Functional Group Interconversion of Alkylidenemalononitriles to Primary Alcohols by a Cooperative Redox Operation

Article abstract of DOI:10.1055/s-0040-1707184

Functional group interconversions are essential chemical processes enabling synthesis. In this report, we describe a strategy to convert alkylidenemalononitriles into primary alcohols in one step. The reaction relies on a choreographed redox process invol

Full text of DOI:10.1055/s-0040-1707184

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2020, 52, A–I
paper
A
en
F. Emmetiere, A. J. Grenning
Paper
Synthesis
Functional Group Interconversion of Alkylidenemalononitriles to
Primary Alcohols by a Cooperative Redox Operation
Fabien Emmetiere
NaBH4 and O2 (1 atm)
Alexander J. Grenning*
0
0
0
0-0
0
0
2-8
1
8
2-
9
4
6
4
alternating redox operations
NC
R1 R2
NC
CN
OH
O
R1 R2
R1 R2
Department of Chemistry, University of Florida,
PO Box 117200, Gainesville, FL 32611-7200, USA
grenning@ufl.edu
via
Received: 11.05.2020
Accepted after revision: 09.06.2020
Published online: 21.07.2020
would be generally valuable to chemical synthesis and (2)
the transformation would require a cooperative redox oper-
ation: Could a reductant and an oxidant cohabitate a reac-
tion medium to achieve an alternating reduction/oxida-
tion/reduction sequence without neutralizing themselves?
If conditions and compatible reductant and oxidant could
be identified, then alkylidenemalononitriles could be di-
rectly converted into 1° alcohols (Scheme 1B). While there
are obvious challenges to redox transformations of this
type, there are known and effective combinations of reduc-
tant/oxidant for chemical transformations.22–27 For exam-
ple, molecular oxygen is compatible with mild reductants
such as borohydrides (NaBH4, Bu4NBH4)25,28–33 and silanes
(Et3SiH and PhSiH3)34–38 and these redox partners have been
utilized to achieve a variety of transformations, such as aer-
obic oxidation of alkenes or hydrogenation reactions.39,40 In
terms of other oxidants, tert-butyl hydroperoxide has been
used in combination with PhSiH3 to achieve alkene reduc-
tions via metal-catalyzed hydrogen atom transfer (HAT).41–
44 As a final example, Toste and co-workers have shown that
phase separation of oxopiperidinium (oxidant; aqueous
phase) and Hantzsch ester (reductant; solid phase) could al-
low for controlled redox transformation.45 Inspired by this
DOI: 10.1055/s-0040-1707184; Art ID: ss-2020-m0253-op
Abstract Functional group interconversions are essential chemical
processes enabling synthesis. In this report, we describe a strategy to
convert alkylidenemalononitriles into primary alcohols in one step. The
reaction relies on a choreographed redox process involving alkylidene
reduction, malononitrile oxidation, and acylcyanide reduction where
molecular oxygen and NaBH4 work cooperatively. The method was ap-
plied to a variety of carbon skeletons and was utilized to synthesize
complex terpenoid architectures.
Key words Knoevenagel adducts, malononitriles, oxidative decyana-
tion, redox processes, terpenoid synthesis
Alkylidenemalononitriles are easily available, versatile
building blocks that can be manipulated in various ways.1
For example, they can undergo conjugate addition2–5 or re-
duction6,7 to yield alkylmalononitriles. In turn, alkylmalo-
nonitriles can be processed to malonic acid derivatives,8 re-
duced to 1,3-diamines,9,10 and undergo reductive11,12 and
oxidative decyanation reactions.13–18 Most relevant to this
work, Hayashi and co-workers developed an elegant oxida-
tive protocol to convert malononitriles into amides or es-
ters using molecular oxygen as the oxidant via the interme-
diacy of an acylcyanide (Scheme 1A).19,20 We have been de-
veloping routes to a variety of complex scaffolds where
alkylmalononitriles and/or alkylidenemalononitriles are
key intermediates.21 As such, we have invested interest in
developing new alkylidenemalononitrile functional group
interconversion reactions.
Inspired by Hayashi’s work, we proposed that alkyliden-
emalononitriles could be converted into 1° alcohols by si-
multaneous reaction with a reductant and an oxidant.
While each fundamental step in the sequence is well under-
stood (conjugate reduction, malononitrile oxidation, acyl-
cyanide reduction), we were intrigued by this sequence for
two main reasons: (1) Alkylidenemalononitriles are valu-
able building blocks and new ways to manipulate them
A:
O
NR2
R1 R2
OR
R1 R2
HNR2
HOR
Hayashi et al.
2016
NC
CN
O
CN
O2
R1 R2
R1 R2
[O]
O
Hayashi et al.
2019
B:
NC
compatible
oxidant
H
H
CN
O
CN
R1 R2
reduction
NC
CN
HO
R1 R2
R1 R2
R1 R2
and
reductant?
reduction
oxidation
Scheme 1 A: Relevant oxidative decyanation strategies.19,20 B: This
report: alkylidenemalononitrile functional group interconversion to 1°
alcohol by a redox transformation.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
F. Emmetiere, A. J. Grenning
Paper
Synthesis
literature precedent, we now report that the combination
of oxygen and NaBH4 can interconvert alkylidenemalononi-
triles to 1° alcohols by an alternating reduction/oxida-
tion/reduction sequence.
Having found the optimized conditions, we next ex-
plored the scope utilizing a variety of alkylidenemalononi-
triles (Scheme 2). The initial model substrate 1 was convert-
ed into its respective 1° alcohol 3a in 62% yield. A variety of
other arene-containing products 3b–3d were successfully
prepared. As the transformation was optimized for a mild
reductant, NaBH4, chemoselective transformation of the al-
kylidenemalononitrile can be achieved over other reducible
functional groups such as esters, alkenes, and carbamates
(e.g., 3e–3g, respectively). Considering this, we prepared an
-ester-functionalized alkylidenemalononitrile which can
undergo the desired functional group interconversion to
the 1° alcohol with concomitant lactonization to 3m in 65%
yield. Similarly, oxygen is a fairly gentle oxidant. We found
that e–-rich arenes (3h), and to a less extent pyridines (3i),
could be tolerated in the transformation. We also uncovered
some functional groups that were only modestly tolerated
including allenes, phenols, alkylamines, and alkynes (3j–3l,
3n, respectively). We suspect that these compounds are
sensitive to the NaBH4/O2 conditions. An increased toler-
ance to these functional groups will be investigated in the
future.
To begin our studies, we optimized the proposed redox
functional group interconversion as described in Table 1.
Utilizing model substrate 1, our first success was realized
when the transformation was performed in polar solvents
with oxygen (1 atm) as the oxidant and NaBH4 as the reduc-
tant (entries 2–4). Choice of solvent was crucial as we ob-
served significant amounts of methyl ester byproduct in
methanol19,20 and no conversion in nonpolar solvents due to
insolubility of the NaBH4, presumably (entry 1). As previ-
ously reported by Hayashi and co-workers,19,20 the reaction
had to be performed under strictly anhydrous conditions to
prevent the formation of carboxylic acid byproducts. The
use of molecular sieves was therefore imperative to maxi-
mize conversion into the desired product. Addition of po-
tassium carbonate in the reaction mixture favored the for-
mation of desired product 3a (entries 5, 6). We speculate
that the addition of a base in the system results in a higher
concentration of alkylmalononitrile anion, which the trans-
formation must progress through. Finally, by adjusting the
reaction time and temperature to 1.5 hours and 50 °C re-
spectively, we were able to form 3a as a sole product during
this transformation (entry 8). Interestingly, the reaction
could be conducted under a constant flow of air (entry 9),
though the transformation was significantly slower. It
should also be noted that the conversion from 1 into 2
and/or 3a was excellent in all cases. Indeed, reduction of the
alkylidenemalononitrile was extremely facile (completed
within minutes, observable by TLC). We found that the rate-
determining step was the oxidation from 2 to 3a which was
considerably slower.
NaBH4 (4 equiv.)
NC
CN
OH
malononitrile
+
O
2 (1 atm), K2CO3 (2 equiv.)
R1 R2
R1 R2
ketone/aldehyde
DMF (0.1 M), 50 °C
3 Å MS, 1.5–3 h
HO
HO
OH
HO
Ph
Ph
Ph
3d, 65%,
2.5:1 dr
3a, 62%
HO
3b, 75%
3c, 53%
HO
HO
OMe
HO
OMe
Boc
N
Table 1 Optimization of the Reaction Conditions
CO2Et
3g, 45%
11:1 dr
3f, 90%
14:2:1:1
mixture of isomers
3e, 56%
2:1 dr
3h, 60%
HO
NaBH4 (4 equiv.)
Base, O2 (2 equiv.)
NC
Ph
CN
Ph
NC
Ph
CN
Ph
OH
Ph
HO
HO
Ph
HO
Solvent (0.1 M), 3 Å MS
OH
1
2
3a
•
N
N
OMe
Entry Base
Solvent
Temp
(°C)
Time
(h)
Ratio
2/3a
% Conversion
(NMR)
Bn
(2 equiv.) (0.1 M)
3k, 22%
3i, ~20%*
3j, 11%
3l, 17%
1
2
3
4
5
6
7
8
9a
–
toluene
DMSO
MeCN
DMF
rt
1
1
0:0
0
95
NC
CN
CO2Me
OH
CO2Me
O
O
as
–
rt
50:50
47:53
33:66
40:60
30:70
17:83
0:100
73:27
above
–
rt
1
97
3m
65%
–
rt
1
96
intermediate
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
MeCN
DMF
rt
1
98
NC
CN
HO
NC
CN
as
rt
1
>99
>99
>99
>99
above
DMF
rt
4.5
1.5
12
3n, 22%
20:1 dr
OH
OH
O
DMF
50
50
*3i was obtained as an impure mixture (see NMR spectra for more details)
DMF
Scheme 2 Reaction scope
a Reaction performed under air instead of O2.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

C
F. Emmetiere, A. J. Grenning
Paper
Synthesis
Based on our scope from Scheme 2 and a comparison of
literature strategies to prepare some of these molecules, it
became apparent that this sequence (Knoevenagel conden-
sation and redox functional group interconversion) is an at-
tractive alternative to the known methods. For example, it
is common to take a commercial ketone and yield the tar-
geted alcohol 3g by Wittig olefination and BH3 reduction
(Scheme 3).46,47 Knoevenagel condensation and O2/NaBH4
functional group interconversion have the potential to be a
more practical/operationally simple two-step sequence as
it avoids pyrophoric and air-sensitive butyllithium and bo-
ranes.
A: Synthesis of 1,6-hexenols by Cope rearrangement and redox functional
group interconversion
NC
R1
CN
[3,3]
R3
NC
NC
HO
R1
R2
NaBH4
O2
R3
R1
R3
NC
R1
CN
R2
R2
R3
H2 [3,3]
R2
B:The above sequence yields similar products to the oxy-Cope rearrangement
HO
R1
HO
R1
O
[3,3]
R1
R3
R3
R3
R2
R2
R2
Scheme 4 Routes to building blocks with 1,5-enols
n-BuLi
BH3
Boc
N
THF
27%
90%
Ph
HO
Me
NC
P
R4
R4
R3
O
Ph
NaBH4 (4 equiv.)
Ph
NC
R1
CN
R2
HO
R1
O
2 (1 atm), K2CO3 (2 equiv.)
Boc
N
Boc
N
NC
CN
Boc
NaBH4
O2
R3
DMF (0.1 M), 50 °C
3 Å MS, 1.5–3 h
NH4OAc
(cat)
CN
R2
3g
starting materials:
N
Tol/AcOH
DMF
45%
11:1 dr
Ph
Δ
100% conv.
used crude
NC
CN
H
CN
CN
CN
NC
NC
NC
Ph
Scheme 3 Comparison of a common literature route to this report’s
method for converting a ketone into a homologated alcohol
H
Ph
H
H
H
Bn
Bn
Bn OAc
2d, 2:1 dr
O
O
2a, >20:1 dr
2b, >20:1 dr
2c, 10:1 dr
products:
Having a better understanding of the substrate scope
and limitations for alkylidenemalononitrile redox function-
al group interconversion to 1° alcohols, we wished to apply
this transformation to -allyl-alkylidenemalononitriles
(Scheme 4A and Scheme 5). Such scaffolds would be readily
available from alkylidenemalononitriles and allylic electro-
philes by deconjugative allylation yielding 3,3-dicyano-1,5-
dienes followed by thermal Cope rearrangement.21,48–53
Thus alkylidenemalononitrile redox functional group inter-
conversion to 1° alcohols would provide a straightforward
route to 1,6-hexenols 4a–4d. Notably, such products would
bear resemblance to ‘oxy-Cope products’,54–57 but via an al-
ternative route (Scheme 4A vs Scheme 4B). To examine this,
we prepared several -allyl-alkylidenemalononitriles or re-
duced variants. Regarding the reduced variants, in some of
our previous work, we developed ‘reductive Cope rear-
rangements’ to promote thermodynamically favorable Cope
rearrangements.49,53 2b–2d (Scheme 5) were prepared as
such. Regarding the redox functional group interconversion
to 1° alcohols, the reaction was successful at yielding a vari-
ety of 1,6-hexenols with unique substitution patterns and
functional groups. In this regard, 4a bears a ketal and a 1,3-
diphenylallyl moiety, 4b is monoterpene derived (myrte-
nol), and 4d has an additional ester functional group.
Ph
HO
HO
HO
HO
H
O
*
H
Ph
Ph
H
H
H
H
Bn
Bn
Bn OAc
4a, 41%
3.5:1 dr
(+12%a)
O
4b, 67%
>20:1 dr
4c, 59%
10:1 dr
4d, 39%
2:1 dr
a plus an additional 12% of ø epimeric product at starred position; total yield =
41%+12% = 53% yield
Scheme 5 Synthesis of 5-hexen-1-ols by redox functional group inter-
conversion
from a common precursor 4a, we were able to access 6,7-
bicyclic ring system 5a in four steps: (i) alcohol oxidation,
(ii) Brown allylation, (iii) ring-closing metathesis, and (iv)
alcohol oxidation. Notably, multiple consecutive steps
could be telescoped reducing the need of intermediate puri-
fications (see the Supporting Information for details). Thus,
yields are reported after the final step when chromato-
graphic purification was performed. 5a maps well onto the
daphnane and tigliane terpenoid scaffolds, among others,
and bears a variety of other functionality for further chemi-
cal transformation. A few other related scaffolds 6–9 were
prepared by similar telescoped sequences.
1,6-Hexenols, such as those prepared in Scheme 5, are
polyfunctional and can be utilized in chemical synthesis to
make valuable scaffolds. As final aspect of this study, we
aimed to demonstrate that terpenoid-like scaffolds can be
accessed by straightforward sequences (Scheme 6). Starting
In conclusion, we have developed a strategy to convert
alkylidenemalononitriles into primary alcohols. The reac-
tion relies on a choreographed redox process involving al-
kylidene reduction, malononitrile oxidation, and acylcya-
nide reduction where molecular oxygen and NaBH4 work
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

D
F. Emmetiere, A. J. Grenning
Paper
Synthesis
along with 3 Å molecular sieves (~20 mg/mL of solvent). Using an O2
balloon, O2 gas was gently bubbled though the reaction mixture using
a long needle through the reaction flask septum. O2 was bubbled for
10 min. After 10 min, NaBH4 (4 equiv. for alkylidenemalononitriles
and 2 equiv. for alkylmalononitriles) was then added and the reaction
mixture was stirred for 2–5 min (until effervescence stopped). Then,
K2CO3 (2 equiv.) was added and the reaction mixture was heated at
50 °C. O2 was bubbled through the mixture until reaction completion.
Once completion was achieved (monitored by TLC), the reaction mix-
ture was cooled to rt and the O2 balloon was removed. The excess
NaBH4 was slowly quenched with H2O (1 mL) and the reaction mix-
ture was diluted with 2 M HCl(aq) (5 times the reaction volume). The
resulting aqueous mixture was extracted with EtOAc three times (2
times the aqueous phase volume). The combined organic layers were
washed with 2 M HCl(aq) (equal volume as the organic phase) and
brine (equal volume as the organic phase), and dried over Na2SO4. The
EtOAc was removed under reduced pressure and the crude was puri-
fied via silica gel column chromatography (Hex/EtOAc).
common
precursor
Ph
Ph
HO
7
Daphnane
family
H
O
7
Tigliane
family
H
H
6
6
O
4a
i
6,5 analogue route
6,6 analogue route
iv, iii, i
v, iii, i
ii, iii
O
H
O
H
H
Ph
H
6
7
H
6
5
H
Ph
Ph
H
6
6
H
H
O
O
O
O
O
O
7a
5a
6a
14% 3 steps (60% brsm)
33% (4 steps)
38% (4 steps)
O
O
HO
i, v, iii, i
i, v, iii, i
OAc
Ph
R = Ph
from 4c
62% (4 steps)
R = CH2OAc
from 4d
52% (4 steps)
R
Reduction of Alkylidenemalononitriles with NaBH4; General Pro-
cedure B
H
8
9
Bn
Ph
Ph
The corresponding alkylidenemalononitrile adduct (1 equiv.) was dis-
solved in MeOH (0.3 M) at 0 °C in a flame-dried Schlenk flask under
N2. NaBH4 (1.5 equiv.) was then added and the reaction progress was
monitored by TLC. Once completion was achieved, the excess NaBH4
was slowly quenched with H2O (1 mL) and the reaction mixture was
diluted with H2O (5 times the reaction volume). The resulting aque-
ous mixture was extracted with EtOAc three times (2 times the aque-
ous phase volume). The combined organic layers were washed with
brine (equal volume as the organic phase) and dried over Na2SO4. The
solvents were removed under reduced pressure and the crude was
purified via silica gel column chromatography (Hex/EtOAc) or used as
crude when sufficiently pure.
Conditions: i) 1.5 equiv. PCC, DCM, rt. ii) 2 equiv. MePPh3Br, 2.5 equiv. tBuOK,
THF, 0 °C. iii) 1 mol% Grubbs II, toluene, 80 °C. iv) 1.5 equiv. allylboronic acid
pinacol ester, toluene, 80 °C. v) 1.3 equiv. vinylmagnesium bromide, THF, –78 °C.
Scheme 6 Proof-of-concept syntheses toward terpene natural prod-
ucts
cooperatively. The method was applied to a variety of car-
bon skeletons and was utilized to synthesize complex ter-
penoid architectures. Future directions will include utiliza-
tion of the transformation in synthesis and further optimi-
zation and scope studies as needed.
Oxidation of Primary or Secondary Alcohols to Aldehydes or Ke-
tones; General Procedure C
The corresponding alcohol (1 equiv.) was dissolved in DCM (0.2 M) at
rt and pyridinium chlorochromate (1.5 equiv.) was added. The reac-
tion progress was monitored by TLC. After completion, the reaction
mixture was filtered through a short pad of silica gel with elution
with the corresponding Hex/EtOAc mixture. The solvents were re-
moved under reduced pressure and the crude was purified via silica
gel column chromatography (Hex/EtOAc) or used as crude when suf-
ficiently pure.
All commercial materials were used without further purification.
Knoevenagel adducts were synthesized from modified literature pro-
cedures that are referenced along the way. All other synthetic proto-
cols are outlined below. 1H NMR and 13C NMR spectra were recorded
in CDCl3 using a 400 MHz or 600 MHz Varian VNMRS spectrometer
(with CHCl3 residual peak as an internal standard) unless specified
otherwise. All 13C NMR spectra were recorded with complete proton
decoupling. HRMS data were recorded on an Agilent Time-of-Flight
6200 spectrometer. Reaction progress was monitored by TLC and vi-
sualized by UV light (fluorescence observed by eye after excitation
under UV light), phosphomolybdic acid stain, and KMnO4 stain. Com-
pounds were purified via silica gel column chromatography using
hexanes/ethyl acetate (Hex/EtOAc) solvent mixtures unless specified
otherwise. Notation: Hex/EtOAc 10% reads as ‘mixture of 10% ethyl
acetate in hexanes’. All reactions were carried out using anhydrous
solvents obtained dried by passing through activated alumina col-
umns. Solvents used for oxidative decyanations were freeze–pump–
thawed three times before use.
TiCl4-Catalyzed Allylboration of Aldehydes; General Procedure D-1
The corresponding aldehyde (1 equiv.) was dissolved in toluene (0.2
M) at rt in a flame-dried Schlenk flask under N2. Allylboronic acid pin-
acol ester (1.5 equiv.) was then added dropwise at rt, followed by TiCl4
(1 mol%). After reaction completion, the mixture was diluted with
H2O (same volume as the reaction mixture) and extracted with EtOAc
three times (1/3 of the total volume each time). The combined organ-
ic layers were washed with brine (equal volume as the organic phase)
and dried over Na2SO4. The solvents were removed under reduced
pressure and the crude was purified via silica gel column chromatog-
raphy (Hex/EtOAc) or used as crude when sufficiently pure.
One-Pot Oxidative Decyanation of Alkylidenemalononitriles to Al-
cohols; General Procedures A-1 and A-2
Allylboration of Aldehydes; General Procedure D-2
The corresponding alkylidenemalononitrile (procedure A-1) or alkyl-
malononitrile (procedure A-2) substrate (1 equiv.) was dissolved in
DMF (0.1 M) in a flame-dried Schlenk flask under positive pressure N2
The corresponding aldehyde (1 equiv.) was dissolved in toluene (0.2
M) at rt in a flame-dried Schlenk flask under N2. Allylboronic acid pin-
acol ester (1.5 equiv.) was then added dropwise at rt and the reaction
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

E
F. Emmetiere, A. J. Grenning
Paper
Synthesis
mixture was heated at 80 °C. After reaction completion, the mixture
was diluted with H2O (same volume as the reaction mixture) and ex-
tracted with EtOAc three times (1/3 of the total volume each time).
The combined organic layers were washed with brine (equal volume
as the organic phase) and dried over Na2SO4. The solvents were re-
moved under reduced pressure and the crude was purified via silica
gel column chromatography (Hex/EtOAc) or used as crude when suf-
ficiently pure.
1H NMR (400 MHz, CDCl3):  = 7.15–7.07 (m, 4 H), 3.69–3.60 (m, 2 H),
2.91 (dd, J = 11.7, 1.9 Hz, 1 H), 2.87 (m, 2 H), 2.60–2.46 (m, 1 H), 2.06–
1.93 (m, 2 H), 1.90–1.78 (m, 1 H), 1.46 (tddd, J = 11.6, 9.9, 5.8, 1.9 Hz, 1
H).
13C NMR (101 MHz, CDCl3):  = 136.9, 136.0, 129.3, 129.0, 125.7,
125.7, 67.8, 37.2, 32.5, 28.8, 26.0.
(1,2,3,4-Tetrahydronaphthalen-1-yl)methanol (3c)
Prepared from general procedure A-1 (pale yellow oil, 44 mg, 53%).
Solvent system for chromatography: Hex/EtOAc 10%. 1H and 13C NMR
data matched reported values.60
1H NMR (400 MHz, CDCl3):  = 7.25–7.08 (m, 4 H), 3.81 (d, J = 6.4 Hz, 2
H), 3.04–2.94 (m, 1 H), 2.77 (td, J = 5.8, 3.5 Hz, 2 H), 1.96–1.81 (m, 3
H), 1.81–1.70 (m, 1 H), 1.49 (bs, J = 6.5 Hz, 1 H).
Grignard Addition to Aldehydes; General Procedure E
The corresponding aldehyde (1 equiv.) was dissolved in THF (0.2 M) in
a flame-dried Schlenk flask under N2. The reaction mixture was then
cooled to –78 °C. Vinylmagnesium bromide solution (1.3 equiv., 1 M
in THF) was added and the reaction mixture was stirred at –78 °C. Af-
ter reaction completion, the mixture was allowed to reach rt and was
quenched with 2 M HCl(aq) (3 times the reaction volume). The result-
ing mixture was extracted 3 times with EtOAc (1/3 of the total vol-
ume, 3 times). The combined organic layers were washed with brine
(equal volume as the organic phase) and dried over Na2SO4. The sol-
vents were removed under reduced pressure and the crude was puri-
fied via silica gel column chromatography (Hex/EtOAc) or used as
crude when sufficiently pure.
13C NMR (101 MHz, CDCl3):  = 138.3, 136.8, 129.5, 128.9, 126.3,
125.8, 67.3, 40.4, 29.9, 25.3, 19.9.
(4-Phenylcyclohexyl)methanol (3d)
Prepared from general procedure A-1 (colorless oil, 56 mg, 65%, 2.5:1
dr). Solvent system for chromatography: Hex/EtOAc 20%. 1H and 13C
NMR data matched reported values.61 See 1H and 13C NMR spectra of
3d in the supporting information for more details.
Ring-Closing Metathesis; General Procedure F
The corresponding diene (1 equiv.) was dissolved in toluene (0.05 M)
in a flame-dried Schlenk flask under N2. Grubbs 2nd generation cata-
lyst (1 mol%) was then added and the reaction mixture was stirred at
80 °C overnight. After reaction completion, the toluene was removed
under reduced pressure and the residue was purified via silica gel col-
umn chromatography (Hex/EtOAc).
Ethyl 4-(Hydroxymethyl)cyclohexane-1-carboxylate (3e)
Prepared from general procedure A-1 (colorless oil, 25 mg, 56%, 2:1
dr). Solvent system for chromatography: Hex/EtOAc 20%. 1H and 13C
NMR data matched reported values.62 See 1H and 13C NMR spectra of
3e in the supporting information for more details.
((5R)-2-Methyl-5-(prop-1-en-2-yl)cyclohexyl)methanol (3f)
Wittig Reaction on Aldehydes; General Procedure G
Prepared from general procedure A-1 (colorless oil, 56 mg, 90%,
14:2:1:1 mixture of isomers, major reported). Solvent system for
chromatography: Hex/EtOAc 10%.
1H NMR (400 MHz, CDCl3):  = 4.68 (dd, J = 1.8, 1.1 Hz, 2 H), 3.52 (dd,
J = 10.6, 7.6 Hz, 1 H), 3.45 (dd, J = 10.5, 7.0 Hz, 1 H), 2.03 (dq, J = 7.1,
3.9 Hz, 1 H), 1.91 (tt, J = 12.1, 3.4 Hz, 1 H), 1.78 (ddd, J = 12.6, 7.9, 3.7
Hz, 1 H), 1.72 (s, 3 H), 1.65–1.59 (m, 1 H), 1.57 (q, J = 3.6 Hz, 1 H),
1.55–1.49 (m, 2 H), 1.40 (dd, J = 13.2, 4.4 Hz, 1 H), 1.36–1.31 (m, 1 H),
1.09 (q, J = 12.6 Hz, 1 H), 0.84 (d, J = 7.2 Hz, 3 H).
Methyltriphenylphosphonium bromide (2 equiv.) was dissolved in
THF (1 mL) and cooled to 0 °C. Potassium tert-butoxide (2.5 equiv.)
was then added at 0 °C and the reaction mixture was stirred at this
temperature for 15 min. After 15 min, the desired aldehyde (1 equiv.)
in THF (0.4 mL, 0.1 M final concentration) was added dropwise at
0 °C. The reaction mixture was slowly allowed to reach rt overnight.
After 14 h, the reaction mixture was quenched with a saturated
NH4Cl(aq) solution (10 mL) and was extracted with EtOAc (3 × 5 mL).
The combined organic layers were washed with brine (15 mL) and
dried over Na2SO4. The solvents were removed under reduced pres-
sure and the residue was purified via silica gel column chromatogra-
phy (Hex/EtOAc).
13C NMR (101 MHz, CDCl3):  = 150.8, 108.3, 66.5, 45.4, 43.3, 33.4,
28.5, 28.3, 25.9, 21.1, 12.1.
HRMS (ESI-TOF): m/z [M + NH4]+ calcd for C11H24NO: 186.1552;
found: 186.1556.
2-Benzyl-3-phenylpropan-1-ol (3a)
Prepared from general procedure A-1 (colorless oil, 54.7 mg, 62%).
Solvent system for chromatography: Hex/EtOAc 15%. 1H and 13C NMR
data matched reported values.58
1H NMR (600 MHz, CDCl3):  = 7.29 (m, 4 H), 7.23–7.16 (m, 6 H), 3.50
(d, J = 4.9 Hz, 2 H), 2.70 (dd, J = 13.7, 8.0 Hz, 2 H), 2.66 (dd, J = 13.7, 6.5
Hz, 2 H), 2.19–2.10 (m, 1 H).
tert-Butyl (1R,3S,5S)-3-(Hydroxymethyl)-8-azabicyclo[3.2.1]oc-
tane-8-carboxylate (3g)
Prepared from general procedure A-1 (pale yellow oil, 20 mg, 45%,
11:1 dr). Solvent system for chromatography: Hex/EtOAc 30% to 40%.
1H and 13C NMR data matched reported values.47
1H NMR (400 MHz, toluene-d8, 80 °C):  = 4.21 (bs, 2 H), 3.10 (d, J = 6.0
Hz, 2 H), 1.79–1.58 (m, 4 H), 1.46 (s, 9 H), 1.43–1.37 (m, 2 H), 1.37–
1.32 (m, 2 H), 1.32–1.27 (m, 2 H).
13C NMR (151 MHz, CDCl3):  = 140.6, 129.3, 128.5, 126.1, 64.2, 44.7,
37.6.
13C NMR (101 MHz, toluene-d8, 80 °C):  = 153.0, 78.0, 67.5, 53.3, 33.8,
(1,2,3,4-Tetrahydronaphthalen-2-yl)methanol (3b)
31.3, 28.2, 28.0.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C13H24NO3: 242.1761; found:
242.1750.
Prepared from general procedure A-2 (pale yellow oil, 31 mg, 75%).
Solvent system for chromatography: Hex/EtOAc 20%. 1H and 13C NMR
data matched reported values.59
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

F
F. Emmetiere, A. J. Grenning
Paper
Synthesis
3-(3,4-Dimethoxyphenyl)-2-methylpropan-1-ol (3h)
1H NMR (400 MHz, CDCl3):  = 5.88–5.77 (m, 1 H), 5.77–5.66 (m, 1 H),
5.18–5.14 (m, 2 H), 5.14–5.07 (m, 2 H), 4.29 (dd, J = 8.9, 8.0 Hz, 1 H),
3.80 (dd, J = 10.0, 8.9 Hz, 1 H), 2.59 (ddq, J = 10.0, 8.1, 7.1 Hz, 1 H), 2.45
(ddt, J = 14.1, 6.3, 1.3 Hz, 1 H), 2.34 (ddt, J = 14.2, 7.2, 1.3 Hz, 1 H), 2.24
(ddt, J = 12.9, 8.5, 0.8 Hz, 1 H), 2.19 (ddt, J = 13.1, 7.6, 1.1 Hz, 1 H), 1.05
(d, J = 7.0 Hz, 3 H).
13C NMR (101 MHz, CDCl3):  = 180.0, 133.1, 132.8, 119.5, 119.4, 71.4,
48.3, 39.3, 37.0, 35.9, 11.2.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C11H17O2: 181.1223; found:
Prepared from general procedure A-1 (colorless oil, 52 mg, 60%).
Solvent system for chromatography: Hex/EtOAc 30%. 1H and 13C NMR
data matched reported values.63
1H NMR (400 MHz, CDCl3):  = 6.82–6.76 (m, 1 H), 6.73–6.68 (m, 2 H),
3.86 (dd, J = 3.8, 0.9 Hz, 6 H), 3.53 (ddt, J = 10.5, 5.9, 0.9 Hz, 1 H), 3.48
(ddt, J = 10.4, 6.0, 0.9 Hz, 1 H), 2.70 (dd, J = 13.5, 6.4 Hz, 1 H), 2.38 (dd,
J = 13.6, 8.0 Hz, 1 H), 2.00–1.85 (m, 1 H), 1.42 (bs, 1 H), 0.92 (dd, J =
6.8, 1.0 Hz, 3 H).
13C NMR (101 MHz, CDCl3):  = 148.9, 147.4, 133.3, 121.1, 112.4,
181.1218.
111.19, 67.9, 56.0, 39.5, 38.0, 16.7.
(1S,2S,3R)-3-(Hydroxymethyl)-2-methyl-2-(prop-2-yn-1-yl)cyclo-
pentan-1-ol (3n)
2-(Pyridin-3-yl)ethan-1-ol (3i)
Prepared from general procedure A-2 (pale yellow oil, 18 mg, 22%,
20:1 dr). Solvent system for chromatography: Hex/EtOAc 20% to 30%.
Prepared from general procedure A-1 (yellow oil, 36 mg, 20%, im-
pure). Solvent system for chromatography: Hex/EtOAc 40%. 1H and 13
NMR data matched reported values.64
C
1H NMR (400 MHz, CDCl3):  = 3.79 (dd, J = 11.1, 2.6 Hz, 1 H), 3.75 (dd,
J = 5.8, 2.1 Hz, 1 H), 3.55 (dd, J = 11.1, 3.7 Hz, 1 H), 2.37 (t, J = 2.9 Hz, 2
H), 2.12–2.03 (m, 1 H), 1.99 (t, J = 2.6 Hz, 1 H), 1.94–1.86 (m, 1 H), 1.81
(dddd, J = 11.3, 9.6, 6.5, 3.1 Hz, 1 H), 1.65 (dddd, J = 13.4, 9.7, 3.4, 1.7
Hz, 1 H), 1.11 (s, 3 H).
13C NMR (101 MHz, CDCl3):  = 83.1, 80.0, 70.1, 63.1, 48.2, 48.0, 32.4,
26.1, 24.3, 22.1.
1H NMR (600 MHz, CDCl3):  = 8.47 (s, 1 H), 8.42 (d, J = 5.8 Hz, 1 H),
7.82 (dt, J = 7.8, 1.6 Hz, 1 H), 7.43 (dd, J = 7.9, 5.7 Hz, 1 H), 3.87 (t, J =
6.2 Hz, 2 H), 2.89 (t, J = 6.2 Hz, 2 H).
13C NMR (151 MHz, CDCl3):  = 147.8, 145.4, 140.0, 137.6, 125.1, 62.1,
35.8.
2-Cyclopropylhexa-4,5-dien-1-ol (3j)
((7S,8S)-7-((R,E)-1,3-Diphenylallyl)-1,4-dioxaspiro[4.5]decan-8-
yl)methanol (4a)
Prepared from general procedure A-2 (colorless oil, 2 mg, 11%).
Solvent system for chromatography: Hex/EtOAc 5% to 20%.
Prepared from general procedure A-1 (white foam, 265 mg and 72 mg
for 4a and iso-4a respectively, 53%, 3.5:1 dr, separable diastereomers,
major reported). Solvent system for chromatography: Hex/EtOAc 25%
to 30%. Characterization of iso-4a is available in the Supporting Infor-
mation.
1H NMR (400 MHz, CDCl3):  = 7.34–7.24 (m, 6 H), 7.23–7.15 (m, 4 H),
6.45 (d, J = 15.8 Hz, 1 H), 6.34 (dd, J = 15.8, 9.2 Hz, 1 H), 3.95 (dd, J =
10.7, 4.7 Hz, 1 H), 3.90–3.80 (m, 2 H), 3.79–3.64 (m, 3 H), 3.27 (dd, J =
11.7, 9.2 Hz, 1 H), 2.36 (tt, J = 12.0, 4.3 Hz, 1 H), 2.14 (dt, J = 9.4, 4.2 Hz,
1 H), 2.07 (dt, J = 9.9, 2.6 Hz, 1 H), 1.71–1.63 (m, 2 H), 1.64–1.57 (m, 1
H), 1.35–1.17 (m, 3 H).
1H NMR (600 MHz, CDCl3):  = 5.15 (dq, J = 7.9, 6.8 Hz, 1 H), 4.66 (dt,
J = 6.8, 2.8 Hz, 2 H), 3.68 (d, J = 5.7 Hz, 2 H), 2.25–2.13 (m, 2 H), 1.50
(bs, 1 H), 0.87 (ddq, J = 9.5, 7.3, 5.8 Hz, 1 H), 0.65–0.56 (m, 1 H), 0.52–
0.47 (m, 2 H), 0.23–0.17 (m, 1 H), 0.16–0.12 (m, 1 H).
13C NMR (151 MHz, CDCl3):  = 209.1, 88.0, 74.5, 66.4, 46.5, 31.1, 13.1,
3.8, 3.4.
5-(2-Hydroxyethyl)-2-methoxyphenol (3k)
Prepared from general procedure A-1 (pale yellow oil, 21 mg, 22%).
Solvent system for chromatography: Hex/EtOAc 30%. 1H and 13C NMR
data matched reported values.65
1H NMR (400 MHz, CDCl3):  = 6.81 (s, 1 H), 6.79 (d, J = 6.0 Hz, 1 H),
6.70 (dd, J = 8.2, 2.1 Hz, 1 H), 3.87 (s, 3 H), 3.82 (t, J = 6.5 Hz, 2 H), 2.77
(t, J = 6.5 Hz, 2 H).
13C NMR (101 MHz, CDCl3):  = 143.8, 137.6, 133.2, 130.6, 129.2,
128.9, 128.1, 127.7, 126.8, 126.6, 109.5, 64.5, 64.5, 59.1, 53.0, 42.5,
37.1, 35.2, 30.4, 24.8.
13C NMR (101 MHz, CDCl3):  = 145.8, 145.4, 131.7, 120.6, 115.2,
(S)-3-((1R,3R,5S)-6,6-Dimethyl-2-methylenebicyclo[3.1.1]heptan-
110.9, 63.8, 56.1, 38.6.
3-yl)-4-phenylbutan-1-ol (4b)
Prepared from general procedure A-2 (colorless oil, 60 mg, 67%, >20:1
dr). Solvent system for chromatography: Hex/EtOAc 10%.
(1-Benzylpiperidin-4-yl)methanol (3l)
1H NMR (400 MHz, CDCl3):  = 7.30–7.26 (m, 2 H), 7.20–7.14 (m, 3 H),
4.93 (t, J = 1.8 Hz, 1 H), 4.87 (dd, J = 2.5, 1.4 Hz, 1 H), 3.58 (ddd, J =
10.5, 7.4, 5.8 Hz, 1 H), 3.47 (dt, J = 10.5, 7.3 Hz, 1 H), 3.00–2.87 (m, 2
H), 2.54 (t, J = 5.6 Hz, 1 H), 2.36 (dtd, J = 9.9, 6.0, 2.0 Hz, 1 H), 2.26
(ddd, J = 8.3, 4.6, 2.1 Hz, 1 H), 2.19 (t, J = 11.8 Hz, 1 H), 2.05 (tt, J = 5.9,
2.9 Hz, 1 H), 1.96 (dddd, J = 13.9, 10.6, 3.3, 1.9 Hz, 1 H), 1.74 (ddd, J =
13.7, 5.8, 2.9 Hz, 1 H), 1.60–1.48 (m, 2 H), 1.29 (s, 3 H), 1.21 (d, J = 9.9
Hz, 1 H), 0.88 (s, 3 H).
13C NMR (101 MHz, CDCl3):  = 154.8, 141.9, 129.4, 128.4, 125.9,
107.4, 61.7, 53.4, 41.6, 41.1, 40.4, 36.9, 36.1, 33.6, 29.2, 26.4, 22.1.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C20H29O: 285.2213; found:
Prepared from general procedure A-1 (colorless oil, 72 mg, 17%).
Solvent system for chromatography: Hex/EtOAc 20%. 1H and 13C NMR
data matched reported values.66
1H NMR (400 MHz, methanol-d4):  = 7.44 (dd, J = 6.7, 3.0 Hz, 2 H),
7.39–7.35 (m, 3 H), 4.01 (s, 2 H), 3.40 (d, J = 6.5 Hz, 2 H), 2.93 (dt, J =
11.9, 2.3 Hz, 2 H), 2.61 (ddd, J = 13.4, 11.9, 3.2 Hz, 2 H), 1.99 (qd, J =
13.0, 3.8 Hz, 2 H), 1.56 (ddt, J = 13.9, 3.5, 1.7 Hz, 2 H), 1.36 (dddd, J =
16.6, 12.3, 6.6, 2.4 Hz, 1 H).
13C NMR (101 MHz, methanol-d4):  = 134.4, 132.3, 129.8, 129.0, 71.2,
67.5, 57.6, 38.7, 25.4.
285.2220.
3,3-Diallyl-4-methyldihydrofuran-2(3H)-one (3m)
Prepared from general procedure A-1 (colorless oil, 90 mg, 65%).
Solvent system for chromatography: Hex/EtOAc 5%.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

G
F. Emmetiere, A. J. Grenning
Paper
Synthesis
(3S,4S)-3-Benzyl-4-phenylhex-5-en-1-ol (4c)
(4aS,9R,9aS)-9-Phenyl-3,4,4a,6,9,9a-hexahydrospiro[benzo[7]an-
nulene-2,2′-[1,3]dioxolan]-5(1H)-one (5a)
Prepared from general procedure A-2 (pale yellow oil, 44 mg, 59%,
10:1 dr, major reported). Solvent system for chromatography:
Hex/EtOAc 10%.
1H NMR (400 MHz, CDCl3):  = 7.26 (m, 5 H), 7.21–7.12 (m, 5 H), 6.08
(ddd, J = 17.0, 10.2, 9.3 Hz, 1 H), 5.19 (dd, J = 10.2, 1.8 Hz, 1 H), 5.12
(ddd, J = 17.0, 1.8, 0.9 Hz, 1 H), 3.60–3.48 (m, 2 H), 3.30 (dd, J = 9.4, 6.7
Hz, 1 H), 2.65 (dd, J = 13.8, 6.2 Hz, 1 H), 2.46 (dd, J = 13.8, 8.0 Hz, 1 H),
2.30–2.19 (m, 1 H), 1.73 (dddd, J = 13.9, 7.8, 7.0, 4.3 Hz, 1 H), 1.59–
1.49 (m, 1 H), 0.95 (bs, 1 H).
Prepared from 5a-SI-2 and iso-5a-SI-2 mixture via general procedure
F followed by general procedure C (white solid, 15 mg, 41% over 2
steps, 11:1 inseparable mixture of ,- and ,-unsaturated ketone,
major reported). The intermediate after general procedure F was used
crude without further purification. Solvent system for chromatogra-
phy: Hex/EtOAc 5%.
1H NMR (600 MHz, CDCl3):  = 7.32 (t, J = 7.3 Hz, 2 H), 7.24 (m, 3 H, J =
5.8, 5.4, 2.8 Hz, 3 H), 5.91 (ddd, J = 10.3, 6.0, 2.3 Hz, 1 H), 5.85 (dddd,
J = 10.5, 7.2, 3.7, 1.8 Hz, 1 H), 3.86 (td, J = 6.6, 6.2 Hz, 1 H), 3.80 (dt, J =
7.0, 5.9 Hz, 1 H), 3.78–3.73 (m, 1 H), 3.67 (dt, J = 7.1, 6.1 Hz, 1 H),
3.39–3.34 (m, 1 H), 3.29 (dd, J = 11.5, 5.8 Hz, 1 H), 3.18–3.12 (m, 1 H),
3.06 (dd, J = 19.6, 7.1 Hz, 1 H), 2.62 (tdd, J = 11.4, 6.7, 3.9 Hz, 1 H), 2.16
(td, J = 13.0, 4.6 Hz, 1 H), 2.02–1.95 (m, 1 H), 1.65 (tt, J = 13.5, 4.8 Hz, 1
H), 1.58 (ddt, J = 12.3, 4.8, 2.8 Hz, 1 H), 1.49 (ddd, J = 13.5, 3.9, 2.4 Hz,
1 H), 1.35 (dd, J = 13.4, 11.7 Hz, 1 H).
13C NMR (101 MHz, CDCl3):  = 143.8, 141.1, 139.2, 129.2, 128.6,
128.5, 128.1, 126.4, 126.1, 117.0, 61.3, 53.3, 42.0, 38.7, 33.6.
(2S,3S)-3-Benzyl-5-hydroxy-2-vinylpentyl Acetate (4d)
Prepared from general procedure A-2 (colorless oil, 17.5 mg, 39%, 2:1
dr, major reported). Solvent system for chromatography: Hex/EtOAc
20% to 30%.
1H NMR (400 MHz, CDCl3):  = 7.31–7.12 (m, 5 H), 5.74 (ddd, J = 17.2,
10.4, 8.6 Hz, 1 H), 5.23–5.17 (m, 1 H), 5.15–5.09 (m, 1 H), 4.16 (dd, J =
7.1, 3.7 Hz, 1 H), 4.09 (d, J = 7.2 Hz, 1 H), 3.61–3.52 (m, 2 H), 2.80 (dd,
J = 13.7, 5.1 Hz, 1 H), 2.63–2.56 (m, 1 H), 2.38 (dd, J = 13.7, 9.5 Hz, 1 H),
2.06 (s, 3 H), 1.64–1.46 (m, 2 H).
13C NMR (151 MHz, CDCl3):  = 212.3, 143.4, 136.3, 128.8, 128.3,
126.8, 124.2, 109.0, 64.3, 64.2, 50.3, 45.9, 44.5, 44.1, 37.3, 31.6, 29.9,
23.7.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C19H23O3: 299.1642; found:
299.1632.
13C NMR (101 MHz, CDCl3):  = 171.2, 140.9, 136.2, 129.2, 128.5,
126.2, 118.3, 65.4, 60.9, 45.1, 38.0, 37.1, 34.0, 21.1.
(4aS,8R,8aS)-8-Phenyl-4,4a,8,8a-tetrahydro-1H-spiro[naphtha-
lene-2,2′-[1,3]dioxolan]-5(3H)-one (6a)
Prepared from 4a via successive general procedures C, E, F followed by
C again. All intermediates were used crude without further purifica-
tion. The intermediate after procedure F was purified via silica gel col-
umn chromatography (Hex/EtOAc 20%) but not characterized (yellow
oil, 18 mg, 48% over 3 steps, 3:1 dr). Final compound 6a was obtained
after final treatment via general procedure C [white solid, 10 mg, 80%
(or 38% over 4 steps), single diastereomer]. Solvent system for chro-
matography: Hex/EtOAc 5%.
1H NMR (600 MHz, CDCl3):  = 7.35 (t, J = 7.6 Hz, 2 H), 7.30–7.26 (m, 3
H), 6.84 (dd, J = 10.1, 3.8 Hz, 1 H), 6.15 (dd, J = 10.0, 2.0 Hz, 1 H), 4.02–
3.96 (m, 2 H), 3.94–3.89 (m, 3 H), 2.60–2.51 (m, 2 H), 2.22–2.10 (m, 1
H), 1.72 (tdd, J = 12.4, 9.1, 3.0 Hz, 2 H), 1.66–1.54 (m, 3 H).
1-((7S,8S)-7-((R,E)-1,3-Diphenylallyl)-1,4-dioxaspiro[4.5]decan-8-
yl)but-3-en-1-ol (5a-SI-2 and iso-5a-SI-2)
Prepared from 4a via general procedure C followed by general proce-
dure D-2 (white foam, 15 mg and 32 mg respectively, 80% over 2
steps, 2:1 dr). The intermediate after general procedure C was used
crude without further purification. As the newly formed stereocenter
will be obliterated later in the sequence, the stereochemical assign-
ment was not determined. Solvent system for chromatography:
Hex/EtOAc 15%.
Diastereomer 1
1H NMR (400 MHz, CDCl3):  = 7.39–7.27 (m, 6 H), 7.25–7.13 (m, 4 H),
6.51–6.37 (m, 2 H), 5.83 (dddd, J = 19.9, 9.7, 8.0, 6.3 Hz, 1 H), 5.16 (d,
J = 12.3 Hz, 2 H), 4.11–3.99 (m, 2 H), 3.89–3.80 (m, 2 H), 3.77–3.70 (m,
1 H), 3.69–3.61 (m, 1 H), 2.56–2.39 (m, 2 H), 2.12 (dt, J = 13.9, 8.2 Hz,
1 H), 1.99 (dd, J = 9.3, 4.2 Hz, 1 H), 1.87–1.78 (m, 1 H), 1.74–1.65 (m, 1
H), 1.63–1.52 (m, 3 H), 1.41–1.33 (m, 1 H).
13C NMR (151 MHz, CDCl3):  = 201.3, 151.0, 141.4, 128.8, 128.7,
128.7, 127.2, 108.8, 64.7, 64.2, 45.0, 44.8, 42.6, 37.0, 33.4, 23.0.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C18H21O3: 285.1485; found:
285.1480.
(7R,8R)-7-((R,E)-1,3-Diphenylallyl)-8-vinyl-1,4-dioxaspiro[4.5]de-
cane (7a-SI-2)
13C NMR (101 MHz, CDCl3):  = 144.8, 137.8, 135.3, 134.7, 128.8,
128.6, 128.1, 127.1, 127.1, 126.2, 126.2, 119.0, 109.3, 69.3, 64.4, 64.0,
51.5, 40.9 (overlapping signals), 34.8, 32.5, 24.8.
Prepared from 4a via general procedure C followed by general proce-
dure G (colorless oil, 11 mg, 22%, 94% brsm, >20:1 dr). Solvent system
for chromatography: Hex/EtOAc 5% to 10%.
Diastereomer 2
1H NMR (600 MHz, CDCl3):  = 7.32–7.26 (m, 6 H), 7.23–7.15 (m, 4 H),
6.35 (d, J = 15.7 Hz, 1 H), 6.25 (dd, J = 15.7, 9.2 Hz, 1 H), 6.13 (ddd, J =
17.0, 10.3, 9.2 Hz, 1 H), 5.21 (dd, J = 10.3, 2.1 Hz, 1 H), 5.14 (dd, J =
17.1, 1.6 Hz, 1 H), 3.91–3.82 (m, 2 H), 3.79–3.71 (m, 2 H), 3.19 (dd, J =
11.3, 9.2 Hz, 1 H), 2.69 (dd, J = 9.0, 3.9 Hz, 1 H), 2.24 (ddt, J = 12.8, 11.3,
3.8 Hz, 1 H), 1.87 (tt, J = 14.9, 4.5 Hz, 1 H), 1.77–1.69 (m, 2 H), 1.58
(ddt, J = 13.0, 4.6, 2.5 Hz, 1 H), 1.33 (t, J = 13.2 Hz, 1 H), 1.30–1.26 (m,
1 H).
1H NMR (400 MHz, CDCl3):  = 7.37–7.26 (m, 7 H), 7.25–7.15 (m, 3 H),
6.43 (d, J = 15.7 Hz, 1 H), 6.29 (dd, J = 15.8, 9.5 Hz, 1 H), 5.74 (dddd, J =
16.2, 10.1, 8.2, 6.1 Hz, 1 H), 5.16–5.06 (m, 2 H), 4.22 (ddd, J = 8.9, 4.0,
2.5 Hz, 1 H), 3.90–3.80 (m, 2 H), 3.77–3.66 (m, 2 H), 3.61 (dd, J = 11.6,
9.4 Hz, 1 H), 2.41 (tt, J = 12.1, 3.9 Hz, 1 H), 2.34–2.20 (m, 2 H), 2.15 (td,
J = 13.2, 4.6 Hz, 1 H), 2.04 (dt, J = 14.1, 2.2 Hz, 1 H), 1.89 (t, J = 12.7 Hz,
1 H), 1.84 (d, J = 5.3 Hz, 1 H), 1.70 (tt, J = 13.7, 4.9 Hz, 1 H), 1.63–1.52
(m, 2 H).
13C NMR (151 MHz, CDCl3):  = 143.4, 137.7, 136.3, 132.8, 130.5,
128.8, 128.6, 128.0, 127.1, 126.3, 126.2, 117.5, 109.5, 64.2, 64.2, 53.1,
42.4, 39.6, 34.7, 30.5, 30.2.
13C NMR (101 MHz, CDCl3):  = 144.0, 137.5, 135.6, 133.9, 130.3,
128.8, 128.6, 128.0, 127.2, 126.3, 126.2, 118.6, 110.1, 70.1, 64.1, 64.0,
52.3, 42.9, 41.8, 35.5, 32.7, 23.7.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

H
F. Emmetiere, A. J. Grenning
Paper
Synthesis
(3R,3aR,7aR)-3-Phenyl-3,3a,4,6,7,7a-hexahydrospiro[indene-5,2′-
[1,3]dioxolane] (7a)
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1707184. Additional experimental
Prepared from 7a-SI-2 via general procedure F (colorless oil, 5 mg,
64%). Solvent system for chromatography: Hex/EtOAc 5%.
details and spectroscopic reprints (1H and 13C NMR) are available.
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1H NMR (600 MHz, CDCl3):  = 7.29 (dd, J = 8.3, 7.1 Hz, 2 H), 7.23–7.17
(m, 3 H), 5.93 (dt, J = 5.8, 2.4 Hz, 1 H), 5.76 (dt, J = 5.8, 1.6 Hz, 1 H),
4.05–3.98 (m, 2 H), 3.97–3.89 (m, 2 H), 3.87 (dq, J = 7.7, 2.0 Hz, 1 H),
2.77–2.66 (m, 1 H), 2.28 (qd, J = 7.1, 4.9 Hz, 1 H), 1.86–1.81 (m, 1 H),
1.78 (ddd, J = 14.1, 5.0, 1.7 Hz, 1 H), 1.74–1.72 (m, 1 H), 1.69 (dd, J =
14.1, 6.8 Hz, 1 H), 1.63–1.57 (m, 2 H).
References
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13C NMR (151 MHz, CDCl3):  = 144.5, 136.5, 134.1, 128.8, 128.4,
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(1R,2S)-2-Benzyl-2,3-dihydro-[1,1′-biphenyl]-4(1H)-one (8)
Prepared from 4c via successive general procedures C, E, F followed by
C again. All intermediates were used crude without further purifica-
tion. The intermediate after procedure F was purified via silica gel col-
umn chromatography (Hex/EtOAc 10%) but not characterized (27 mg,
62% over 3 steps). Final compound 8 was obtained after general pro-
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1H NMR (600 MHz, CDCl3):  = 7.43–7.31 (m, 3 H), 7.24 (tt, J = 6.1, 1.6
Hz, 4 H), 7.22–7.16 (m, 1 H), 7.02–6.98 (m, 2 H), 6.86 (dd, J = 10.1, 2.7
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2.49–2.43 (m, 1 H), 2.43–2.39 (m, 1 H), 2.21 (dd, J = 16.2, 11.2 Hz, 1 H).
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13C NMR (151 MHz, CDCl3):  = 199.5, 152.8, 141.8, 139.0, 129.4,
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((1R,6S)-6-Benzyl-4-oxocyclohex-2-en-1-yl)methyl Acetate (9)
Prepared from 4d via successive general procedures C, E, F followed by
C again. All intermediates were used crude without further purifica-
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vent system for chromatography: Hex/EtOAc 30%.
1H NMR (600 MHz, CDCl3):  = 7.33–7.27 (m, 2 H), 7.25–7.19 (m, 1 H),
7.17–7.10 (m, 2 H), 6.88 (dd, J = 10.1, 4.6 Hz, 1 H), 6.12 (dd, J = 10.1,
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(m, 2 H), 2.44–2.33 (m, 2 H), 2.08 (s, 3 H).
13C NMR (151 MHz, CDCl3):  = 198.9, 170.9, 149.2, 138.9, 131.0,
129.1, 128.8, 126.7, 63.2, 40.8, 38.5, 38.3, 37.9, 21.1.
HRMS (ESI-TOF): m/z [M + NH4]+ calcd for C16H22NO3: 276.1594;
found: 276.1601.
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Funding Information
This material is based upon work supported by the National Science
Foundation under Grant No. 1844443. We thank the College of Liberal
Arts and Sciences and the Department of Chemistry at the University
of Florida for start-up funds. We thank the Mass Spectrometry Re-
search and Education Center and their funding source: NIH S10
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© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I