the tyrosine protein
phosphatase PTB1B (key regulator of insulin-receptor activity), the
dual specific phosphatase VHR, and the serine/threonine phos-
phatase PP1 implied in the regulation of the cell cycle much more
effectively. While these data suggested that such derivatives rep-
resent a promising new class of selective phosphatase inhibitors,
only one other pathway for the enantioselective synthesis of TMC-
69-6H has been described in the literature so far.5
In this context, it seems worthwhile to develop new synthetic
routes in order to prepare this compound with high enantiose-
lectivity. Herein, we report a new flexible strategy, which allows the
enantioselective synthesis of TMC-69-6H from the readily accessi-
ble 4-hydroxy-2-pyridone 3 via a novel domino proline-mediated
* Corresponding author. Tel.: þ33 549453959; fax: þ33 549453501; e-mail
address: brigitte.renoux@univ-poitiers.fr (B. Renoux).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.11.025

434
S. Vuong et al. / Tetrahedron 68 (2012) 433e439
Table 1
Enantioselective crotylation
aldol reaction/olefin homologation followed by tandem ring-
closing and cross metathesis (Scheme 2).
OBn OH
OBn O
8(R)
8(R)
H
OR
N
OH
10(R)
Cl
N
OBn
Cl
N
5
OBn
O
7(R)O
O
Hydrogenation
Hydrogénolysis
7(R)
(7R,8R)-6
Cl
OR
N
OH
TMC-69-6H
N-oxydation
Reaction
Brown10
Reactants
Results ee; de; Yield
Etherification
Metathesis
de >95%; ee 60%
yield 23%
Enantioselective
domino
aldol-homolagation
OH
OR OH
(R)
CHO
(R)
de >95%; ee 10%
yield 8%
Hall12
Formylation
Cl
N
H
O
Cl
N
OR
Scheme 2. Retrosynthetic pathway.
de >95%; ee 30%
yield 73%
Nakajima13
2. Results
Yamamoto14
No reaction
No reaction
The pyridone 36 was prepared by condensation of phenyl-
acetonitrile and malonylchloride using Davis conditions.7 Com-
pound 3 was then successively submitted to the ReimereTiemann
formylation (NaOH, CHCl3)8 and di-O-benzylation (BnBr, K2CO3,
DMF)9 to afford the pyridine 5 in 54% yield (Fig. 1).
Yamamoto15
Leighton16
de >98%; ee 99%
yield 80%
OH
O
O
4 days, rt
72%
CN
+
Cl
Cl
Cl
N
3
O
46%
CHCl3, NaOH, H2O
diastereo- and enantio-selectivity, we were unable to reproduce this
result. Indeed, all the other attempts led to low yield combined with
poor ee. In summary, despite our extensive investigations, no gen-
eral method using simple and stable allylation reagents conducted
to the stereo-controlled formation of the key intermediate 6. Within
this framework, most the classical methods reported in the litera-
ture suffer from one or more drawbacks such as air or moisture
sensitivity, the need for a multistep preparation of chiral reagents,
unreproductibility or incompatibility with aldehydes. These failures
prompted us to develop an efficient alternative to replace the
somewhat capricious crotylation reaction for the preparation of 6.
For this purpose, we investigated a simple proline-mediated
aldolizationehomologation synthetic sequence, which requires
neither the handling of sensitive reactants nor the use of complex
catalyst (Fig. 2). In order to evaluate the validity of this strategy, we
first undertook the synthesis of the alcohol 6 in the course of a two-
BnBr
O
O
OBn O
DMF, K2CO3
H
H
54%
Cl
N
O
Cl
N
5
OBn
4
Fig. 1. Pyridone construction.
With this intermediate in hands, we envisioned the synthesis of
6 using well-known stereoselective carbonyl allylation methods.
Reagents of boron, silicon, and tin are amongst the most popular
crotyl transfer agents for achiral aldehydes where both diastereo-
and enantio-selectivity are orchestrated by a chiral element in the
nucleophilic partner.
Our first attempt was conducted with Brown’s (E)-crotyldiiso-
pinocamphenylborane10 in dry THF. Under these conditions, al-
though the anti homoallylic alcohol 6 was obtained in low yield, an
excellent diastereoselectivity was recorded without any detectable
trace of the syn stereoisomer (Table 1). The moderate ee of 6 was
measured by HPLC analysis of the corresponding O-methyl-
mandelate derivatives.11 At this stage, we decided to pursue our
investigations using other stereoselective crotylation procedures
such as the scandium-catalyzed crotylboration described by Hall12
or the method proposed by Nakajima13 for addition of allyl-
chlororosilane in the presence chiral amine N-oxide. However, in
our hands both methods gave disappointing results. Furthermore,
no reaction was observed using Yamamoto’s procedure with either
crotyltributyltin and catalytic amount of (R)-BINAP$Ag(I) complex14
or crotyltrimethoxysilane and the (R)-BINAP$AgF catalyst15 (in each
case, the starting material was recovered). Finally, we carried out the
synthesis of the homocrotylic alcohol 6 using Leighton’s 1,2-
diaminochlorocrotylsilane reagent.16 In this case, while 6 was ob-
tained once in a satisfying 80% yield with an efficient control of both
step procedure. Thus, using MacMillan’s protocol,17 the
L-proline-
catalyzed cross aldol reaction between the aldehyde 5 and propio-
naldehyde afforded the aldol adduct 7 in a 44% yield with an
excellent control of the stereoselectivity (>99% ee, >99% de). The
moderate yield obtained in this case was due to tricky purification of
7 by flash column chromatography. Aldehyde 7 was then submitted
to Tebbe’s homologation conditions18 to furnish the expected
homoallylic alcohol (7R,8R)-6 without loss of stereoselectivity. In
the light of these results, we next investigated the one-pot synthesis
of 6 from the aldehyde 5 via the same aldol/homologation sequence.
In this case, we were delighted to isolate the expected compound 6
in 56% yield after purification by flash column chromatography with
excellent diastereo- and enantio-selectivities. The synthesis was
pursued by the conversion of intermediate 6 into the propargyl
ether 8 in the presence of NaH and propargyl bromide (88%).
Then, both the construction of the pyran moiety and the in-
troduction of the side chain were investigated via two successive
metathesis reactions conducted one pot (Fig. 3).

S. Vuong et al. / Tetrahedron 68 (2012) 433e439
435
Fig. 2. Homocrotylic alcohol via stereoselective proline-catalyzed-aldolization/
homologation.
Fig. 4. Hydrogenation and hydrogenolysis.
distilled over CaH2. Chemicals were of analytical grade from com-
mercial sources and were used without further purification. The
reaction progress was monitored on precoated silica gel TLC plates
MACHEREY-NAGEL ALUGRAMÒ SIL G/UV254 (0.2 mm silica gel 60).
Spots were visualized under 254 nm UV light and/or by dipping the
TLC plate into a solution of 3 g of phosphomolybdic acid in 100 mL
of ethanol followed by heating with a hot gun. Flash column
chromatography was performed using MACHEREY-NAGEL silica gel
Fig. 3. Etherification and enyne-cross metathesis.
The enyne metathesis was carried with Grubbs I catalyst in
CH2Cl2 at room temperature.19 After 12 h under these conditions,
ethylene gas was removed and the reaction mixture was concen-
trated to optimal cross metathesis dilution. The alkene 96 was then
added and the mixture was heated at 50 ꢀC for 24 h to afford the
expected diene 10 in 70% overall yield.20 Reduction of double bonds
and hydrogenolysis of both chloride and benzyl groups by catalytic
hydrogenation furnished the pyridone (7R,8R,10R)-11 and its C10
epimer (7R,8R,10S)-12 in 22% and 10% yields, respectively, after
purification by flash column chromatography.
60 (15e40 mm) as the stationary phase. All reactions were moni-
tored by TLC on Merck silica gel 60F254. Flash column chromatog-
raphy was performed on silica gel (0.02e0.045 mm). 1H and 13C
spectra were recorded on Bruker DPX 300 spectrometer. Chemical
shifts (d) are reported in parts per million (ppm) from high to low
The partially reduced product (7R,8R)-13 was also recovered in
10% yield (Fig. 4). Finally, the synthesis of (17R) and (17S)-TMC-69-
6H can be completed from pyridones 11 and 12, respectively,
field and referenced to residual solvent. Coupling constant (J) are
reported in hertz (Hz). Standard abbreviations indicating multi-
plicity are used as follows: br¼broad, s¼singlet, d¼doublet,
through the N-oxidation procedure previously described by
€
t¼triplet, m¼multiplet. Melting points were measured on a Buchi
4
€
Furstner and co-workers.
Melting Point B-545 instrument and are uncorrected. High reso-
lution ESI mass spectrometry was carried out by the CRMPO
ꢀ
(Centre Regional de Mesures Physiques de l’Ouest), at the Univer-
3. Conclusion
sity of Rennes 1. IR spectra were obtained with a PerkinElmer
Spectrum BX spectrophotometer. High resolution mass spectros-
copy analyses were realized at the University of Amiens with a Q-
TOF Ultima Global hybrid quadrupole time-of-flight instrument
(Waters-Micromass). Melting points were determined using
In summary, a concise and efficient formal synthesis of TMC-69-
6H has been achieved. The practical one-pot tandem ring-closing
and cross metathesis serves as a versatile method for the forma-
tion and functionalization of the pyran moiety. Furthermore, we
developed a novel enantioselective domino aldol/olefin homolo-
gation reaction, which appears as a valuable alternative to classical
stereoselective crotylation methods. Expansion of this work is un-
derway in our laboratory.
€
a Buchi B-545 apparatus. Optical rotations were measured on
a Schmidt HH8 Polarimeter.
4.2. 6-Chloro-4-hydroxy-5-phenyl(1H)-pyridin-2-on 3
4. Experimental section
4.1. General
A solution of freshly distilled malonyl dichloride (10 g,
70.9 mmol, 2.1 equiv) was added to phenylacetonitrile (4 mL,
33.8 mmol, 1 equiv). The reaction mixture was stirred for 4 days at
room temperature and the resulting solid was triturated in dioxane,
filtered, and washed with diethyl ether. Crystallization in dioxane
afforded the expected pyridinone 3 as a pale yellow solid (4.5 g,
72%). Mp¼301 ꢀC (lit. 298e300 ꢀC). IR (neat, cmꢁ1): 3279, 2615,
All reactions were performed under an atmosphere of N2. Unless
otherwise stated, solvents used were of HPLC quality. The solvents
were dried by conventional methods before use. Et2O and THF were
distilled over sodium/benzophenone and dichloromethane was
1643, 1601, 1219, 695. 1H NMR (300 MHz, DMSO-d6)
d 7.41e7.20

436
S. Vuong et al. / Tetrahedron 68 (2012) 433e439
(m, 5H), 6.14 (s, 1H). 13C NMR (75 MHz, DMSO-d6)
d
165.9, 162.8,
10.3 Hz), 4.90 (dd, 1H, J¼1.7, 17.9 Hz), 4.74 (dd, 1H, J¼8.8, 10.3 Hz),
145.6, 133.9, 130.5, 127.8, 127.2, 116.9, 94.1. HRMS (ESI) [MþNa]þ
4.36 (s, 2H), 2.97 (d, 1H, J¼10.3 Hz), 2.69 (m, 1H), 0.82 (d, 3H). 13
C
calcd for C11H9NO2Na: 244.0141, found 244.0135.
NMR (75 MHz, CDCl3) d 165.0, 160.6, 147.3, 141.4, 136.7, 136.0, 134.4,
131.1e128.6, 124.8, 117.1, 115.0, 75.8, 71.5, 69.4, 44.5, 17.5. HRMS
(ESI) [MþNa]þ calcd for C30H28ClNO3Na: 508.1655, found 508.1648.
Chiral HPLC: CHIRALCEL OD-H column, 0.46 cmꢂ25 cm, flowrate
1 mL/min (DEA/i-PrOH/hexane 0.1:0.5:99.4), UV 254 nM. tR: (SS)
17.290 min, (RR) 18.160 min, ee 60%.
4.3. 6-Chloro-4-hydroxy-2-oxo-5-phenyl-1,2-dihydropyridine-
3-carbaldehyde 4
Anhydrous chloroform (7.8 mL) was added slowly to 6-chloro-4-
hydroxy-5-phenyl(1H)-pyridin-2-on 3 (2 g, 9 mmol, 1 equiv) dis-
solved in an aqueous solution of NaOH 35% (20 mL) at 80 ꢀC. The
reaction mixture was stirred for 20 h and the resulting precipitate
was filtered and washed successively with a cold solution of HCl 6 N
and cold water. The aldehyde 4 was obtained as a beige solid (1 g,
46%). Mp¼250 ꢀC. IR (neat, cmꢁ1): 2725, 1650,1614, 1551, 1234, 702.
4.5.2. Hall’s method. 4.5.2.1. (1R,2R,3R,4S)-1,7,7-Trimethyl-2-
phenylbicyclo[2.2.1]-heptane-2,3-diol. A 1 M THF solution of L-
Selectride (15 mL, 15.05 mmol, 1 equiv) was added to a solution of
camphorquinone (2.5 g, 15.05 mmol, 1 equiv) in THF (50 mL) at
0 ꢀC. The temperature was kept below 5 ꢀC throughout the addi-
tion. The mixture was stirred for an additional 30 min. THF (50 mL)
was added to a separate flame dried round-bottom flask containing
CeCl3$7H2O (6.75 g,18.05 mmol,1.2 equiv) previously dried for 18 h
at 140 ꢀC under vacuum. The slurry was stirred at 0 ꢀC and a 3 M
solution of phenylmagnesium bromide in diethyl ether (6 mL,
18 mmol, 1.2 equiv) was added slowly. The resulting white sus-
pension was stirred for 30 min. The reduction reaction mixture of
camphorquinone was then slowly added to the suspension. The
resulting suspension was warmed up to room temperature and
stirred for 3 h. The reaction mixture was poured over a saturated
aqueous solution of ammonium chloride, extracted with diethyl
ether, dried over anhydrous magnesium sulfate, filtered, and the
solvent was evaporated. The resulting residue was then dissolved in
28 mL of a mixture THF/H2O (2:1), 1 M aqueous sodium hydroxide
(25 mL), and 30% H2O2 (10 mL). The biphasic mixture was stirred at
room temperature for 3 h. The mixture was extracted with diethyl
ether. The combined organic layers were washed with brine, dried
over anhydrous magnesium sulfate, filtered, and the solvent was
evaporated. The resulting oil was purified by flash column chro-
matography (EtOAc/petroleum ether 5:95) and then recrystallized
in petroleum ether to afford the expected alcohol as a white pow-
der (1.7 g, 48%). Rf¼0.5 (EtOAc/petroleum ether 5:95). Mp¼116 ꢀC.
1H NMR (300 MHz, DMSO-d6)
d C
9.95 (s, 1H), 7.44e7.28 (m, 5H). 13
NMR (75 MHz, DMSO-d6)
d 192.3, 174.6, 163.8, 143.2, 132.6, 130.9,
128.1, 127.7, 115.3, 106.4. HRMS (ESI) [MþNa]þ calcd for
C12H8ClNO3Na: 272.0090, found 272.0093.
4.4. 2,4-Bis(benzyloxy)-6-chloro-5-phenylpyridine-3-
carbaldehyde 5
To
a
solution of 6-chloro-4-hydroxy-2-oxo-5-phenyl-1,2-
dihydropyridine-3-carbaldehyde 4 (500 mg, 2 mmol, 1 equiv) in
DMF (2 mL) at 70 ꢀC were added K2CO3 (830 mg, 6 mmol, 3 equiv)
and benzylbromide (0.72 mL, 6 mmol, 3 equiv). After 2 h, the re-
action mixture was cooled, diluted with water and then extracted
with a mixture EtOAc/toluene 2:1. The organic layer was washed
with a saturated aqueous solution of ammonium chloride, dried
over anhydrous magnesium sulfate, and the solvents were removed
under reduced pressure. The crude product was purified by flash
column chromatography (EtOAc/petroleum ether 3:97) to give the
expected product 5 as a white solid (464 mg, 54%). Rf¼0.7 (EtOAc/
petroleum ether 10:90). Mp¼128 ꢀC. IR (neat, cmꢁ1): 3058, 2863,
1690, 1537, 1089, 697. 1H NMR (300 MHz, CDCl3)
d
10.38 (s, 1H),
7.54e6.93 (m, 15H), 5.54 (s, 2H), 4.62 (s, 2H). 13C NMR (75 MHz,
CDCl3)
d
187.6, 168.1, 162.9, 153.5, 136.1e133.1, 130.7e128.3, 125.6,
1H NMR (300 MHz, CDCl3)
d 7.60e7.50 (m, 2H), 7.37e7.20 (m, 3H),
111.8, 77.5, 69.4. HRMS (ESI) [MþNa]þ calcd for C26H20ClNO3Na:
4.40 (d, 1H, J¼6.4 Hz), 2.93 (s, 1H), 2.64 (d, 1H, J¼6.4 Hz), 1.91 (m,
452.1029, found 452.1036.
1H),1.78e1.70 (m, 1H),1.34 (s, 3H),1.22e1.14 (m, 2H), 1.03e0.96 (m,
1H), 0.93 (s, 3H), 0.89 (s, 3H). 13C NMR (75 MHz, CDCl3)
d 144.6,
4.5. Crotylation procedures
127.8, 127.3, 127.0, 84.4, 80.6, 53.4, 52.0, 50.8, 30.5, 24.5, 23.3, 22.5,
10.1.
4.5.1. Brown’s method. 4.5.1.1. (1R,2R)-1-(2,4-bis(benzyloxy)-6-
chloro-5-phenylpyridin-3-yl)-2-methylbut-3-en-1-ol 6. To a stirred
mixture of potassium tert-butoxide (67 mg, 0.55 mmol, 1.2 equiv,
dried at 80 ꢀC/0.5 mm for 8 h) in THF (0.55 mL) and trans-2-butene
(0.1 mL, 1.15 mmol, 2.5 equiv) was added n-butyllithium (2.5 M in
hexane, 0.22 mL, 0.55 mmol, 1.2 equiv) at ꢁ78 ꢀC. The reaction
mixture was stirred at ꢁ45 ꢀC for 10 min and was subsequently
cooled down to ꢁ78 ꢀC. (þ)-Methoxydiisopinocamphenylborane
(1 M in ether, 0.7 mL, 0.70 mmol, 1.5 equiv) was added and the
mixture was stirred at ꢁ78 ꢀC for 30 min. Boron trifluoride etherate
(0.1 mL, 0.80 mmol, 1.7 equiv) was added dropwise. A solution of
the aldehyde 5 (200 mg, 0.46 mmol, 1 equiv) in THF (0.46 mL) was
then added with a syringe pump (flow rate 5 mL/h) at ꢁ78 ꢀC. The
mixture was stirred at this temperature for 4 h, treated with
0.40 mL of 3 N NaOH and 0.16 mL of 30% H2O2, and refluxed for 1 h.
The aqueous layer was extracted with dichloromethane. The or-
ganic layer was washed with water and brine, and dried over
magnesium sulfate. The solvent was removed under reduced
pressure and the crude mixture was purified by flash column
chromatography (EtOAc/petroleum ether 10:90) to furnish the ex-
pected alcohol 6 as a yellow oil (51 mg, 23%). Rf¼0.3 (EtOAc/pe-
troleum ether 10:90). IR (neat, cmꢁ1): 3561, 3063, 3031, 2963, 1579,
4.5.2.2. (1R,2R,3R,4S)-2,3-O-[(E)-2-Butenylboryl]-2-phenyl-1,7,7-
trimethylbornanediol. To a stirred mixture of potassium tert-but-
oxide (1.55 g, 12.7 mmol, 1 equiv, dried at 80 ꢀC/0.5 mm for 12 h),
THF (37 mL) and trans-2-butene (1.4 mL, 14.6 mmol, 1.2 equiv) was
added n-butyllithium (1.6 M in hexane, 9 mL, 14.3 mmol, 1.1 equiv)
at ꢁ78 ꢀC. The mixture was stirred at ꢁ50 ꢀC for 15 min and cooled
down to ꢁ78 ꢀC. Triisopropylborate (3.5 mL, 15.1 mmol, 1.2 equiv)
was then added dropwise. The mixture was stirred for 2 h at ꢁ78 ꢀC
and treated with 10 mL of 1 N HCl. The aqueous layer was extracted
with diethyl ether. (1R,2R,3R,4S)-1,7,7-Trimethyl-2-phenylbicyclo
[2.2.1]-heptane-2,3-diol (440 mg, 1.7 mmol, 1 equiv) were added
and 1 g of magnesium sulfate to the organic layer. The mixture was
then stirred for 45 min at room temperature. After filtration, re-
moval of the solvents and purification by flash column chroma-
tography (EtOAc/petroleum ether 5:95 previously stabilized with
Et3N/petroleum ether 5:95), the expected product was obtained as
a colorless oil (217 mg, 42%). Rf¼0.3 (EtOAc/petroleum ether 5:95).
1H NMR (300 MHz, CDCl3)
d 7.44e7.26 (m, 5H), 5.46e5.30 (m, 2H),
4.72 (d, 1H, J¼5.1 Hz), 2.15 (d, 1H, J¼5.1 Hz), 1.90e1.80 (m, 1H),
1.61e1.57 (m, 5H), 1.35e1.25 (m, 5H), 1.04e0.96 (m, 1H), 0.96 (s,
3H), 0.92 (s, 3H). 13C NMR (75 MHz, CDCl3)
d 141.9, 127.5, 127.4,
1070, 696. 1H NMR (300 MHz, CDCl3)
(ddd, 1H, J¼8.2, 10.3, 17.3 Hz), 5.42 (s, 2H), 5.00 (dd, 1H, J¼1.7,
d
7.46e6.88 (m, 15H), 5.75
126.9, 125.8, 125.4, 95.8, 88.7, 52.1, 50.3, 48.9, 29.7, 24.9, 23.7, 20.9,
18.2, 9.5.

S. Vuong et al. / Tetrahedron 68 (2012) 433e439
437
4.5.2.3. (1R,2R)-1-(2,4-Bis(benzyloxy)-6-chloro-5-phenylpyridin-
3-yl)-2-methylbut-3-en-1-ol 6. To stirred solution of tri-
filtrate under reduce pressure gave the expected product as a col-
orless liquid (11.3 g, 65%). Teb¼140 ꢀC (760 mmHg). 1H NMR
a
fluoromethanesulfonate scandium (10 mg, 0.02 mmol, 0.09 equiv)
in dichloromethane (1 mL) at ꢁ78 ꢀC were added the aldehyde 5
(116 mg, 0.27 mmol, 1 equiv) and a solution of (1R,2R,3R,4S)-2,3-O-
[(E)-2-butenylboryl]-2-phenyl-1,7,7-trimethylbornanediol (90 mg,
0.3 mmol, 1.1 equiv) in dichloromethane (0.4 mL). The mixture was
stirred for 16 h and a solution of 1 M DIBAL-H in toluene (0.54 mL,
0.54 mmol, 2 equiv) was then added. The mixture was stirred for
30 min at ꢁ78 ꢀC and treated with 4 mL of 1 N HCl. The solution
was allowed to warm up to room temperature. The aqueous layer
was extracted with EtOAc. The combined organics were dried over
magnesium sulfate, filtered, and the solvent was evaporated. The
resulting oil was purified by flash column chromatography
(EtOAc/petroleum ether 5:95) to afford the alcohol 6 as a colorless
oil (10 mg, 8%). The analytical data are identical to those
obtained by the Brown’s method. Chiral HPLC: CHIRALCEL OD-H
column, 0.46 cmꢂ25 cm, flowrate 1 mL/min (DEA/i-PrOH/hexane
0.1:0.5:99.4), UV 254 nM. tR: (SS) 16.459 min, (RR) 17.222 min, ee
10%.
(300 MHz, CDCl3)
d
: 5.62 (m, 1H, J¼1.5, 6.4, 15.0 Hz), 5.40 (m, 1H,
J¼1.5, 7.5, 15.0 Hz), 2.26 (d, 2H, J¼7.5 Hz), 1.72 (d, 3H, J¼6.4 Hz). 13C
NMR (75 MHz, CDCl3) d: 130.9, 119.6, 29.6, 18.6.
4.5.3.5. (1R,2R)-1-(2,4-Bis(benzyloxy)-6-chloro-5-phenylpyridin-
3-yl)-2-methylbut-3-en-1-ol 6. To a solution of (S)-3,30-dimethyl-
2,20-biquinoline-N,N0-dioxide (37 mg, 0.12 mmol, 0.1 equiv), alde-
hyde (500 mg, 1.16 mmol, 1 equiv), and diisopropylamine (1 mL,
5.8 mmol, 5 equiv) in dichloromethane (1 mL) at ꢁ78 ꢀC under N2
atmosphere was added ((E)-but-2-enyl)-trichlorosilane (0.2 mL,
1.44 mmol, 1.6 equiv). After 2 days under these conditions, the
resulting mixture was quenched with saturated aqueous NaHCO3.
The aqueous layer was extracted with EtOAc and the organic layers
were washed with brine, dried over magnesium sulfate, filtered,
and the solvent was evaporated. The residue was purified by flash
column chromatography (EtOAc/petroleum ether 10:90) to furnish
6 as a colorless oil (413 mg, 73%).The analytical data are identical to
those obtained by the Brown’s method. Chiral HPLC: CHIRALCEL
OD-H column, 0.46 cmꢂ25 cm, flowrate 1 mL/min (DEA/i-PrOH/
hexane 0.1:0.5:99.4), UV 254 nM. tR: (SS) 14.609 min, (RR)
15.303 min, ee 30%.
4.5.3. Nakajima’s method. 4.5.3.1. 3,30-Dimethyl-2,20-biquinoline.
To a stirred solution of 2-aminobenzaldehyde (600 mg, 4.95 mmol,
1.7 equiv) in ethanol (9.9 mL) was added 0.88 M NaOH
(0.5 mL, 0.44 mmol, 0.15 equiv). The mixture was refluxed. 3,4-
Hexanedione (0.35 mL, 2.87 mmol, 1 equiv) was then added
slowly. The mixture was refluxed overnight. The solvents were
evaporated and the residue was purified by flash column chroma-
tography (CH2Cl2 to EtOAc/CH2Cl2 10:90) to give the expected
product as white needles (398 mg, 50%). Rf¼0.1 (CH2Cl2).
4.5.4. Leighton’s method. 4.5.4.1. (1S,2S)-N,N0-Bis-(4-bromobenzyl)-
cyclohexane-1,2-diamine. To
minocyclohexane$ -tartrate (9.9 g, 37.5 mmol, 1 equiv) in water
(173 mL) were added K2CO3 (9.6 g, 75 mmol, 2 equiv), ethanol
(86 mL), and solution of methanesulfonic acid (0.24 mL,
a
solution of (1S,2S)-(ꢁ)-dia-
D
a
3.75 mmol, 0.1 equiv) and bromobenzaldehyde (13.9 g, 75 mmol,
2 equiv) in CH2Cl2 (173 mL). The reaction mixture was stirred for
12 h at room temperature, refluxed for 1 h, and concentrated. The
resulting residue was diluted in water and filtered. The solid was
dissolved in methanol (43 mL), the reaction mixture was cooled at
0 ꢀC, and NaBH4 (3.1 g, 82.5 mmol, 2.2 equiv) was added portion-
wise. The reaction mixture was then refluxed for 1 h and concen-
trated. The residue was dissolved in an aqueous solution of 1 N
NaOH and extracted with a mixture of EtOAc/petroleum ether. The
organic layers were washed with brine, concentrated, and purified
by flash column chromatography (EtOAc/petroleum ether 15:85 to
EtOAc) to afford the expected product as a yellow oil (10.8 g, 65%).
Rf¼0.3 (EtOAc/petroleum ether 50:50). 1H NMR (300 MHz, CDCl3)
Mp¼142 ꢀC (lit. 143e144 ꢀC). 1H NMR (300 MHz, CDCl3)
d 8.09 (d,
2H), 8.07 (s, 2H), 7.79 (d, 2H, J¼8 Hz), 7.65 (t, 2H, J¼1, 7, 8 Hz), 7.54
(td, 2H, J¼1, 7, 8 Hz), 2.29 (s, 6H). 13C NMR (75 MHz, CDCl3)
d 159.5,
146.8, 137.2, 129.9, 129.7, 129.2, 128.5, 127.3, 127.2, 19.5.
4.5.3.2. (ꢃ)-3,30-Dimethyl-2,2-biquinoline-N,N0-dioxide. m-Chlor-
operbenzoic acid (70%, 673 mg, 2.73 mmol, 2.2 equiv) was added
portionwise to a solution of 3,30-dimethyl-2,20-biquinoline (350 mg,
1.24 mmol, 1 equiv) in dichloromethane (3.5 mL) at 0 ꢀC. The mix-
ture was stirred for 5 h at room temperature. The reaction mixture
was washed successively with saturated NaHCO3 and brine, dried
over magnesium sulfate and the solvent was evaporated. The crude
product was recrystallized from ethanol to afford the expected
product as colorless needles (212 mg, 54%). Mp 272 ꢀC (lit. 270 ꢀC).
d
7.42 (d, 2H, J¼8.4 Hz), 7.17 (d, 2H, J¼8.4 Hz), 3.84 (d, 2H,
J¼13.4 Hz), 3.59 (d, 2H, J¼13.4 Hz), 2.25e2.12 (m, 4H),1.83e1.71 (m,
1H NMR (300 MHz, CDCl3)
d
: 8.73 (d, 2H, J¼8 Hz), 7.89e7.67 (m, 8H),
4H),1.29e1.18 (m, 2H), 1.06e0.99 (m, 2H). 13C NMR (75 MHz, CDCl3)
2.28 (s, 6H). 13C NMR (75 MHz, CDCl3)
129.5, 127.8, 125.8, 120.5, 18.4.
d
: 140.7, 132.1, 130.5, 129.8,
d
140.3, 131.8, 130.2, 121.0, 61.2, 50.5, 31.9, 25.4. HRMS (ESI) [MþH]þ
calcd for C20H25Br2N2: 451.0384, found 451.0392.
4.5.3.3. (S)-3,30-Dimethyl-2,20-biquinoline-N,N0-dioxide. n-Hex-
ane (7.4 mL) was added to a hot clear solution of (ꢃ)-3,30-dimethyl-
2,2-biquinoline-N,N0-dioxide (180 mg, 0.6 mmol, 1 equiv) and (R)-
(þ)-2,20-binaphthol (155 mg, 0.54 mmol, 0.9 equiv) in dichloro-
methane (9 mL). The mixture was allowed to stand for 12 h at room
temperature to precipitate. The solid was purified by flash column
chromatography (CH2Cl2 to MeOH/CH2Cl2 2:98) to furnish the ex-
pected product as white needles (91 mg, 48%). Rf¼0.5 (MeOH/
4.5.4.2. (3aS,7aS)-1,3-Bis(4-bromobenzyl)-2-((E)-but-2-enyl)-2-
chloro-octahydro-1H-benzo[d]-[1,3,2]-diazasilole. To a solution of
((E)-but-2-enyl)-trichlorosilane (2 mL, 13.2 mmol, 1.1 equiv) in
CH2Cl2 (24 mL) at 0 ꢀ C was added DBU (3.9 mL, 26.4 mmol,
2.2 equiv). A solution of (1S,2S)-N,N0-bis-(4-bromobenzyl)-cyclo-
hexane-1,2-diamine (5.43 g, 12 mmol, 1 equiv) in CH2Cl2 (12 mL)
was then added slowly. The reaction mixture was allowed to warm
to room temperature. After 12 h, the reaction mixture was con-
centrated under reduced pressure. The resulting residue was di-
luted in pentane (36 mL) and vigorously stirred overnight to ensure
complete precipitation of DBU salts. The suspension was filtered in
an inert atmosphere glovebox. The resulting filtrate was concen-
trated and washed with pentane to furnish the expected product as
CH2Cl2 5:95) mp 251 ꢀC (lit. 247e249 ꢀC). [
(lit. ꢁ120 (c 1.01, CHCl3)).
a
]
D
20 ꢁ115 (c 1.00, CHCl3)
4.5.3.4. ((E)-But-2-enyl)-trichlorosilane. A mixture of (E)-crotyl
chloride (9 mL, 92 mmol, 1 equiv), trichlorosilane (13.4 mL,
132.5 mmol, 1.44 equiv) in anhydrous diethylether (10 mL) was
a white powder (3.9 g, 58%). 1H NMR (300 MHz, CDCl3)
d 7.50e7.23
added dropwise to
a
suspension of CuCl (3 g, 30.4 mmol,
(m, 8H), 5.32e5.17 (m, 2H), 4.15e3.96 (m, 2H), 3.86e3.70 (m, 2H),
0.33 equiv) and Et3N (14.2 mL, 100.3 mmol, 1.09 equiv) in anhy-
drous diethylether (30 mL) at room temperature. After 1 h 30 at this
temperature, the reaction mixture was filtered. Distillation of the
2.80e2.66 (m, 2H), 1.71e1.50 (m, 9H), 1.34e0.85 (m, 4H). 13C NMR
(75 MHz, CDCl3)
d 134.28, 131.92, 131.06, 129.82, 128.99, 122.39,
58.33, 48.06, 29.33, 24.28, 18.20, 17.97.

438
S. Vuong et al. / Tetrahedron 68 (2012) 433e439
4.5.4.3. (1R,2R)-1-(2,4-Bis(benzyloxy)-6-chloro-5-phenylpyridin-
3-yl)-2-methylbut-3-en-1-ol 6. To solution of diamine (1 g,
J¼2.6 Hz), 7.67e6.92 (m, 15H), 5.48 (s, 2H), 5.25 (d, 1H, J¼10.0 Hz),
a
4.41 (s, 2H), 3.33 (d, 1H, J¼10.2 Hz), 3.00 (m, 1H), 0.88 (d, 3H,
J¼7.2 Hz).
1.75 mmol, 7.6 equiv) in CH2Cl2 (3.4 mL) at 0 ꢀC under inert atmo-
sphere was added aldehyde 5 (100 mg, 0.23 mmol, 1 equiv). After 2
days, the reaction mixture was quenched with a solution of 1 N HCl
and the aqueous layer was extracted with EtOAc. The organic layers
were dried over anhydrous magnesium sulfate, concentrated, and
the residue was purified by flash column chromatography (EtOAc/
petroleum ether 5:95) to furnish 6 as a colorless oil (89 mg, 80%).
4.7.2. (1R,2R)-1-(2,4-Bis(benzyloxy)-6-chloro-5-phenylpyridin-3-
yl)-2-methylbut-3-en-1-ol 6. To a solution of aldehyde (640 mg,
1.3 mmol, 1 equiv) in THF (52 mL) at 0 ꢀC was added Tebbe’s re-
agent (0.5 M in toluene, 4 mL, 2 mmol, 1.5 equiv). After 1 h, the
reaction mixture was quenched with an aqueous solution of 10%
NaOH, diluted in diethyl ether, and filtered through Celite. After
removal of the solvents, the residue was purified by flash column
chromatography (EtOAc/petroleum ether 10:90) to furnish the
homoallylic alcohol 6 as a colorless oil (292 mg, 47%). The analytical
data are identical to those obtained by the Leighton’s method.
Chiral HPLC: CHIRALCEL OD-H column, 0.46 cmꢂ25 cm, flowrate
1 mL/min (DEA/i-PrOH/hexane 0.1:0.5:99.4), UV 254 nM. tR (RR)
19.609 min, ee>99%.
[
a
]
20 þ14.6 (c 1.80 CHCl3). The analytical data are identical to those
D
obtained by the Brown’s method. Chiral HPLC: CHIRALCEL OD-H
column, 0.46 cmꢂ25 cm, flowrate 1 mL/min (DEA/i-PrOH/hexane
0.1:0.5:99.4), UV 254 nM. tR: (RR) 22.444 min, ee>99%.
4.6. O-Methylmandelate derivatives
4.6.1. (10R,20R)-(2,4-Bis(benzyloxy)-6-chloro-5-phenylpyridin0-3-yl)-
0
ꢀ
a-acetophenylacetate and (1 S,2 S)-
2-methylbut-3-en-1-yl (R)-(ꢁ)-
(2,4-bis(benzyloxy)-6-chloro-5-phenylpyridin-3-yl)-2-methylbut-3-
en-1-yl (R)-(ꢁ)- -acetophenylacetate. (R)-(ꢁ)- -Acetophenylacetic
4.8. Method ‘one-pot aldolization/homologation’
a
a
acid (39 mg, 0.2 mmol, 1.1 equiv) was added to a white suspension
prepared by the addition of oxalyl chloride (0.16 mL, 0.18 mmol,
1 equiv) to a solution of DMF (0.2 mL) in acetonitrile (5.6 mL) at
0 ꢀC. After 5 min, a solution of alcohol (90 mg, 0.18 mmol, 1 equiv)
in pyridine (0.3 mL) was added. The reaction mixture was stirred at
0 ꢀC for 2 h and was then diluted with diethyl ether (14 mL). The
organic layer was washed with an aqueous saturated solution of
NaHCO3, dried over magnesium sulfate, filtered, and concentrated.
The residue was purified by flash column chromatography (EtOAc/
petroleum ether 10:90) to afford a mixture of esters as a colorless
oil (73 mg, 65%). Rf¼0.3 (EtOAc/petroleum ether 10:90). IR (neat,
cmꢁ1): 3294, 3031, 2965, 1578, 1069, 697.
4.8.1. (1R,2R)-1-(2,4-Bis(benzyloxy)-6-chloro-5-phenylpyridin-3-yl)-
2-methylbut-3-en-1-ol 6. To a solution of aldehyde (0.3 g, 0.7 mmol,
1 equiv) and (L)-proline (16 mg, 0.14 mmol, 0.2 equiv) in DMF
(0.7 mL) at 0 ꢀC was added slowly a solution of freshly distilled
propionaldehyde (0.1 mL, 1.5 mmol, 2 equiv) in DMF (0.5 mL). After
3 days, the solvent was removed under reduced pressure and the
crude product was dissolved in THF (12 mL). The Tebbe’s reagent
(0.5 M in toluene, 0.9 mL, 1.5 equiv) was then added at 0 ꢀC. After
1 h, the reaction mixture was quenched with an aqueous solution
of 10% NaOH, diluted in diethyl ether, and filtered through Celite.
After removal of the solvents, the residue was purified by flash
column chromatography (EtOAc/petroleum ether 10:90) to furnish
the expected product as a colorless oil (189 mg, 56%) (99% ee, >99%
de). The analytical data are identical to those obtained by the
Leighton’s method.
The esters were separated by semi-preparative HPLC. HPLC
(H2O/CH3CN 15:85), UV 254 nM. tR: (RRR)¼7.338 min, (SSR)¼
8.136 min.
4.6.2. (10R,20R)-(2,4-Bis(benzyloxy)-6-chloro-5-phenylpyridin-3-yl)-
4.8.2. (10R,20R)-2,4-Bis(benzyloxy)-6-chloro-3-(2-methyl-1-prop-2-
ynyloxybut-3-enyl)-5-phenylpyridine 8. To a solution of alcohol
(1.12 g, 2.31 mmol, 1 equiv) in freshly distilled THF (6 mL) was
added NaH (60%, 277 mg, 6.93 mmol, 3 equiv). The resulting mix-
ture was refluxed for 1 h. 3-Bromoprop-1-yne (80% in toluene,
0.5 mL, 4.62 mmol, 2 equiv) was then added and the reaction
mixture was stirred at room temperature overnight. The reaction
mixture was then diluted in ethanol, quenched with a saturated
aqueous solution of NH4Cl. The aqueous layer was extracted with
dichloromethane and the organic layers were dried over anhydrous
magnesium sulfate, filtered, and concentrated. The resulting resi-
due was purified by flash column chromatography (EtOAc/petro-
leum ether 5:95) to afford the ether product 8 as a colorless
2-methylbut-3-en-1-yl
(300 MHz, CDCl3)
(R)-(ꢁ)-
a
-acetophenylacetate. 1H
NMR
ꢀ
d
7.44e7.15 (m, 20H), 6.13 (d, 1H, J¼10.5 Hz), 5.87
(s, 1H), 5.65 (m, 1H, J¼1.8, 8.3, 17.1 Hz), 5.34 (d, 1H), 4.99 (m, 3H),
4.36 (m, 1H), 4.01 (m, 1H), 3.15 (m, 1H), 2.00 (s, 3H), 0.70 (d, 3H,
J¼6.9 Hz). 13C NMR (75 MHz, CDCl3)
d 170.2, 168.4, 165.6, 160.7,
148.1, 140.4, 136.8, 135.9, 133.9,133.7, 129.1, 127.5, 124.2, 116.0, 112.6,
75.0, 74.7, 72.8, 68.5, 40.3, 20.8, 16.8.
4.6.3. (10S,20S)-(2,4-Bis(benzyloxy)-6-chloro-5-phenylpyridin-3-yl)-
2-methylbut-3-en-1-yl
(300 MHz, CDCl3)
7.59e6.95 (m, 20H), 6.15 (d, 1H, J¼10.5 Hz), 5.80
(s, 1H), 5.55e5.32 (m, 3H), 4.60e4.38 (m, 4H), 3.08 (m, 1H), 2.14 (s,
3H), 0.72 (d, 3H). 13C NMR (75 MHz, CDCl3)
170.3, 168.3, 165.7,
(R)-(ꢁ)-
a
-acetophenylacetate. 1H
NMR
d
d
oil (1.05 g, 88%). Rf¼0.3 (EtOAc/petroleum ether 5:95). [
a
]
20 þ41.4 (c
D
160.9,148.2,139.8,137.0,136.1,134.0,133.8,130.9,127.9,124.7,115.6,
113.0, 75.1, 74.7, 72.7, 68.9, 40.9, 20.9, 16.8.
4.00, CHCl3). 1H NMR (300 MHz, CDCl3)
d
7.54e6.94 (m, 15H), 5.99
(ddd, 1H, J¼1.5, 9.8, 17.5 Hz), 5.48 (d, 1H, J¼12.6 Hz), 5.45 (d, 1H,
J¼12.6 Hz), 5.04 (m, 2H), 4.82 (d, 1H, J¼10.0 Hz), 4.57 (sl, 1H), 4.23
(sl, 1H), 4.11 (dd, 1H, J¼2.4, 15.9 Hz), 3.98 (d, 1H, J¼15.9 Hz), 3.19 (m,
1H), 2.26 (t, 1H, J¼2.4 Hz), 0.77 (d, 3H, J¼7 Hz). 13C NMR (75 MHz,
4.7. Method aldolization and homologation
4.7.1. (2S,3R)-3-(2,4-Bis(benzyloxy)-6-chloro-5-phenylpyridin-3-yl)-
3-hydroxy-2-propanal 7. To a solution of aldehyde (1.3 g, 3 mmol,
CDCl3) d 166.4, 161.4, 147.3, 142.3, 136.9e133.9, 130.8, 127.8, 114.2,
80.3, 75.1, 74.0, 68.5, 56.7, 40.3, 16.8. HRMS (ESI) [MþNa]þ calcd for
1 equiv) and (L)-proline (69 mg, 0.6 mmol, 0.2 equiv) in DMF (3 mL)
C33H30ClNO3Na: 546.1812, found 546.1794.
at 0 ꢀC was added slowly a solution of freshly distilled propio-
naldehyde (0.4 mL, 6 mmol, 2 equiv) in DMF (1.8 mL). After 3 days,
the reaction was quenched with water and extracted with EtOAc/
toluene 2:1. The organic layers were dried over anhydrous mag-
nesium sulfate, filtered, and concentrated. The purification by flash
column chromatography (EtOAc/petroleum ether 20:80) gave the
aldehyde 7 as a colorless oil (634 mg, 44%). Rf¼0.3 (EtOAc/petro-
4.8.3. 2,4-Bis(benzyloxy)-6-chloro-3-[(20R,30R)-3,6-dihydro-3-
methyl-5-(6-methylocta-1,5-dienyl)-2H-pyran-2-yl]-5-
phenylpyridine and 2,4-bis(benzyloxy)-6-chloro-3-[(20R,30R)-3,6-
dihydro-3-methyl-5-(6-methylocta-1,6-dienyl)-2H-pyran-2-yl]-5-
phenylpyridine 10. Grubbs
I
catalyst (18 mg, 0.022 mmol,
0.05 equiv) was added to a solution of ether (230 mg, 0.44 mmol,
1 equiv) in CH2Cl2 (5 mL). The mixture was stirred overnight at
leum ether 20:80). 1H NMR (300 MHz, CDCl3)
d 9.72 (d, 1H,

S. Vuong et al. / Tetrahedron 68 (2012) 433e439
439
room temperature under ethylene atmosphere. The half of the
solvent was then evaporated. The diene (109 mg, 0.88 mmol,
2 equiv) was then added and the reaction mixture was heated at
50 ꢀC for 24 h under nitrogen atmosphere. The mixture was then
filtered through Celite and the solvent was evaporated. The
resulting residue was then purified by flash column chromatogra-
(m, 9H). HRMS (ESI) [MþNa]þ calcd for C26H35NO3Na: 432.2514,
found 432.2519.
Acknowledgements
We thank CNRS for financial support.
Supplementary data
phy (EtOAc/petroleum ether 1:99) to afford the diene 10 as a col-
20
orless oil (186 mg,70%). Rf¼0.4 (EtOAc/petroleum ether 5:95). [
a]
D
þ25.6 (c 1.40 CHCl3). 1H NMR (300 MHz, CDCl3)
d 7.48e6.83 (m,
15H), 6.01 (d, 1H, J¼16.0 Hz), 5.56 (sl, 1H), 5.59 (m, 3H), 5.46e5.42
Experimental procedures tabulated data for new compounds.
Copies of 1H, 13C, NMR spectra of compounds 3e13. Supplementary
data associated with this article can be found in online version, at
doi:10.1016/j.tet.2011.11.025.
(m, 1H), 4.67e4.25 (m, 5H), 3.32 (m, 1H), 2.11e0.94 (m, 12H), 0.80
(d, 3H, J¼7.1 Hz). 13C NMR (75 MHz, CDCl3)
d 173.3, 161.2, 147.7,
137.1e133.5, 130.9e122.3, 115.4, 76.1, 75.5, 68.8, 66.4, 33.7, 33.5,
32.8, 32.5, 32.4, 29.8, 28.0, 27.8, 17.3, 16.1, 13.0. HRMS (ESI) [MþNa]þ
calcd for C40H42ClNO3Na: 642.2751, found 642.2756.
References and notes
4.8.4. 3-((20R,30R,50R)-Tetrahydro-3-methyl-5-(6-methyloctyl)-2H-
pyran-2-yl)-4-hydroxy-5-phenylpyridin-2(1H)-one 11. A solution of
diene (70 mg, 0.11 mmol) and Pd/C (10%, 14 mg) in EtOAc (3 mL)
was stirred under H2 atmosphere (5 bar) at 45 ꢀC for 24 h. The
mixture was then filtered through Celite and concentrated. The
resulting residue was purified by flash column chromatography
(EtOAc/petroleum ether 20:80 to 50:50) to furnish the product 11
as a colorless oil (8 mg, 22%). Rf¼0.3 (EtOAc/petroleum ether
1. Jessen, H. J.; Gademann, K. Nat. Prod. Rep. 2010, 27, 1168e1185.
2. Hirano, N.; Khono, J.; Tsunoda, S.; Nishio, M.; Kishi, N.; Okuda, T.; Kawano, K.;
Komatsubara, S.; Nakanishi, N. J. Antibiot. 2001, 54, 421e427.
3. Khono, J.; Hirano, N.; Sugawara, K.; Nishio, M.; Hashiyama, T.; Nakanishi, N.;
Komatsubara, S. Tetrahedron 2001, 57, 1731e1735.
€
4. (a) Furstner, A.; Feyen, F.; Prinz, H.; Waldmann, H. Angew. Chem., Int. Ed. 2003,
€
42, 5361e5364; (b) Furstner, A.; Feyen, F.; Prinz, H.; Waldmann, H. Tetrahedron
2004, 60, 9543e9558.
5. Sugawara, K.; Imanishi, Y.; Hashiyama, T. Heterocycles 2007, 71, 597e607.
6. Brondel, N.; Renoux, B.; Gesson, J. P. Tetrahedron Lett. 2006, 47, 9305e9308.
7. Davis, S. J.; Elvidge, J. A.; Foster, A. B. J. Chem. Soc. 1962, 3638e3644.
8. Sugasawa, T.; Sasakura, K.; Toyoda, T. Chem. Pharm. Bull. 1974, 22, 763e770.
9. Fresneda, P. M.; Molina, P.; Bleda, J. A. Tetrahedron 2001, 57, 2355e2363.
10. (a) Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc. 1986, 108, 5919e5923; (b) Brown,
H. C.; Bhat, K. S.; Randad, R. S. J. Org. Chem. 1989, 54, 1570e1576.
11. (a) Dale, J. A.; Mosher, H. A. J. Am. Chem. Soc. 1968, 90, 3732e3737; (b) Dale, J. A.;
Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512e519; (c) Trost, B. M.; Belletire, J. L.;
Godleski, S.; McDougal, P. G.; Balkovec, J. M. J. Org. Chem. 1986, 51, 2370e2374;
(d) For determination of the absolute configuration of both enantiomers by
NMR see Supplementary data.
50/50). [
a]
20 þ91.4 (c 0.14 CHCl3). 1H NMR (300 MHz, CDCl3)
d 9.67
D
(sl, 1H), 7.46e7.33 (m, 6H), 4.66 (d, 1H, J¼10.8 Hz), 3.97 (d, 1H
J¼11.7 Hz), 3.73 (dd, 1H, J¼2.1, 11.7 Hz), 2.09 (m, 1H), 1.76 (d, 1H,
J¼12.2 Hz), 1.67e1.52 (m, 4H), 1.28e1.08 (m, 11H), 0.89e0.82 (m,
9H). 13C NMR (75 MHz, CDCl3)
d. 164.17, 134. 03, 133.5, 129.26,
128.45, 127.53, 115.79, 110.18, 81.45, 72.6, 36.28, 34.18, 32.04, 31.18,
30.99, 29.79, 29.47, 27.96, 22.82, 18.18, 14.26. HRMS (ESI) [MþNa]þ
calcd for C26H37NO3Na: 434.2671, found 434.2674.
12. Lachance, H.; Lu, X.; Gravel, M.; Hall, D. G. J. Am. Chem. Soc. 2003, 125,
10160e10161.
13. Nakajima, M.; Saito, M.; Shiro, M.; Hashimoto, S.-I. J. Am. Chem. Soc. 1998, 120,
6419e6420.
14. Yanagisawa, A.; Ishiba, A.; Nakashima, H.; Yamamoto, H. Synlett 1997, 88e90.
15. Yanagisawa, A.; Kageyama, H.; Nkatsuka, Y.; Asakawa, K.; Matsumoto, Y.; Ya-
mamoto, H. Angew. Chem., Int. Ed. 1999, 38, 3701e3703.
16. Hackman, B. M.; Lombardi, P. J.; Leighton, J. L. Org. Lett. 2004, 6, 4375e4377;
Burns, N. Z.; Hackman, B. M.; Ng, P. Y.; Powelson, I. A.; Leighton, J. L. Angew.
Chem., Int. Ed. 2006, 45, 3811e3813; Kim, H.; Ho, S.; Leighton, J. L. J. Am. Chem.
Soc. 2011, 133, 6517e6520.
4.8.5. 3-((20R,30R,50S)-Tetrahydro-3-methyl-5-(6-methyloctyl)-2H-py-
ran-2-yl)-4-hydroxy-5-phenylpyridin-2(1H)-one 12. Rf¼0.4 (EtOAc/
petroleum ether50:50). 1H NMR (300 MHz, CDCl3)
d 7.47e7.25 (m,
6H), 4.62 (d, 1H, J¼10.2 Hz), 4.04 (dd,1H, J¼2.8,11.7 Hz), 3.17 (dd,1H,
J¼11.3,11.3 Hz),1.96e1.45 (m, 6H),1.40e1.08 (m,11H), 0.89e0.82 (m,
9H).13C NMR (75 MHz, CDCl3)
d 164.61,162.52,132.356,130.7,128.15,
127.99, 115.89, 107.39, 80.26, 74.00, 39.12, 36.57, 36.13, 32.07, 31.90,
29.76, 29.71, 29.60, 29.53, 29.326, 26.489, 22.685, 17.92, 14.11. HRMS
(ESI) [MþNa]þ calcd for C26H37NO3Na: 434.2671, found 434.2667.
17. Northrup, A.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 6798e6799; (b)
List, B. Tetrahedron 2002, 58, 5573e5590.
18. (a) Tebbe, F. N.; Parshall, G. W.; Reddy, G. S. J. Am. Chem. Soc. 1978, 100,
3611e3613; (b) Nicolaou, K. C.; Snyder, S. A.; Huang, X.; Simonsen, K. B.;
Koumbis, A. E.; Bigot, A. J. Am. Chem. Soc. 2004, 126, 10162e10173.
19. (a) Schrock, R. R.; Murdzek, J. S.; Bazan, G. C.; Robins, J.; DiMare, M.; O’Regan, M.
J. Am. Chem. Soc. 1990, 112, 3875e3886; (b) Nguyen, S.-B. T.; Johnson, L. K.;
Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1992, 114, 3974e3975.
0
0
ꢀ
4.8.6. 3-((2 R,3 R)-3,6-Dihydro-3-methyl-5-(6-methyloctyl)-2H-py-
ꢀ
ran-2-yl)-4-hydroxy-5-phenylpyridin-2(1H)-one 13. Rf¼0.5 (EtOAc/
petroleum ether 50:50). 1H NMR (300 MHz, CDCl3)
d 7.46e7.32 (m,
ꢀ €
20. Arjona, O.; Csaky, A. G.; Murcia, M. C.; Plumet, J. Tetrahedron Lett. 2000, 41,
6H), 5.38 (sl, 1H), 4.72 (d, 1H, J¼9.8 Hz), 4.23 (d, 1H, J¼9.8 Hz), 4.15
9777e9779; (b) Royer, F.; Vilain, C.; Elkaïm, L.; Grimaud, L. Org. Lett. 2003, 5,
2007e2009.
(d, 1H, J¼15.7 Hz), 2.59 (m, 1H), 1.92e1.08 (m, 13H), 1.03e0.85