A stereoselective approach to γ-functionalized carbonyls exploiting the Cu-promoted SN2′ reaction

Article abstract of DOI:10.1021/jo102213d

While several efficient processes exist to effect the stereoselective creation of carbon-carbon bonds in the α- and β-position of carbonyls, functionalization of the γ-position is much more challenging. We disclose an alternative methodology exploiting the Cu-promoted S _N2′ reaction to achieve the addition of various nucleophiles upon the allylic lactones 5a-d which lead to the generation of the desired γ-functionalized α,β-unsaturated aldehydes 6 following in situ hydrolysis.

Full text of DOI:10.1021/jo102213d

ARTICLE
pubs.acs.org/joc
A Stereoselective Approach to γ-Functionalized Carbonyls Exploiting
the Cu-Promoted SN20 Reaction
Eric Bond, Anne-Marie Beausoleil, Jennifer Howell, Alicia Wong, and Jo€el Robichaud*
Department of Medicinal Chemistry, Merck Frosst Canada Inc., 16711 Trans Canada Highway, Kirkland, Quꢀebec, H9H 3L1, Canada
S Supporting Information
b
ABSTRACT: While several efficient processes exist to effect the
stereoselective creation of carbon-carbon bonds in the R- and
β-position of carbonyls, functionalization of the γ-position is
much more challenging. We disclose an alternative methodol-
ogy exploiting the Cu-promoted SN20 reaction to achieve the
addition of various nucleophiles upon the allylic lactones 5a-d
which lead to the generation of the desired γ-functionalized R,β-unsaturated aldehydes 6 following in situ hydrolysis.
’ INTRODUCTION
The stereoselective formation of carbon-carbon bonds ranks
as one of the most important reactions of organic chemistry.
Among the various chemical handles utilized to perform this
reaction the carbonyl remains among the most powerful func-
tionalities. Stereoselective introduction of substituents either
at the R- or β-positions (Figure 1) can be readily achieved
respectively via stereoselective alkylation1 and Michael addition.2
Achieving similar results at the γ-position is inherently more
difficult3 as it is too far removed from the carbonyl to allow direct
functionalization, especially in a stereoselective manner.
Figure 2. The design of a system exploiting the Cu-promoted SN20
reaction to carry out stereoselective γ-functionalization.
purpose of (1) masking the sensitive carbonyl, (2) tethering the
leaving group in the R-position, and (3) providing the required
chiral bias for high stereoselectivity.
Further refinement of our model led to the inclusion of
another key component. While the Cu-promoted SN20 reaction
Figure 1. Stereoselective functionalization utilizing the carbonyl group.
proceeds via an anti attack,9 free rotation around the allylic bond
exposes both faces of the alkene, thereby precluding high
stereoselectivity. Trost,10 however, demonstrated that in systems
where the leaving group was locked within a ring, very high
stereoselectivity could be achieved only if the reactive double
bond, outside the ring, was of Z geometry. These results can be
rationalized by virtue of A1,3-strain11 in one of the two reactive
conformers, thereby selectively exposing only one face to attack.
Incorporation of all of the requisite aforementioned elements
within our strategy led to the design of the system depicted in
Figure 2. Nucleophilic attack upon such a chiral allylic system
would perform a stereoselective SN20 reaction generating, after
Despite these challenges, a growing number of methodologies
have been developed to address this gap and allow for the
synthesis of various O-,4 S-,5 N-,6 and C-substituted7 γ-functio-
nalized carbonyls. In our efforts to broaden the scope of these
technologies, we have devised a complementary stereoselective
approach that exploits the versatility of the Cu-promoted SN20
reaction.8
Inspired by Nakai’s work7b that utilizes Evans’ oxazolidinone
imide chemistry to prepare chiral allylic carbonates which under-
go Pd(0)-catalyzed allylic substitution to afford the γ-functiona-
lized products, our strategy (Figure 2) analogously generates the
electrophilic center in the γ-position by removing the double
bond from conjugation and activating it with a leaving group at
the R-position. Our auxiliary, however, must serve the triple
Received: November 15, 2010
Published: March 10, 2011
r
2011 American Chemical Society
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|

The Journal of Organic Chemistry
ARTICLE
unmasking of the carbonyl group, the desired γ-substituted
product. Of further interest is the fact that the final product
bears a versatile R,β-unsaturated system that is poised for further
chemical transformations.
Table 1. Stereoselective Synthesis of γ-Alkylated Aldehydes
6a-f via the Cu-Promoted SN20 Reaction
’ RESULTS AND DISCUSSION
Our synthesis (Scheme 1) begins with commercially available
amino-menthol 1,12 which was alkylated with bromoacetic acid
to afford the zwitterion 2 in 73% yield. Condensation of amino-
acid 2 with glyoxal in 1,4-dioxane afforded the carboxy-lactol 3 in
82% yield.13 Deprotonation of 3 with sodium hydride followed
by addition of the appropriately substituted organo-cerium
reagents produced the desired lactones 4a-d with yields ranging
between 40% and 46%. Upon workup of these reactions, the
crude 1H NMR indicated partial lactonization that was driven to
completion by stripping down the crude product several times
with MePh and a small amount of AcOH. The diastereomeric
ratio of these additions varied between 4:1 to 5:1 in favor of the
indicated stereochemistry.14 Semihydrogenation of these alkynes
(4a-d) using Brown’s P-2 Ni method15 afforded the corre-
sponding cis alkenes 5a-d (with Z/E > 99:1)16 in yields ranging
between 70% and 96%. The structural assignment of 5a was
rigorously ascertained with the help of NMR experiments (see
the Supporting Information). With these key intermediates in
our hands, we then turned our attention to performing the crucial
Cu-promoted SN20 reaction using a variety of nucleophiles.
a ee determinations were established by using chiral HPLC conditions
developed to resolve the racemates. b ee was determined by using the
saturated alcohol. c ee was determined by using chiral HPLC conditions
to resolve the Mosher’s ester of the allylic alcohol.
Scheme 1. Synthesis of the Key Precursors 5a-da
Table 2. Stereoselective Synthesis of γ-Arylated and
γ-Alkenylated Aldehydes 6g-j via the Cu-Promoted SN20
Reaction
a Reagents and conditionsy: (a) BrCH2CO2H, NaOH, H2O/EtOH, rt-
80 °C, 73%; (b) Glyoxal, 1,4-dioxane, 70 °C, 1 h, 82%; (c) NaH, THF,
0 °C, then Cl2CeCCR, -78 °C, then AcOH/MePH; (d) H2, NaBH4,
Ni(OAc)2, TMEDA, EtOH, 0 °C to rt.
Treatment of these differentially substituted allylic lactones
5a-d (Table 1) with 2.5 equiv of primary (entries 1-4),
secondary (entry 5), and tertiary (entry 6) monoalkyl copper
reagents effected the desired SN20 reaction, which afforded,
following in situ hydrolysis using aqueous formic acid, the desired
γ-functionalized aldehydes 6a-f.17 Reaction yields varied be-
tween 52% and 72% along with stereoselectivies ranging between
85% and 98% ee. An authentic standard of compound 6a was
synthesized (data not shown) which confirmed that the stereo-
chemical outcome of the SN20 reaction was as predicted and
served as validation for our model.
a ee determinations were established by using chiral HPLC conditions
developed to resolve the racemates.
of nucleophile along with higher reaction temperature and time.
Aware that the lesser reactivity of the aryl-copper species was
likely the source of the problem, we turned our attention to Lewis
acid activation of the reaction. After screening a variety of Lewis
It was found that extending this methodology to include aryl
copper nucleophiles was only possible by utilizing a large excess
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ARTICLE
acids, copper sources, and reaction conditions (data not shown),
we discovered that the combination of a substoichiometric
be stored in the freezer and utilized within 24 h as it slowly reverts back to
the starting material. 1H NMR (major epimer, 400 MHz, d6-DMSO) δ7.75
(d, J = 6.4 Hz, 1H, exchangeable proton), 5.25 (d, J = 5.4 Hz, 1H), 4.51 (s,
1H), 3.63 (d, J = 17.8 Hz, 1H), 3.33 (d, J = 17.8 Hz, 1H), 3.61-3.45 (m,
1H, embedded in the DMSO signal), 1.83-1.77 (m, 1H), 1.72-1.63 (m,
1H), 1.59-1.45 (m, 3H), 1.28-0.81 (m, 3H), 1.08 (s, 3H), 1.06 (s, 3H),
0.88 (d, J = 6.4 Hz, 3H). 13C NMR (101 MHz, d6-DMSO) δ 168.8, 96.3,
82.2, 75.6, 55.7, 44.3, 44.1, 41.1, 34.8, 31.2, 25.4, 24.8, 22.6, 19.0. HRMS
calcd for C14H24NO4 (M þ H)þ 270.1715, found 270.1670. [R]22D -39.0
[c 0.55, EtOH].
General Procedure for the Addition-Lactonization Reac-
tion. A solution of the organo-cerium reagent was prepared by adding
the corresponding Grignard reagent (2 equiv) to dry CeCl3 (2.1 equiv)
in dry THF (0.2 M) at -40 °C, and the reaction was stirred for 30 min.
To lactol 3 in dry THF (0.2 M) at 0 °C was added 60% NaH (1 equiv)
and the reaction was stirred for 15 min and then cooled to -78 °C. The
organo-cerium reagent was then transferred via syringe to the deproto-
nated lactol 3 and, after 30 min, the reaction was raised to -40 °C and
stirred for an additional 30 min. The reaction was quenched by the
addition of saturated NH4Cl and diluted with EtOAc and brine, then the
crude product was extracted with EtOAc (3ꢀ) and dried over Na2SO4.
The reaction afforded only partial lactonization and was completed by
addition of toluene along with acetic acid (a few hundred microliters)
and concentrating it in vacuo on a rotavap with the bath adjusted at
70 °C. This process was repeated several times until all of the
intermediate was completely lactonized as judged by TLC and LCMS.
amount of BF3 OEt2 along with a higher order cuprate
3
(Table 2) afforded results comparable to those obtained with
the alkyl nucleophiles.
Thus, treatment of the allylic lactone 5d with 2.0 equiv of
various higher order aryl cuprates (entries 1-3) in the presence
of 0.5 equiv of BF3 OEt2 afforded, again following hydrolysis
3
with aqueous formic acid, the desired γ-functionalized aldehydes
6g-i. Chemical yields varied between 51% and 75% along with
stereoselectivities ranging from 92% to 98% ee. The utilization of
a vinylic nucleophile (entry 4) also proved possible, furnishing
the desired γ-functionalized aldehyde 6j in 43% yield and 95% ee.
’ CONCLUSION
In summary, we have established a general stereoselective
approach that allows the preparation of γ-functionalized alde-
hydes via a 5-step sequence beginning from commercially
available amino-menthol 1. This methodology exploits the
potential of the Cu-promoted SN20 reaction allowing the stereo-
selective introduction of substituents upon our scaffolds 5a-d.
Further efforts are currently underway to expand the scope of this
methodology to include transition metal catalysis as well as
extending the range of nucleophiles to include various
heteroatoms.
(1S,6aS,9R,10aR,11aS)-6,6,9-Trimethyl-1-(phenylethynyl)
octahydro-6H-[1,4]oxazino[3,4-b][1,3]benzoxazin-3(4H)-one
(4a): The crude 1H NMR showed a ratio of 4:1 for the two diastereoi-
somers. The crude product was then purified by flash chromatography
over SiO2 (EtOAc/Hex, 2:8) to afford the major nonpolar product 4a
(275 mg, 40% yield) and the minor product (70 mg, 10% yield). 1H NMR
(400 MHz, d4-MeOH) δ 7.47-7.45 (m, 2H), 7.39-7.33 (m, 3H), 5.41
(d, J = 2.2 Hz, 1H), 4.98 (d, J = 2.2 Hz, 1H), 3.82 (d, J = 18.2 Hz, 1H), 3.63
(d, J = 18.2 Hz, 1H), 3.69-3.66 (m, 1H), 1.97-1.94 (m, 1H), 1.75-1.72
(m, 1H), 1.66-1.61 (m, 2H), 1.54-1.45 (m, 1H), 1.26 (s, 3H), 1.15 (s,
3H), 1.12-0.93 (m, 3H), 0.95 (d, J = 6.6 Hz, 3H). 13C NMR (101 MHz,
CDCl3) δ 168.5, 131.5, 128.8, 128.2, 121.8, 87.3, 81.9, 79.8, 77.1, 71.8,
56.3, 43.2, 42.4, 40.5, 34.6, 31.3, 24.5, 24.3, 21.2, 20.0. Minor (more polar)
’ EXPERIMENTAL SECTION
({2-[(1S,2R,4R)-2-Hydroxy-4-methylcyclohexyl]propan-2-yl}
amino)acetic acid (2): To R-bromoacetic acid (5.75 g, 43.86 mmol, 1.5
equiv) in water (10 mL) at 0 °C was added 10 N NaOH until the pH was
approximately 12. The l-8-amino-menthol 1 (5.0 g, 29.24 mmol) was
dissolved in a minimal amount of EtOH and added to the reaction, which
was gradually warmed to 80 °C. After 1 h another 0.5 equiv of R-
bromoacetic acid (again dissolved in a minimal amount of water and
basified with 10 N NaOH) was added to the reaction mixture, which was
then stirred at 90 °C for another hour. The reaction was then cooled to rt
and concentrated in vacuo to remove all of the EtOH. The crude product
was directly purified by flash chromatography over SiO2 (NH4OH/
MeOH/DCM, 1:9:90, then 2:18:80) to afford the desired amino-acid
auxiliary 2 as a white solid (4.86 g, 73% yield). Alternatively, compound 2
could also be purified by reverse-phase flash chromatography over C18
Lichroprep (column loaded using MeCN/H2O, 2:8 þ 0.1% HCO2H, then
washed and eluted with MeCN/H2O 5:95 þ 0.1% HCO2H, then 1:9 þ
0.1% HCO2H, then 2:8 þ 0.1% HCO2H). The fractions were concentrated
to remove most of the MeCN and lyophilized to afford the desired product
as the HCO2H salt as a white solid. 1H NMR (500 MHz, D2O) δ 3.66 (dt,
J = 4.0, 10.7 Hz, 1H), 3.49 (d, J = 16.1 Hz, 1H), 3.41 (d, J = 16.1 Hz, 1H),
1.82-1.79 (m, 1H), 1.68-1.64 (m, 1H), 1.62-1.58 (m, 1H), 1.56-1.50
(m, 1H), 1.40-1.33 (m, 1H), 1.24 (s, 3H), 1.21 (d, J = 6.5 Hz, 1H), 1.48 (s,
3H), 1.04-0.94 (m, 2H), 0.86-0.78 (m, 1H), 0.79 (d, J = 6.6 Hz, 3H). 13C
NMR (101 MHz, D2O) δ 172.0, 71.91, 62.1, 47.1, 43.6, 42.7, 33.5, 30.6,
24.9, 22.2, 21.0, 18.4. HRMS calcd for C12H24NO3 (M þ H)þ 230.1753,
found 230.1751. [R]22D -21.9 [c 1.75, H2O].
1
isomer: H NMR (400 MHz, d4-MeOH) δ 7.50 (d, J = 1.4 Hz, 2H),
7.49-7.36 (m, 3H), 5.45 (d, J = 2.3Hz, 1H), 5.02 (d, J = 2.4Hz, 1H), 3.76
(dd, J = 18.2, 92.9 Hz, 2H), 3.74-3.69 (m, 1H), 2.00-1.97 (m, 1H),
1.78-1.75 (m, 1H), 1.70-1.64 (m, 2H), 1.58-1.52 (m, 1H), 1.29 (s,
3H), 1.18 (s, 3H), 1.20-0.97 (m, 3H), 0.98 (d, J = 6.6 Hz, 3H).
(1S,6aS,9R,10aR,11aS)-6,6,9-trimethyl-1-(oct-1-yn-1-yl)
octahydro-6H-[1,4]oxazino[3,4-b][1,3]benzoxazin-3(4H)-
1
one (4b): The crude H NMR showed a ratio of 5:1 for the two
diastereoisomers. The crude product was purified by flash chromatography
over SiO2 (EtOAc/Hex, 2:8) to afford the major nonpolar product 4b (400
mg, 45% yield). 1H NMR (400 MHz, CDCl3) δ 4.82 (s, 1H), 4.55 (s, 1H),
3.58-3.25 (m, 3H), 2.06 (t, J = 7.0 Hz, 2H), 1.79-1.68 (m, 1H), 1.60-
1.51 (m, 1H), 1.48-1.39 (m, 1H), 1.38-1.30 (m, 4H), 1.25-1.18 (m,
2H), 1.27-0.99 (m, 4H), 1.02 (s, 3H), 0.97 (s, 3H), 0.93-0.67 (m, 9H).
13C NMR (101 MHz, CDCl3) δ 168.0, 89.1, 82.1, 76.4, 74.8, 71.8, 56.0,
43.9, 43.8, 40.9, 34.8, 31.3, 31.3, 28.4, 28.2, 25.3, 24.8, 22.6, 22.1, 19.4, 18.7,
14.1. Minor (more polar) isomer: 1H NMR (400 MHz, CDCl3) δ 5.09 (s,
1H), 4.74 (s, 1H), 3.83-3.49 (m, 3H), 2.40-2.15 (m, 2H), 2.06-1.95 (m,
1H), 1.81-1.65 (m, 2H), 1.68-1.44 (m, 4H), 1.52-1.31 (m, 2H), 1.46-
1.18 (m, 4H), 1.23 (s, 3H), 1.13 (s, 3H), 1.09-0.85 (m, 9H). 13C NMR
(101 MHz, CDCl3) δ 167.7, 89.6, 79.9, 77.2, 73.2, 71.6, 56.4, 43.9, 42.5,
40.8, 34.9, 31.5, 31.4, 28.5, 28.2, 25.4, 24.9, 22.6, 22.1, 21.1, 18.9, 14.1.
(1S,6aS,9R,10aR,11aS)-6,6,9-trimethyl-1-(3-phenylprop-1-
yn-1-yl)octahydro-6H-[1,4]oxazino[3,4-b][1,3]benzoxazin-3
(4H)-one (4c): The crude 1H NMR showed a ratio of 5:1 for the two
(6aS,9R,10aR,11aS)-1-Hydroxy-6,6,9-trimethyloctahydro-
6H-[1,4]oxazino[3,4-b][1,3]benzoxazin-3(4H)-one (3): To the
amino-acid auxiliary 2 (900 mg, 3.92 mmol) in 1,4-dioxane (40 mL) was
added an aqueous solution of glyoxal (40% w/w, 2.25 mL, 19.6 mmol) and
the reaction was heated at 70 °C for 1 h. The solvent was removed in vacuo
and the crude product was directly purified by flash chromatography over
SiO2 (EtOAc/Hex 75:25 þ 0.1% AcOH) to afford the desired product 3
(869 mg, 82% yield) as a white solid (exists as an inconsequential 5:1
mixture of epimers at the carboxy-lactol position). The compound should
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diastereoisomers. The crude product was purified by flash chromatogra-
phy over SiO2 (EtOAc/Hex, 2:8) to afford the major nonpolar product 4c
(262 mg, 46% yield). 1H NMR (400 MHz, CDCl3) δ7.25-7.14(m, 4H),
7.14-7.07 (m, 1H), 4.94 (d, J = 2.7 Hz, 1H), 4.66 (d, J = 2.7 Hz, 1H),
3.65-3.30 (m, 5H), 1.82-1.73 (m, 1H), 1.64-1.55 (m, 1H), 1.53-1.44
(m, 1H), 1.42-1.32 (m, 2H), 1.07 (s, 3H), 1.03 (s, 3H), 1.05-0.80 (m,
3H), 0.81 (d, J = 6.5 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 167.8,
135.7, 128.4, 127.8, 126.7, 86.3, 81.8, 76.7, 76.5, 71.6, 56.0, 43.9, 43.6, 40.8,
34.7, 31.3, 25.3, 25.0, 24.7, 22.1, 19.5. HRMS calcd for C23H30NO3 (M þ
H)þ 368.2220, found 368.2234. Minor (more polar) isomer (21 mg, 4%
yield): 1H NMR (400 MHz, CDCl3) δ 7.42 (d, J = 7.5 Hz, 2H), 7.35 (t,
J = 7.5 Hz, 2H), 7.32-7.24 (m, 1H), 5.16 (s, 1H), 4.80 (d, J = 2.4 Hz, 1H),
3.83-3.52 (m, 5H), 2.10-2.00 (m, 1H), 1.81-1.72 (m, 1H), 1.69-1.48
(m, 3H), 1.24 (s, 3H), 1.23-0.99 (m, 3H), 1.15 (s, 3H), 0.99 (d, J = 6.6
Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 167.4, 135.8, 128.4, 127.8,
126.6, 86.6, 79.8, 77.0, 75.6, 71.4, 56.3, 43.7, 42.5, 40.7, 34.7, 31.4, 25.3,
25.1, 24.7, 22.1, 20.7.
(1S,6aS,9R,10aR,11aS)-6,6,9-trimethyl-1-(4-phenylbut-1-yn-
1-yl)octahydro-6H-[1,4]oxazino[3,4-b][1,3]benzoxazin-3(4H)-
one (4d): The crude 1H NMR showed a ratio of 5:1 for the two
diastereoisomers. The crude product was then purified by flash chroma-
tography over SiO2 (EtOAc/Hex, 2:8) to afford the major nonpolar
product 4d (333 mg, 43% yield). 1H NMR (400 MHz, CDCl3) δ 7.27-
7.19 (m, 2H), 7.19-7.13 (m, 3H), 4.91 (s, 1H), 4.61 (s, 1H), 3.66-3.32
(m, 3H), 2.77 (t, J = 7.4 Hz, 2H), 2.47 (t, J = 7.5 Hz, 2H), 1.88-1.78 (m,
1H), 1.71-1.61 (m, 1H), 1.62-1.49 (m, 1H), 1.45-1.35 (m, 2H), 1.09
(s, 3H), 1.07 (s, 3H), 1.04-0.87 (m, 3H), 0.87 (d, J = 6.9 Hz, 3H). 13C
NMR (101 MHz, CDCl3) δ 167.8, 140.3, 128.4, 128.3, 126.3, 88.1, 81.9,
76.4, 75.6, 71.7, 55.9, 43.8, 43.8, 40.8, 34.7, 34.5, 31.3, 25.3, 24.7, 22.1, 20.9,
19.3. HRMS calcd for C24H32NO3 (M þ Li)þ 388.2478, found 388.2478.
[R]22D -42.8 [c 0.96, EtOH]. Minor (more polar) isomer: 1H NMR (400
MHz, CDCl3) δ 7.36-7.23 (m, 5H), 5.08 (s, 1H), 4.72 (s, 1H), 3.79-
3.47 (m, 3H), 2.89 (t, J = 7.5 Hz, 2H), 2.59 (t, J = 7.6 Hz, 2H), 2.06-1.95
(m, 1H), 1.82-1.72 (m, 1H), 1.66-1.52 (m, 3H), 1.39-0.96 (m, 3H),
1.23 (s, 3H), 1.13 (s, 3H), 0.98 (d, J = 6.3 Hz, 3H).
General Procedure for the P-2 Ni Semihydrogenation
Reaction. To Ni(OAc)2(H2O)4 (0.35 equiv) in EtOH (0.1 M) under
N2 was added a solution of NaBH4 in EtOH (1.0 M, 0.35 equiv) and a
fine black precipitate was formed. A hydrogen balloon was then added
and the reaction was stirred for 30 min at RT. TMEDA (1.4 equiv) was
then added and the reaction mixture was cooled to 0 °C. The alkyne 4 in
EtOH (0.1 M) was added via syringe and the reaction was stirred for 15
min. The reaction was warmed to rt and stirred another 45 min. The
reaction vessel was purged with dry nitrogen and diluted with DCM.
Water was added and the crude product was extracted with DCM (2ꢀ),
then the combined organic fractions were dried over Na2SO4, filtered,
and concentrated in vacuo.
(1S,6aS,9R,10aR,11aS)-6,6,9-trimethyl-1-(2-phenylethenyl)
octahydro-6H-[1,4]oxazino[3,4-b][1,3]benzoxazin-3(4H)-one
(5a): The crude product was purified by flash chromatography over SiO2
(EtOAc/Hex, 2:8) to afford the desired alkene 5a (96 mg, 96% yield) as a
yellow oil. 1H NMR (400 MHz, d4-MeOH) δ 7.44-7.32 (m, 5H), 6.87
(d, J = 11.6 Hz, 1H), 5.85 (dd, J = 11.5, 9.9 Hz, 1H), 5.12 (dd, J = 9.5, 2.0
Hz, 1H), 4.76 (d, J = 2.4 Hz, 1H), 3.80 (d, J = 18.3 Hz, 1H), 3.60 (d, J =
18.3 Hz, 1H), 3.63-3.57 (m, 1H), 1.92-1.88 (m, 1H), 1.77-1.74 (m,
1H), 1.69-1.51 (m, 3H), 1.23 (s, 3H), 1.20 (s, 3H), 1.17-0.98 (m, 3H),
0.96 (s, J = 6.7 Hz, 3H). 13C NMR (101 MHz, d4-MeOH) δ 170.7, 136.8,
136.4, 129.7, 129.5, 128.9, 127.0, 82.8, 78.5, 77.7, 57.1, 44.9, 44.6, 41.9,
36.0, 32.5, 25.7, 25.6, 22.6, 20.1.
J = 10.9, 7.6 Hz, 1H), 5.48 (t, J = 10.0 Hz, 1H), 5.06 (dd, J = 9.2, 2.5
Hz, 1H), 4.50 (d, J = 2.6 Hz, 1H), 3.77-3.40 (m, 3H), 2.21-2.02 (m,
2H), 1.95-1.87 (m, 1H), 1.75-1.68 (m, 1H), 1.63-1.56 (m, 1H),
1.54-1.43 (m, 2H), 1.43-1.34 (m, 2H), 1.34-1.25 (m, 6H), 1.14 (s,
3H), 1.12 (s, 3H), 1.12-0.94 (m, 3H), 0.94 (d, J= 6.5 Hz, 3H), 0.89 (t, J=
6.7 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 168.6, 136.7, 124.9, 81.9,
76.9, 76.4, 55.8, 43.9, 43.8, 40.9, 34.8, 31.7, 31.4, 29.3, 28.9, 27.9, 25.4, 24.8,
22.6, 22.2, 19.6, 14.1.
(1S,6aS,9R,10aR,11aS)-6,6,9-trimethyl-1-[(1Z)-3-phenylprop-
1-en-1-yl]octahydro-6H-[1,4]oxazino[3,4-b][1,3]benzoxazin-3
(4H)-one (5c): The crude product was purified by flash chromatography
over SiO2 (EtOAc/Hex, 2:8) to afford the desired product 5c (92 mg, 70%
yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.22-7.14 (m, 2H),
7.10 (d, J = 7.6 Hz, 3H), 5.82-5.71 (m, 1H), 5.52 (t, J = 10.0 Hz, 1H),
5.11-5.05 (m, 1H), 4.41 (m, 1H), 3.70-3.22 (m, 5H), 1.85-1.75 (m,
1H), 1.66-1.57 (m, 1H), 1.53-1.46 (m, 1H), 1.45-1.35(m, 2H), 1.02(s,
6H), 1.33-0.85 (m, 3H), 0.84 (d, J = 6.6 Hz, 3H). 13C NMR (101 MHz,
CDCl3) δ 168.3, 139.3, 134.6, 128.5, 128.4, 126.2, 125.8, 81.7, 76.7, 76.2,
55.7, 43.9, 43.9, 40.8, 34.7, 34.0, 31.2, 25.3, 24.7, 22.1, 19.2.
(1S,6aS,9R,10aR,11aS)-6,6,9-Trimethyl-1-[(1Z)-4-phenylbut-
1-en-1-yl]octahydro-6H-[1,4]oxazino[3,4-b][1,3]benzoxazin-
3(4H)-one (5d): The crude product was purified by flash chromatog-
raphy over SiO2 (EtOAc/Hex, 2:8) to afford the desired product 5d (268
mg, 83% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.32 (t, J =
7.4 Hz, 2H), 7.22 (t, J = 8.5 Hz, 3H), 5.74 (q, J = 8.9 Hz, 1H), 5.53 (1 H, t,
J = 10.1 Hz), 4.96 (1 H, d, J = 9.4 Hz), 4.21 (s, 1H), 3.74 (d, J = 17.7 Hz,
1H), 3.51 (d, J = 17.7 Hz, 1H), 3.46-3.37 (m, 1H), 2.87-2.76 (m, 1H),
2.76-2.62 (m, 1H), 2.56-2.46 (m, 2H), 1.96-1.86 (m, 1H), 1.75 (s,
1H), 1.65-1.54 (m, 1H), 1.55-1.42 (m, 3H), 1.12 (s, 3H), 1.11 (s, 4H),
1.04 (d, J = 28.2 Hz, 1H), 0.97 (d, J = 6.5 Hz, 4H). 13C NMR (101 MHz,
CDCl3) δ 168.3, 141.1, 134.9, 128.5, 128.2, 125.9, 125.7, 81.4, 76.5, 76.2,
55.6, 43.7, 43.4, 40.7, 35.3, 34.7, 31.3, 29.6, 25.3, 24.7, 22.1, 19.7. HRMS
m/e calcd (M þ Hþ) 384.2533, found 384.2543. HRMS calcd for
C24H34NO3 (M þ H)þ 384.2533, found 384.25426. [R]22 -80.7 [c
D
1.14, CHCl3].
General Procedure for the Cu-Promoted SN20 Reaction of
Alkyl Nucleophiles. To CuBr Me2S (2.5 equiv) under an inert
3
atmosphere of dry nitrogen was added dry THF and Me2S (7:3, 0.1
M). The suspension was cooled to -40 °C and the corresponding
Grignard reagent (2.5 equiv) was added dropwise. After being stirred for
15 min, the solution was cooled to -78 °C and 5 in a minimal amount of
THF was added dropwise. The mixture was warmed to -20 °C and
stirred for another 30 min. The reaction was quenched with H2O (a few
milliliters), warmed to rt, a large excess of formic acid was added (5-
10 mL), and the reaction mixture was stirred overnight at 50 °C. Brine
was then added and the crude product was extracted with Et2O (3ꢀ).
The combined organic fractions were dried over Na2SO4, filtered, and
concentrated in vacuo.
(2E,4R)-4-Phenylhex-2-enal (6a): The crude product was puri-
fied by flash chromatography on SiO2 (Et2O/Hex, 2:8) to yield the
desired γ-substituted aldehyde 6a (45 mg, 55% yield). 1H NMR
(400 MHz, CDCl3) δ 9.55 (d, J = 7.8 Hz, 1H), 7.39-7.35 (m, 2H),
7.33-7.27 (m, 1H), 7.22-7.20 (m, 2H), 6.96 (dd, J = 7.5, 15.6 Hz, 1H),
6.13 (dd, J = 7.9, 15.7 Hz, 1H), 3.46 (dd, J = 7.5, 14.9 Hz, 1H), 1.95-1.82
(m, 2H), 0.94 (t, J = 7.4 Hz, 3H). HRMS calcd for C12H14O (M þ H)þ
175.1117, found 175.1116. [R]22 -11.5 [c 1.00, H2O]. Chiral HPLC
D
resolution conditions of the saturated alcohol (prepared by reducing
the aldehyde with NaBH4 in MeOH, and hydrogenating the alkene with
Pd/C in EtOAc): column purchased from Regis Technology Inc., (R,R)
Whelk-O1 (4.6 ꢀ 250 mm), 2% IPA/98% hexanes, 1.0 mL/min, 220 nM,
ee = 98%.
(1S,6aS,9R,10aR,11aS)-6,6,9-trimethyl-1-[(1Z)-oct-1-en-1-yl]
octahydro-6H-[1,4]oxazino[3,4-b][1,3]benzoxazin-3(4H)-one
(5b): The crude product was purified by flash chromatography over SiO2
(EtOAc/Hex, 15:85) to afford the desired product 5b (310 mg, 77%
yield) as a yellow oil. 1H NMR (500 MHz, CDCl3) δ 5.70 (dt,
(2E,4S)-4-Ethyldec-2-enal (6b): The crude product was purified
by flash chromatography on SiO2 (Et2O/Hex, 2:8) to yield the desired
1
γ-substituted aldehyde 6b (22 mg, 67% yield). H NMR (400 MHz,
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The Journal of Organic Chemistry
ARTICLE
CDCl3) δ 9.54 (d, J = 7.9 Hz, 1H), 6.65 (dd, J = 15.6, 9.0 Hz, 1H),
6.11 (dd, J = 15.6, 7.9 Hz, 1H), 2.41-2.07 (m, 1H), 1.61-1.49 (m, 2H),
1.48-1.35 (m, 2H), 1.51-1.05 (m, 8H), 0.98-0.82 (m, 6H).
13C NMR (101 MHz, CDCl3) δ 194.2, 163.3, 132.9, 44.8, 34.0, 31.7,
for 15 min, the solution was cooled to -78 °C and a solution of
BF3 OEt2 (1.0 M in THF, 0.5 equiv) was added dropwise. After
3
5 min of stirring, allylic compound 5 (in a minimal amount of THF)
was added dropwise and the reaction mixture was stirred for another
30 min. The reaction was quenched with H2O (a few milliters),
warmed to rt, a large excess of formic acid was added (5-10 mL), and
the reaction mixture was stirred overnight at 50 °C. Brine was then
added and the crude product was extracted with Et2O (3ꢀ). The
combined organic fractions were dried over Na2SO4, filtered, and
concentrated in vacuo.
29.3, 27.2, 27.1, 22.6, 14.1, 11.6. [R]22 þ1.1 [c 0.71, CHCl3].
D
Chiral HPLC resolution conditions of the Mosher ester of the
corresponding allylic alcohol (prepared by reducing the aldehyde
using NaBH4 in MeOH): Chiralcel OJ (4.6 ꢀ 250 mm), 2%
EtOH/98% hexanes, 1.0 mL/min, 220 nM, Rt = 4.7 and 6.8 min,
ee = 92%.
(2E,4S)-4-Benzylhex-2-enal (6c): The crude product was puri-
fied by flash chromatography on SiO2 (EtOAc/Hex, 2:8) to afford the
desired γ-substituted aldehyde 6c (33 mg, 72% yield). 1H NMR (400 MHz,
CDCl3) δ 9.40 (d, J = 7.9 Hz, 1H), 7.24-7.16 (m, 2H), 7.15-7.08 (m,
1H), 7.08-7.02 (m, 2H), 6.58 (dd, J = 15.7, 8.6 Hz, 1H), 5.93 (dd, J = 15.7,
7.8 Hz, 1H), 2.81-2.69 (m, 1H), 2.67-2.56 (m, 1H), 2.54-2.42 (m, 1H),
1.64-1.47 (m, 1H), 1.44-1.29 (m, 1H), 0.84 (t, J= 7.5 Hz, 3H). 13CNMR
(101 MHz, CDCl3) δ 193.1, 160.8, 138.3, 132.3, 128.2, 127.6, 125.5, 45.4,
39.6, 25.6, 10.8. HRMS calcd for C13H17O (M þ H)þ 189.1266, found
189.1266. [R]22D þ42.1 [c 1.1, CHCl3]. Chiral HPLC resolution condi-
tions: Chiralcel OJ (4.6 ꢀ 250 mm), 5% EtOH/95% hexanes þ 0.25%
Et3N, 1.0 mL/min, 220 nM, Rt = 6.4 and 10.0 min, ee = 85%.
(2E,4S)-4,6-Diphenylhex-2-enal (6g): The crude product was
purified by flash chromatography on SiO2 (Et2O/Hex, 2:8) to yield the
desired γ-substituted aldehyde 6g (12 mg, 56% yield). 1H NMR (400
MHz, CDCl3) δ 9.56 (d, J = 7.9 Hz, 1H), 7.44-7.37 (m, 2H), 7.36-
7.29 (m, 3H), 7.27-7.21 (m, 3H), 7.20-7.14 (m, 2H), 6.97 (dd, J =
15.7, 7.4 Hz, 1H), 6.14 (dd, J = 15.7, 7.8 Hz, 1H), 3.63-3.54 (m, 1H),
2.63 (t, J = 7.8 Hz, 2H), 2.22 (q, J = 7.7 Hz, 2H). 13C NMR (101 MHz,
CDCl3) δ 193.9, 160.7, 141.2, 141.1, 132.0, 129.0, 128.5, 128.4, 127.9,
127.3, 126.2, 48.1, 36.1, 33.4. HRMS calcd for C18H19O (M þ H)þ
251.1430, found 251.1410. [R]22D þ8.3 [c 0.90, CHCl3]. Chiral HPLC
resolution conditions: Chiralcel OJ (4.6 ꢀ 250 mm), 20% IPA/20%
EtOH/60% hexanes, 1.0 mL/min, 220 nM, Rt = 6.4 and 8.3 min,
ee = 98%.
(2E,4S)-4-Ethyl-6-phenylhex-2-enal (6d): The crude product
was purified by flash chromatography on SiO2 (Et2O/Hex, 2:8) to yield
(2E,4S)-4-(4-Methoxyphenyl)-6-phenylhex-2-enal (6h): The
crude productwaspurified by flash chromatography on SiO2 (Et2O/Hex,
2:8) to afford the desired γ-substituted aldehyde 6h (21 mg, 51% yield).
1H NMR (400 MHz, CDCl3) δ 9.55 (d, J = 7.81 Hz, 1H), 7.36-7.28 (m,
3H), 7.23 (t, J = 7.3 Hz, 1H), 7.20-7.12 (m, 3H), 6.98-6.89 (m, 3H),
6.11 (dd, J = 15.6, 7.8 Hz, 1H), 3.85 (s, 3H), 3.54 (q, J = 7.4 Hz, 1H),
2.69-2.55 (m, 2H), 2.24-2.10 (m, 2H). 13C NMR (101 MHz, CDCl3)
δ 194.0, 161.1, 158.8, 141.3, 132.9, 131.7, 128.9, 128.5, 128.4, 126.1,
114.4, 55.3, 47.3, 36.1, 33.4. HRMS calcd for C19H21O2 (M þ H)þ
1
the desired γ-substituted aldehyde 6d (42 mg, 72% yield). H NMR
(400 MHz, CDCl3) δ 9.57 (d, J = 7.9 Hz, 1H), 7.32 (t, J = 7.5 Hz, 2H),
7.27-7.16 (m, 3H), 6.69 (dd, J = 15.7, 9.0 Hz, 1H), 6.16 (dd, J = 15.7,
7.9 Hz, 1H), 2.73-2.53 (m, 2H), 2.37-2.25 (m, 1H), 1.95-1.83 (m,
1H), 1.81-1.67 (m, 1H), 1.69-1.57 (m, 1H), 1.55-1.40 (m, 1H),
0.92 (t, J = 7.5 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 194.1, 162.5,
141.7, 133.4, 128.5, 128.4, 126.0, 44.2, 35.6, 33.5, 27.2, 11.5. HRMS
calcd for C14H19O (M þ H)þ 203.1430, found 203.1429. [R]22D þ12.8
[c 0.293, CHCl3]. Chiral HPLC resolution conditions: Chiralpak AD
(4.6 ꢀ 250 mm), 10% MeOH/10% IPA/80% hexanes, 1.0 mL/min, 220
nM, Rt = 6.7 and 7.2 min, ee = 98%.
(2E,4R)-4-Cyclohexyl-6-phenylhex-2-enal (6e): The crude
product was purified by flash chromatography on SiO2 (Et2O/Hex,
2:8) to yield the desired γ-substituted aldehyde 6e (11 mg, 52% yield).
1H NMR (400 MHz, CDCl3) δ 9.57 (d, J = 7.9 Hz, 1H), 7.35-7.27
(m, 2H), 7.26-7.14 (m, 3H), 6.74 (dd, J = 15.6, 9.7 Hz, 1H), 6.13 (dd, J =
15.6, 7.9 Hz, 1H), 2.69-2.59 (m, 1H), 2.55-2.45 (m, 1H), 2.25-2.19
(m, 1H), 2.00-1.91 (m, 1H), 1.81-1.63 (m, 6H), 1.35-0.85 (m, 6H).
13C NMR (101 MHz, CDCl3) δ 193.9, 161.6, 141.8, 134.2, 128.5, 128.4,
126.0, 48.6, 41.8, 33.8, 33.0, 31.0, 29.9, 26.5. [R]22D þ3.3 [c 0.92, CHCl3].
Chiral HPLC resolution conditions: Chiralcel OJ (4.6 ꢀ 250 mm), 2% IPA,
2% EtOH, 96% hexanes þ 0.25% Et3N, 1.0 mL/min, 220 nM, Rt = 6.3 and
8.0 min, ee = 96%.
281.1536, found 281.1531. [R]22 þ5.7 [c 0.70, CHCl3]. Chiral
D
HPLC resolution conditions: Chiralcel OJ (4.6 ꢀ 250 mm), 20%
IPA/20% EtOH/60% hexanes, 1.0 mL/min, 220 nM, Rt = 11.2 and
16.2 min, ee = 96%.
(2E,4S)-4-(4-Fluorophenyl)-6-phenylhex-2-enal (6i): The
crude product was purified by flash chromatography on SiO2 (Et2O/Hex,
2:8) to yield the desired γ-substituted aldehyde 6i (29 mg, 75% yield). 1H
NMR (400 HMz, CDCl3) δ 9.61 (d, J = 7.8 Hz, 1H), 7.41-7.09 (m, 9H),
6.98 (dd, J = 15.9, 7.1 Hz, 1H), 6.15 (dd, J = 15.6, 7.8 Hz, 1H), 3.63 (q, J =
8.0 Hz, 1H), 2.69-2.63 (m, 2H), 2.30-2.17 (m, 2H). 13C NMR (101
MHz, CDCl3) δ 193.8, 141.0, 132.0, 129.4, 129.3, 128.6, 128.4, 126.2,
116.2, 116.0, 115.8, 47.3, 36.1, 33.3. [R]22D 3.93 [c 0.535, CHCl3]. Chiral
HPLC resolution conditions: Chiralcel OJ (4.6 ꢀ 250 mm), 25% EtOH/
75% hexanes, 1.0 mL/min, 220 nM, Rt = 11.3 and 16.0 min, ee = 92%.
(2E,4R,5E)-4-(2-Phenylethyl)hepta-2,5-dienal (6j): The
crude product was purified by flash chromatography on SiO2 (Et2O/Hex,
2:8) to afford the desired γ-substituted aldehyde 6j (7 mg, 43% yield).
1HNMR (400 MHz, CDCl3) δ 9.54 (d, J = 7.83 Hz, 1H), 7.37-7.26 (m,
2H), 7.27-7.17 (m, 3H), 6.75 (dd, J = 15.6, 7.0 Hz, 1H), 6.13 (dd, J =
15.6, 7.8 Hz, 1 H), 5.76-5.67 (m, 1 H), 5.35-5.26 (m, 1H), 3.41-3.32
(m, 1H), 2.80-2.56 (m, 2H), 1.98-1.73 (m, 2H), 1.63
(d, J = 7.0 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 194.1, 160.2,
(2E,4S)-5,5-Dimethyl-4-(2-phenylethyl)hex-2-enal (6f): The
crude product was purified by flash chromatography on SiO2 (Et2O/Hex,
2:8) to afford the desired γ-substituted aldehyde 6f (48 mg, 68% yield).
1H NMR (400 MHz, CDCl3) δ 9.61 (d, J = 7.9 Hz, 1H), 7.36-7.28 (m,
2H), 7.27-7.15 (m, 3H), 6.76 (dd, J = 15.6, 10.3 Hz, 1H), 6.16 (dd,
J = 15.5, 7.9 Hz, 1H), 2.70-2.60 (m, 1H), 2.47-2.35 (m, 1H), 2.11-1.96
(m, 2H), 1.71-1.56(m, 1H), 0.94 (s, 9H). 13CNMR (101 MHz, CDCl3)
δ 193.8, 160.6, 141.7, 135.0, 128.5, 128.4, 126.0, 53.6, 34.4, 33.5, 30.5,
27.7. HRMS calcd for C16H23O (M þ H)þ 231.1743, found 231.1752.
141.4, 131.6, 129.8, 128.5, 128.4, 127.2, 39.9, 36.0, 33.2, 29.7. [R]22
-
D
31.4 [c 0.35, CHCl3]. Chiral HPLC resolution conditions: Chiralcel OD
(4.6 ꢀ 250 mm), 5% IPA/95% hexanes, 1.0 mL/min, 220 nM, Rt = 10.5
and 13.5 min, ee = 95%.
[R]22 -7.3 [c 2.13, CHCl3]. Chiral HPLC resolution conditions:
D
Chiralcel OJ (4.6 ꢀ 250 mm), 2% IPA/98% hexanes, 1.0 mL/min,
220 nM, Rt = 9.4 and 10.7 min, ee = 94%.
General Procedure for the Cu-Promoted SN20 Reaction
of Aryl and Vinyl Nucleophiles. To CuI (2 equiv) under an inert
atmosphere of dry nitrogen was added dry THF (0.1 M). The
suspension was cooled to -40 °C and the corresponding Grignard
reagent (4 equiv) was added dropwise at -40 °C. After being stirred
’ ASSOCIATED CONTENT
1
Supporting Information. Copies of H and 13C NMR
S
b
spectra for all new compounds, all NMR data for the structural
assignment of compound 5a, and all chiral HPLC
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The Journal of Organic Chemistry
ARTICLE
chromatograms for compounds 6a-j. This material is available
free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: robichaud5@videotron.ca.
’ ACKNOWLEDGMENT
We thank Serge Plamondon, Jeancarlo De Luca, and Denis
Deschenes for chiral HPLC analysis, and Dan Sorensen and
Laird Trimble for NMR analysis.
’ REFERENCES
(1) For a review on the stereoselective R-alkylation of carbonyls, see:
Evans, D. A.; Helmchen, G.; Rueping, M. In Asymmetric Synthesis the
Essentials; WILEY-VCH: Weinheim, Germany, 2007.
(2) For a review on the stereoselective β-alkylation of carbonyls, see:
Perlmutter, P. In Conjugate Addition Reactions in Organic Synthesis;
Pergamon Press: New York, 1992.
(3) For a review on the approach utilizing the catalytic asymmetric
vinylogous aldol reactions, see: Denmark, S. E.; Heemstra, J. R., Jr.;
Beutner, G. L. Angew. Chem., Int. Ed. 2005, 44, 4682.
::
(4) (a) Alvarez-Ibarra, C.; Csꢀaky, A. G.; Gꢀomez de la Oliva, C.
Tetrahedron Lett. 1999, 40, 8465. (b) Zhang, C.; Lu, X. Synlett 1995, 645.
(c) Trost, B. M. J. Am. Chem. Soc. 1994, 116, 10819.
(5) Sun, J.; Fu, G. C. J. Am. Chem. Soc. 2010, 132, 4568.
(6) (a) Bertelsen, S.; Marigo, M.; Brandes, S.; Dinꢀer, P.; Jørgensen,
K. A. J. Am. Chem. Soc. 2006, 128, 12973. (b) Trost, B. M.; Dake, G. R.
J. Org. Chem. 1997, 62, 5670.
(7) (a) Smith, S. W.; Fu, G. C. J. Am. Chem. Soc. 2010, 131, 14231.
(b) Nakai, T.; Sugiura, M.; Yagi, Y.; Wei, S.-Y. Tetrahedron Lett. 1998,
39, 4351. (c) Chen, Z.; Zhu, G.; Jiang, Q.; Xiao, D.; Cao, P.; Zhang, X. J.
Org. Chem. 1998, 63, 5631. (d) Zhang, C.; Lu, X. Synlett 1995, 645. (e)
Trost, B. M.; Li, C.-J. J. Am. Chem. Soc. 1994, 116, 3167.
(8) For a review on the copper-catalyzed asymmetric allylic
substitution, see: Alexakis, A.; Malan, C.; Lea, L.; Tissot-Croset, K.;
Polet, D.; Falciola, C. Chimia 2006, 60, 124.
(9) For a review on the stereochemistry and regiochemistry in the
nucleophilic and organometallic displacement reactions of allylic
compounds, see: Magid, R. M. Tetrahedron 1980, 36, 1901.
(10) Trost, B. M.; Klun, T. P. J. Org. Chem. 1980, 45, 4256.
(11) For a review on allylic 1,3-strain as a controlling factor in
stereoselective transformations, see: Hoffmann, R. W. Chem. Rev. 1989,
89, 1841.
(12) Amino-menthol is commercially available but can be easily
prepared in a 2-step process using the procedure in the following:
Lawrence, N. J.; Banks, R. E.; Besheesh, M. K.; Popplewell, A. L.;
Pritchard, R. G. Chem. Commun. 1996, 1629.
(13) This reaction afforded an inconsequential mixture of diaster-
eoisomers at the carboxy-lactol functionality.
(14) The rigorous structural assignment was conducted for com-
pound 5a and its stereoisomer with the help of NMR experiments (see
the Supporting Information.
(15) Brown, C. A.; Ahuja, V. K. J. Org. Chem. 1973, 38, 2226.
(16) While the standard Lindlar hydrogenation conditions were
efficient in the hydrogenation of 4a to 5a, this procedure afforded
varying levels of selectivity (as low 15:85) in other cases. Brown’s P-2 Ni
procedure15 proved to be highly stereoselective.
(17) While the recovery of the chiral auxiliary 2 was possible, its high
aqueous solubility and the presence of the copper species rendered its
isolation and purification processes relatively complex and inefficient.
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