Directed hydrogenation of acyclic homoallylic alcohols: Enantioselective syntheses of (+)- and (-)-laurenditerpenol

Article abstract of DOI:10.1021/jo401461x

Laurenditerpenol is the first marine natural product shown to inhibit hypoxia-inducible factor 1 (HIF-1) activation. Preclinical studies support that the inhibition of HIF-1 is one of the molecular targets for antitumor drug discovery. The synthetically c

Full text of DOI:10.1021/jo401461x

Article
pubs.acs.org/joc
Directed Hydrogenation of Acyclic Homoallylic Alcohols:
Enantioselective Syntheses of (+)- and (−)-Laurenditerpenol
,
†
†
‡
†,§
Amar G. Chittiboyina,* Prabhakar Peddikotla, Mitchell A. Avery, and Ikhlas A. Khan
†
‡
§
National Center for Natural Products Research, Department of Medicinal Chemistry, and Department of Pharmacognosy, School
of Pharmacy, University of Mississippi, University, Mississippi 38677, United States
*
S Supporting Information
ABSTRACT: Laurenditerpenol is the first marine natural product shown to inhibit
hypoxia-inducible factor 1 (HIF-1) activation. Preclinical studies support that the
inhibition of HIF-1 is one of the molecular targets for antitumor drug discovery. The
synthetically challenging molecular architecture of laurenditerpenol, its absolute
stereostructure, and the biological activity of several diastereoisomers were accomplished
by our group in 2007 by diastereoselective synthesis. Herein, we report enantioselective
syntheses of both enantiomers of laurenditerpenol involving sequential Michael addition
and remote homoallylic hydroxyl group-directed asymmetric hydrogenation at ambient
temperature and pressure as key reaction steps. The current approach is elegant and overall more efficient than the ones
previously reported in the literature.
1
6
INTRODUCTION
Jung and Im, formal synthesis using chiral oxazaborolidinium
■
triflimide-catalyzed Diels−Alder reaction by Corey and co-
Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that
is activated in response to deprived oxygen conditions in solid
tumors as a result of genetic adaptations that activate
17
workers, and, more recently, low-yielding convergent total
synthesis of (−)-laurenditerpenol have been accomplished
through an organolithium to aldehyde nucleophilic addition by
1
,2
oncogenes and inactivate tumor-suppressing genes.
It
1
8
Pitsinos et al.
controls the expression of genes influencing angiogenesis,
glucose metabolism, cell proliferation, survival, and invasion of
solid tumors and is therefore considered to be a central
regulator of major adaptive responses to hypoxia in cancer
3
−8
progression.
Moreover, hypoxia is known to induce tumor
9
−11
radioresistance through the activation of HIF-1.
Consistent
with these findings, there is clinical evidence that both the size
of the intratumoral hypoxic fraction and the level of HIF-1α
correlate with poor prognosis after radiation therapy. A growing
number of anticancer agents including natural products have
been shown to inhibit HIF-1 activity from submicromolar to
RESULTS AND DISCUSSION
■
1
5
In our earlier approach, three bottleneck issues were
identified: linear, multistep synthesis; low-yielding epimeriza-
tion to create the necessary chirality at C-6 position; and
recognition of the unstable nature of a ketal allyl bromide. All of
these three issues were necessary to make all the possible
isomers for determination of the absolute configuration of 1.
Thus, in order to develop an elegant, efficient, and
enantioselective synthetic route for (−)-laurenditerpenol,
these issues need to be addressed. Herein we report an
improved and enantioselective syntheses of both (−)- and
+)-laurenditerpenol starting from the corresponding (+)- or
−)-citronellal (5) chirons. Our retrosynthetic strategy is
outlined in Scheme 1, wherein the introduction of the required
chirality (S) at the nonfunctional C-7 position was envisioned
by use of the C1 chirality (S) of isopulegol as a remote
directing group in asymmetric hydrogenation. The envisioned
analysis is the result of our previous approach that eliminated
12
nanomolar concentrations. A recent tumor xenograft model
suggests that HIF-1 inhibitors suppress the translocation of
cancer cells that survive radiation therapy and decrease the
13
incidence of postirradiation tumor recurrence.
Laurenditerpenol 1 is a marine bicyclic diterpene isolated
14
from red algae Laurencia intricata that was found to inhibit
hypoxia (1% O )-induced HIF-1 activation in a T47D-cell-
2
based luciferase reporter assay with an IC50 value of 0.4 μM.
Mitochondrial respiration studies suggest that laurenditerpenol
is the first member of a structurally novel class of marine
natural product-based mitochondrial inhibitors that block
mitochondrial oxygen consumption and promote the degrada-
(
(
14
tion of HIF-1α protein under hypoxic conditions. Laurendi-
terpenol (C H O ) is unique because a fifth of its carbons are
20
34
2
15
nonfunctional chiral centers. In 2007, our group successfully
achieved the installation of nonfunctional chiral centers and
total synthesis of laurenditerpenol from eight plausible
stereoisomers. Subsequently, convergent racemic synthesis by
Received: July 9, 2013
Published: August 28, 2013
©
2013 American Chemical Society
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Article
Scheme 1. Retrosynthetic Analysis of (−)-Laurenditerpenol 1
unstable intermediates and obvious construction strategies
leading to a rather straightforward sulfone-mediated C−C bond
formation between allyl bromide 6 and sulfone 4. Additionally,
isopulegol would serve as a chiral synthon to give the required
stereochemistry at C-6 position and would yield stable allyl
bromide 6. The asymmetric double Michael/Diels−Alder
addition of crotonates or amides 2 to the furanone 3 enolate
can provide the 7-oxabicyclo[2.2.1]heptane scaffold for 4 with
appropriately adorned chirality and substituents.
Table 1. Chiral Auxiliary Induced Double Michael Addition
of Lithium Enolate of Furanone 3 to α,β-Unsaturated
Crotonates/Amides 2
The synthetic endeavor commenced with the excellent
diastereoselectivity observed between lithium enolate 3 and
19,20
methyl crotonate 2f to yield (±)-6-exo-keto ester 8f.
The
formation of the resulting adduct was due to either an “anion-
assisted” Diels−Alder reaction or sequential Michael additions.
To gain further insights into the mechanism and to perform
chiral synthesis, representative crotonates 2a and 2d and
amides 2b, 2c, and 2e were prepared by tethering the
appropriate chiral auxiliary and subjecting the product to the
lithium enolate of furanone 3. Crotonates 2a and 2d yielded the
compd
R1
Me
adduct 8 yield, de (%)
adduct 9 yield, de (%)
2
2
2
2
2
2
a
b
c
82, 55
a
Me
Me
Me
80, 75
84, 90
d
76, 60
20, 95
69
b
e
f
CO Et
65, 58
2
6-exo-keto esters 8a and 8d with poor diastereoselectivity
Me
ranging between 55% and 69%, whereas the crotonamides 2b
a
Instead of Et O/cyclohexane (3:1), the following were used as
solvent at −78 °C: Et O gave 9b (80, 76); THF gave 9b (78, 80); and
toluene gave 9b (70, 78). Instead of Et O/cyclohexane (3:1), the
2
and 2c furnished only mono-Michael adducts 9b and 9c in 80−
2
b
85% yield with >75% diastereomeric excess (de). On the basis
2
of these results, if product formation were due to a Diels−Alder
cycloaddition, all the crotonates or amides 2 would have
yielded the bicyclic compound 8. The exclusive formation of 9
in the case of amides 2b and 2c suggests that the formation of
adduct was due to mono-Michael addition and not “anion-
assisted” Diels−Alder reaction. Chemical discrimination in the
formation of bicyclic 8 or monocyclic 9 products can be
attributed to the reactivity of the resulting enolates (after initial
addition of furanone enolate to α,β-unsaturated double bond)
of crotonates and crotonamides in the second Michael addition.
Additionally, the product distribution is highly sensitive to
temperature, solvent, and solubility of the substrates 2 (see
Table 1).
following were used as solvent: Et O at −78 °C gave 9e (75, 60); Et O
2
2
at 0 °C gave 9e (76, 60); and Et O/cyclohexane (3:2) at 0 °C gave no
2
8
e product.
chemical resolution, was found to be highly practical. Both
enantiomers of sulfone 12 were prepared on a multigram scale
starting from 8f via thioketalization, saponification, resolution
with (S)-(−)-4-benzyl-2-oxazolidinone, desulfurization, reduc-
15
tion, iodination, and sulfonation to yield the corresponding
enantiomers (−)-12 [80%, three steps from (+)-10] and
(+)-12 [87%, three steps from (+)-11] as crystalline solids
(Scheme 2).
24
Following the synthetic strategy, ZnCl -catalyzed intra-
2
An attempt to perform intramolecular Michael addition on
molecular Prins cyclization of (S)-citronellal resulted in 70%
(+)-isopulegol and 11% (−)-neo-isopulegol with the required
C6 stereochemistry. The major (+)-isopulegol, (+)-13, was
separated via purification, silyl protection, and regioselective
adducts 9 proved to be difficult even with boron and titanium
2
1
triflates. A chiral lithium enolate of furanone 3 with a chiral
2
2
ternary complex derived from the dimethyl ether of (R,R)-
+)-hydrobenzoin proved unsuccessful in achieving chiral
induction in the sequential Michael addition. Finally, induction
25
(
allylic bromination with N-bromosuccinimide (NBS) employ-
ing Yamanaka conditions, which furnished bromide (+)-14 in
92% yield (two steps) (Scheme 3).
23
was achieved with fumaric ester amide 2e, wherein both
mono- (9e, 65% yield with 58% de) and double-Michael
adducts (8e, 20% yield with 95% de) were isolated (Table 1).
To achieve substantial amounts of 7-oxabicyclo[2.2.1]-
heptane intermediate 12, the earlier method, which relied on
Stereoselective alkylation of bromide (+)-14 with sulfone
(−)-12 was successfully achieved to furnish (+)-15a and
(+)-15b in 80% yield with good diastereoselectivity (diaster-
eomeric ratio, dr, 85:12) (Scheme 3). The presence of additive
9
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The Journal of Organic Chemistry
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Scheme 2. Synthesis and Chemical Resolution of 7-Oxabicyclo[2.2.1]heptane Fragment
Scheme 3. Synthesis of Allyl Bromide and Alkylation with Sulfone, (+)-12
Scheme 4. Substrate-Induced Asymmetric Hydrogenation with Crabtree’s Catalyst to Create a Remote Asymmetric Center at
a
C7: Synthesis of (−)-Laurenditerpenol 1
a
In the inset, hydrogen atoms are shown only on iridium metal, and all other H atoms and ligands are omitted for clarity.
hexamethylphosphoramide (HMPA) proved to be critical for
the successful transformation. The absolute stereochemistry of
newly created center at C9 in the major isomer (+)-15a was
confirmed with coupling constants and 2D NMR data. The
resulting olefinic 1,1-disubstituted homoallylic hydroxy com-
pound (+)-15a was subjected to TBS deprotection followed by
C1 and alkene between C7−C19, a rigid, chairlike intermediate
results to furnish the 7S isomer with extremely high
diastereoselectivity, >98% (see inset in Scheme 4).
Directed hydrogenation of the free alcohol derived from 15b
also yielded S-configuration at C7, suggesting that the
stereochemical outcome of the reaction was dictated solely by
the hydroxyl group and was independent of the stereochemistry
at the C9 position. However, the reduction in this case was
found to be sluggish (24 h with 15 mol % catalyst) and resulted
in 85% 16b and 10% 1,1,2-trisubstituted allylic alcohol. This
may be due to steric factors and higher pyridine concentration.
The free hydroxyl group was found, as expected, to be
2
6
hydrogenation with Crabtree’s cationic iridium catalyst
Ir(COD)(py)(PCy )]PF at atmospheric pressure and room
[
3
6
temperature. Directed hydrogenations at ambient conditions
are scarce, and the majority of the reported methods involve
27
elevated temperature and pressure. As anticipated, due to
simultaneous coordination of iridium to the hydroxyl group of
9
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Scheme 5. Enantioselective Synthesis of Unnatural (+)-Laurenditerpenol 1
necessary for the reduction of the 1,1-acyclic homoallylic
alcohols, and the isomerized trisubstituted 1,1,2-trialkyl olefin
did not react under these conditions. Interestingly, diaster-
eoselectivity of the directed hydrogenation was found to be
influenced by the presence of a bulky phenylsulfonyl group at
the C9 position. Thus, in the absence of the phenylsulfonyl
group, hydrogenation gave the desired product with 86%
diastereoselectivity at the newly created C7 center. In view of
the superior stereoselectivity observed with phenylsulfonyl-
substituted homoallylic alcohols, desulfonylation was per-
formed after the hydrogenation step, using sodium−mercury
in MeOH at room temperature to produce the secondary
alcohol (−)-17 in 85% yield. Dess−Martin periodinane
oxidation and regioselective enolization with lithium diisopro-
pylamide (LDA), followed by addition of PhSeCl, produced the
corresponding selenoethers (3:2 ratio of diastereomers), which
were further subjected to oxidative elimination to yield α,β-
unsaturated ketone (−)-19, whose NMR and other analytical
yield from commercially available 2,5-dimethylfuran-3(2H)-
one.
EXPERIMENTAL SECTION
■
General Methods. All reactions were performed under an
atmosphere of argon with oven-dried glassware and standard
syringe/septa techniques. All reactions were magnetically stirred with
Teflon stir bars, and temperatures were measured externally. Solvents
were distilled under an argon atmosphere prior to use. The solvents
tetrahydrofuran (THF) and Et O were distilled from sodium
2
benzophenone, while CH Cl2 and cyclohexane were dried over
2
P O . Triethylamine and hexamethylphosphoramide (HMPA) were
2 5
distilled from CaH2. Ethanol and methanol used were bottle-grade
solvents. All reagents obtained commercially were used without further
purification. The reaction progress was monitored on precoated silica
gel thin-layer chromatography (TLC) plates. Spots were visualized
under 254 nm UV light and/or by dipping the TLC plate into a
solution of 2 mL of anisaldehyde, 10 mL of glacial acetic acid, and 5
mL of H SO in 340 mL of EtOH, followed by heating with a heat
2
4
15
data were in agreement with previously reported data.
gun. Column chromatography was performed with silica gel (230−400
Finally, chemoselective reduction of the unsaturated ketone
under Luche conditions at −20 °C produced separable
laurenditerpenol (−)-1 and its C1 epimer in 82% yield with
mesh). All the solvents (hexanes, ethyl acetate, CH Cl , Et O) were
2
2
2
1
13
distilled prior to use for column chromatography. H and C NMR
spectra were measured in CDCl or C D on 400 MHz (100 MHz) or
3
6
6
5
00 MHz (125 MHz) machines. Chemical shifts were reported in
7
:3 ratio.
parts per million (ppm) downfield from tetramethylsilane (δ) as the
internal standard, and coupling constants are in hertz (Hz).
Assignment of proton resonances were confirmed by correlated
spectroscopy. IR spectra were recorded by use of a universal
attenuated total reflection sampling accessory (diamond ATR) on an
Agilent Cary 630 FT-IR spectrometer. High-resolution mass spectra
were recorded on an Agilent electrospray ionization quadrupole time-
of-flight (ESI-QTOF) instrument.
Following the same synthetic sequence, starting from sulfone
(
+)-12 and bromide (−)-14 prepared from commercially
available isopulegol, resulted in (+)-laurenditerpenol 1 in seven
steps with 29% overall yield (Scheme 5).
CONCLUSIONS
■
(
In summary, efficient and enantioselective syntheses of natural
−)-laurenditerpenol and its (+)-enantiomer were successfully
Syntheses. 1. (±)-Methyl 1,3,4-Trimethyl-5-oxo-7-oxabicyclo-
2.2.1]heptane-2-carboxylate, (±)-8f. To a freshly prepared solution
[
achieved starting from citronellal chirons. Crabtree’s iridium
catalyst at atmospheric pressure and ambient temperature
proved to be an efficient cationic metal catalyst for the
reduction of acyclic 1,1-disubstituted olefins with excellent
stereocontrol. The scope, generality, substrate tolerance, and
stereochemical factors associated with chiral induction in
hydrogenation of acyclic homoallylic alcohols are under
investigation. Overall, the current approach is elegant and
more efficient than the ones previously reported in the
literature by other synthetic sequences. The naturally occurring
of lithium diisopropylamine (31.2 mL, 220 mmol) in cyclohexane/
diethyl ether at 1:3 ratio (400 mL) was added furanone 3 (22.4 g, 200
mmol) at −78 °C. The mixture was stirred for 1 h at −78 °C. Then a
solution of methyl crotonate 2f (20 g, 200 mmol) in 1:3 cyclohexane/
ether (100 mL) was added slowly to the enolate solution at −78 °C,
and the resulting yellow colored mixture was stirred at the same
temperature. After 5 h, the reaction mixture was quenched with
saturated NH Cl solution (100 mL) and extracted with ether (3 × 100
4
mL). The combined layers were dried over anhydrous MgSO and
4
filtered, and the solvent was removed under reduced pressure. The
resulting product (± )-8f was distilled under high vacuum to yield a
2
0
(−)-laurenditerpenol was achieved in 14 steps with 8% overall
yellow viscous liquid (29.25 g, 69%; 95−100 °C at 1 mmHg). IR
9
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Article
−
1
1
(
cm ) 2975, 2932, 1762, 1729, 1436, 1380, 1163, 1017, and 867. H
NMR (400 MHz, chloroform-d) δ 3.66 (s, 3H), 2.49 (d, J = 17.8 Hz,
H), 2.39 (dd, J = 5.5, 2.1 Hz, 1H), 2.26 (qd, J = 6.9, 5.4 Hz, 1H), 2.14
dd, J = 17.9, 2.2 Hz, 1H), 1.59 (s, 3H), 1.24 (s, 3H), 1.04 (d, J = 6.9
(q, J = 6.6 Hz, 2H), 2.86 (dd, J = 13.4, 9.3 Hz, 1H), 2.08 (dd, J = 14.3,
1
3
1.8 Hz,1H), 1.49 (s, 3H), 1.40 (s, 3H), 1.08 (d, J = 7.0 Hz, 3H).
C
1
(
NMR (100 MHz, CDCl ) δ 172.3, 153.0, 135.0, 129.5 (2C), 128.9
3
(2C), 127.4, 92.7, 85.1, 76.9, 65.7, 59.2, 55.9, 52.2, 43.5, 40.4, 40.1,
37.4, 20.8, 18.7, 12.9. ESI-HRMS calcd for C H NO S , 434.1460
13
Hz, 3H). C NMR (100 MHz, CDCl ) δ 212.4, 172.0, 88.6, 82.9,
1.4, 52.2, 45.3, 40.1, 21.5, 16.2, 11.1. ESI-HRMS calcd for C H O ,
13.1127 [M + H] ; found, 213.1127.
. (±)-1,4,6-Trimethyl-7-oxaspiro(bicyclo[2.2.1]heptane-2,2′-
1,3]dithiolane)-5-carboxylic Acid, (±)-20. To a solution of bicyclic
keto methyl ester 8f (25.0 g, 118 mmol) in anhydrous benzene (300
mL) were added p-toluenesulfonic acid (p-TSA; 2.0 g, 11.8 mmol) and
ethanedithiol (19.8 mL, 235 mmol). The resulting mixture was stirred
for 12 h under reflux temperature and water was removed by use of a
Dean−Stark apparatus. After 6 h, the reaction mixture was cooled to
room temperature and concentrated under reduced pressure to give
crude residue, which was subjected to saponification without further
purification. The crude product was dissolved in methanol (300 mL),
3
22 28
4 2
+
6
2
[M + H] ; found, 434.1461.
11
17
4
+
4. (+)-(S)-4-Benzyl-3-[(1R,2R,3R,4S)-1,3,4-trimethyl-7-oxabicyclo-
[2.2.1]heptane-2-carbonyl]oxazolidin-2-one, (+)-10. To a suspen-
sion of Raney-2800 Ni (80 mL) in ethanol (40 mL) was added a
solution of (+)-21a (6.0 g, 13.85 mmol) in 60 mL of ethanol/THF
(8:2 v/v; THF is necessary to solubilize the starting material). The
reaction mixture was refluxed for 3 h, cooled to room temperature and
allowed to settle to two layers. The supernatant layer was carefully
decanted, then another 60 mL of EtOH/THF (8:2) was added, and
the mixture was stirred and decanted; the washings were repeated
three more times. The combined cloudy white organic layer was
filtered over Celite and concentrated under reduced pressure to give a
crude solid. The crude product was purified by silica gel column
chromatography (hexanes/EtOAc, 9:1) to give (+)-10 in 98% (4.6 g)
2
[
2
N LiOH in water (145 mL) was added at room temperature, and the
mixture was stirred for 2 h at 40 °C. The reaction mixture was cooled
to room temperature, diluted with water (100 mL), and extracted with
EtOAc (3 × 100 mL). The resulting aqueous layer was cooled to 0 °C,
and the pH was carefully adjusted to 2 with 2 N HCl. The resulting
pale cream-colored solid was filtered and dried under vacuum to
−1
yield as a white solid. [α] = +71.6 (c = 0.9, CHCl ). IR (cm ) 2966,
2
D
3
1
917, 2849, 1773, 1686, 1376, 1205, and 699, H NMR (400 MHz,
chloroform-d) δ 7.37−7.32 (m, 2H), 7.29 (dd, J = 7.9, 2.3 Hz, 1H),
7.25−7.22 (m, 2H), 4.79 (ddt, J = 9.8, 7.6, 3.6 Hz, 1H), 4.24−4.13 (m,
2H), 4.00 (dd, J = 4.9, 1.8 Hz, 1H), 3.30 (dd, J = 13.2, 3.6 Hz, 1H),
2.70 (dd, J = 13.2, 9.9 Hz, 1H), 2.37 (qd, J = 7.1, 4.8 Hz, 1H), 1.93
−1
furnish (± )-20 as a pale white solid (29.7 g, 92%). IR (cm ) 2922,
1
1
698, 1422, 1375, 1273, 1220, 1121, 892, and 778. H NMR (400
MHz, chloroform-d) δ 3.28 (ddt, J = 7.1, 5.0, 2.0 Hz, 3H), 3.06−2.97
m, 1H), 2.88−2.79 (m, 2H), 2.31 (dd, J = 6.4, 2.2 Hz, 1H), 2.21 (dd,
(dddd, J = 29.8, 11.1, 9.0, 4.2 Hz, 2H), 1.71 (td, J = 11.5, 3.5 Hz, 1H),
(
1
3
.53 (s, 3H), 1.50−1.44 (m, 1H), 1.36 (s, 3H), 0.96 (d, J = 7.1 Hz,
J = 14.4, 2.3 Hz, 1H), 1.52 (s, 3H), 1.46 (s, 3H), 1.08 (d, J = 6.9 Hz,
13
H). C NMR (100 MHz, CDCl ) δ 173.2, 153.3, 135.2, 129.4 (2C),
3
3
5
H). 13C NMR (100 MHz, CDCl ) δ 178.0, 91.9, 83.9, 76.8, 62.4,
3
129.1 (2C), 127.5, 86.5, 86.3, 66.0, 60.2, 55.5, 46.1, 38.8, 38.7, 34.0,
3.4, 41.9, 40.7, 40.5, 21.1, 19.0, 13.1. ESI-HRMS calcd for
C H O S , 275.0776 [M + H] ; found, 275.0777.
. Chemical Resolution of 7-Oxabicyclo[2.2.1]heptane. The acid
± )-20 (17.0 g, 62 mmol) was dissolved in anhydrous dichloro-
methane (DCM; 300 mL). Triethylamine (36 mL, 257 mmol) was
added, and the solution was cooled to 0 °C. To the resulting cold
solution was added pivaloyl chloride (7.62 mL, 62 mmol), and the
mixture was stirred for an additional 1 h at 0 °C. Then solid LiCl (2.19
g, 51.6 mmol) and (S)-4-benzyloxazolidin-2-one (9.14 g, 51.6 mmol)
were added in one portion, and stirring was continued. After 12 h,
TLC indicated formation of two new spots along with a small amount
of starting material oxazolidinone. The whole reaction mixture was
concentrated, diluted with water (300 mL), and extracted with DCM
3 × 100 mL). The combined organic layers were washed with 1 N
HCl (125 mL), 1 N NaOH (125 mL), and brine (75 mL), dried over
MgSO , filtered, and concentrated under reduced pressure. The
resulting viscous crude product was subjected to partial crystallization
with hot ether as a solvent. The compound (+)-21a was partially
soluble in ether, and (+)-21b was freely soluble in hot ether. After
repeated crystallization, (+)-21a (11.3 g) and (+)-21b (11.2 g) were
obtained in 42% and 41.6% yield, respectively.
+
2
1.2, 18.4, 17.9. ESI-HRMS calcd for C H NO , 344.1862 [M + H] ;
+
20 26 4
12
19
3 2
found, 344.1860.
3
5
. (−)-[(1R,2S,3R,4S)-1,3,4-Trimethyl-7-oxabicyclo[2.2.1]heptan-
(
2
-yl]methanol, (−)-22. To a suspension of LiAlH (1.0 g, 26.3
4
mmol) in anhydrous ether (20 mL) at 0 °C was added dropwise
(+)-10 (3.6 g, 10.5 mmol) in ether (20 mL). The reaction mixture was
stirred for 5 h at 0 °C, carefully quenched with saturated NH Cl (5
4
mL) solution, and stirred for an additional 1 h at room temperature.
The resulting white suspension was filtered over anhydrous MgSO4,
washed thoroughly with ether (2 × 20 mL), and concentrated under
reduced pressure. The crude residue was purified by silica gel column
chromatography (hexanes/Et O, 7:3) to produce (−)-22 as a white
2
−1
solid in 95% yield. [α] = −7.23 (c = 0.7, CHCl ). IR (cm ) 3434,
961, 2923, 2879, 1455, 1374, 1016, and 853. H NMR (400 MHz,
D
3
(
1
2
chloroform-d) δ 3.73 (dd, J = 10.8, 7.1 Hz, 1H), 3.63 (dd, J = 10.7, 7.8
Hz, 1H), 1.87−1.77 (m, 2H), 1.64 (td, J = 13.2, 12.6, 3.9 Hz, 1H),
4
1
0
6
.57−1.48 (m, 3H), 1.45 (s, 3H), 1.43−1.36 (m, 1H), 1.30 (s, 3H),
28
13
.96 (d, J = 6.9 Hz, 3H). C NMR (100 MHz, CDCl ) δ 84.8, 84.7,
3
4.2, 60.1, 46.0, 39.0, 32.1, 21.5, 18.6, 17.8. ESI-HRMS calcd for
+
C H O , 171.1385 [M + H] ; found, 171.1383.
10
19
2
6
. (−)-(1R,2R,3R,4S)-2-(Iodomethyl)-1,3,4-trimethyl-7-oxabicyclo-
(
+)-(S)-4-Benzyl-3-[(1R,4R,5R,6R)-1,4,6-Trimethyl-7-oxaspiro-
bicyclo[2.2.1]heptane-2,2′-[1,3]dithiolan)-5-ylcarbonyl]oxazolidin-
-one, (+)-21a. White solid; [α] = +40.9 (c = 1.0, CHCl ). IR
[
2.2.1]heptane, (−)-23. To a solution of alcohol (−)-22 (1.5 g, 8.82
(
2
(
(
4
6
3
2
7
1
4
mmol) in anhydrous DCM (60 mL) were added imidazole (1.8 g, 26.4
mmol) and triphenylphosphine (3.46 g, 13.2 mmol) at room
temperature. The reaction mixture was stirred for 30 min and then
cooled to 0 °C. Iodine (2.24 g, 17.63 mmol) was added to the
resulting cold solution, and the mixture was allowed to stir for 12 h at
room temperatureand then diluted with water (30 mL) and extracted
with DCM (2 × 25 mL). The combined organic layer was washed with
1 N Na S O (20 mL), dried over anhydrous MgSO , filtered, and
D
3
−1
1
cm ) 2991, 2935, 1774, 1682, 1384, 1188, 1054, and 697. H NMR
400 MHz, chloroform-d) δ 7.36−7.27 (m, 3H), 7.23−7.20 (m, 2H),
.80 (ddt, J = 9.8, 7.5, 3.5 Hz, 1H), 4.24−4.14 (m, 2H), 4.03 (dd, J =
.3, 1.6 Hz, 1H), 3.35−3.26 (m, 4H), 3.11 (d, J = 14.2 Hz, 1H), 3.08−
.01 (m, 1H), 3.01−2.94 (m, 1H), 2.71 (dd, J = 13.3, 9.8 Hz, 1H),
.10 (dd, J = 14.1, 1.7 Hz, 1H), 1.49 (s, 3H), 1.43 (s, 3H), 1.03 (d, J =
.0 Hz, 3H). 13C NMR (100 MHz, CDCl ) δ 172.3, 153.1, 135.0,
2
2
3
4
3
concentrated under reduced pressure to give crude residue, which was
29.4 (2C), 129.0 (2C), 127.4, 92.8, 85.3, 77.0, 65.9, 59.3, 55.4, 52.1,
3.2, 40.4, 40.0, 38.3, 20.7, 18.7, 12.9. ESI-HRMS calcd for
C H NO S , 434.1460 [M + H] ; found, 434.1465.
purified by silica gel column chromatography (hexanes/Et O, 9:1) to
2
+
yield (−)-23 (2.3 g) as a white solid in 94% yield. [α] = −40.6 (c =
D
22
28
4 2
−
1
1
1
.03, CHCl ). IR (cm ) 2964, 2871, 1449, 1377, 1189, and 863. H
3
(
+)-(S)-4-Benzyl-3-[(1S,4S,5S,6S)-1,4,6-trimethyl-7-oxaspiro-
NMR (400 MHz, chloroform-d) δ 3.12 (dd, J = 7.9, 3.9 Hz, 2H), 1.78
(dtt, J = 13.7, 6.3, 3.0 Hz, 2H), 1.66−1.51 (m, 2H), 1.48−1.40 (m,
(
2
(
(
(
bicyclo[2.2.1]heptane-2,2′-[1,3]dithiolan)-5-ylcarbonyl]oxazolidin-
-one, (+)-21b. White solid; [α] = +27.7 (c = 2.0, CHCl ). IR
D 3
−1
1
13
cm ) 2969, 2925, 1775, 1685, 1374, 1188, 1107, and 703. H NMR
400 MHz, chloroform-d) δ 7.31 (dt, J = 14.7, 6.9 Hz, 3H), 7.23−7.20
m, 2H), 4.74−4.66 (m, 1H), 4.17 (d, J = 4.8 Hz, 2H), 4.07 (dd, J =
2H), 1.39 (s, 3H), 1.25 (s, 3H), 1.00 (d, J = 6.9 Hz, 3H). C NMR
(100 MHz, CDCl ) δ 85.7, 84.9, 60.1, 50.5, 38.6, 31.7, 20.8, 18.6, 18.2,
3
+
6.0. ESI-HRMS calcd for C H IO, 281.0402 [M + H] ; found,
10
18
6
.5, 1.6 Hz, 1H), 3.33−3.26 (m, 4H), 3.09 (d, J = 14.2 Hz, 1H), 3.01
281.0405.
9
227
dx.doi.org/10.1021/jo401461x | J. Org. Chem. 2013, 78, 9223−9232

The Journal of Organic Chemistry
Article
7
. (−)-(1S,2R,3R,4R)-1,2,4-Trimethyl-3-[(phenylsulfonyl)methyl]-
114.0, 77.0, 49.3, 45.5, 39.7, 34.6, 32.0, 31.7, 26.0 (3C), 22.4, 18.1,
+
7
-oxabicyclo[2.2.1]heptane, (−)-12. To a suspension of anhydrous
−4.0, −4.5. ESI-HRMS calcd for C H BrOSi, 347.1406 [M + H] ;
16
32
sodium benzene sulfinate (2.05 g, 12.5 mmol) in hydrous N,N-
dimethylformamide (DMF) (40 mL) was added iodo compound
−)-23 (2.0 g, 7.14 mmol). The mixture was stirred for 12 h at 60 °C
and then cooled, diluted with water (100 mL), and extracted with
EtOAc (3 × 25 mL). The combined organic layer was dried over
MgSO , filtered, evaporated under reduced pressure, and purified by
silica gel column chromatography (hexanes/EtOAc, 8:2) to furnish
found, 347.1403.
10. Alkylation with Allyl Bromide (+)-14. In a 100 mL oven-dried
two-neck round-bottom flask, (−)-12 (1.2 g, 4.08 mmol) was
dissolved in anhydrous THF (20 mL) and cooled to −40 °C. To
the resulting cold solution were added freshly distilled HMPA (0.2
mL) and n-BuLi (2.37 mL of 2.5 M in hexanes, 6.1 mmol), and the
mixture was stirred for 2 h at −40 °C. After 2 h, bromide (+)-14 (2.83
g, 8.15 mmol) in anhydrous THF (20 mL) was added and stirring was
continued. After 5 h at −40 °C, TLC indicated formation of two new
nonpolar spots along with some amount of starting material (−)-12.
(
4
(
−)-12 (1.95 g) as a white solid in 95% yield. [α] = −15.07 (c = 0.96,
CHCl ). IR (cm ) 3059, 2969, 2935, 1446, 1304, 1141, and 865. H
D
−1
1
3
NMR (400 MHz, chloroform-d) δ 7.90 (d, J = 7.4 Hz, 2H), 7.67−7.62
(
m, 1H), 7.56 (dd, J = 8.4, 7.0 Hz, 2H), 3.07−3.03 (m, 2H), 1.79−
The reaction mixture was quenched with saturated NH Cl solution
4
1
1
1
3
.66 (m, 2H), 1.63−1.57 (m, 2H), 1.56−1.39 (m, 2H), 1.28 (s, 3H),
(10 mL) and then extracted with EtOAc (2 × 25 mL). The combined
.26 (s, 3H), 1.02 (d, J = 6.7 Hz, 3H). 13C NMR (100 MHz, CDCl ) δ
3
organic layers were dried over anhydrous MgSO and concentrated
4
39.7, 133.8, 129.4 (2C), 128.0 (2C), 85.6, 85.1, 58.9, 50.5, 48.6, 38.5,
under reduced pressure to give a crude residue, which was purified by
silica gel column chromatography (hexanes/EtOAc, 8.5:1.5) to yield
2.6, 19.8, 18.1, 18.0. ESI-HRMS calcd for C H O S, 295.1368 [M +
16
23
3
+
H] ; found, 295.1369.
. (+)-(1S,2R,5S)-5-Methyl-2-(prop-1-en-2-yl)cyclohexanol,
+)-13. An oven-dried 250 mL round-bottom flask was charged with
(+)-15a (1.53 g, 70%) and (+)-15b (0.23 g, 10%) as viscous liquids.
8
(
+)-tert-Butyldimethyl{[(1S,2R,5S)-5-methyl-2-[(S)-4-(phenylsul-
(
fonyl)-4-[(1R,2R,3R,4S)-1,3,4-trimethyl-7-oxabicyclo[2.2.1]heptan-2-
freshly prepared anhydrous ZnCl (0.35 g, 2.6 mmol) and anhydrous
yl]but-1-en-2-yl]cyclohexyl]oxy}silane, (+)-15a. [α] = +8.7 (c =
0.99, CHCl ). IR (cm ) 2951, 2926, 2855, 1446, 1305, 1144, 1060,
and 831. H NMR (400 MHz, chloroform-d) δ 7.85 (dd, J = 8.2, 1.3
2
D
−1
diethyl ether (10 mL). The solution was further diluted with
anhydrous DCM (40 mL) and cooled to −78 °C. To the resulting
cold solution was added (S)-citronellal 5 (4.0 g, 25.93 mmol) in 80
mL of DCM at −78 °C; the mixture was stirred for 2 h at the same
temperature and then allowed to warm to room temperature for an
additional 12 h. TLC indicated two new spots in the ratio of 3:1. The
reaction mixture was concentrated under reduced pressure to give a
crude residue, which was purified by silica gel column chromatography
3
1
Hz, 2H), 7.64−7.59 (m, 1H), 7.56−7.51 (m, 2H), 5.00 (s, 1H), 4.89
(s, 1H), 3.48 (td, J = 10.1, 4.2 Hz, 1H), 3.20 (dt, J = 9.6, 2.2 Hz, 1H),
2.92 (dd, J = 16.2, 9.4 Hz, 1H), 2.38 (d, J = 16.2 Hz, 1H), 1.84 (dddt, J
= 19.7, 12.3, 7.7, 3.9 Hz, 4H), 1.74 (td, J = 6.7, 3.3 Hz, 2H), 1.68−1.57
(m, 4H), 1.55−1.40 (m, 4H), 1.28 (s, 3H), 1.02 (s, 3H), 1.00 (d, J =
6.8 Hz, 3H), 0.92 (d, J = 6.5 Hz, 3H), 0.83 (s, 9H), 0.02 (s, 3H),
13
(
hexanes/Et O, 7:3) to yield (+)-isopulegol 13 (2.8 g, 70%) as a major
compound, along with 0.44 g (11%) of (−)-neoisopulegol. [α]D
11.9 (c = 2.0, CHCl ). IR (cm ) 3369, 3072, 2920, 2968, 1644,
−0.02 (s, 3H). C NMR (100 MHz, CDCl ) δ 148.9, 138.7, 133.6,
2
3
2
4
=
129.3 (2C), 129.1 (2C), 111.8, 85.6, 85.5, 76.8, 61.3, 55.4, 50.9, 45.8,
41.9, 39.3, 35.1, 34.8, 33.1, 31.7, 31.7, 26.1 (3C), 22.3, 19.8, 18.4, 18.3,
18.2, −4.0, −4.2. ESI-HRMS calcd for C H O SSi, 561.3434 [M +
−1
+
1
3
1
447, 1374, 1094, 1026, and 883. H NMR (400 MHz, chloroform-d)
32
53
4
+
δ 4.85−4.79 (m, 2H), 3.41 (td, J = 10.4, 4.3 Hz, 1H), 2.03 (s, 1H),
H] ; found, 561.3434.
1
1
3
.98 (ddt, J = 9.6, 4.2, 1.8 Hz, 1H), 1.83 (ddd, J = 13.0, 9.9, 3.4 Hz,
H), 1.67−1.66 (m, 3H), 1.64−1.59 (m, 2H), 1.45 (tdt, J = 11.9, 6.5,
.3 Hz, 1H), 1.33−1.21 (m, 1H), 0.98−0.91 (m, 2H), 0.89 (d, J = 6.6
(+)-tert-Butyldimethyl{[(1S,2R,5S)-5-methyl-2-[(R)-4-(phenylsul-
fonyl)-4-[(1R,2R,3R,4S)-1,3,4-trimethyl-7-oxabicyclo[2.2.1]heptan-2-
yl]but-1-en-2-yl]cyclohexyl]oxy}silane, (+)-15b). [α]
= +37.5 (c =
0.93, CHCl ). IR (cm ) 2952, 2926, 2856, 1446, 1304, 1146, 1060,
3
D
13
−1
Hz, 3H). C NMR (100 MHz, CDCl ) δ 146.7, 112.7, 70.4, 54.1, 42.
3
1
8
[
, 34.4, 31.5, 29.7, 22.2, 19.2. ESI-HRMS calcd for C H O, 155.1436
and 832. H NMR (400 MHz, chloroform-d) δ 7.89 (d, J = 7.4 Hz,
2H), 7.62 (t, J = 7.3 Hz, 1H), 7.54 (t, J = 7.6 Hz, 2H), 4.74 (d, J = 8.3
Hz, 2H), 3.19 (td, J = 10.2, 4.1 Hz, 1H), 3.03 (dt, J = 8.3, 3.1 Hz, 1H),
2.63 (p, J = 6.7 Hz, 1H), 2.57−2.51 (m, 1H), 2.34 (ddd, J = 12.8, 9.2,
4.2 Hz, 1H), 2.27 (dd, J = 15.2, 8.3 Hz, 1H), 1.93 (ddd, J = 11.3, 9.1,
4.6 Hz, 1H), 1.83−1.79 (m, 1H), 1.65 (ddt, J = 11.7, 7.8, 4.1 Hz, 2H),
1.54−1.46 (m, 4H), 1.32 (d, J = 2.7 Hz, 7H), 1.09 (d, J = 6.7 Hz, 3H),
1.00 (dd, J = 13.1, 3.4 Hz, 1H), 0.81 (d, J = 6.5 Hz, 3H), 0.79 (s, 9H),
10
19
+
M + H] ; found, 155.1430.
. (+)-{[(1S,2R,5S)-2-(3-Bromoprop-1-en-2-yl)-5-methylcyclo-
hexyl]oxy}(tert-butyl)dimethylsilane, (+)-14. To a solution of
+)-13 (2.0 g, 12 mmol) in anhydrous DCM (40 mL) was added
9
(
N,N-diisopropylethylamine (DIPEA; 4.4 mL, 25.7 mmol), and the
mixture was stirred for 30 min at 0 °C. tert-Butyldimethylsilyl
trifluoromethanesulfonate (TBSOTf; 3.4 g, 15.4 mmol) in DCM (20
mL) was added dropwise to the reaction mixture at 0 °C, and stirring
was continued for 5 h at room temperature. The reaction mixture was
13
0.64−0.46 (m, 2H), −0.08 (s, 3H), −0.14 (s, 3H). C NMR (100
MHz, CDCl ) δ 148.2, 139.9, 133.4, 129.3 (2C), 128.7 (2C), 111.3,
3
quenched with saturated NH Cl (30 mL) and extracted with DCM (3
85.7, 85.7, 76.8, 61.8, 58.7, 50.4, 45.4, 43.0, 41.3, 39.4, 34.6, 33.9, 31.4,
4
×
50 mL). The combined organic layers were evaporated under
31.4, 26.0 (3C), 22.3, 21.9, 19.2, 18.2, 18.1, −4.0, −4.2. ESI-HRMS
+
reduced pressure to give crude TBS-protected (+)-isopulegol, which
was subjected to allylic bromination without further purification. The
crude residue (3.2 g, 11.9 mmol) was dissolved in 30 mL of DCM/
THF (4:1, v/v), N-bromosuccinimide (2.5 g, 14.1 mmol) was added,
and the mixture was cooled to 0 °C. After 5 min, trimethylsilyl
chloride (TMSCl; 64.3 mg, 5 mol %) and Yb(OTf) (369 mg, 5 mol
) were added at 0 °C, and stirring was continued for 5 h at room
calcd for C H O SSi, 561.3434 [M + H] ; found, 561.3431.
32
53
4
11. (−)-(1S,2R,5S)-5-Methyl-2-{4-(phenylsulfonyl)-4-
[(1R,2R,3R,4S)-1,3,4-trimethyl-7-oxabicyclo[2.2.1]heptan-2-yl]but-1-
en-2-yl}cyclohexanol, (−)-24a. To a solution of (+)-15a (1.0 g, 1.78
mmol) in anhydrous DCM (10 mL) at 0 °C was added dropwise a 2
M solution TFA in DCM (10 mL), and stirring was continued for 2 h
at 0 °C. The reaction mixture was carefully quenched with saturated
3
%
temperature. The reaction mixture was quenched with saturated
NH Cl, diluted with DCM (30 mL), washed with NaHCO , Na SO ,
NaHCO
layer was dried over MgSO
and purified by silica gel column chromatography (hexanes/EtOAc,
8:2) to give (−)-24a (0.715 g, 90%) as a white solid. [α] = −7.06 (c
). IR (cm ) 3503, 2950, 2924, 2871, 1446, 1379, 1303,
3
solution and extracted with DCM (2 × 10 mL). The organic
, concentrated under reduced pressure,
4
3
2
3
4
and H O, and dried over MgSO . The organic layer was concentrated
and purified by silica gel column chromatography with hexanes to yield
compound (+)-14 (3.8 g) in 92% yield as a colorless liquid. [α]
2
4
D
−1
=
= 0.81, CHCl
3
D
−1
1
+
81.03 (c = 2.0, CHCl ). IR (cm ) 2951, 2926, 2855, 1458, 1361,
1143, 1083, and 867. H NMR (500 MHz, chloroform-d) δ 7.90 (dt, J
= 7.2, 1.3 Hz, 2H), 7.69−7.65 (m, 1H), 7.58 (t, J = 7.7 Hz, 2H), 5.05
(s, 1H), 4.95 (s, 1H), 3.58 (td, J = 10.4, 4.2 Hz, 1H), 3.37 (dt, J = 9.0,
2.0 Hz, 1H), 2.79 (dd, J = 18.0, 8.9 Hz, 2H), 2.46 (dq, J = 18.4, 2.1 Hz,
1H), 2.04 (dtd, J = 12.7, 3.9, 1.9 Hz, 1H), 1.89 (dqd, J = 9.3, 4.0, 2.7,
2.2 Hz, 2H), 1.81−1.75 (m, 1H), 1.68 (dtd, J = 13.3, 7.2, 6.6, 3.4 Hz,
4H), 1.52 (ddt, J = 12.6, 6.2, 3.8 Hz, 2H), 1.48−1.40 (m, 2H), 1.32 (s,
3H), 1.27 (d, J = 2.4 Hz, 1H), 1.23 (dd, J = 13.1, 3.2 Hz, 1H), 1.07 (d,
3
1
1
1
1
1
1
100, 1060, and 830. H NMR (400 MHz, chloroform-d) δ 5.24 (s,
H), 4.99 (s, 1H), 4.07 (dd, J = 9.8, 1.1 Hz, 1H), 4.00 (d, J = 9.7 Hz,
H), 3.46 (td, J = 10.2, 4.2 Hz, 1H), 2.04 (ddd, J = 13.0, 9.7, 3.8 Hz,
H), 1.86 (dtd, J = 12.9, 3.9, 2.0 Hz, 1H), 1.78 (dq, J = 10.2, 3.3 Hz,
H), 1.71−1.60 (m, 1H), 1.51−1.44 (m, 1H), 1.36 (dd, J = 13.1, 3.5
Hz, 1H), 1.10−1.00 (m, 2H), 0.93 (d, J = 6.6 Hz, 3H), 0.85 (s, 9H),
.02 (s, 3H), −0.05 (s, 3H). C NMR (100 MHz, CDCl ) δ 149.9,
13
0
3
9
228
dx.doi.org/10.1021/jo401461x | J. Org. Chem. 2013, 78, 9223−9232

The Journal of Organic Chemistry
Article
J = 6.7 Hz, 3H), 1.01 (s, 3H), 0.96 (d, J = 6.5 Hz, 3H), 13C NMR (125
prepared from (+)-24b (0.15 g, 0.34 mmol) as a white solid, along
with 5% trisubstituted olefin. [α] = +12.1 (c = 1.8, CHCl ). IR
MHz, CDCl ) δ 148.4, 137.8, 133.9, 129.3 (2C), 129.3 (2C), 110.1,
3
D
3
−1
8
3
5.7, 85.6, 72.6, 61.2, 55.0, 53.4, 43.4, 42.3, 39.0, 34.6, 32.9, 31.6 (2C),
1.5, 22.3, 19.6, 18.4, 18.3. ESI-HRMS calcd for C H O S, 447.2569
(cm ) 3491, 2958, 2921, 2871, 1447, 1379, 1303, 1143, 1082, and
1
866. H NMR (400 MHz, chloroform-d) δ 7.90 (d, J = 7.4 Hz, 2H),
26
39
4
+
[
M + H] ; found, 447.2569.
2. (+)-(1S,2R,5S)-5-methyl-2-{(R)-4-(phenylsulfonyl)-4-
(1R,2R,3R,4S)-1,3,4-trimethyl-7-oxabicyclo[2.2.1]heptan-2-yl]but-1-
7.63 (t, J = 7.4 Hz, 1H), 7.55 (t, J = 7.5 Hz, 2H), 3.21 (td, J = 10.4, 4.2
Hz, 1H), 2.98 (ddd, J = 9.0, 5.8, 3.4 Hz, 1H), 2.47 (p, J = 6.6 Hz, 1H),
2.11 (td, J = 11.8, 10.4, 4.0 Hz, 1H), 1.97 (dp, J = 6.9, 4.0, 3.6 Hz, 1H),
1
[
en-2-yl}cyclohexanol, (+)-24b. By the same procedure as for (−)-24a
1
.93−1.87 (m, 1H), 1.85−1.79 (m, 1H), 1.76 (td, J = 5.7, 2.3 Hz, 1H),
(
section 11), (+)-24b (0.178 g, 90%) was prepared from (+)-15b
0.250 g, 0.45 mmol) as a white solid. [α] = +13.9 (c = 2.5, CHCl ).
1
.70−1.57 (m, 4H), 1.54−1.49 (m, 2H), 1.45 (s, 3H), 1.32 (s, 3H),
(
D
3
1.18 (d, J = 6.7 Hz, 1H), 1.08 (d, J = 6.8 Hz, 3H), 0.88 (t, J = 6.9 Hz,
−1
13
IR (cm ) 3511, 2955, 2922, 2869, 1446, 1378, 1301, 1142, 1083, and
8
6H), 0.79−0.72 (m, 2H), 0.25 (d, J = 6.8 Hz, 3H). C NMR (100
MHz, CDCl ) δ 139.7, 133.6, 129.1 (2C), 128.9 (2C), 85.9, 85.2, 70.8,
1
66. H NMR (400 MHz, chloroform-d) δ 7.92−7.89 (m, 2H), 7.63
3
(
(
dd, J = 8.3, 6.3 Hz, 1H), 7.55 (t, J = 7.6 Hz, 2H), 4.90 (s, 1H), 4.82
s, 1H), 3.49 (td, J = 7.3, 4.0 Hz, 1H), 3.27 (td, J = 10.3, 4.2 Hz, 1H),
62.9, 58.8, 49.5, 45.2, 44.5, 39.2, 36.6, 34.3, 33.5, 31.6, 27.9, 23.4, 22.2,
21.9, 19.0, 18.2, 12.4. ESI-HRMS calcd for C H O S, 466.2744 [M +
26
42
5
+
2.59 (dd, J = 17.9, 6.8 Hz, 1H), 2.45−2.38 (m, 1H), 2.06 (dd, J = 5.3,
2.0 Hz, 1H), 1.94 (ddq, J = 13.5, 9.1, 4.7 Hz, 2H), 1.85 (ddd, J = 7.7,
4.9, 2.1 Hz, 1H), 1.66−1.58 (m, 4H), 1.50 (ddd, J = 13.2, 6.1, 2.6 Hz,
3H), 1.45 (s, 3H), 1.27 (s, 3H), 1.13 (td, J = 12.9, 3.5 Hz, 2H), 1.06
H O] ; found, 466.2741.
2
16. (−)-(1S,2R,5S)-5-Methyl-2-{(S)-4-[(1R,2R,3R,4S)-1,3,4-trimeth-
yl-7-oxabicyclo[2.2.1]heptan-2-yl]butan-2-yl}cyclohexanol, (−)-17.
Both (−)-16a and (+)-16b were subjected to desulfonylation by use
of sodium−mercury. For example, (−)-16a (0.4 g, 0.89 mmol) was
dissolved in methanol (10 mL), and Na−Hg granules (0.24g, 1.07
mmol) were added. The reaction mixture was stirred for 30 min at
room temperature and then concentrated under reduced pressure to
give a crude residue, which was purified by silica gel column
chromatography (hexanes/EtOAc, 8.5:1.5) to yield (−)-17 (0.233 g,
85%) as a colorless viscous liquid. [α] = −4.86 (c = 0.4, CHCl ). IR
(
d, J = 6.7 Hz, 3H), 0.90 (d, J = 6.6 Hz, 3H), 0.82 (dd, J = 13.3, 10.2
13
Hz, 2H). C NMR (100 MHz, CDCl ) δ 146.7, 139.7, 133.8, 129.2
3
(
3
2C), 128.8 (2C), 111.9, 86.0, 84.9, 71.7, 63.2, 57.1, 53.1, 46.1, 43.2,
8.8, 34.5, 33.9, 33.5, 31.5, 30.6, 22.9, 22.2, 18.6, 18.2. ESI-HRMS
+
calcd for C H O S, 447.2569 [M + H] ; found, 447.2575.
26
39
4
1
3. (+)-(1S,2R,5S)-5-Methyl-2-{4-[(1R,2R,3R,4S)-1,3,4-trimethyl-7-
oxabicyclo[2.2.1]heptan-2-yl]but-1-en-2-yl}cyclohexanol, (+)-15c.
Both (−)-24a and (+)-24b were subjected to desulfonylation with
sodium−mercury. For example, (−)-24a (0.035 g, 0.078 mmol) was
dissolved in methanol (2 mL), and sodium−mercury granules (0.021g,
D
3
−1
1
(cm ) 3416, 2955, 2920, 2866, 1455, 1378, 1215, 1038, and 864. H
NMR (400 MHz, chloroform-d) δ 3.43 (td, J = 10.4, 4.3 Hz, 1H),
2.01−1.94 (m, 2H), 1.84 (ddd, J = 12.5, 8.9, 4.0 Hz, 1H), 1.70−1.49
(m, 6H), 1.41 (ddd, J = 12.3, 5.4, 2.1 Hz, 2H), 1.34 (s, 3H), 1.30 (d, J
= 1.8 Hz, 2H), 1.27 (s, 3H), 1.25 (d, J = 1.5 Hz, 2H), 1.17 (dq, J = 9.5,
2.7 Hz, 2H), 1.03−0.97 (m, 2H), 0.91 (d, J = 6.7 Hz, 6H), 0.87 (d, J =
0.094 mmol) were added. The mixture was stirred for 30 min at room
temperature and then concentrated under reduced pressure to give a
crude residue, which was purified by silica gel column chromatography
3.6 Hz, 1H), 0.80 (d, J = 6.9 Hz, 3H). 13C NMR (100 MHz, CDCl ) δ
(
hexanes/EtOAc, 8.5:1.5) to yield (+)-15c (0.030 g, 85%) as a
3
−1
colorless viscous liquid. [α]D = +3.48 (c = 0.9, CHCl ). IR (cm )
3
85.9, 84.8, 71.3, 58.5, 48.9, 48.9, 45.2, 39.2, 35.0, 34.7, 32.2, 31.8, 31.5,
30.6, 23.3, 22.3, 20.8, 19.4, 18.2, 14.0. ESI-HRMS calcd for C H O ,
3
1
451, 2951, 2920, 2870, 1639, 1449, 1376, 1221, 1048, and 866. H
2
0
37
2
+
NMR (400 MHz, chloroform-d) δ 4.92−4.90 (m, 2H), 4.87 (s, 1H),
309.2794 [M + H] ; found, 309.2790.
3
3
=
.51 (td, J = 10.4, 4.3 Hz, 1H), 2.15−1.93 (m, 4H), 1.89−1.80 (m,
H), 1.69 (td, J = 5.5, 4.6, 2.8 Hz, 1H), 1.66−1.62 (m, 1H), 1.58 (dd, J
17. (−)-(2R,5S)-5-Methyl-2-{(S)-4-[(1R,2R,3R,4S)-1,3,4-trimethyl-7-
oxabicyclo[2.2.1]heptan-2-yl]butan-2-yl}cyclohexanone, (−)-18. To
a solution of (−)-17 (0.2 g, 0.64 mmol) in anhydrous DCM (10 mL)
was added Dess−Martin periodinane (0.302 g, 0.71 mmol) at 0 °C.
The reaction mixture was stirred for 3 h at room temperature. After
completion of the reaction (as indicated by TLC), the reaction mixture
was concentrated under reduced pressure to give a crude residue,
which was purified by silica gel column chromatography (hexanes/
12.3, 4.2 Hz, 2H), 1.51 (ddd, J = 11.7, 7.7, 4.4 Hz, 2H), 1.36 (s, 5H),
1
.27 (s, 3H), 1.24−1.18 (m, 2H), 1.00−0.96 (m, 1H), 0.94 (d, J = 3.3
13
Hz, 3H), 0.92 (d, J = 6.0 Hz, 3H). C NMR (100 MHz, CDCl ) δ
3
1
3
51.5, 110.3, 85.7, 84.8, 71.6, 58.1, 53.6, 48.8, 42.9, 39.2, 34. 7, 33.6,
2.3, 31.6, 31.0, 30.7, 22.3, 20. 8, 19.4, 18.2. ESI-HRMS calcd for
+
C H O , 324.2659 [M + H O] ; found, 324.2658.
20
34
2
2
1
4. (−)-(1S,2R,5S)-5-Methyl-2-{(2S,4S)-4-(phenylsulfonyl)-4-
EtOAc, 9:1) to yield (−)-18 (0.180 g, 95%) as a colorless liquid. [α]
D
−1
[
(1R,2R,3R,4S)-1,3,4-trimethyl-7-oxabicyclo[2.2.1]heptan-2-yl]-
= −4.73 (c = 0.6, CHCl ). IR (cm ) 3464, 2955, 2920, 2871, 1455,
3
1
butan-2-yl}cyclohexanol, (−)-16a. To a solution of (−)-24a (0.5 g,
.12 mmol) in anhydrous DCM (10 mL) was added [Ir(COD)(py)-
PCy )]PF (Crabtree’s catalyst; 45 mg, 0.05 mmol). The reaction
1378, 1215, 1038, and 864. H NMR (400 MHz, benzene-d ) δ 2.34−
6
1
2.27 (m, 1H), 2.21 (p, J = 6.1 Hz, 1H), 1.86 (dt, J = 13.0, 5.1 Hz, 1H),
1.79 (ddd, J = 14.1, 10.0, 3.9 Hz, 1H), 1.69 (ddt, J = 13.0, 6.0, 3.5 Hz,
1H), 1.65−1.53 (m, 2H), 1.52−1.34 (m, 5H), 1.40 (s, 3H), 1.29 (s,
3H), 1.24 (t, J = 4.7 Hz, 5H), 1.20−1.14 (m, 2H), 0.98 (d, J = 6.8 Hz,
(
3
6
mixture was stirred for 2 h under H gas at atmospheric pressure and
2
room temperature and then concentrated under reduced pressure and
purified by silica gel column chromatography (hexanes/EtOAc,
1
3
3H), 0.92 (d, J = 6.8 Hz, 3H), 0.71 (d, J = 6.3 Hz, 3H). C NMR (100
8
.5:1.5) to yield (−)-16a (450 mg, 90%) as a white solid. [α]
=
MHz, C D6) δ 209.5, 85.5, 84.4, 58.9, 54.2, 50.7, 49.3, 39.6, 35.0, 35.0,
D
6
−1
−
6.68 (c = 0.8, CHCl ). IR (cm ) 3495, 2951, 2922, 2870, 1446,
34.1, 32.7, 31.5, 30.8, 27.2, 22.4, 21.1, 19.7, 18.4, 16.3. ESI-HRMS
3
1
+
1
379, 1302, 1142, 1083, and 865. H NMR (400 MHz, chloroform-d)
calcd for C H O , 307.2637 [M + H] ; found, 307.2635.
20
35
2
δ 7.90 (d, J = 7.7 Hz, 2H), 7.64 (t, J = 7.3 Hz, 1H), 7.56 (t, J = 7.6 Hz,
18. (−)-(R)-3-Methyl-6-{(S)-4-[(1R,2R,3R,4S)-1,3,4-trimethyl-7-
oxabicyclo[2.2.1]heptan-2-yl]butan-2-yl}cyclohex-2-enone, (−)-19.
In a 25-mL two-neck round-bottom flask, (−)-18 (0.12 g, 0.3 mmol)
was dissolved in anhydrous THF (6 mL) and cooled to −78 °C. A 2.0
M solution of lithium diisopropylamide (LDA; 0.25 mL, 0.47 mmol)
was added and the mixture was stirred at the same temperature. After 1
h, phenylselenyl chloride (0.104 g, 0.54 mmol) in anhydrous THF (2
mL) was added, and stirring was continued for an additional 4 h at
2
2
H), 3.33 (td, J = 10.4, 4.2 Hz, 1H), 3.00 (dt, J = 8.6, 3.1 Hz, 1H),
.39 (q, J = 7.9, 7.1 Hz, 1H), 2.07−1.93 (m, 3H), 1.86 (dt, J = 5.0, 2.5
Hz, 1H), 1.73 (dddd, J = 22.2, 13.4, 7.9, 4.0 Hz, 3H), 1.61 (td, J =
1
1
1
3
3.7, 13.0, 3.6 Hz, 2H), 1.54−1.48 (m, 2H), 1.45 (t, J = 4.8 Hz, 1H),
.43−1.40 (m, 1H), 1.36 (t, J = 3.3 Hz, 1H), 1.33 (d, J = 3.2 Hz, 1H),
.29 (s, 3H), 1.17−1.07 (m, 2H), 1.03 (s, 3H), 0.98 (d, J = 6.6 Hz,
13
H), 0.90 (d, J = 6.4 Hz, 3H), 0.84 (d, J = 7.0 Hz, 3H). C NMR (100
−
78 °C. The reaction mixture was quenched with saturated NH Cl
MHz, CDCl ) δ 138.6, 133.7, 129.3 (2C), 129.3 (2C), 85.7, 85.4, 71.2,
4
3
solution and extracted with Et O (2 × 15 mL). The ether layer was
6
1
1.3, 55.4, 49.3, 45.2, 42.1, 39.1, 34.6, 32.9, 32.8, 31.7, 29.5, 23.6, 22.3,
9.9, 18.5, 18.3, 14.1. ESI-HRMS calcd for C H O S, 449.2726 [M +
2
dried over MgSO and concentrated under reduced pressure. The
4
26
41
4
+
crude residue (0.18 g) was dissolved in DCM (5 mL) and cooled to 0
H] ; found, 449.2731.
5. (+)-(1S,2R,5S)-5-Methyl-2-{(2S,4R)-4-(phenylsulfonyl)-4-
(1R,2R,3R,4S)-1,3,4-trimethyl-7-oxabicyclo[2.2.1]heptan-2-yl]-
butan-2-yl)cyclohexanol, (+)-16b. By the same procedure as for
−)-16a (section 14), the diastereomer (+)-16b (0.127 g, 85%) was
°
C, and pyridine (0.37 mL, 0.47 mmol) and 30% H O (0.66 mL, 0.58
1
2 2
[
mmol) were added. The reaction mixture was was stirred for 2 h at 0
°C and then concentrated under reduced pressure to give a crude
residue, which was purified by silica gel column chromatography
(
9
229
dx.doi.org/10.1021/jo401461x | J. Org. Chem. 2013, 78, 9223−9232

The Journal of Organic Chemistry
Article
(
hexanes/EtOAc, 9:1) to yield (−)-19 (0.1 g, 85%) as a pale yellow
85.4, 84.9, 58.7, 50.4, 48.3, 38.4, 32.5, 19.6, 17.9, 17.8. ESI-HRMS
−1
+
liquid. [α] = −35.9 (c = 0.3, CHCl ). IR (cm ) 2963, 2923, 2870,
1
δ 5.88−5.83 (m, 1H), 2.33−2.28 (m, 2H), 2.14 (dt, J = 12.0, 4.3 Hz,
1
8
2
1
MHz, CDCl ) δ 201.1, 161.3, 127.2, 85.8, 84.8, 58.3, 50.0, 48.9, 39.2,
3
HRMS calcd for C H O , 305.2481 [M + H] ; found, 305.2486.
calcd for C H O S, 295.1368 [M + H] ; found, 295.1368.
D
3
16 23
3
1
664, 1450, 1376, 1207, and 866. H NMR (400 MHz, chloroform-d)
24. (−)-{[(1R,2S,5R)-2-(3-Bromoprop-1-en-2-yl)-5-
methylcyclohexyl]oxy}(tert-butyl)dimethylsilane, (−)-14. By follow-
ing the same procedure for the preparation of (+)-14 (section 9),
(−)-14 (4.49 g, 86%) was prepared from commercially available
H), 1.93 (s, 3H), 1.90 (q, J = 4.3 Hz, 1H), 1.81 (dddd, J = 16.6, 12.8,
.2, 4.7 Hz, 3H), 1.63−1.49 (m, 3H), 1.41 (ddd, J = 12.4, 5.6, 2.3 Hz,
H), 1.34 (s, 3H), 1.32−1.28 (m, 3H), 1.27 (s, 3H), 1.19−1.13 (m,
H), 0.90 (d, J = 6.9 Hz, 3H), 0.81 (d, J = 6.8 Hz, 3H). 13C NMR (100
(−)-isopulegol (2.5 g, 16.1 mmol) as a colorless low-melting solid.
−1
[α]
= −86.31 (c = 2.0, CHCl
). IR (cm ) 2955, 2926, 2855, 1461,
D
3
1
1361, 1099, 1060, and 830. H NMR (500 MHz, chloroform-d) δ 5.24
(s, 1H), 4.99 (s, 1H), 4.08−3.98 (m, 2H), 3.48−3.42 (m, 1H), 2.06−
2.00 (m, 1H), 1.85 (ddt, J = 12.7, 4.1, 1.9 Hz, 1H), 1.80−1.75 (m,
1H), 1.67−1.62 (m, 1H), 1.50−1.44 (m, 1H), 1.36 (ddd, J = 13.2, 3.9,
1.3 Hz, 1H), 1.04 (tdd, J = 12.2, 10.7, 1.4 Hz, 2H), 0.92 (dd, J = 6.7,
3
4.2, 32.2, 31.2, 30.9, 30.2, 24.3, 22.7, 20.8, 19.4, 18.2, 15.9. ESI-
+
20
33
2
1
9. (−)-(1S,6R)-3-Methyl-6-{(S)-4-[(1R,2R,3R,4S)-1,3,4-trimethyl-7-
oxabicyclo[2.2.1]heptan-2-yl]butan-2-yl}cyclohex-2-enol, (−)-1. To
a solution of (−)-19 (0.08 g, 0.26 mmol) in methanol (5 mL) were
added CeCl (0.07 g, 1.1 mmol) and NaBH (0.005 g, 0.5 mmol) at
1
3
1.4 Hz, 3H), 0.83 (s, 9H), 0.01 (s, 3H), −0.06 (s, 3H). C NMR (125
MHz, CDCl ) δ 149.9, 114.0, 77.0, 49.2, 45.4, 40.0, 34.6, 31.9, 31.7,
3
4
3
−
20 °C, and stirring was continued for an additional 3 h at the same
26.0 (3C), 22.4, 18.1, −4.0, −4.6. ESI-HRMS calcd for C H BrOSi,
1
6
32
+
temperature. After completion of the reaction as monitored by TLC,
the reaction mixture was concentrated under reduced pressure and
purified by silica gel column chromatography (hexanes/EtOAc, 8:2) to
give the final compound (−)-laurenditerpenol, (−)-1, as a viscous
colorless liquid (46.7 mg, 58%). All the spectral data are matched with
347.1406 [M + H] ; found, 347.1406.
25. Alkylation with Allyl Bromide (−)-14. By following the same
procedure for the preparation of (+)-15a and (+)-15b (section 10),
(−)-15a (1.94 g, 68%) and (−)-15b (0.2 g, 7%) were prepared from
(+)-12 (1.5 g, 5.1 mmol) as viscous liquids.
1
reported data.
(−)-tert-Butyldimethyl{[(1R,2S,5R)-5-methyl-2-{(R)-4-(phenylsul-
2
0. (+)-(S)-4-Benzyl-3-[(1S,2S,3S,4R)-1,3,4-trimethyl-7-
fonyl)-4-[(1S,2S,3S,4R)-1,3,4-trimethyl-7-oxabicyclo[2.2.1]heptan-2-
oxabicyclo[2.2.1]heptane-2-carbonyl]oxazolidin-2-one, (+)-11. By
following the same procedure for the preparation of (+)-10 (section
4
yl]but-1-en-2-yl}cyclohexyl]oxy}silane, (−)-15a. [α] = −9.1 (c = 1.0,
D
−1
CHCl ). IR (cm ) 2958, 2926, 2855, 1446, 1305, 1145, 1060, and
832. H NMR (500 MHz, chloroform-d) δ 7.85 (dd, J = 8.2, 1.2 Hz,
3
1
), (+)-11 (6.0 g, 96%) was prepared from (+)-21b (8.0 g, 18.47
−1
mmol) as a white solid. [α]D = +31.5 (c = 0.9, CHCl ). IR (cm )
2H), 7.63−7.58 (m, 1H), 7.52 (dd, J = 8.3, 6.9 Hz, 2H), 4.99 (s, 1H),
4.88 (s, 1H), 3.48 (td, J = 10.2, 4.2 Hz, 1H), 3.20 (dt, J = 9.3, 2.2 Hz,
1H), 2.91 (dd, J = 16.2, 9.3 Hz, 1H), 2.40 − 2.36 (m, 1H), 1.85 (dddd,
J = 17.7, 12.7, 6.7, 3.2 Hz, 3H), 1.78−1.70 (m, 3H), 1.66−1.58 (m,
4H), 1.54−1.40 (m, 4H), 1.28 (s, 3H), 1.02 (s, 3H), 0.99 (d, J = 6.9
Hz, 3H), 0.91 (d, J = 6.5 Hz, 3H), 0.83 (s, 9H), 0.01 (s, 3H), −0.02 (s,
3
1
2
966, 2923, 2872, 1776, 1697, 1375, 1195, and 702. H NMR (400
MHz, chloroform-d) δ 7.33 (t, J = 7.2 Hz, 2H), 7.30−7.27 (m, 1H),
.21 (d, J = 7.3 Hz, 2H), 4.66 (dq, J = 8.7, 4.4 Hz, 1H), 4.17 (d, J = 4.8
Hz, 2H), 4.02 (dd, J = 5.1, 1.7 Hz, 1H), 3.29 (dd, J = 13.4, 3.2 Hz,
H), 2.83 (dd, J = 13.4, 9.4 Hz, 1H), 2.43−2.34 (m, 1H), 1.99 (ddd, J
12.2, 9.2, 3.9 Hz, 1H), 1.88 (ddd, J = 14.2, 9.1, 4.9 Hz, 1H), 1.70 (td,
7
1
=
3H). 13C NMR (125 MHz, CDCl ) δ 148.97, 138.90, 133.60, 129.38
3
J = 12.0, 3.9 Hz, 1H), 1.49 (d, J = 7.3 Hz, 1H), 1.45 (s, 3H), 1.36 (s,
(2C), 129.14 (2C), 111.78, 85.64, 85.47, 76.79, 61.42, 55.46, 50.99,
45.83, 42.00, 39.32, 35.16, 34.88, 33.16, 31.76, 31.72, 26.14 (3C),
22.35, 19.85, 18.43, 18.29, 18.24, −4.00, −4.19. ESI-HRMS calcd for
3
1
5
H), 1.00 (d, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl ) δ 173.2,
3
53.1, 135.3, 129.5 (2C), 129.1 (2C), 127.5, 86.5, 86.2, 65.8, 60.1,
6.3, 46.6, 38.8, 37.7, 34.0, 21.2, 18.4, 17.9. ESI-HRMS calcd for
+
C H O SSi, 561.3435 [M + H] ; found, 561.3430.
32
53
4
+
C H NO , 344.1862 [M + H] ; found, 344.1861.
(−)-tert-Butyldimethyl{[(1R,2S,5R)-5-methyl-2-{(S)-4-(phenylsul-
20
26
4
2
1. (+)-[(1S,2R,3S,4R)-1,3,4-Trimethyl-7-oxabicyclo[2.2.1]heptan-
fonyl)-4-[(1S,2S,3S,4R)-1,3,4-trimethyl-7-oxabicyclo[2.2.1]heptan-2-
2
-yl]methanol, (+)-22. By following the same procedure for the
yl]but-1-en-2-yl}cyclohexyl]oxy}silane, (−)-15b. [α] = −39.2 (c =
D
−1
preparation of (−)-22 (section 5), the enantiomeric compound (+)-22
1.0, CHCl ). IR (cm ) 2955, 2925, 2870, 1447, 1304, 1144, 1083, and
734. H NMR (500 MHz, chloroform-d) δ 7.90 (d, J = 7.8 Hz, 2H),
3
1
(
2.37 g, 96%) was prepared from (+)-11 (5.0 g, 14.6 mmol) as a white
−1
solid. [α]D = +6.66 (c = 0.6, CHCl ). IR (cm ) 3436, 2962, 2924,
7.64 (dd, J = 8.5, 6.2 Hz, 1H), 7.55 (t, J = 7.6 Hz, 2H), 4.77 (s, 1H),
4.75 (s, 1H), 3.22 (td, J = 10.1, 4.0 Hz, 1H), 3.06 (dt, J = 8.4, 3.2 Hz,
1H), 2.64 (p, J = 6.8 Hz, 1H), 2.56 (d, J = 14.6 Hz, 1H), 2.35 (ddd, J =
12.7, 9.0, 4.1 Hz, 1H), 2.29 (dd, J = 15.1, 8.3 Hz, 1H), 1.94 (ddd, J =
11.5, 9.1, 4.6 Hz, 1H), 1.83 (dt, J = 6.1, 2.9 Hz, 1H), 1.66 (td, J = 11.9,
3.9 Hz, 2H), 1.53 (ddd, J = 16.7, 8.1, 4.5 Hz, 4H), 1.34 (s, 7H), 1.11
(d, J = 6.7 Hz, 3H), 1.02 (dd, J = 13.1, 3.4 Hz, 1H), 0.83 (d, J = 6.6
Hz, 3H), 0.81 (s, 9H), 0.62 − 0.52 (m, 2H), −0.06 (s, 3H), −0.11 (s,
3
1
2
877, 1455, 1374, 1016, and 852. H NMR (400 MHz, chloroform-d)
δ 3.67 (dd, J = 10.8, 7.0 Hz, 1H), 3.57 (dd, J = 10.8, 7.7 Hz, 1H), 2.21
s, 1H), 1.79 (ddd, J = 12.1, 9.3, 4.0 Hz, 1H), 1.59 (td, J = 13.1, 12.6,
(
5
.8 Hz, 1H), 1.52−1.43 (m, 3H), 1.41 (s, 3H), 1.36 (dd, J = 7.2, 5.0
13
Hz, 1H), 1.25 (s, 3H), 0.91 (d, J = 6.8 Hz, 3H). C NMR (100 MHz,
CDCl ) δ 85.0, 84.8, 64.1, 60.1, 46.1, 39.0, 32.2, 21.6, 18.7, 17.9. ESI-
3
+
HRMS calcd for C H O , 171.1385 [M + H] ; found, 171.1384.
10
19
2
3H). 13C NMR (125 MHz, CDCl ) δ 148.34, 140.12, 133.42, 129.31,
2
2. (+)-(1S,2S,3S,4R)-2-(Iodomethyl)-1,3,4-trimethyl-7-
3
oxabicyclo[2.2.1]heptane, (+)-23. By following the same procedure
for the preparation of (−)-23 (section 6), the enantiomer (+)-23 (3.1
128.83, 111.30, 85.74, 76.82, 61.95, 58.76, 50.54, 45.50, 43.15, 41.24,
39.52, 34.68, 34.01, 31.49, 26.09, 22.33, 21.97, 19.25, 18.28, 18.15,
+
g, 95%) was prepared from (+)-22 (2.0 g, 11.76 mmol). [α] = +37.79
−4.14, −4.33. ESI-HRMS calcd for C H O SSi, 561.3435 [M + H] ;
D
32 52
4
−1
(
c = 0.6, CHCl ). IR (cm ) 2967, 2899, 1459, 1374, 1188, and 872.
found, 561.3438.
3
1
H NMR (500 MHz, chloroform-d) δ 3.18 (m, 2H), 1.84 (m, 2H),
26. (+)-(1R,2S,5R)-5-Methyl-2-{(S)-4-(phenylsulfonyl)-4-
[(1S,2S,3S,4R)-1,3,4-trimethyl-7-oxa bicyclo[2.2.1]heptan-2-yl]but-
1-en-2-yl}cyclohexanol, (+)-24a. By following the same procedure
for the preparation of (−)-24a (section 11), the enantiomeric
compound (+)-24a (0.86 g, 90%) was prepared from (−)-15a (1.2
1
.68 (td, J = 12.24, 3.95 Hz, 1H), 1.59 (m, 1H), 1.51 (m, 1H), 1.46
13
(
m, 4H), 1.31 (s, 3H), 1.07 (d, J = 6.84 Hz, 3H). C NMR (125
MHz, CDCl ) δ 85.8, 84.9, 60.2, 50.6, 38.8, 31.9, 21.1, 18.8, 18.4, 6.3.
3
+
ESI-HRMS calcd for C H IO, 281.0402 [M + H] ; found, 281.0405.
10
18
−1
2
3. (+)-(1R,2S,3S,4S)-1,2,4-Trimethyl-3-[(phenylsulfonyl)methyl]-
g, 2.1 mmol) as a white solid. [α] = +6.9 (c = 0.8, CHCl ). IR (cm )
D
3
1
7
-oxabicyclo[2.2.1]heptane, (+)-12. By following the same procedure
3531, 2916, 1445, 1379, 1304, 1144, 1084, and 734. H NMR (500
MHz, chloroform-d) δ 7.87 (dd, J = 7.3, 1.7 Hz, 2H), 7.63 (dd, J = 8.4,
6.4 Hz, 1H), 7.55 (t, J = 7.6 Hz, 2H), 5.01 (d, J = 1.6 Hz, 1H), 4.91 (s,
1H), 3.52 (td, J = 10.4, 4.2 Hz, 1H), 3.35 (dt, J = 8.6, 2.3 Hz, 1H),
2.76 (dd, J = 18.1, 8.7 Hz, 1H), 2.45−2.40 (m, 1H), 2.01−1.93 (m,
2H), 1.89−1.81 (m, 2H), 1.75 (p, J = 6.6 Hz, 1H), 1.67−1.59 (m,
4H), 1.53−1.45 (m, 2H), 1.44−1.34 (m, 2H), 1.29 (s, 3H), 1.26−1.23
for the preparation of (−)-12 (section 7), the enantiomer (+)-12
(
+
1
2.46 g, 95%) was prepared from (+)-23 (2.5 g, 8.9 mmol). [α] =
D
−1
15.41 (c = 0.3, CHCl ). IR (cm ) 2964, 2926, 2875, 1446, 1298,
3
1
131, and 866. H NMR (400 MHz, chloroform-d) δ 7.90 (d, J = 8.0
Hz, 2H), 7.68−7.61 (m, 1H), 7.57 (d, J = 8.8 Hz, 2H), 3.05 (d, J = 7.2
Hz, 2H), 1.73 (d, J = 16.6 Hz, 2H), 1.58 (dd, J = 17.3, 9.8 Hz, 2H),
1
.53−1.38 (m, 2H), 1.27 (d, J = 7.8 Hz, 6H), 1.02 (d, J = 6.8 Hz, 3H).
(m, 1H), 1.20 (dd, J = 12.8, 3.4 Hz, 1H), 1.04 (d, J = 6.7 Hz, 3H), 1.01
1
3
13
C NMR (100 MHz, CDCl ) δ 139.5, 133.7, 129.3 (2C), 127.8 (2C),
(s, 3H), 0.93 (d, J = 6.5 Hz, 3H). C NMR (125 MHz, CDCl ) δ
3
3
9
230
dx.doi.org/10.1021/jo401461x | J. Org. Chem. 2013, 78, 9223−9232

The Journal of Organic Chemistry
Article
1
6
1
48.5, 138.0, 133.9, 129.3 (2C), 129.3 (2C), 110.1, 85.7, 85.6, 72.6,
1.0, 55.1, 53.4, 43.4, 42.4, 39.0, 34.7, 32.9, 31.7 (2C), 31.6, 22.3, 19.7,
14.5, 10.1, 4.0 Hz, 1H), 1.68 (ddt, J = 12.7, 6.1, 3.4 Hz, 1H), 1.64−
1.53 (m, 2H), 1.51−1.34 (m, 5H), 1.40 (s, 3H), 1.29 (s, 3H), 1.28−
1.20 (m, 5H), 1.20−1.14 (m, 2H), 0.99 (d, J = 6.8 Hz, 3H), 0.93 (d, J
+
8.4, 18.3. ESI-HRMS calcd for C H O S, 447.2569 [M + H] ;
26
39
4
= 6.8 Hz, 3H), 0.70 (d, J = 6.3 Hz, 3H). 13C NMR (125 MHz, C
D ) δ
found, 447.2565.
6 6
2
7. (−)-(1R,2S,5R)-5-Methyl-2-{(R)-4-(phenylsulfonyl)-4-
209.5, 85.5, 84.4, 58.9, 54.2, 50.7, 49.3, 39.6, 35.0, 34.9, 34.0, 32.7,
31.5, 30.8, 27.1, 22.4, 21.1, 19.7, 18.4, 16.3. ESI-HRMS calcd for
[
(1S,2S,3S,4R)-1,3,4-trimethyl-7-oxabicyclo[2.2.1]heptan-2-yl]but-1-
+
en-2-yl}cyclohexanol, (−)-24b. By following the same procedure for
the preparation of (+)-24b (section 12), its enantiomer (−)-24b (214
mg, 90%) was prepared from (−)-15b (300 mg, 0.53 mmol) as a white
solid. [α] = −14.2 (c = 2.2, CHCl ). IR (cm ) 3467, 2912, 2868,
447, 1289, 1143, and 726. H NMR (500 MHz, chloroform-d) δ 7.90
C H O , 307.2637 [M + H] ; found, 307.2638.
20
35
2
31. (+)-(S)-3-Methyl-6-{(R)-4-[(1S,2S,3S,4R)-1,3,4-trimethyl-7-
oxabicyclo[2.2.1]heptan-2-yl]butan-2-yl}cyclohex-2-enone, (+)-19.
By following the same procedure for the preparation of (−)-19
(section 18), the enantiomeric compound (+)-19 (0.047 g, 85%) was
−1
D
3
1
1
(
dd, J = 8.3, 1.2 Hz, 2H), 7.65−7.60 (m, 1H), 7.57−7.51 (m, 2H),
prepared from (+)-18 (0.06g, 0.15 mmol) as a pale yellow liquid. [α]
D
−1
4
1
2
1
1
1
0
.90 (s, 1H), 4.81 (d, J = 1.8 Hz, 1H), 3.48 (ddd, J = 8.2, 6.8, 4.0 Hz,
H), 3.26 (td, J = 10.3, 4.2 Hz, 1H), 2.58 (dd, J = 17.8, 6.8 Hz, 1H),
.44−2.37 (m, 1H), 2.05 (td, J = 6.8, 4.8 Hz, 1H), 1.93 (dddd, J =
4.1, 9.5, 6.9, 3.9 Hz, 2H), 1.84 (td, J = 5.1, 2.4 Hz, 1H), 1.82 (s, 1H),
.66−1.56 (m, 4H), 1.49 (dtd, J = 12.7, 6.1, 2.7 Hz, 2H), 1.44 (s, 3H),
.27 (s, 3H), 1.12 (td, J = 12.9, 3.5 Hz, 2H), 1.05 (d, J = 6.7 Hz, 3H),
= +34.83 (c = 1.47, CHCl ). IR (cm ) 2969, 2926, 2865, 1661, 1457,
3
1
1377, 1209, and 874. H NMR (400 MHz, chloroform-d) δ 5.83 (dd, J
= 2.6, 1.3 Hz, 1H), 2.28 (dt, J = 14.4, 6.7 Hz, 3H), 2.11 (dt, J = 12.0,
4.3 Hz, 1H), 1.94−1.86 (m, 4H), 1.79 (dtd, J = 15.3, 8.1, 7.3, 3.2 Hz,
2H), 1.61−1.44 (m, 2H), 1.38 (ddd, J = 12.2, 5.5, 2.0 Hz, 1H), 1.31 (s,
3H), 1.30−1.26 (m, 3H), 1.25−1.22 (m, 5H), 1.13 (td, J = 6.7, 3.6 Hz,
1
3
13
1
H), 0.88 (d, J = 6.9 Hz, 3H), 0.78 (d, J = 6.8 Hz, 3H). C NMR (100
.89 (d, J = 6.5 Hz, 3H), 0.86−0.79 (m, 2H). C NMR (125 MHz,
MHz, CDCl ) δ 201.9, 161.1, 127.2, 85.7, 84.8, 58.3, 50.0, 48.9, 39.2,
CDCl ) δ 146.8, 139.7, 133.7, 129.2, 128.7, 111.9, 86.0, 84.8, 71.7,
6
1
3
3
3
4.1, 32.2, 31.2, 30.8, 30.1, 24.2, 22.7, 20.7, 19.3, 18.1, 15.9. ESI-
3.2, 57.1, 53.1, 46.0, 43.2, 38.8, 34.5, 33.9, 33.5, 31.5, 30.6, 22.9, 22.2,
+
+
HRMS calcd for C H NO , 322.2740 [M + NH ] ; found, 322.2741.
8.5, 18.2. ESI-HRMS calcd for C H O S, 447.2569 [M + H] ;
20 36 2 4
26
39
4
3
2. (+)-(1R,6S)-3-Methyl-6-{(R)-4-[(1S,2S,3S,4R)-1,3,4-trimethyl-7-
found, 447.2547.
oxabicyclo[2.2.1]heptan-2-yl]butan-2-yl}cyclohex-2-enol, (+)-1. By
following the same procedure for the preparation of (−)-1 (section
2
8. (+)-(1R,2S,5R)-5-Methyl-2-{(2R,4R)-4-(phenylsulfonyl)-4-
[
(1S,2S,3S,4R)-1,3,4-trimethyl-7-oxabicyclo[2.2.1]heptan-2-yl]-
1
9), the unnatural isomer (+)-laurenditerpenol (+)-1 (5.6 mg, 56%)
butan-2-yl}cyclohexanol, (+)-16a. By following the same procedure
for the preparation of (−)-16a (section 14), the enantiomer (+)-16a
was prepared from (+)-19 (10 mg, 0.026 mmol). [α] = +86.0 (c =
D
−
1
0
.15, CHCl ). IR (cm ) 3431, 2962, 2925, 2871, 1449, 1376, 1130,
(
450 mg, 90%) was prepared from (+)-24a (0.5 g, 1.12 mmol) as a
3
1
−1
and 864. H NMR (300 MHz, chloroform-d) δ 5.64 (dd, J = 4.5, 2.2
Hz, 1H), 4.12 (s, 1H), 2.08−1.93 (m, 2H), 1.90−1.80 (m, 1H), 1.70
white solid. [α]D = +6.5 (c = 0.8, CHCl ). IR (cm ) 3482, 2952,
3
1
2
921, 2870, 1446, 1302, 1142, 1082, and 731. H NMR (500 MHz,
chloroform-d) δ 7.94−7.91 (m, 2H), 7.67 (t, J = 7.4 Hz, 1H), 7.59 (t, J
7.6 Hz, 2H), 3.36 (td, J = 10.4, 4.3 Hz, 1H), 3.03 (dt, J = 8.6, 3.0 Hz,
H), 2.42 (tdd, J = 13.6, 6.7, 4.3 Hz, 1H), 2.09−1.97 (m, 3H), 1.89
dt, J = 5.2, 2.3 Hz, 1H), 1.82−1.71 (m, 3H), 1.64 (ddd, J = 16.3, 9.2,
.5 Hz, 2H), 1.52 (ddt, J = 10.5, 6.8, 3.8 Hz, 2H), 1.45 (dd, J = 5.1, 2.4
Hz, 1H), 1.42 (dd, J = 6.6, 3.2 Hz, 1H), 1.41−1.38 (m, 1H), 1.38−
.35 (m, 1H), 1.32 (s, 3H), 1.16 (ddt, J = 12.9, 9.9, 4.9 Hz, 2H), 1.07
(
s, 3H), 1.68 (s, 1H), 1.64−1.59 (m, 2H), 1.56 (d, J = 3.9 Hz, 1H),
1
1
0
8
2
.54−1.40 (m, 2H), 1.35 (s, 3H), 1.34−1.28 (m, 5H), 1.27 (s, 3H),
=
1
(
3
.22−1.12 (m, 2H), 1.06 (d, J = 6.9 Hz, 1H), 0.95 (d, J = 7.3 Hz, 3H),
.92 (d, J = 7.5 Hz, 3H). 13C NMR (75 MHz, CDCl ) δ 139.9, 123.9,
3
5.9, 84.8, 65.5, 58.5, 49.0, 44.4, 39.3, 33.6, 33.5, 32.3, 31.7, 29.2, 23.5,
0.8, 20.6, 19.4, 18.2, 17.3. ESI-HRMS calcd for C H O , 307.2637
20 35
2
+
[
M + H] ; found, 307.2636.
1
(
6
1
3
s, 3H), 1.01 (d, J = 6.7 Hz, 3H), 0.93 (d, J = 6.6 Hz, 3H), 0.87 (d, J =
.9 Hz, 3H). 13C NMR (125 MHz, CDCl ) δ 138.67, 133.73, 129.34,
ASSOCIATED CONTENT
3
■
*
1
29.29, 85.75, 85.44, 71.23, 61.38, 55.44, 49.35, 45.29, 42.13, 39.16,
S
Supporting Information
13
4.60, 32.98, 32.88, 31.74, 29.84, 29.55, 23.66, 22.28, 19.91, 18.55,
H NMR, C NMR, HRMS, and IR spectra for all compounds.
+
1
8.33, 14.13. ESI-HRMS calcd for C H O S, 466.2742 [M + H O] ;
26
42
5
2
This material is available free of charge via the Internet at
http://pubs.acs.org.
found, 446.2747.
2
9. (−)-(1R,2S,5R)-5-Methyl-2-{(2R,4S)-4-(phenylsulfonyl)-4-
[
(1S,2S,3S,4R)-1,3,4-trimethyl-7-oxabicyclo[2.2.1]heptan-2-yl]-
AUTHOR INFORMATION
Corresponding Author
*E-mail amar@olemiss.edu.
Notes
butan-2-yl}cyclohexanol, (−)-16b. By following the same procedure
for the preparation of (+)-16b (section 15), the enantiomer (−)-16b
■
(
127 mg, 85%) was prepared from (−)-24b (150 mg, 0.34 mmol) as a
−
1
white solid. [α] = −12.5 (c = 2.0, CHCl ). IR (cm ) 3482, 2952,
2
MHz, chloroform-d) δ 7.91 (dd, J = 7.2, 1.8 Hz, 2H), 7.67−7.62 (m,
D
3
1
921, 2870, 1446, 1379, 1302, 1142, 1082, and 736. H NMR (400
The authors declare no competing financial interest.
1
3
4
1
3
H), 7.58 (dt, J = 8.8, 6.3 Hz, 2H), 3.22 (td, J = 10.4, 4.3 Hz, 1H),
.04−2.95 (m, 1H), 2.48 (p, J = 6.5 Hz, 1H), 2.12 (ddd, J = 12.3, 9.1,
.1 Hz, 1H), 2.02−1.87 (m, 3H), 1.84−1.80 (m, 1H), 1.80−1.73 (m,
H), 1.69−1.58 (m, 5H), 1.55−1.49 (m, 3H), 1.46 (s, 3H), 1.33 (s,
H), 1.19 (d, J = 6.7 Hz, 1H), 1.09 (d, J = 6.7 Hz, 3H), 0.88 (d, J = 6.7
ACKNOWLEDGMENTS
■
This study was supported in part by United States Department
of Agriculture, Agricultural Research Service, Specific Cooper-
ative Agreement 58-6408-2-0009. We are thankful to Professor
Jon Parcher for valuable insights in editing our manuscript and
Dr. Bharathi Avula for help with high-resolution mass
spectrometry.
13
Hz, 3H), 0.80−0.72 (m, 2H), 0.26 (d, J = 6.9 Hz, 3H). C NMR (100
MHz, CDCl ) δ 139.7, 133.6, 129.1, 128.8, 85.9, 85.1, 70.7, 62.9, 58.8,
4
1
3
9.5, 45.2, 44.5, 39.2, 36.5, 34.3, 33.4, 31.6, 27.8, 23.3, 22.2, 21.9, 19.0,
+
8.2, 12.3. ESI-HRMS calcd for C H O S, 466.2742 [M + H O] ;
26
42
5
2
found, 446.2742.
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■
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3
1
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