Diastereoselective synthesis of complex cis-hexahydroindanes by reductive alkylation

Article abstract of DOI:10.1021/jo400670y

An efficient and operationally simple approach to complex cis-hexahydroindanes is reported. Upon Birch reduction of unprotected, C4-alkylated tetrahydroindanols and electrophilic trapping of the tetrasubstituted enolate, cis-fused products are formed with a new stereogenic quaternary carbon. The reaction is convergent, completely diastereoselective, and shows a broad scope with regard to the electrophile.

Full text of DOI:10.1021/jo400670y

Note
pubs.acs.org/joc
Diastereoselective Synthesis of Complex cis-Hexahydroindanes by
Reductive Alkylation
Hilan Z. Kaplan, Victor L. Rendina, and Jason S. Kingsbury*,†
Department of Chemistry, Eugene F. Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467, United States
S
* Supporting Information
ABSTRACT: An efficient and operationally simple approach to
complex cis-hexahydroindanes is reported. Upon Birch reduction
of unprotected, C4-alkylated tetrahydroindanols and electrophilic
trapping of the tetrasubstituted enolate, cis-fused products are
formed with a new stereogenic quaternary carbon. The reaction is
convergent, completely diastereoselective, and shows a broad
scope with regard to the electrophile.
uccess in preparing any complex molecule relies on our
ability to generate C−C bonds in a direct and stereo-
fully substituted α-carbon. In addition, initial work at further
transforming the products has revealed a facile transannular
acyloin-type rearrangement19 made possible by the densely
adorned nature of the tetrahydroindane scaffold.
S
controlled fashion. Multi-bond-forming reactions, as well as
those giving rise to contiguous chiral carbon atoms, continue to
be of high value in synthetic planning.1,2 Recently, in the course
of designing an approach to the family of cis-fused, biologically
active sesquiterpene quinones,3−6 we had occasion to test
dissolving metal reduction on an unprotected lower homologue
of the Wieland Miescher ketone (see 1, Scheme 1). In ene-
We began our study by refining a multigram scale entry to
chiral tetrasubstituted enone 1. The efficiency of a known20 D-
phenylalanine-catalyzed Hajos-Parrish synthesis of C4-alkyl
tetrahydroindanones has been improved by minimizing solvent
and sonicating the reaction mixture.21 Enantiomeric excess is
high (92%) under these conditions, but we sought to obtain the
substrate in optically pure form. As detailed below,
enantioenrichment by recrystallization (92→98% ee) is
possible for the α-alcohol (1) obtained by stereoselective
borohydride reduction of the diketone.22 As shown below in
entry 1 of Table 1, dissolution of this material in Li−NH3/THF
at −78 °C and trapping with benzyl bromide provides
ketocarbinol 4 as a single diastereomer in 70% yield. No
epimeric product could be detected; the only byproducts derive
from protonation or O-alkylation of the tetrasubstituted
enolate. Relative configuration in the major product has been
confirmed via X-ray analysis for single crystals of racemic 4
(Supporting Information). This result supports the prior
findings of Lhomett and Paquette16,17 and additionally
highlights an inherent preference for convex approach of the
electrophile during alkylation of the putative lithium enolate.
Remaining entries in the table suggest that the reaction is a
general solution to building various complex cis-hydroindanes.
For instance, the same high level of 1,2-induction occurs for
prenylation (entry 2), and the product 5 contains a key
stereotriad found in the Clerodane diterpene core.18,23,24 Entry
3 reveals that ortho substitution is well-tolerated in a synthesis
of 7, and reaction efficiency remains high with a deactivating
chlorine substituent (entry 4). The latter result is also of
interest in that no competitive dehalogenation of the arene
occurs (53% of 10). We also find that higher yields are possible
Scheme 1. Projected Conformational Bias in a
Stereoselective Birch Alkylation of Tetrahydroindanol 1
decalone ([4.4.0]-bicyclic) settings, Birch alkylation7 serves well
to forge a thermodynamically favored trans ring fusion.8−14
However, two known cases of dissolving metal reduction on
tetrahydroindane ([4.3.0]-bicyclic) substrates have shown a
kinetic15 preference for a cis ring juncture.16,17 Interestingly, in
neither case was the potential for diastereoselective alkylation at
the resulting metal enolate explored. We surmised that upon
hydrogen atom abstraction by the radical anion to give 2, face-
selective quaternization of the α-carbon would be facilitated by
the cup-shaped nature of the intermediate (→3, Scheme 1).18
Herein, we report a data set consistent with this logic.
Specifically, we widen the literature precedent to include 10
examples of cis-hexahydroindanone synthesis, each attesting to
a high level of diastereochemical control over formation of the
Received: March 30, 2013
Published: April 4, 2013
© 2013 American Chemical Society
4620
dx.doi.org/10.1021/jo400670y | J. Org. Chem. 2013, 78, 4620−4626

The Journal of Organic Chemistry
Note
5.0 equiv of each electrophile (Table 1) is based on extensive
optimization to maximize the yield of product. In certain cases,
this is a disadvantage since the electrophile can be more
valuable than enone 1. Reducing the amount of trapping agent
still results in a clean transformation, but the product is
obtained in lower yield. For instance, if only 2.0 equiv of the
complex electrophile 18 is utilized in entry 10, 19 is recovered
in 53% yield, corresponding to a 10% decrease in efficiency. To
an extent, this is explained by the presence of small amounts of
the very nonpolar 1,2-diarylethane in unpurified reaction
mixtures. The byproduct derives from background reductive
dimerization induced by the minor 0.5 molar equiv excess of
lithium (3 equiv total) used to ensure complete two-electron
reduction of the enone.25
Table 1. Scope of the Birch Reductive Alkylation with
Tetrahydroindanol 1
a
Some additional findings on the enone functionalization
warrant mention. First, the noncommercial electrophiles shown
in Table 1 (for entries 3−10) are readily available on multigram
scale by the fully optimized procedures provided in the
Experimental Section. Second, attempts to replicate these
results with the ethylene ketal 2016 under the standard Birch
conditions of Table 1 gave cis-fused products but with a
noticeable reduction in yield. A greater steric hindrance by the
protecting group may account for this, but there is also a clear
benefit to having a stoichiometric proton source internal to the
enone substrate (α-hydroxyl in 1). Further evidence for this
assertion comes in the form of a 10−15% reduction in chemical
yield for cis-fused products when the TBS ether 2122 is used as
the starting material. Even though the identity of the protecting
group does not change the stereochemical outcome, the greater
efficiencies observed with the free cyclopentanol are intriguing.
Two equivalents of lithium is required for this reaction, and 3
equiv (a 0.5 molar excess) was utilized in practice because of
the oxide layer in commercial samples of Li wire and the need
to prevent premature bleaching of the deep blue reaction
mixtures prior to addition of the electrophile. At least 4 equiv of
the metal would be needed if the internal hydroxylic proton was
immediately lost to reduction in the form of dihydrogen. These
considerations imply that enone reduction is much faster than
formation of the lithium alkoxide. At this point, we cannot rule
out the possibility that the more efficient reactions observed for
tetrahydroindanol 1 benefit from intramolecular hydrogen
atom abstraction by the radical anion formed via kinetically
favored, one-electron reduction of the enone. Simple models do
not convincingly demonstrate that the cyclopentyl carbinol is
close enough in proximity to the β-carbon to allow for internal
delivery, but with the potential for participation by a molecule
of solvent (NH3; see 22), the process is likely facilitated relative
to intermolecular alternatives.26
a
Conditions: 3 equiv of Li in NH3, −78 to −33 °C, 1 h; then −78 °C,
b
c
5 equiv of RCH2X. After column chromatography. Inseparable 14:1
mixture favoring 5.
with recourse to benzylic iodides as electrophiles (81% of 10;
see entries 3 and 5 versus 4). The closing five entries (6−10) of
Table 1 are noteworthy due to the hindered nature of each
trapping agent as well as the observed retention of both benzyl
and 4-methoxybenzyl ethers under the reaction conditions. All
transformations have proven reproducible and robust, with no
noticeable diminution in purified yield on scales ranging from
0.2 to 5 mmol (∼1 g) of substrate 1. The recommendation for
Finally, further transformation of the hexahydroindanol
products is successful in spite of steric crowding imposed by
the new quaternary center. We document here an interesting
reaction outcome that, though unforeseen, can now be
expected from the entire class of 5,6-bicyclic derivatives
synthesized. As shown in Scheme 2, unprotected 10 does
furnish an ene-carbinol under the very forcing yet precedented
Wittig conditions27 provided (→23, methyltriphenyl-
4621
dx.doi.org/10.1021/jo400670y | J. Org. Chem. 2013, 78, 4620−4626

The Journal of Organic Chemistry
Note
Scheme 2. Further Transformation Reveals a Remarkably Facile and Unexpected Rearrangement
General Procedure for Reductive Alkylation. A two-neck 250
mL round-bottom flask equipped with a coldfinger condenser and
magnetic stir bar was charged with lithium wire (58.0 mg, 8.36 mmol,
3.00 equiv), evacuated, and flame-dried again. After backfilling with
argon, the apparatus was cooled to −78 °C, and ammonia (36 mL)
was freshly distilled from sodium metal into the reaction flask, forming
a deep blue solution. A solution of enone 121,22,36 (499 mg, 2.77
mmol, 1.00 equiv) in 20 mL of THF was added over 30 min, at which
point the mixture was warmed to a gentle reflux and stirred for 1 h.
The solution was then recooled to −78 °C and diluted with 14 mL of
THF. In a separate flask, a solution of the electrophile (13.9 mmol,
5.00 equiv) in 15 mL of THF was precooled to −78 °C and added as
rapidly as possible to the blue solution via syringe. Immediately, the
deep blue color bleached to white, and stirring was continued at −78
°C for 8 h. The reaction mixture was then allowed to gradually warm
to room temperature with concomitant evaporation of ammonia. The
basic solution was acidified by the addition of 200 mL of saturated
NH4Cl, and the product was extracted with Et2O (3 × 75 mL). The
combined organics were washed with H2O (200 mL) and saturated
NaCl (200 mL), dried over Na2SO4, filtered, and concentrated.
Purification was achieved by column chromatography on silica gel.
(1R,3aR,4S,7aR)-4-Benzyl-1-hydroxy-4,7a-dimethylhexa-
hydro-1H-inden-5(6H)-one (4). From enone 1 (50.0 mg, 0.277
mmol, 1.00 equiv) and benzyl bromide (165 μL, 1.39 mmol, 5.00
equiv), 4 was recovered as a white solid (52.6 mg, 69.7%): mp 117−
120 °C. X-ray quality single crystals were obtained by crystallization
from hot ethyl acetate and hexanes (1:2 v/v): Rf = 0.45 (45% ethyl
acetate in hexanes); [α]D20 = −1.49 (c 1.08, CHCl3); 1H NMR (CDCl3,
500 MHz) δ 7.26−7.17 (m, 3H), 7.03−7.00 (m, 2H), 3.84−3.79 (m,
1H), 3.28 (d, J = 13.7 Hz, 1H), 2.82−2.73 (m, 2H), 2.35 (ddd, J =
16.4, 6.4, 5.4 Hz, 1H), 2.18 (dd, J = 10.7, 8.5 Hz, 1H), 2.07−2.00 (m,
1H), 1.90−1.76 (m, 3H), 1.56−1.46 (m, 2H), 1.35 (s, 3H), 1.28−1.15
(m, 1H), 0.89 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 215.9, 137.5,
130.2, 128.2, 126.6, 81.6, 53.5, 52.3, 44.5, 43.2, 35.6, 32.4, 31.2, 26.4,
23.5, 20.7; IR (neat) 3473, 2959, 2871, 1701, 1452, 1090, 979, 753,
701 cm −1; HRMS (ESI+) calcd for C18H25O2 [M + H]+ 273.1855;
found 273.1857.
phosphonium iodide, dimsyl sodium, 75 °C), but it is the
exclusive result of transannular hydride migration and
subsequent cyclopentanone methylenation. This type of internal
redox event finds precedent in Prelog’s work28 with less
substituted cis-fused hydroxy hydroindanones as well as bridged
bicyclic settings that are conformationally locked.29−31 In the
present case, the positioning of two quaternary carbons 1,3
within the cyclohexanone leads to a syn-pentane interaction in
either chair conformer. This renders the stereoelectronically
favorable boat conformation (see 24, Scheme 2) accessible
under the reaction conditions. Adding validity to this assertion
are the facts that (1) TOCSY NMR data rigorously establish
the connectivity pictured in 23, and an X-ray structure32 of the
methylene cyclopentane has been secured; (2) the isotopically
labeled starting material 10-d (prepared by diketone reduction
with NaBD4)33 selectively translocates deuterium to the
anticipated position in product 23-d under identical reaction
conditions; (3) the corresponding cyclohexanone and cyclo-
pentanone sodium alkoxides are in equilibrium by NMR when
exposed to base in the absence of the Wittig salt;34 and (4) as
shown in Scheme 2, preventing alkoxide formation via TBS
protection leads to the initially targeted exocyclic methylene
cyclohexane 25 in good yield.
To conclude, a concise entry to complex cis-hexahydroinda-
nols has been developed. Lithium−ammonia reduction of the
corresponding tetrahydroindanol generates a cis-fused enolate
that has been functionalized with a range of hindered
electrophiles in high yield with perfect stereocontrol. We
hope that our findings encourage other synthetic chemists to
capitalize on the simplicity of the dissolving metal conditions in
building other fused 5,6-bicyclic structures with a cis juncture.
EXPERIMENTAL SECTION
■
All reactions were carried out in flame-dried glassware under an
atmosphere of dry argon35 using standard Schlenk and vacuum line
techniques. Enone 1 and other starting materials made by literature
protocols are noted as such in the procedure in which they first appear.
High-resolution mass spectral data were obtained with a TOF detector
with data acquisition in real time (DART).
(1R,3aR,4S,7aR)-1-Hydroxy-4,7a-dimethyl-4-(3-methylbut-2-
en-1-yl)hexahydro-1H-inden-5(6H)one (5). From racemic enone
1 (100 mg, 0.555 mmol, 1.00 equiv) and prenyl bromide (330 μL, 2.78
mmol, 5.00 equiv), 5 was recovered as a colorless oil (106 mg, 76.0%).
The product was a 14:1 mixture with the uncharacterized minor α-
1
epimer as determined by H NMR. Analytically pure material was
4622
dx.doi.org/10.1021/jo400670y | J. Org. Chem. 2013, 78, 4620−4626

The Journal of Organic Chemistry
Note
obtained by combining only the later eluting fractions: Rf = 0.35 (40%
ethyl acetate in hexanes); H NMR (CDCl3, 500 MHz) δ 5.02−4.96
80.9%): mp 165−168 °C; Rf = 0.33 (60% ethyl acetate in hexanes);
[α]2D0 = −27.64 (c 1.13, CHCl3); 1H NMR (CDCl3, 500 MHz) δ 6.37
(d, J = 2.7 Hz, 1H), 6.15 (d, J = 2.7 Hz, 1H), 3.86−3.79 (m, 4H), 3.74
(s, 3H), 3.51 (d, J = 13.9 Hz, 1H), 3.0 (d, J = 13.9 Hz, 1H), 2.87 (ddd,
J = 15.2, 9.3, 5.6 Hz, 1H), 2.38−2.30 (m, 1H), 2.22 (dd, J = 11.0, 8.3
Hz, 1H), 2.07−1.99 (m, 1H), 1.97−1.76 (m, 3H), 1.34 (s, 3H), 1.17
(dddd, J = 9.3, 9.3, 9.3, 9.3 Hz, 1H), 0.90 (s, 3H); 13C NMR (CDCl3,
125 MHz) δ 215.4, 158.2, 155.9, 137.5, 115.6, 108.0, 98.3, 81.4, 56.3,
55.8, 55.6, 52.3, 42.9, 41.5, 35.4, 32.6, 31.4, 26.8, 23.7, 19.7; IR (neat)
3448, 2958, 2878, 1697, 1590, 1455, 1330, 1203, 1163, 1084, 979, 753
cm−1; HRMS (ESI+) calcd for C20H28ClO4 [M + H]+ 367.1676; found
367.1684.
1
(m, 1H), 3.75 (ddd, J = 5.4, 5.4, 5.4 Hz, 1H), 2.65−2.57 (m, 1H), 2.49
(dd, J = 14.7, 7.3 Hz, 1H), 2.27, 2.14 (m, 3H), 2.06−1.98 (m, 1H),
1.86 (dddd, J = 16.4, 8.3, 8.3, 2.4 Hz, 1H), 1.74−1.68 (m, 5H), 1.60 (s,
3H), 1.53−1.45 (m, 2H), 1.30 (s, 3H), 1.20−1.12 (m, 1H), 0.95 (s,
3H); 13C NMR (CDCl3, 125 MHz) δ 216.7, 134.4, 119.2, 81.7, 52.7,
51.6, 43.2, 36.7, 35.1, 32.4, 31.2, 26.8, 26.1, 23.2, 20.6, 18.2; IR (neat)
2441, 2961, 2928, 2872, 1699, 1451, 1376, 1052, 978 cm −1; HRMS
(ESI+) calcd for C16H27O2 [M + H]+ 251.2011; found 251.2014.
2-(Iodomethyl)-1,4-dimethoxybenzene (6). From 2-(bromo-
methyl)-1,4-dimethoxybenzene37 (1.18 g, 5.09 mmol, 1.00 equiv), 6
was obtained by treatment with NaI (1.53 g, 10.2 mmol, 2.00 equiv) in
8.5 mL of distilled acetone (12 h, 23 °C). The mixture was filtered
through Celite, concentrated, dissolved in 20 mL of CH2Cl2, and
washed with 15 mL of 50% Na2S2O3. Drying, filtration, and
concentration provided 6 as a yellow solid (1.39 g, 97.8%): mp 62−
64 °C; 1H NMR (CDCl3, 500 MHz) δ 6.86 (d, J = 2.9 Hz, 1H), 6.80−
6.74 (m, 2H), 4.45 (s, 2H), 3.86 (s, 3H), 3.76 (s, 3H); 13C NMR
(CDCl3, 125 MHz) δ 153.4, 151.5, 128.4, 115.7, 114.6, 112.2, 56.1,
55.9, 1.3; IR (neat) 3040, 2942, 2831, 1498, 1462, 1223, 1154, 1040,
800, 700, 507 cm−1; HRMS (ESI+) calcd for C9H12IO2 [M + H]+
278.9882; found 278.9882.
2-(Bromomethyl)-1-chloro-4-methoxy-3-(4-methoxybenzyl-
oxy)benzene (11). Starting from PMB-protected o-vanillin,39 (3-
methoxy-2-(4-methoxybenzyloxy)phenyl)methanol is available from
aldehyde reduction (NaBH4, EtOH, 10 min, 23 °C, 96%). The
resulting white solid (11.4 g, 41.7 mmol, 1.00 equiv), mp 67−70 °C,
was used without purification. Chlorination at the 6 position by
treatment with 1,3-dichloro-5,5-dimethylhydantoin (9.86 g, 50.0
mmol, 1.20 equiv) in 83 mL of CH2Cl2 (20 h, 4 °C) and conventional
aqueous workup (as described for 6) left a residue that was purified by
flash chromatography to give a white solid (9.13 g, 70.9%): mp 76−78
1
°C; Rf = 0.29 (30% ethyl acetate in hexanes); H NMR (CDCl3, 500
MHz) δ 7.35 (d, J = 8.5 Hz, 2H), 7.10 (d, J = 8.8 Hz, 1H), 6.90 (d, J =
8.3 Hz, 2H), 6.84 (d, J = 8.8 Hz, 1H), 5.03 (s, 2H), 4.69 (d, J = 6.8 Hz,
2H), 3.89 (s, 3H), 3.81 (s, 3H), 2.08 (t, J = 6.8 Hz, 1H); 13C NMR
(CDCl3, 125 MHz) δ 159.9, 151.9, 147.3, 132.9, 130.5, 129.3, 125.9,
124.9, 114.1, 112.9, 75.6, 58.3, 56.2, 55.4; IR (neat) 3440, 2958, 2897,
2837, 1612, 1514, 1473, 1440, 1271, 1250, 1175, 1013 cm−1; HRMS
(ESI+) calcd for C16H16ClO4 [M − H]+ 307.0737; found 307.0744.
The benzyl alcohol (623 mg, 2.02 mmol, 1.00 equiv), CBr4 (872 mg,
2.64 mmol, 1.30 equiv), and PPh3 (689 mg, 2.63 mmol, 1.30 equiv)
were dissolved in 4.0 mL of THF at 0 °C and warmed to 23 °C after
10 min. After diluting with water (20 mL) and extracting with CH2Cl2
(3 × 20 mL), the combined organic layers were dried, filtered, and
concentrated. Purification by flash chromatography gave 11 as a white
solid (785 mg, quantitative): mp 80−84 °C; Rf = 0.52 (33% ethyl
(1R,3aR,4S,7aR)-4-(2,5-dimethoxybenzyl)-1-hydroxy-4,7a-
dimethylhexahydro-1H-inden-5(6H)-one (7). From enone 1
(50.0 mg, 0.277 mmol, 1.00 equiv) and iodide 6 (540 mg, 1.94
mmol, 7.00 equiv),38 7 was recovered as a white solid (71.6 mg,
77.8%): mp 104−106 °C; Rf = 0.38 (60% ethyl acetate in hexanes);
[α]2D0 = −20.20 (c 1.72, CHCl3); H NMR (CDCl3, 500 MHz) δ
1
6.72−6.66 (m, 2H), 6.58 (d, J = 3.2 Hz, 1H), 3.81 (dd, J = 12.3, 6.1
Hz, 1H), 3.73 (s, 3H), 3.70 (d, J = 13.4 Hz, 1H), 3.64 (s, 3H), 2.87
(ddd, J = 16.7, 8.3, 5.4 Hz, 1H), 2.38 (d, J = 13.4 Hz, 1H), 2.22 (ddd, J
= 16.6, 8.5, 5.4 Hz, 1H), 2.12 (dd, J = 12.0, 8.3 Hz, 1H), 2.04−1.95
(m, 2H), 1.85 (dddd, J = 15.6, 7.8, 7.8, 2.0 Hz, 1H), 1.79−1.71 (m,
2H), 1.52−1.43 (m, 1H), 1.35 (s, 3H), 1.15−1.04 (m, 1H), 0.84 (s,
3H); 13C NMR (CDCl3, 125 MHz) δ 214.7, 152.9, 151.8, 127.0,
119.1, 111.8, 110.8, 81.2, 56.2, 55.8, 55.1, 51.8, 42.6, 40.5, 35.2, 32.2,
31.4, 27.3, 24.1, 20.3; IR (neat) 3449, 2956, 1699, 1501, 1464, 1224,
1049, 802, 713 cm−1; HRMS (ESI+) calcd for C20H29O4 [M + H]+
333.2066; found 333.2069.
1-(Bromomethyl)-2-chloro-3,5-dimethoxybenzene (8). Com-
mericially available (3,5-dimethoxyphenyl)methanol (10.4 g, 62.0
mmol, 1.0 equiv) was chlorinated in 310 mL of CCl4 (reflux, 48 h)
with N-chlorosuccinimide (7.86 g, 58.9 mmol, 0.950 equiv). After
conventional aqueous workup, the chloro-alcohol was recrystallized to
afford a white solid (9.00 g, 71.7%) from Et2O/hexanes (5:1 v/v): mp
88−90 °C. Bromide 8 was obtained as a white solid (3.0 g, 82%) from
2.80 g (13.8 mmol, 1.00 equiv) of the chloro-alcohol by exposure to
PBr3 (0.49 mL, 5.1 mmol, 0.37 equiv) in 46 mL of benzene: mp 100−
102 °C; 1H NMR (CDCl3, 500 MHz) δ 6.58 (d, J = 2.8 Hz, 1H), 6.48
(d, J = 2.8 Hz, 1H), 4.57 (s, 2H), 3.88 (s, 3H), 3.82 (s, 3H); 13C NMR
(CDCl3, 125 MHz) δ 158.9, 156.3, 136.9, 114.6, 106.7, 100.3, 56.4,
55.7, 31.1; IR (neat) 3097, 2975, 1585, 1470, 1432, 1334, 1200, 1165,
1082, 1030, 951, 819, 721, 673, 610 cm−1; HRMS (ESI+) calcd for
C9H1179Br37ClO2 [M + H]+ 266.9601; found 266.9601.
2-Chloro-1-(iodomethyl)-3,5-dimethoxybenzene (9). From
benzyl bromide 8 (502 mg, 1.89 mmol, 1.00 equiv) and NaI (566
mg, 3.78 mmol, 2.00 equiv) in 3.2 mL of distilled acetone (12 h, 23
°C) using the workup described for 6, concentration gave 9 as a white
solid (539 mg, 91.3%): mp 127−129 °C; 1H NMR (CDCl3, 500
MHz) δ 6.54 (d, J = 2.7 Hz, 1H), 6.44 (d, J = 2.7 Hz, 1H), 4.50 (s,
2H), 3.87 (s, 3H), 3.80 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ
158.9, 156.4, 138.3, 114.2, 106.0, 99.9, 56.4, 55.7, 3.1; IR (neat) 3058,
2939, 1586, 1469, 1418, 1332, 1204, 1156, 1076, 1030, 951, 818, 675
cm−1; HRMS (ESI+) calcd for C9H11ClIO2 [M + H]+ 312.9492; found
312.9490.
1
acetate in hexanes); H NMR (CDCl3, 500 MHz) δ 7.45 (d, J = 8.6
Hz, 2H), 7.11 (d, J = 8.8 Hz, 1H), 6.93 (d, J = 8.6 Hz, 2H), 6.86 (d, J
= 8.8 Hz, 1H), 5.10 (s, 2H), 4.63 (s, 2H), 3.89 (s, 3H), 3.83 (s, 3H);
13C NMR (CDCl3, 125 MHz) δ 159.8, 151.9, 147.4, 130.5, 130.4,
129.4, 126.3, 125.0, 114.0, 113.4, 74.9, 56.2, 55.4, 25.6; IR (neat) 3002,
2959, 2836, 1612, 1583, 1514, 1474, 1272, 1250, 1174, 1076, 974, 804
cm−1; HRMS (ESI+) calcd for C16H15BrClO3 [M − H]+ 368.9893;
found 368.9878.
1-Chloro-2-(iodomethyl)-4-methoxy-3-(4-methoxybenzyl-
oxy)benzene (12). From benzyl bromide 11 (483 mg, 1.30 mmol,
1.00 equiv) by treatment with NaI (390 mg, 2.60 mmol, 2.00 equiv) in
2.2 mL of distilled acetone (12 h, 23 °C), 12 was obtained. The
workup was by direct analogy to that of 6, affording 12 as a pale yellow
solid (542 mg, 99.6%): mp 85−88 °C; Rf = 0.52 (33% ethyl acetate in
1
hexanes); H NMR (CDCl3, 500 MHz) δ 7.47 (d, J = 8.8 Hz, 2H),
7.07 (d, J = 8.8 Hz, 1H) 6.94 (d, J = 8.6 Hz, 2H), 6.82 (d, J = 8.8 Hz,
1H), 5.15 (s, 2H), 4.52 (s, 2H), 3.88 (s, 3H), 3.83 (s, 3H); 13C NMR
(CDCl3, 125 MHz) δ 159.8, 151.9, 146.8, 131.8, 130.3, 129.5, 125.9,
125.0, 114.0, 112.9, 73.8, 56.2, 55.4, −2.4; IR (neat) 2935, 2835, 1612,
1514, 1473, 1370, 1272, 1250, 1174, 1107, 1071, 1034, 972, 801 cm−1;
HRMS (ESI+) calcd for C16H15ClIO3 [M + H]+ 416.9754; found
416.9753.
(1R,3aR,4S,7aR)-4-(6-Chloro-3-methoxy-2-((4-methoxy-
benzyl)oxy)benzyl)-1-hydroxy-4,7a-dimethylhexahydro-1H-
inden-5(6H)-one (13). From racemic enone 1 (65.6 mg, 0.366
mmol, 1.00 equiv) and iodide 12 (766 mg, 1.83 mmol, 5.00 equiv),38
13 was recovered as a white solid (136 mg, 78.6%): mp 50−56 °C; Rf
= 0.25 (50% ethyl acetate in hexanes); 1H NMR (CDCl3, 500 MHz) δ
7.29 (d, J = 8.8 Hz, 2H), 7.03 (d, J = 8.8 Hz, 1H), 6.88 (d, J = 8.8 Hz,
2H), 6.75 (d, J = 8.8 Hz, 1H), 4.98 (d, J = 11.2 Hz, 1H), 4.82 (d, J =
11.0 Hz, 1H), 3.84 (s, 3H), 3.81 (s, 3H), 3.72 (dd, J = 6.1, 6.1 Hz,
1H), 3.39 (d, J = 13.2 Hz, 1H), 2.84 (d, J = 13.7 Hz, 1H), 2.67 (ddd, J
= 13.7, 7.8, 5.6 Hz, 1H), 2.09 (dd, J = 11.7, 8.0 Hz, 1H), 2.05−1.91
(1R,3aR,4S,7aR)-4-(2-Chloro-3,5-dimethoxybenzyl)-1-hy-
droxy-4,7a-dimethylhexahydro-1H-inden-5(6H)-one (10). From
enone 1 (56.2 mg, 0.312 mmol, 1.00 equiv) and iodide 9 (488 mg,
1.56 mmol, 5.00 equiv),38 10 was recovered as a white solid (92.6 mg,
4623
dx.doi.org/10.1021/jo400670y | J. Org. Chem. 2013, 78, 4620−4626

The Journal of Organic Chemistry
Note
(m, 2H), 1.78 (ddd, J = 15.4, 7.8, 2.0 Hz, 1H), 1.74−1.67 (m, 1H),
1.58−1.48 (m, 2H), 1.47−1.38 (m, 1H), 1.18 (s, 3H), 1.05−0.92 (m,
1H), 0.78 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 214.8, 159.8,
151.2, 147.9, 130.6, 130.5, 129.8, 127.2, 124.30, 113.9, 111.9, 81.1,
74.8, 57.0, 56.1, 55.4, 51.8, 42.3, 37.2, 35.0, 32.3, 31.5, 27.2, 23.9, 19.1;
IR (neat) 3471, 2859, 2872, 1700, 1612, 1514, 1466, 1276, 1251, 1143,
940 cm−1; HRMS (ESI+) calcd for C27H33ClO5 [M − OH]+
455.1989; found 455.1982.
5-(Benzyloxy)-4-(bromomethyl)benzo[d][1,3]dioxole (18).
Commercial sesamol was converted to (5-(benzyloxy)benzo[d][1,3]-
dioxol-4-yl)methanol by a routine sequence involving benzylation
(BnBr, K2CO3, DMF, 23 °C, 99%), formylation (n-BuLi, THF, −78
°C; DMF, 70%), and reduction (NaBH4, 9:1 THF/H2O, 23 °C, 90%).
To this alcohol (3.50 g, 13.5 mmol, 1.00 equiv) in 80 mL of Et2O was
added pyridine (54.2 μL, 0.678 mmol, 0.0500 equiv). PBr3 (1.28 mL,
13.6 mmol, 1.00 equiv) was introduced over 35 min by syringe pump.
The resulting cloudy mixture was stirred for 40 min, quenched with
H2O (50 mL), and extracted with Et2O (3 × 50 mL). The combined
organics were washed with H2O (50 mL) and saturated NaCl (50
mL), dried over MgSO4, filtered, and concentrated to give 18 as a
white solid (4.32 g, 99.3%): mp 91−93 °C; Rf = 0.55 (30% ethyl
1-(Bromomethyl)-3-methoxy-2-(4-methoxybenzyloxy)-
benzene (14). From the same alcohol above with conditions detailed
for 11 (CBr4, PPh3, THF, 0 °C, 10 min). Purification by flash
chromatography gave 14 as a white solid (834 mg, 89.2%): mp 50−52
1
°C; Rf = 0.42 (20% ethyl acetate in hexanes); H NMR (CDCl3, 500
1
MHz) δ 7.45 (d, J = 8.6 Hz, 2H), 7.05 (d, J = 7.8 Hz, 1H), 6.97 (dd, J
= 7.5, 1.2 Hz, 1H), 6.95−6.89 (m, 3H), 5.10 (s, 2H), 4.50 (s, 2H),
3.90 (s, 3H), 3.83 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 159.7,
153.1, 146.3, 132.4, 130.3, 129.9, 124.4, 122.8, 114.0, 113.2, 74.5, 56.0,
55.4, 28.6; IR (neat) 2957, 2936, 2836, 1612, 1586, 1514, 1479, 1374,
1271, 1250, 1174, 1070 cm−1; HRMS (ESI+) calcd for C16H16BrO3
[M − H]+ 335.0283; found 335.0271.
acetate in hexanes); H NMR (CDCl3, 500 MHz) δ 7.49−7.46 (m,
2H), 7.42−7.38 (m, 2H), 7.35−7.33 (m, 1H), 6.67 (d, J = 8.4 Hz,
1H), 6.33 (d, J = 8.4 Hz, 1H), 6.01 (s, 2H), 5.08 (s, 2H), 4.59 (s, 2H);
13C NMR (CDCl3, 125 MHz) δ 151.9, 147.1, 141.8, 137.0, 128.7,
128.0, 127.3, 110.2, 107.9, 104.1, 101.9, 71.1, 22.2; IR (neat) 3031,
2777, 1644, 1462, 1243, 1160, 1058, 924, 737 cm−1. HRMS (ESI+)
calcd for C15H14BrO3 [M + H]+ 321.0126; found 321.0117.
(1R,3aR,4S,7aR)-1-Hydroxy-4-(3-methoxy-2-((4-methoxy-
benzyl)oxy)benzyl)-4,7a-dimethylhexahydro-1H-inden-5(6H)-
one (15). From racemic enone 1 (51.0 mg, 0.283 mmol, 1.00 equiv)
and bromide 14 (473 mg, 1.40 mmol, 5.00 equiv),38 15 was recovered
as a sticky foam (65.4 mg, 52.7%): Rf = 0.26 (50% ethyl acetate in
(1R,3aR,4S,7aR)-4-((5-(Benzyloxy)benzo[d][1,3]dioxol-4-yl)-
methyl)-1-hydroxy-4,7a-dimethylhexahydro-1H-inden-5(6H)-
one (19). From racemic enone 1 (49.2 mg, 0.273 mmol, 1.00 equiv)
and bromide 18 (437 mg, 1.36 mmol, 5.00 equiv), 19 was recovered as
a white solid (72.8 mg, 63.1%): mp 150−152 °C; Rf = 0.32 (60% ethyl
1
1
hexanes); H NMR (CDCl3, 500 MHz) δ 7.31 (d, J = 8.8 Hz, 2H),
acetate in hexanes); H NMR (CDCl3, 500 MHz) δ 7.41−7.36 (m,
6.92 (dd, J = 8.1, 8.1 Hz, 1H), 6.88 (d, J = 8.8 Hz, 2H), 6.80 (dd, J =
8.3, 1.5 Hz, 1H), 6.56 (dd, J = 7.8, 1.5 Hz, 1H), 4.98 (d, J = 11.0 Hz,
1H), 4.83 (d, J = 11.0 Hz, 1H), 3.85 (s, 3H), 3.82 (s, 3H), 3.73 (ddd, J
= 5.6, 5.6, 5.6 Hz, 1H), 3.36 (d, J = 13.4 Hz, 1H), 2.70 (ddd, J = 14.5,
8.8, 5.6 Hz, 1H), 2.50 (d, J = 13.4 Hz, 1H), 2.12 (ddd, J = 10.0, 7.6, 5.4
Hz, 1H), 2.07−2.02 (m, 1H), 2.0−1.92 (m, 1H), 1.80 (dddd, J = 16.1,
8.3, 8.3, 2.4 Hz, 1H), 1.76−1.69 (m, 1H), 1.62−1.56 (m, 2H), 1.47−
1.40 (m, 1H), 1.19 (s, 3H), 1.11−1.02 (m, 1H), 0.82 (s, 3H); 13C
NMR (CDCl3, 125 MHz) δ 215.4, 159.6, 152.6, 146.8, 131.7, 130.4,
130.2, 123.8, 123.2, 113.9, 111.2, 81.4, 74.6, 55.9, 55.6, 55.4, 52.1, 42.7,
39.0, 35.2, 32.3, 31.4, 27.0, 23.8, 20.3; IR (neat) 3431, 2956, 2836,
1700, 1611, 1584, 1514, 1474, 1302, 1250, 1174, 1083 cm−1; HRMS
(ESI+) calcd for C27H34O5 [M + H]+ 439.2484; found 439.2489.
2-(Benzyloxy)-4-chloro-3-(iodomethyl)-1-methoxybenzene
(16). From (2-(benzyloxy)-3-methoxyphenyl)methanol40 with the
same aryl chlorination (92%), bromination (88%), and iodination
procedures described above for 12, concentration gave 16 as a pale
yellow solid that was used without purification (38.0 g, 98.1%): mp
72−75 °C; 1H NMR (CDCl3, 500 MHz) δ 7.56−7.52 (m, 2H), 7.43−
7.34 (m, 3H), 7.08 (d, J = 8.8 Hz, 1H), 6.83 (d, J = 8.8 Hz, 1H), 5.22
(s, 2H), 4.55 (s, 2H), 3.88 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ
151.9, 146.8, 137.3, 131.8, 128.6, 128.4, 128.3, 125.9, 125.1, 112.8,
74.0, 56.2, −2.7; IR (neat) 3006, 2974, 2839, 1575, 1471, 1460, 1430,
1366, 1267, 1223, 1099, 1064, 964, 883, 797, 747, 693 cm−1; HRMS
(ESI+) calcd for C15H18ClINO2 [M + NH4]+ 406.0071; found
406.0075.
4H), 7.35−7.29 (m, 1H), 6.67 (d, J = 8.5 Hz, 1H), 6.27 (d, J = 8.5 Hz,
1H), 5.87 (d, J = 1.5 Hz, 1H), 5.80 (d, J = 1.5 Hz, 1H), 4.93 (d, J =
11.5 Hz, 1H), 4.88 (d, J = 11.5 Hz, 1H), 3.74 (ddd, J = 6.1, 6.1, 6.1 Hz,
1H), 3.47 (d, J = 13.4 Hz, 1H), 2.69 (d, J = 13.4 Hz, 1H), 2.61 (ddd, J
= 16.8, 8.5, 5.4 Hz, 1H), 2.13 (dd, J = 12.2, 8.3 Hz, 1H), 2.02−1.91
(m, 2H), 1.84 (dddd, J = 15.6, 7.8, 7.8, 2.0 Hz, 1H), 1.73 (ddd, J =
13.9, 8.0, 5.6 Hz, 1H), 1.54−1.40 (m, 3H), 1.28 (s, 3H), 1.10−1.00
(m, 1H), 0.89 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 215.1, 152.7,
147.6, 141.1, 137.2, 128.6, 128.1, 128.0, 109.9, 105.9, 103.3, 100.8,
81.1, 71.0, 56.3, 52.2, 42.4, 35.1, 33.7, 32.1, 31.3, 27.4, 24.0, 19.9; IR
(neat) 3440, 2958, 2979, 1697, 1458, 1377, 1243, 1102, 1052, 930, 735
cm−1; HRMS (ESI+) calcd for C26H31O5 [M + H]+ 423.2172; found
423.2174.
(3aR,4S,5R,7aR)-4-(2-Chloro-3,5-dimethoxybenzyl)-4,7a-di-
methyl-1-methyleneoctahydro-1H-inden-5-ol (23). A dimsyl
sodium solution was prepared from NaH (35.1 mg, 1.46 mmol, 7.00
equiv) and 1.5 mL of dry DMSO in a two-neck 25 mL round-bottom
flask equipped with a magnetic stir bar by heating at 75 °C for 1 h.41
At room temperature, a solution of Ph3PCH3I (764 mg, 1.88 mmol,
9.00 equiv) in 2.6 mL of DMSO was added over 30 min, turning the
mixture bright yellow. After 30 min of additional stirring, a solution of
racemic 10 (76.3 mg, 0.208 mmol, 1.00 equiv) in 0.58 mL of DMSO
was added, and the reaction was heated at 75 °C for 16 h. The
resulting amber solution was acidified with 5 mL of saturated NH4Cl,
diluted with H2O (15 mL), and washed with Et2O (3 × 15 mL). The
combined organics were washed with H2O (15 mL) and saturated
NaCl (15 mL), dried over Na2SO4, filtered, and concentrated.
Purification by flash chromatography gave 23 as a white solid (61 mg,
(1R,3aR,4S,7aR)-4-(2-(Benzyloxy)-6-chloro-3-methoxy-
benzyl)-1-hydroxy-4,7a-dimethylhexahydro-1H-inden-5(6H)-
one (17). From enone 1 (499 mg, 2.77 mmol, 1.00 equiv) and iodide
16 (5.40 g, 13.9 mmol, 5.00 equiv), 17 was recovered as a white solid
(968 mg, 78.9%): mp 45−50 °C; Rf = 0.33 (50% ethyl acetate in
1
81%): mp 117−119 °C; Rf = 0.33 (60% Et2O in pentane); H NMR
(CDCl3, 500 MHz) δ 6.69 (d, J = 2.7 Hz, 1H), 6.38 (d, J = 2.7 Hz,
1H), 4.75−4.71 (m, 2H), 3.86 (s, 3H), 3.78 (s, 3H), 3.61−3.57 (m,
1H), 2.97−2.89 (m, 2H), 2.57−2.47 (m, 1H), 2.42−2.32 (m, 1H),
2.09−1.90 (m, 2H), 1.82−1.65 (m, 4H), 1.57−1.50 (m, 1H), 1.49 (d, J
= 4.6 Hz, 1H), 1.11 (s, 3H), 0.67 (s, 3H); 13C NMR (CDCl3, 125
MHz) δ 159.9, 158.1, 155.7, 139.2, 115.8, 109.0, 101.4, 97.6, 72.5,
56.3, 55.6, 51.7, 45.0, 42.0, 38.4, 31.3, 30.6, 27.8, 25.6, 23.3, 18.4; IR
(neat) 3556, 2949, 1588, 1454, 1287, 1201, 1161, 1082, 1034, 907,
730, 632 cm−1; HRMS (ESI+) calcd for C21H28ClO2 [M − OH]+
347.1778; found 347.1766.
1
hexanes); [α]2D0 = −32.50 (c 0.86, CHCl3); H NMR (CDCl3, 500
MHz) δ 7.40−7.31 (m, 5H), 7.05 (d, J = 8.8 Hz, 1H), 6.76 (d, J = 8.8
Hz, 1H), 5.04 (d, J = 11.2 Hz, 1H), 4.89 (d, J = 11.5 Hz, 1H), 3.83 (s,
3H), 3.71 (ddd, J = 6.1, 6.1, 6.1 Hz, 1H), 3.42 (d, J = 13.7 Hz, 1H),
2.87 (d, J = 13.7 Hz, 1H), 2.65 (dddd, J = 13.7, 5.4, 5.4, 5.4 Hz, 1H),
2.10 (dd, J = 11.7, 8.1 Hz, 1H), 2.04−1.90 (m, 2H), 1.83−1.74 (m,
1H), 1.73−1.62 (m, 1H), 1.56−1.47 (m, 2H), 1.47−1.38 (m, 1H),
1.17 (s, 3H), 1.08−0.93 (m, 1H), 0.79 (s, 3H); 13C NMR (CDCl3,
125 MHz) δ 214.8, 151.1, 147.9, 137.6, 130.4, 128.8, 128.6, 128.3,
127.2, 124.4, 111.9, 81.0, 75.2, 57.0, 56.1, 51.8, 42.3, 37.2, 35.0, 32.3,
31.5, 27.2, 23.9, 19.1; IR (neat) 3430, 2956, 2872, 1697, 1576, 1463,
1375, 1275, 1214, 1077, 974, 798, 749, 697 cm−1; HRMS (ESI+) calcd
for C26H32ClO4 [M + H]+ 443.1989; found 443.2005.
tert-Butyl(((1R,3aS,4S,7aR)-4-(2-Chloro-3,5-dimethoxyben-
zyl)-4,7a-dimethyl-5-methyleneoctahydro-1H-inden-1-yl)oxy)-
dimethylsilane (25). The secondary carbinol in 10 was protected as
its TBS ether by standard means (Et3N, TBSOTf, CH2Cl2, 3 h, −78
°C). Dimsyl sodium was then prepared as above from NaH (32.6 mg,
4624
dx.doi.org/10.1021/jo400670y | J. Org. Chem. 2013, 78, 4620−4626

The Journal of Organic Chemistry
Note
1.36 mmol, 7.40 equiv) and 1.5 mL of dry DMSO.41 At room
temperature, a solution of Ph3PCH3Br (624 mg, 1.75 mmol, 9.50
equiv) in 2.4 mL of DMSO was added over 30 min, turning the
mixture bright yellow. After 30 more minutes of stirring, a solution of
the TBS ether (93.4 mg, 0.184 mmol, 1.00 equiv) in 0.56 mL of
DMSO and 0.50 mL of THF was added, and the reaction was heated
at 75 °C for 16 h. The resulting amber solution was worked up by
analogy to 23, giving 25 as a white solid (95.0 mg, quantitative): mp
97−98 °C; Rf = 0.33 in 50% Et2O in pentane; [α]2D0 = +32.36 (c 1.00,
CHCl3); 1H NMR (CDCl3, 500 MHz) δ 6.35 (d, J = 2.7 Hz, 1H), 6.21
(d, J = 2.7 Hz, 1H), 4.93 (s, 1H), 4.42 (s, 1H), 3.85 (s, 3H), 3.73 (s,
3H), 3.55 (dd, J = 5.9, 1.5 Hz, 1H), 3.25 (d, J = 13.5 Hz, 1H), 3.01 (d,
J = 13.4 Hz, 1H), 2.71 (ddd, J = 13.7, 13.7, 5.4 Hz, 1H), 2.24−2.18
(m, 1H), 2.09−2.02 (m, 1H), 1.98−1.89 (m, 1H), 1.84−1.74 (m, 1H),
1.47−1.22 (m, 7H), 0.92 (s, 9H), 0.81 (s, 3H), 0.5 (s, 3H), 0.4 (s,
3H); 13C NMR (CDCl3, 125 MHz) δ 157.5, 155.4, 151.3, 139.5,
115.8, 112.0, 108.0, 97.8, 84.3, 56.3, 55.4, 55.0, 46.0, 44.3, 41.5, 33.8,
31.6, 29.9, 26.7, 26.1, 23.3, 22.4, 18.3, −4.3, −4.7; IR (neat) 2953,
2930, 2856, 1590, 1455, 1371, 1285, 1255, 1202, 1163, 1074, 1004,
833, 722 cm−1; HRMS (ESI+) calcd for C27H44ClO3Si [M + H]+
479.2748; found 479.2733.
(10) Ling, T.; Poupon, E.; Rueden, E. J.; Theodorakis, E. A. Org. Lett.
2002, 4, 819−822.
(11) Corey, E. J.; Roberts, B. E. J. Am. Chem. Soc. 1997, 119, 12425−
12431.
(12) An, J.; Wiemer, D. F. J. Org. Chem. 1996, 61, 8775−8779.
(13) Stahl, P.; Kissau, L.; Mazitschek, R.; Huwe, A.; Furet, P.;
Giannis, A.; Waldmann, H. J. Am. Chem. Soc. 2001, 123, 11586−
11593.
(14) Ling, T.; Poupon, E.; Rueden, E. J.; Kim, S. H.; Theodorakis, E.
A. J. Am. Chem. Soc. 2002, 124, 12261−12267.
(15) Stork, G.; Darling, S. D. J. Am. Chem. Soc. 1964, 86, 1761−1768.
(16) Renoud-Grappin, M.; Vanucci, C.; Lhommet, G. J. Org. Chem.
1994, 59, 3902−3905.
(17) Paquette, L. A.; Wang, T.-Z.; Sivik, M. R. J. Am. Chem. Soc.
1994, 116, 11323−11334.
(18) A direct entry to 3 would streamline access to a number of arene
or quinone sesquiterpenes and Clerodane diterpenes when coupled
with a late-stage 1-C ring expansion. For catalysis of methylene
insertion, see: Dabrowski, J. A.; Moebius, D. C.; Wommack, A. J.;
Kornahrens, A. F.; Kingsbury, J. S. Org. Lett. 2010, 12, 3598−3601.
(19) Paquette, L. A.; Hofferberth, J. E. The α-Hydroxy Ketone (α-
Ketol) and Related Rearrangments. In Organic Reactions; John Wiley
and Sons: New York, 2004.
ASSOCIATED CONTENT
* Supporting Information
■
(20) Corey, E. J.; Virgil, S. C. J. Am. Chem. Soc. 1990, 112, 6429−
6431.
S
X-ray crystallographic data for compound 4 (CCDC reference
(21) Shigehisa, H.; Mizutani, T.; Tosaki, S.-Y.; Ohshima, T.;
Shibasaki, M. Tetrahedron 2005, 61, 5057−5065.
(22) Hagiwara, H.; Sakai, H.; Uchiyama, T.; Ito, Y.; Morita, N.;
Hoshi, T.; Suzuki, T.; Ando, M. J. Chem. Soc., Perkin Trans. 1 2002, 5,
583.
number 911293) and copies of the H and 13C NMR spectra
1
for all numbered compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: jason.kingsbury@pomona.edu.
(23) Díaz, S.; Cuesta, J.; Asensio Gonzal
Chem. 2003, 68, 7400−7406.
(24) A review on the synthesis of Clerodane diterpenoids:
Tokoroyama, T. Synthesis 2000, 5, 611−633.
́
ez, A.; Bonjoch, J. J. Org.
■
Present Address
(25) Despite the presence of excess alkylating agent, in no cases, have
we isolated α-quaternary products in which the free cyclopentanol has
undergone a Williamson etherification. Here steric factors may play a
role; the secondary hydroxyl group is syn-coplanar with the angular
methyl group in the solid state structure of 4 (provided as Supporting
Information).
†Department of Chemistry, Pomona College, 645 North
College Avenue, Seaver North, Claremont, CA 91711.
Notes
The authors declare no competing financial interest.
(26) Attempts to reproduce the yields reported herein by using protic
additives common in other Birch alkylations, such as tert-butanol and
water, gave inferior results with either 1 or 21.
(27) Sarma, A. S.; Chattopadhyay, P. J. Org. Chem. 1982, 47, 1727−
1731.
(28) Acklin, W.; Prelog, V. Helv. Chim. Acta 1959, 42, 1239−1247.
(29) Parker, W.; Stevenson, J. R. Chem. Commun. 1969, 1289.
(30) Wicha, J.; Caspi, E. J. Org. Chem. 1973, 38, 1280.
(31) Shepherd, J. M.; Singh, D.; Wilder, P., Jr. Tetrahedron Lett. 1974,
15, 2743.
(32) X-ray coordinates for the product derived from subjecting 19 to
the Wittig conditions shown in Scheme 2 are available in the
Cambridge Crystallographic Databank (CCDC reference number
911292).
ACKNOWLEDGMENTS
■
This work was supported by generous startup funds from
Boston College. We are grateful to Jennifer A. Dabrowski and
Dr. Bo Li, X-ray Facilities Director, for X-ray analyses. We also
thank Dr. Andrew Wommack, Samantha A. Goetz, and Lauren
E. Zajac for vital experimental support.
REFERENCES
■
(1) For an overview of cascade and multi-bond-forming reactions,
see: Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem., Int.
Ed. 2006, 45, 7134−7186.
(2) Corey, E. J. Angew. Chem., Int. Ed. 2002, 41, 1650−1667 and
references therein.
(33) Greater than 98 atom % D sodium borodeuteride was utilized in
the preparation of 10-d. If any of the protio form 10 was present in
(3) Theodorakis, E. A.; Ling, T.; Rueden, E. J.; Poupon, E.; Kim, S.
H. Strategies Tactics Org. Synth. 2004, 5, 111−131.
(4) Marcos, I. S.; Conde, A.; Moro, R. F.; Basabe, P.; Diez, D.;
Urones, J. G. Mini-Rev. Org. Chem. 2010, 7, 230−254.
(5) Oda, T.; Wang, W.; Ukai, K.; Nakazawa, T.; Mochizuki, M. Mar.
Drugs 2007, 5, 151−156.
1
this sample, it was beyond the limits of H NMR detection.
(34) At 75 °C, the temperature at which Wittig reaction is successful,
the ratio of cyclopentanone to cyclohexanone products is 6:1
according to 1H NMR spectroscopy in the case of structure 19.
Upon cooling to 23 °C and performing an aqueous workup, the ratio
does not change.
(35) The reaction cannot be carried out under nitrogen gas since it
reacts with lithium metal to form lithium nitride. See: Masdupuy, E.;
Gallais, F.; Gibb, T. R. P.; Warren, H. O. Inorganic Syntheses; John
Wiley & Sons, Inc.: Hoboken, NJ, 2007; Vol. 4.
(6) Utkina, N.; Denisenko, V. A.; Krasokhin, V. B. J. Nat. Prod. 2010,
73, 788−791.
(7) Dutcher, J. S.; MacMillan, J. G.; Heathcock, C. H. J. Org. Chem.
1976, 41, 2663−2669.
(8) Bruner, S. D.; Radeke, H. S.; Tallarico, J. A.; Snapper, M. L. J.
Org. Chem. 1995, 60, 1114−1115.
(36) Enantioenrichment from 92 to >98% ee was achieved by
recrystallization of 1 from a hot 3:1 (v/v) mixture of diethyl ether in
hexanes.
(9) Poigny, S.; Guyot, M.; Samadi, M. J. Org. Chem. 1998, 63, 5890−
5894.
4625
dx.doi.org/10.1021/jo400670y | J. Org. Chem. 2013, 78, 4620−4626

The Journal of Organic Chemistry
Note
(37) Kostikov, A. P.; Popik, V. V. J. Org. Chem. 2007, 72, 9190−9194.
(38) The electrophile was not precooled due to a lack of solubility
below room temperature.
(39) Nichols, A. L.; Zhang, P.; Martin, S. F. Org. Lett. 2011, 13,
4696−4699.
(40) Speicher, A.; Holz, J. Tetrahedron Lett. 2010, 51, 2986−2989.
(41) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1345−
1364.
4626
dx.doi.org/10.1021/jo400670y | J. Org. Chem. 2013, 78, 4620−4626