Preparation of Cyclohexenones from Acyclic (Pentadienyl)iron(1+) Cations: Synthetic Studies Directed toward the A-Ring of Dihydrotachysterols

Article abstract of DOI:10.1002/ejoc.201402615

The reaction of tricarbonyl(3-methylpentadienyl)iron(1+) cation (7) with stabilized carbon nucleophiles affords 4-methyl-5-substituted cyclohexenones. Reaction of 7 with sodium bis[(+)-2-phenylcyclohexyl]malonate afforded a mixture of diastereomers (de = 60 %); the diastereomeric allylic alcohols resulting from Luche reduction of this mixture were separable by column chromatography. Issues in diastereoselectivity in approaches to synthons for the A-ring of the tachysterols from these cyclohexenones are reported. The reaction of (3-methylpentadienyl)Fe(CO)₃ ⁺ cation (7) with stabilized carbon nucleophiles affords cyclohexenones. Reaction of 7 with a non-racemic C2 chiral nucleophile dihydrotachysterol analogs proceeds with good diastereoselectivity. Issues in diastereoselectivity in approaches to synthons for the A-ring of the tachysterols from these cyclohexenones are reported.

Full text of DOI:10.1002/ejoc.201402615

FULL PAPER
DOI: 10.1002/ejoc.201402615
Preparation of Cyclohexenones from Acyclic (Pentadienyl)iron(1+) Cations:
Synthetic Studies Directed toward the A-Ring of Dihydrotachysterols
[a]
[a]
Charles F. Manful and William A. Donaldson*
Keywords: Synthetic methods / Nucleophilic addition / Carbonylation / Steroids
The reaction of tricarbonyl(3-methylpentadienyl)iron(1+) cat-
ion (7) with stabilized carbon nucleophiles affords 4-methyl-
resulting from Luche reduction of this mixture were separa-
ble by column chromatography. Issues in diastereoselectivity
in approaches to synthons for the A-ring of the tachysterols
from these cyclohexenones are reported.
5
-substituted cyclohexenones. Reaction of 7 with sodium
bis[(+)-2-phenylcyclohexyl]malonate afforded a mixture of
diastereomers (de = 60%); the diastereomeric allylic alcohols
Introduction
Dihydrotachysterol (DHT , 1, Scheme 1) is one of sev-
2
2
eral by-products of irradiation of ergosterol. This steroid
raises serum levels of calcium and is orally administered for
the treatment of parathyroid tetany, renal osteodystrophy
and hypothyroidism.[ The structure of 1 was eventually
1]
[2a]
confirmed by preparation from (5E)-vitamin D2. This as
well as other means of semi-synthesis by reduction of the
1
0,19-olefin invariably produce mixtures of the desired 10S-
[2,3]
and unnatural 10R-diastereomers.
In vivo metabolism of
DHT2 in rats produces 25-hydroxydihydrotachysterol2,
1
α,25-dihydroxy- and 1β,25-dihydrotachysterol2 (2–4
[
4]
respectively). The metabolite 25-OH-DHT (2) is more
2
active than 1 in binding to the chick intestinal receptor for
1
α,25-dihydroxy vitamin D , and thus 2 “could be responsi-
3
Scheme 1. Dihydrotachysterols and retrosynthetic dissection.
[3]
ble for the therapeutic effectiveness” of 1. Of the two triol
metabolites the 1α-stereoisomer 3 exhibits good binding to
the mammalian vitamin D receptor [VDR], while 4 showed iron product (Ϯ)-8 while reaction with the sodium salt
poor binding. It has been speculated “... that 1α,25-di- gives a 4,5-disubstituted cyclohexenone product (Ϯ)-9a
[
8]
hydroxylated DHTs represent promising analogs worthy of (Scheme 2). Furthermore, reaction of 7 with sodium bis-
study for cell differentiation as well as calcemic proper- [(–)-8-phenylmenthyl]malonate gave a single diastereomer
[
4b]
[5]
ties.”
complished by coupling the chiral phosphine oxide 5 with this methodology towards preparation of A-ring synthons
Total syntheses of 1 and 2 have been ac- (–)-9b. We herein report our studies toward application of
[
9–11]
an appropriate CD ketone via the Lythgoe olefination strat- for dihydrotachysterol.
[
6]
egy. The phosphine oxide 5 is prepared from enoate 6 (4
[5]
steps) which is in turn prepared from expensive (S)-car-
[
7]
vone.
We have previously reported that the regioselectivity for
attack by malonate nucleophiles on the (3-methylpen-
+
tadienyl)Fe(CO)3 cation 7 is dependent on the nature of
the counterion; reaction with the lithium salt gives a (diene)-
[
a] Department of Chemistry, Marquette University,
P. O. Box 1881, Milwaukee, WI 53201-1881, USA
E-mail: william.donaldson@marquette.edu
http://www.marquette.edu/chem/Donaldson.shtml
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402615.
+
Scheme 2. Reaction of (3-methylpentadienyl)Fe(CO)
with malonate nucleophiles (ref. ).
3
cation 7
[8]
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C. F. Manful, W. A. Donaldson
FULL PAPER
Results and Discussion
malonyl chloride or phenylsulfonylacetyl chloride gave the
[
15]
corresponding esters (+)-11
or (–)-12 respectively
The reaction of (pentadienyl)iron cation 7 with sodium
methyl phenylsulfonylacetate, followed by work-up with so-
dium hydrogen carbonate gave a mixture of diastereomeric
cyclohexenones (Ϯ)-9c/cЈ which were partially separable by
column chromatography (Scheme 3, Table 1). In a similar
fashion, reaction of 7 with sodium triethyl phosphonylacet-
ate gave a mixture of diastereomeric cyclohexenones (Ϯ)-
(
Scheme 4). Reaction of 7 with the sodium salt of (+)-11
gave a mixture of two diastereomers 9e/9eЈ in a 1:5 ratio as
determined by H NMR spectroscopy (Scheme 3, Table 1).
Attempted separation of this mixture was unsuccessful.
Luche reduction of this mixture gave a separable mixture
of two allylic alcohols 13 and 14. Assignment of the abso-
lute configuration at the carbinol carbon of 14 was based
on the H NMR chemical shifts of the alkenyl proton (H )
of the derived (S)- and (R)-Mosher’s esters 15 and 16 (δ =
5
1
[16]
9
9
d/dЈ. While it was not possible to separate the mixture of
d/dЈ, Horner–Emmons olefination of the mixture gave a
1
2
single product (Ϯ)-10.
.42 and 5.32 ppm respectively). These relative chemical
shifts are consistent with an (S)-stereochemical assignment
[
17]
at C1.
These results might be anticipated since the
(1S,2R)-phenylcyclohexyl auxiliary is known to direct the
generation of asymmetric centers with an absolute configu-
ration opposite to that obtained when using the 8-phen-
[
18]
ylmenthyl auxiliary.
Scheme 4. Preparation of optically active nucleophiles.
Reaction of 7 with the sodium salt of (–)-12 gave a mix-
ture of four diastereomers 9f (Scheme 3, Table 1). Catalytic
hydrogenation of this mixture, followed by reductive desulf-
onylation gave a mixture of diastereomeric cyclohexanones
Scheme 3. Preparation of 4-methyl-5-substituted-cyclohexenones
9c–f (MPTA = α-methoxy-α-trifluoromethylphenylacetic acid).
17 and 18 (ca. 3:2 ratio). Since attempted separation of this
mixture was unsuccessful and since the diastereomers were
produced in a nearly equimolar ratio, the relative configura-
tion of each was not determined. The low diastereoselectiv-
ity observed for the addition of the anion derived from C1
symmetric (–)-12 [as compared to the C2 anion derived
from (+)-11] might be attributed to multiple orientations
Table 1. Addition of stabilized carbon nucleophiles to pentadienyl
cation 7.
R
RЈ
Product (yield)
Product (yield)
CO
CO
CO
CO
2
2
2
2
Me
Et
R*
SO
2
Ph
(Ϯ)-9c/cЈ (72%)
(Ϯ)-9d/dЈ (84%)
9e/9eЈ (60%, 1:5)
9f (87%, 3:3:3:1)
–
P(O)(OEt)
CO R*
SO Ph
2
(Ϯ)-10 (98%)
13/14 (86%, 1:5)
[
a]
2
R*
2
17/18 (52%, 3:2) possible for this nucleophile as well as the ability of this
nucleophile to react from either the si- or the re-face.
[a] (R* = 1S,2R-phenylcyclohexyl).
Elaboration of the cyclohexenones (Ϯ)-9a or (Ϯ)-9c/cЈ to
The cyclohexenones 9c and 9d were assigned as the cis-
a dihydrotachysterol A-ring fragment was attempted
stereoisomer based on their NMR spectroscopic data. The (Scheme 5). To this end, catalytic hydrogenation of 9a gave
signals at ca. δ = 6.95–7.05 (dd, 1 H) for each were assigned the cyclohexanone (Ϯ)-19a. Hydride reduction of 19a gave
to the H3 olefinic proton. The H3-H4 coupling constant the cyclohexanol (Ϯ)-20a. Alternatively, this same cyclo-
for each (ca. 6 Hz) are similar to those observed for (Ϯ)- hexanol could be prepared by (i) Luche reduction of 9a to
9
a and (–)-9b, and these are consistent with the couplings afford the cyclohexenol (Ϯ)-21a, followed by (ii) hydrogen-
[12]
reported for cis-4,5-dimethylcyclohexenone.
ation. In a similar fashion, processing of the diastereomeric
The absolute configuration of (–)-9b is opposite to that mixture of phenylsulfonylacetates 9c/cЈ along the same reac-
desired for the A-ring of the tachysterols. While (–)-8-phen- tion conditions gave (Ϯ)-19c/cЈ, (Ϯ)-20c/cЈ and (Ϯ)-21c/cЈ,
ylmenthol is commercially available, preparation of the respectively (Scheme 5). While 19c–21c were isolated as a
pseudoenantiomer (1S,2R,R)-5-methyl-2-(1-methyl-1-phen- mixture of diastereomers at the indicated carbon (*), a
[13]
ylethyl)cyclohexanol is laborious. For this reason, we de- clean sample of one or both diastereomers was isolated for
cided to explore an alternative chiral auxilary for this trans- 20c/cЈ and 21c/cЈ after careful column chromatography. The
formation. Toward this end, reaction of (1S,2R)-phenyl- relative configuration about the cyclohexyl ring of 20a and
[
14]
1
cyclohexanol (prepared from 1-phenylcyclohexene)
with 20c were assigned on the basis of their H NMR spectro-
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Cyclohexenones from Acyclic (Pentadienyl)iron(1+) Cations
scopic data. In particular, the signal for the alcohol methine protons, while the pair of multiplets at δ = 4.05 (m, 1 H)
proton of each exhibited two large couplings (20a: δ = 3.60, and δ = 3.98 (s, 1 H) ppm were assigned to the 5-H protons.
tt, J = 2.8, 10.3 Hz; 20c: δ = 3.58, tt, J = 4.6, 11.1 Hz).
These large couplings are consistent with axial-axial cou-
plings indicating that the hydroxy group occupies an equa-
torial orientation in each. The signal for the alcohol meth-
ine proton of 20cЈ is relatively broad but it appears at a
similar chemical shift (δ = 3.68–3.57, m) indicative of an
equatorial orientation for the alcohol functionality in this
diastereomer as well. While the diastereomeric mixtures
could be separated by careful column chromatography in
certain cases, it proved more convenient to carry these mix-
tures forward.
Scheme 6. Generation of enoates via α-selenation/elimination (rea-
gents: a: p-nitrobenzoic acid/diethyl azodicarboxylate/PPh , b: Mg/
3
MeOH).
Scheme 5. Attempted syntheses of dihydrotachysterol A ring frag-
ments.
In contrast, α-deprotonation of (Ϯ)-25, followed by reac-
tion with phenylselenyl chloride and subsequent oxidative
elimination of phenylselenic acid afforded only the enoate
While Krapcho decarbomethoxylation[19] of 20a gave the
ester (Ϯ)-22, the attempted reductive desulfonylation of
(
Ϯ)-Z-28. The structural assignment for 28 was based on
20c/cЈ was unsuccessful (Scheme 6). Toward this end, reac-
1
its H NMR spectroscopic data (Scheme 7). In particular,
tion of 20c/cЈ with tert-butyldiphenylsilyl chloride afforded
the silyl ether (Ϯ)-23c/cЈ as a mixture of diastereomers.
Notably, reductive desulfonylation of the mixture of dia-
stereomers 23c/cЈ gave (Ϯ)-24 as a single diastereomer. Al-
ternatively, reaction of 22 with p-nitrobenzoic acid under
Mitsunobu conditions[ gave the PNB ester (Ϯ)-25 with
inversion of configuration at the carbinol carbon. Hand-
schuh and Voelter reported that treatment of methyl 17-
hydroxy-3-oxo-α-(phenylsulfonyl)-androst-4-ene-6-acetate
20]
with base proceeded via elimination to afford the 6-carb-
oxymethylene derivative.[
21]
Unfortunately, in our hands
treatment of the mixture of (Ϯ)-23c/cЈ under similar reac-
tion conditions gave a complex mixture of unidentified
products. Alternatively, Posner[
22a]
reported the preparation
of A-ring synthons for vitamin D analogs via elimination
of in situ generated α-sulfoxide esters, while the groups of
Ito[
22b]
and Crich
[22c]
reported the preparation of carboxy-
methylene cyclohexanones via the elimination of α-sele-
noxide esters. Following these precedents, deprotonation of
(Ϯ)-24, followed by reaction with phenylselenyl chloride
gave a mixture of diastereomeric α-phenylselenyl esters
which upon oxidation with sodium periodate gave a mix-
ture of E-26 and Z-27. Attempted separation of this mix-
ture was unsuccessful. The structural assignment for these
stereoisomers was based on their H NMR spectroscopic
data. In particular, the pair of singlets at δ = 5.73 (s, 1 H)
Scheme 7. Structure of (Ϯ)-Z-28. Dashed arrows signify COSY in-
teractions, solid double-headed arrows signify NOESY interac-
tions. Rationale for the stereochemical outcome of the a-phenyl-
1
and δ = 5.36 (s, 1 H) ppm were assigned to the α-olefinic selenation/elimination sequence for 24 and 25.
Eur. J. Org. Chem. 2014, 6787–6795
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6789

C. F. Manful, W. A. Donaldson
FULL PAPER
the singlet at δ = 5.61 ppm was assigned to the α-olefinic Experimental Section
proton, while the multiplet at δ = 5.44 ppm was assigned to
Methyl 2-(3Ј-Methyl-6Ј-oxo-1Ј-cyclohexen-4Ј-yl)-2-(phenylsulfonyl)-
acetate (؎)-9c/cЈ: To a stirring suspension of NaH (33 mg,
5
-H. The assignment of this latter signal was further sup-
ported by COSY crosspeaks with the signals for 6-Hax and
-Heq (δ = 2.78 and 2.46 ppm respectively). Finally assign-
ment of the broad multiplet at δ = 4.25–4.15 ppm to 2-H
2
0.82 mmol) in freshly distilled THF (13 mL) under N at 0 °C was
6
added dropwise methyl phenylsulfonylacetate. The reaction mixture
was stirred at this temperature for 1 h. Salt 7 (200 mg, 0.546 mmol)
was aided by a COSY crosspeak with the 2-Me doublet at was added in one portion and the mixture stirred at room tempera-
δ = 1.22 ppm. The lack of any NOESY crosspeaks between ture for 2 h. The reaction was diluted with CH
the α-olefinic proton signal (δ = 5.61 ppm) and the signals saturated NaHCO /MeOH (26 mL) and stirred at room tempera-
ture for 24 h. The reaction was finally quenched with water and the
organic components extracted into CH Cl , dried (Na SO ) and
concentrated. The residue was purified by column chromatography
SiO , hexanes/ethyl acetate, 4:1) to afford a mixture of two dia-
2 2
Cl (13 mL) and
3
for 2-Me or 2-H, and the appearance of a crosspeak with
-Heq (δ = 2.46 ppm) lead to the assignment of the Z-
2
2
2
4
6
stereochemistry for the exocyclic olefin. Enoate 28 exists
predominantly in the 2-Me/OPNB diaxial conformer as evi-
denced by (i) the narrow half-width of the signal for 5-H
(
2
stereomeric cyclohexenones 9c and 9cЈ (ca. 1:1, 126 mg, 72%) as a
yellow oil along with a trace amount of iron diene products. The
mixture of diastereomers could be partially separated by subjecting
the mixture to a second chromatographic purification and isolation
(1/2W = 7.4 Hz) indicative of a lack of axial–axial cou-
plings, (ii) a NOESY crosspeak between the signal for 2-
Me and 6-H , and (iii) the relatively large downfield shift of the leading and trailing fractions.
ax
for 2-H due to the deshielding anisotropy of the Z-enoate
c/9cЈ: IR (neat): ν˜ = 1743, 1678, 1327, 1149 cm–1. 13C NMR
75 MHz, CDCl ): δ = 196.7 and 196.6 (C1), 165.9 and 165.8
CO R), 155.5, 154.2, 137.5, 134.83, 134.78, 129.43, 129.39, 129.35,
9
(
(
functionality. The higher energy of the 2-Me/OPNB diequa-
3
[
23]
torial conformer (Ϯ)-28Ј is due to the 1,3-allylic strain
2
between the ester substituent and 2-Me present in this con- 128.2, 127.9, 74.1 and 72.3 [CH(SO Ph)CO Me], 53.22 and 53.17
2
2
former; this strain is absent in the 2-Me/OPNB diaxial con- (OMe), 36.6, 36.4, 36.2, 31.8, 31.7, 12.4 and 12.3 (4-Me) ppm.
former 28. A similar methyl axial conformational prefer- HRMS (ESI): calcd. for C16 SNa 345.0767, found 345.0772.
ence has been reported for (Z)-(2-methylcyclohexylidene)-
18 5
H O
c: 1H NMR (400 MHz, CDCl
9
3
): δ = 7.91 (d, J = 7.6 Hz, 2 H,
ArH), 7.72 (t, J = 7.4 Hz, 1 H, ArH), 7.60 (t, J = 7.6 Hz, 2 H,
Exclusive formation of the Z-stereoisomer is rationalized ArH), 7.07 (dd, J = 5.8, 10.4 Hz, 1 H, 3-H), 5.99 (d, J = 10.4 Hz,
Ph)CO Me], 3.47 (s,
[
24]
acetic acid.
in the following manner. Electrophilic attack of phenyl- 1 H, 2-H), 4.15 [d, J = 9.6 Hz, 1 H, CH(SO
2
2
3
6
H, OMe), 3.25–3.15 (m, 2 H), 2.41 (dd, J = 13.4, 16.8 Hz, 1 H,
-H), 2.13 (dd, J = 3.6, 16.8 Hz, 1 H, 6Ј-H), 1.23 (d, J = 6.4 Hz, 3
H, 4-Me) ppm.
selenyl chloride on the ester enolate 29 derived from 25 oc-
curs preferentially on the si-face opposite to the steric bulk
of the 2-Me substituent to afford the α-selenyl ester 30. Oxi-
3
dation of 30 leads to an α-selenyl oxide, which undergoes a 9cЈ: (300 MHz, CDCl H
, deconvoluted from mixture of 9c/cЈ): 1
NMR: δ = 7.55–7.95 (m, 5 H, ArH), 6.92 (dd, J = 6.3, 9.9 Hz, 1
H, 3-H), 5.97 (d, J = 9.9 Hz, 1 H, 2-H), 4.10 [d, J = 11.7 Hz, 1 H,
syn-elimination to generate 28Ј, which undergoes a chair-
chair inversion the more stable conformer 28. Attempts to
isomerize (Ϯ)-28 to the presumably more stable E-isomer
using either acid, iodine or photochemically were unsuc-
cessful. In contrast, since the C2-methyl substituent occu-
pies an axial orientation in the ester enoate 31 derived from
4, phenylselenyl chloride can approach equally well from
either the si- or the re-face to form the a-phenylseleno esters
2 and 33 respectively. Oxidation and concerted syn-elimi-
CH(SO
.00 (m, 1 H), 2.52 (dd, J = 13.5, 17.1 Hz, 1 H, 6-H), 2.42–2.32
m, 1 H, 6Ј-H), 1.04 (d, J = 6.9 Hz, 3 H, 3-Me) ppm.
2 2
Ph)CO Me], 3.52 (s, 3 H, OMe), 3.24–3.18 (m, 1 H), 3.12–
3
(
Triethyl 2-(2-Methyl-5-oxocyclohex-3-en-1-yl)phosphonoacetate
؎)-9d/dЈ: To an ice-cold stirring suspension of NaH (13.5 mg,
.546 mmol) in dry THF (10 mL) was added triethyl phospho-
noacetate (0.122 mg, 0.546 mmol). The mixture was stirred at 0 °C
for 10–15 min. Solid cation 7 (0.20 g, 0.55 mmol) was added in one
portion and the reaction mixture stirred for 2 h at room tempera-
(
0
2
3
nation of 32 affords Z-26, while oxidation and concerted
syn-elimination of 33 affords Z-27.
ture. The reaction mixture was diluted with CH
methanolic NaHCO (10 mL each) and stirred overnight at room
temperature. Water (20 mL) was added and the mixture extracted
several times with CH Cl . The combined extracts were dried
MgSO ) and concentrated. The residue was purified by flash col-
2 2
Cl and saturated
3
Conclusions
2
2
(
4
The preparation of 3-methyl-4-substituted cyclo-
hexenones by reaction of (3-methylpentadienyl)Fe(CO)3+
umn chromatography (SiO , diethyl ether/hexanes 0Ǟ50% gradi-
2
ent) to afford 9d/dЈ as a yellowish oil (164 mg, 84%) as well as an
cation with stabilized carbon nucleophiles has been ex-
tended to phenylsulfonylacetates and triethyl phosphono-
acetates. Use of the chiral nucleophile sodium bis[(+)-2-
phenylcyclohexyl]malonate led to a diastereomerically en-
riched cyclohexenone which possesses the opposite absolute
unquantified trace of (diene)iron complex. IR (neat): ν˜ = 1736,
–
1 1
1
6
(
680, 1258 cm . H NMR (400 MHz, CDCl
.1, 10.1 Hz, 1 H, 3-H), 5.92 (d, J = 6.1 Hz, 1 H, 2-H), 4.32–4.03
CH ), 3.08–2.73 (m, 5 H), 1.37–1.19 (m, 9 H,
), 1.10 (d, J = 6.7 Hz, 3 H, 4-Me) ppm. HRMS (ESI):
3
): δ = 6.99 (dd, J =
m, 6 H, OCH
2
3
2 3
OCH CH
configuration about the cyclohexenone ring compared to calcd. for C H O PNa 355.1285, found 355.1281.
1
2
25
6
our previously reported results. Finally, functional group
manipulation of the cyclohexenones (Ϯ)-9a and (Ϯ)-19c/cЈ
illustrate issues in controlling the stereoselective formation
Ethyl 2-(2-Methyl-5-oxocyclohex-3-en-1-yl)propenoate (؎)-10: To
an ice-cold stirring suspension of NaH (43 mg, 0.11 mmol) in dry
THF (5 mL) was added a mixture of diastereomers 9d/dЈ (40 mg,
of the C5-C-6 olefin in synthons which could be used for 0.11 mmol). The mixture was stirred at 0 °C for 30 min, and para-
the synthesis of DHT analogs. formaldehyde (3.2 mg, 0.11 mmol) added. The reaction mixture
2
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Cyclohexenones from Acyclic (Pentadienyl)iron(1+) Cations
was stirred for 1 h at room temperature. The reaction mixture was ture was stirred at room temperature for 24 h. The reaction was
diluted with H
The combined extracts were dried (MgSO
residue was purified by flash column chromatography (SiO
ether/hexanes, 0Ǟ25% gradient) to afford (Ϯ)-10 as a pale yellow
2
O (10 mL) and extracted several times with CH
) and concentrated. The
, diethyl
2
Cl
2
.
quenched with water (20 mL), extracted several times with CH
and the combined extracts were dried (Na SO ) and concentrated.
Purification of the residue by column chromatography (SiO , ethyl
acetate/hexanes, 0Ǟ25% gradient) gave an inseparable mixture
of two diastereomeric cyclohexenones 9e and 9eЈ (241 mg,
2 2
Cl ,
4
2
4
2
2
–1
–1 1
oil (20 mg, 98%). IR (neat): ν˜ = 1714, 16 cm 83cm . H NMR
(
(
400 MHz, CDCl
s, 1 H, C=CH ), 5.99 (d, J = 9.5 Hz, 1 H, 2-H), 5.48 (s, 1 H, 146 °C. HRMS (ESI): calcd. for C34
), 4.22 (q, J = 7.5 Hz, 2 H, OCH
.94–2.81 (m, 1 H), 2.66–2.53 (m, 1 H), 2.39–2.28 (m, 1 H), 1.31
t, J = 7.1 Hz, 3 H, OCH CH ), 0.88 (d, J = 6.6 Hz, 3 H, 4-Me)
ppm. C NMR (100 MHz, CDCl ): δ = 199.3 (C1), 168.0 (CO R),
55.6, 140.9, 127.6, 125.3, 60.9 (OCH CH ), 38.1, 37.1, 32.1, 14.2
OCH CH ), 12.6 (4-Me) ppm. HRMS (ESI): calcd. for
Na 439.2100, found 439.2091.
3
): δ = 7.02 (dd, J = 4.1, 9.5 Hz, 1 H, 3-H), 6.39 0.455 mmol, 1:5 ratio, 60% total) as a colorless solid, m.p. 144–
2
40 5
H O Na 551.2768, found
C=CH
2
(
2
2
CH
3
), 3.54–3.41 (m, 1 H),
551.2757.
1
9
e: H NMR (300 MHz, CDCl
3
): δ = 7.30–7.08 (m, 10 H, Ph), 6.67
2
3
(
dd, J = 6.3, 10.2 Hz, 1 H, 3-H), 5.78 (d, J = 9.9 Hz, 1 H, 2-H),
1
3
3
2
5
2
6
0
.00 (dt, J = 4.5, 10.8 Hz, 1 H), 4.95 (dt, J = 4.5, 10.5 Hz, 1 H),
.79 (d, J = 11.7 Hz, 1 H, CHE ), 2.66 (dt, J = 3.3, 11.1 Hz, 1 H,
-H), 2.56 (dt, J = 3.6, 11.1 Hz, 1 H, 6Ј-H), 2.40–1.10 (m, 20 H),
1
(
(
2
3
2
2
3
C
12
H
16
O
6
)
2
13
.17 (d, J = 6.9 Hz, 3 H, 4-Me) ppm. C NMR (75 MHz, CDCl
R), 166.6 (CO R), 155.4 (C-3), 143.2,
42.7, 128.7, 128.6, 128.5, 127.7, 127.6, 127.5, 127.1, 126.7, 77.8
C-2Ј), 54.7 [CH(CO R*) ], 49.7, 49.5, 36.1, 36.0, 34.4, 34.2, 32.2,
1.9, 30.6, 25.8, 24.8, 11.5 (4-Me) ppm.
3
):
δ = 197.4 (C=O), 167.0 (CO
2
2
Bis[(1S,2R)-2-phenylcyclohexyl] Malonate (+)-11: To a stirring solu-
tion of (1S,2R)-2-phenylcyclohexanol (360 mg, 2.03 mmol) in
freshly distilled CH
2
1
over a 5 min period, and the mixture was stirred at 0 °C for 30 min
and at room temperature for 24 h. The solvent was evaporated un- cyclohexyl] 2-[(3R,4S,6R)-6-Hydroxy-3-methyl-1-cyclohexen-4-yl]-
der a N
1
(
3
2
2
2
Cl
.03 mmol). The reaction mixture was stirred under N
h. Malonyl dichloride (143 mg, 1.02 mmol) was added dropwise
2
at 0 °C was added triethylamine (206 mg,
2
at 0 °C for
Bis[(1S,2R)-2-phenylcyclohexyl] 2-[(3S,4R,6S)-6-Hydroxy-3-methyl-
1-cyclohexen-4-yl]propanedioate (+)-14 and Bis[(1S,2R)-2-phenyl-
2
stream and the residue purified by column chromatog-
, hexanes/ethyl acetate = 5:1) to afford (+)-11 (208 mg,
propanedioate (–)-13: To the mixture of chiral cyclohexenones (9e/
9eЈ, 100 mg, 0.189 mmol) in MeOH (10 mL) at 0 °C was added
CeCl ·7H O (149 mg, 0.400 mmol). The mixture was stirred vigor-
raphy (SiO
2
20
7
0
1
CH
2
D
6%) as a colorless solid, m.p. 114–116 °C. [α] = +13.5 (c =
3
2
1
.0169, CH
0 H, ArH), 4.98 (dt, J = 4.2, 10.6 Hz, 2 H, 1-H), 2.80 [s, 2 H,
(CO R*) ], 2.63 (dt, J = 3.5, 11.6 Hz, 2 H, 2-H), 2.17–2.08 (m,
H), 2.00–1.75 (m, 6 H), 1.65–1.30 (m, 8 H) ppm. C NMR
75 MHz, CDCl ): δ = 165.8 (CO Me), 142.9 (Ar), 128.4 (Ar),
2 2 3
Cl ). H NMR (300 MHz, CDCl ): δ = 7.35–7.15 (m, ously until homogeneous (ca. 15 min). Solid NaBH4 (29 mg,
0.76 mmol) was added in small portions and stirring continued at
room temperature for 3 h. The reaction was quenched with water,
extracted with diethyl ether, dried (MgSO ) and concentrated. Puri-
2
2
2
13
4
(
3
2
fication of the residue by flash column chromatography (SiO , ethyl
2
1
2
4
27.6 (Ar), 126.5 (Ar), 77.0 (CHOR), 49.4, 41.5, 33.9, 32.0, 25.8, acetate/hexanes, 0Ǟ40% gradient) to afforded two isomeric cyclo-
4.7 ppm. HRMS (ESI): calcd. for C27
43.2193.
H
32
O
4
Na 443.2193, found
hexenols (–)-13 (less polar, 21 mg, colorless oil) and (+)-14 (more
polar, 65 mg, colorless oil) in 86% overall yield.
(+)-14: [α]2
0
1
(
1S,2R)-2-Phenylcyclohexyl (Phenylsulfonyl)acetate (–)-12: To
D 2 2
= +20.6 (c = 0.00156, CH Cl ). H NMR (300 MHz,
(phenylsulfonyl)acetic acid (100 mg, 0.499 mmol) under N
2
was CDCl
3
): δ = 7.35–7.10 (m, 10 H, ArH), 5.38–5.35 (narrow m, 2 H,
added dropwise oxalyl chloride (78 mg, 0.62 mmol). The mixture
was stirred at room temperature for 1 h, and then the excess oxalyl
chloride was removed under vacuum. The crude acid chloride was
dissolved in benzene (5 mL), and (1S,2R)-2-phenylcyclohexanol
CH=CH), 5.12 (dt, J = 4.5, 10.5 Hz, 1 H, CHOR), 5.03 (dt, J =
4.2, 10.8 Hz, 1 H, CHЈOR), 3.47 (dd, J = 6.3, 9.3 Hz, 1 H, CHOH),
2.78 [d, J = 12.3 Hz, 1 H, CH(CO R*) ], 2.70 (dt, J = 3.9, 11.7 Hz,
2 2
1 H), 2.61 (dt, J = 3.9, 11.7 Hz, 1 H), 2.14–1.20 (m, 19 H), 0.80
(dt, J = 9.9, 12.6 Hz, 1 H), 0.62 (dd, J = 6.3, 11.1 Hz, 1 H), 0.06
(105 mg, 0.599 mmol) was added in one portion. The mixture was
1
3
heated at reflux for 48 h. After this time, the solvent was evaporated
under vacuum and the residue purified by column chromatography
(d, J = 7.5 Hz, 3 H, 2-Me) ppm. C NMR (75 MHz, CDCl
3
): δ =
167.8 (CO R*), 167.1 (CO R*), 143.8, 143.1, 134.5, 128.76, 128.74,
2
2
(
ethyl acetate/hexanes, 0Ǟ20% gradient) to afford (–)-12 (115 mg, 128.5, 127.8, 127.6, 126.7, 126.3, 76.6, 76.5, 67.8, 55.8, 49.6, 49.5,
4%) as a viscous oil. [α]2
): δ = 7.67 (dd, J = 1.2, 8.1 Hz, 2 H, ArH), 7.57 ppm. A satisfactory HRMS spectrum was not obtained for this
dt, J = 1.2, 8.1 Hz, 1 H, ArH), 7.44 (dt, J = 1.2, 8.1 Hz, 2 H,
compound.
0
= –5.1 (c = 0.0049, CH
). H NMR
1
6
D
2
Cl
2
35.4, 34.9, 34.6, 32.1, 32.0, 30.7, 30.0, 25.9, 24.9, 24.8, 13.9 (2-Me)
(300 MHz, CDCl
3
(
ArH), 7.19–6.97 (m, 5 H, ArH), 4.86 (dt, J = 4.2, 10.5 Hz, 1 H, 1-
H), 3.76 (d, J = 14.4 Hz, 1 H, SCHHЈCO R*), 3.70 (d, J = 14.4 Hz,
R*), 2.51 (dt, J = 3.7, 11.6 Hz, 1 H, 2-H), 2.00–
20
). 1H NMR (300 MHz,
(
–)-13: [α]
D
= –31 (c = 0.0014, CH
Cl
2 2
2
CDCl
): δ = 7.33–7.10 (m, 10 H, ArH), 5.35 (d, J = 10.2 Hz, 1 H,
CH=CH), 5.24 (ddd, J = 1.4, 5.0, 10.1 Hz, 1 H, CH=CH), 5.08–
.93 (m, 2 H), 3.85 (dt, J = 1.2, 7.9 Hz, 1 H), 2.77 [d, J = 12.0 Hz,
H, CH(CO R*) ], 2.67 (dt, J = 3.3, 11.4 Hz, 1 H), 2.60 (dt, J =
.2, 11.6 Hz, 1 H), 2.10–1.70 (m, 9 H), 1.58–1.10 (m, 11 H), 0.60–
.49 (m, 1 H), 0.47 (d, J = 7.2 Hz, 3 H, 2-Me) ppm. C NMR
3 2 2
75 MHz, CDCl ): δ = 168.1 (CO Me), 167.2 (CO Me), 143.7,
3
1
H, SCHHЈCO
.92 (m, 1 H), 1.87–1.62 (m, 3 H), 1.50–1.15 (m, 4 H) ppm.
): δ = 161.7 (CO R*), 142.6, 138.8, 134.3,
29.3, 128.7, 128.5, 127.6, 126.8, 78.7 (CHOR), 60.9
SCH CO R*), 49.4, 33.9, 32.0, 25.7, 24.8 ppm. HRMS (ESI):
calcd. for C20 SNa 381.1131, found 381.1127.
2
1
3
1
C
4
1
3
0
NMR (75 MHz, CDCl
3
2
2
2
1
(
2
2
13
22 4
H O
(
1
5
2
43.2, 134.9, 128.7, 128.3, 128.0, 127.5, 126.6, 126.4, 77.0, 67.8,
5.9, 49.8, 49.4, 35.6, 34.9, 34.4, 32.1, 32.0, 30.4, 29.8, 25.9, 25.85,
4.8, 14.3 (2-Me) ppm. A satisfactory HRMS spectrum was not
Bis[(1S,2R)-2-phenylcyclohexyl] 2-(3-Methyl-6-oxo-1-cyclohexen-4-
yl)propanedioate (9e/9eЈ): To a stirring suspension of NaH (48 mg,
1
.1 mmol) in freshly distilled THF (10 mL) under N
added dropwise a solution of (+)-11 (320 mg, 0.761 mmol) in THF
3 mL). The reaction mixture was stirred at 0 °C for 1 h, and then
2
at 0 °C was
obtained for this compound.
(
S-(–)-(α)-MTPA Ester 15: To a solution of (+)-14 (15 mg,
0.028 mmol) in freshly distilled THF (3 mL) was added S-(–)-(α)-
MTPA (26 mg, 0.11 mmol). The mixture was homogenized and
then DCC (23 mg, 0.11 mmol) and DMAP (0.5 mg, 0.004 mmol)
solid cation 7 (418 mg, 1.14 mmol) was added in one portion. The
reaction mixture was stirred for 2 h at 0 °C and then diluted with
CH Cl (13 mL) and saturated NaHCO /MeOH (15 mL). The mix-
2 2 3
Eur. J. Org. Chem. 2014, 6787–6795
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6791

C. F. Manful, W. A. Donaldson
FULL PAPER
were added successively with stirring. After 4 h the reaction mixture
was heated at reflux for 12 h. Upon completion consumption of
the starting material the solvent was removed under a stream of
(10% w/w, 15 mg) was added and the flask was connected to a Parr
hydrogenation apparatus. The reaction mixture was maintained un-
der H
released and the solvent removed. The residue was suspended in
ethyl acetate/hexanes, 0Ǟ40% gradient) to afford 15 as a colorless ethyl acetate and filtered through a pad of celite. The filter bed was
2
(45 psi) and stirred for 24 h after which the pressure was
2 2
N . The product was purified by column chromatography (SiO ,
1
oil quantitatively. H NMR (300 MHz, CDCl
1
7
3
): δ = 7.58–7.16 (m, washed several times with ethyl acetate and the extracts concen-
5 H, ArH), 5.49 (dd, J = 5.2, 6.4 Hz, 1 H, 3-H), 5.42 (d, J = trated under reduced pressure. The crude residue was purified by
.0 Hz, 1 H, 2-H), 5.13–4.95 (m, 3 H), 3.56 (s, 3 H, OMe), 2.71 [d, flash column chromatography (SiO ethyl acetate/hexanes,
R*) ], 2.66–2.60 (m, 2 H), 2.17–1.65 (m, 15Ǟ30% gradient) to afford (Ϯ)-19a as a pale yellow oil (82 mg,
0 H), 1.54–0.89 (m, 10 H), 0.00 (d, J = 7.5 Hz, 3 H, 4-Me) ppm.
2
,
J = 7.4 Hz, 1 H, CH(CO
2
2
–
1
1
1
73%). IR (neat): ν˜ = 1735, 1666 cm . H NMR (300 MHz,
CDCl ): δ = 3.76 (s, 3 H, OMe), 3.74 (s, 3 H, OMe), 3.40 [d, J =
0.8 Hz, 1 H, CH(CO Me) ], 2.72 (ddt, J = 3.5, 5.6, 11.1 Hz, 1 H),
.53–2.01 (m, 5 H), 1.97–1.85 (m, 2 H), 1.07 (d, J = 6.9 Hz, 3 H,
3
R-(+)-(α)-MTPA 16: Esterification of (+)-14 (15 mg, 0.028 mmol)
with R-(+)-(α)-MTPA (26 mg, 0.11 mmol) was carried out in a
fashion similar to the reaction of (+)-14 with (S)-MTPA. The prod-
1
2
4
1
2
2
13
-Me) ppm. C NMR (75 MHz, CDCl
68.36, 55.3, 53.0, 52.9, 40.9, 40.7, 36.4, 31.6, 28.7, 11.9 (2-Me)
Na 507.2201, found
3
): δ = 209.4, 168.42,
uct was purified by (SiO
to afford 16 as a colorless solid quantitatively, m.p. 130–132 °C. H
NMR (300 MHz, CDCl ): δ = 7.56–7.14 (m, 15 H, ArH), 5.57 (dd,
J = 5.4, 6.0 Hz, 1 H, 3-H), 5.32 (d, J = 6.8 Hz, 1 H, 2-H), 5.16–
2
, ethyl acetate/hexanes, 0Ǟ40% gradient)
1
ppm. HRMS (ESI): calcd. for (C12
07.2210.
18 5 2
H O )
3
5
Dimethyl
؎)-21a: The reduction of (Ϯ)-9a (33 mg, 0.14 mmol) under Luche
conditions in methanol (2.5 mL) with CeCl ·7H (57 mg,
.15 mmol) and NaBH (25 mg, 0.65 mmol) was carried out in a
fashion similar to the reduction of 9e/9eЈ. Purification of the resi-
due by flash chromatography (SiO , diethyl ether/hexanes, 0Ǟ75%
gradient) to afford (Ϯ)-21a as a pale yellow oil (26 mg, 78%). IR
2-(5-Hydroxy-2-methylcyclohex-3-en-1-yl)propandioate
4
1
.85 (m, 3 H), 3.57 (s, 3 H, OMe), 2.78–2.56 (d & m, 3 H), 2.16–
.65 (m, 10 H), 1.47–0.89 (m, 10 H), 0.00 (d, J = 7.4 Hz, 3 H, 4-
(
Me) ppm.
3
2
O
0
4
(
(
1S,2R)-2-Phenylcyclohexyl
17 and 18): To a stirred suspension of NaH (83 mg, 2.1 mmol) in
at 0 °C was added dropwise
–)-12 (542 mg, 1.51 mmol). The reaction mixture was stirred for
2-(2-Methyl-4-oxocyclohexyl)acetate
2
freshly distilled THF (34 mL) under N
(
2
–1 1
(
(
1
neat): ν˜ = 3404, 1735 cm . H NMR (300 MHz, CDCl
ddd, J = 1.8, 5.0, 10.2 Hz, 1 H, CH=CH), 5.61 (br. d, J = 10.2 Hz,
H, CH=CH), 4.32 (br. t, J = 8.1 Hz, 1 H, CHOH), 3.75 (s, 3 H,
OMe), 3.73 (s, 3 H, OMe), 3.38 [d, J = 11.4 Hz, 1 H, CH(CO Me) ],
.57 (dddd, J = 2.1, 5.1, 11.8, 13.5 Hz, 1 H), 2.33 (br. q, J = 6.0 Hz,
H), 1.77 (br. dd, J = 6.2, 11.8 Hz, 1 H), 1.68 (br. s, 1 H), 1.36
3
): δ = 5.70
1
h, and then solid cation 7 (500 mg, 1.37 mmol) was added in one
portion. The mixture was warmed to room temperature and stirred
for 2 h. The reaction mixture was diluted with CH Cl (34 mL) and
saturated NaHCO /MeOH (44 mL) and stirred at room tempera-
ture for 24 h. The reaction mixture was quenched with water, ex-
tracted several times with CH Cl , dried (Na SO ) and concen-
trated. The residue was purified by column chromatography (SiO
2
2
2
2
3
2
1
2
2
2
4
(
dt, J = 9.9, 12.6 Hz, 1 H), 0.90 (d, J = 6.9 Hz, 3 H, 2-Me) ppm.
,
13
2
C NMR (75 MHz, CDCl
34.6 (CH=CH), 129.9 (CH=CH), 68.2 (CHOH), 55.2
CH(CO Me) ], 52.9 (OMe), 52.8 (OMe), 36.3, 31.3, 30.8, 14.6 (2-
Me) ppm. HRMS (ESI): calcd. for (C12 Na 507.2201, found
07.2213.
3 2 2
): δ = 169.3 (CO Me), 168.5 (CO Me),
hexanes/ethyl acetate = 4:1) to afford an inseparable mixture of
four diastereomeric cyclohexenones (ca. 1:3:3:3 ratio) (560 mg,
1
[
2
2
87%) as a pale oil. This mixture was used in the next step without
18 5 2
H O )
further characterization. Catalytic hydrogenation of the mixture of
isomeric cyclohexenones (182 mg, 0.388 mmol) in MeOH in the
presence of 10% Pd/C was carried out in a fashion similar to the
preparation of 19a. Purification of the residue by column
5
Dimethyl 2-(5-Hydroxy-2-methylcyclohexyl)propandioate (؎)-20a:
Catalytic hydrogenation of (Ϯ)-21a (56 mg, 0.23 mmol) in meth-
anol in the presence of 10% Pd/C under N (45 psi) was carried
2
out in a fashion similar to the reduction of (Ϯ)-9a. The residue was
suspended in ethyl acetate (10 mL) and filtered through a pad of
celite. The filter bed was washed several times with ethyl acetate
and the extracts concentrated under reduced pressure to afford (Ϯ)-
chromatography (SiO
an inseparable mixture of four diastereomeric cyclohexanones (ca.
:3:3:1 ratio) as a colorless foamy solid (141 mg, 78%). This mix-
2
, acetone/hexanes, 0Ǟ20% gradient) gave
3
ture was used in the next step without further characterization.
Reductive desulfonylation of the mixture of diastereomeric cyclo-
hexanones (145 mg, 0.309 mmol) in MeOH with added activated
Mg (54.2 mg, 2.25 mmol) was carried out in a fashion similar to
the preparation of 24. Purification of the residue by column
chromatography (hexanes/ethyl acetate = 4:1) gave an inseparable
2
1
3
1
3
0a as a colorless oil (52 mg, 91%). IR (neat): ν˜ = 3471, 2910, 1675,
–
1 1
448 cm . H NMR (400 MHz, CDCl
.72 (s, 3 H, OMe), 3.74–3.70 (m, 1 H, 5-H), 3.30 [d, J = 8.7 Hz,
H, CH(CO Me) ], 2.31 (tt, J = 3.6, 11.4 Hz, 1 H), 1.89 (tdd, J =
.6, 7.6, 10.8 Hz, 1 H), 1.70 (dd, J = 3.6, 8.0 Hz, 1 H), 1.57–1.52
3
): δ = 3.73 (s, 3 H, OMe),
2
2
mixture of two diastereomers 17 and 18 (ca. 3:2 ratio) (68 mg,
1
(m, 1 H), 1.45–1.20 (m, 5 H), 0.89 (d, J = 5.4 Hz, 3 H, 2-Me) ppm.
0
.21 mmol, 67%) as a colorless oil. H NMR (300 MHz, CDCl
3
):
1
3
C NMR (100 MHz, CDCl
3
): δ = 169.3 (CO
2 2
Me), 168.9 (CO Me),
δ = 7.25–7.05 (m, 5H ArH), 4.95 (dt, J = 4.2, 10.6 Hz, 1 H,
CHOR), 2.65–2.52 (m, 1 H), 2.25–1.18 (m, 18 H), 0.79 and 0.65
7
0.7 (C-5), 55.7 [CH(CO Me)
2
2
], 52.7 (OMe), 39.6, 33.7, 31.0, 29.5,
13
28.4, 12.2 (2-Me) ppm. A satisfactory HRMS spectrum was not
obtained for this compound.
(
2ϫd, J = 6.9 Hz, 3 H, 2-Me) ppm. C NMR (75 MHz, CDCl
3
):
δ = 210.9 (C=O), 171.8 (CO R*), 171.4 (CO R*), 143.4, 143.3,
2
2
1
7
3
1
29.0, 128.65, 128.59, 128.55, 127.71, 127.66, 126.71, 126.67, 77.4,
6.3, 50.09, 50.06, 43.9, 43.6, 38.3, 38.2, 37.95, 37.88, 37.5, 37.0,
4.36, 34.34, 32.58, 32.53, 31.7, 31.24, 31.17, 30.8, 30.3, 29.91,
9.87, 26.0, 24.9, 13.4 (2-Me), 12.8 (2-Me) ppm. HRMS (ESI):
Hydride reduction of 19a (36 mg, 0.15 mmol) with NaBH
anol afforded 20a (31 mg, 93%).
4
in meth-
Methyl 2-(5-Hydroxy-2-methylcyclohexyl)acetate (؎)-22: To a stir-
ring solution of (Ϯ)-20a (40 mg, 0.17 mmol) in DMSO (10 mL)
was added LiI (70 mg, 1.4 mmol) and H O (70 mg, 3.9 mmol). The
2
28 3
calcd. for C21H O Na 351.1931, found 351.1926.
Dimethyl 2-(2-Methyl-5-oxocyclohexyl)propanedioate (؎)-19a: The
cyclohexenone (Ϯ)-9a (112 mg, 0.467 mmol) was dissolved in meth-
anol (10 mL) and the resultant solution transferred into a small
heavy-walled hydrogenation flask. Palladium on activated carbon
reaction mixture was stirred at room temperature until all the inor-
ganic salts had dissolved and then heated to reflux at 150 °C for
24 h. After completion the reaction mixture was cooled to room
2 2
temperature, diluted with water and extracted with CH Cl . The
6792
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 6787–6795

Cyclohexenones from Acyclic (Pentadienyl)iron(1+) Cations
combined organic extracts were washed with 10% aqueous HCl
stereomer. The relative stereochemical assignments of these dia-
stereomers was arbitrary.
3
(15 mL) followed by saturated aqueous NaHCO (38 mL), dried
(
2
=
2
MgSO ) and concentrated under reduced pressure to afford (Ϯ)-
4
1
2
0c: H NMR (300 MHz, CDCl
3
): δ = 7.89 (d, J = 7.8 Hz, 2 H,
1
2 as a colorless oil (23 mg, 79%). H NMR (300 MHz, CDCl
3
): δ
ArH), 7.67 (t, J = 7.2 Hz, 1 H, ArH), 7.56 (t, J = 7.6 Hz, 2 H,
ArH), 4.03 [d, J = 9.6 Hz, 1 H, CH(SO Ph)CO Me], 3.58 (tt, J =
.6, 11.1 Hz, 1 H, CHOH), 3.45 (s, 3 H, OMe), 2.55–2.44 (m, 2 H),
3.68 (s, 3 H, OMe), 3.68–3.58 (m, 1 H, 5-H), 2.34–2.17 (m, 2 H),
2
2
.14–2.00 (m, 1 H), 1.87–1.20 (m, 8 H), 0.86 (d, J = 8.1 Hz, 3 H,
4
1
(
1
5
2
-Me) ppm. 13C NMR (75 MHz, CDCl
3
): δ = 173.8 (CO Me), 70.8
2
.80–1.23 (m, 7 H), 0.98 (d, J = 7.2 Hz, 3 H, 2-Me) ppm. 1 C NMR
): δ = 166.8 (CO Me), 138.1 (Ph), 134.5 (Ph),
29.4 (Ph), 129.3 (Ph), 73.6 [CH(SO Ph)CO Me], 70.7 (CHOH),
2.9 (OMe), 38.6, 33.4, 30.9, 29.4, 28.5, 12.1 (2-Me) ppm. HRMS
3
(
C-5), 51.8 (OMe), 38.8, 36.1, 36.0, 30.8, 30.4, 29.8, 12.5 (2-Me)
ppm. HRMS (ESI): calcd. for C10 Na 209.1148, found
09.1148.
75 MHz, CDCl
3
2
18 3
H O
2
2
2
Methyl
؎)-19c/cЈ: Hydrogenation of the mixture of diastereomeric cyclo-
hexenones 9c/cЈ (378 mg, 1.17 mmol) in MeOH (20 mL) in the pres-
ence of 10% Pd/C under H (45 psi) was carried out in a fashion
similar to the hydrogenation of 9a. Purification of the residue
by flash column chromatography (SiO , ethyl acetate/hexanes,
Ǟ80% gradient) gave an inseparable mixture of 19c/19cЈ as a pale
2-(2Ј-Methyl-5Ј-oxocyclohexyl)-2-(phenylsulfonyl)acetate
12 22 5
(ESI): calcd. for C H O SNa 349.1080, found 349.1080.
(
1
2
0cЈ: H NMR (300 MHz, CDCl
ArH), 7.67 (t, J = 7.8 Hz, 1 H, ArH), 7.56 (t, J = 7.5 Hz, 2 H,
ArH), 4.00 [d, J = 11.7 Hz, 1 H, CH(SO Ph)CO Me], 3.68–3.57
m, 1 H, CHOH), 3.42 (s, 3 H, OMe), 2.52 (br. d, J = 12.0 Hz, 1
H), 2.45 (td, J = 3.3, 12.0 Hz, 1 H), 1.80–1.35 (m, 7 H), 0.87 (d, J
3
): δ = 7.89 (d, J = 7.5 Hz, 2 H,
2
2
2
(
2
0
1
3
1
= 6.9 Hz, 3 H, 2-Me) ppm. C NMR (75 MHz, CDCl
CO Me), 138.1 (Ph), 134.4 (Ph), 129.3 (Ph), 129.2 (Ph), 75.0
CH(SO Ph)CO Me], 70.3 (CHOH), 52.9 (OMe), 38.4, 33.5, 30.7,
9.4, 28.8, 12.4 (2-Me) ppm.
3
): δ = 166.6
oil (370 mg, 98%). 19c/cЈ: H NMR (400 MHz, CDCl
.95 (m, 2 H, ArH), 7.68–7.75 (m, 1 H, ArH), 7.55–7.64 (m, 2 H,
ArH), 4.04 and 4.08 [d, J = 10.4, and d, J = 10.8 Hz, 1 H total,
CH(SO Ph)CO Me], 3.40 and 3.54 (2ϫs, 3H total, OMe), 2.80–
.12 (m, 1 H), 2.70–2.80 (m, 1 H), 2.25–2.50 (m, 3 H), 1.80–2.10
3
): δ = 7.87–
(
[
2
2
7
2
2
2
2
3
(
Hydride reduction of the mixture of diastereomeric cyclohexanones
m, 3 H), 1.08 and 1.19 (d, J = 7.2, and d, J = 7.2 Hz, 3H total, 2- 19c/cЈ (168 mg, 0.484 mmol) with NaBH in methanol afforded the
4
Me) ppm. HRMS (ESI): calcd. for C16
H
20
O
5
SNa 347.0924, found
same mixture of 20c/cЈ (103 mg, 61%).
Methyl 2-[5Ј-(tert-Butyldiphenylsilyl)oxy-2Ј-methylcyclohexyl]-2-
phenylsulfonyl)acetate (؎)-23c/cЈ: To a solution of diastereomeric
cyclohexanols 20c/cЈ (435 mg, 1.33 mmol) in CH Cl (50 mL) at
°C was added imidazole (182 mg, 2.67 mmol). The reaction mix-
347.0921.
Methyl 2-(6Ј-Hydroxy-3Ј-methyl-1-cyclohexen-4Ј-yl)-2-(phenylsulf-
onyl)acetate (؎)-21c/cЈ: Hydride reduction of the mixture of dia-
stereomeric cyclohexenones 9c/cЈ (83 mg, 0.26 mmol) in methanol
(
2
2
0
with CeCl
.28 mmol) was carried out in a fashion similar to the preparation
of 21a. Purification of the residue by flash column chromatography
SiO , ethyl acetate/hexanes, 5%Ǟ20% gradient) afforded a mix-
ture of diastereomers 21c/21cЈ (ca. 3:4 ratio) as a pale yellow oil
78 mg, 94% yield). Careful rechromatography of this mixture gave
3
·7H
2
O
(97 mg, 0.26 mmol) and NaBH
4
(10 mg,
2
ture was stirred under N for 15 min. Solid tert-butyldiphenylsilyl
0
chloride (561 mg, 2.00 mmol) was added slowly with vigorous stir-
ring. After addition was complete the mixture was stirred at room
temperature overnight and quenched with water. The resulting mix-
(
2
ture was extracted several times with Et
tracts dried (MgSO ) and concentrated. The residue was purified
by column chromatography (SiO , acetone/hexanes, 5Ǟ20% gra-
2
O, and the combined ex-
(
4
a pure sample of each diastereomer. The relative stereochemical
assignments of these diastereomers was arbitrary.
2
dient) to afford a mixture of protected cyclohexanols 23c/cЈ
(744 mg, 99%) as a pale yellow oil. This mixture was partially sepa-
rable by careful rechromatography.
1
2
1c: H NMR (300 MHz, CDCl
3
): δ = 7.90 (d, J = 7.8 Hz, 2 H,
ArH), 7.69 (t, J = 7.5 Hz, 1 H, ArH), 7.58 (t, J = 7.5 Hz, 2 H,
ArH), 5.76 (ddd, J = 1.2, 4.5, 10.2 Hz, 1 H), 5.60 (d, J = 10.2 Hz,
1
2
3
4
2
7
3c: H NMR (300 MHz, CDCl
3
): δ = 7.75–7.35 (m, 15 H, ArH),
Ph)CO Me], 3.55–3.45 (s & m,
1
H), 4.35–4.25 (br. m, 1 H, CHOH), 4.09 [d, J = 9.6 Hz, 1 H,
CH(SO Ph)CO Me], 3.49 (s, 3 H, OMe), 2.80–2.68 (m, 2 H), 1.70–
.55 (m, 2 H), 1.44 (dt, J = 10.2, 12.3 Hz, 1 H), 1.07 (d, J = 6.6 Hz,
H, 3-Me) ppm. 13C NMR (75 MHz, CDCl
): δ = 166.7 (CO Me),
38.2, 134.60, 134.57, 129.4, 129.3, 73.1 [CH(SO Ph)CO Me], 68.3
.96 [d, J = 11.4 Hz, 1 H, CH(SO
2
2
2
2
H total, CHOSi and OMe), 2.47 (br. d, J = 12.9 Hz, 1 H), 2.20–
.15 (m, 1 H), 1.63–1.20 (m, 6 H), 1.08 (s, 9 H, tBu), 0.87 (d, J =
.2 Hz, 3 H, 2-Me) ppm.
1
3
1
3
2
2
2
1
2
3
3cЈ: H NMR (300 MHz, CDCl
3
): δ = 7.85–7.30 (m, 15 H, ArH),
Ph)CO Me], 3.65–3.53 (m, 1 H,
(
(
CHOH), 53.0 (OMe), 35.6, 31.5, 31.2, 14.8 (2-Me) ppm. HRMS
.97 [d, J = 10.5 Hz, 1 H, CH(SO
2
2
ESI): calcd. for C16
H
20
O
5
SNa 347.0924, found 347.0921.
CHOSi), 3.30 (s, 3 H, OMe), 2.45–2.20 (m, 2 H), 1.20–1.65 (m, 6
H), 1.02 (s, 9 H, tBu), 0.97 (d, J = 6.9 Hz, 3 H, 2-Me) ppm.
1
2
1cЈ: H NMR (300 MHz, CDCl
3
): δ = 7.89 (d, J = 7.8 Hz, 2 H,
ArH), 7.68 (t, J = 7.5 Hz, 1 H, ArH), 7.58 (t, J = 7.5 Hz, 2 H,
ArH), 5.61 (s, 2 H, CH=CH), 4.32–4.23 (br. m, 1 H, CHOH), 4.04
23c/cЈ: 13C NMR (75 MHz, CDCl
(CO Me), 139.6, 139.3, 137.06, 137.00, 136.90, 136.86, 135.64,
dd, J = 5.2, 12.1 Hz, 1 H), 2.57 (ddt, J = 1.8, 4.5, 11.4 Hz, 1 H), 135.60, 135.54, 135.44, 135.36, 131.03, 131.00, 130.41, 130.38,
3 2
): δ = 167.9 (CO Me), 167.8
[
(
d, J = 11.7 Hz, 1 H, CH(SO
2
Ph)CO
2
Me], 3.47 (s, 3 H, OMe), 2.72
2
2
6
.15–2.00 (m, 2 H), 1.53 (dt, J = 10.3, 12.7 Hz, 1 H), 0.89 (d, J = 130.30, 130.27, 129.0, 128.9, 128.7, 76.1, 74.3, 73.7, 73.3, 53.3
.9 Hz, 3 H, 3-Me) ppm.
(OMe), 53.2 (OMe), 40.0, 39.9, 34.9, 34.4, 31.8, 31.7, 30.7, 30.5,
0.4, 29.7, 27.7, 27.6, 20.1 (SitBu), 20.0 (SitBu), 12.6 (2-Me), 12.5
2-Me) ppm. HRMS (ESI): calcd. for C32 SiSNa 587.2258,
3
(
Methyl 2-[5Ј-Hydroxy-2Ј-methylcyclohexyl]-2-(phenylsulfonyl)acet-
ate (؎)-20c/cЈ: Catalytic hydrogenation of the diastereomeric mix-
40 5
H O
found 587.2256.
ture of cyclohexenols 21c/cЈ (35 mg, 0.11 mmol) in MeOH with H
2
in the presence of 10% Pd/C catalyst was carried out in a fashion
similar as the reduction of cyclohexenone 9a. The residue was puri-
Methyl 2-[5Ј-(tert-Butyldiphenylsilyl)oxy-2Ј-methylcyclohexyl]acet-
ate (؎)-24: To a solution of diastereomeric silyl ethers 23c/cЈ
(68 mg, 0.12 mmol) in MeOH (10 mL) was added Mg (21 mg,
0.87 mmol). The reaction mixture was stirred at 50 °C until gas
evolution started at which stage the heating source was removed
and stirring continued at room temperature. Additional Mg (21 mg,
fied by flash column chromatography (SiO
2
, ethyl acetate/hexanes,
30Ǟ50% gradient) to afford a mixture of diastereomeric cyclo-
hexanols 20c/cЈ (27 mg, 78%) as a pale yellow oil. Careful rechro-
matography of this mixture gave a pure sample of each dia-
Eur. J. Org. Chem. 2014, 6787–6795
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6793

C. F. Manful, W. A. Donaldson
FULL PAPER
6
X) was added at 50 °C successively until all starting material had
been consumed as indicated by TLC. The solvent was evaporated
and the mixture redissolved in CH Cl . The mixture was filtered,
washed (brine), dried (MgSO ) and concentrated to give (Ϯ)-24 as
a single diastereomer (52 mg, quantitative). This compound was
CDCl
3
): δ = 7.52–7.64 (m, 4 H, Ph), 7.50–7.33 (m, 6 H), 5.74 (s,
0.5 H), 5.36 (d, J = 1.5 Hz, 0.5 H), 4.05–3.98 (m, 0.5 H), 3.90–3.80
(m, 0.5 H), 3.65 and 3.64 (2ϫs, 3H total), 2.57 (dd, J = 2.7,
14.1 Hz, 0.5 H), 2.45 (dt, J = 0.9, 12.3 Hz, 0.5 H), 2.26–2.18 (m,
0.5 H), 2.16 (dd, J = 5.0, 13.3 Hz, 0.5 H), 1.78–1.50 (m, 5 H), 1.13
2
2
4
used in the next step without further purification. 1H NMR and 1.12 (d, J = 7.2, and d, J = 6.3 Hz, 3H total), 1.07 and 1.04
1
3
(
300 MHz, CDCl
Ph), 3.70–3.62 (s & m, 4H total, OMe & CHOSi), 2.26 (dd, J =
.8, 15.0 Hz, 1 H, CH CO Me), 2.20 (dd, J = 8.1, 15.0 Hz, 1 H,
CH CO Me), 2.00–1.85 (m, 1 H), 1.79–1.30 (m, 7 H), 1.09 (s, 9 H,
tBu), 0.88 (d, J = 7.5 Hz, 3 H, 2-Me) ppm. C NMR (75 MHz,
CDCl ): δ = 173.6 (CO
29.6, 127.7, 127.6, 72.2 (CHOSi), 51.5 (OMe), 38.6, 36.3, 36.0,
0.6, 30.3, 30.1, 27.2, 19.3 (tBu), 12.6 (2-Me) ppm. HRMS (ESI):
SiNa 447.2326, found 447.2324.
-(2-Methoxy-2-oxoethyl)-4-methylcyclohexyl 4-Nitrobenzoate (؎)- solution of the crude (Ϯ)-27 (35 mg, 0.10 mmol) in dry THF
5: To a mixture of (Ϯ)-22 (27 mg, 0.15 mmol), p-nitrobenzoic
(2 mL). The mixture was stirred at –78 °C under N for 30 min. A
3
): δ = 7.75–7.70 (m, 4 H, Ph), 7.40–7.35 (m, 6 H,
(2ϫs, 9H total) ppm. C NMR (75 MHz, CDCl
3
): δ = 167.6
(CO Me), 166.9 (CO Me), 164.7, 163.6, 136.1, 136.0, 135.9, 134.9,
2
2
7
2
2
134.53, 134.5, 134.3, 129.9, 129.8, 129.7, 128.8, 128.77, 127.7,
114.3, 113.7, 73.2 (C-5), 71.2 (C-5), 51.1 (OMe), 42.9, 39.3, 36.8,
32.2, 31.2, 30.3, 29.8, 29.6, 27.2, 27.1, 19.4, 19.3, 18.6, 18.4 ppm.
2
2
13
3
2
Me), 135.96, 135.94, 135.93, 134.89, 134.76, HRMS (ESI): calcd. for C26
Methyl 2-Methyl-5-(p-nitrobenzoyloxy)-Z-cyclohexylideneacetate
؎)-28: To a stirring solution of LDA (2.0 m in heptane, 0.26 mL,
.3 mmol) in dry THF (1 mL) at –78 °C was added dropwise a
34 3
H O SiNa 445.2169, found 445.2168.
1
3
(
1
36 3
calcd. for C26H O
3
2
2
acid (99.3 mg, 0.594 mmol) and triphenylphosphine (156 mg,
.594 mmol), under N , was added freshly distilled THF (5 mL).
The mixture was stirred at room temperature until homogeneous
ca. 15 min). The reaction mixture was cooled to 0 °C and a solu-
tion of diethyl azodicarboxylate (259 mg, 0.594 mmol, 40wt.-% residue purified by column chromatography (SiO
solution of PhSeCl (40 mg, 0.21 mmol) in dry THF (0.5 mL) was
added dropwise rapidly with vigorous stirring. The reaction mix-
ture was slowly warmed to room temperature and stirred for 24 h
0
2
(
under N
2
. The solvent was evaporated under an N
2
stream and the
, ethyl acetate/
2
solution in toluene) was added slowly over 10 min. The mixture
was stirred vigorously at 0 °C for 30 min after which the cold bath
was removed and stirring continued at room temperature for 24 h.
Upon completion of the reaction as indicated by TLC the solvent
hexanes, 0Ǟ20% gradient) the crude phenylseleno compound
(46 mg, 90%) as green oil. Owing to the susceptibility of the latter
to slow oxidation by air the crude compound was used without
further purification. To a stirring solution of the crude phenylse-
leno compound (15 mg, 0.031 mmol) in MeOH (2 mL) was added
was evaporated under an N
by column chromatography (SiO
gradient) to afford (Ϯ)-25 (46 mg, 94%) as a pale oil. H NMR
300 MHz, CDCl
H total, ArH), 5.30–5.22 (m, 1 H, CHOPNB), 3.68 (s, 3 H, concentrated under a N
CO Me), 2.55–2.45 (m, 1 H), 2.35 (dd, J = 6.7, 15.2 Hz, 1 H,
umn chromatography (SiO
CHHЈCO
Me), ent) to afford (Ϯ)-Z-28 as a pale yellow oil (10 mg, 98%). H NMR
(300 MHz, CDCl ): δ = 8.29 and 8.16 ppm (AAЈBBЈ, JAB = 8.4 Hz,
4H total, ArH), 5.61 (s, 1 H, C=CHCO Me), 5.44 (m, 1/2width =
7.4 Hz, 1 H, CHOPNB), 4.25–4.15 (br. m, 1 H, 2-H), 3.71 (s, 3 H,
1.3 (C-4), 51.3 (OMe), 35.7, 32.7, 31.6, 30.9, 27.2, 26.1, 13.6 (2- OMe), 2.78 (td, J = 2.4, 15.3 Hz, 1 H, 6-H), 2.46 (br. d, J =
Na 358.1261, found
15.0 Hz, 1 H, 6Ј-H), 2.07–1.89 (m, 4 H), 1.22 (d, J = 7.5 Hz, 3 H, 2-
2
stream and the residue was purified
, ethyl acetate/hexanes, 0Ǟ40%
NaIO
der N
4
(13 mg, 0.61 mmol). The mixture was stirred vigorously un-
for 6 d. The reaction was quenched with water. The resulting
2
1
2
(
3
): δ = 8.30 and 8.22 ppm (AAЈBBЈ, JAB = 9.2 Hz, mixture was extracted several times with Et
stream. The residue was purified by col-
, diethyl ether/hexanes, 0Ǟ10% gradi-
2 4
O, dried (MgSO ) and
4
2
2
2
1
2
Me), 2.24 (dd, J = 8.7, 15.3 Hz, 1 H, CHHЈCO
2
1
2
1
7
.99–1.64 (m, 6 H), 1.48–1.38 (m, 1 H), 0.94 (d, J = 7.2 Hz, 3 H,
3
-Me) ppm. 13C NMR ([D
63.6 (ArCO
6
]DMSO, 75 MHz): δ = 172.8 (CO
2
Me),
2
2
R), 150.2 (Ar), 135.6 (Ar), 130.6 (Ar), 124.0 (Ar),
Me) ppm. HRMS (ESI): calcd. for C17
58.1260.
H21NO
6
1
3
3
Me) ppm. C NMR (75 MHz, CDCl
3
): δ = 166.6 (CO
R), 162.2 (C-1), 150.8 (Ar), 136.1 (Ar), 130.9 (Ar), 123.8
Ar), 116.0 (C=CHCO Me), 73.0 (C-5), 51.2 (OMe), 36.8, 30.4,
7.4, 24.5, 18.2 (2-Me) ppm. HRMS (ESI): calcd. for
Na 356.1105, found 356.1104.
Supporting Information (see footnote on the first page of this arti-
2
Me), 164.1
(
(
ArCO
2
Methyl 5-(tert-Butyldiphenylsilyloxy)-2-methylcyclohexylideneacet-
ate (؎)-Z-26 and (؎)-E-27: To a stirring solution of LDA in hept-
anes (0.08 mL, 2.0 m, 0.2 mmol) in dry THF (2 mL) at –78 °C was
added dropwise a solution of (Ϯ)-24 (30 mg, 0.071 mmol) in dry
2
2
17 6
C H19NO
THF (2 mL). The mixture was stirred at –78 °C under N
2
for
1
13
cle): Copies of the H and/or C NMR spectra of compounds
30 min. A solution of phenylselenyl chloride (27 mg, 0.14 mmol) in
9
2
c/9cЈ, 9d/9dЈ, 9e/9eЈ, 10–16, 17/18, 19a, 19c/cЈ, 20a, 20c, 20cЈ, 21a,
1, 21c, 22, 23c, 23cЈ, 24–28.
dry THF (0.5 mL) was added dropwise rapidly with vigorous stir-
ring. The reaction mixture was slowly warmed to room temperature
and stirred for 24 h under N
water and the resulting mixture was extracted several times with
Et O. The combined extracts were washed with saturated aqueous
NaHCO , dried (MgSO ) and concentrated. The residue was puri-
fied by column chromatography (SiO , hexanes/ethyl acetate, 20:1)
to afford a mixture of two diastereomeric phenylseleno compounds
38 mg, 92%) as a bright green oil. To a stirring solution of the
phenylseleno compounds (27 mg, 0.046 mmol) in MeOH (3 mL)
2
. The reaction was quenched with
Acknowledgments
2
3
4
This work was supported by the National Science Foundation
2
(
0
NSF), grant CHE-0848870 and instrumentation grant CHE-
521323. High-resolution mass spectra were obtained at the Old
Dominion University COSMIC facility.
(
was added NaIO
orously under N
4
(23 mg, 0.11 mmol). The mixture was stirred vig-
overnight. The reaction was quenched with water.
[
[
1] a) C. M. MacBryde, JAMA J. Am. Med. Assoc. 1938, 111, 304–
2
3
07; b) M. R. Haussler, P. E. Cordy, JAMA J. Am. Med. Assoc.
The resulting mixture was extracted several times with Et
the combined extracts washed with saturated NaHCO
MgSO ) and concentrated. The residue was purified by column
chromatography (SiO , hexanes/ethyl acetate = 20:1) to afford an
inseparable mixture of unsaturated esters (Ϯ)-Z-26 and (Ϯ)-E-27
2
O, and
1982, 247, 841–844.
3
, dried
2] a) A. Mourino, W. H. Okamura, J. Org. Chem. 1978, 43, 1653–
(
4
1656; b) A. W. Messing, F. P. Ross, A. W. Norman, W. H. Oka-
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1
(ca. 1:1) (15 mg, 77%) as a colorless oil. H NMR (300 MHz,
6794
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 6787–6795

Cyclohexenones from Acyclic (Pentadienyl)iron(1+) Cations
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1
4% overall yield: G. R. Stephenson, J. Chem. Soc. Perkin
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2
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2
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[
10] The synthesis of 4- and 5-substituted cyclohexenones has been
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4
9; c) G. R. Stephenson, S. T. Astley, I. M. Palotai, P. W. How-
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Received: May 21, 2014
Published Online: September 4, 2014
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