Asymmetric synthesis of cis-7-methoxycalamenene via the intramolecular buchner reaction of an α-diazoketone

Article abstract of DOI:10.1021/jo202499j

The asymmetric synthesis of cis-7-methoxycalamenene 1 has been accomplished using the intramolecular Buchner reaction of α-diazoketone 7 as the key step in the synthetic route. Upon reduction of the equilibrating azulenone structure 8, the resulting azulenol 9 rearranges to dihydronaphthalene 10 containing the 6,6-membered bicyclic ring system characteristic of 1, by means of an acid-catalyzed aromatization process. Transformation of 10 to 1 is accomplished through a three-step reaction sequence.

Full text of DOI:10.1021/jo202499j

Note
pubs.acs.org/joc
Asymmetric Synthesis of cis-7-Methoxycalamenene via the
Intramolecular Buchner Reaction of an α-Diazoketone
Paul A. McDowell,† David A. Foley,† Patrick O’Leary,†,§ Alan Ford,† and Anita R. Maguire*,‡
†Department of Chemistry, Analytical and Biological Chemistry Research Facility, University College Cork, Cork, Ireland
‡Department of Chemistry & School of Pharmacy, Analytical and Biological Chemistry Research Facility,
University College Cork, Cork, Ireland
S
* Supporting Information
ABSTRACT: The asymmetric synthesis of cis-7-methoxyca-
lamenene 1 has been accomplished using the intramolecular
Buchner reaction of α-diazoketone 7 as the key step in the
synthetic route. Upon reduction of the equilibrating azulenone
structure 8, the resulting azulenol 9 rearranges to dihydro-
naphthalene 10 containing the 6,6-membered bicyclic ring
system characteristic of 1, by means of an acid-catalyzed
aromatization process. Transformation of 10 to 1 is
accomplished through a three-step reaction sequence.
he intramolecular version of the transition-metal-catalyzed
Buchner reaction of α-diazoketones was first reported by
sesquiterpenoid family are found as natural products in the foliage of
Cupressus bakeri, a species of cypress native to the United States.
The isolation of this sequiterpene family from the Madagascan
shrub, Tarenna madagascariensis, has been reported.11 The
isolation of 1 in particular from a cell culture of liverwort has
been documented.12 The synthesis of 1 has been described in the
literature as a single enantiomer,13 while other synthetic routes have
also been documented involving the preparation of 1 as a racemic
mixture of cis and trans isomers14 and as the individual cis and trans
isomers in racemic form.15
The enantioenriched dihydrocinnamic acid 6 was synthesized
from 5, which had been described by Hruby et al.16−18 as part of
their synthesis of novel amino acids (Scheme 1). Hydrolysis of the
β-substituted acyl oxazolidinone 5 following the procedure
described by Evans et al.19 afforded acid 6 with an enantiopurity
of 96% ee determined by chiral HPLC (Scheme 1).
The α-diazocarbonyl precursor 7 was generated in two
synthetic steps from 6 via initial acid chloride formation
followed by treatment with diazoethane.20 Cyclization of 7 to
azulenone 8 was performed via the standard procedure for this
transformation2−6 (Scheme 2). The cyclization is found to be
rapid, with reaction completion obtained once the diazoketone
addition is complete. The synthesis of the corresponding racemic
series was conducted in parallel with the enantiopure series as
shown in Scheme 2. The synthesis of the racemic dihydrocinnamic
acid ( )-6 and subsequent transformation to the corresponding
azulenone ( )-8 have been previously described by our research
team.4
T
Julia et al.1 This process, involving the rhodium-catalyzed
reaction of an α-diazoketone and addition of the resulting
carbenoid to an aromatic system has been extensively studied
over many years.2−6 Many aspects of this transformation have
been investigated, including diastereo-, regio-, and enantiose-
lectivity.2−6 The proposed mechanism for the cyclization
involves initial cyclopropanation of the aromatic ring to form
the norcaradiene tautomer, which is in dynamic equilibrium
with the cycloheptatriene tautomer by means of a reversible
electrocyclic ring-opening process.7,8 Upon ring-opening, the
relative stereochemistry between the substituent at the C(3)
position and the bridgehead methyl group remains intact.
Our interest in the intramolecular Buchner process has
extended to the synthesis of compounds possessing the bicyclo-
[5.3.0]decane skeleton, characteristic of many sesquiterpenoid
natural products, from readily available dihydrocinnamic acid
precursors. Synthetic approaches to this ring system have been
extensively reviewed.9,10 The asymmetric synthesis of cis-7-methoxy-
calamenene 1 using the intramolecular Buchner process is
outlined.
cis-7-Methoxycalamenene 1, a cadinane sesquiterpene, contains
Received: December 5, 2011
Published: January 19, 2012
the bicyclo[4.4.0]decane carbon framework. The cis calamenene
© 2012 American Chemical Society
2035
dx.doi.org/10.1021/jo202499j | J. Org. Chem. 2012, 77, 2035−2040

The Journal of Organic Chemistry
Note
the trans isomer predominating, whereby the substituent at the
C(3) position and the bridgehead methyl group are trans to each
other. Although the cyclization proceeds with high diastereo-
control, equilibration of the trans and cis isomers initiated by
the presence of the methoxy group takes place,4 resulting in the
formation of the trans and cis isomers in an approximate ratio
of 70:30.
Scheme 1. Synthesis of 6
Reduction of 8 to azulenol 9 was conducted as illustrated in
Scheme 3. The azulenol 9 exists as an inseparable mixture of
diastereomers, the major diastereomer 9a being where the
hydroxyl substituent and the bridgehead methyl group are trans
to each other. This major diastereomer, 9a, is derived from the
trans azulenone isomer 8a. The stereochemistry of the minor
diastereomer 9b has not been determined. It is envisaged that
9b could either be the epimer of 9a at C(1) or that formation
of 9b is due to reduction of the cis azulenone isomer 8b. Upon
reduction, the complex dynamic nature of the bicyclic system is
greatly simplified. The two diastereomers 9a/9b can no longer
interconvert, and even though both exist in dynamic equilibrium
with their norcaradiene tautomers, the cycloheptatriene tautomer
predominates to a very large extent.
(a) (COCl)2, Et2O, 0 °C to rt, 64%. (b) 3, n-BuLi, THF, −78 to 0 °C,
72%. (c) p-MeOPhMgBr, CuBr·SMe2, THF, −15 °C to rt, 68%. (d)
30% H2O2, LiOH·H2O, THF/H2O, 0 °C, 6, 84%, ee = 96%.
On exposure to p-toluenesulfonic acid, azulenol 9 is found to
undergo an interesting rearrangement resulting in the formation of
dihydronaphthalenes 10 and 11. The crude mixture of 10 and 11
was then conveniently methylated in situ, forming the methoxy
dihydronaphthalene 10 (Scheme 3), which has been reported by
Gatti et al. as an intermediate in the latter stages of their asymmetric
synthesis of 1.13 While the synthesis undertaken clearly leads to
(S)-10, it is worth noting that the sign of the specific rotation is
opposite to that described by Gatti et al. for the same com-
pound {[α]D20 = +68.45 (c 1.0, CHCl3); lit.13 [α]D20 = −40.5
(c 1.03, CHCl3)}.13 However, transformation of 10 through to
1 proceeded as expected giving (−)-1, confirming the absolute
stereochemistry of the intermediate and the final product.
The formation of dihydronaphthalenes from azulenol precursors
has not previously been described in the literature. Although 9 exists
predominantly as the cycloheptatriene form, the aromatization
process presumably takes place via the minor norcaradiene tautomer
(Scheme 4). Protonation of 9 followed by loss of water leads to a
cyclopropane-stabilized carbocation, which undergoes ring-opening
to give the cationic spiro intermediate 12, enabled by the presence
of the electron donating methoxy substituent. Ring expansion
of 12 to the bicyclic cationic intermediate 13 is followed by
rearomatization, giving 10. The intermediate 12 can also undergo
Scheme 2. Synthesis of 8
(a) (COCl)2, Et2O, 0 °C to rt. (b) CH3CHN2, Et2O, −20 °C to rt,
65% in two steps. (c) Rh2(OAc)4, CH2Cl2, reflux, 8, 84%.
In general, the cyclization of related α-diazoketones with unsub-
stituted phenyl rings are found to be highly diastereoselective with
Scheme 3. Synthesis of 10
(a) NaBH4, EtOH, 0 °C to rt, 95%. (b) p-TsOH·H2O, toluene, rt. (c) CH3I, K2CO3, acetone, reflux, 10, 53% in two steps.
2036
dx.doi.org/10.1021/jo202499j | J. Org. Chem. 2012, 77, 2035−2040

The Journal of Organic Chemistry
Note
10 over palladium on carbon gave the cis diastereomer 15. The
formyl group was regioselectively introduced to the aromatic ring
using Vilsmeier chemistry followed by reduction of the resulting
aldehyde 16 to the final product 1 over palladium on carbon. The
observed specific rotation of [α]D20 = −32.0 (c 1.0, CHCl3) was in
good agreement with the corresponding value of [α]D20 = −30.3
(c 0.92, CHCl3) reported in the literature.13 The enantiopurity of
(−)-1 was determined to be 95% ee by chiral HPLC.
Scheme 4. Formation of Dihydronaphthalenes 10 and 11
from 9
The synthetic plan outlined above involves six steps from the
enantiopure dihydrocinnamic acid precursor 6 to the methoxy
dihydronaphthalene 10 in a yield of 17%, a more concise
synthesis than that previously reported.13 The overall yield
obtained for (−)-1 of 7% from (S)-6 also compares favorably
with the corresponding yield of 3% in the synthesis described
by Gatti et al.13 All reaction steps in this work are simple and
proceed with good yields. The work outlined above demonstrates
the synthetic utility of the intramolecular Buchner cyclization of
α-diazoketones in the area of sesquiterpenoid natural product
synthesis. The methoxy dihydronaphthalene 10 has also been used
as an intermediate in a number of other syntheses.21−23 Hence, the
synthesis of (S)-10 via this methodology could also be used as a
route to other structurally related sesquiterpenes.
EXPERIMENTAL SECTION
■
demethylation or exchange with water, forming the spiro dienone
14, which can rearrange and rearomatize as before, yielding 11. This
demethylation occurs in competition with the skeletal rearrange-
ment resulting in the formation of both products 10 and 11.
Thus, while the intramolecular Buchner reaction of
α-diazoketones provides a facile route to the bicyclo[5.3.0]decane
ring system characteristic of many sesquiterpenoid natural prod-
ucts, this transformation also allows access to the bicyclo[4.4.0]-
decane skeleton, characteristic of 1, via the same azulenone inter-
mediate 8. The reduction of 8 and subsequent acid-catalyzed
aromatization of 9 forming dihydronaphthalenes 10 and 11 is a
novel and convenient way of obtaining a 6,6-membered fused
ring system from the corresponding 7,5-membered bicyclic
structure. The tautomerisation between the norcaradiene and
cycloheptatriene tautomers is critical in allowing the formation
of both ring systems from the same azulenone structure 8.
The remaining steps in the synthesis were conducted following
the route described by Gatti et al.13 (Scheme 5). Hydrogenation of
General Experimental Methods. All reactions were carried out
under a nitrogen atmosphere. Where necessary, solvents were
routinely dried and distilled prior to use. Diazoethane solutions in
ether were freshly prepared prior to use and were used undistilled. All
commercial reagents were used as received unless otherwise stated.
Rhodium(II) acetate dimer was kindly donated by Johnson Matthey.
Organic phases were dried using anhydrous magnesium sulfate.
1
Diastereomeric ratios (d.r.) were determined by H NMR spectros-
copy. In the cases of minor diastereomers, spectral characteristics
reported are those that were easily distinguished from those due to the
major diastereomer. Cyclization efficiency (%) was determined by H
1
NMR spectroscopy.
Infrared (IR) spectra were obtained as films on NaCl plates or as
KBr disks, and wavelengths (v) are reported in cm−1. 1H and 13C NMR
spectra were recorded in CDCl3 (300 and 75.5 MHz, respectively)
unless otherwise stated. Chemical shifts (δ) are given downfield from
tetramethylsilane. Melting points obtained are uncorrected. Flash
column chromatography was carried out using Kieselgel 60, 0.040−
0.063 mm (Merck). Thin layer chromatography (TLC) was carried
out on precoated silica gel plates (Merck 60 PF254). Enantiopurity of
chiral compounds was determined by chiral HPLC performed on a
Chiralpak ASH or Chiralcel OJH column. Details of the column
conditions and mobile phases employed are included under the
corresponding compounds. Optical rotations were measured at 589
nm in a 10 cm cell; concentrations (c) are expressed in g/100 mL.
[α]D20 is the specific rotation of a compound and is expressed in units
of 10−1 deg cm2 g−1. Specific rotations were employed to confirm the
enantiomeric series. High resolution mass spectrometry (HRMS) was
performed on a TOF instrument in electrospray ionization (ESI)
mode; samples were made up in acetonitrile.
Scheme 5. Synthesis of 1
(E)-4-Methyl-pent-2-enoic acid 2.24 This was prepared following
the procedure described by Pirrung et al.24 from isobutyraldehyde
(5.48 g, 7.60 × 10−2 mol), malonic acid (5.00 g, 4.80 × 10−2 mol),
pyridine (15 mL), and morpholine (75 μL) to give the acid 2 (5.00 g,
91%) as a colorless oil: IR (NaCl) 2967, 1699, 1652 cm−1; δH (300
MHz, CDCl3) 1.08 (d, J = 6.9 Hz, 6H), 2.43−2.56 (m, 1H), 5.78 (dd,
J = 15.6, 1.5 Hz, 1H), 7.07 (dd, J = 15.8, 6.9 Hz, 1H).
(4S,2E)-3-(2′-Isohexenyl)-4-phenyl-2-oxazolidinone 4.16,18
Butyllithium (1.90 M in hexanes, 13.18 mL, 2.50 × 10−2 mol) was
added dropwise to a stirring solution of (4S)-4-phenyl-2-oxazolidinone
3 (4.09 g, 2.50 × 10−2 mol) in THF (110 mL) at −78 °C. The
resulting solution was stirred for 20 min at −78 °C. A solution of (E)-
4-methylpent-2-enoyl chloride (3.69 g, 2.78 × 10−2 mol) [prepared
(a) H2, 1 atm, Pd/C, EtOH, 89%. (b) P2O3Cl4, DMF, 0 °C to reflux,
72%. (c) H2, 1 atm, Pd/C, EtOH, 1 89%, ee = 95% by chiral HPLC.
2037
dx.doi.org/10.1021/jo202499j | J. Org. Chem. 2012, 77, 2035−2040

The Journal of Organic Chemistry
Note
from 2 (4.97 g, 4.35 × 10−2 mol) in ether (50 mL) and oxalyl chloride
(8.29 g, 6.53 × 10−2 mol) and purified by distillation at atmospheric
pressure (158 °C)] in THF (10 mL) was added dropwise at −78 °C.
The temperature was maintained at −78 °C for 30 min and was
allowed to warm to 0 °C over 1.5 h. The reaction mixture was
quenched with saturated aqueous ammonium chloride (30 mL), and
the volatiles were removed under reduced pressure. Ethyl acetate
(70 mL) was added, and the organic phase was separated and washed
with saturated aqueous sodium bicarbonate (2 × 40 mL) and brine
(60 mL), dried, and concentrated under reduced pressure to give the
crude oxazolidinone. Purification by flash column chromatography on
silica gel eluting with gradient ethyl acetate/hexane (20:80−40:60)
gave the oxazolidinone 4 (4.64 g, 72%) as a white solid: mp 101−103
obtained for this compound were in agreement with that described for
the corresponding racemate ( )-7;4 IR (film) 2959−2836, 2072,
1634, 1513 cm−1; δH (300 MHz, CDCl3) 0.73 (d, J = 6.9 Hz, 3H), 0.96
(d, J = 6.6 Hz, 3H), 1.72−2.01 (m, 4H), 2.65−2.81 (m, 2H), 2.84−
2.95 (m, 1H), 3.78 (s, 3H), 6.76−6.84 (m, 2H), 7.00−7.08 (m, 2H).
trans-(3S,8aR)-3-Isopropyl-6-methoxy-8a-methyl-2,3-dihy-
droazulen-1(8aH)-one 8a and cis-(3S,8aS)-3-Isopropyl-6-me-
thoxy-8a-methyl-2,3-dihydroazulen-1(8aH)-one 8b. A solution
of 7 (4.13 g, 1.59 × 10−2 mol) in dichloromethane (70 mL) was added
dropwise over 2 h to a solution of rhodium(II) acetate (0.5 mg) in
dichloromethane (100 mL) heated under reflux (another 0.5 mg of
rhodium(II) acetate was added halfway through the diazoketone
addition). The reaction progress was monitored by TLC and was
complete once all the diazoketone had been added. Evaporation of the
solvent at reduced pressure gave the crude product as a brown oil.
°C (lit.16 103−104 °C); [α]D20 = +112.0 (c 1.0, CHCl3) {lit.16 [α]D20
=
+103.1 (c 1.0, CHCl3)}; IR (KBr) 2965−2870, 1776, 1686, 1632 cm−1;
δH (300 MHz, CDCl3) 1.06, 1.07 (2 × d, 2 × J = 6.9 Hz, 2 × 3H),
2.45−2.58 (m, 1H), 4.26 (dd, J = 8.7, 3.9 Hz, 1H), 4.68 (t, J = 8.7 Hz,
1H), 5.48 (dd, J = 8.7, 3.9 Hz, 1H), 7.05 (dd, J = 15.5, 6.9 Hz, 1H),
7.22 (dd, J = 15.5, 1.2 Hz, 1H), 7.28−7.43 (m, 5H).
1
A H NMR spectrum of the crude reaction mixture estimated the
efficiency of the cyclization (% azulenone compared to aromatic
byproduct) as 82%, and the diastereomeric ratio of the azulenones
formed: diastereomeric ratio, trans-8a/cis-8b, 71:29. Purification by
flash column chromatography on silica gel, eluting with ethyl acetate/
hexane (10:90) gave the azulenone 8a/8b (3.11 g, 84%) as a pale
yellow oil. The diastereomeric ratio of the purified product was
estimated as trans-8a/cis-8b 70:30. Spectral characteristics obtained for
this compound were in agreement with that described for the
corresponding racemate ( )-8.4 IR (film) 2958, 1746, 1712, 1645 cm−1;
[α]D20 = +14.15 (c 1.0, CHCl3). Spectral characteristics for trans-8a: δH
(300 MHz, CDCl3) 0.76 (s, 3H), 0.80 (d, J = 6.6 Hz, 3H), 0.89 (d, J = 6.9
Hz, 3H), 1.61−1.72 (m, 1H), 1.99 (dd, J = 17.4, 6.9 Hz, 1H), 2.41−2.61
(m, 2H), 3.61 (s, 3H), 3.69 (br d, J = 7.5 Hz, 1H), 5.34 (br dd, J = 7.7,
2.1 Hz, 1H), 5.85 (dd, J = 9.0, 2.1 Hz, 1H), 6.06 (d, J = 9.0 Hz, 1H).
Spectral characteristics for cis-8b: δH (300 MHz CDCl3) 0.84 (s, 3H),
0.88 (d, J = 6.6 Hz, 3H), 0.98 (d, J = 6.9 Hz, 3H), 2.30−2.37 (m, 2H),
2.67−2.77 (m, 1H), 3.63 (s, 3H), 4.70 (br d, J = 9.9 Hz, 1H), 5.74−5.78
(m, 2H), 6.16 (dd, J = 8.4, 1.5 Hz, 1H).
(3′S,4S)-3-[3′-(4″-Methoxyphenyl)-4′-methylpentanoyl)-4-
phenyloxazolidin-2-one 5.17,18 This was prepared following the
procedure outlined by Hruby et al.17 from 4 (4.53 g, 1.75 × 10−2 mol),
p-bromoanisole (5.89 g, 3.15 × 10−2 mol), magnesium (0.76 g, 3.15 ×
10−2 mol), iodine (catalytic amount), and copper(I)bromide
dimethylsulfide complex (6.48 g, 3.15 × 10−2 mol). Purification by
flash column chromatograpy on silica gel eluting with gradient ethyl
acetate/hexane (5:95−40:60) gave the substituted acyl oxazolidinone
5 (4.39 g, 68%) as a white solid: mp 78−80 °C (lit.18 85−86 °C);
[α]D20 = +55.6 (c 1.0, CHCl3) {lit.18 [α]D20 = +54.7 (c 1.02, CHCl3)}; IR
(KBr) 2965−2834, 1786, 1726, 1611, 1515 cm−1; δH (300 MHz,
CDCl3) 0.72 (d, J = 6.6 Hz, 3H), 0.95 (d, J = 6.6 Hz, 3H), 1.75−1.89
(m, 1H), 2.82−2.92 (m, 1H), 3.06 (dd, J = 15.6, 5.1 Hz, 1H), 3.72
(dd, J = 15.9, 5.7 Hz, 1H), 3.78 (s, 3H), 4.05 (dd, J = 8.9, 4.2 Hz, 1H),
4.54 (t, J = 8.7 Hz, 1H), 5.28 (dd, J = 8.0, 3.3 Hz, 1H), 6.72−6.82
(m, 4H), 7.00−7.07 (m, 2H), 7.11−7.21 (m, 3H).
(1S,3S,8aR)-3-Isopropyl-6-methoxy-8a-methyl-1,2,3,8a-tet-
rahydroazulen-1-ol 9a and (3S)-3-Isopropyl-6-methoxy-8a-
methyl-1,2,3,8a-tetrahydroazulen-1-ol 9b. A solution of 8a/8b
(3.03 g, trans-8a/cis-8b 70:30, 1.30 × 10−2 mol] in ethanol (30 mL)
was added dropwise to a stirring suspension of sodium borohydride
(2.47 g, 6.50 × 10−2 mol) in ethanol (40 mL) at 0 °C. The reaction
mixture was stirred for 3.5 h while slowly returning to room tempe-
rature. The reaction was quenched by the dropwise addition of water
(30 mL) at 0 °C. The volatiles were removed under reduced pressure,
and the resulting aqueous suspension was extracted with ether (3 ×
20 mL). The combined organic phases were washed with brine (35 mL)
and dried, and the solvent was removed under reduced pressure to give
the azulenols 9a/9b (2.89 g, 95%) as a colorless oil. A 1H NMR spectrum
of the crude reaction mixture estimated the diastereomeric ratio of the
azulenols formed: diastereomeric ratio, 9a/9b, 70:30. This material was
used without any purification: [α]D20 = +138.4 (c 1.0, CHCl3); IR (film)
3383, 2956−2830, 1622, 1464 cm−1. Spectral characteristics for the major
diastereomer 9a: δH (300 MHz CDCl3) 0.56 (d, J = 6.6 Hz, 3H), 0.71
(s, 3H), 0.95 (d, J = 6.9 Hz, 3H), 1.11−1.22 (m, 1H), 1.78−2.20 (m,
3H), 2.53−2.67 (br m, 1H), 3.65 (s, 3H), 4.00−4.14 (overlapping dd, J =
9.8, 6.0 Hz, 1H), 5.52 (d, J = 10.2 Hz, 1H), 5.79−5.85 (m, 1H), 5.92−
6.00 (m, 2H). δC (CDCl3, 75.5 MHz) 16.2 (CH3), 17.2 (CH3), 21.9
(CH3), 28.2 (CH), 33.2 (CH2), 46.0 (CH), 48.2 (C), 54.7 (CH3), 80.5
(CH), 104.2 (CH), 116.4 (CH), 117.4 (CH), 119.1 (CH), 133.0 (C),
157.3 (C). Spectral characteristics for the minor diastereomer 9b: δH (300
MHz, CDCl3) 0.78 (s, 3H), 0.86 (d, J = 6.9 Hz, 3H), 0.98 (d, J = 6.9 Hz,
3H), 3.61 (s, 3H), 5.20 (d, J = 10.5 Hz, 1H), 5.55−5.58 (m, 2H), 5.72
(dd, J = 7.4, 1.5 Hz, 1H); δC (CDCl3, 75.5 MHz) 11.5 (CH3), 15.8
(CH3), 27.7 (CH), 31.3 (CH2), 45.6 (CH), 54.5 (CH3), 80.8 (CH),
101.4 (CH), 115.5 (CH), 123.0 (CH), 135.7 (CH), 143.1 (C), 157.0
(C). HRMS-TOF (m/z) [M + H]+ calcd for C15H23O2 235.1698, found
235.1697.
(3S)-3-(4′-Methoxyphenyl)-4-methylpentanoic Acid 6. To
a −10 °C precooled solution of 5 (4.23 g, 1.15 × 10−2 mol) in
THF (83 mL) and water (17 mL) was added hydrogen peroxide (30%
w/w, 11.04 mL, 9.78 × 10−2 mol). A solution of lithium hydroxide
monohydrate (1.26 g, 2.99 × 10−2 mol) in water (17 mL) was added
dropwise to the resulting slurry. The reaction mixture was allowed to
warm to 0 °C, stirred at 0 °C for 2 h, and quenched by the careful
addition of aqueous sodium sulfite (1.6 M, 30 mL). The organic
solvent was evaporated under reduced pressure, and the resulting
aqueous suspension was extracted with dichloromethane (4 × 40 mL).
The remaining aqueous phase was cooled to 0 °C, acidified to pH 1
with aqueous hydrochloric acid (10%), and again extracted with
dichloromethane (5 × 40 mL). The combined organic extracts were
dried and concentrated under reduced pressure to give the crude acid
as an off-white solid. Purification by flash column chromatography on
silica gel eluting with gradient ethyl acetate/hexane (10:90−40:60)
gave the acid 6 (2.15 g, 84%, 96% ee) as a white solid: mp 71−73 °C;
[α]D20 = −26.6° (c 1.0, CHCl3); spectral characteristics obtained for
this compound were in agreement with that described for the
corresponding racemate ( )-6;4 IR (KBr) 2961−2835, 1721, 1610,
1514 cm−1; δH (300 MHz, CDCl3) 0.73 (d, J = 6.6 Hz, 3H), 0.91
(d, J = 6.9 Hz, 3H), 1.74−1.86 (m, 1H), 2.50−2.62 (m, 1H), 2.71−
2.87 (m, 2H), 3.77 (s, 3H), 6.77−6.84 (m, 2H), 7.01−7.07 (m, 2H).
HPLC: tR (R) = 21.89 min, tR (S) = 26.33 min [Chiralpak ASH;
flow rate 0.50 mL min−1; UV detector (λ = 252 nm); hexane/
isopropanol (95:5); 25 °C].
(5S)-2-Diazo-5-(4′-methoxyphenyl)-6-methylheptan-3-one
7. This was prepared following the procedure described for the
corresponding racemate ( )-74 from 6 (4.12 g, 1.85 × 10−2 mol) in
ether (32 mL), oxalyl chloride (3.53 g, 2.78 × 10−2 mol), and a
solution of diazoethane in ether25 [prepared from N-ethyl-N-
nitrosourea26 (21.71 g, 1.85 × 10−1 mol)]. Purification by flash
column chromatography on silica gel, using ethyl acetate/hexane
(15:85) as eluant, gave the α-diazoketone 11 (3.12 g, 65%) as an
orange oil: [α]D20 = +41.7 (c 1.0, CHCl3); spectral characteristics
(1S)-1-Isopropyl-6-methoxy-4-methyl-1,2-dihydronaphtha-
lene 10.13 Solid p-toluenesulfonic acid monohydrate (4.68 g, 2.46 ×
10−2 mol) was added to a solution of 9a/9b [2.89 g, 9a/9b 70:30, 1.23 ×
10−2 mol] in toluene (200 mL), and the suspension was stirred at room
2038
dx.doi.org/10.1021/jo202499j | J. Org. Chem. 2012, 77, 2035−2040

The Journal of Organic Chemistry
Note
temperature for 24 h. The reaction mixture was then washed with
water (50 mL), saturated aqueous sodium bicarbonate (2 × 50 mL),
water (50 mL), and brine (70 mL). The organic phase was dried and
concentrated under reduced pressure to give the crude dihydronaph-
thalenes 10 and 11 (3.26 g) as a dark brown oil. A 1H NMR spectrum
of the crude reaction mixture estimated the ratio of dihydronaph-
thalenes formed as 10/11 1:0.95.
obtained for this compound were in agreement with that described in
the literature;13 IR (film) 2957, 1503, 1464 cm−1; δH (300 MHz
CDCl3) 0.75 (d, J 6.9 Hz, 3H), 1.02 (d, J 6.9 Hz, 3H), 1.27 (d, J
7.2 Hz, 3H), 1.57−1.88 (m, 4H), 2.13−2.29 (m, 1H), 2.17 (s, 3 H),
2.50−2.60 (m, 1H), 2.78−2.92 (m, 1H), 3.80 (s, 3H), 6.58 (s, 1H),
6.97 (s, 1H); δC (CDCl3, 75.5 MHz) 16.0 (CH3), 17.5 (CH3), 19.6
(CH2), 21.4 (CH3), 23.4 (CH3), 28.8 (CH2), 31.1 (CH), 33.1 (CH),
42.9 (CH), 55.2 (CH3), 109.7 (CH), 123.6 (C), 130.3 (CH), 131.4
(C), 141.3 (C), 155.5 (C). C16H24O requires C, 82.70; H, 10.41%.
Found: C, 82.61; H, 10.37. HPLC: tR (S,S) = 18.41 min, tR (R,R) =
21.72 min [Chiralcel OJH; flow rate 0.25 mL min−1; UV detector
(λ = 254 nm); hexane/isopropanol (99.5:0.5); 25 °C].
Potassium carbonate (1.88 g, 1.36 × 10−2 mol) was added to a
solution of 10 and 11 (3.23 g, 10/11 1:0.95) in acetone (100 mL).
Methyl iodide (1.02 mL, 1.64 × 10−2 mol) was then added dropwise.
The reaction mixture was heated under reflux for 22 h. The suspension
was cooled to room temperature, filtered, and rinsed with acetone. The
organic washings were combined and concentrated under reduced pressure,
and the resulting residue was purified by flash column chromatography
on silica gel eluting with ethyl acetate/hexane (10:90), to give the
ASSOCIATED CONTENT
■
S
* Supporting Information
dihydronaphthalene 10 (1.41 g, 53%) as a pale brown oil: [α]D20
=
1H NMR spectra for all compounds. 13C NMR spectra for
compounds 9, 10, 15, 16, and 1. HPLC traces for compounds
6 and 1. This material is available free of charge via the Internet
at http://pubs.acs.org.
+68.45 (c 1.0, CHCl3) {lit.13 [α]D20 = −40.5 (c 1.03, CHCl3)}; spectral
characteristics obtained for this compound were in agreement with
that described in the literature;13 IR (film) 2955−2833, 1604, 1571
cm−1; δH (300 MHz, CDCl3) 0.79 (d, J 6.9 Hz, 3H), 0.88 (d, J 6.9 Hz,
3H), 1.79−1.92 (m, 1H), 2.01 (d, J 1.8 Hz, 3H), 2.26−2.40 (br m,
3H), 3.81 (s, 3H), 5.74 (br s, 1H), 6.69 (dd, J 8.4, 2.7 Hz, 1H), 6.80
(d, J 2.7 Hz, 1H), 7.02 (d, J 8.4 Hz, 1H); δC (CDCl3, 75.5 MHz) 19.1
(CH3), 20.3 (CH3), 21.4 (CH3), 25.8 (CH2), 30.3 (CH), 43.6 (CH),
55.3 (CH3), 109.4 (CH), 110.5 (CH), 124.7 (CH), 129.2 (CH), 131.4
(C), 131.6 (C), 136.6 (C), 158.2 (C). C15H20O requires C, 83.28; H,
9.32%. Found: C, 83.32; H, 9.41.
AUTHOR INFORMATION
Corresponding Author
*E-mail: a.maguire@ucc.ie.
■
Present Address
§School of Chemistry, National University Of Ireland, Galway,
University Road, Galway, Ireland.
(1S,4S)-1-Isopropyl-6-methoxy-4-methyl-1,2,3,4-tetrahydro-
naphthalene 15.13 This was prepared following the procedure
described by Gatti et al.13 from 10 (1.15 g, 5.32 × 10−3 mol) and
palladium on carbon (116 mg, 5% by wt) in ethanol (20 mL).
Purification by flash column chromatography on silica gel eluting with
ethyl acetate/hexane (5:95) gave the tetrahydronaphthalene 15 (1.04 g,
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
89%) as a colorless oil: [α]D20 = −30.8 (c 1.0, CHCl3) {lit.13 [α]D20
=
The financial support of the National University of Ireland,
Enterprise Ireland, Pfizer, the Irish Research Council for Science,
Engineering and Technology (IRCSET), and GlaxoSmithKline
(GSK) through the IRCSET Enterprise Embark Initiative is
gratefully acknowledged.
−34.8 (c 2.47, CHCl3)}; spectral characteristics obtained for this
compound were in agreement with that described in the literature;13
IR (film) 2957, 1611, 1502 cm−1; δH (300 MHz, CDCl3) 0.76 (d, J 6.9
Hz, 3H), 1.02 (d, J 6.9 Hz, 3H), 1.27 (d, J 6.9 Hz, 3H), 1.57−1.88 (m,
4H), 2.14−2.27 (m, 1H), 2.53−2.64 (m, 1H), 2.80−2.92 (m, 1H),
3.78 (s, 3H), 6.65−6.73 (m, 2H), 7.12 (d, J = 9.6 Hz, 1H); δC (CDCl3,
75.5 MHz) 17.5 (CH3), 19.7 (CH2), 21.3 (CH3), 23.3 (CH3), 28.6
(CH2), 31.1 (CH), 33.2 (CH), 43.0 (CH), 55.1 (CH3), 111.3 (CH),
113.3 (CH), 129.1 (CH), 132.1 (C), 144.2 (C), 157.2 (C). C15H22O
requires C, 82.52; H, 10.16%. Found: C, 82.67; H, 9.91.
REFERENCES
■
(1) Constantino, A.; Linstrumelle, G.; Julia, S. Bull. Soc. Chim. Fr.
1970, 3, 907−912.
(2) Maguire, A. R.; Buckley, N. R.; O’Leary, P.; Ferguson, G. Chem
Commun. 1996, 2595−2596.
(5S,8S)-8-Isopropyl-3-methoxy-5-methyl-5,6,7,8-tetrahydro-
naphthalene-2-carbaldehyde 16.13 This was prepared following
the procedure described by Gatti et al.13 from 15 (1.02 g, 4.67 ×
10−3 mol) and pyrophosphoryl chloride (1.03 mL, 7.47 × 10−3 mol) in
DMF (0.54 mL, 7.00 × 10−3 mol). Purification by flash column
chromatography on silica gel eluting with ethyl acetate/hexane (5:95)
gave the aldehyde 16 (0.83 g, 72%) as a white solid: mp 64−66 °C
(lit.13 54−56 °C); [α]D20 = −61.0 (c 1.0, CHCl3) {lit.13 [α]D20 = −72.0
(c 0.9, CHCl3)}; spectral characteristics obtained for this compound
were in agreement with that described in the literature;13 IR (film)
2958, 1675, 1607 cm−1; δH (300 MHz, CDCl3) 0.74 (d, J 6.6 Hz, 3H),
1.02 (d, J 6.6 Hz, 3H), 1.30 (d, J 7.2 Hz, 3H), 1.61−1.90 (m, 4H),
2.23−2.36 (m, 1H), 2.57−2.67 (m, 1H), 2.85−2.98 (m, 1H), 3.90
(s, 3H), 6.72 (s, 1H), 7.69 (s, 1H), 10.40 (s, 1H); δC (CDCl3, 75.5
MHz) 17.2 (CH3), 19.0 (CH2), 21.1 (CH3), 23.0 (CH3), 28.3 (CH2),
30.9 (CH), 33.9 (CH), 42.7 (CH), 55.5 (CH3), 111.3 (CH), 122.7
(C), 128.3 (CH), 132.4 (C), 152.4 (C), 159.5 (C), 189.8 (COH).
C16H22O2 requires C, 78.01; H, 9.00%. Found: C, 77.98; H, 8.77.
(1S,4S)-1-Isopropyl-6-methoxy-4,7-dimethyl-1,2,3,4-tetrahy-
dronaphthalene 1.13 This was prepared following the procedure
described by Gatti et al.13 from 16 (0.77 g, 3.13 × 10−3 mol) and
palladium on carbon (77 mg, 5% by wt) in ethanol (20 mL).
Purification by flash column chromatography on silica gel eluting with
ethyl acetate/hexane (2:98) as eluent gave 1 (0.65 g, 89%, 95% ee) as
a colorless oil: [α]D20 −32.0 (c 1.0, CHCl3) {lit.12 [α]D20 −29.0 (c 0.2,
CHCl3), lit.13 [α]D20 −30.3 (c 0.92, CHCl3)}; spectral characteristics
(3) Maguire, A. R.; Buckley, N. R.; O’Leary, P.; Ferguson, G. J. Chem.
Soc., Perkin Trans. 1 1998, 4077−4091.
(4) Maguire, A. R.; O’Leary, P.; Harrington, F.; Lawrence, S. E.;
Blake, A. J. J. Org. Chem. 2001, 66, 7166−7177.
(5) O’Keeffe, S.; Harrington, F.; Maguire, A. R. Synlett 2007, 15,
2367−2370.
(6) O’Neill, S.; O’Keeffe, S.; Harrington, F.; Maguire, A. R. Synlett
2009, 14, 2312−2314.
(7) McNamara, O. A.; Maguire, A. R. Tetrahedron 2011, 67 (1),
9−40.
(8) Maier, G. Angew. Chem., Int. Ed. Engl. 1967, 6, 402−413.
(9) Foley, D. A.; Maguire, A. R. Tetrahedron 2010, 66 (6), 1131−
1175.
(10) Reisman, S. E.; Nani, R. R.; Levin, S. Synlett 2011, 17, 2437−
2442.
(11) Salmoun, M.; Braekman, J. C.; Ranarivelo, Y.; Rasamoelisendra, R.;
Ralambomanana, D.; Dewelle, J.; Darro, F.; Kiss, R. Nat. Prod. Res. 2007,
21 (2), 111−120.
(12) Nabeta, K.; Katayama, K.; Nakagawara, S.; Katoh, K.
Phytochemistry 1992, 32, 117−122.
(13) Brenna, E.; Dei Negri, C.; Fuganti, C.; Gatti, F. G.; Serra, S.
Tetrahedron: Asymmetry 2004, 15, 335−340.
(14) Alexander, J.; Rao, G. S. K. Tetrahedron 1971, 27, 645−651.
(15) Uemura, M.; Isobe, K.; Take, K.; Hayashi, Y. J. Org. Chem. 1983,
48, 3855−3858.
2039
dx.doi.org/10.1021/jo202499j | J. Org. Chem. 2012, 77, 2035−2040

The Journal of Organic Chemistry
Note
(16) Liao, S.; Shenderovich, M. D.; Lin, J.; Hruby, V. J. Tetrahedron
1997, 53, 16645−16662.
(17) Liao, S.; Han, Y.; Qiu, W.; Bruck, M.; Hruby, V. J. Tetrahedron
Lett. 1996, 37, 7917−7920.
(18) Lin, J.; Liao, S.; Han, Y.; Qiu, W.; Hruby, V. J. Tetrahedron:
Asymmetry 1997, 8, 3213−3221.
(19) Evans, D. A.; Britton, T. C.; Ellman, J. A. Tetrahedron Lett. 1987,
28, 6141−6144.
(20) Arndt, F.; Eistert, B.; Partale, W. Ber. Dtsch. Chem. Ges. 1927,
60B, 1364−1370.
(21) Tanaka, J.; Miyake, T.; Iwasaki, N.; Adachi, K. Bull. Chem. Soc.
Jpn. 1992, 65, 2851−2853.
(22) McCormick, J. P.; Pachlatko, J. P.; Schafer, T. R. Tetrahedron
Lett. 1978, 3993−3994.
(23) Benincori, T.; Bruno, S.; Celentano, G.; Pilati, T.; Ponti, A.;
Rizzo, S.; Sada, M.; Sannicolo, F. Helv. Chim. Acta 2005, 88, 1776−
1789.
(24) Pirrung, M. C.; Han, H.; Ludwig, R. T. J. Org. Chem. 1994, 59,
2430−2436.
(25) Arndt F. Organic Syntheses; Wiley: New York, 1943; Coll. Vol. 2,
p 461.
(26) Marshall, J. A.; Partridge, J. J. J. Org. Chem. 1968, 33, 4090−
4097.
2040
dx.doi.org/10.1021/jo202499j | J. Org. Chem. 2012, 77, 2035−2040