Stereoselective synthesis of the bacterial DNA primase inhibitor?Sch 642305 and its C-4 epimer

Article abstract of DOI:10.1016/j.tet.2007.09.080

A convergent stereoselective synthesis of the bacterial DNA primase inhibitor Sch 642305 and its non-natural epimer at C-4 is described. A key aspect was the construction of a trans-2,3-disubstituted cyclohexanone system by means of a stereoselective Mich

Full text of DOI:10.1016/j.tet.2007.09.080

Tetrahedron 63 (2007) 12131–12137
Stereoselective synthesis of the bacterial DNA primase
inhibitor Sch 642305 and its C-4 epimer
a
Jorge Garcıa-Fortanet, Miguel Carda and J. Alberto Marco
a,
b
*
ꢀ
aDepart. de Q. Inorgaꢀnica y Orgaꢀnica, Univ. Jaume I, Castelloꢀn, E-12080 Castelloꢀn, Spain
bDepart. de Q. Orgaꢀnica, Univ. de Valencia, E-46100 Burjassot, Valencia, Spain
Received 8 August 2007; revised 24 September 2007; accepted 25 September 2007
Available online 2 October 2007
Abstract—A convergent stereoselective synthesis of the bacterial DNA primase inhibitor Sch 642305 and its non-natural epimer at C-4 is
described. A key aspect was the construction of a trans-2,3-disubstituted cyclohexanone system by means of a stereoselective Michael ad-
dition/a-alkylation sequence. The macrolactone ring of either stereoisomer was created using the Mitsunobu and Yamaguchi procedures, re-
spectively.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
the fungus Penicillium verrucosum (culture ILF-16214). Its
structure, including the relative and absolute configuration
(Fig. 1), was established on the basis of thorough NMR
studies and an X-ray diffraction analysis of a crystalline
derivative.9 More recently, compound 1 has also been iso-
lated from a microbial source and found to be a potent inhib-
itor of the HIV-1 Tat-dependent transactivation.10
Bacterial infections due to the rapid emergence of antibiotic-
resistant strains have become a serious threat to public health
worldwide.1 Concerns of antibiotic resistance issues have
brought an urgent sense to the discovery and development
of new classes of antibacterial drugs. Mechanism-based
drug discovery approaches are being explored to identify
novel antimicrobial agents that may potentially provide
alternative treatments for infectious diseases. Bacterial DNA
primase (DnaG) is a DNA-dependent RNA polymerase that
is required for the replication of chromosomal DNA.2,3 Ge-
netic validation of DnaG indicated that inhibition of bacterial
primase causes a rapid cidal response of bacteria.4,5 Interac-
tion of primase, encoded by DnaG, with the single-stranded
DNA template is mediated by contacts with the replicative
DNA helicase encoded by DnaB.6,7 In the cell, the helicase
progresses along the duplex DNA and mediates unwinding
to a single-stranded DNA template. The DNA primase asso-
ciates with the helicase and intermittently initiates synthesis
of ss RNA primers, required for de novo DNA synthesis.
While replication of the leading-strand DNA requires only
one RNA primer, replication of the lagging-strand DNA re-
quires >2000 primer sites. Since interruption of this process
would cause a catastrophic event in bacterial chromosome
replication, the primase enzyme constitutes an attractive
target for drug discovery.8 Very recently, a natural compound
of fungal origin has been shown to display a marked ability
as a primase inhibitor (EC50, 70 mM). The compound, named
Sch 642305 (1), was isolated from the fermentation broth of
OH
1
12
2
O
11
10
12a
9
8 O
8a
4
7
5
O
6
1
4βMe
4αMe
2
Figure 1. Structures of Sch 642305 1 and its C-4 epimer 2.
Compound 1 contains a medium-sized (10-membered) lac-
tone condensed with a cyclohexane ring. This bicyclic
system has not been previously reported in any compound
of natural origin.11 Due to its interesting biological proper-
ties, lactone 1 has attracted the attention of the synthetic
community. Four syntheses of 1 have been published in
the last two years.12 In two of these syntheses, the lactone
ring was created with the aid of the Yamaguchi macrolacto-
nization procedure13 whereas in the others, macrocycliza-
tion was performed via olefinic ring-closing metathesis.14
With the aim of performing structure–activity relationship
studies, we have now performed syntheses of lactone 1 as
well of 2, its non-natural epimer at C-4.
Our retrosynthetic concept for the preparation of compound
Sch 642305 1 and its epimer 2 is shown in Scheme 1. Both
* Corresponding author. Tel.: +34 964 728242; fax: +34 964 728214;
e-mail: mcarda@qio.uji.es
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.09.080

12132
J. Garcꢀıa-Fortanet et al. / Tetrahedron 63 (2007) 12131–12137
OH
BrMg
1:
1
TBSO
O
OBn
12
2
O
O
11
10
CuI cat., -30 °C
1: 9-BBN, THF
12a
CO2Et
OBn
9
2: NaH, BnBr,
THF, RT, 16 h
74% overall
2: NaOH, H2O2
91%
8 O
8a
8
7
4
7
5
O
6
1
2
4βMe
4αMe
OBn
OBn
3
Ph3P, imidazole, I2
CH2Cl2, 90%
I
OH
9
6
TBSO
OTBS
5
OEt
CO2Et
OBn
OTBS
6 (4 eq), TASF (1.1 eq),
no solvent, 0 °C, 16 h
I
OBn
CO2Et
ref. 20
O
4
4 + 5
73%
6
TASF = tris(dimethylamino)
sulfonium difluorotrimethyl-
siliconate
OTBS
10
Scheme 1. Retrosynthetic analysis for lactones 1 and 2 (bicyclic system
numbered according to the IUPAC).
OTBS
OTBS
CO2Et
H2, Pd/C,
AcOEt
85%
lactones can be referred to ester 3 via lactone opening (with
inversion at C-4 in the case of 1), hydroxyl protection, and
reduction of the olefinic bond. Since 3 is a trans-2,3-dialkyl-
ated cyclohexanone, a disconnection to cyclohexenone 4
via a Michael addition/enolate alkylation sequence seemed
a convenient route.15,16 The necessary nucleophilic and
electrophilic synthons materialize here into ketene silyl
acetal 517 and iodide 6, respectively. Various methods for
the preparation of enone 4 in enantioenriched form have
been previously reported in the literature.18
CO2Et
O
OH
O
OBn
11
3
OTBS
1: TMSOK (10 eq), THF,
0 °C, 16 h
2: Ph3P, DIAD,
toluene, 30 min.
O
O
32% overall
O
12
OTBS
1: NaHMDS, THF,
-78 °C, 15 min.
2: TESCl, 30 min.
2. Results and discussion
O
TBAF
ref. 12
O
1
Scheme 2 depicts the details of the synthesis. Iodide 619 was
prepared from the commercially available propylene oxide
(R)-7 as the chiral starting material. Epoxide ring opening
with an allyl cuprate reagent followed by O-benzylation
gave ether 8. Hydroboration–oxidation of the latter gave
primary alcohol 9, which was transformed into 6.
3: Pd(OAc)2, MeCN, RT, 3 d
74% overall
O
13
OTBS
1. TMSOK (10 eq), THF,
0 °C, 16 h
O
2. 2,4,6-Cl3C6H2COCl,
O
iPr2NEt, DMAP
11
The Lewis acid-catalyzed Michael reaction of enol silane 5
with enone 4 has been reported to yield silyl enol ether 10
as the only product.20 Treatment of 10 with iodide 6 in the
presence of TASF provided ester 3 as the sole stereoisomer
detectable by NMR.21,22 The reaction was best carried out
with an excess of liquid iodide 6 in the absence of solvent.
The TAS enolate,21 formed as a reactive intermediate during
the reaction, is highly prone to protonation with formation of
the corresponding 3,4-disubstituted cyclohexanone (see
Section 4). Even with the outmost care in drying the solvent,
we were unable to prevent the formation of small amounts of
this side product. When using 6 as the ‘solvent’, however,
formation of the undesired ketone could be minimized.
15% overall
O
14
OTBS
1. NaHMDS, THF,
-78 °C, 15 min.
2. Et3SiCl, 30 min.
O
O
TBAF
71%
2
3. Pd(OAc)2, MeCN, RT, 3 d
70% overall
O
15
Scheme 2. Stereoselective synthesis of 1 and 2.
previous syntheses of 1 and was thus converted into the latter
compound by means of desilylation.12c
Hydrogenolytic cleavage of the benzyl group in 3 gave
hydroxy ester 11. The hydrolysis of the ethyl ester group
proved troublesome, due to the sensitivity of 11 to base-
catalyzed epimerization, as well as to silyl cleavage. Ester
cleavage took place finally in the presence of an excess of
potassium trimethylsilanolate (TMSOK)23 at 0 ꢀC. The re-
sulting crude hydroxy acid was then subjected to ring closure
by means of the Mitsunobu procedure24 to yield lactone 12.
Creation of the conjugated double bond was performed as
reported12d by means of the Saegusa method25 and gave
enone 13, which had already been obtained in one of the
In addition to 1, lactone 2, its epimer at C-4, was prepared for
structure–activity relationship studies. As before, hydroxy
ester 11 was the starting material. After ester cleavage
with TMSOK, the crude hydroxy acid was subjected to
various conditions for macrolactonization. Unfortunately,
after many failed attempts,26 only the Yamaguchi proce-
dure13 was able to provide lactone 14 in low yield. These
disappointing results are in contrast with the fair yield
(73%) obtained in the macrolactonization of the correspond-
ing hydroxy acid epimeric at C-4.12c Indeed, it has often
been shown that minor stereochemical changes exert a major

J. Garcꢀıa-Fortanet et al. / Tetrahedron 63 (2007) 12131–12137
12133
influence on the course of macrocyclization reactions,
particularly in the case of medium-sized rings.24 Finally,
compound 14 was synthetically manipulated in the same
way as above to yield 2.27,28
dissolved in dry Et2O (15 mL) and added dropwise to the
solution of the organocopper reagent. The reaction mixture
was then stirred for 4 h at the same temperature. Work-up
(Et2O) afforded a yellowish oil, which was used in crude
form in the next step.
3. Conclusions
A 60% commercial suspension of sodium hydride in mineral
oil (2.82 g, equivalent to ca. 70 mmol of NaH) was stirred
under N2 with dry hexane. The suspension was decanted
and the supernatant liquid was removed with a syringe.
This operation was repeated once more with dry THF. After
covering the solid NaH with dry THF (180 mL), a solution of
the crude alcohol from above in dry THF (25 mL) was then
added via syringe. The solution was stirred at room temper-
ature for 30 min. Benzyl bromide (7.75 mL, 65 mmol) and
tetra-n-butylammonium iodide (75 mg, ca. 0.2 mmol) were
then added to the reaction mixture, which was stirred for
16 h at room temperature. Work-up (extraction with Et2O)
and column chromatography on silica gel (hexane–EtOAc,
98:2) afforded benzyl ether 8 (6.05 g, 74% overall for the
two steps): oil; [a]D ꢁ32.9 (c 1, CHCl3); 1H NMR
(500 MHz, CDCl3) d 7.45–7.30 (5H, m), 5.87 (1H, ddt,
J¼17, 10.5, 6.5 Hz), 5.07 (1H, dq, J¼17, 2 Hz), 5.00 (1H,
br d, J¼10.5 Hz), 4.62 (1H, d, J¼11.7 Hz), 4.50 (1H, d,
J¼11.7 Hz), 3.59 (1H, apparent sext, Jw6 Hz), 2.30–2.15
(2H, m), 1.80–1.75 (1H, m), 1.65–1.55 (1H, m), 1.25 (3H,
d, J¼6 Hz); 13C NMR (125 MHz, CDCl3) d 139.1 (C),
138.6, 128.3 (ꢂ2), 127.6 (ꢂ2), 127.3, 74.2 (CH), 114.4,
70.3, 35.9, 29.8 (CH2), 19.6 (CH3); HR EIMS m/z (% rel
int.) 190.1359 (M+, 1), 91 (100). Calcd for C13H18O,
190.1357.
The total synthesis of the bioactive metabolite Sch 642305 1
has been performed in a completely stereoselective way and
with an overall yield of 12.5% based on the known chiral
enone 4 (longest linear sequence, 8 steps). This compares
well with the most recent published synthesis12d (12% over-
all yield from 4 through a partly related reaction sequence)
as well as with the three first syntheses,12a–c which are longer
(>12 steps) and/or contain unselective steps. Furthermore,
lactone 2, an epimer of 1, has been prepared for pharmaco-
logical studies.
4. Experimental
4.1. General
1H/13C NMR spectra were measured at 500/125 MHz in
CDCl3 solution at 25 ꢀC. The signals of the deuterated
solvent (CDCl3) were taken as the reference (the singlet at
1
d 7.25 for H NMR and the triplet centered at 77.00 ppm
for 13C NMR data). Carbon atom types (C, CH, CH2, CH3)
were determined with the DEPT pulse sequence. Mass spec-
tra were run by the electron impact (EIMS, 70 eV) or the fast
atom bombardment mode (FABMS, m-nitrobenzyl alcohol
matrix) on a VG AutoSpec mass spectrometer. IR data are
given only for compounds with relevant functions (OH,
C]O) and were recorded as oily films on NaCl plates
(oils) or as KBr pellets (solids). Optical rotations were mea-
sured at 25 ꢀC. Reactions which required an inert atmosphere
were carried out under N2 with flame-dried glassware. Et2O
and THF were freshly distilled from sodium/benzophenone
ketyl and transferred via syringe. Dichloromethane was
freshly distilled from CaH2. Tertiary amines were freshly
distilled from KOH. Toluene was freshly distilled from
sodium wire. Commercially available reagents were used as
received. Unless detailed otherwise, ‘work-up’ means pour-
ing the reaction mixture into brine, followed by extraction
with the solvent indicated in parenthesis. If the reaction
medium was acidic (basic), an additional washing with 5%
aq NaHCO3 (aq NH4Cl) was performed. Drying over anhy-
drous Na2SO4 and elimination of the solvent under reduced
pressure were followed by chromatography of the residue
on a silica gel column (60–200 mm) with the indicated eluent.
Where it was necessary to filter a solution through a Celite
pad, the pad was additionally washed with the same solvent
used, and the washings incorporated to the main organic
layer.
4.1.2. (R)-5-Benzyloxyhexan-1-ol (9). A solution of com-
pound 8 (3.8 g, 20 mmol) in dry THF (120 mL) was treated
at 0 ꢀC under N2 with 9-BBN (4.88 g, 40 mmol). The reac-
tion mixture was then stirred for 16 h at room temperature
and then quenched by addition of MeOH (40 mL), 6 M aq
NaOH (15 mL), and 30% H2O2 (25 mL). The resulting
mixture was then stirred at 50 ꢀC for 1 h and worked up
(extraction with Et2O). Column chromatography on silica
gel (hexanes–EtOAc, 7:3) afforded the desired alcohol 9
(3.79 g, 91%): oil; [a]D ꢁ27.3 (c 1, CHCl3); 1H NMR
(500 MHz, CDCl3) d 7.35–7.25 (5H, m), 4.58 (1H, d,
J¼12 Hz), 4.46 (1H, d, J¼12 Hz), 3.60 (2H, br t,
J¼6.5 Hz), 3.54 (1H, apparent sext, Jw6 Hz), 2.00 (1H, br
s, OH), 1.65–1.40 (6H, br m), 1.21 (3H, d, J¼6 Hz); 13C
NMR (125 MHz, CDCl3) d 139.0 (C), 128.3 (ꢂ2), 127.6
(ꢂ2), 127.4, 74.8 (CH), 70.3, 62.6, 36.3, 32.7, 21.7 (CH2),
19.5 (CH3); IR nmax 3380 (br, OH) cmꢁ1; HR EIMS m/z (%
rel int.) 208.1462 (M+, 1), 107 (20), 91 (100). Calcd for
C13H20O2, 208.1463.
4.1.3. (R)-2-Benzyloxy-6-iodohexane (6). Alcohol 9 (2.08 g,
10 mmol) was dissolved under N2 in dry CH2Cl2 (40 mL),
cooled to 0 ꢀC and treated sequentially with imidazole
(2.72 g, 40 mmol), triphenylphosphine (2.75 g, 10.5 mmol),
and I2 (3.04 g, 12 mmol). The mixture was stirred at 0 ꢀC
for 5 min and then at room temperature for 3 h. Work-up
(extraction with CH2Cl2) and column chromatography on
silica gel (hexanes–EtOAc, 9:1) afforded iodide 6 (2.86 g,
90%): oil; [a]D ꢁ21.9 (c 0.85, CHCl3); 1H NMR (500 MHz,
CDCl3) d 7.40–7.25 (5H, m), 4.60 (1H, d, J¼11.7 Hz), 4.48
(1H, d, J¼11.7 Hz), 3.57 (1H, apparent sext, Jw6 Hz), 3.20
4.1.1. (R)-5-Benzyloxyhex-1-ene (8). CuI (1.14 g, 6 mmol)
was gently heated in vacuo under N2 until the solid turned
light yellow. The flask was then cooled to ꢁ30 ꢀC, followed
by addition of dry Et2O (125 mL). A 1 M solution of allyl-
magnesium bromide in Et2O (60 mL, 60 mmol) was then
slowly added dropwise via syringe. The mixture was stirred
for 5 min at ꢁ30 ꢀC. Epoxide (R)-7 (2.5 g, 43 mmol) was

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J. Garcꢀıa-Fortanet et al. / Tetrahedron 63 (2007) 12131–12137
(2H, t, J¼7 Hz), 1.85 (2H, apparent quint, Jw7 Hz), 1.65–1.45
(4H, br m), 1.23 (3H, d, J¼6 Hz); 13C NMR (125 MHz,
CDCl3) d 139.0 (C), 128.3 (ꢂ2), 127.6 (ꢂ2), 127.4, 74.4
(CH), 70.3, 35.5, 33.5, 26.5, 6.9 (CH2), 19.5 (CH3); HR
EIMS m/z (% rel int.) 318.0492 (M+, 1), 135 (17), 91 (100).
Calcd for C13H19IO, 318.0480.
then filtered through Celite. Solvent removal in vacuo and
column chromatography on silica gel (hexanes–EtOAc, 7:3)
gave alcohol 11 (493 mg, 85%): oil; [a]D +19.3 (c 0.6,
1
CHCl3); H NMR (500 MHz, CDCl3) d 4.13 (1H, m), 4.10
(2H, q, J¼7 Hz), 3.74 (1H, apparent sext, Jw6 Hz), 2.59
(1H, td, J¼13, 6 Hz), 2.52 (1H, dd, J¼16.5, 9 Hz), 2.42
(1H, m), 2.30–2.15 (3H, m), 1.97 (1H, m), 1.80 (1H, m),
1.70 (1H, br s, OH), 1.55–1.50 (2H, m), 1.45–1.35 (3H, m),
1.30–1.20 (3H, m), 1.23 (3H, t, J¼7 Hz), 1.13 (3H, d,
J¼6 Hz), 0.90 (9H, s), 0.06 (3H, s), 0.04 (3H, s); 13C NMR
(125 MHz) d 211.6, 172.7, 18.1 (C), 67.8, 67.5, 49.4, 43.7
(CH), 60.4, 39.0, 35.9, 34.4, 32.5, 26.7, 26.3, 25.9 (CH2),
25.8 (ꢂ3), 23.4, 14.2, ꢁ4.5, ꢁ5.3 (CH3); IR nmax 3450 (br,
OH), 1733 (ester C]O), 1713 (ketone C]O) cmꢁ1; HR
4.1.4. Ethyl 2-[(1R,2R,6S)-2-{(R)-5-benzyloxyhexyl}-6-
(tert-butyldimethylsilyloxy)-3-oxocyclohexyl]acetate (3).
Silyl enol ether 1020 (857 mg, 2 mmol) was mixed under
N2 with iodide 6 (2.54 g, 8 mmol) and treated with TASF
(606 mg, 2.2 mmol). The oily mixture was stirred at 0 ꢀC
for 16 h and then worked up. Column chromatography on sil-
ica gel (hexanes–EtOAc, 98:2/9:1) gave ketone 3 (737 mg,
73%) as a single stereoisomer: oil; [a]D +14.1 (c 1.4, CHCl3);
1H NMR (500 MHz, CDCl3) d 7.35–7.25 (5H, m), 4.56 (1H,
d, J¼11.7 Hz), 4.45 (1H, d, J¼11.7 Hz), 4.16 (1H, m), 4.13
(2H, q, J¼7 Hz), 3.50 (1H, apparent sext, Jw6 Hz), 2.62
(1H, td, J¼13, 6 Hz), 2.55 (1H, dd, J¼16.5, 9 Hz), 2.45
(1H, m), 2.35–2.20 (3H, m), 2.00 (1H, m), 1.85 (1H, m),
1.65–1.50 (4H, m), 1.50–1.40 (2H, m), 1.35–1.25 (2H, m),
1.26 (3H, t, J¼7 Hz), 1.17 (3H, d, J¼6 Hz), 0.93 (9H, s),
0.09 (3H, s), 0.08 (3H, s); 13C NMR (125 MHz) d 211.6,
172.7, 139.2, 18.1 (C), 128.3 (ꢂ2), 127.6 (ꢂ2), 127.3,
74.9, 67.5, 49.5, 43.9 (CH), 70.3, 60.5, 36.5, 36.0, 34.4,
32.6, 27.0, 26.5 (one methylene signal is missing, most likely
overlapped by the intense tert-butyl signal at 25.9 ppm)
(CH2), 25.9 (ꢂ3), 19.6, 14.2, ꢁ4.4, ꢁ5.3 (CH3); IR nmax
1733 (ester C]O), 1714 (ketone C]O) cmꢁ1; HR EIMS
t
EIMS m/z (% rel int.) 399.2568 (M+ꢁMe, 3), 357 (M+ꢁ Bu,
98), 339 (100). Calcd for C22H42O5SiꢁMe, 399.2566.
4.1.6. (4S,8aR,12S,12aR)-12-(tert-Butyldimethylsilyl-
oxy)-4-methyloctahydro-1H-benzo[d]oxecine-2,9(10H,-
11H)-dione (12). A solution of alcohol 11 (415 mg, 1 mmol)
was dissolved under N2 in dry THF (30 mL), cooled to 0 ꢀC,
and treated with TMSOK (1.28 g, 10 mmol). The mixture
was stirred for 16 h at room temperature. After this time,
a 0.5 M aq solution of citric acid (30 mL) was added, and
the stirring was continued for 20 min. Work-up (extraction
with EtOAc) provided a hydroxy acid, which was used in
crude form in the next step.
A solution of Ph3P (1.31 g, 5 mmol) in dry toluene (175 mL)
was treated dropwise under N2 with DIAD (990 mL,
5.02 mmol). After stirring at room temperature for 20 min,
the crude hydroxy acid from above was dissolved in dry
toluene (15 mL) and added to the mixture, which was subse-
quently stirred for 30 min. Work-up (extraction with EtOAc)
and column chromatography on silica gel (hexanes–EtOAc,
8:2) furnished lactone 12 (118 mg, 32% overall for the two
steps) as an amorphous solid: [a]D ꢁ21.2 (c 1, CHCl3),
t
m/z (% rel int.) 504.3250 (M+, 1), 447 (M+ꢁ Bu, 18), 91
(100). Calcd for C29H48O5Si, 504.3271.
Further eluted from the column were 145 mg (18%) of
ketone i, formed through proton transfer to the intermediate
TAS enolate.
OTBS
lit.12d [a]D ꢁ22.2 (c 0.37, CHCl3); H NMR (500 MHz,
CO2Et
1
CDCl3) d 5.05 (1H, m), 4.02 (1H, m), 2.66 (1H, td,
J¼14.5, 6.5 Hz), 2.60–2.45 (4H, br m), 2.20 (1H, m),
2.15–1.95 (3H, m), 1.85–1.75 (3H, m), 1.35–1.20 (4H, br
m), 1.25 (3H, d, J¼6 Hz), 0.91 (9H, s), 0.10 (3H, s), 0.08
(3H, s); 13C NMR (125 MHz) d 211.7, 171.6, 18.3 (C),
73.0, 71.0, 50.1, 40.3 (CH), 40.9, 35.1, 32.0, 29.7, 23.2,
21.6, 18.1 (CH2), 25.9 (ꢂ3), 23.0, ꢁ4.4, ꢁ4.9 (CH3); IR
nmax 1723 (br, ketone and lactone C]O) cmꢁ1; HR EIMS
i
O
4.1.4.1. Ethyl 2-[(1S,2S)-2-(tert-butyldimethylsilyl-
oxy)-5-oxo-cyclohexyl]acetate (i). Formed as a side prod-
uct during the alkylation of 10 with 6 (see main text): oil;
1
[a]D +24.5 (c 1.06, CHCl3); H NMR (500 MHz, CDCl3)
d 4.00 (3H, m), 2.50 (1H, td, J¼14.2, 6.3 Hz), 2.40–2.30
(2H, m), 2.25 (1H, m), 2.10–2.00 (3H, br m), 1.95 (1H, m),
1.70 (1H, br t, Jw13 Hz), 1.13 (3H, t, J¼7 Hz), 0.82 (9H, s),
0.00 (3H, s), ꢁ0.02 (3H, s); 13C NMR (125 MHz, CDCl3)
d 209.7, 171.6, 17.8 (C), 67.1, 39.7 (CH), 60.1, 41.9, 36.9,
35.2, 32.4 (CH2), 25.6 (ꢂ3), 14.0, ꢁ4.8, ꢁ5.5 (CH3); IR
nmax 1733 (ester C]O), 1717 (ketone C]O) cmꢁ1; HR
EIMS m/z (% rel int.) 299.1667 (M+ꢁMe, 1), 257
t
m/z (% rel int.) 353.2137 (M+ꢁMe, 3), 311 (M+ꢁ Bu,
100), 219 (30). Calcd for C20H36O4SiꢁMe, 353.2148.
4.1.7. (4S,8aR,12S,12aR)-12-(tert-Butyldimethylsilyl-
oxy)-4-methyl-4,5,6,7,8,8a-hexahydro-1H-benzo[d]-
oxecine-2,9(12H,12aH)-dione (13). A solution of lactone
12 (92 mg, 0.25 mmol) was dissolved under N2 in dry
THF (1.5 mL), cooled to ꢁ78 ꢀC, and treated at this temper-
ature with NaHMDS (300 mL of a 1 M solution in THF,
0.3 mmol). The mixture was further stirred for 15 min. Tri-
ethylsilyl chloride (50 mg, 0.33 mmol) dissolved in dry THF
(500 mL) was then added, and the stirring was continued at
the same temperature for 30 min. The reaction mixture
was then filtered through a pad of silica gel and the pad
was eluted with hexanes–EtOAc (8:2). After removal of all
volatiles under reduced pressure, a silyl enol ether was
obtained and used in crude form in the next step.
t
(M+ꢁ Bu, 65), 75 (100). Calcd for C16H30O4SiꢁMe,
299.1678.
4.1.5. Ethyl 2-[(1R,2R,6S)-6-(tert-butyldimethylsilyloxy)-
2-{(R)-5-hydroxyhexyl}-3-oxocyclohexyl]acetate (11).
Pd/C (10%, 900 mg) was suspended in dry EtOAc (25 mL)
under an H2 atmosphere and stirred for 15 min. Benzyl ether
3 (707 mg, 1.4 mmol) dissolved in EtOAc (5 mL) was then
added via syringe. The mixture was stirred at room temper-
ature and ambient pressure for 3 h (TLC monitoring!), and

J. Garcꢀıa-Fortanet et al. / Tetrahedron 63 (2007) 12131–12137
12135
The crude compound from above was dissolved under N2 in
dry, degassed MeCN (10 mL). After addition of Pd(OAc)2
(280 mg, 1.25 mmol), the mixture was stirred at room tem-
perature until consumption of the starting material (about
3 d, TLC monitoring). The reaction mixture was then filtered
through Celite, and the filter was further washed with
EtOAc. Removal of all volatiles under reduced pressure
and column chromatography on silica gel (hexanes–EtOAc,
9:1) afforded lactone 13 (68 mg, 74% overall for the two
steps) as a white solid: 103–105 ꢀC, lit.12c mp 104–106 ꢀC;
[a]D +53.2 (c 1.1, CHCl3), lit.12c [a]D +56 (c 1, CHCl3),
was treated with TMSOK as described above for the synthe-
sis of 12. This gave a crude hydroxy acid, used in the next
step.
A solution of the crude hydroxy acid in dry CH2Cl2 (25 mL)
was treated dropwise under N2 at room temperature with
N,N-diisopropyl ethylamine (130 mL, 0.75 mmol) and then
with 2,4,6-trichlorobenzoyl chloride (78 mL, 0.5 mmol).
After stirring at room temperature for 1 h, DMAP (30 mg,
0.25 mmol) was added to the mixture, which was subse-
quently stirred for 2 h. Work-up (extraction with CH2Cl2)
and column chromatography on silica gel (hexanes–EtOAc,
9:1) provided lactone 14 (14 mg, 15% overall) as an
oil: [a]D +16.1 (c 0.35, CHCl3); 1H NMR (500 MHz,
CDCl3) d 4.96 (1H, m), 4.06 (1H, m), 2.74 (1H, br d,
J¼11 Hz), 2.64 (1H, td, J¼14, 6.5 Hz), 2.60 (1H, m),
2.45 (1H, dd, J¼12, 10.5 Hz), 2.30–2.20 (2H, br m),
2.10–1.80 (3H, br m), 1.75–1.45 (6H, br m), 1.28 (3H, d,
J¼6 Hz), 1.11 (1H, m), 0.93 (9H, s), 0.10 (6H, s); 13C
NMR (125 MHz) d 211.3, 174.5, 18.1 (C), 72.7, 72.5,
49.9, 40.9 (CH), 45.9, 35.2, 32.5, 31.5, 31.0, 24.0, 20.9
(CH2), 25.9 (ꢂ3), 22.6, ꢁ4.3, ꢁ4.8 (CH3); IR nmax 1727
(ketone and lactone C]O) cmꢁ1; HR EIMS m/z (% rel
1
lit.12d [a]D +52.1 (c 0.48, CHCl3); H NMR (500 MHz,
CDCl3) d 6.85 (1H, dd, J¼9.9, 5.5 Hz), 5.95 (1H, d, J¼
9.9 Hz), 5.08 (1H, m), 4.22 (1H, dd, J¼5.2, 3.2 Hz), 2.81
(1H, tt, J¼11, 2.5 Hz), 2.72 (1H, dt, J¼11, 3.5 Hz), 2.57
(1H, dd, J¼17, 11 Hz), 2.48 (1H, dd, J¼17, 2 Hz), 2.25–
2.05 (2H, m), 1.80 (1H, m), 1.60 (1H, m), 1.40–1.20 (3H,
br m), 1.26 (3H, d, J¼6.5 Hz), 1.10 (1H, ddd, J¼14.5,
10.5, 3 Hz), 0.88 (9H, s), 0.10 (3H, s), 0.08 (3H, s); 13C
NMR (125 MHz) d 200.4, 171.5, 18.3 (C), 146.7, 130.1,
73.1, 67.6, 46.6, 37.3 (CH), 39.3, 29.7, 23.1, 22.9, 21.6
(CH2), 25.8 (ꢂ3), 18.1, ꢁ3.9, ꢁ4.8 (CH3); IR nmax 1726 (lac-
tone C]O), 1680 (ketone C]O) cmꢁ1; HR EIMS m/z (% rel
t
t
int.) 351.2005 (M+ꢁMe, 1), 309 (M+ꢁ Bu, 20), 117 (100), 75
int.) 353.2145 (M+ꢁMe, 2), 311 (M+ꢁ Bu, 100), 219 (30),
(46). Calcd for C20H34O4SiꢁMe, 351.1991.
159 (100), 125 (30), 75 (62). Calcd for C20H36O4SiꢁMe,
353.1248.
4.1.8. (4S,8aR,12S,12aR)-12-Hydroxy-4-methyl-4,5,6,7,-
8,8a-hexahydro-1H-benzo[d]oxecine-2,9(12H,12aH)-
dione (Sch 642305, 1). Desilylation of lactone 13 was
performed as reported.12 This gave lactone 1: white solid,
mp 149–151 ꢀC (lit.9 for natural Sch 642305, mp 143–
145 ꢀC, lit.12b for synthetic Sch 642305, mp 142–144 ꢀC,
lit.12c for synthetic Sch 642305, mp 151–153 ꢀC); [a]D +59
(c 0.3, CHCl3), [a]D +75.3 (c 0.11, MeOH) {lit.9 for natural
Sch 642305, [a]D +67.44 (c 0.5, MeOH), lit.12a for syn-
thetic Sch 642305, [a]D +71 (c 0.31, MeOH), lit.12b for syn-
thetic Sch 642305, [a]D +62.4 (c 0.87, MeOH), lit.12c for
synthetic Sch 642305, [a]D +74 (c 0.50, MeOH), lit.12d
for synthetic Sch 642305, [a]D +76.1 (c 0.92, MeOH)}.
1H NMR (500 MHz, CD3OD) d 7.05 (1H, dd, J¼9.8,
5.5 Hz), 5.98 (1H, d, J¼9.8 Hz), 5.07 (1H, m), 4.23 (1H,
dd, J¼5.5, 3.8 Hz), 2.84 (1H, tt, J¼11.5, 3 Hz), 2.70 (1H,
dd, J¼17, 2.5 Hz), 2.68 (1H, dt, J¼11, 4 Hz), 2.56
(1H, dd, J¼17, 11.5 Hz), 2.25–2.10 (2H, m), 1.87 (1H,
m), 1.60 (1H, m), 1.45–1.20 (3H, br m), 1.29 (3H, d,
4.1.10. (4R,8aR,12S,12aR)-12-(tert-Butyldimethylsilyl-
oxy)-4-methyl-4,5,6,7,8,8a-hexahydro-1H-benzo[d]-
oxecine-2,9(12H,12aH)-dione (15). A solution of lactone
14 (11 mg, 0.03 mmol) was subjected to the same reaction
sequence and conditions as those used in the conversion of
12 into 13. This furnished lactone 15 (8 mg, 70% overall)
as an oil: [a]D +100.9 (c 0.22, CHCl3); 1H NMR
(500 MHz, CDCl3) d 6.78 (1H, dd, J¼9.9, 5.6 Hz), 5.95
(1H, d, J¼9.9 Hz), 5.00 (1H, apparent quint, Jw7 Hz), 4.26
(1H, dd, J¼5.5, 1.8 Hz), 2.92 (1H, m), 2.55–2.45 (2H, m),
2.27 (1H, m), 2.05–1.80 (4H, br m), 1.65–1.45 (3H, br m),
1.27 (3H, d, J¼6.5 Hz), 1.00 (1H, m), 0.89 (9H, s), 0.12
(3H, s), 0.09 (3H, s); 13C NMR (125 MHz) d 200.7, 174.6,
18.1 (C), 145.8, 129.8, 72.9, 69.3, 46.7, 41.6 (CH), 39.7,
31.3, 30.3, 30.2, 24.8, 21.6 (CH2), 25.8 (ꢂ3), 21.4, ꢁ3.8,
ꢁ4.8 (CH3); IR nmax 1725 (lactone C]O), 1685 (ketone
C]O) cmꢁ1; HR EIMS m/z (% rel int.) 351.1968
t
(M+ꢁMe, 2), 309 (M+ꢁ Bu, 100), 189 (60), 117 (46). Calcd
1
J¼6.5 Hz), 1.12 (1H, ddd, J¼14.5, 10.5, 3 Hz); H NMR
for C20H34O4SiꢁMe, 351.1991.
(500 MHz, CDCl3) d 6.96 (1H, dd, J¼9.9, 5.7 Hz), 6.03
(1H, d, J¼9.9 Hz), 5.10 (1H, m), 4.30 (1H, dd, J¼5.5,
3.6 Hz), 2.82 (1H, m), 2.70–2.65 (3H, m), 2.20–2.05 (3H,
m), 1.80 (1H, m), 1.64 (1H, m), 1.40–1.15 (4H, br m),
1.27 (3H, d, J¼6.5 Hz); 13C NMR (125 MHz, CD3OD)
d 202.3, 173.7 (C), 149.5, 130.6, 74.7, 67.1, 47.8, 37.8
(CH), 39.8, 30.9, 24.2, 24.1, 22.6 (CH2), 18.6 (CH3); 13C
NMR (125 MHz, CDCl3) d 199.9, 171.7 (C), 145.9,
130.7, 73.4, 67.0, 45.8, 36.8 (CH), 38.7, 30.2, 22.9, 22.7,
22.2 (CH2), 18.5 (CH3). IR nmax 3450 (br, OH), 1723 (lac-
tone C]O), 1677 (ketone C]O) cmꢁ1; HR EIMS m/z (%
rel int.) 252.1360 (M+, 1), 152 (65), 107 (40), 84 (82), 82
(100), 55 (91). Calcd for C14H20O4, 252.1361.
4.1.11. (4R,8aR,12S,12aR)-12-Hydroxy-4-methyl-
4,5,6,7,8,8a-hexahydro-1H-benzo[d]oxecine-2,9(12H,12aH)-
dione (2). Lactone 15 (7 mg, 0.02 mmol) was desilylated un-
der the same conditions reported for the conversion of 13
into 1. This gave 2 (3.5 mg, 71%): white solid, mp 125–
1
127 ꢀC; [a]D +67.1 (c 0.3, CHCl3); H NMR (500 MHz,
CDCl3) d 6.89 (1H, dd, J¼9.9, 5.7 Hz), 6.02 (1H, d,
J¼9.9 Hz), 5.00 (1H, m), 4.32 (1H, m), 2.81 (1H, dt,
J¼11.5, 3.7 Hz), 2.65–2.55 (2H, m), 2.40 (1H, d,
J¼12 Hz), 2.05 (1H, m), 1.90–1.80 (2H, m), 1.70–1.50
(5H, br m), 1.26 (3H, d, J¼6.5 Hz), 1.05 (1H, m); 13C
NMR (125 MHz) d 200.0, 174.3 (C), 145.0, 130.7, 73.0,
68.6, 46.5, 39.1 (CH), 40.9, 31.2, 29.7, 24.6, 21.7 (CH2),
21.2 (CH3); IR nmax 3420 (br, OH), 1724 (lactone C]O),
1680 (ketone C]O) cmꢁ1; HR EIMS m/z (% rel int.)
252.1358 (M+, 1), 234 (M+ꢁH2O, 3), 152 (100). Calcd for
4.1.9. (4R,8aR,12S,12aR)-12-(tert-Butyldimethylsilyl-
oxy)-4-methyloctahydro-1H-benzo[d]oxecine-2,9(10H,11H)-
dione (14). A solution of alcohol 11 (104 mg, 0.25 mmol)

12136
J. Garcꢀıa-Fortanet et al. / Tetrahedron 63 (2007) 12131–12137
14. (a) Maier, M. E. Angew. Chem., Int. Ed. 2000, 39, 2073–2077;
(b) Prunet, J. Angew. Chem., Int. Ed. 2003, 42, 2826–2830.
15. (a) Chapdelaine, M. J.; Hulce, M. Org. React. 1990, 38, 225–
653; (b) For further examples of sequential Michael addition/
a-alkylation processes, see: Tanaka, J.; Kanemasa, S.;
Ninomiya, Y.; Tsuge, O. Bull. Chem. Soc. Jpn. 1990, 63,
476–483; Enders, D.; Bettray, W.; Raabe, G.; Runsink, J.
Synthesis 1994, 1322–1326.
16. For the use of sequential reactions in synthesis, see, for exam-
ple: (a) Bunce, R. A. Tetrahedron 1995, 51, 13103–13159; (b)
Tietze, L. F. Chem. Rev. 1996, 96, 115–136; (c) Rodriguez, J.
Synlett 1999, 505–518; (d) Gorobets, E. V.; Miftakhov,
M. S.; Valeev, F. A. Russ. Chem. Rev. 2000, 69, 1001–1019;
(e) Chapman, C. J.; Frost, C. G. Synthesis 2007, 1–21.
C14H20O4, 252.1361. Anal. Calcd: C, 66.65; H, 7.99. Found:
C, 66.80; H, 8.10.
Acknowledgements
Financial support has been granted by the Spanish Ministry
of Education and Science (projects CTQ2005-06688-C02-
01 and CTQ2005-06688-C02-02), and by the Generalitat
Valenciana (projects ACOMP07-023 and ACOMP07-025).
J.G.-F. thanks the Universitat Jaume I for a postdoctoral
fellowship. The authors further thank Prof. G. Mehta from
the Department of Organic Chemistry at the Indian Institute
of Science, Bangalore, India, for his kind sending of NMR
spectra of his synthetic 2 in both CD3OD and CDCl3.
17. Kita, Y.; Segawa, J.; Haruta, J.; Yasuda, H.; Tamura, Y.
J. Chem. Soc., Perkin Trans. 1 1982, 1099–1104.
18. For the preparation of optically enriched 4-hydroxycyclo-
hex-2-enone and derivatives thereof, see: (a) Dumortier, L.;
Liu, P.; Dobbelaere, S.; Van der Eycken, J.; Vandewalle, M.
Synlett 1992, 243–245; (b) Barros, M. T.; Maycock, C. D.;
Ventura, M. R. J. Chem. Soc., Perkin Trans. 1 2001, 166–
173; (c) Yu, L.; Zhang, R.; Wang, Z. J. Chem. Soc., Perkin
Trans. 1 2001, 2958–2961; (d) Evarts, J. B., Jr.; Fuchs, P. L.
Tetrahedron Lett. 2001, 42, 3673–3675; (e) Nising, C. F.;
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J. Garcꢀıa-Fortanet et al. / Tetrahedron 63 (2007) 12131–12137
12137
26. Assayed conditions: (a) DCC, DMAP, CH2Cl2 (Neises, B.;
Steglich, W. Angew. Chem., Int. Ed. Engl. 1978, 90, 556–557):
no reaction took place after 4 days at room tempera-
ture, whereas rapid decomposition was observed at reflux;
(b) (PyS)2, PPh3, toluene (Corey, E. J.; Nicolaou, K. C. J.
Am. Chem. Soc. 1974, 96, 5614–5616): no reaction took place
at room temperature and slow decomposition was observed at
reflux. Addition of Et3N (Hansen, T. V.; Stenstrom, Y.
Tetrahedron: Asymmetry 2001, 12, 1407–1409) only acceler-
ated the decomposition; (c) The Yamaguchi method under
the standard conditions13 at either 0 ꢀC or room temperature
gave only decomposition, as did the conditions reported for
compound 1 itself.12c Only the conditions described in
Section 4 gave isolable amounts of 2.
27. Compound 2 has been reported to be formed during attempts at
synthesizing 1: Mehta, G.; Shinde, H. M. Tetrahedron Lett.
2005, 46, 6633–6636.
28. The NMR spectra of lactone 2 in Ref. 27 were measured
in CD3OD but erroneously reported in the paper as having been
determined in CDCl3 (personal communication of Prof. G.
Mehta, see: Acknowledgements). A comparison of the NMR
data in CDCl3 has confirmed the identity of his and our product.