Chiral a-substituted allylboronates in a one-pot three-component asymmetric allylic alkylation/carbonyl allylation reaction sequence -Applications to the syntheses of (+)-(3R,5R)-3-hydroxy-5-decanolide and (-)-massoialactone

Article abstract of DOI:10.1139/V09-036

The use of different organomagnesium reagents in the copper-catalyzed allylic alkylation of 3-chloropropenyl with chiral phosphoramidite ligands produces the desired a-substituted allylic boronate reagents in high and with modest to high enantioselectivities (up to 96% ee). The size of the incoming alkyl substituent the organomagnesium reagent was found to impact the yield and selectivity of the allylic alkylation. A one-pot for the preparation of these chiral allylic boronates followed by a Lewis acid (BF3) catalyzed addition to aldehydes the desired allylboration products, homoallylic secondary alcohols, in good yields and very high diastereoselectivity.three-component reaction methodology was applied to the syntheses of two lactone-containing natural , (-)-massoialactone and (+)-(3R,5R)-3-hydroxy-5-decanolide. The key step of these syntheses involved the pot enantioselective copper-catalyzed allylic alkylation/allylboration reaction with a benzylic aldehyde, and the desired product in 87% yield, 92% e,and high E/Z selectivity in a ratio of 22:1. Remarkably, the alkylation step of this sequential reaction was performed with a low catalyst loading of 2 mol% on a scale >15 mmol that can provide multiple grams of the three-component product.

Full text of DOI:10.1139/V09-036

650
Chiral a-substituted allylboronates in a one-pot
three-component asymmetric allylic alkylation/
carbonyl allylation reaction sequence —
Applications to the syntheses of (+)-(3R,5R)-3-
hydroxy-5-decanolide and (–)-massoialactone
Lisa Carosi and Dennis G. Hall
Abstract: The use of different organomagnesium reagents in the copper-catalyzed allylic alkylation of 3-chloropropenyl
boronates with chiral phosphoramidite ligands produces the desired a-substituted allylic boronate reagents in high
regioselectivity and with modest to high enantioselectivities (up to 96% ee). The size of the incoming alkyl substituent
from the organomagnesium reagent was found to impact the yield and selectivity of the allylic alkylation. A one-pot
procedure for the preparation of these chiral allylic boronates followed by a Lewis acid (BF3) catalyzed addition to aldehydes
delivers the desired allylboration products, homoallylic secondary alcohols, in good yields and very high diastereose-
lectivity. This three-component reaction methodology was applied to the syntheses of two lactone-containing natural
products, (–)-massoialactone and (+)-(3R,5R)-3-hydroxy-5-decanolide. The key step of these syntheses involved the
one-pot enantioselective copper-catalyzed allylic alkylation/allylboration reaction with a benzylic aldehyde, and
afforded the desired product in 87% yield, 92% ee, and high E/Z selectivity in a ratio of 22:1. Remarkably, the
allylic alkylation step of this sequential reaction was performed with a low catalyst loading of 2 mol% on a scale
of >15 mmol that can provide multiple grams of the three-component product.
Key words: allylboration, allylic alkylation, boronic esters, carbonyl allylation, copper catalysis.
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Resume : L’utilisation de divers reactifs organomagnesiens dans une reaction d’alkylation allylique des boronates 3-chlo-
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ropropenyles catalysee par le cuivre et un ligand chiral de type phosphoramidite produit les reactifs boronates allyli-
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ques a-substitues avec une haute regioselectivite et une enantioselectivite variant de modeste a elevee (jusqu’a 96 %
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ee). Il fut observe que la grosseur du substituant alkyle sur le reactif organomagnesien joue un role determinant sur
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le rendement chimique et la selectivite de l’alkylation allylique. Une procedure reactionnelle de type « one-pot » pour
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la preparation des boronates allyliques chiraux est suivie d’une addition sur les aldehydes catalysee par un acide de
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Lewis (BF3) qui mena aux produits desires d’allylboration, les alcools secondaires homoallyliques, avec un bon rende-
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ment chimique et une diastereoselectivite tres elevee. Cette reaction a trois-composants fut par la suite appliquee a
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une synthese de deux produits naturels, la (–)-massoialactone and la (+)-(3R,5R)-3-hydroxy-5-decanolide. L’etape-cle
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de ces syntheses impliqua la reaction « one-pot » catalytique enantioselective d’alkylation allylique/allylboration avec
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un aldehyde benzylique, produisant le produit desire dans un rendement chimique de 87 %, avec un ee de 92 % et
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une selectivite E/Z elevee dans un ratio de 22 :1. Il est remarquable de constater que l’etape d’alkylation allylique de
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cette reaction sequentielle fut realisee avec une faible charge catalytique de 2 mol% sur une echelle superieure a
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15 mmol qui permet d’isoler plusieurs grammes du produit de reaction a trois-composants.
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Mots-cles : alkylation allylique, allylation de composes carbonyles, allylboration, catalyse du cuivre, esters boroniques.
agents to achiral aldehydes, three strategies were set forth to
Introduction
provide control of the enantiofacial selectivity of the reac-
tion: (1) the use of ‘‘B-chiral’’ allylic boranes and boronates
where the two nonallylic substituents on the boron are chiral
directors such as terpene units,2 a chiral diol,3 or a chiral dia-
mine;4 (2) the use of a chiral Lewis or Brønsted acid catalyst
with achiral reagents;5 and (3) the use of optically pure a-
substituted allylboronates of type 1,6 also called ‘‘C-chiral’’
or ‘‘a-chiral’’ allylboronates. Amongst these methods, the
use of B-chiral allylic boron reagents has been in use for a
long time and is still the method of choice even though it is
far from ideal, as it uses a stoichiometric amount of chiral di-
rectors. Nevertheless, this class of reagents has been widely
Over the past three decades, additions of allylic boron re-
agents have undergone tremendous developments and have
emerged as one of the most powerful methods for stereose-
lective C–C bond formation.1 In additions of allylic boron re-
Received 7 January 2009. Accepted 25 February 2009.
Published on the NRC Research Press Web site at
canjchem.nrc.ca on 24 April 2009.
L. Carosi and D.G. Hall.1 Department of Chemistry, University
of Alberta, Edmonton, AB T6G 2G2, Canada.
1Corresponding author (e-mail: dennis.hall@ualberta.ca).
Can. J. Chem. 87: 650–661 (2009)
doi:10.1139/V09-036
Published by NRC Research Press

Carosi and Hall
651
Scheme 1. Optimal conditions for the one-pot three-component
Fig. 1. Possible transition structures in additions of a-substituted
allylboronates 1 to aldehydes.
allylic alkylation/aldehyde allylation with substrate 7 and exempli-
fied with benzaldehyde.
used in the synthesis of acetate and propionate units found in
numerous polyketide natural products.1b In contrast, chiral a-
substituted allylboronate reagents of type 1 have undergone
modest development and applications, which is likely due to
their stepwise preparation and the difficulty to control the
enantiofacial selectivity of their additions to carbonyl com-
pounds.
tivity for transition state 3 leading to the E isomer 5.7
Furthermore, the use of Lewis or Brønsted acid catalysis
can provide improved selectivity for the E isomer.8 Recent
density functional theory (DFT) calculations by Sakata
and Fujimoto9 have shown that under Lewis acid
activation, the transition state displays a shorter B–O bond
and a longer B–C bond with the aldehyde. Compared to
the uncatalyzed reaction, this longer B–C bond alleviates
the unfavorable steric interactions between the boronic
ester and the a-substituent in transition state 3. As a
result, the use of Lewis acid catalysis can afford high
selectivity for the E isomer even with the bulky pinacol
boronic ester.8
Selectivity with a-substituted allylboronates
Hoffmann and co-workers6 have demonstrated that the re-
agent-controlled additions of optically enriched a-substituted
allylboronates (1) to achiral aldehydes (2) proceed with near
perfect transfer of chirality from the chiral reagent to the
allylic alcohol product. As seen in Fig. 1, the two possible
transition states lead to diastereomeric homoallylic alcohol
products, 5 and 6, which have opposite stereochemistry at
the alcohol center and opposite alkene geometry. Hence, the
E/Z proportion in the reaction products mirrors the enantio-
selectivity of the reaction process.6 The proportion of E and
Z diastereomers is dependent on the nature of the a-substituent
and on the structure of the boronic ester. The selectivity
between transition states 3 and 4 can be explained in terms
of dipolar effects and steric effects. With a nonpolar a-
substituent (R1) such as an alkyl group, steric effects are dom-
inant. It is known that the use of a nonpolar a-substituent
leads to mixtures of products 5 and 6 with a modest selec-
tivity for product 5. In fact, there are unfavorable interactions
in both transition states. In the chairlike transition structure,
3, the unfavorable nonbonding interactions between the
boronic ester and the pseudo-equatorial a-substituent (R1)
can be aggravated by the use of a large boronic ester or a
bulky a-substituent.7 In contrast, transition structure 4, with
the a-substituent at the pseudo-axial position, suffers from
1,3-allylic strain between the a-substituent and the pseudo-
axial olefinic hydrogen. One transition state can be favored
over the other by changing the size of the boronic ester.7
Hence, the use of the bulky pinacol boronic ester will pro-
vide a modest selectivity for transition state 4 leading to
the Z isomer 6. On the other hand, the use of the smaller
2,2-dimethyl-1,3-propanediol boronic ester provides selec-
Enantioselective approaches to a-substituted allylboronates
The preparation of a-substituted allylboron reagents is lim-
ited to the more stable allylic boronic esters because allylic
dialkyl boranes undergo a rapid 1,3-borotropic shift at and
below ambient temperatures.1e,10 Hoffmann and co-workers6
pioneered the preparation and applications of acyclic opti-
cally enriched a-substituted allylboronates. Equations [1]–[4]
show examples of preparative methods for chiral a-substi-
tuted allylic boronates (pin = OCMe2CMe2O). Until the mid-
1990s, methods to access these reagents were limited to the
asymmetric Matteson homologation reaction using
a
stoichiometric chiral directing group,11 which may subse-
quently be exchanged through a transesterification reaction
(eq. [1]). Recently, additional methods to access chiral a-
substituted allylboronates were reported. For example, a
[3,3] sigmatropic rearrangement reaction of chiral 3-hydroxy
propenyl boronates was developed (eq. [2]).12 The ideal
approach would be catalytic and would avoid the use of stoi-
chiometric chiral directors. Such methods were also reported
and include the use of a palladium-catalyzed enantioselective
diboration of allenes (eq. [3]),13 and the use of a copper-
catalyzed enantioselective allylic substitution of allylic
carbonates with diboron reagents (eq. [4]),14a,14b or an
iridium-catalyzed variant.14c
Published by NRC Research Press

652
Can. J. Chem. Vol. 87, 2009
Table 1. Exploration of the scope of the Grignard reagent with
7 under the optimal conditions of Scheme 1.
½1ꢀ
½2ꢀ
½3ꢀ
SN2’/SN2
Entry R1MgXa
Product ratiob
ee (%)c
96
86
88
1
2
3
4
EtMgBr
n-BuMgBr
(4-Pentenyl)MgBr
(Cyclohexyl)MgBr
1a
1b
1c
1d
7:1
11:1
17:1
12:1
69
Note: Reaction conditions: ligand 8 and CuTC were premixed at RT,
then 7 was added, followed by R1MgX at –78 8C. Typical reaction
scale: 1.0 mmol at 0.3 mol/L concentration.
½4ꢀ
aFrom halide-free 3 mol/L solutions in Et2O.
1
bMeasured by H NMR spectroscopy of an aliquot of the crude
reaction mixtures.
cMeasured by chiral HPLC of isocyanate derivatives (11) of oxidation
products (10) of boronates (1) as shown in the above scheme.
In 2007, we reported a new preparative method based on
size and length. We then used these reagents in the allylic
substitution reaction with the 3-chloropropenyl boronate (7)
using our previously optimized reaction conditions. The out-
come of this study is summarized in Table 1. In this initial
study, the enantioselectivity was measured on carbamate
derivatives (11), which were obtained from the boronate oxi-
dation products (10). It is well-established that this oxidation
process occurs with near perfect retention of stereochemis-
try.17 Because of the volatility of alcohols 10, no yields were
compiled for this derivatization process.
We found that the use of linear organomagnesium re-
agents allow for a higher level of enantioselectivity. The
length of the alkyl chain also affects the SN2’/SN2 regiose-
lectivity and the level of enantioselectivity. The short
ethylmagnesium bromide reagent afforded the best enantio-
selectivity, giving 1a with 96% ee (Table 1, entry 1),
whereas the longer butylmagnesium or pentenylmagnesium
bromide provided very good, albeit lower enantioselectivity
(Table 1, entries 2–3). On the other hand, the bulkier cyclo-
hexylmagnesium bromide gave a much lower level of enan-
tioselectivity (Table 1, entry 4). With this data in hand, we
set out to gain information on the behavior of the chiral a-
substituted allylboronates in their additions to aldehydes.
Performing the one-pot allylic alkylation/aldehyde allylation
protocol with our previously optimized reaction conditions
allowed us to verify the efficiency of the chirality transfer
a copper-catalyzed enantioselective allylic substitution reac-
tion (Scheme 1).15 We were able to employ the resulting
chiral a-substituted allylboronates (1) in a one-pot sequential
protocol initiated by the enantioselective copper-catalyzed
allylic alkylation and followed by an aldehyde allylation.
The optimal combination of alkenylboronate (7) and chiral
phosphoramidite (8)16 led to reagent 1 with up to 96% ee.
This protocol resulted in a new enantioselective multi-
component route to homoallylic alcohols. Even though the
preliminary communication included the scope and limita-
tions of the three-component reaction sequence with regards
to the aldehyde, it provided little information on the scope
of the alkyl a-substituent (i.e., the organomagnesium re-
agent). Herein we report on the scope of the reaction with
regards to the alkyl a-substituent, and on the application of
this methodology to the synthesis of two small a-lactone
natural products.
Results and discussion
Reaction scope
Our preliminary results on the nature of the Grignard re-
agent had indicated that the size of the organomagnesium al-
kyl group had an important effect on the enantioselectivity of
the allylic substitution reaction.15 To further investigate this
trend, we prepared aliphatic Grignard reagents with various
Published by NRC Research Press

Carosi and Hall
653
Table 2. Exploration of the scope of a-substituted allylboronates
1a–1d in the one-pot three-component reaction from 7 under the
optimal conditions of Scheme 1.
Scheme 2. Retrosynthesis of (–)-massoialactone from (+)-(3R,5R)-
3-hydroxy-5-decanolide using the one-pot three component allylic
alkylation/aldehyde allylation.
Entry R1MgXa
Product E/Z
ratiob
Yield ee
(%)c
(%)d
1
2
3
4
EtMgBr
n-BuMgBr
(4-Pentenyl)MgBr
(Cyclohexyl)MgBr
9a
9b
9c
9d
18:1
75
52
40
41
92
85
83
68
99:1
98:2
99:1
Note: Reaction conditions: ligand 8 and CuTC were premixed at RT,
then 7 was added, followed by R1MgX at –78 8C. Typical reaction scale:
1.0 mmol at 0.3 mol/L concentration.
aFrom halide-free 3 mol/L solutions in Et2O.
bMeasured by HPLC-MS of crude reaction mixtures.
cIsolated yields.
dMeasured by chiral HPLC of pure products (9).
from reagents 1a–1d to the homoallylic alcohol products
9a–9d. Indeed, the enantioselectivity level found in the chi-
ral a-substituted allylboronates (Table 1) was representative
of that found in the benzaldehyde allylation products
(Table 2). Larger a-substituents proved to be favorable in
providing high selectivity for the E isomer. Unfortunately,
the overall efficiency of the transformation was negatively
affected by the use of larger a-substituents as lower yields
were obtained with the butylmagnesium, pentenylmagne-
sium, and cyclohexylmagnesium bromides (respective prod-
ucts are 9b–9d in Table 2, entries 2–4). Small amounts of
the undesired allylic alcohol products resulting from the
1,3-borotropic shift of the allylboronates, followed by alde-
hyde allylboration, were found in these cases. Trombini and
co-workers18 had found that with a-substituted allylboro-
nates, the nature of the boronic ester has a big influence on
the propensity of the 1,3-borotropic shift to take place. For
instance, the 2,2-dimethyl-1,3-propanediol boronic ester is
known to undergo this shift more easily than the correspond-
ing pinacol ester. Nevertheless, as demonstrated with the
preparation of 9a from reagent 1a (Table 2, entry 1), our ap-
proach to homoallylic alcohols via a one-pot enantioselec-
tive copper-catalyzed allylic alkylation/aldehyde allylation
reaction sequence allows for high selectivity of the desired
products (9) in good yield from two steps.
and (–)-massoialactone (13 and 12 in Scheme 2). (+)-(3R,5R)-
3-Hydroxy-5-decanolide was isolated in 1971 from the cul-
ture liquor of the fungus Cephalosporium recifei NRRL
5161.19 This metabolite is part of the trans-b-hydroxy-
d-lactone family, which is known to inhibit the enzyme
HMG-CoA reductase, thus it is potentially a cholesterol-
lowering agent.20 (–)-Massoialactone’s structure is related
to (+)-(3R,5R)-3-hydroxy-5-decanolide’s structure as it
lacks the 3-hydroxy group, which is replaced by the
a,b-unsaturation. (–)-Massoialactone has antibacterial and
antifungal activity,21 it is a skin irritant, and can be
isolated from many different natural sources. Abe22 first
isolated (–)-massoialactone in 1937 from the bark oil of
Cryptocarya massoia, an oil used for centuries in native
medicine. It was found to be the defense secretion of
two species of formicin ants of the genus Camponotus
found in western Australia.23 Numerous syntheses of both
(+)-(3R,5R)-3-hydroxy-5-decanolide and (–)-massoialactone
have been reported.24 As well, separate syntheses for
(+)-(3R,5R)-3-hydroxy-5-decanolide25 or for (–)-massoialac-
tone26 have been published. Various strategies were used to
introduce chirality, including stereoselective reduction with
Baker’s yeast,24a,24b,25a enzymatic lactonization,24d dynamic
kinetic resolution of starting material,26c metal-catalyzed
enantioselective reduction,26e allylboration with a chiral auxil-
iary,26a and simply using the chiral pool.24c, 24e, 24f, 26b, 26d, 26f
Amongst all those strategies, the most efficient synthesis
Application to the synthesis of lactone natural products
Our next objective was to demonstrate the versatility
of this methodology with an application in target-
oriented synthesis. As targets, we selected two naturally
occurring d-lactones: (+)-(3R,5R)-3-hydroxy-5-decanolide
Published by NRC Research Press

654
Can. J. Chem. Vol. 87, 2009
of (–)-massoialactone to date features the chiral auxiliary
directed allylboration reaction as the key initial step fol-
lowed by esterification and ring closing metathesis provid-
ing (–)-massoialactone with an overall yield of 49%.26a
Retrosynthetically, we first planned to access (–)-massoia-
lactone, 12, from (+)-(3R,5R)-3-hydroxy-5-decanolide (13)
through a dehydration reaction (Scheme 2). Our strategy to
access (+)-(3R,5R)-3-hydroxy-5-decanolide was to perform
the lactonization reaction from the open chain intermediate
14. This intermediate could be accessed through a Birch re-
duction followed by ozonolysis of the aromatic precursor 15,
which in turn could be synthesized from our key enantiose-
lective copper-catalyzed allylic alkylation/aldehyde allyla-
tion one-pot reaction sequence with benzylic aldehyde 16.
The use of reagent 1a, assembled from 7 and EtMgBr, will
provide the requisite pentyl side chain of 12 and 13 follow-
ing hydrogenation of the disubstituted alkene of 15.
Scheme 3. Synthesis of (–)-massoialactone and (+)-(3R,5R)-3-
hydroxy-5-decanolide.
Even though aldehyde 16 is commercially available, its
prohibitive price prompted us to find a more affordable
source. Therefore, it was synthesized in two steps: reduction
of the inexpensive (3-methoxyphenyl)acetic acid, 17, fol-
lowed by Dess–Martin periodinane oxidation. This sequence
provided aldehyde 16 in high yield (eq. [5]).27
½5ꢀ
From 16, the key step of one-pot enantioselective copper-
catalyzed allylic substitution/allylboration reaction afforded
the desired product 15 in 87% yield, 92% ee, and high E/Z
selectivity with a ratio of 22:1 (Scheme 3). Furthermore,
scale-up of this key step was straightforward: the catalyst
loading had to be lowered to 2 mol% to provide a constantly
high E selectivity and the allylboration reaction had to be
performed at –30 8C to ensure reaction completion. Addi-
tionally, the reaction was performed on up to 16 mmol of
starting material 7 resulting in over 2 g of pure product 15.
Hydrogenation of 15 was first attempted with palladium
on charcoal but when this reaction was performed on a
larger scale, isomerization of the alcohol’s stereogenic cen-
ter was observed, providing product 18 with only 76% ee.
In this event, hydrogenation of the double bond was per-
formed with Adams catalyst to afford the desired product
18 in 98% yield with 88% ee. The decrease in enantiomeric
excess observed under these conditions, from 92% ee for the
starting material 15 to 88% ee for the product 18, is ex-
pected. This decrease is due to the diastereomeric nature of
the inseparable E and Z mixture of 15 obtained after the al-
lylboration step. From 18, the carbonyl and the 1,3-diol moi-
eties of 14 were introduced in a three-step sequence. First, a
Birch reduction with in situ protection of the alcohol with
DIBAL-H provided diene 19 in moderate yield with recov-
erable unreacted starting material. A longer reaction time, a
higher reaction temperature, or the addition of more lithium
did not provide a better conversion. On the other hand,
Birch reduction without in situ protection of the alcohol af-
forded a full, but messy conversion of the starting material
with a lower yield. Therefore, we chose to use the Birch re-
duction with in situ protection of the alcohol. Following this
sequence, ozonolysis of diene 19 and immediate stereoselec-
tive 1,3-syn reduction of the ketone afforded compound 14
in 44% yield for the two steps. Hydrolysis of the methyl es-
ter was performed with sodium hydroxide in methanol and
water. Letting acid 20 stand at room temperature for 6 d
formed the desired natural product in 71% yield (eq. [6]).
Published by NRC Research Press

Carosi and Hall
655
was visualized with UV light and 5% phosphomolybdic acid
in EtOH (PMA); or 1% potassium permanganate in water
(KMnO4); or 5% vanillin, 4% concentrated sulfuric acid in
ethanol (vanillin); or 4% ammonium molybdate, 0.08% ce-
rium (IV) sulfate in 10% aqueous sulfuric acid. Flash chroma-
tography was performed on Silicycle SiliaFlash1 F60 ultra
pure silica gel 230–400 mesh or on a Teledyne Isco Combi-
flash1 Companion1 automated flash instrument. NMR spec-
tra were recorded on Varian INOVA-300, INOVA-400, or
INOVA-500 MHz instruments. The residual solvent protons
(1H) or the solvent carbons (13C) were used as internal stand-
ards. 1H NMR data are presented as follows: chemical shift in
ppm downfield from tetramethylsilane (multiplicity, integra-
tion, coupling constant). The accuracy of coupling constants
is deemed to be 0.4 Hz. High-resolution mass spectra were
recorded by the University of Alberta Mass Spectrometry
Services Laboratory using either electron impact (EI) or elec-
trospray (ES). Infrared spectra were obtained on a Nicolet
½6ꢀ
Alternatively, (+)-(3R,5R)-3-hydroxy-5-decanolide (13)
could be accessed from 20 by forming the mixed anhydride,
which self-cyclized immediately in 86% yield.28 Thus, the
synthesis of (+)-(3R,5R)-3-hydroxy-5-decanolide was com-
pleted in five or six steps with an overall yield of 15%. Op-
tical rotation for pure (+)-(3R,5R)-3-hydroxy-5-decanolide
(13) ([a]2D0: +25.58 (c 1.2, CHCl3)) matched that from its
natural source (lit.20 [a]D25: +27.48 (c 11.7, CHCl3)).
On the other hand, (–)-massoialactone (12) was also
formed from intermediate 20 by performing the cyclization,
which was immediately followed by dehydration with
DMAP in refluxing toluene. This sequence provided
(–)-massoialactone in six steps with an overall yield of
13%.Theopticalrotationofsynthetic(–)-massoialactone([a]2D0:
–74.28 (c 1.0, CHCl3)) was lower than that of its natural
source (lit.23 [a]D25: –918 (c 1.0, CHCl3)), but all other ana-
lytical data for the sample of synthetic (–)-massoialactone
agreed to that reported in the literature. It is interesting to
note that the high-dilution Yamaguchi lactonization of 20
has been alleged to provide the macrocyclic dimeric lac-
tone verbalactone,29 which is also a natural substance.30
However, under several conditions and after numerous at-
tempts, in our hands verbalactone was never isolated, and
the only products observed were 12 and 13.
Magna-IR 760 instrument equipped with
a Nic-Plan
microscope. Elemental analyses were performed on a Carlo
Erba EA1108 system. Optical rotations were obtained with a
PerkinElmer 241 polarimeter. Infrared spectra, elemental
analyses, and optical rotations were recorded by the Univer-
sity of Alberta Analytical and Instrumentation Laboratory.
General procedure for the synthesis and characterization
of chiral a-substituted allylboronates (1a–1d)
Copper thiophene carboxylate (CuTC) (9.5 mg,
0.050 mmol) and ligand 8 (0.054 mmol) were charged in a
25 mL round-bottom flask equipped with a magnetic stirrer.
The flask was purged three times with a light vacuum and
argon sequence. Dichloromethane (1.5 mL) was added and
the mixture was stirred for 30 min at room temperature. In
the meantime, a solution of boronic ester 7 (0.19 g,
1.0 mmol) in dichloromethane (0.5 mL) was prepared. The
solution of 7 was added dropwise and the reaction mixture
was stirred another 5 min at room temperature before cool-
ing to –78 8C (the reaction turned to a blue-green color).
The Grignard reagent (3.0 mol/L in Et2O, 1.2 mmol) diluted
with dichloromethane (0.6 mL) was added at –78 8C over
4 h using a syringe pump, keeping the needle immersed in
the reaction mixture. The reaction mixture turned to a bright
yellow color after about 3.5 h of addition. Once the addition
was complete, the mixture was stirred for another 1.5–2 h
at –78 8C. At that point a small aliquot was taken to verify
for completion of reaction and for SN2/SN2’ ratio measure-
Conclusion
In summary, the one-pot three-component enantioselec-
tive copper-catalyzed allylic substitution/allylation reaction
sequence proved to be efficient with regards to various chi-
ral a-alkyl allylboronate reagents. The a-substituent was
used in a productive way for the short syntheses of two
natural products: (+)-(3R,5R)-3-hydroxy-5-decanolide and
(–)-massoialactone.
1
ment by H NMR of chiral a-substituted allylboronates (1a–
1d). In situ oxidation to alcohols 10a–10d was performed
using the following sequence: water (0.5 mL) and
tetrahydrofuran (2 mL) were added and the reaction mixture
was brought to 0 8C. An aqueous 3 mol/L solution of so-
dium acetate (1 mL, 3 mmol) was added followed by 30%
aqueous hydrogen peroxide (0.6 mL, 5 mmol). The mixture
was stirred overnight while being allowed to reach room
temperature. After this time, an aqueous saturated solution
of sodium sulfite (1.5 mL) was added and the mixture was
stirred for 15 min at room temperature. The mixture was
then extracted three times with Et2O. The combined organic
phases were washed once with a saturated aqueous solution
of ammonium chloride and once with brine. It was dried
over anhydrous sodium sulfate, filtered, and partially con-
Experimental
Unless otherwise noted, all reactions were performed under
an argon atmosphere using flame-dried glassware. Toluene,
hexanes, and dichloromethane were distilled over CaH2. THF
and Et2O were distilled over sodium/benzophenone ketyl.
Ethylmagnesium bromide was purchased from Sigma-Aldrich
as a 3.0 mol/L solution in Et2O and titrated using a literature
procedure.31 Other Grignard reagents were prepared32 and ti-
trated using literature procedures. Alkenylboronate 7 was pre-
pared according to refs. 15 and 17. Ligand 8 was prepared
according to refs. 15 and 16a. Thin layer chromatography
(TLC) was performed on Merck Silica Gel 60 F254 plates and
Published by NRC Research Press

656
Can. J. Chem. Vol. 87, 2009
centrated in vacuo due to high volatility of the allylic alco-
hol product. The isocyanate derivative was synthesized as
follows: the allylic alcohol solution was cooled to 0 8C,
dichloromethane (1 mL) was added followed by pyridine
(0.17 mL, 2.0 mmol) and phenylisocyanate (0.17 mL,
1.5 mmol). The mixture was stirred overnight while being
allowed to reach room temperature. It was quenched with
water and the water layer was extracted three times with di-
chloromethane. The combined organic phases were dried
over anhydrous magnesium sulfate, filtered, and concen-
trated in vacuo to afford the crude isocyanate derivatives
11a–11d. Although yields for these products were not com-
piled due to the high volatility of alcohols (10a–10d), ana-
lytical samples were characterized as follows.
C15H19O2N: 245.1416; found: 245.1414. HPLC: Chiralcel
OD, 25 8C, 5% i-PrOH hexanes, 0.60 mL/min, UV detec-
tion at 280 nm, major peak at 18.4 min, minor peak at
26.7 min, 88% ee.
(3S)-3-[Phenylcarbamic ester]-3-cyclohexyl-1-propene
(11d) for chiral a-substituted allylboronate (1d)
Flash chromatography (100% hexane to 2% EtOAc–hexane)
yielded a white solid (136 mg, 53% yield). TLC (25%
EtOAc–hexane, UV, PMA): 0.56. [a]2D0: +18.78 (c 1.0,
CHCl3). IR (CHCl3 cast film, cm–1): 3319, 3061, 2928,
1
2854, 1704, 1602, 1542, 1444, 1230, 1050, 751. H NMR
(500 MHz, CDCl3) d: 7.39–7.36 (m, 2H), 7.30–7.26 (m,
2H), 7.03 (dd, 1H, J = 7.4, 7.4 Hz), 6.58 (br s, 1H), 5.79
(ddd, 1H, J = 17.4, 10.5, 7.0 Hz), 5.27 (ddd, 1H, J = 17.2,
1.5, 1.5 Hz), 5.21 (ddd, 1H, J = 10.5, 1.5, 1.5 Hz), 5.03 (dd,
1H, J = 6.8, 6.8 Hz), 1.83–1.57 (m, 6H), 1.28–1.01 (m, 5H).
13C NMR (100 MHz, CDCl3) d: 153.03, 137.96, 135.17,
128.93, 123.20, 118.53, 117.45, 79.82, 41.66, 28.53, 28.34,
26.30, 25.90, 25.88. HRMS (EI, m/z) calcd. for C16H21O2N:
259.1572; found: 259.1575. HPLC: Chiralcel OD, 25 8C,
5% i-PrOH hexanes, 0.60 mL/min, UV detection at 280 nm,
major peak at 14.9 min, minor peak at 16.4 min, 69% ee.
(3S)-3-[Phenylcarbamic ester] 1-pentene (11a) for chiral a-
substituted allylboronate (1a)
Flash chromatography (5% Et2O–pentane) yielded a col-
orless oil (52 mg, 25% yield), which had satisfactory analyt-
ical data (NMR, MS) as reported in the literature.15 TLC
(30% Et2O–pentane, UV, PMA): 0.53. HPLC followed a lit-
erature procedure: Chiralcel OD, 25 8C, 20% i-PrOH hex-
anes, 0.60 mL/min, UV detection at 280 nm, major peak at
9.8 min, minor peak at 11.6 min, 96% ee.
General procedure for the one-pot protocol of
enantioselective copper-catalyzed allylic substitution/
aldehyde allylation — Preparation of homoallylic
(3S)-3-[Phenylcarbamic ester] hept-1-ene (11b) for chiral
a-substituted allylboronate (1b)
Flash chromatography (100% hexane to 2% EtOAc–
hexane) yielded a colorless oil (82 mg, 34% yield). TLC
(25% EtOAc–hexane, UV, PMA): 0.53. [a]2D0: +5.78 (c
1.2, CHCl3). IR (neat, cm–1): 3322, 3061, 2957, 2872,
alcohols (9a–9d)
Copper thiophene carboxylate (CuTC) (9.5 mg,
0.050 mmol) and ligand 8 (33 mg, 0.054 mmol) were
charged in a flame-dried 25 mL round-bottom flask
equipped with a magnetic stirrer. The flask was purged three
times with a light vacuum and argon sequence. Dichlorome-
thane (1.5 mL) was added and the mixture was stirred for
30 min at room temperature. In the meantime, a solution of
boronic ester 7 (188 mg, 1.0 mmol) in dichloromethane
(0.5 mL) was prepared. The solution of 7 was added drop-
wise to the reaction mixture and stirred for 5 min at room
temperature (the reaction mixture turned to a blue-green
color) before cooling to –78 8C. The Grignard reagent
(3.0 mol/L in Et2O, 1.2 mmol) diluted with dichloromethane
(0.6 mL) was added at –78 8C over 4 h using a syringe
pump, keeping the needle immersed in the reaction mixture.
The reaction mixture turned to a bright yellow color after
about 3.5 h of addition. Once the addition was complete,
the mixture was stirred another 1.5–2 h at –78 8C. The alde-
hyde (0.7–0.8 mmol) was added at –78 8C immediately fol-
lowed by boron trifluoride diethyl etherate (BF3-OEt2)
(0.10 mL, 0.80 mmol). The reaction mixture was stirred ap-
proximately 24 h at –78 8C and 16 h at –30 8C. The reaction
was cooled back to –78 8C and was quenched with the addi-
tion of a saturated aqueous solution of sodium bicarbonate
(1.5 mL). The mixture was then warmed up to room temper-
ature over 3 h and stirred for an additional 30 min at room
temperature. The phases were separated and the aqueous
phase was extracted three times using dichloromethane. The
combined organic extracts were dried over anhydrous so-
dium sulfate, filtered, and concentrated in vacuo.
1
1700, 1601, 1539, 1444, 1313, 1228, 1120, 752, 692. H
NMR (500 MHz, CDCl3) d: 7.39–7.29 (m, 4H), 7.06 (dd,
1H, J = 7.4, 7.4 Hz), 6.58 (br s, 1H), 5.83 (ddd, 1H, J =
17.3, 10.7, 6.6 Hz), 5.31 (ddd, 1H, J = 17.3, 1.3, 1.3 Hz),
5.23 (ddd, 1H, J = 6.6, 6.6, 6.6 Hz), 5.20 (ddd, 1H, J =
10.6, 1.3, 1.3 Hz), 1.75–1.68 (m, 1H), 1.67–1.60 (m, 1H),
1.40–1.32 (m, 4H), 0.91 (t, 3H, J = 7.1 Hz). 13C NMR
(100 MHz, CDCl3) d: 153.06, 138.00, 136.81, 129.01,
123.30, 118.56, 116.64, 75.82, 34.11, 27.23, 22.50, 14.0.
HRMS (EI, m/z) calcd. for C14H19O2N: 233.1416; found:
233.1414. HPLC: Chiralcel OD, 25 8C, 5% i-PrOH hex-
anes, 0.60 mL/min, UV detection at 280 nm, major peak
at 16.3 min, minor peak at 19.8 min, 86% ee.
(3S)-3-[Phenylcarbamic ester] 1,7-octadiene (11c) for
chiral a-substituted allylboronate (1c)
Flash chromatography (100% hexane to 2% EtOAc–
hexane) yielded a colorless oil (62 mg, 25% yield). TLC
(25% EtOAc–hexane, UV, PMA): 0.52. [a]2D0: +9.68 (c
1.0, CHCl3). IR (CHCl3 cast film, cm–1): 3322, 3078,
2940, 1705, 1602, 1537, 1445, 1313, 1226, 1052, 915,
753. 1H NMR (500 MHz, CDCl3) d: 7.37–7.35 (m, 2H),
7.30–7.26 (m, 2H), 7.03 (dd, 1H, J = 7.3, 7.3, Hz), 6.58
(br s, 1H), 5.84–5.74 (m, 2H), 5.29 (ddd, 1H, J = 17.2,
1.3, 1.3 Hz), 5.24 (ddd, 1H, J = 6.2, 6.2, 6.2 Hz), 5.18
(ddd, 1H, J = 10.5, 1.3, 1.3 Hz), 5.03–4.98 (m, 1H),
4.97–4.94 (m, 1H), 2.12–2.07 (m, 2H), 1.75–1.61 (m, 2H),
1.52–1.44 (m, 2H). 13C NMR (100 MHz, CDCl3) d: 152.9,
138.3, 137.9, 136.6, 129.0, 123.3, 118.6, 116.8, 114.9,
75.6, 33.8, 33.4, 24.3. HRMS (EI, m/z) calcd. for
(3E,1R)-1-Phenyl-3-hexen-1-ol (9a)
Flash chromatography (100% hexanes to 5% EtOAc–
Published by NRC Research Press

Carosi and Hall
657
hexanes) yielded a colorless oil (108 mg, 75%), which
gave satisfactory analytical data (NMR, MS) as reported
in the literature.15,33 TLC: (20% EtOAc–hexanes, UV,
PMA) 0.34. [a]2D0: +57.48 (c 1.0, CHCl3). HPLC for E/Z
ratio measurement on the crude product: Zorbax SB-C18
4.6 mm ꢁ 150 mm, 5 mm, 40 8C, mobile phase A: 0.05%
formic acid – H2O, mobile phase B: 0.05% formic acid –
MeOH, program: 70:30 at 0 min, 64.5% of B at 55 min,
80% of B at 58 min, 30% of B at 58.01 min, 1 mL/min,
UV detection at 220 nm, retention times: (3Z)-1-phenyl-3-
hexen-1-ol, 44.5 min; (3E)-1-phenyl-3-hexen-1-ol, 45.8 min.
HPLC for enantiomeric excess measurement on purified
product is based on a literature procedure:15 Chiralcel OD,
10 8C, 5% i-PrOH hexane, 0.3 mL/min, UV detection at
220 nm, retention times: (3E,1R)-1-phenyl-3-hexen-1-ol,
25.8 min; (3Z,1R or 1S)-1-phenyl-3-hexen-1-ol, 29.4 min;
(3E,1S)-1-phenyl-3-hexen-1-ol, 32.0 min; (3Z,1R or 1S)-1-
phenyl-3-hexen-1-ol, 35.2 min; 92% ee.
mobile phase A: 0.05% formic acid – H2O, mobile phase B:
0.05% formic acid – MeOH, program: 70:30 at 0 min,
64.5% of B at 110 min, 30% of B at 110.01 min, 1 mL/min,
UV detection at 210 nm, retention times: (3Z)-1-phenyl-
3,8-nonadien-1-ol, 104.4 min; (3E)-1-phenyl-3,8-nonadien-
1-ol, 106.7 min. HPLC for enantiomeric excess measurement
on purified product: Chiralcel OD, 10 8C, 2% i-PrOH hex-
ane, 0.5 mL/min, UV detection at 270 nm, retention times:
(3E,1R)-1-phenyl-3,8-nonadien-1-ol, 25.6 min; (3E,1S)-1-
phenyl-3,8-nonadien-1-ol, 33.2 min; 83% ee.
(3E,1R)-4-Cyclohexyl-1-phenyl-3-buten-1-ol (9d)
Flash chromatography using an automated flash system
(4 g SiO2 column, 10 column volumes (CV) 100% petro-
leum ether, 20 CV 100% petroleum ether to 5% EtOAc,
30 CV 5% EtOAc, 10 CV 5% EtOAc to 50% EtOAc)
yielded a colorless oil (74 mg, 41%), which gave satisfactory
analytical data (NMR, MS) as reported in the literature.35
Note: 46 mg (23%) of the borotropic shift/allylation product
was also isolated. TLC (10% EtOAc–petroleum ether,
PMA): 0.28. [a]2D0: +23.28 (c 1.0 CHCl3). HPLC for E/Z ratio
measurement on crude product: Zorbax SB-C18 4.6 mm ꢁ
150 mm, 5 mm, 40 8C, mobile phase A: 0.05% formic acid
– H2O, mobile phase B: 0.05% formic acid – acetonitrile,
program: 50:50 at 0 min, 95% of B at 25 min, 50% of B at
25.01 min, 1 mL/min, UV detection at 210 nm, retention
times: (3Z)-4-cyclohexyl-1-phenyl-3-buten-1-ol, 12.6 min;
(3E)-4-cyclohexyl-1-phenyl-3-buten-1-ol, 13.2 min. HPLC
for enantiomeric excess measurement on purified product:
Chiralcel OD, 10 8C, 2% i-PrOH hexane, 0.5 mL/min, UV
detection at 220 nm, retention times: (3E,1R)-4-cyclohexyl-
1-phenyl-3-buten-1-ol, 23.4 min; (3E,1S)-4-cyclohexyl-1-
phenyl-3-buten-1-ol, 33.4 min; 68% ee.
(3E,1R)-1-Phenyl-3-octen-1-ol (9b)
Flash chromatography using an automated flash system
(4 g SiO2 column, 10 column volumes (CV) 100% petro-
leum ether, 20 CV 100% petroleum ether to 5% EtOAc,
30 CV 5% EtOAc, 10 CV 5% EtOAc to 50% EtOAc)
yielded a colorless oil (84 mg, 52%), which gave satisfac-
tory analytical data (NMR, MS) as reported in the litera-
ture.34 Note: 34 mg (21%) of the borotropic shift/allylation
product was also isolated. TLC (10% EtOAc–petroleum
ether, PMA): 0.28. [a]D20: +32.28 (c 1.0, CHCl3). HPLC for
E/Z ratio measurement on crude product: Zorbax SB-C18
4.6 mm ꢁ 150 mm, 5 mm, 40 8C, mobile phase A: 0.05%
formic acid – H2O, mobile phase B: 0.05% formic acid –
MeOH, program: 70:30 at 0 min, 64.5% of B at 110 min,
30% of B at 110.01 min, 1 mL/min, UV detection at 210 nm,
retention times: (3Z)-1-phenyl-3-octen-1-ol, 104.4 min; (3E)-
1-phenyl-3-octen-3-ol, 106.9 min. HPLC for enantiomeric ex-
cess measurement on purified product: Chiralcel OD, 10 8C,
2% i-PrOH hexane, 0.5 mL/min, UV detection at 254 nm, re-
tention times: (3E,1R)-1-phenyl-3-octen-1-ol, 22.7 min;
(3E,1S)-1-phenyl-3-octen-1-ol, 26.5 min; 85% ee.
Experimental procedures in the syntheses of (+)-(3R,5R)-
3-hydroxy-5-decanolide (13) and (–)-massoialactone (12)
2-(3-Methoxyphenyl) ethanol
This compound was synthesized following a literature pro-
cedure27a and yielded a colorless oil (4.33 g, 95%), which
gave satisfactory analytical data (NMR, MS), as reported in
the literature,27b and was used without further purification.
(3E,1R)-1-Phenyl-3,8-nonadien-1-ol (9c)
Flash chromatography using an automated flash system
(4 g SiO2 column, 10 column volumes (CV) 100% petro-
leum ether, 20 CV 100% petroleum ether to 5% EtOAc,
30 CV 5% EtOAc, 10 CV 5% EtOAc to 50% EtOAc)
yielded a colorless oil (68 mg, 40%). Note: 41 mg (24%) of
the borotropic shift/allylation product was also isolated. TLC
(10% EtOAc–petroleum ether, PMA): 0.24. [a]2D0: +30.98 (c
1.0, CHCl3). IR (CHCl3 cast film, cm–1): 3378, 3030, 2927,
(3-Methoxyphenyl) acetaldehyde (16)
This compound was synthesized following
a pub-
lished procedure.27c Flash chromatography (5% Et2O–
dichloromethane) yielded a light yellow oil (1.74 g, 93%).
TLC (50% Et2O–dichloromethane, UV, KMnO4): 0.38. IR
(CH2Cl2 cast film, cm–1): 3004, 2941, 2837, 2728, 1723,
1602, 1492, 1258, 1152, 1042, 782, 697. 1H NMR
(400 MHz, CDCl3) d: 9.74 (t, 1H, J = 2.4 Hz), 7.30 (dd,
1H, J = 7.9, 7.9 Hz), 6.88–6.76 (m, 3H), 3.82 (s, 3H),
3.66 (d, 2H, J = 2.4 Hz). 13C NMR (100 MHz, CDCl3) d:
199.3, 160.1, 133.2, 130.0, 121.9, 115.3, 112.8, 55.2, 50.6.
HRMS (EI, m/z) calcd. for C9H10O2: 150.0681; found:
150.0683. Anal. calcd. for C9H10O2: C 71.98, H 6.71;
found: C 71.78, H 6.71.
1
2855, 1640, 1454, 970, 911. H NMR (500 MHz, CDCl3) d:
7.36–7.35 (m, 4H), 7.29–7.27 (m, 1H), 5.78 (dddd, 1H, J =
17.0, 10.3, 6.7, 6.7 Hz), 5.55 (dm, 1H, J = 15.1 Hz), 5.39
(dm, 1H, J = 15.5 Hz), 4.98 (dm, 1H, J = 17.1 Hz), 4.93
(dm, 1H, J = 10.2 Hz), 4.67 (ddd, 1H, J = 8.0, 4.9,
3.2 Hz), 2.50–2.38 (m, 2H), 2.06–2.00 (m, 5H), 1.48–1.42
(m, 2H). 13C NMR (100 MHz, CDCl3) d: 144.0, 138.7,
134.6, 128.3, 127.4, 125.8 (2C), 114.5, 73.5, 42.8, 33.2,
32.0, 28.5. HRMS (EI, m/z) calcd. for C15H20O: 216.1514;
found: 216.1520. HPLC for E/Z ratio measurement on crude
product: Zorbax SB-C18 4.6 mm ꢁ 150 mm, 5 mm, 40 8C,
(4E,2R)-1-(3-Methoxyphenyl)-4-heptene-2-ol (15)
Copper thiophene carboxylate (CuTC) (61 mg,
0.32 mmol) and ligand 8 (240 mg, 0.39 mmol) were charged
in a flame-dried 100 mL round-bottom flask equipped with a
Published by NRC Research Press

658
Can. J. Chem. Vol. 87, 2009
magnetic stirrer. The flask was purged three times with a
light vacuum and argon sequence. Dichloromethane
(24 mL) was added and the mixture was stirred for 30 min
at room temperature. In the meantime, a solution of boronic
ester 7 (3.01 g, 16.0 mmol) in dichloromethane (8 mL) was
prepared. The solution of 7 was added dropwise to the reac-
tion mixture and stirred for 5 min at room temperature (the
reaction mixture turned to a blue-green color) before cooling
to –78 8C. Ethylmagnesium bromide (3.0 mol/L in Et2O,
19 mmol) diluted with dichloromethane (10 mL) was added
at –78 8C over 4 h using a syringe pump, keeping the needle
immersed in the reaction mixture. The reaction mixture
turned to a bright yellow color after about 3.5 h of addition.
Once the addition was complete, the mixture was stirred for
another 2 h at –78 8C. Boron trifluoride diethyl etherate
(BF3-OEt2) (2.0 mL, 16 mmol) was added immediately fol-
lowed by (3-methoxyphenyl) acetaldehyde (16) (1.65 g,
11.0 mmol) at –78 8C. The reaction mixture was stirred for
approximately 24 h at –78 8C and 16 h at –30 8C. The reac-
tion was quenched at –78 8C via the addition of a saturated
aqueous solution of sodium bicarbonate (20 mL). The mix-
ture was then warmed up to room temperature over 3 h and
stirred for an additional 30 min at room temperature. The
phases were separated and the aqueous phase was extracted
three times using dichloromethane. The combined organic
extracts were dried over anhydrous sodium sulfate, filtered,
and concentrated in vacuo.
Flash chromatography (100% hexanes to 20% Et2O–
hexanes) yielded a colorless oil as an inseparable mixture
of E/Z isomers 15 in a 22:1 ratio (2.12 g, 87%). TLC
(50% Et2O–hexanes, UV, PMA): 0.27. [a]2D0: –2.98 (c 1.0,
CHCl3). IR (CHCl3 cast film, cm–1): 3421, 2961, 2934,
1602, 1585, 1489, 1261, 1046. 1H NMR (400 MHz,
CDCl3) d: 7.23, (dd, 1H, J = 8.9, 7.5 Hz), 6.79–6.76 (m,
3H), 5.62 (dm, 1H, J = 15.1 Hz), 5.45 (dm, 1H, J =
15.5 Hz), 3.88–3.81 (m, 1H), 3.81 (s, 3H), 2.79 (dd, 1H,
J = 13.6, 5.1 Hz), 2.70 (dd, 1H, J = 13.6, 7.9 Hz), 2.29–
2.27 (m, 1H), 2.17–2.15 (m, 1H), 2.10–2.02 (m, 2H), 1.71
(d, 1H, J = 3.2 Hz), 1.00 (t, 3H, J = 7.4 Hz). 13C NMR
(100 MHz, CDCl3) d: 159.6, 140.1, 136.1, 129.3, 124.5,
121.7, 115.0, 111.7, 71.8, 55.0, 43.2, 39.9, 25.6, 13.7.
HRMS (EI, m/z) calcd. for C14H20O2: 220.1463; found:
220.1461. HPLC for enantiomeric excess: Chiralcel OD,
10 8C, 2% i-PrOH hexane, 0.7 mL/min, UV detection at
280 nm, retention times: (4E,2S)-1-(3-methoxyphenyl)-4-
heptene-2-ol, 20.8 min; (4Z,2R or 2S)-1-(3-methoxyphenyl)-
4-heptene-2-ol, 22.7 min; (4E,2R)-1-(3-methoxyphenyl)-4-
heptene-2-ol, 28.2 min; (4Z,2R or 2S)-1-(3-methoxyphenyl)-
4-heptene-2-ol, 30.2 min; 92% ee.
EtOAc. The filtrate was concentrated in vacuo. Flash chro-
matography on a short column (30% Et2O–hexanes) yielded
a yellow oil (2.10 g, 98%). TLC: (50% Et2O–hexanes, UV,
KMnO4, vanillin (blue stain)) 0.33. Note: even though the
product and the starting material have the same Rf, the prod-
uct took longer to stain with KMnO4. [a]2D0: –10.48 (c 1.0,
CHCl3). IR (CHCl3 cast film, cm–1): 3407, 2931, 2858,
1
1602, 1489, 1465, 1259, 1154, 1046. H NMR (400 MHz,
CDCl3) d: 7.24 (ddd, 1H, J = 7.4, 7.4, 1.2 Hz), 6.83–6.78
(m, 3H), 3.82–3.81 (m, 1H), 3.81 (s, 3H), 2.82 (dd, 1H, J =
13.5, 4.2 Hz), 2.63 (dd, 1H, J = 13.6, 8.5 Hz), 1.57–1.51
(m, 4H), 1.34–1.31 (m, 5H), 0.91 (t, 3H, J = 6.9 Hz). 13C
NMR (100 MHz, CDCl3) d: 159.7, 140.2, 129.4, 121.6,
115.0, 111.7, 72.5, 55.0, 44.0, 36.7, 31.8, 25.3, 22.6, 13.9.
HRMS (EI, m/z) calcd. for C14H22O2: 222.1620; found:
222.1621. Anal. calcd. for C9H10O2: C 71.98, H 6.71; found:
C 71.78, H 6.71. HPLC for enantiomeric excess: Chiralcel
OD, 10 8C, 2% i-PrOH hexane, 0.7 mL/min, UV detection
at 280 nm, retention times: (2S)-1-(3-methoxyphenyl)-2-
heptanol, 21.0 min; (2R)-1-(3-methoxyphenyl)-2-heptanol,
28.8 min; 88% ee.
(2R)-1-(5-Methoxy cyclohexadienyl)-2-heptanol (19)
This compound was synthesized following a literature
procedure performed on a different substrate.36 Flash chro-
matography (100% petroleum ether to 6% EtOAc–petroleum
ether) yielded a colorless oil (239 mg, 46%) along with
starting material (152 mg, 65% yield brsm). TLC: (20%
EtOAc–petroleum ether, vanillin (red stain)): 0.38.
[a]2D0: –8.18 (c 1.0, CHCl3). IR (microscope, cm–1): 3418,
1
2930, 1695, 1665, 1467, 1390, 1222, 1136, 1024, 776. H
NMR (400 MHz, CDCl3) d: 5.56 (brs, 1H), 4.64 (dd, 1H,
J = 3.6, 3.6 Hz), 3.80–3.69 (m, 1H), 3.56 (s, 3H), 2.87–
2.81 (m, 2H), 2.78–2.68 (m, 1H), 2.66–2.56 (m, 1H), 2.19
(br d, 1H, J =13.8 Hz), 2.09 (dd, 1H, J = 13.8, 9.1 Hz),
1.63 (br s, 1H), 1.49–1.43 (m, 3H), 1.37–1.27 (m, 5H),
0.90 (t, 3H, J = 6.9 Hz). 13C NMR (100 MHz, CDCl3) d:
152.7, 131.3, 122.1, 90.2, 68.5, 53.9, 45.3, 37.0, 31.9, 31.6,
26.8, 25.4, 22.6, 14.0. HRMS (EI, m/z) calcd. for
C14H24O2: 224.1776; found: 224.1781. Anal. calcd. for
C14H24O2: C 74.95, H 10.78; found: C 74.94, H 10.81.
(3R,5R)-Methyl 3,5-dihydroxydecanoate (14)
Ozonolysis was performed following modified literature
procedures performed on different substrates.36,37 In a three-
neck flask equipped with a CaCl2 drying tube, a solution of
(2R)-1-(5-methoxy cyclohexadienyl)-2-heptanol (19) (0.22 g,
1.0 mmol) in dichloromethane (4.2 mL) and methanol
(1.8 mL) was prepared and pyridine (90 mL, 1.1 mmol) was
added. The solution was cooled to –78 8C and a light stream
of ozone was bubbled through until the reaction was satu-
rated at which point the reaction mixture turned blue and
the color persisted. Ozone was removed with oxygen until
the blue color disappeared. Dimethyl sulfide (3 mL) was
added at –78 8C and the reaction mixture was stirred for 1 h
at room temperature. A saturated sodium chloride solution
was added, the layers were separated, and the aqueous layer
was extracted four times with dichloromethane. The com-
bined organic extracts were dried over anhydrous sodium
sulfate, filtered, and concentrated in vacuo. The unstable
crude material was immediately used in the following step.
(2R)-1-(3-Methoxyphenyl)-2-heptanol (18)
(4E,2R)-1-(3-Methoxyphenyl)-4-heptene-2-ol (15) (2.12 g,
9.6 mmol) was charged in a flame-dried flask under argon.
Ethyl acetate (100 mL) and Adams’s catalyst (PtO2)
(108 mg, 0.48 mmol) were added and the flask was purged
three times with a light vacuum and argon sequence and
three times with a light vacuum and H2 sequence. The reac-
tion mixture was stirred for 1.5 h at room temperature under
an atmospheric pressure of H2 (using a H2 balloon). The re-
action mixture was then purged with a light vacuum and ar-
gon sequence before being filtered on celite and rinsed with
Published by NRC Research Press

Carosi and Hall
659
The reaction was stirred at 0 8C for 1 h. In the meantime,
a three-neck flask equipped with a condenser in one neck,
a 25 cm Vigreux column in the other, and a rubber septum
in the third neck, was charged with DMAP (0.99 g,
8.1 mmol) and toluene (27 mL) and was heated at reflux
so that 15 cm of the Vigreux column (isolated with cotton)
would be heated with the refluxing toluene. The first
reaction mixture, containing the mixed anhydride, was
transferred to a syringe and added over 2 h using a syringe
pump, at the top of the Vigreux column to the DMAP
solution in refluxing toluene. Once the addition was
complete the reaction mixture was refluxed for another 2 h.
The reaction mixture was cooled to room temperature and
the solvents were evaporated in vacuo. Flash chromatography
(30% EtOAc–hexanes to 80% EtOAc–hexanes) afforded
(–)-massoialactone (12) (30 mg, 67%) as a light yellow oil
with a strong coconut fragrance. TLC (40% EtOAc–hexanes,
0.08% cerium (IV) sulfate in 10% aqueous sulfuric acid):
0.44. [a]2D0: –74.28 (c 1.0, CHCl3) (lit.23 [a]2D5: –918 (c 1.0,
CHCl3)). IR (neat, cm–1): 3056, 2955, 2862, 1725, 1389,
1251, 1040, 816. 1H NMR (300 MHz, CDCl3) d: 6.88
(ddd, 1H, J = 9.7, 3.6, 3.6 Hz), 6.03 (ddd, 1H, J = 9.7,
1.5, 1.5 Hz), 4.47–4.38 (m, 1H), 2.36–2.31 (m, 2H), 1.87–
1.27 (m, 8H), 0.90 (t, 3H, J = 6.9 Hz). 13C NMR
(100 MHz, CDCl3) d: 164.6, 145.0, 121.5, 78.1, 34.9,
31.6, 29.4, 24.5, 22.5, 14.0. HRMS (EI, m/z) calcd. for
C10H16O2: 168.1150; found: 168.1150.
The ketone reduction was performed following a modifi-
cation of a literature procedure.37,38 Crude (5R)-methyl-5-
hydroxy-3-oxodecanoate was charged in a flame-dried flask
under argon. It was diluted with THF (12 mL) and methanol
(3 mL) and cooled to –78 8C for dropwise addition of diethyl-
methoxyborane (1.1 mL, 1.1 mmol) as a 1.0 mol/L solu-
tion in THF. The reaction mixture was stirred for 15 min
at –78 8C and sodium borohydride (0.19 g, 5.1 mmol) was
added in one portion. The reaction mixture was stirred for
3 h at –78 8C and was quenched with the addition of a
saturated aqueous solution of ammonium chloride. The re-
action flask was brought carefully to room temperature as
gas evolution occurred. The reaction was stirred at room
temperature until no more gas evolution was observed.
The phases were separated and the aqueous phase was
extracted three times with Et2O. The combined organic
extracts were dried over anhydrous sodium sulfate, filtered,
and concentrated in vacuo. The resulting boronate was
purified on a short pad of silica (1% MeOH, 50% Et2O–
hexanes) and the diol was freed by performing the follow-
ing cycle four times: addition of MeOH and evaporation in
vacuo. The resulting oil (96 mg, 44% for two steps) was
used without further purification as flash chromatography
on the free diol resulted in decomposition. TLC (80%
EtOAc–hexanes, 0.08% cerium (IV) sulfate in 10% aque-
ous sulfuric acid): 0.40. [a]2D0: –17.78 (c 1.1, CHCl3). IR
(neat, cm–1): 3406, 2932, 1738, 1439, 1164. 1H NMR
(400 MHz, CDCl3) d: 4.30–4.23 (m, 1H), 3.86 (br s, 1H),
3.70 (s, 3H), 3.30 (br s, 1H), 2.49–2.48 (m, 2H), 1.61–1.53
(m, 2H), 1.50–1.37 (m, 3H), 1.34–1.24 (m, 6H), 0.87 (t,
3H, J = 6.8 Hz). 13C NMR (100 MHz, CDCl3) d: 172.8,
72.2, 69.0, 51.8, 42.2, 41.6, 37.8, 31.8, 25.0, 22.6, 14.0.
HRMS (ES, m/z) calcd. for C11H22O4 (M + Na): 241.1410;
found: 241.1410.
(+)-(3R,5R)-3-Hydroxy-5-decanolide (13)
In a flame-dried flask under argon, (3R,5R)-3,5-dihydrox-
ydecanoic acid (20) (25 mg, 0.12 mmol) was charged,
diluted with THF (1 mL), and cooled to 0 8C. Freshly
distilled triethylamine (0.10 mL, 0.72 mmol) was added
followed by freshly distilled 2,4,6-trichlorobenzoyl chloride
(30 mL, 0.18 mmol). The reaction was stirred at 0 8C for
1 h and solvents were removed in vacuo. Flash chromatog-
raphy (30% EtOAc-hexanes to 50% EtOAc-hexanes)
afforded (+)-(3R,5R)-3-Hydroxy-5-decanolide 13 (19 mg,
86%) as a colorless oil. TLC (80% EtOAc–hexanes, 0.08%
cerium (IV) sulfate in 10% aqueous sulfuric acid): 0.31.
[a]D20: +25.488 (c 1.2, CHCl3) (lit.19 [a]2D0: +27.48 (c 11.7,
CHCl3)). IR (CHCl3 cast film, cm–1): 3415, 2932, 2861,
(3R,5R)- 3,5-Dihydroxydecanoic acid (20)
(3R,5R)-Methyl 3,5-dihydroxydecanoate (14) (0.20 g,
0.92 mmol) was diluted with MeOH (20 mL) and water
(3 mL). The reaction flask was cooled to 0 8C and sodium
hydroxide (3 mL, 18 mmol) as a 6 mol/L aqueous solution
was added. The reaction was stirred at 0 8C for 1 h, and a
sodium hydroxide/citric acid pH 5 buffer was added fol-
lowed by a 1 mol/L aqueous citric acid solution until pH 5
was reached (measured with a pH meter). The aqueous
phase was extracted three times with EtOAc. The combined
organic extracts were washed once with brine, dried over
anhydrous sodium sulfate, filtered, and concentrated in va-
cuo to afford a colorless oil (175 mg, 93%) containing 13%
of cyclized product. This compound was used immediately,
without purification, in subsequent reactions since it rapidly
cyclized upon standing.
1
1713, 1256, 1069. H NMR (500 MHz, CDCl3) d: 4.69 (dm,
1H, J = 11.0 Hz), 4.41–4.40 (m, 1H), 2.75 (1H, dd, J =
17.6, 5.1 Hz), 2.62 (ddd, 1H, J = 17.6, 3.7, 1.7 Hz), 1.96
(dm, 1H, J = 14.5 Hz), 1.75 (ddd, 1H, J = 14.6, 11.4,
3.4 Hz), 1.73–1.69 (m, 1H), 1.63–1.49 (m, 2H), 1.45–1.38
(m, 2H), 1.34–1.29 (m, 4H), 0.90 (t, 3H, J = 6.4 Hz). 13C
NMR (100 MHz, CDCl3) d: 170.8, 76.0, 62.7, 38.6, 35.9,
31.5, 24.5, 22.5, 13.9. HRMS (ES, m/z) calcd. for C10H18O3
(M + Na): 209.1148, found: 209.1150.
Supplementary data
(–)-Massoialactone (12)
This compound was prepared following a modification
of a literature procedure.28b,29 In a flame-dried flask under
argon, (3R,5R)-3,5-dihydroxydecanoic acid (20) (56 mg,
0.27 mmol) was added, then diluted with THF (27 mL)
Supplementary data for this article are available on the
journal Web site (canjchem.nrc.ca) or may be purchased
from the Depository of Unpublished Data, Document Deliv-
ery, CISTI, National Research Council Canada, Ottawa, ON
K1A 0R6, Canada. DUD 3915. For more information on ob-
taining material refer to cisti-icist.nrc-cnrc.gc.ca/cms/
unpub_e.shtml.
and cooled to
0 8C. Freshly distilled triethylamine
(0.23 mL, 1.6 mmol) was added followed by freshly dis-
tilled 2,4,6-trichlorobenzoyl chloride (65 mL, 0.41 mmol).
Published by NRC Research Press

660
Can. J. Chem. Vol. 87, 2009
(10) Brown, H. C.; Rangaishenvi, M. V.; Jayaraman, S. Organo-
metallics 1992, 11, 1948. doi:10.1021/om00041a029.
(11) Matteson, D. S. Tetrahedron 1998, 54, 10555. doi:10.1016/
S0040-4020(98)00321-4.
Aknowledgements
This work was funded by the Natural Sciences and Engi-
neering Research Council (NSERC) of Canada and the Uni-
versity of Alberta. LC thanks NSERC for a postgraduate
scholarship and Novartis pharmaceuticals of Canada for a
graduate scholarship. We thank Dr. Klaus Ditrich (BASF)
for the generous gift of (S)-1-(2-methoxyphenyl) ethylamine
and Mr. Eric Pelletier (University of Alberta) and Supelco
Analytical for help with HPLC analyses.
¨
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