Stereoselective Synthesis of Isochromanones by an Asymmetric Ortho-Lithiation Strategy: Synthetic Access to the Isochromanone Core of the Ajudazols

Article abstract of DOI:10.1021/acs.joc.5b02781

Full details on the design, development, and application of a highly stereoselective strategy for the synthesis of isochromanones are reported. The method is based on an asymmetric ortho lithiation with aldehyde electrophiles and utilizes the chiral memor

Full text of DOI:10.1021/acs.joc.5b02781

Article
pubs.acs.org/joc
Stereoselective Synthesis of Isochromanones by an Asymmetric
Ortho-Lithiation Strategy: Synthetic Access to the Isochromanone
Core of the Ajudazols
Sebastian Essig†,§ and Dirk Menche*,‡
†Institut fur Organische Chemie, Ruprecht-Karls Universitat Heidelberg, Im Neuenheimer Feld 270, 69120 Heidelberg, Germany
̈
̈
‡Kekule-
́
Institut fur Organische Chemie und Biochemie, Universitat Bonn, Gerhard-Domagk-Straße 1, 53121 Bonn, Germany
̈
̈
S
* Supporting Information
ABSTRACT: Full details on the design, development, and
application of a highly stereoselective strategy for the synthesis
of isochromanones are reported. The method is based on an
asymmetric ortho lithiation with aldehyde electrophiles and
utilizes the chiral memory of a preoriented atropisomeric
amide axis for stereocontrol. For direct transformation of
sterically hindered amides to isochromanones, efficient and
mild one-pot protocols involving either O-alkylation or acidic
microwave activation were developed. The procedures may be
applied also to highly functionalized as well as stereochemically complex and sensitive substrates and demonstrate a high
protective group tolerance. Furthermore, asymmetric crotylborations of axially chiral amides were studied in detail. These
methodologies enable a general access to all possible stereoisomers of hydroxyl-isochromanones with up to three contiguous
stereocenters. The true applicability of our approach was finally demonstrated by synthesis of the authentic anti,anti-configured
isochromanone core of the ajudazols, highly potent inhibitors of the mitochondrial respiratory chain from myxobacteria.
activities.15 On a molecular level they are described as highly
INTRODUCTION
■
effective inhibitors of the mitochondrial respiratory chain by
selective binding to complex I (NADH-dehydrogenase). The
NADH oxidation level in beef heart submitochondrial particles
was inhibited at an IC50 value of 13.0 ng/mL (22.0 nM) for
ajudazol A (1) and 10.9 ng/mL (18.4 nM) for ajudazol B (2).
However, despite the high relevance of isochomanones as
bioactive substructures in a variety of natural products, a
general synthetic access to these structural elements is largely
missing. Especially, the generation of hydroxyl-isochromanones
has proved to be particularly challenging, which has also
prevented a total synthesis of the ajudazols for a long time.16 In
the past, different approaches for synthesis of isochromanones
have been described in the literature on the basis of
intramolecular Diels−Alder reactions (IMDA),16a,b,17 rear-
rangement reactions,16c−e gold catalysis,18 and asymmetric
iodolactonization reactions.19 These approaches have been
limited, however, by apparent difficulties to either install
substituents into the isochromanone core structure or to
flexibly control the stereochemistry of such substituents.
Additionally, C8-hydroxyl-substituted isochromanones such as
the ajudazols (1, 2) are known to be labile under basic
conditions and can undergo translactonization reactions to
form thermodynamically more stable five-membered-ring
analogues.10,19c
Isochromanones are key structural features in a variety of
natural products and bioactive agents.1 A remarkable variety of
potent biological activities have been reported for these
compounds, which include cytostatic potencies,2 ACE inhib-
itory effects,3 plant growth regulation,4 effects on the central
nervous system,5 and immunomodulatory,6 antinoceptive,
antiplasmodic,1d and antidiabetic activities.7 Two isochroma-
none-based structures (AC-7954 and FL 68)8 are presently in
clinical phase II studies for cardiovascular diseases and
diabetes.9
Within the context of a natural product total synthesis of the
ajudazols A (1) and B (2) (Figure 1),10 we became interested
in the development of an efficient route to hydroxyl-substituted
isochromanones. These are also present in a number of
bioactive natural products, including benaphtamycin (3),11
thailandolid B (4),12 hydroxyochratoxin (5),13 and bergenin
(6).14
The ajudazols are distinguished by a hydroxyl-isochroma-
none with three consecutive anti,anti-configured stereocenters
(C8−C10) together with an extended side chain that contains an
oxazole, a Z,Z-diene, and a 3-methoxybutenoic acid amide as
structural features. So far, two ajudazols have been reported.10
The main metabolite, ajudazol A (1), bears an exo-methylene
group next to the oxazole (C15), while ajudazol B (2) has a
methyl group at this position. The first biological character-
ization revealed that the ajudazols are potent antifungal agents
but have only weak antibacterial and antiproliferative
Received: December 8, 2015
© XXXX American Chemical Society
A
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Scheme 1. Various Conventional (Upper Half) and
Asymmetric (Lower Half) Ortho-Lithiation Approaches
Explored for Synthesis of the Ajudazol Isochromanone
Fragment
Figure 1. Natural products with hydroxyl-isochromanone motives.
For these reasons we designed a conceptually novel approach
for the construction of isochromanones on the basis of
asymmetric ortho lithiation as a key step. Herein, we discuss
the design of our strategies and approaches that we initially
developed for the isochromanone fragment of the ajudazols but
that are also generally useful for other compounds with
stereochemically complex isochromanone motifs.20
Scheme 2. Conventional Ortho-Lithiation Approaches for
the Construction of Suitable Precursors for Further
Stereoselective Transformation to Isochromanone 28
RESULTS AND DISCUSSION
■
Exploratory Study of Ortholithiation-Based Strategies
for the Synthesis of Isochromanones. Ortho-lithiation
reactions have been demonstrated as a reliable and efficient tool
for the effective substitution of aromatic compounds with
various electrophiles, and multiple applications have been
reported.21 Direct metalation groups (DMGs), typically tertiary
amides, carbamates, and ethers, control the regioselectivity of
the metalation reaction and direct the subsequent electrophilic
ipso substitution to the ortho position of the DMG.22 Inspired
by the ajudazols, we were attracted to study the potential
utilization of this reaction type for synthesis of hydroxyl-
isochromanones by a modular functionalization of 3-methyl-
salicylic acid in a short and regioselective sequence (Scheme 1).
The flexible exchange of the electrophile thereby opens up
several possibilities to generate the correct stereochemistry of
the three consecutive stereocenters. As outlined in Scheme 1,
we explored both conventional and asymmetric ortho-lithiation
approaches. This would generate different precursors for
further transformations such as iodolactonizations (8, 9),
reductions (11), aldol reactions (12), crotylation (12),
epoxidation (16, 18), and direct lactonization reactions (14).
In a first model study a precursor (21) for a Z-configured
double bond was built up by the ortho lithiation of 19 and
reaction of the resulting lithiated intermediate with DMF. A
subsequent Wittig reaction of 20 to alkene 21 should then
allow introduction of the C8/C9 stereochemistry by an
asymmetric dihydroxylation23 (Scheme 2, left part). Although
moderate selectivities (Z:E = 7:3) of the Wittig reaction could
be compensated by HPLC separation of the two isomers, the
further functionalization of Z-21 by asymmetric dihydroxylation
was limited by moderate yields (51%) and selectivities (d.r. =
B
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3.5:1) and a lack of regioselective protection strategies for the
generated C8-alcohol. In contrast to the highly reliable
asymmetric dihydroxylation of E-configured alkenes, the
selectivities of Z-configured substrates are known to be highly
substrate dependent.24
Scheme 3. First Asymmetric Ortho-Lithiation Approach of
Sulfoxide 32 with Complex Aldehyde 35 Leading to
(8S,9R,10R)-37
Alkene precursors such as 21 can potentially also be directly
transformed into isochromanone 28 by an iodolactonization
approach (Scheme 2, middle part).25 To test this hypothesis,
we also synthesized different analogues of 21 by ortho
iodination of 19 and modular Suzuki cross-coupling of 22
and 23.26 We then explored different conditions for the
iodolactonization.26 Although the desired 6-endo-trig cyclization
product 28 could be obtained in a regioselective and
diastereoselective way, the outcome of the reaction was highly
sensitive to the nature of the side-chain substituents and also a
stereoselective control of the reaction by substrate induction,
chiral catalysts,27 or auxiliaries19a,28 appeared to be difficult.26
In order to increase the selectivity of the cyclization process,
we additionally envisioned a precursor for a C8-anti-reduction
strategy and introduced two of the three stereocenters of the
isochromanone into Weinreb amide 2529 by an asymmetric
crotylboration (see Scheme 3 and the Supporting Information).
Ortho lithiation of 19 and substitution with 25 led to product
26 in moderate yields (Scheme 2, right part).
However, cyclization of 26 to 27 could not be realized under
several acidic conditions and only decomposition of the starting
material was observed. In addition, anti-reduction of 26 with
Zn(BH4)2 failed.30
Finally we tested whether these problems could be solved by
using aldehyde 13 as an electrophile. This strategy would
generate the C8-stereocenter directly to form the corresponding
alcohol (Scheme 1). In general, ortho lithiations with aldehydes
have been less well investigated in comparison to other
electrophiles and ortho lithiations with complex aldehydes such
as 13 are nearly unknown.31 However, in our initial attempts
with aldehyde 13 we could detect significant amounts of the
desired product 14 (67%). Unfortunately, the observed
substrate-induced stereoselectivity in the sense of a moderate
Felkin−Anh control was not sufficient (d.r. = 2.1/1).
Therefore, a continuation of this study by establishing a
suitable orthogonal protection group strategy to enable a
regioselective cyclization was not pursued.
Isochromanone Strategy of the First Generation:
Strength and Weakness of an Asymmetric Ortho-
Lithiation Approach. The difficulties of the conventional
ortho-lithiation approaches described above made us think
about options for an asymmetric control of this reaction type
(Scheme 1, lower half). The development of stereoselective
ortho-lithiation reactions has been a considerable methodo-
logical challenge for many years, and several approaches based
on chiral DMGs,32 chiral chelating reagents such as sparteine,33
and chiral bases34 are limited by either low stereoselectivity or
narrow substrate scope. In 2002 a pioneering study35 of the
Clayden group demonstrated that a combination of a tertiary
amide as DMG and a chiral sulfoxide36 acting as an easily
removable temporary stereogenic center37 can potentially solve
these problems. According to their approach, a chiral sulfoxide
leads by chirality transfer to a preorientation of the nonplanar
amide axis of the DMG,38 as shown for example for the
conversion of 30 to 32 (Scheme 3). This orientation is retained
after cleavage of the sulfoxide by tert-BuLi during the ortho-
lithiation reaction at low temperatures (chiral memory).
Electrophilic attack of the resulting atropochiral aryllithium
species with an aldehyde then allows the generation of chiral
benzylic alcohols (viz. 32−37) with high asymmetric induction
in the sense of a “self-regeneration of the stereocenter” (SRS
principle).39 Nevertheless, the true applicability of this method
has been restricted by apparent difficulties resulting from
cleavage of the tertiary amide DMG, the control of the ring size
in the case of alternative cyclization reactions, and the lability of
the newly generated benzylic alcohol with regard to
epimerization.40 In contrast, the use of such a type of
asymmetric ortho lithiation as key step in the isochromanone
synthesis of the ajudazols seemed to be particularly rewarding
in terms of modularity and elegance and we therefore tried to
find solutions for these challenges.
In order to build up the aromatic reaction partner, the
phenol group of 3-methylsalicylic acid (29) was first protected
by methylation, as shown in Scheme 3. A methyl group was
chosen due to the high stability toward alkyllithium species and
a reported positive influence on the selectivity of the
asymmetric ortho lithiation.35,40a After conversion to the acid
chloride by treatment with thionyl chloride and amide coupling
with diisoproylamine, the sterically hindered but configuration-
ally labile amide axis of 30 was subsequently fixed by ortho
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lithiation with Andersen reagent 3141 to yield S-sulfoxide 32. A
diisopropyl group was chosen in order to obtain a higher
configurational stability of the amide axis in comparison to a
diethyl group. The required aldehyde reaction partner 35 for
this sulfoxide was then built up from ethyl glyoxalate 33 by
asymmetric crotylboration (70%, d.r. = 98:2, 90% ee).20,42 The
correct absolute configuration of the resulting alcohol 33a was
subsequently confirmed by Mosher ester analysis.43 Use of the
Roush reagent (compound 50; Table 4)44 instead of the shown
Brown reagent 51 for asymmetric crotylboration resulted in
higher yields (81%) but lower enantioselectivity (71% ee). For
protection of the newly generated alcohol, a tert-butyldime-
thylsilyl (TBS) group was chosen, which should allow different
options for an orthogonal protection of the subsequently
generated hydroxyl-bearing stereocenter at C8. TBS-ester 34
could then be further transformed to aldehyde 35 using a
sequential reduction oxidation procedure (82%, two steps).
The pivotal asymmetric substitution of lithiated 32 with
aldehyde 35 then generated the desired anti,anti product 37
in high selectivity (d.r. > 95:5).45 In accordance with the
literature,38a the preferred formation of 37 can be rationalized
by transition states 36a,b. In contrast to 36a, which leads to the
observed anti,anti product 37, formation of intermediate 36b to
give syn,anti product 37 is significantly disfavored by steric
interaction of the TBS group of the attacking aldehyde 35 with
the aromatic ring of the aryllithium species. It is surprising to
note that in both postulated transition states the attack of the
electrophile occurs from the diisopropylamide-containing site
due to a space-demanding Li-THF cluster shielding the
opposite side.38a,d
However, the protection of this hydroxyl group is necessary in
order to control the subsequent cyclization toward the desired
6-ring product.46 We initially assumed that the spatial demand
of the nearby TBS and diisoproylamide groups of 37
diminished the chemical accessibility of the C8-alcohol.
Therefore, we tried to reduce the size of this protecting
group. However, also smaller protecting groups such as MEM
(entries 8 and 9, Table 1) and acetyl (entries 10 and 12, Table
1) could not be successfully installed. Even protection with a
methyl group (entries 13 and 14, Table 1)the smallest
possible protection strategy we could think offailed, and no
C8-protected product could be detected. However, during these
protection studies cleavage of the tertiary amide and formation
of a five-membered lactone was unexpectedly observed. This
finding opened up an efficient and mild protocol for the
cleavage of the tertiary amide.
Therefore, we then tried to combine this protocol with a
TBS de- and reprotection strategy (Scheme 4). Initial attempts
Scheme 4. Attempts To Generate Isochromanones by TBS
De- and Reprotection and O-Alkylation
As anticipated, the subsequent conversion of 37 into the
desired isochromanone 39 proved challenging (Table 1).
Several strategies to introduce a p-methoxybenzyl (PMB)
protecting group at the C8-alcohol (38) which is orthogonal to
the C9-TBS-protected alcohol failed (entries 1−7, Table 1).
Table 1. Study of Different Orthogonal Protecting Groups
for the C8-Alcohol of 37
to regioselectively introduce a TBS group at the benzylic
hydroxyl after deprotection of the hydroxyl group at C9 with
TASF51 using TBSOTf or TBSCl gave nearly no conversion or
were inefficient. Additionally, amide cleavage of 40 with
MeOTf to generate 39a under the same conditions as used
before in order to form the six-membered lactone did not result
in any conversion.
Evidence from the literature suggested that methyl-protected
phenol groups in positions ortho to the amide can prevent
amide cleavage.52 We therefore tried to deprotect the phenol
entry
R
protection conditions
NaH, PMBCl, DMF
yield
1
PMB
53
group of 40 by several strategies, including BCl3, MgI2·
2
NaH, PMBCl, THF
OEt2,54 LiCl,55 PhSH,56 and PPh2Li,57 to yield compound 41.
However, none of these efforts were successful. In summary,
these results suggested that an inappropriate phenolic
protecting group was chosen.
3
NaH, PMBBr, THF
4
NaH, PMBBr, TBAI, DMF
PMB-OC(CCl3)NH, CSA, THF
PMB-OC(CCl3)NH, TfOH, Et2O
PMB-OC(CCl3)NH, Sc(OTf)3, toluene47
MEMCl, DIPEA, CH2Cl2
NaH, MEMCl, THF
5
6
a
a
a
The Correct Order Makes a Difference: Isochroma-
none Strategy of the Second Generation. Our first
experiences with an asymmetric ortho-lithiation approach
with a complex aldehyde electrophile had clearly shown that,
although the key step worked efficiently and selectively, a
successful transformation into an isochromanone highly
depends on a suitable protecting group strategy. For this
reason we changed our previous approach in two ways: (1) we
evaluated the stability and orthogonality of different protecting
groups for the phenolic hydroxyl group, and (2) we reduced
the functional complexity of the ortho-lithiation system to allow
7
8
MEM
Ac
9
10
11
12
13
14
(Ac)2O, DMAP, Pyr
(Ac)2O, DMAP, NEt3, CH2Cl2
a
a
b
b
48
(Ac)2O, I2
49
Me
MeOTf, 2,6-DTBMP, CH2Cl2
50
Me3OBF4, Proton Sponge, CH2Cl2
a
b
No conversion, recovery of the starting material. O-Alkylation and
cleavage of the diisopropylamide was observed.
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an easy introduction of a C8-protecting group by changing the
order of ortho lithiation and crotylboration.
As shown in Table 2, several protecting groups, which are
known to be orthogonal to a secondary TBS-protected alcohol,
installation of an orthogonal PMB protecting group at the
newly generated stereocenter with PMB-trichloroacetimidate
and Sc(OTf)3 was possible. However, this approach was not
47
further pursued due to expected deprotection problems at a
later stage of the synthesis. In order to cleave the tertiary amide,
we tested next an O-alkylation strategy for a direct trans-
formation of amides to esters which was inspired by our
findings during the aforementioned methyl protection attempts.
We initially used a known protocol based on alkylation with
Meerwein’s salt (entries 1−5, Table 3).52b However, the yields
of this reaction were only moderate, although we detected full
conversion of the starting material. These could not be further
improved by modifications of the methylation conditions, use
of an alternative solvent, or modified workup conditions
(NaHCO3, Na2CO3, K3PO4, NaOH).
Table 2. Study of Different Protecting Group Strategies for
the Asymmetric Ortho-Lithation with Acrolein
ab
,
yield (%)
step 2
entry
R
step 1
step 3
Small improvements were only obtained by using the MeOTf
protocol discovered above (entries 6−8, Table 3). For
conversion to ester 47 with either protocol an unprotected
phenol seemed to be crucial, in agreement with a precedent
from the literature.52b
1
2
3
4
5
6
PMB
TBS
Ac
90 (44a)
98 (44b)
88 (44c)
97 (44d)
68 (44e)
− (30)
78 (45a)
85 (45b)
− (45c)
88 (45d)
82 (45e)
82 (32)
71 (46a)
39 (46b)
− (46c)
92 (46d)
68 (46e)
allyl
Bn
The free phenol group of 47 was subsequently protected by
PMB to avoid side reactions in the subsequent ozonolysis of
the double bond (Table 4). The ozonolysis has to be carefully
monitored and worked up to avoid deprotection of the PMB
group and racemization of the stereocenter. The resulting
aldehyde (+)-48 (83%, two steps) served as the starting
material for an asymmetric crotylboration, allowing the
introduction of the remaining two stereocenters. In our initial
attempts we could efficiently perform this reaction with the
Roush reagent (E,S,S)-50 in 95% yield (entry 1, Table 4). This
reagent was chosen due to its convenient storage, high stability,
and easy removability.44 Under consideration of the postulated
mechanism for crotylboration reactions,42b,60 saponification of
the ester was expected to give the desired anti,anti-configured
isochromanone (Scheme 6). In contrast, the observed 3J
Me
73 (46f)
a
b
43 was obtained from deprotection of 30 with MgI2·OEt2. For
detailed protection conditions see the Experimental Section.
could be installed efficiently at the phenolic alcohol of 43,
which was efficiently (95%) generated by methyl deprotection
of 30 with MgI2·OEt2.54 After introduction of various
protecting groups, the chiral sulfoxide could subsequently be
obtained in high yields by ortho lithation with Andersen
reagent 31.41 Only the acetyl-containing compound 44c (entry
3, Table 2) was deprotected under these conditions. In the final
asymmetric ortho lithiation with acrolein as a simplified
electrophile, significant differences in the observed yield
became apparent between the different protecting groups.
Surprisingly, the highest yields were obtained with an allyl-
protected aromatic system (44d−46d, entry 4, Table 2).
In this case quenching the reaction mixture has to be strictly
done at −78 °C to avoid deprotection which may be caused by
tert-BuLi-induced Wittig rearrangement of the allyl group.58 To
test the orthogonality of this protecting group strategy, we
introduced a TBS protecting group at the C8-stereocenter of
46d (Table 3). The phenolic allyl group could then efficiently
be removed under basic conditions by Pd(PPh3)4-catalyzed
isomerization59 without affecting the TBS group. In addition,
1
coupling constant between H8 and H9 in the H NMR spectra
of the generated lactone 54 (Scheme 5) was only 2.1 Hz, which
was significantly too low for an anti,anti system and the
chemical shifts of these protons completely differed from those
of the isochromanone part of the ajudazols.
After various efforts to determine the structure of 54 by
derivatization and NMR analysis, we could finally crystallize 54
(Scheme 5). An X-ray structure analysis showed unexpectedly
that 54 is a syn,anti-configured five-membered lactone. In
1
combination with additional analysis of H,29Si-HMBC data of
precursor 49, this finding revealed a migration of the TBS
protecting group during the crotylboration and also indicated
the existence of an alternative transition state60a,b,61 (see the
discussion below) which leads to the syn,anti configuration of
49. Although migration of silyl groups has been described for
aldol reactions,62 we could not find a literature precedence for
allyl- and crotylboration reactions. In addition, crotylboration of
a very similar ortho-unsubstituted aldehyde has been reported
to clearly give the desired product.63
Table 3. Cleavage of Tertiary Amide 46d by O-Alkylation
entry
conditions
solvent
yield (%)
We then tried to influence the outcome of the crotylboration
by (a) changing the stereochemistry of the aldehyde substrate
48 (entry 2, Table 4) or by (b) exchange of the crotylboration
reagent (entries 3−5, Table 4). However, both strategies
showed no effect.65 The substrate overcontrolled the influence
of the crotylboration reagent, leading in all cases to a syn,anti-
configured product with d.r. > 99:1. In addition, replacement of
the crotylboration by an iridium-catalyzed66 crotylation reaction
known for its different transition state (entry 6, Table 4)67
1
2
3
4
5
6
7
8
Me3OBF4 (5 equiv), Na2HPO4 (2.5 equiv)
Me3OBF4 (3 equiv). Na2HPO4 (1.5 equiv)
Me3OBF4 (2 equiv)
MeCN
MeCN
CH2Cl2
MeCN
MeCN
CH2Cl2
CH2Cl2
CH2Cl2
54
55
15
51
49
53
59
62
Me3OBF4 (3 equiv), Na2HPO4 (1.5 equiv)
Me3OBF4 (3 equiv), Na2HPO4 (1.5 equiv)
MeOTf (2 equiv), 2,6-DTBMP (4 equiv)
MeOTf (2 equiv), 2,6-DTBMP (4 equiv)
MeOTf (2 equiv), 2,6-DTBMP (4 equiv)
E
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We then evaluated whether a modification of the reaction
sequence could make a difference in the outcome of the
crotylboration. Therefore, we changed the order of amide
cleavage and crotylboration, as an atropochiral tertiary amide
instead of an ester should potentially act as an additional
element for stereoinduction. Due to the obvious instability of
allyl protecting groups against the ozonolysis conditions the
bis-TBS-protected compound 55 was used as the starting
material for this sequence (Scheme 6). After crotylboration of
Table 4. Generation and Crotylboration of Aromatic
Aldehyde 48
Scheme 6. Crotylboration of an Amide-Containing Aromatic
Aldehyde Leading to syn,anti-57 via an Unconventional
Cornforth Transition State
a
b
d.r. > 99:1 for all reactions. Decomposition.
Scheme 5. Cyclization of Crotylboration Product 49 Leading
to syn,anti-Configured Five-Membered Lactone 54
the intermediate aldehyde with either Roush reagent (E,S,S)-50
or trifluoroborate (E)-5268 only the product 57 could be
obtained in high yield and diastereoselectivity (d.r. > 99:1).
However, X-ray structure analysis of this product revealed 57 to
be again syn,anti-configured. In contrast to the crotylboration of
the ester-containing substrate 48, no migration of the silyl
protecting group could be detected during the crotylboration
with the modified amide aldehyde derived from 55. We
speculate that the repeated occurrence of the syn,anti-
configured product during the crotylboration can be rational-
ized by the preference of the uncommon Cornforth transition
state 56b61 to the normal transition state 56a.42b,60 Substituents
of the aromatic ring in this Cornforth transition state 56b are
closer to the borane and can potentially stabilize this transition
state, leading exclusively to the syn,anti product.
failed due to the decomposition of the starting material.
Oxidation of the generated C8-alcohol with DMP and reduction
with NaBH4 also generated again the same configuration (69%
over two steps).
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Furthermore, the steric repulsion of the diisopropylamide-
containing aryl substituent and the methyl group of the
crotylborane is reduced in transition state 56b in comparison to
the case for 56a.
problem by variation of the protecting group and synthesized a
TBS-protected analogue of 17. Unexpectedly, after asymmetric
ortho lithiation between 45d and 17b we observed the
exclusive formation of alcohol 62, bearing an aldehyde function
(Scheme 7, middle part). These findings suggested that the
protecting group has a significant influence on the position
where the electrophile is attacked by the aryllithium species. A
TBS protecting group directs an opening of the epoxide, while
in contrast a PMB group allows the attack of the aldehyde
function.
A strong hydrogen bond between the newly generated
alcohol at C9 and the carbonyl function of the amide appearing
in the X-ray structure of 57 may additionally contribute to this
explanation. Although the configuration at C8 in 57 was wrong,
this product could still be transformed into the corresponding
Isochromanone syn,anti-42 by selective TBS deprotection of
the phenolic TBS group and cyclization via amide cleavage with
Meerwein salt in moderate yields (37%, two steps).52b
As we were unable to influence the stereochemistry of the
crotylboration, we tried to investigate whether this step could
be replaced by an asymmetric epoxidation,69 as one of the most
reliable transformations in asymmetric synthesis.70 We there-
fore first focused on an efficient synthesis of the aldehyde
electrophile 17 with an appended chiral epoxide.71 Asymmetric
ortho lithiation of 45d with a PMB-protected version of
epoxyaldehyde 17a then gave alcohol 59 without affecting the
epoxide (Scheme 7, left part). After TBS protection we
Therefore, we modified the route again and planned to
introduce the epoxide at a later stage of the synthesis (Scheme
7, right part). Accordingly, we evaluated allylic alcohol 63,
which was obtained by coupling of 45d with 58, protection of
the newly generated secondary alcohol with TBS, and careful
TBS deprotection of the primary alcohol with TBAF.
Subsequent asymmetric epoxidation of 63 with L-(+)-DET71
then gave the desired epoxide with a free primary alcohol
function. Unfortunately, opening of the epoxide of this
substrate with methyllithium cuprates,71a,72 methylmagnesium
73
cuprates,75 or AlMe3 to obtain compound 65 was also not
successful.
Scheme 7. Asymmetric Ortho-Lithation of 45d with
Complex Epoxide-Containing Aldehydes for a
Stereoselective Epoxide-Opening Strategy
Isochromanone Strategy of the Third Generation:
Orthogonal Silyl Protection and Efficient Amide Cleav-
age Leading to Success. While all attempts to reduce the
complexity of the aldehyde electrophile by introducing some of
the three consecutive stereocenters of the ajudazol core
structure at a later stage failed, the newly acquired knowledge
should finally help us to overcome the limitations of the initial
asymmetric ortho-lithiation approach with complex aldehyde
35. Our first strategy (Scheme 3) that clearly generated the
desired anti,anti configuration among C8, C9, and C10 could
now be combined with the newly developed protecting group
strategy for the phenol and the protocol for the amide cleavage
by O-alkylation. The last remaining challenge was finally the
identification of a suitable orthogonal protecting group strategy
for the C8 and C9 alcohols. We therefore focused on selectivity
improvements of the previously applied de- and reprotection
strategy (Table 2) and synthesized the required allyl-group- and
TBS-group-containing precursor 66 by asymmetric ortho
lithiation of 45d (Scheme 8). Subsequently, the free diol 67
could be efficiently obtained by deprotection of 66 with TASF
as a mild fluoride source.51
This compound could also be crystallized, and an X-ray
structure analysis confirmed the correct anti,anti configuration.
However, the reprotection of diol 67 under various conditions
with different silyl sources (TBSCl, TBSOTf, TESCl,
TESOTf), amounts (0.2−2.0 equiv), and temperatures (−78
to 0 °C) generated the desired C8 monoprotected compound
68 as only a minor product, preventing us from performing a
cyclization of 68 at this stage. In contrast, when the reaction
was executed with greater amounts of TBSOTf (>0.5 equiv)
the double-TBS-protected diol 69 could always be identified as
the main product. Notably, a C9 monoprotected byproduct has
never been detected. Selective monodeprotection of 69, which
was reported in the literature for various substrates with
TBAF,76 CSA,77 and HF·pyridine78 to obtain 68, did not solve
this problem and either led to complete deprotection or gave
no conversion.
explored several approaches for a regioselective opening of the
epoxide group of 60 with methyllithium cuprates71a,72 or
AlMe3.73 In all cases we could not observe any conversion to
64. For this reason we modified 60 by deprotection of the
primary PMB group with DDQ or other reagents in order to
increase the reactivity of 61, as reported71a,72,73 for other
substrates. However, this led to complete decomposition of 60,
which may possibly be caused by the sensitivity of the allyl
groups to radical conditions.74 We tried next to solve this
The observation that the double-TBS-protected compound
69 may be obtained clearly demonstrated that installing two
protecting groups at C8 and C9 is in general possible and
inspired us to think about an orthogonal silyl protecting group
G
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Scheme 8. Optimization Attempts of a TBS De- and
Reprotection Strategy with Asymmetric Ortho-Lithiation
Product 66
Table 5. Study of Different Protocols for Amide Cleavage of
41 To Form Isochromanone 42
a
yield
(%)
entry
1
conditions
solvent
MeCN
T
t
(MeO)3BF4 (3.0 equiv),
Na2HPO4 (1.5 equiv),
then NaHCO3
room
temp
4 h/
24 h
2
MeOTf (2 equiv), 2,6-
DTBMP (4 equiv),
then NaHCO3
CH2Cl2 room
temp
6 h/
14 h
3
4
6 N NaOH (60 equiv)
KOtBu (6 equiv), H2O
(2.0 equiv)
EtOH
THF
ΔT
ΔT
14 h
6 h
b
5
6
KOAc (20 equiv)
xylene
THF
ΔT
ΔT
24 h
24 h
LiBH3·pyrolidine
(1.2 equiv)
c
strategy. Consequently, we replaced the TBS group by a
triethylsilyl (TES) group and synthesized TES-protected
aldehyde 70 by transformation of crotylboration product 33a
(Scheme 9). In contrast to the synthesis of TBS-protected 34
7
8
MeSO3H (5 equiv)
AcOH (250 equiv)
THF
ΔT
room
temp
20 h
24 h
b
c
9
AcOH (250 equiv)
AcOH (25 equiv)
HCOOH (25 equiv)
ΔT
24 h
7 days
24 h
24 h
traces
10
11
12
toluene ΔT
toluene ΔT
toluene ΔT
39
b
Scheme 9. Successful Asymmetric Ortho-Lithiation
Approach Leading to anti,anti-Configured Isochromanone
72 by an Orthogonal Silyl Protecting Group Strategy
AcOH (25 equiv), H2O
(50 equiv)
b
13
14
15
AcOH (25 equiv)
THF
ΔT
24 h
3 h
AcOH (25 equiv), MW
toluene 130 °C
toluene 150 °C
81
d
AcOH (30 equiv), MW,
71b
3.5 h
86
a
Compound 41 was generated by the mild acidic deprotection of 71b
with charcoal: for experimental details, see the Experimental Section.
b
c
Deprotection of the TBS group. No conversion, recovery of the
d
starting material. TES-protected starting material 71b was used.
and TASF failed, we could finally generate 41 by using slightly
acidic activated charcoal.79
However, when we tried to cleave the tertiary amide of
compound 41 (Table 5) with the previously applied O-
alkylation protocols (entries 1 and 2, Table 5) we could not
detect the desired product, although the starting material was
fully converted. In addition, variation of the reaction conditions
did not lead to any improvements. Due to the high stability of
tertiary amide, the cleavage of this substrate class is known to
be difficult to achieve.40b,80
We therefore screened several basic (entries 3−5, Table
5)40a,81 and reductive (entry 6, Table 5)80c cleavage conditions
which were previously reported for the cleavage of amides, but
all of these attempts were not successful. We next focused on
the exploration of acidic cleavage conditions (entries 7−15,
Table 5), which obviously require a fine balance between
sufficient acidity to cleave the amide of substrate 41 and not too
strong acidity in order to prevent acidic deprotection of the
TBS group. In this context methanesulfonic acid (entry 7,
Table 5)35 or formic acid (entry 12, Table 5) were too acidic
(pKa = −1.92 and 3.77, respectively) and caused TBS
deprotection. First traces of isochromanone 42 could be
observed after refluxing 41 in anhydrous acetic acid (pKa =
4.76, entry 9, Table 5). The choice of a suitable cosolvent
seems to be crucial for the success of this protocol. With
the conditions for the reduction of TES-protected 34a have to
be carefully optimized by using exactly 2.1 equiv of DIBAl-H in
order to avoid deprotection of the TES group. Asymmetric
ortho lithiation with sulfoxide 45d then led to alcohol 71
without affecting the TES protecting group by tert-BuLi (d.r. >
95:5).
In the next sequence the C8-alcohol was TBS protected with
TBSOTf followed by selective removal of the phenolic allyl
group under basic conditions by Pd(PPh3)4 catalysis.59 In order
to generate the required precursor 41 (Table 5) for amide
cleavage and cyclization, we developed next a protocol for
selective cleavage of the TES group in the presence of the TBS
group. While initial attempts with HF·pyridine, TFA, TBAF,
H
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Article
toluene, detectable yields of 39% (entry 10, Table 5) could be
obtained, whereas the use of other cosolvents such as water
(entry 12, Table 5) and THF (entry 13, Table 5) either
deprotected the TBS group or gave no conversion. Significant
improvements of the yield of up to 81% and minimization of
the reaction time (7 days to 3 h) could be achieved by the
assistance of microwave irradiation (entry 14, Table 5).82
Notably, simultaneous cleavage of the TES group of 71b in a
one-pot process could also be achieved (entry 15, Table 5) and
further increases the effectiveness of the protocol. The free
phenol group of 41 and 71b proved to be essential for the
cleavage, as allyl-protected 71a could not be cyclized under
these conditions. The determination of the absolute and
relative configurations of 72 by NMR methods proved
Scheme 10. Preparation of Aryl Iodide 78 for a Projected
Synthesis of Aza-Isochromanone Analogues Such as 80 by a
Radical Axial to Central Chirality Transfer
3
challenging. The J coupling constant between H8 and H9
was still very low (3.4 Hz). Although we could crystallize the
direct cyclization precursor 41 (see the Supporting Informa-
tion), the configuration of the C9-stereocenter could be
inverted during amide cleavage and cyclization by a carbocation
to form syn,syn-42. We therefore synthesized syn,syn-42 in the
same way as anti,anti-42 starting from crotylboration of 33 with
(Z,R,R)-50 (for details see the Experimental Section).
However, the H8/H9 coupling constant of syn,syn-42 was very
similar to the that of anti,anti-42 (2.9 Hz). Absolute certainty
could finally only be obtained by crystallization and an absolute
X-ray structure analysis of 72, indicating the formation of the
desired six-membered lactone with complete configurational
retention during the cyclization.83 In total, the final stereo-
selective route allowed the efficient synthesis of the anti,anti-
configured isochromanone 72 in nine steps with an overall yield
of 29%. As an alternative way to avoid the complex protective
group strategies, we also considered a replacement of the
lactone by a lactam moiety instead. Such 6-ring lactams are
much more stable in comparison to the corresponding lactones,
and unfavorable translactonization processes would also be
avoided. Eventually, this will be of importance for the
development of more stable analogues, which would require a
general approach to lactams of general type 80. As shown in
Scheme 10, such lactams may be accessible by a radical transfer
process involving the generation of an aromatic radical (79)
and subsequent cyclization in a 6-exo-type fashion. These
studies were carried out by Florian Wolf in our group.
Additionally, a relay of the axial chirality to the centrochirality
may even be possible to set the newly generated center with
asymmetric induction. Radical reactions are in general fast and
are therefore prime candidates for this kind of chirality transfer.
However, examples are rare. In the past ring strain84 and
conformational effects85 have been elegantly used to transfer
chirality from a radical or biradical precursor to the
corresponding product starting with centrosymmetric C
radicals. In contrast, the relay of axial chirality to centrochiral
compounds is much less advanced and reported examples
mainly involve the cyclization of an axially chiral o-iodoaniline
such as 78.86 Accordingly, the axially chiral benzamide 78,
which was in this first model study used as a racemate, was
generated from the protected 3-methylsalicylic acid derivative
73 and amine 74, involving amide formation to 75, iodination,
TBS deprotection of derived 76, and Grieco elimination of 76
with 77.87 An axially chiral version of 78 should be accessible by
iodination of a chiral sulfoxide bearing precursor similar to 45d.
With achiral 78 in hand, first studies involving the trans-
formation to 80 were initiated, using tributyltin hydride88 or
tris(trimethylsilyl)silane89 in the presence of triethylborane and
oxygen. However, no traces of the desired lactam 80 could be
detected, suggesting that a modified substrate and more
extensive studies would be required to enable this promising
transformation.
CONCLUSIONS
■
In summary, we have reported an efficient novel method for the
synthesis of hydroxyl-isochromanones, which present key
structural features of the ajudazols and a range of bioactive
natural products and simplified structures. The procedure relies
on application of an asymmetric ortho-lithiation strategy and
subsequent one-pot cleavage and direct transformation of the
chiral amide axis to the targeted six-membered lactones. The
applicability and protecting group tolerance of this synthetically
easily feasible procedure have been demonstrated. In addition,
asymmetric crotylborations of axially chiral amides were studied
in detail, revealing excellent degrees of asymmetric induction of
these highly useful C−C coupling reactions that are purely
based on substrate control. The developed strategies are
generally applicable, allowing an access to all possible
stereoisomers of hydroxyl-isochromanones with up to three
contiguous stereocenters. Furthermore, we have developed
efficient protocols for the cleavage of sterically highly hindered
amides, which involve either O-alkylation of the amide with
MeOTf or the utilization of acetic acid under microwave
activation. These mild procedures were effectively applied even
to sensitive substrates, including labile stereogenic centers and
protective groups or esters that are prone to translactonizations.
The true applicability of this novel isochromanone synthesis
was demonstrated in a highly concise synthesis of the authentic
isochromanone core of the ajudazols, whose total synthesis
served as an inspiration for this study, including an effective
generation of three anti,anti-configured contiguous stereogenic
centers. Importantly, this scalable process presents the first and
so far only synthetic route to this labile fragment, which further
underlines the high significance of these results.
I
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N,N-Diethyl-2-methoxy-3-methylbenzamide (19). A solution
of acid 29b (1.0 g, 6.02 mmol, 1.0 equiv) in dry CH2Cl2 (30 mL) was
treated with fresh distilled SOCl2 (2.2 mL, 30.09 mmol, 5.0 equiv),
and the mixture was refluxed for 5 h. After evaporation of unreacted
SOCl2 on a rotary evaporator, the residual solution was resolved in dry
CH2Cl2 (50 mL) and cooled to 0 °C. A solution of diethylamine (3.1
mL, 30.09 mmol, 5.0 equiv) in dry CH2Cl2 (15 mL) was added
dropwise, and the mixture was stirred for 14 h overnight. Then water
(30 mL) was added, the organic layer was separated, and the aqueous
layer was extracted with 3 × 50 mL of Et2O. The combined organic
layers were washed with an aqueous HCl solution (2 M, 10 mL), an
aqueous NaOH solution (2 M, 10 mL), and water (10 mL) and were
dried over MgSO4. After removal of the solvent the resulting yellow oil
was purified by column chromatography on silica gel (petroleum
ether/ethyl acetate 3/1) to give the title compound 19 (1.18 g, 5.31
mmol) in 88% yield as a clear oil. TLC: Rf = 0.23 (petroleum ether/
EXPERIMENTAL SECTION
■
Materials and Methods. Starting materials and reagents were
obtained from commercial sources and used as received unless
otherwise specified. The following reagents and building blocks were
prepared according to literature procedures: Andersen reagent 31,90
Roush reagent 50,44b potassium (2-butenyl)trifluoroborate 52,91
IBX,92 and Dess−Martin periodinane.93 Unless stated otherwise, all
nonaqueous reactions were performed in flame-dried glassware under
an atmosphere of argon. The progress of the reactions was monitored
by thin-layer chromatography (TLC) analysis (Polygram Sil G/UV254
on plastic). Flash column chromatography was performed by using
silica gel S (pore size 60 Å, 0.040−0.063 mm, Sigma-Aldrich).
Preparative high performance liquid chromatography (PHPLC) was
carried out on a Eurospher II 100 RP C-18, 5 μm, 250 × 16.0 mm
column (Knauer) with precolumn (30 × 16.0 mmg). Optical rotations
were measured in a 1 dm cuvette, using a sodium lamp. 1H NMR and
13C NMR spectra were recorded at room temperature with 1H
operating frequencies of 300, 400, 500, and 600 MHz and with 13C
operating frequencies of 75, 100, 125, and 150 MHz. The chemical
shifts are reported in parts per million (ppm) and are given in δ units
relative to deuterated solvents as internal standard (CDCl3 7.27 ppm,
77.0 ppm).94 Coupling constants are given in hertz (Hz). Chemical
shifts associated with the major rotamers are marked with an asterisk
(*), the minor rotamers are marked with a hash (#), the major
diastereomers are marked with a superscript a (a), the minor
diastereomer are marked with a superscript b (b), both diastereomers
are marked with a superscript c (c). IUPAC names and atom
numbering were generated using the program ChemBioDraw Ultra
13.0.
1
ethyl acetate 3/1). H NMR (CDCl3, 300 MHz): δ 1.01 (t, J = 7.14
Hz, 3 H), 1.25 (t, J = 7.14 Hz, 3 H), 2.28 (s, 3 H), 3.14 (quin, J = 7.14
Hz, 2 H), 3.24−3.46 (m, 1 H), 3.68−3.89 (m, 1 H), 3.78 (s, 3 H),
6.97−7.08 (m, 2 H), 7.17 (dd, J = 6.59 Hz, 2.20 Hz, 1 H). 13C NMR
(CDCl3, 75 MHz): δ 12.7, 13.8, 15.9, 38.8, 42.9, 61.3, 124.0, 125.1,
131.2, 131.4, 131.6, 154.0, 169.1. HRMS (EI-TOF): calculated for
[M]+ = C13H19O2N, 221.1416; found, 221.1425 (Δ = +0.9 mmu).
N,N-Diethyl-6-formyl-2-methoxy-3-methylbenzamide (20).
To a stirred solution of N,N-diethylbenzamide (19; 120 mg, 0.54
mmol, 1.0 equiv) and TMEDA (98 μL, 0.651 mmol, 1.2 equiv) in dry
THF (10 mL) at −78 °C (acetone/dry ice) was added dropwise a
solution of sec-BuLi in hexane (1.4 M, 0.46 mL, 0.65 mmol, 1.2 equiv).
The mixture was stirred at −78 °C for 1 h, and then a solution of
DMF (84 μL, 1.08 mmol, 2.0 equiv) in dry THF (2 mL) was injected
into the lithiated solution at −78 °C. After 1 h the cooling bath was
removed and the solution was stirred at room temperature for 3 h. The
mixture was quenched with saturated aqueous NH4Cl solution (10
mL) and extracted with 3 × 20 mL of Et2O, and the combined organic
layers were dried over MgSO4 and evaporated to give a residue which
was purified by flash column chromatography on silica gel (n-hexane/
ethyl acetate 2/1) to afford the yellowish oil 20 (127 mg, 0.51 mmol)
Methyl 2-Methoxy-3-methylbenzoate (29a). 3-Methylsalicylic
acid (29; 15.0 g, 98.6 mmol) was stirred at room temperature with
benzyltributylammonium chloride (6.2 g, 19.7 mmol, 0.20 equiv)
mol), NaOH (12.0 g, 300 mmol, 3.0 equiv), and dimethyl sulfate (37.5
mL, 394 mmol, 4.0 equiv) in a mixture of H2O (400 mL) and CH2Cl2
(400 mL) for 24 h. The organic layer was separated, and the aqueous
phase was extracted with 3 × 150 mL of CH2Cl2. The combined
organic phases were stirred with a 15% aqueous NH4OH solution
(150 mL) for 2 h. After the separation of the organic layer, the solvent
was evaporated and the residue was taken up in Et2O (200 mL) and
stirred with 50 mL of a 15% aqueous NH4OH solution for 2 h. The
ethereal phase was separated, the aqueous layer was extracted with 3 ×
50 mL of Et2O, and the combined ether solutions were dried over
MgSO4, filtered, and evaporated to give a yellow liquid which was
distilled (bp 112−114 °C, 6.4 mbar) to afford 29a in 96% yield as a
colorless liquid (17.1 g, 95.0 mmol). TLC: Rf = 0.70 (petroleum
1
in 94% yield. TLC: Rf = 0.22 (n-hexane/ethyl acetate 2/1). H NMR
(CDCl3, 300 MHz): δ 0.99 (t, J = 7.18 Hz, 3 H), 1.30 (t, J = 7.18 Hz, 3
H), 2.36 (s, 3 H), 3.08 (qd, J = 7.19 Hz, J = 1.72 Hz, 2 H), 3.54 (dq, J
= 13.81 Hz, J = 6.99 Hz, 1 H), 3.71 (dq, J = 13.75 Hz, J = 7.12 Hz, 1
H), 3.81 (s, 3 H), 7.32 (d, J = 7.80 Hz, 1 H), 7.60 (d, J = 7.80 Hz, 1
H), 9.92 (s, 1 H). 13C NMR (CDCl3, 75 MHz): δ 12.5, 13.6, 16.5,
39.0, 43.0, 61.7, 125.2, 131.7, 132.0, 133.7, 139.2, 147.2, 154.5, 166.1,
190.0. HRMS (EI-TOF): calculated for [M]+ = C14H19O3N, 249.1365;
found, 249.1366 (Δ = +0.1 mmu).
1
ether/ethyl acetate 3/1). H NMR (CDCl3, 300 MHz): δ 2.32 (3 H,
(Z)-N,N-Diethyl-2-methoxy-3-methyl-6-(pent-1-enyl)-
benzamide (21). To a white slurry of n-Bu4PBr (841 mg, 2.11 mmol,
1.5 equiv) in dry THF (8 mL) was added a solution of NaHMDS in
THF (1 M, 2.0 mL, 1.97 mmol, 1.4 equiv). The resulting red mixture
was cooled to −78 °C (acetone/dry ice) and treated with the aldehyde
20 (350 mg, 1.40 mmol, 1.0 equiv) in dry THF (2 mL) in a dropwise
manner. After it was stirred for 2 h at −78 °C, the mixture was warmed
to room temperature and stirred for 14 h overnight. Then the mixture
was partitioned between H2O (5 mL) and Et2O (5 mL), followed by
an extraction with 3 × 10 mL of Et2O. The combined organic layers
were washed with brine (7 mL) and dried over MgSO4. Evaporation of
the solvent under reduce pressure and purification by column
chromatography on silica gel (n-hexane/ethyl acetate 3/1) gave a 7/
3 mixture of the E/Z-alkene 21 (358 mg, 1.24 mmol, 88%). The E/Z
isomers could be separated by preparative HPLC on silica gel (n-
hexane/ethyl acetate 9/1; Nucleosil 100-7; flow 25 mL; retention time
(E-21) 22 min; retention time (Z-21) 24 min). TLC: Rf = 0.50 (n-
hexane/ethyl acetate 3/1). 1H NMR Z-21 (CDCl3, 300 MHz): δ 0.92
(t, J = 7.33 Hz, 3 H), 0.99 (t, J = 7.18 Hz, 3 H), 1.25 (t, J = 7.10 Hz, 3
H), 1.35−1.55 (m, 2 H), 2.14−2.30 (m, 2 H), 2.29 (s, 3 H), 3.05 (mC,
2 H), 3.44−3.70 (m, 2 H), 3.78 (s, 3 H), 5.66 (dt, J = 11.70 Hz, J =
7.25 Hz, 1 H), 6.32 (d, J = 11.55 Hz, 1 H), 7.01 (d, J = 7.96 Hz, 1 H),
7.12 (d, J = 7.80 Hz, 1 H). 13C NMR Z-21 (CDCl3, 75 MHz): δ 12.6,
13.7, 13.9, 15.8, 23.0, 30.8, 38.6, 42.7, 61.5, 124.9, 125.5, 129.6, 130.5,
s), 3.83 (3 H, s), 3.91 (3 H, s), 7.05 (1 H, dd, J = 7.7 Hz), 7.31−7.36
(1 H, m), 7.63 (1 H, dd, J = 7.9 Hz, J = 1.3 Hz). 13C NMR (CDCl3, 75
MHz): δ 15.9, 52.0, 61.4, 123.4, 124.5, 129.0, 132.7, 135.1, 158.3,
166.8. HRMS (EI-TOF): calculated for [M]+ = C10H12O3, 180.0886;
found, 180.0893 (Δ = +0.7 mmu).
2-Methoxy-3-methylbenzoic Acid (29b). Methyl 2-methoxy-3-
methylbenzoate (29a; 8.0 g. 44.4 mmol, 1.0 equiv) was dissolved in
dry methanol (25 mL), and the mixture was heated to 35 °C. After the
mixture was stirred for 10 min, a solution of anhydrous KOH (5.0 g,
88.8 mmol, 2.0 equiv) in dry MeOH (10 mL) was added and the
contents were stirred for 45 min The reaction was quenched by the
addition of 50 mL of water, unreactive ester was removed by extraction
with 2 × 15 mL of Et2O, and the remaining aqueous mixture was
acidified to pH 2 with 6 N HCl. After the extraction with 3 × 50 mL of
Et2O the recent combined ether extracts were dried with MgSO4 and
the solvent was removed in vacuo to yield acid 29b (7.1 g, 42.5 mmol)
in 94% as a white solid. TLC: Rf = 0.19 (petroleum ether/ethyl acetate
1
3/1). H NMR (CDCl3, 300 MHz): δ 2.37 (3 H, s), 3.92 (3 H, s),
7.17 (1 H, t, J = 7.7 Hz), 7.43 (1 H, dd, J = 7.5 Hz, J = 0.9 Hz), 7.94 (1
H, dd, J = 7.9 Hz, J = 1.3 Hz), 9.76 (1 H, br s). 13C NMR (CDCl3, 75
MHz): δ 15.9, 62.0, 122.1, 124.8, 130.6, 131.8, 136.8, 158.0, 167.3.
HRMS (EI-TOF): calculated for [M]+ = C9H10O3, 166.0694; found,
166.0721 (Δ = +2.7 mmu). Mp: 48−49 °C.
J
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Article
131.1, 133.3, 133.9, 154.1, 168.1. HRMS (ESI-TOF, arginine):
calculated for [M + H]+ = C18H27O2N, 290.2115; found, 290.2115
(Δ = 0 mmu).
3.34−3.47 (m, 1 H), 2.40 (dt, J = 13.7, 7.1 Hz, 1 H), 1.26 (s, 12 H),
1.01 (d, J = 6.9 Hz, 3 H), 0.88 (s, 9 H), 0.03 (s, 6 H). 13C NMR
(CDCl3, 75 MHz): δ −5.3, −5.3, 15.6, 18.3, 24.7, 24.8 (2 C), (2 C),
25.9 (3 C), 42.0, 67.4, 83.0 (2 C), 118.0 (br s), 156.4. HRMS (ESI-
TOF): calculated for [M + H]+ = C17H36BO3Si, 327.2527; found,
327.2522 (Δ = −0.5 mmu).
(E)-6-(4-tert-Butyldimethylsilyloxy-3-methyl-but-1-enyl)-
N,N-diethyl-2-methoxy-3-methylbenzamide (24). Borane 23
(1.41 g, 4.32 mmol, 1.0 equiv), iodide 22 (1.50 g, 4.32 mmol, 1.0
equiv), Pd(PPh3)4 (250 mg, 22 μmmol, 5 mol %), and NaOH (2 N,
4.3 mL, 8.64 mmol, 2.0 equiv) were dissolved in 20 mL of dioxane and
refluxed for 3 h. The reaction mixture was quenched with water and
extracted with Et2O (3 × 50 mL), and the combined extracts were
dried over MgSO4. The solvent was removed in vacuo and the residue
purified by flash column chromatography (silica gel, petroleum ether/
ethyl acetate 2/1) to afford 1.45 g of the title compound 24 (81%) as a
faintly yellow oil. TLC: Rf = 0.68 (petroleum ether/ethyl acetate 1/1).
1H NMR (CDCl3, 300 MHz): δ 7.18−7.23 (m, 1 H), 7.08−7.12 (m, 1
H), 6.28−6.35 (m, 1 H), 6.09−6.17 (m, 1 H), 3.77 (s, 3 H), 3.40−3.65
(m, 4 H), 3.06 (ddd, J = 7.1, 4.1, 1.9 Hz, 2 H), 2.45 (dt, J = 13.4, 6.6
Hz, 1 H), 2.27 (s, 3 H), 1.28 (t, J = 7.0 Hz, 4 H), 1.05 (dd, J = 6.7, 3.4
Hz, 3 H), 1.00 (t, J = 7.1 Hz, 3 H), 0.89 (s, 9 H), 0.04 (s, 3 H), 0.04 (s,
3 H). 13C NMR (CDCl3, 75 MHz): δ −5.4, −5.4, 12.8, 13.8, 15.7,
16.5, 18.3, 25.9 (3 C), 38.8, 40.0, 42.9, 61.5, 68.1, 120.7, 125.7, 129.7,
130.2, 131.1, 133.6, 134.9, 154.2, 168.1. HRMS (ESI-TOF): calculated
for [M + H]+ = C24H42NO3Si, 420.2934; found, 420.2930 (Δ = −0.4
mmu).
N,N-Diethyl-6-iodo-2-methoxy-3-methylbenzamide (22).
N,N-Diethyl-2-methoxy-3-methylbenzamide (19; 2 g, 9.0 mmol, 1
equiv) was mixed with TMEDA (1.25 g, 11 mmol, 1.2 equiv) in 200
mL of dry THF and cooled to −78 °C. sec-BuLi (7.2 mL, 11 mmol, 1.2
equiv) was added dropwise, and the resulting mixture was stirred at
−78 °C for 30 min. Iodine (1.4 g, 11 mmol, 1.2 equiv) was dissolved
in dry THF (10 mL) and added dropwise until the iodine color was
persistent. After a further 1 h of stirring at −78 °C, the mixture was
quenched by addition of saturated sodium thiosulfate solution (20
mL) and extracted with diethyl ether (3 × 50 mL). The organic
extracts were washed with water and dried over MgSO4, and the
solvent was removed in vacuo, yielding 2.12 g of N,N-diethyl-6-iodo-2-
methoxy-3-methylbenzamide (22) as a pale yellow oil in 66% yield.
TLC: Rf = 0.53 (petroleum ether/ethyl acetate 1/1). 1H NMR
(CDCl3, 300 MHz): δ 0.94 (3 H, t, J = 7.3 Hz), 1.14 (3 H, t, J = 7.1
Hz), 2.09 (3 H, s), 2.95 (2 H, m), 3.27−3.44 (1 H, m), 3.44−3.58 (1
H, m), 3.61 (3 H, s), 6.74 (1 H, d, J = 8.2 Hz), 7.28 (1 H, d, J = 8.0
Hz). 13C NMR (CDCl3, 75 MHz): δ 12.0, 13.3, 15.3, 38.4, 42.5, 61.2,
89.3, 131.3, 132.1, 134.0, 136.8, 154.5, 167.4. HRMS (ESI-TOF):
calculated for [M + H]+ = C13H19INO2, 348.0460; found, 348.0457 (Δ
= −0.3 mmu).
3-((tert-Butyldimethylsilyl)oxy)-2-methylpropan-1-ol (23a).
2-Methylpropane-1,3-diol (9.0 g, 0.1 mol, 1.0 equiv) was dissolved
in 150 mL of dry THF, and NaH (4.0 g, 60%, 0.1 mol, 1.0 equiv) was
added in portions over 15 min. The resulting mixture was stirred for
45 min, and TBSCl (15.4 g, 0.1 mol, 1.0 equiv) was added in one
portion. After it was stirred at room temperature for 3 days, the
reaction mixture was quenched with water, extracted with diethyl ether
(3 × 100 mL), and washed with water, and the organic layers were
dried over MgSO4. The solvents were removed in vacuo, and the
residue was purified by flash column chromatography on silica gel
(petroleum ether/ethyl acetate 4/1) to yield 3-butyldimethylsilyloxy-2-
methylpropan-1-ol (23a; 11.4 g, 56%) as a colorless liquid. TLC: Rf =
0.68 (petroleum ether/ethyl acetate 1/1). 1H NMR (CDCl3, 300
MHz): δ 0.00 (6 H, s), 0.78 (3 H, d, J = 6.9 Hz), 0.83 (9 H, s), 1.83 (1
H, m), 3.32 (1 H, br s), 3.43−3.50 (1 H, m), 3.52 (2 H, d, J = 5.8 Hz),
3.62 (1 H, dd, J = 9.9, 4.9 Hz). 13C NMR (CDCl3, 75 MHz): δ −5.7,
−3.7, 13.0, 18.1, 25.7 (3 C), 37.1, 67.4, 68.0. HRMS (ESI-TOF):
calculated for [M + H]+ = C10H25O2Si, 205.1624; found, 205.1617 (Δ
= −0.7 mmu).
Ethyl (2R,3R)-2-Hydroxy-3-methylpent-4-enoate (33a). To a
stirred mixture of KOtBu (7.76 g, 16.0 mmol, 1.03 equiv, dried at 1.0
mbar/80 °C/12 h) in dry THF (35 mL) was added liquid trans-2-
butene (10.5 g, 188 mmol, 2.8 equiv) via transfer by cannula at −78
°C (acetone/dry ice). Then a solution of n-BuLi (2.5 M in hexane,
26.8 mL, 67.0 mmol, 1.0 equiv) was added dropwise within 30 min via
syringe driver. Thirty minutes after complete addition of n-BuLi the
mixture was stirred at −45 °C (acetone/dry ice) for 10 min. The
resulting orange solution was recooled to −78 °C, and to it was added
dropwise a solution of (+)-(Ipc)2BOMe (25.1 g, 79.2 mmol, 1.18
equiv) in dry Et2O (80 mL). After the reaction mixture was stirred at
−78 °C for 30 min, BF3·OEt2 (12.1 mL, 96.0 mmol, 1.4 equiv) was
added dropwise within 20 min via syringe, followed by a technical
solution of ethyl glyoxalate 33 in toluene (ca. 4.9 M, 34.2 mL, 168
mmol, 2.5 equiv) within 30 min. The mixture was now stirred at −78
°C for 4 h and after the removal of the cooling bath treated with an
aqueous NaOH solution (1 N, 150 mL, 2.25 equiv) and carefully with
H2O2 (30%, 21.0 mL). Then the contents were stirred for 2 h at room
temperature. The organic layer was separated, the aqueous layer was
extracted with 3 × 100 mL of Et2O, and the combined organic layers
were washed with water (30 mL) and brine (30 mL) and dried over
MgSO4. After removal of the solvents the residue was purified by flash
column chromatography on silica gel (petroleum ether/ethyl acetate
10/1) to yield 70% of anti-33a (7.43 g, 47.0 mmol, d.r. = 98:2, ee =
90% determined by Mosher ester analysis) as a colorless liquid with a
fruity odor. TLC: Rf = 0.33 (petroleum ether/ethyl acetate 10/1).
[α]2D3 = −4.9 (c 1.0, CHCl3). 1H NMR (CDCl3, 300 MHz): δ 1.16 (3
H, d, J = 7.0 Hz)a, 1.30 (3 H, t, J = 7.1 Hz)a, 1.37 (1 H, d, J = 7.0 Hz)b,
1.51 (1 H, t, J = 7.1 Hz)b, 2.17−2.28 (1 H, m)b, 2.49 (1 H, br s)b,
2.59−2.72 (1 H, m)a, 2.74 (1 H, br s)a, 4.11 (1 H, d, J = 3.3 Hz)a, 4.16
(1 H, d, J = 2.6 Hz)b, 4.14−4.33 (2 H, m)a, 4.34−4.50 (1 H, m)b,
5.01−5.07 (1 H, m)a, 5.07−5.11 (1 H, m)a, 5.11−5.13 (1 H, m)b,
(E)-4-(Butyldimethylsilyloxy)-(4,4,5,5-tetramethyl-1,3,2-di-
oxaborolan-2-yl)-3-methylbut-1-ene (23). Alcohol 23a (5.0 g,
24.4 mmol, 1 equiv) was dissolved in dry CH2Cl2, and Dess−Martin
periodinane (25 g, 59 mmol, 2.4 equiv) was added. The resulting
mixture was stirred for 2.5 h at room temperature and quenched with
satured sodium thiosulfate solution (20 mL) and saturated NaHCO3
solution (20 mL). The organic phase was separated and the water
phase extracted with DCM (2 × 50 mL); the combined organic
extracts were washed with water, dried over MgSO4, and filtered
through a pad of silica gel. After removal of the solvent in vacuo, the
crude aldehyde 23b (∼3.0 g, 15 mmol, 1 equiv) and dichlorome-
thylboronic acid pinacol ester (6.3 g, 30 mmol, 2.0 equiv) were
dissolved in dry THF (50 mL) and added slowly to a suspension of
CrCl2 (15 g, 120 mmol, 8.0 equiv) in THF (100 mL) with cooling in
an ice bath. LiI (7.5 g, 60 mmol, 4.0 equiv) was dissolved in 80 mL of
THF and added to the mixture. The resulting suspension was stirred at
room temperature for 16 h. The crude reaction mixture was filtered
through a pad of Celite, water was added, the phases were separated,
and the water phase was extracted with diethyl ether (2 × 50 mL). The
combined organic phases were washed with water and dried over
MgSO4, and the solvent was removed in vacuo. After purification by
flash column chromatography (silica gel, petroleum ether/ethyl acetate
10/1), 3.13 g of (E)-4-(butyldimethylsilyloxy-3-methylbut-1-enyl)-
boronic acid pinacol ester 23 could be obtained as a colorless liquid in
39% yield over two steps. TLC: Rf = 0.75 (petroleum ether/ethyl
5.14−5.18 (1 H, m)b, 5.68−5.82 (1 H, m)a, 5.79−5.92 (1 H, m)b. 13
C
NMR (CDCl3, 75 MHz): δ 13.5b, 14.2a, 15.1b, 16.3a, 41.6b, 41.9a, 61.6a,
64.1b, 73.8b, 74.3a, 115.5b, 116.4a, 137.6a, 139.4b, 174.2a. HRMS (EI-
TOF): calculated for [M]+ = C8H14O3, 158.0943; found, 158.0951 (Δ
= +0.8 mmu).
Ethyl (2R,3R)-2-((tert-Butyldimethylsilyl)oxy)-3-methylpent-
4-enoate (34). To an ice-cooled solution of the ester 33a (2.43 g,
15.4 mmol, 1.0 equiv) in dry CH2Cl2 (120 mL) were added 2,6-
lutidine (7.13 mL, 61.4 mmol, 4.0 equiv) and TBSOTf (10.6 mL, 46.1
mmol, 3.0 equiv). The resulting mixture was stirred at room
temperature for 4 h. The reaction mixture was quenched with
1
acetate 4/1). H NMR (CDCl3, 300 MHz): δ 6.55 (dd, J = 18.1, 6.9
Hz, 1 H), 5.46 (d, J = 19.5 Hz, 1H), 3.57 (dd, J = 9.9, 6.0 Hz, 1 H),
K
DOI: 10.1021/acs.joc.5b02781
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The Journal of Organic Chemistry
Article
saturated aqueous NaHCO3 solution (40 mL) and extracted with 3 ×
40 mL of CH2Cl2. The combined organic layers were dried over
MgSO4 and concentrated in vacuo. Flash column chromatography on
silica gel (petroleum ether/ethyl acetate 60/1) afforded 93% of silyl
ether 34 (3.9 g, 14.4 mmol) as a pale yellow liquid. TLC: Rf = 0.17
(petroleum ether/ethyl acetate 60/1). [α]2D3 = +20.7 (c 1.0, CHCl3).
1H NMR (CDCl3, 300 MHz): δ 0.04 (3H, s), 0.08 (3H, s), 0.92 (s, 9
H), 1.07 (3 H, d, J = 7.0 Hz), 1.27 (3 H, t, J = 7.1 Hz), 2.55−2.70 (1
H, m), 4.07 (1 H, d, J = 4.8 Hz), 4.17 (2 H, mc), 4.99 (1 H, s), 5.01−
5.06 (1 H, m), 5.82 (1 H, ddd, J = 17.2, 10.4, 8.2 Hz). 13C NMR
(CDCl3, 75 MHz) δ −5.3, −4.9, 14.3, 16.8, 18.3, 25.7 (3 C), 42.8,
60.5, 76.3, 115.3, 139.0, 172.9. HRMS (ESI-TOF, arginine): calculated
for [M + H]+ = C14H29O3Si, 273.1880; found, 273.1881 (Δ = −0.1
mmu).
(ESI-TOF, arginine): calculated for [M + H]+ = C25H42NO4Si,
448.2878; found, 448.2878 (Δ = 0 mmu).
N,N-Diisopropyl-2-methoxy-3-methylbenzamide (30). The
procedure described above for 19 was performed with acid 29b (1.0
g, 6.02 mmol, 1.0 equiv), SOCl2 (2.2 mL, 30.1 mmol, 5.0 equiv), and
diisopropylamine (4.25 mL, 30.1 mmol, 5.0 equiv) to give compound
30 (1.22 g, 4.89 mmol) in 81% yield as a white solid after purification
by flash column chromatography on silica gel (petroleum ether/ethyl
acetate 7/1). TLC: Rf = 0.35 (petroleum ether/ethyl acetate 5/1). 1H
NMR (CDCl3, 300 MHz): 1.05 (3 H, d, J = 6.7 Hz), 1.18 (3 H, d, J =
6.7 Hz), 1.56 (3 H, d, J = 2.8 Hz), 1.59 (3 H, d, J = 2.8 Hz), 2.30 (3 H,
s), 3.52 (1 H, spt, J = 6.9 Hz), 3.69 (1 H, spt, J = 6.7 Hz), 3.81 (3 H,
s,), 7.01 (2 H, d, J = 5.0 Hz), 7.12−7.21 (m, 1 H). 13C NMR (CDCl3,
75 MHz): δ 16.0, 20.2, 20.4, 20.7, 20.7, 45.7, 51.1, 61.3, 124.0, 124.7,
131.2, 131.4, 132.6, 154.1, 168.9. HRMS (ESI-TOF, arginine):
calculated for [M + H]+ = C15H24O2N, 250.1800; found, 250.1802
(Δ = +0.2 mmu). Mp: 89−91 °C.
(2R,3R)-2-(tert-Butyldimethylsilyloxy)-N-methoxy-N,3-dime-
thylpent-4-enamide (25). Weinreb’s amine hydrochloride MeNH-
(OMe)·HCl (161 mg, 1.65 mmol, 3.0 equiv) was dissolved in dry
THF (2 mL), and TBS-protected ester 34 (150 mg, 0.55 mmol) in dry
THF (0.5 mL) was added. The mixture was cooled to −20 °C
(acetone/dry ice), and a solution of i-PrMgCl in THF (2.0 M in THF,
1.65 mL, 3.30 mmol, 6.0 equiv) was injected dropwise over 30 min.
The mixture was stirred for an additional 1 h at −20 °C, the bath was
then removed, and the mixture was stirred for 1 h at room
temperature. The reaction was quenched with the dropwise addition
of a half-saturated aqueous NH4Cl solution (2.5 mL). After extraction
of the aqueous layer with 3 × 15 mL of Et2O, the combined organic
layers were dried over anhydrous MgSO4, filtered, and concentrated in
vacuo. The residue was purified by flash column chromatography on
silica gel (petroleum ether/ethyl acetate 9/1) to afford Weinreb‘s
(S)-N,N-Diisopropyl-2-methoxy-3-methyl-6-(p-tolylsulfinyl)-
benzamide (32). A representative procedure for the construction of
the chiral sulfoxides is as follows. In a stirred solution of the amide 32
(5.50 g, 22.1 mmol, 1.0 equiv) and TMEDA (3.66 mL, 24.3 mmol, 1.1
equiv) in dry THF (110 mL, 0.2 M) at −78 °C (acetone/dry ice) was
injected dropwise sec-BuLi (1.4 M in hexane, 17.3 mL, 24.3 mmol, 1.1
equiv) within 15 min. The lithiated solution was stirred at −78 °C for
20 min, and then it was cannulated to a solution of (1R,2S,5R,SS)-
(−)-menthyl p-toluenesulfinate (31; 13.0 g, 44.1 mmol, 2.0 equiv) in
dry THF (110 mL, 0.2 M). After 1.5 h the mixture was quenched with
saturated aqueous NH4Cl solution (200 mL) at −78 °C, br ught up to
room temperature, and extracted with 3 × 200 mL of Et2O. The
combined organic layers were dried over MgSO4 and filtered, and the
solvent was evaporated under reduced pressure to give a residue which
was purified by flash column chromatography on silica gel (petroleum
ether/ethyl acetate 9/1 to 1/1) to afford the white crystalline sulfoxide
32 (7.03 g, 18.1 mmol) in 82% yield. TLC: Rf = 0.25 (petroleum
amide 25 (146 mg, 0.51 mmol) in 92% yield as a colorless oil. [α]D23
=
+25.5 (c 1.0, CHCl3). TLC: Rf = 0.30 (petroleum ether/ethyl acetate
9/1). 1H NMR (CDCl3, 300 MHz): δ 0.06 (d, J = 3.74 Hz, 6 H), 0.91
(s, 9 H), 1.04 (d, J = 6.86 Hz, 3 H), 2.62 (sxt, J = 6.74 Hz, 1 H), 3.22
(s, 3 H), 3.71 (s, 3 H), 4.30−4.45 (m, 1 H), 4.97−5.03 (m, 1 H), 5.05
(s, 1 H), 5.78−5.95 (m, 1 H). 13C NMR (CDCl3, 75.48 MHz): δ −5.1,
−4.7, 16.6, 18.3, 25.8 (3 C), 32.8, 41.8, 61.1, 74.0, 115.1, 139.9, 147.2.
HRMS (ESI-TOF, arginine): calculated for [M + H]+ = C14H30O3NSi,
288.1989; found, 288.1988 (Δ = +0.1 mmu).
ether/ethyl acetate 3/1). [α]2D3 = −117.3 (c 1.0, CHCl3): H NMR
1
(CDCl3, 300 MHz): δ 1.22 (3 H, d, J = 6.7 Hz), 1.26 (3 H, d, J = 6.7
Hz), 1.63 (6 H, t, J = 6.9 Hz), 2.29 (3 H, s), 2.35 (3 H, s), 3.60 (1 H,
sxt, J = 6.7 Hz), 3.74 (1 H, sxt, J = 6.8 Hz,), 3.81 (3 H, s), 7.25 (3 H,
dd, J = 8.3 Hz, 2.2 Hz,), 7.43 (1 H, d, J = 8.0 Hz,), 7.73 (2 H, d, J = 8.3
Hz). 13C NMR (CDCl3, 75 MHz): δ 16.2, 20.3, 20.3, 20.6, 21.0, 21.3,
46.2, 51.8, 61.5, 120.6, 124.5 (2 C), 129.7 (2 C), 132.2, 132.3, 135.1,
140.7, 142.0, 142.1, 153.4, 165.2. HRMS (ESI-TOF, arginine):
calculated for [M + H]+ = C22H30O3NS, 388.1941; found, 388.1941
(Δ = 0 mmu). Mp: 95−96 °C.
6-((2R,3R)-2-(tert-Butyldimethylsilyloxy)-3-methylpent-4-
enoyl)-N,N-diethyl-2-methoxy-3-methylbenzamide (26). To a
stirred solution of N,N-diethylbenzamide (19; 219 mg, 0.99 mmol, 2.3
equiv) and TMEDA (103 μL, 0.68 mmol, 1.6 equiv) in Et2O (5 mL)
at −78 °C (acetone/dry ice) was added dropwise a solution of sec-
BuLi in hexane (1.4 M, 0.5 mL, 0.69 mmol, 1.6 equiv) within 30 min,
The mixture was stirred at −78 °C for 3 h, and then a solution of
Weinreb’s amide 25 (123 mg, 0.43 mmol, 1.0 equiv) in dry Et2O (1.5
mL) was injected into the lithiated solution at −78 °C within 20 min.
After 3 h the cooling bath was removed and the solution was stirred at
room temperature overnight (14 h). The mixture was quenched with
saturated aqueous NH4Cl solution (3 mL) and extracted with 3 × 20
mL of Et2O, and the combined organic layers were dried over MgSO4
and evaporated to give a residue which was purified by flash column
chromatography on silica gel (petroleum ether/ethyl acetate 9/1) to
afford the white solid 26 (107 mg, 0.24 mmol) in 56% yield. TLC: Rf =
0.25 (petroleum ether/ethyl acetate 9/1). [α]2D3 = +30.8 (c 1.0,
CHCl3). 1H NMR (CDCl3, 300 MHz): δ −0.14 (s, 3 H)#, −0.03 (s, 3
H)#, 0.06 (d, J = 1.56 Hz, 3 H)*, 0.11 (d, J = 2.18 Hz, 2 H)*, 0.85−
1.00 (m, 9 H), 0.97−1.05 (m, 3 H), 1.08 (dd, J = 6.80 Hz, J = 2.50 Hz,
3 H), 1.16 (d, J = 6.86 Hz, 3 H)#, 1.23−1.36 (m, 3 H)*, 2.33 (s, 3
H)*, 2.36 (s, 3 H)#, 2.59−2.72 (m, 1 H), 2.83 (dd, J = 11.16 Hz, J =
5.07 Hz, 2 H), 2.94−3.26 (m, 1 H), 3.36−3.49 (m, 1 H), 3.77 (s, 3
H)*, 3.79 (s, 3H)#, 4.03 (dd, J = 12.48 Hz, J = 3.28 Hz, 1 H), 4.27 (d,
J = 7.33 Hz, 1 H)#,4.50 (d, J = 4.68 Hz, 1 H)#, 4.94−5.22 (m, 2 H),
5.65−5.99 (m, 1 H), 7.21 (dd, J = 10.69 Hz, 8.04 Hz, 1 H), 7.57 (d, J
= 7.96 Hz, 1 H)*, 8.00 (d, J = 8.11 Hz, 1 H)#. 13C NMR (CDCl3, 75
MHz): δ −5.3#, −5.2*, −5.0*, −4.8#, 12.5, 13.2*, 13.3#, 15.3, 16.3#,
16.4*, 16.9, 25.3*, 25.4#, 25.6*, 25.7#, 25.8*, 25.9#, 41.1, 42.6*, 42.6#,
42.9, 43.1, 61.5*, 61.7#, 75.2, 77.6, 81.6, 83.8, 115.4*, 115.6#, 117.2,
125.8*, 126.4#, 130.0*, 130.7#, 137.8#, 138.4*, 139.2*, 139.8#. HRMS
(2R,3R)-2-(tert-Butyldimethylsilyloxy)-3-methylpent-4-en-1-
al (35). A stirred solution of the TBS-protected ester 34 (850 mg, 3.12
mmol, 1.0 equiv) in dry CH2Cl2 (15 mL) was cooled to −78 °C
(acetone/dry ice). Then a solution of DIBAl-H (1.0 M in CH2Cl2,
14.3 mL, 9.36 mmol, 3.0 equiv) was injected dropwise over a period of
30 min. The reaction mixture was warmed to room temperature
overnight (12 h) and poured into a saturated solution of potassium
sodium tartrate (50 mL). Et2O (30 mL) was added, and the mixture
was stirred vigorously until two phases appeared. Extraction with 3 ×
50 mL of CH2Cl2, drying over MgSO4, and evaporation of the solvent
yielded 91% of liquid alcohol 34a (657 mg, 2.85 mmol), which was
used in the following reaction without further purification. TLC: Rf =
0.28 (petroleum ether/ethyl acetate 30/1).
Oxalyl chloride (273 μL, 3.19 mmol, 1.35 equiv) was dissolved in
dry CH2Cl2 (10 mL). The mixture was cooled to −78 °C, and a
solution of DMSO (435 μL, 6.14 mmol, 2.6 equiv) in dry CH2Cl2 (3
mL) was added within 5 min. The mixture was stirred at this
temperature for 25 min before a solution of TBS-protected alcohol
34a (544 mg, 2.36 mmol, 1.0 equiv) in dry CH2Cl2 (3 mL) was added
dropwise. After it was stirred for 1 h, the mixture was treated with dry
NEt3 (1.31 mL, 9.44 mmol, 4.0 equiv) and stirring was continued at
−78 °C for 30 min before the mixture was slowly warmed to room
temperature over 1.5 h. Then water was added, the phases were
separated, and the aqueous phase was extracted with 3 × 20 mL of
CH2Cl2. The combined organic layers were washed with brine (2 × 20
mL), and the solvent was evaporated under reduced pressure. Flash
L
DOI: 10.1021/acs.joc.5b02781
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The Journal of Organic Chemistry
Article
column chromatography on silica gel (petroleum ether/ethyl acetate
70/1) yielded 85% of the TBS-protected aldehyde 35 (461 mg, 2.02
mmol) as a colorless liquid. TLC: Rf = 0.30 (petroleum ether/ethyl
22.3, 25.8 (3 C), 33.5, 45.8, 50.9, 61.3, 77.6, 78.5, 114.1, 123.6, 129.8,
130.2, 132.1, 138.0, 139.7, 154.1, 167.8. HRMS (ESI-TOF, arginine):
calculated for [M + H]+ = C27H48NO4Si, 478.3347; found, 478.3342
(Δ = −0.5 mmu).
1
acetate 70/1). [α]2D3 = +15.7 (c 0.5, CHCl3). H NMR (CDCl3, 300
2-Hydroxy-N,N-diisopropyl-3-methylbenzamide (43). A sol-
ution of MgI2, prepared from a refluxing mixture of magnesium
turnings (124 mg, 10.0 mmol, 1.25 equiv) and iodine (2.34 g, 9.22
mmol, 1.15 equiv) in Et2O (15 mL) and toluene (30 mL), was added
dropwise to a stirred mixture of 30 (2.0 g, 8.02 mmol, 1.0 equiv) in
toluene (35 mL). The mixture was then refluxed for 12 h and cooled,
and water (20 mL) was added. The resulting mixture was acidified to
pH 3 with 1 M HCl and extracted with 3 × 50 mL of Et2O, and the
combined organic layers were dried over MgSO4. After removal of the
solvent the residue was purified by flash column chromatography on
silica gel (petroleum ether/ethyl acetate 9/1 to 5/1) to give the title
compound 43 (1.80 g, 7.65 mmol) in 95% yield as a yellow solid.
TLC: Rf = 0.51 (petroleum ether/ethyl acetate 5/1). 1H NMR
(CDCl3, 300 MHz): 1.38 (6 H, s), 1.41 (6 H, s), 2.27 (3 H, s), 3.80−
4.09 (2 H, m), 6.74 (1 H, dd, J = 7.6 Hz), 7.03 (1 H, dd, J = 7.9, 1.6
Hz), 7.10−7.22 (1 H, m), 9.20 (1 H, br s.). 13C NMR (CDCl3, 75
MHz): δ 15.9, 21.0 (4 C), 48.9 (2 C), 117.9, 119.5, 124.2, 127.0,
MHz): δ 0.06 (3 H, s), 0.08 (3 H, s), 0.94 (s, 9 H), 1.10 (3 H, d, J =
7.0 Hz), 2.54−2.67 (1 H, m), 3.85 (1 H, dd, J = 4.4, 1.8 Hz), 5.02−
5.09 (m, 2 H), 5.70−5.90 (m, 1 H), 9.56 (1 H, d, J = 2.2 Hz). 13C
NMR (CDCl3, 75 MHz): δ −5.1, −4.6, 16.3, 18.2, 25.7 (3 C), 41.6,
81.0, 116.0, 138.2, 204.5. HRMS (ESI-TOF, arginine): calculated for
[M + Na]+ = C12H24O2SiNa, 251.1340; found, 251.1338 (Δ = −0.2
mmu).
6-((1S,2R,3R)-2-((tert-Butyldimethylsilyl)oxy)-1-hydroxy-3-
methylpent-4-en-1-yl)-N,N-diisopropyl-2-methoxy-3-methyl-
benzamide (37). A solution of tert-BuLi (1.7 M, 0.39 mL, 656 μmol,
3.0 equiv) was added dropwise to a stirred solution of sulfoxide 31
(212 mg, 547 μmol, 2.5 equiv) in dry THF (8 mL) at −90 °C. After 5
min the TBS-protected aldehyde 35 (50.0 mg, 218 μmol, 1.0 equiv) in
THF (1.0 mL) was added dropwise at −90 °C within 2 min. After it
was stirred for 45 min at −90 °C, the mixture was quenched with
water (10 mL) and the solution was stirred for 20 min at room
temperature. The organic layer was separated, the aqueous layer was
extracted with 3 × 20 mL of Et2O, and the combined organic layers
were dried over MgSO4 and evaporated to give a residue which was
purified by flash column chromatography on silica gel (petroleum
ether/ethyl acetate 9/1 to 1/1) to afford the alcohol 37 (74 mg, 154
μmol) as a colorless oil in 71% yield. TLC: Rf = 0.31 (petroleum
ether/ethyl acetate 5/1). [α]2D3 = +76.0 (c 1.0, CHCl3). 1H NMR
(CDCl3, 300 MHz): δ −0.48 (s, 3 H), 0.09 (s, 3 H), 0.76 (s, 9 H),
1.06 (d, J = 6.71 Hz, 3 H), 1.19 (dd, J = 13.26 Hz, J = 6.86 Hz, 6 H),
1.57 (dd, J = 6.79 Hz, J = 3.67 Hz, 6 H), 2.27 (s, 3 H), 2.78 (quin, J =
7.22 Hz, 1 H), 3.07 (br s, 1 H), 3.53 (dt, J = 13.53 Hz, J = 6.73 Hz, 1
H), 3.73 (s, 3 H), 4.19 (dd, J = 8.82 Hz, J = 2.11 Hz, 1 H), 4.43 (d, J =
8.89 Hz, 1 H), 4.99−5.15 (m, 2 H), 6.01 (ddd, J = 17.44 Hz, J = 10.26,
J = 8.04 Hz, 1 H), 7.14 (s, 2 H). 13C NMR (CDCl3, 125 MHz): δ
−4.3, −4.2, 15.9, 16.4, 20.3, 20.5, 20.5, 21.1, 26.5 (3 C), 41.7, 46.0,
51.8, 61.1, 72.8, 77.7, 114.9, 123.9, 131.1, 132.2, 133.2, 138.7, 140.0,
141.0, 154.0, 169.1. HRMS (ESI-TOF, arginine): calculated for [M +
H]+ = C27H48NO4Si, 478.3347; found, 478.3346 (Δ = −0.1 mmu).
6-((1S,2R,3R)-1-((tert-Butyldimethylsilyl)oxy)-2-hydroxy-3-
methylpent-4-en-1-yl)-N,N-diisopropyl-2-methoxy-3-methyl-
benzamide (40). To a solution of C9-TBS-protected 37 (35.5 mg,
72.2 μmol, 1.0 equiv) in DMF (1.5 mL) was added tris-
(dimethylamino)sulfoniumdifluorotrimethyl silicate (TASF; 260 mg,
721 μmol, 10.0 equiv). The reaction was monitored by TLC until the
starting material was consumed (14 h). The reaction mixture was then
diluted with EtOAc (10 mL) and washed with water (3 × 5 mL). The
aqueous layer was extracted with 3 × 10 mL of EtOAc, and the
combined organic layers were washed again with water (10 mL), dried
over MgSO4, filtered, and concentrated in vacuo. Purification by flash
column chromatography on silica gel (petroleum ether/ethyl acetate
1/1 to pure ethyl acetate) afforded diol 37a (24.6 mg, 65.1 μmol) in
90% yield as a yellow oil. To a solution of diol 37a (23.5 mg, 62.3
μmol, 1.0 equiv) in CH2Cl2 (3 mL) at −78 °C were added 2,6-lutidine
(22 μL, 187 μmol, 3.0 equiv) and TBSOTf (16 μL, 68.5 μmol, 1.1
equiv). The resulting mixture was stirred at −78 °C for 3 h; it was then
warmed to −40 °C within 1.5 h and finally to 0 °C while stirring was
continued for an additional 3 h. Subsequently, the reaction mixture
was quenched with saturated aqueous NaHCO3 solution (5 mL) and
extracted with 3 × 5 mL of CH2Cl2. The combined organic layers were
dried over MgSO4 and concentrated in vacuo. Flash column
chromatography on silica gel (petroleum ether/ethyl acetate 9/1 to
3/1) afforded 13% of C8-TBS-protected alcohol 40 (4.0 mg, 8.13
μmol) as a pale yellow liquid. TLC: Rf = 0.21 (petroleum ether/ethyl
132.5, 156.2, 171.5. HRMS (EI-TOF): calculated for [M]+
=
C14H21O2N, 235.1572; found, 235.1581 (Δ = +0.9 mmu). Mp:
110−112 °C.
N,N-Diisopropyl-2-((4-methoxybenzyl)oxy)-3-methylbenza-
mide (44a). To an ice-cooled suspension of NaH (60% dispersion in
mineral oil, 81.6 mg, 2.04 mmol, 1.60 equiv) in DMF (5 mL) was
added dropwise a solution of phenol 43 (300 mg, 1.27 mmol, 1.0
equiv) in DMF (4 mL), and the resultant mixture was stirred for 0.5 h.
PMBCl (309 μL, 2.29 mmol, 1.80 equiv) was added, and the mixture
was heated at 60 °C for 15 h before it was cooled to room
temperature. Then EtOAc (10 mL) and H2O (10 mL) were added,
the mixture was extracted with 3 × 10 mL of EtOAc, and the organic
layers were dried over MgSO4, filtered, and concentrated under
reduced pressure. Flash column chromatography (petroleum ether/
ethyl acetate 9/1) furnished PMB ether 44a (407 mg, 1.14 mmol,
90%) as a white solid. TLC: Rf = 0.29 (petroleum ether/ethyl acetate
9/1). 1H NMR (CDCl3, 300 MHz): 1.03 (3 H, d, J = 6.6 Hz), 1.12 (3
H, d, J = 6.6 Hz), 1.56 (3 H, d, J = 6.6 Hz), 1.57 (3 H, d, J = 6.7 Hz),
2.27 (3 H, s), 3.49 (1 H, spt, J = 6.7 Hz), 3.69 (1 H, spt, J = 6.6 Hz),
3.82 (3 H, s), 4.81 (1 H, d, J = 10.5 Hz), 5.04 (1 H, d, J = 10.6 Hz),
6.89 (2 H, m, J = 8.5 Hz), 7.04 (2 H, d, J = 4.7 Hz), 7.09−7.21 (1 H,
m), 7.38 (2 H, m, J = 8.4 Hz). 13C NMR (CDCl3, 75 MHz): δ 16.4,
20.5, 20.6 (3 C), 45.6, 51.0, 55.2, 75.4, 113.7 (2 C), 124.1, 124.7, 129.8
(2 C), 129.9, 131.0, 131.9, 133.5, 152.8, 159.3, 169.0. HRMS (ESI-
TOF, arginine): calculated for [M + H]+ = C22H30O3N, 356.2226;
found, 356.2236 (Δ = +1.0 mmu). Mp: 81−82 °C.
2-((tert-Butyldimethylsilyl)oxy)-N,N-diisopropyl-3-methyl-
benzamide (44b). To an ice-cooled solution of phenol 43 (600 mg,
3.79 mmol, 1.0 equiv) in dry CH2Cl2 (15 mL) were added 2,6-lutidine
(370 μL, 3.19 mmol, 2.5 equiv) and TBSOTf (529 μL, 2.29 mmol, 1.8
equiv). The resulting mixture was stirred at room temperature
overnight (14 h), and then water (10 mL) was added followed by
extraction with 3 × 10 mL of CH2Cl2. The combined organic layers
were dried over MgSO4, filtered, and concentrated in vacuo. Flash
column chromatography on silica gel (petroleum ether/ethyl acetate
15/1) afforded 98% of silyl ether 44b (438 mg, 1.25 mmol) as a
colorless liquid. TLC: Rf = 0.25 (petroleum ether/ethyl acetate 15/1).
1H NMR (CDCl3, 300 MHz): 0.13 (3 H, s), 0.27 (3 H, s), 0.95 (3 H,
d, J = 6.6 Hz), 1.03 (9 H, s), 1.18 (3 H, d, J = 6.8 Hz), 1.51 (3 H, d, J =
6.8 Hz), 1.55 (3 H, d, J = 6.9 Hz), 2.26 (3 H, s), 3.48 (1 H, spt, J = 6.9
Hz), 3.56 (1 H, spt, J = 6.7 Hz), 6.83−6.97 (2 H, m), 7.07−7.13 (1 H,
m). 13C NMR (CDCl3, 75 MHz): δ −3.9, −2.8, 18.2, 18.8, 20.3, 20.4,
20.9, 21.4, 26.4 (3 C), 45.6, 50.4, 121.7, 125.2, 129.4, 131.1, 131.7,
149.0, 169.4. HRMS (ESI-TOF, arginine): calculated for [M + H]+ =
C20H36O2NSi, 350.2510; found, 350.2513 (Δ = +0.3 mmu).
acetate 9/1). [α]2D3 = +46.0 (c 1.0, CHCl3). H NMR (CDCl3, 600
1
MHz): δ −0.21 (3 H, s), 0.10 (3 H, s), 0.75 (3 H, d, J = 7.0 Hz), 0.95
(9 H, s), 1.10−1.14 (6 H, m), 1.55−1.64 (6 H, m), 1.59−1.62 (1 H,
m), 2.27 (3 H, s), 3.46−3.54 (2 H, m), 3.72 (3 H, s), 4.10−4.13 (1 H,
m), 4.76 (1 H, d, J = 2.9 Hz), 4.86−4.97 (2 H, m), 5.72−5.89 (1 H,
m), 7.14 (1 H, d, J = 8.1 Hz), 7.35 (1 H, d, J = 8.1 Hz). 13C NMR
(CDCl3, 150 MHz) δ −4.9, −4.5, 18.5, 18.8, 19.9 (2 C), 21.0, 22.3,
2-(Diisopropylcarbamoyl)-6-methylphenyl Acetate (44c). To
a stirred mixture of phenol 43 (275 mg, 1.17 mmol, 1.0 equiv) and
iodine (29 mg, 0.12 mmol, 0.1 equiv) was added Ac2O (132 μL, 1.40
mmol, 1.2 equiv), and the mixture was stirred in an ultrasonic bath at
M
DOI: 10.1021/acs.joc.5b02781
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The Journal of Organic Chemistry
Article
room temperature for 15 min. After completion of the reaction, the
iodine was destroyed by adding a saturated solution of NaS2O3 (15
mL). Et2O (10 mL) was added, and the phases were separated. The
organic phase was washed with saturated NaHCO3 solution (2 × 15
mL) and brine (2 × 15 mL), dried over MgSO4, filtered, and
concentrated to give the product 44c in 88% yield as a white solid
(285 mg, 1.03 mmol). TLC: Rf = 0.16 (petroleum ether/ethyl acetate
5/1). 1H NMR (CDCl3, 300 MHz): 1.11 (6 H, d, J = 6.6 Hz), 1.53 (3
H, d, J = 6.0 Hz), 1.55 (3 H, d, J = 6.0 Hz), 2.19 (3 H, s), 2.28 (3 H,
s), 3.48 (1 H, spt, J = 6.8 Hz), 3.78 (1 H, spt, J = 6.7 Hz), 7.02−7.09
(1 H, m), 7.15 (1 H, dd, J = 7.4 Hz), 7.19−7.25 (1 H, m). 13C NMR
(CDCl3, 75 MHz): δ 16.3, 20.4, 20.5 (3 C), 20.9, 45.8, 50.9, 123.7,
125.9, 131.0, 131.7, 132.1, 145.5, 167.1, 168.5. HRMS (ESI-TOF,
arginine): calculated for [M + H]+ = C16H24O3N, 278.1751; found,
278.1752 (Δ = +0.1 mmu). Mp: 71−73 °C.
3.82 (3 H, s), 4.77 (1 H, d, J = 10.6 Hz), 5.01 (1 H, d, J = 10.5 Hz),
6.83−6.97 (6 H, m), 7.11 (2 H, d, J = 8.0 Hz), 7.37 (2 H, d, J = 8.0
Hz). 13C NMR (CDCl3, 101 MHz): δ 16.4, 20.4, 20.5, 20.6, 20.6, 40.2,
45.6, 50.9, 55.2, 75.4, 113.6 (2 C), 113.8 (2 C), 124.8, 129.8 (4 C),
129.9, 131.4, 131.8, 133.1, 133.2, 137.3, 151.0, 157.9, 159.2, 169.1.
HRMS (ESI-TOF, arginine): calculated for [M + H]+ = C29H36O4NS,
494.2365; found, 494.2361 (Δ = −0.4 mmu). Mp: 112−113 °C.
(S)-2-((tert-Butyldimethylsilyl)oxy)-N,N-diisopropyl-3-meth-
yl-6-(p-tolylsulfinyl)benzamide (45b). The representative proce-
dure given for 32 was carried out with amide 44b (471 mg, 1.35 mmol,
1.0 equiv) to afford the white crystalline sulfoxide 45b after flash
column chromatography on silica gel (petroleum ether/ethyl acetate
9/1 to 3/1) in 85% yield (557 mg, 1.14 mmol). TLC: Rf = 0.34
(petroleum ether/ethyl acetate 3/1). [α]2D3 = −88.3 (c 1.0, CHCl3). 1H
NMR (CDCl3, 300 MHz): 0.11 (3 H, s), 0.30 (3 H, s), 1.02 (9 H, s),
1.18 (3 H, d, J = 6.6 Hz), 1.22 (3 H, d, J = 6.6 Hz), 1.60 (3 H, d, J =
6.6 Hz), 1.62 (3 H, d, J = 6.7 Hz), 2.25 (3 H, s), 2.34 (3 H, s), 3.61 (2
H, spt, J = 6.7 Hz), 7.20 (1 H, d, J = 8.0 Hz), 7.24 (2 H, m, J = 8.0
Hz), 7.31 (1 H, d, J = 8.0 Hz), 7.76 (2 H, m, J = 8.2 Hz). 13C NMR
(CDCl3, 75 MHz): δ −3.7, −2.5, 18.3, 18.8, 20.0, 20.8, 21.0, 21.3, 21.6,
26.4 (3 C), 46.5, 51.2, 118.3, 124.4 (2 C), 129.6 (2 C), 130.3, 132.5,
132.6, 140.3, 142.4, 142.9, 148.8, 165.6. HRMS (ESI-TOF, arginine):
calculated for [M + H]+ = C27H42O3NSSi, 488.2656; found, 488.2654
(Δ = −0.2 mmu). Mp: 88−89 °C.
(S)-2-(Allyloxy)-N,N-diisopropyl-3-methyl-6-(p-tolylsulfinyl)-
benzamide (45d). The representative procedure given for 32 was
carried out with amide 44d (7.00 g, 21.8 mmol, 1.0 equiv) to afford
the white crystalline sulfoxide 45d after flash column chromatography
on silica gel (petroleum ether/ethyl acetate 5/1 to 1/1) in 88% yield
(7.90 g, 19.1 mmol). TLC: Rf = 0.15 (petroleum ether/ethyl acetate 3/
1). [α]2D3 = −94.6 (c 1.0, CHCl3). 1H NMR (CDCl3, 300 MHz): δ 1.23
(3 H, d, J = 7.3 Hz), 1.25 (3 H, d, J = 7.4 Hz), 1.61 (3 H, d, J = 6.9
Hz), 1.64 (3 H, d, J = 6.9 Hz), 2.29 (3 H, s), 2.35 (3 H, s), 3.60 (1 H,
spt, J = 6.9 Hz), 3.76 (1 H, spt, J = 6.7 Hz), 4.32 (1 H, ddt, J = 12.1
Hz, 5.5 Hz, 1.4 Hz), 4.57 (1 H, ddt, J = 12.1 Hz, 5.5 Hz, 1.4 Hz), 5.22
(1 H, dq, J = 10.4 Hz, 1.4 Hz), 5.38 (1 H, dq, J = 17.3 Hz, 1.6 Hz),
6.03 (1 H, ddt, J = 17.1 Hz, 10.6 Hz, 5.5 Hz), 7.16−7.29 (3 H, m),
7.45 (1 H, d, J = 8.0 Hz), 7.73 (2 H, d, J = 7.6 Hz). 13C NMR (CDCl3,
75 MHz): δ 16.4, 20.2, 20.4, 20.6, 21.0, 21.3, 46.2, 51.7, 74.9, 117.3,
120.7, 124.5 (2 C), 129.7 (2 C), 132.3, 132.4, 133.5, 135.4, 140.7,
142.1, 142.2, 152.2, 165.3. HRMS (ESI-TOF, arginine): calculated for
[M + H]+ = C24H32O3NS, 414.2097; found, 414.2099 (Δ = +0.2
mmu). Mp: 99−102 °C.
2-(Allyloxy)-N,N-diisopropyl-3-methylbenzamide (44d). To
an ice-cooled suspension of NaH (60% dispersion in mineral oil, 74.0
mg, 1.85 mmol, 1.40 equiv) in DMF (4 mL) was added dropwise a
solution of phenol 43 (311 mg, 1.32 mmol, 1.0 equiv) in DMF (2
mL), and the resultant mixture was stirred for 1 h. Then allyl iodide
(241 μL, 2.64 mmol, 2.00 equiv) was added and the mixture was
stirred at room temperature for 3 h before EtOAc (10 mL) and H2O
(10 mL) were added. The mixture was extracted with 3 × 15 mL of
EtOAc, dried over MgSO4, filtered, and concentrated under reduced
pressure. Flash column chromatography (petroleum ether/ethyl
acetate 9/1 to 5/1) furnished allyl ether 44d (352 mg, 1.28 mmol)
in 97% yield as a white solid. TLC: Rf = 0.30 (petroleum ether/ethyl
1
acetate 9/1). H NMR (CDCl3, 300 MHz): δ 1.03 (3 H, d, J = 6.7
Hz), 1.18 (3 H, d, J = 6.6 Hz), 1.55 (3 H, d, J = 6.7 Hz), 1.56 (3 H, d, J
= 6.6 Hz), 2.29 (3 H, s), 3.49 (1 H, spt, J = 6.8 Hz), 3.68 (1 H, spt, J =
6.7 Hz), 4.34 (1 H, ddt, J = 12.2 Hz, 5.5 Hz, 1.4 Hz), 4.57 (1 H, ddt, J
= 12.2 Hz, 5.4 Hz, 1.4 Hz), 5.20 (1 H, dq, J = 10.5 Hz, 1.4 Hz), 5.38 (1
H, dq, J = 17.2 Hz, 1.7 Hz), 6.05 (1 H, ddt, J = 17.2 Hz, 10.6 Hz, 5.4
Hz), 6.91−7.08 (2 H, m), 7.10−7.22 (1 H, m). 13C NMR (CDCl3, 75
MHz): δ 16.2, 20.2, 20.5, 20.7, 20.8, 45.6, 51.0, 74.6, 116.9, 124.2,
124.6, 131.0, 131.7, 133.4, 134.1, 152.9, 168.9. HRMS (ESI-TOF,
arginine): calculated for [M + H]+ = C17H26O2N, 276.1958; found,
276.1957 (Δ = −0.1 mmu). Mp: 95−96 °C.
2-(Benzyloxy)-N,N-diisopropyl-3-methylbenzamide (44e).
To an ice-cooled suspension of NaH (60% dispersion in mineral oil,
81.6 mg, 2.04 mmol, 1.60 equiv) in DMF (5 mL) was added dropwise
a solution of phenol 43 (300 mg, 1.27 mmol, 1.0 equiv) in DMF (4
mL), and the resultant mixture was stirred for 0.5 h. BnBr (273 μL,
2.29 mmol, 1.80 equiv) was added, and the mixture was stirred at
room temperature for 18 h before EtOAc (10 mL) and H2O (10 mL)
were added. The mixture was extracted with 3 × 10 mL of EtOAc,
dried over MgSO4, filtered, and concentrated under reduced pressure.
Flash column chromatography (petroleum ether/ethyl acetate 9/1)
furnished benzyl ether 44e (283 mg, 1.27 mmol, 68%) as a white solid.
TLC: Rf = 0.30 (petroleum ether/ethyl acetate 5/1). 1H NMR
(CDCl3, 300 MHz): 1.03 (3 H, d, J = 6.9 Hz), 1.13 (3 H, d, J = 6.6
Hz), 1.57 (3 H, d, J = 6.9 Hz), 1.52 (3 H, d, J = 6.6 Hz), 2.29 (3 H, s),
3.49 (1 H, spt, J = 6.8 Hz), 3.71 (1 H, spt, J = 6.7 Hz), 4.87 (1 H, d, J
= 11.0 Hz), 5.13 (1 H, d, J = 11.0 Hz), 7.04 (1 H, s), 7.06 (1 H, m),
7.15−7.20 (1 H, m), 7.26−7.39 (3 H, m), 7.43−7.46 (1 H, m), 7.47 (1
H, m). 13C NMR (CDCl3, 75 MHz): δ 16.3, 20.4, 20.6, 20.6, 20.7,
45.6, 51.0, 75.6, 124.2, 124.7, 127.7, 127.9 (2 C), 128.2 (2 C), 131.1,
131.8, 133.4, 137.7, 152.8, 169.0. HRMS (ESI-TOF, arginine):
calculated for [M + H]+ = C21H28O2N, 326.2120; found, 326.2115
(Δ = −0.5 mmu). Mp: 84−86 °C.
(S)-2-(Benzyloxy)-N,N-diisopropyl-3-methyl-6-(p-
tolylsulfinyl)benzamide (45e). The representative procedure given
for 32 was carried out with amide 44e (200 mg, 614 μmol, 1.0 equiv)
to afford the white crystalline sulfoxide 45e after flash column
chromatography on silica gel (petroleum ether/ethyl acetate 9/1 to 5/
1) in 82% yield (233 mg, 504 μmol). TLC: Rf = 0.16 (petroleum
ether/ethyl acetate 5/1). [α]2D3 = −56.6° (c 1.0, CHCl3) H NMR
1
(CDCl3, 300 MHz): 1.09 (3 H, d, J = 6.6 Hz), 1.17 (3 H, d, J = 6.6
Hz), 1.45 (3 H, d, J = 6.9 Hz), 1.56 (3 H, d, J = 6.9 Hz), 2.21 (3 H, s),
2.30 (3 H, s), 3.51 (1 H, spt, J = 6.8 Hz), 3.70 (1 H, spt, J = 6.7 Hz),
4.78 (1 H, d, J = 10.7 Hz), 5.05 (1 H, d, J = 10.7 Hz), 7.17−7.23 (3 H,
m), 7.24−7.32 (3 H, m), 7.33−7.38 (2 H, m), 7.40 (1 H, d, J = 8.0
Hz), 7.68 (2 H, d, J = 8.2 Hz). 13C NMR (CDCl3, 75 MHz): δ 16.6,
20.2, 20.5, 20.7, 20.9, 21.4, 46.3, 51.8, 75.9, 120.8, 124.5 (2 C), 127.9
(2 C), 128.0, 128.3 (2 C), 129.8 (2 C), 132.4, 132.5, 135.5, 137.1,
140.7, 142.2, 142.2, 152.1, 165.4. HRMS (ESI-TOF, arginine):
calculated for [M + H]+ = C28H34O3NS, 464.2254; found, 464.2256
(Δ = +0.2 mmu). Mp: 101−103 °C.
(S)-N,N-Diisopropyl-2-((4-methoxybenzyl)oxy)-3-methyl-6-
(p-tolylsulfinyl)benzamide (45a). The representative procedure
given for 32 was carried out with amide 44a (467 mg, 1.31 mmol, 1.0
equiv) to afford the white crystalline sulfoxide 45a after flash column
chromatography on silica gel (petroleum ether/ethyl acetate 5/1 to 1/
1) in 78% yield (508 mg, 1.03 mmol). TLC: Rf = 0.43 (petroleum
(R)-6-(1-Hydroxyallyl)-N,N-diisopropyl-2-methoxy-3-methyl-
benzamide (46f). A representative procedure for the asymmetric
ortho lithiation with acrolein is as follows. A solution of tert-BuLi (1.7
M in pentane, 1.59 mL, 2.71 mmol, 3.0 equiv) was added dropwise to
a stirred solution of sulfoxide 32 (350 mg, 0.90 mmol, 1.0 equiv) in
dry THF (13 mL, 0.07 M) at −90 °C (acetone/liquid nitrogen). After
5 min dry acrolein (362 μL, 5.42 mmol, 6.0 equiv) was added
dropwise within 5 min. The mixture was warmed to −78 °C and
stirred for 0.5 h at this temperature. Then an aqueous solution of
1
ether/ethyl acetate 3/1). [α]2D3 = −72.3 (c 1.0, CHCl3). H NMR
(CDCl3, 300 MHz): 0.98 (3 H, d, J = 6.7 Hz), 1.11 (3 H, d, J = 6.5
Hz), 1.55 (3 H, d, J = 6.5 Hz), 1.55 (3 H, d, J = 6.7 Hz), 2.22 (3 H, s),
3.48 (1 H, spt, J = 6.7 Hz), 3.68 (1 H, spt, J = 6.5 Hz), 3.80 (3 H, s),
N
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Article
NH4Cl (40 mL) was added at −78 °C and the mixture was warmed to
room temperature. Extraction with 3 × 50 mL of Et2O, drying over
MgSO4, filtration, and evaporation of the solvent gave a residue which
was purified by flash column chromatography on silica gel (petroleum
ether/ethyl acetate 5/1 to 2/1) to afford the ortho-lithiation product
46f (202 mg, 0.66 mmol) in 73% yield as a colorless oil. TLC: Rf =
0.41 (petroleum ether/ethyl acetate 2/1). [α]2D3 = +116.6 (c 1.0,
CHCl3). 1H NMR (CDCl3, 300 MHz): 1.03 (3 H, d, J = 6.6 Hz), 1.22
(3 H, d, J = 6.6 Hz), 1.61 (3 H, d, J = 6.7 Hz), 1.60 (3 H, d, J = 6.8
Hz), 2.27 (3 H, s), 3.55 (1 H, spt, J = 6.8 Hz), 3.70 (1 H, spt, J = 6.7
Hz), 3.75 (3 H, s), 5.15 (1 H, dt, J = 4.7, 1.6 Hz), 5.31 (1 H, dt, J =
10.4, 1.6 Hz), 5.47 (1 H, dt, J = 17.1, 1.7 Hz), 6.08 (1 H, ddd, J = 17.2,
10.6, 4.8 Hz), 7.10 (1 H, d, J = 7.8 Hz), 7.16 (1 H, d, J = 7.7 Hz). 13C
NMR (CDCl3, 75 MHz): δ 15.7, 20.1, 20.3, 20.6, 20.9, 46.0, 51.6, 61.0,
70.9, 115.6, 122.9, 130.8, 131.3, 132.0, 137.5, 139.2, 153.7, 168.8.
(R)-2-(Benzyloxy)-6-(1-hydroxyallyl)-N,N-diisopropyl-3-
methylbenzamide (46e). The representative procedure given for
46f was carried out with sulfoxide 45e (77 mg, 166 μmol, 1.0 equiv) to
afford the colorless oil 46e after flash column chromatography on silica
gel (petroleum ether/ethyl acetate 9/1 to 3/1) in 68% yield (43 mg,
112 μmol). TLC: Rf = 0.27 (petroleum ether/ethyl acetate 3/1). [α]D23
= +124.4 (c 1.0, CHCl3). 1H NMR (CDCl3, 400 MHz): 1.01 (3 H, d, J
= 6.8 Hz), 1.14 (3 H, d, J = 6.6 Hz), 1.47 (3 H, d, J = 6.8 Hz), 1.59 (3
H, d, J = 7.0 Hz), 1.72 (1 H, br s), 2.26 (3 H, s), 3.50 (1 H, spt, J = 6.8
Hz), 3.72 (1 H, spt, J = 6.8 Hz), 4.83 (1 H, d, J = 11.2 Hz), 4.99 (1 H,
d, J = 11.2 Hz), 5.14−5.19 (1 H, m), 5.32 (1 H, dt, J = 10.6, 1.7 Hz),
5.48 (1 H, dt, J = 17.2, 1.7 Hz), 6.09 (1 H, ddd, J = 17.1, 10.6, 4.8 Hz),
7.15−7.21 (2 H, m), 7.28−7.39 (3 H, m), 7.40−7.45 (2 H, m). 13C
NMR (CDCl3, 101 MHz): δ 16.0, 20.0, 20.2, 20.3, 20.4, 45.6, 51.1,
70.5, 75.2, 113.3, 123.0, 129.3 (2 C), 129.5, 130.6 (2 C), 131.0, 131.3,
131.9, 138.7, 138.9, 140.2, 152.6, 168.0. HRMS (ESI-TOF, arginine):
calculated for [M + H]+ = C24H32O3N, 382.2382; found, 382.2387 (Δ
= +0.5 mmu).
(R)-2-(Allyloxy)-6-(1-((tert-butyldimethylsilyl)oxy)allyl)-N,N-
diisopropyl-3-methylbenzamide (47a). To an ice-cooled solution
of alcohol 46d (2.80 g, 8.45 mmol, 1.0 equiv) in dry CH2Cl2 (100 mL)
were added 2,6-lutidine (3.92 mL, 33.8 mmol, 4.0 equiv) and TBSOTf
(3.88 mL, 16.9 mmol, 2.0 equiv). The resulting mixture was warmed
to room temperature and stirred overnight (14 h), and then water (50
mL) was added followed by extraction with 3 × 50 mL of CH2Cl2. The
combined organic layers were dried over MgSO4, filtered, and
concentrated in vacuo. Flash column chromatography on silica gel
(petroleum ether/ethyl acetate 30/1) afforded 89% of silyl-protected
alcohol 47a (3.35 g, 7.51 mmol) as a colorless liquid. TLC: Rf = 0.32
(petroleum ether/ethyl acetate 30/1). [α]2D3 = +109.6 (c 1.0, CHCl3).
1H NMR (CDCl3, 300 MHz): δ −0.08 (3 H, s), 0.09 (3 H, s), 0.89 (9
HRMS (ESI-TOF, arginine): calculated for [M + Na]+
=
C18H27O3NNa, 328.1883; found, 328.1886 (Δ = +0.3 mmu).
( R ) - 6 - ( 1 - H y d r o x y a l l y l ) - N , N - d i i s o p r o p y l - 2 - ( ( 4 -
methoxybenzyl)oxy)-3-methylbenzamide (46a). The representa-
tive procedure given for 46f was carried out with sulfoxide 45a (200
mg, 409 μmol, 1.0 equiv) to afford the colorless oil 46a after flash
column chromatography on silica gel (petroleum ether/ethyl acetate
5/1 to 3/1) in 71% yield (119 mg, 289 μmol). TLC: Rf = 0.29
(petroleum ether/ethyl acetate 3/1). [α]2D3 = +96.6 (c 1.0, CHCl3). 1H
NMR (CDCl3, 300 MHz): 1.19 (3 H, d, J = 6.0 Hz), 1.21 (3 H, d, J =
5.8 Hz), 1.61 (3 H, d, J = 6.9 Hz), 1.68 (3 H, d, J = 6.9 Hz), 2.36 (3 H,
s), 3.60 (1 H, spt, J = 6.8 Hz), 3.79 (1 H, spt, J = 6.7 Hz), 3.92 (3 H,
s), 4.84 (1 H, d, J = 10.7 Hz), 5.07 (1 H, d, J = 10.7 Hz), 5.21−5.31 (2
H, m), 5.47−5.56 (1 H, m), 6.13−6.30 (1 H, m), 6.95−7.02 (2 H, m),
7.22−7.31 (2 H, m), 7.43−7.50 (2 H, m). 13C NMR (CDCl3, 75
MHz): δ 16.0, 19.9, 20.2, 20.3, 20.4, 45.6, 51.1, 55.0, 72.6, 75.2, 113.4
(2 C), 113.5, 123.0, 129.3 (2 C), 129.5, 130.6, 131.0, 131.3, 138.7,
140.2, 152.6, 159.0, 168.0. HRMS (ESI-TOF, arginine): calculated for
[M + H]+ = C25H34O4N, 412.2488; found, 412.2484 (Δ = −0.4
mmu).
H, s), 1.04 (3 H, d, J = 6.6 Hz), 1.18 (3 H, d, J = 6.6 Hz), 1.57 (3 H, d,
J = 6.4 Hz), 1.59 (3 H, d, J = 6.4 Hz), 2.26 (3 H, s), 3.48 (1 H, spt, J =
6.5 Hz), 3.57 (1 H, spt, J = 6.6 Hz), 4.25 (1 H, dd, J = 12.2, 5.4 Hz),
4.54 (1 H, dd, J = 12.3, 5.4 Hz), 5.05 (1 H, d, J = 10.2 Hz), 5.18 (1 H,
d, J = 10.5 Hz), 5.23−5.40 (3 H, m), 5.79−5.95 (1 H, m), 5.95−6.11
(1 H, m), 7.15 (1 H, d, J = 8.0 Hz), 7.21 (1 H, d, J = 8.0 Hz). 13C
NMR (CDCl3, 75 MHz): δ −5.2, −4.9, 15.9, 18.1, 20.3, 20.5, 20.8,
21.1, 25.9 (3 C), 45.8, 50.9, 70.8, 74.7, 113.6, 116.8, 123.3, 129.9,
130.8, 131.0, 134.1, 139.5, 141.1, 152.4, 167.5. HRMS (ESI-TOF,
arginine): calculated for [M + Na]+ = C26H43O3NSiNa, 468.2910;
found, 468.2913 (Δ = +0.3 mmu).
(R)-2-((tert-Butyldimethylsilyl)oxy)-6-(1-hydroxyallyl)-N,N-
diisopropyl-3-methylbenzamide (46b). The representative pro-
cedure given for 46f was carried out with sulfoxide 45b (200 mg, 409
μmol, 1.0 equiv) to afford the colorless oil 46b after flash column
chromatography on silica gel (petroleum ether/ethyl acetate 9/1 to 3/
1) in 39% yield (64 mg, 157 μmol). TLC: Rf = 0.32 (petroleum ether/
ethyl acetate 3/1). [α]D23 = +123.6 (c 1.0, CHCl3). H NMR (CDCl3,
1
300 MHz): 0.08 (3 H, s), 0.26 (3 H, s), 0.94 (3 H, d, J = 6.6 Hz), 1.03
(9 H, s), 1.24 (3 H, d, J = 6.9 Hz), 1.59 (6 H, d, J = 6.9 Hz), 2.24 (3 H,
s), 3.54 (1 H, spt, J = 6.7 Hz), 3.62 (1 H, spt, J = 6.6 Hz), 5.06−5.15
(1 H, m), 5.34 (1 H, dt, J = 10.7, 1.6 Hz), 5.50 (1 H, dt, J = 17.1, 1.7
Hz), 6.10 (1 H, ddd, J = 17.2, 10.6, 4.8 Hz), 6.99 (1 H, d, J = 7.7 Hz),
7.12 (1 H, d, J = 8.0 Hz). 13C NMR (CDCl3, 75 MHz): δ −4.1, −2.5,
17.9, 18.8, 20.3, 20.5, 20.7, 21.4, 26.5 (3 C), 46.3, 51.0, 70.6, 115.6,
120.7, 128.9, 130.4, 131.3, 137.2, 139.2, 149.1, 169.7. HRMS (ESI-
TOF, arginine): calculated for [M + H]+ = C23H40O3NSi, 406.2772;
found, 406.2773 (Δ = +0.1 mmu).
(R)-6-(1-((tert-Butyldimethylsilyl)oxy)allyl)-2-hydroxy-N,N-
diisopropyl-3-methylbenzamide (47b). Allyl ether 47a (3.0 g,
6.73 mmol, 1.0 equiv) was dissolved in dry MeOH (70 mL), followed
by the addition of [Pd(Ph3)4] (77.1 mg, 67.3 μmol, 1 mol %). After
the mixture was stirred for 10 min at room temperature, K2CO3 (2.79
g, 20.2 mmol, 3.0 equiv) was added to the resulting yellow solution
and stirring was continued for 3 h until TLC control indicated
complete consumption of the starting material. Then the solvent was
evaporated under reduced pressure and the resulting slurry was
resolved in water (50 mL), acidified with a solution of HCl (1 N) to
pH 5, and extracted with 3 × 50 mL of CH2Cl2. The combined organic
layers were dried over MgSO4 and concentrated in vacuo to afford
phenol 47b (2.73 g, 6.73 mmol) in quantitative yield as a pale yellow
(R)-2-(Allyloxy)-6-(1-hydroxyallyl)-N,N-diisopropyl-3-methyl-
benzamide (46d). The representative procedure given for 46f was
carried out with sulfoxide 45d (5.01 g, 12.1 mmol, 1.0 equiv) to afford
the colorless oil 46d after flash column chromatography on silica gel
(petroleum ether/ethyl acetate 9/1 to 3/1) in 92% yield (3.71 g, 11.1
solid. TLC: Rf = 0.26 (petroleum ether/ethyl acetate 9/1). [α]D23
=
+40.1 (c 1.0, CHCl3). 1H NMR (CDCl3, 300 MHz): δ −0.02 (3 H, s),
0.09 (3 H, s), 0.91 (9 H, s), 1.21−1.51 (12 H, m), 2.13 (3 H, s), 3.63
(2 H, spt, J = 6.6 Hz), 5.03 (1 H, d, J = 10.2 Hz), 5.16 (1 H, d, J = 5.1
Hz), 5.28 (1 H, d, J = 16.9 Hz), 5.64 (1 H, br s), 5.94 (1 H, ddd, J =
16.9, 10.2, 5.3 Hz), 6.91−7.10 (2 H, m). 13C NMR (CDCl3, 75 MHz):
δ −4.8 (2 C), 15.7, 18.2, 20.8 (4 C), 25.8 (3 C), 48.6 (2 C), 72.1,
113.6, 118.7, 124.0, 128.4, 130.6, 138.7, 141.2, 149.5, 168.3. HRMS
(ESI-TOF, arginine): calculated for [M + H]+ = C23H40O3NSi,
406.2778; found, 406.2779 (Δ = +0.1 mmu).
mmol). TLC: Rf = 0.33 (petroleum ether/ethyl acetate 3/1). [α]D23
=
+144.4 (c 1.0, CHCl3). 1H NMR (CDCl3, 300 MHz): δ 1.02 (3 H, d, J
= 6.9 Hz), 1.23 (2 H, d, J = 6.9 Hz), 1.57 (3 H, d, J = 6.9 Hz), 1.60 (3
H, d, J = 6.9 Hz), 2.27 (3 H, s), 3.54 (1 H, spt, J = 6.9 Hz), 3.72 (1 H,
spt, J = 6.8 Hz), 3.84 (1 H, br s), 4.29 (1 H, ddt, J = 12.3, 5.5, 1.4 Hz),
4.47 (1 H, ddt, J = 12.3, 5.7, 1.4 Hz), 5.15 (1 H, d, J = 4.1 Hz), 5.21 (1
H, dd, J = 10.4, 1.4 Hz), 5.32 (1 H, dt, J = 10.7, 1.6 Hz), 5.34−5.39 (1
H, m), 5.48 (1 H, dt, J = 17.3, 1.6 Hz), 5.89−6.06 (1 H, m), 6.06−6.13
(1 H, m), 7.11 (1 H, d, J = 8.0 Hz), 7.17 (1 H, d, J = 8.0 Hz). 13C
NMR (CDCl3, 75 MHz): δ 16.0, 20.1, 20.3, 20.5, 20.8, 46.0, 51.5, 70.8,
74.6, 115.7, 117.2, 123.0, 131.0, 131.3, 132.2, 133.8, 137.4, 139.1,
152.5, 168.9. HRMS (ESI-TOF, arginine): calculated for [M + H]+ =
C20H30O3N, 332.2220; found, 332.2222 (Δ = +0.2 mmu).
Methyl (R)-6-(1-((tert-Butyldimethylsilyl)oxy)allyl)-2-hy-
droxy-3-methylbenzoate (47). To a solution of N,N-diisopropyla-
mide 47b (500 mg, 1.23 mmol, 1.0 equiv) and 2,6-DTBMP (1.01 g,
4.03 mmol, 3.25 equiv) in CH2Cl2 (15 mL) was added MeOTf (305
μL, 2.47 mmol, 2.0 equiv) dropwise. The mixture was then refluxed for
O
DOI: 10.1021/acs.joc.5b02781
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
6 h, cooled to room temperature, and treated with a saturated solution
of NaHCO3 (20 mL). The resulting mixture was stirred for 14 h and
then extracted with 3 × 30 mL of EtOAc. The combined organic layers
were dried over MgSO4 and concentrated under reduced pressure.
After purification by flash column chromatography on silica gel
(petroleum ether/ethyl acetate 30/1) ester 47 (261 mg, 776 μmol)
was obtained in 62% yield as a colorless liquid. TLC: Rf = 0.48
(petroleum ether/ethyl acetate 30/1). [α]2D3 = +74.2 (c 1.0, CHCl3).
1H NMR (CDCl3, 300 MHz): δ −0.01 (3 H, s), 0.06 (3 H, s), 0.92 (9
H, s), 2.25 (3 H, s), 3.97 (3 H, s), 4.92−5.06 (1 H, m), 5.17−5.28 (1
H, m), 5.83−5.98 (1 H, m), 5.99−6.03 (1 H, m), 7.20 (1 H, d, J = 8.0
Hz), 7.30 (1 H, d, J = 8.0 Hz), 11.10 (1 H, s). 13C NMR (CDCl3, 75
MHz): δ −4.9 (2 C), 16.0, 18.4, 25.9 (3 C), 52.1, 71.8, 109.5, 112.5,
117.8, 125.2, 135.5, 141.4, 144.1, 159.8, 171.6. HRMS (ESI-TOF,
arginine): calculated for [M + Na]+ = C18H28O4SiNa, 359.1654; found,
359.1653 (Δ = −0.1 mmu).
NaHCO3 (5 mL) to hydrolyze the borane. The two-phase mixture was
warmed to room temperature and stirred for 1 h before being filtered
through a glass filter. The aqueous layer was extracted with 3 × 15 mL
of Et2O, and the combined organic extracts were dried over MgSO4,
filtered, and concentrated in vacuo. The residue was purified by flash
column chromatography on silica gel (petroleum ether/ethyl acetate
15/1 to 9/1) to yield 95% of 49 (101 mg, 196 μmol) as a colorless
liquid. TLC: Rf = 0.30 (petroleum ether/ethyl acetate 9/1). [α]D23
=
+32.1 (c 1.0, CHCl3). 1H NMR (CDCl3, 300 MHz): δ −0.18 (3 H, s),
0.07 (3 H, s), 0.90 (9 H, s), 1.05 (3 H, d, J = 6.9 Hz), 2.26 (1 H, sxt, J
= 7.0 Hz), 2.32 (3 H, s), 2.58 (1 H, d, J = 5.8 Hz), 3.42−3.54 (1 H,
m), 3.82 (3 H, s), 3.83 (3 H, s), 4.73 (1 H, d, J = 4.7 Hz), 4.80 (1 H, d,
J = 10.3 Hz), 4.86 (1 H, d, J = 10.3 Hz), 5.00−5.13 (2 H, m), 5.92 (1
H, ddd, J = 17.2, 10.6, 7.7 Hz), 6.91 (2 H, m, J = 8.8 Hz), 7.18−7.25
(2 H, m), 7.34 (2 H, m, J = 8.5 Hz). 13C NMR (CDCl3, 75 MHz): δ
−5.3, −4.6, 16.2, 17.6, 18.1, 25.9 (3 C), 39.9, 52.2, 55.3, 75.8, 77.2,
78.7, 113.8 (2 C), 115.1, 123.7, 127.3, 129.3, 129.6 (2 C), 130.9, 132.2,
138.7, 140.2, 153.7, 159.5, 168.4. HRMS (ESI-TOF, arginine):
calculated for [M + H]+ = C29H43O6Si, 515.2828; found, 515.2833
(Δ = +0.5 mmu).
Methyl (R)-6-(1-((tert-Butyldimethylsilyl)oxy)allyl)-2-((4-
methoxybenzyl)oxy)-3-methylbenzoate (47c). To an ice-cooled
suspension of NaH (60% dispersion in mineral oil, 70.0 mg, 482 μmol,
1.40 equiv) in DMF (12 mL) was added dropwise a solution of phenol
47 (421 mg, 1.25 mmol, 1.0 equiv) in DMF (4 mL), and the resultant
mixture was stirred for 30 min. PMBCl (270 μL, 2.0 mmol, 1.60 equiv)
was added, and the mixture was heated to 60 °C for 18 h, before it was
cooled to room temperature. Then CH2Cl2 (10 mL) and H2O (10
mL) were added, and the mixture was extracted with 3 × 25 mL of
CH2Cl2, dried over MgSO4, filtered, and concentrated under reduced
pressure. Flash column chromatography (petroleum ether/ethyl
acetate 50/1 to 15/1) furnished PMB ether 47c (533 mg, 1.17
mmol, 93%) as a colorless liquid. TLC: Rf = 0.24 (petroleum ether/
(S)-3-((1S,2S)-1-((tert-Butyldimethylsilyl)oxy)-2-methylbut-3-
en-1-yl)-7-((4-methoxybenzyl)oxy)-6-methylisobenzofuran-
1(3H)-one (54). Ester 49 (60 mg, 116 μmol, 1.0 equiv) was dissolved
in THF (2 mL) and treated with a solution of NaOH (2.0 M, 2.91 mL,
50 equiv) at room temperature. After 0.5 h water was added (2 mL)
and the reaction mixture was extracted with 3 × 5 mL of Et2O. The
combined organic layers were dried over MgSO4, filtered off, and
concentrated under reduced pressure to give 54 (55 mg, 114 μmol) in
99% yield as a clourless liquid without further purification. TLC: Rf =
0.43 (petroleum ether/ethyl acetate 9/1). [α]2D3 = −11.8 (c 1.0,
ethyl acetate 30/1). [α]D23 = +40.1 (c 1.0, CHCl3): H NMR (CDCl3,
1
1
CHCl3). H NMR (CDCl3, 300 MHz): δ −0.17 (3 H, s), 0.06 (3 H,
300 MHz): δ −0.01 (3 H, s), 0.07 (3 H, s), 0.91 (9 H, s), 2.31 (3 H,
s), 3.83 (3 H, s), 3.83 (3 H, s), 4.85 (2 H, s), 5.03 (1 H, dt, J = 10.3,
1.3 Hz), 5.16−5.36 (2 H, m), 5.95 (1 H, ddd, J = 17.3, 10.3, 5.0 Hz),
6.92 (2 H, d, J = 8.8 Hz), 7.24 (2 H, s), 7.36 (2 H, d, J = 8.5 Hz). 13C
NMR (CDCl3, 75 MHz): δ −5.1, −5.0, 16.1, 18.3, 25.8 (3 C), 52.0,
55.3, 72.9, 75.7, 113.1, 113.8 (2 C), 122.2, 126.6, 129.5, 129.6 (2 C),
130.3, 132.6, 140.4, 141.0, 153.6, 159.5, 168.5. HRMS (ESI-TOF,
arginine): calculated for [M + Na]+ = C26H36O5SiNa, 479.2229; found,
479.2227 (Δ = −0.2 mmu).
s), 0.82 (9 H, s), 1.14 (3 H, d, J = 7.0 Hz), 2.24 (3 H, s), 2.48−2.59 (1
H, m), 3.83 (3 H, s), 3.97 (1 H, dd, J = 4.3, 3.2 Hz), 4.92−5.05 (2 H,
m), 5.10 (1 H, d, J = 10.5 Hz), 5.30 (1 H, d, J = 10.5 Hz), 5.37 (1 H, d,
J = 3.2 Hz), 5.85 (1 H, ddd, J = 17.4, 10.2, 7.7 Hz), 6.91 (2 H, m, J =
8.7 Hz), 7.10 (1 H, d, J = 7.6 Hz), 7.41 (1 H, d, J = 7.7 Hz), 7.46 (2 H,
m, J = 8.7 Hz). 13C NMR (CDCl3, 75 MHz): δ −4.8, −4.6, 16.0, 16.5,
18.1, 25.7 (3 C), 41.4, 55.3, 76.5, 76.5, 80.4, 113.8 (2 C), 115.2, 117.4,
118.6, 129.5, 130.4 (2 C), 132.2, 136.8, 139.8, 148.3, 156.1, 159.6,
168.4. HRMS (ESI-TOF, arginine): calculated for [M + H]+
=
Methyl (S)-6-(1-((tert-Butyldimethylsilyl)oxy)-2-oxoethyl)-2-
((4-methoxybenzyl)oxy)-3-methylbenzoate (48). To a solution
of alkene 47c (105 mg, 229 μmol, 1.0 equiv) in CH2Cl2 (10 mL) were
added 3 drops of a solution of Sudan III in CH2Cl2 (0.05 M), and the
mixture was cooled to −78 °C. Then a stream of O3 was blown
through the reaction flask until the mixture changed from red to
colorless (1.5 min), followed by the addition of Me2S (337 μL, 4.6
mmol, 20 equiv). The mixture was warmed to room temperature
within 1 h, stirred for an additional 3 h, and filtered through a small
pad of Celite to give crude aldehyde 48 (95.0 mg, 207 μmol, 89%) as a
colorless liquid which was used in the next reaction without further
purification. TLC: Rf = 0.18 (petroleum ether/ethyl acetate 9/1). [α]D23
= +30.4 (c 1.0, CHCl3). 1H NMR (CDCl3, 300 MHz): δ 0.01 (3 H, s),
0.11 (3 H, s), 0.92 (9 H, s), 2.31 (3 H, s), 3.83 (3 H, s), 3.83 (3 H, s),
4.80 (1 H, d, J = 10.5 Hz), 4.92 (1 H, d, J = 10.6 Hz), 5.06 (1 H, s),
6.91 (2 H, m, J = 8.7 Hz), 7.13 (1 H, d, J = 8.0 Hz), 7.28 (1 H, d, J =
8.0 Hz), 7.35 (2 H, m, J = 8.7 Hz), 9.60 (1 H, d, J = 1.0 Hz). 13C NMR
(CDCl3, 75 MHz): δ −5.1, −5.0, 16.3, 18.3, 25.7 (3 C), 52.2, 55.3,
75.9, 78.7, 113.8 (2 C), 123.7, 127.0, 129.2, 129.6 (2 C), 132.6, 132.8,
134.7, 154.9, 159.6, 167.8, 199.4. HRMS (ESI-TOF, arginine):
calculated for [M + H]+ = C25H35O6Si, 459.2202; found, 459.2203
(Δ = +0.1 mmu).
(1S,2S,3S)-2-((tert-Butyldimethylsilyl)oxy)-1-(3-((4-
methoxybenzyl)oxy)-4-methyl-2-((methylperoxy)-λ2-methyl)-
phenyl)-3-methylpent-4-en-1-ol (49). A solution of (E,S,S)-
crotylboronate 50 in dry toluene (1.0 M, 455 μL, 2.2 equiv) was
treated with powdered 4 Å molecular sieves (25 mg) and was then
cooled to −78 °C. A solution of aldehyde 48 in toluene (95 mg, 207
μmol, 1.0 equiv, dried by coevaporation of dry toluene) was then
added dropwise within 15 min. The reaction mixture was stirred at
−78 °C for 3 h and then was treated with a saturated solution of
C28H39O5Si, 483.2561; found, 483.2570 (Δ = +0.9 mmu).
(R)-2-((tert-Butyldimethylsilyl)oxy)-6-(1-((tert-
butyldimethylsilyl)oxy)allyl)-N,N-diisopropyl-3-methylbenza-
mide (55). The procedure described above for TBS protection of 46d
was carried out with alcohol 46b (500 mg, 1.23 mmol, 1.0 equiv) to
yield the bis-TBS-protected alcohol 55 (594 mg, 1.23 mmol, 93%) as a
colorless oil after flash column chromatography on silica gel
(petroleum ether/ethyl acetate 15/1). TLC: Rf = 0.33 (petroleum
ether/ethyl acetate 9/1). [α]2D3 = +58.3 (c 1.0, CHCl3). 1H NMR
(CDCl3, 300 MHz): δ −0.10 (3 H, s), 0.05 (3 H, s), 0.09 (3 H, s),
0.29 (3 H, s), 0.85 (9 H, s), 0.97 (3 H, d, J = 6.6 Hz), 1.02 (9 H, s),
1.17 (3 H, d, J = 6.6 Hz), 1.53 (3 H, d, J = 6.9 Hz), 1.61 (3 H, d, J =
6.9 Hz), 2.23 (3 H, s), 3.29−3.47 (1 H, m), 3.47−3.59 (1 H, m),
4.96−5.10 (1 H, m), 5.25−5.39 (2 H, m), 5.81−5.99 (1 H, m), 7.09 (2
H, s). 13C NMR (CDCl3, 75 MHz): δ −5.1, −5.0, −4.2, −2.2, 18.1,
18.2, 18.9, 20.4, 20.9, 21.4, 21.7, 25.9 (3 C), 26.6 (3 C), 45.9, 50.4,
70.5, 113.2, 121.4, 127.4, 128.7, 130.8, 139.8, 141.3, 148.9, 167.5.
HRMS (ESI-TOF, arginine): calculated for [M + H]+
C29H54O3NSi2, 520.3642; found, 520.3638 (Δ = −0.4 mmu).
=
2-((tert-Butyldimethylsilyl)oxy)-6-((1S,2S,3S)-1-((tert-
butyldimethylsilyl)oxy)-2-hydroxy-3-methylpent-4-en-1-yl)-
N,N-diisopropyl-3-methylbenzamide (57). The procedure de-
scribed above for ozonolysis of 47c was carried out with alkene 55
(500 mg, 0.96 mmol, 1.0 equiv) to yield the corresponding aldehyde
55a as a colorless liquid, which was immediately used in the following
crotylboration without further purification.
For crotylboration of 55a, the aldehyde was dissolved in CH2Cl2 (5
mL) and water (5 mL) and treated with potassium (2-butenyl)-
trifluoroborate 52 (311 mg, 1.92 mmol, 2.0 equiv) and TBAI (35.4
mg, 96 μmol, 0.1 equiv). The reaction mixture was then stirred
P
DOI: 10.1021/acs.joc.5b02781
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The Journal of Organic Chemistry
Article
vigorously at room temperature for 1 h and finally diluted with CH2Cl2
(15 mL). The layers were separated, and the aqueous layer was
extracted with CH2Cl2 (3 × 20 mL). The combined organic extracts
were dried over MgSO4, filtered, and concentrated in vacuo. The
residue was purified by flash column chromatography on silica gel
(petroleum ether/ethyl acetate 9/1 to 5/1) to yield 84% of 57 (465
mg, 0.80 mmol) over two steps as a colorless oil. TLC: Rf = 0.33
(petroleum ether/ethyl acetate 9/1). [α]2D3 = +39.6 (c 1.0, CHCl3). 1H
NMR (CDCl3, 300 MHz): δ −0.27 (3 H, s), 0.01 (3 H, s), 0.13 (3 H,
s), 0.28 (3 H, s), 0.87 (9 H, s), 0.98 (3 H, d, J = 6.6 Hz), 1.02 (9 H, s),
1.08 (3 H, d, J = 6.9 Hz), 1.19 (3 H, d, J = 6.8 Hz), 1.56 (3 H, d, J =
6.9 Hz), 1.61 (3 H, d, J = 6.9 Hz), 2.23 (3 H, s), 2.41 (1 H, q, J = 7.0
Hz), 2.48 (1 H, d, J = 9.3 Hz), 3.24 (1 H, dd, J = 9.1, 6.3 Hz), 3.44 (1
H, spt, J = 6.7 Hz), 3.52 (1 H, spt, J = 6.9 Hz), 5.01 (1 H, s), 5.02−
5.13 (2 H, m), 5.84−6.03 (1 H, m), 7.10 (1 H, d, J = 8.0 Hz), 7.27 (1
H, d, J = 8.0 Hz). 13C NMR (CDCl3, 75 MHz): δ −5.0, −4.9, −4.3,
−2.2, 17.2, 18.0, 18.1, 18.9, 20.9, 21.0, 21.0, 21.6, 26.0 (3 C), 26.6 (3
C), 43.1, 46.0, 50.5, 69.7, 77.6, 114.9, 122.3, 128.0, 128.3, 130.6, 138.9,
140.4, 148.9, 167.6. HRMS (ESI-TOF, arginine): calculated for [M +
H]+ = C32H60O4NSi2, 578.4061; found, 578.4046 (Δ = +1.5 mmu).
(3S,4S)-3-((S)-But-3-en-2-yl)-4-((tert-butyldimethylsilyl)oxy)-
8-hydroxy-7-methylisochroman-1-one (syn,anti-42). To a sol-
ution of the bis-TBS-protected alcohol 78 (90 mg, 155 μmol, 1.0
equiv) in THF (5 mL) was added TBAF (1 M in THF, 171 μL, 171
μmol, 1.1 equiv) at 0 °C. The mixture was then stirred at this
temperature for 3 h before water (10 mL) was added. The phases were
separated, and the aqueous phase was extracted with 3 × 15 mL of
EtOAc, dried over MgSO4, and concentrated in vacuo. Purification by
flash column chromatography on silica gel (petroleum ether/ethyl
acetate 12/1 to 5/1) afforded the corresponding phenol 41 (68 mg,
147 μmol) in 94% yield as a colorless oil.
15.1 mL, 83.2 mmol, 2.0 equiv) were added successively. The mixture
was stirred vigorously for 30 min before a solution of allylic alcohol
81a (8.66 g, 41.6 mmol, 1.0 equiv) in CH2Cl2 (80 mL) was added
dropwise. The reaction mixture was then stirred at −20 °C for 32 h
before it was quenched by addition of an aqueous solution of FeSO4
and citric acid. After the mixture was stirred for 15 min, an aqueous
solution of NaOH (1 M, 15 mL) was added and stirring was continued
at 0 °C for 1 h before the phases were separated and extracted with
CH2Cl2 (3 × 30 mL). The combined organic phases were dried over
MgSO4, the solvent was removed in vacuo, and the crude product was
purified by flash column chromatography on silica gel (petroleum
ether/ethyl acetate 9/1) to afford epoxy alcohol 81b as a colorless oil
(7.56 g, 33.7 mmol, 81%).
The obtained epoxide 81c was resolved (2.0 g, 8.92 mmol, 1.0
equiv) in CH2Cl2 (100 mL) and cooled to 0 °C, and Dess−Martin
periodinane (7.57 g, 17.8 mmol, 2.0 equiv) was added in three
portions over a period of 10 min. The white slurry was stirred at this
temperature for 4 h. Silica gel was added, and the solvent was
evaporated. Flash column chromatography on silica gel (petroleum
ether/ethyl acetate 15/1 to 9/1) afforded 71% of aldehyde 17a (1.41
g, 6.34 mmol) as a colorless liquid. [α]2D3 = +22.3 (c 1.0, CHCl3). TLC:
Rf = 0.23 (petroleum ether/ethyl acetate 15/1). 1H NMR (CDCl3, 300
MHz): 3.33 (1 H, dd, J = 6.3, 1.9 Hz), 3.43−3.48 (1 H, m), 3.50−3.60
(1 H, m), 3.76−3.85 (1 H, m), 3.82 (3 H, s), 4.47−4.58 (2 H, m),
6.80−6.95 (2 H, m), 7.21−7.36 (2 H, m), 9.05 (1 H, d, J = 6.1 Hz).
13C NMR (CDCl3, 75 MHz): δ 55.2, 55.3, 56.3, 68.0, 73.2, 113.9 (2
C), 129.4, 129.5, 141.5, 159.4, 197.5. HRMS (EI-TOF): calculated for
[M]+ = C12H14O4, 222.0892; found, 222.0903 (Δ = +1.1 mmu).
(2R,3S)-3-(((tert-Butyldimethylsilyl)oxy)methyl)oxirane-2-
carbaldehyde (17b). (E)-But-2-en-1,4-diole (3.50 g, 39.7 mmol, 1.0
equiv) was dissolved in DMF (15 mL), and imidazole (2.65 g, 38.9
mmol, 0.98 equiv) was added at 0 °C, followed by the addition of
TBSCl (6.00 g, 39.7 mmol, 1.0 equiv). The resulting mixture was
stirred at this temperature for 4 h before it was warmed to room
temperature, and stirring was continued for an additional 14 h. The
reaction mixture was then treated with water (30 mL) and extracted
with 3 × 30 mL of CH2Cl2. The combined organic layers were dried
over MgSO4 and concentrated in vacuo. Flash column chromatog-
raphy on silica gel (petroleum ether/ethyl acetate 30/1) afforded 74%
of mono-TBS-protected 81d (5.96 g, 29.45 mmol) as a colorless oil.
The procedure described above for asymmetric epoxidation of 81a
was carried out with allyl alcohol 81d (5.00 g, 24.7 mmol, 1.0 equiv) to
yield the corresponding epoxide 81e (3.98 g, 18.23 mmol, 74%) after
flash column chromatography on silica gel (petroleum ether/ethyl
acetate 15/1).
To a solution of this phenol 41 and solid Na2HPO4 (30.3 mg, 213
μmol, 1.5 equiv) in MeCN (2 mL) was added Me3OBF4 (63.2 mg,
356 μmol, 3.0 equiv). The mixture was then stirred for 5 h at room
temperature until complete consumption of the starting material and
treated with a saturated solution of NaHCO3 (2 mL). The resulting
mixture was stirred for 14 h at room temperature and then extracted
with 3 × 10 mL of EtOAc. The combined organic layers were dried
over MgSO4 and concentrated under reduced pressure. After
purification by flash column chromatography on silica gel (petroleum
ether/ethyl acetate 30/1 to 15/1) isochromanone syn,anti-42 (19.6
mg, 54.1 μmol) was obtained in 39% yield as a colorless oil. TLC: Rf =
0.33 (petroleum ether/ethyl acetate 15/1). [α]2D3 = +14.3 (c 1.0,
1
CHCl3). H NMR (CDCl3, 300 MHz): δ −0.21 (3 H, s), 0.03 (3 H,
s), 0.80 (9 H, s), 1.14 (3 H, d, J = 7.2 Hz), 2.29 (3 H, s), 2.47−2.64 (1
H, m), 3.90 (1 H, t, J = 3.9 Hz), 5.00−5.12 (2 H, m), 5.42 (1 H, d, J =
3.6 Hz), 5.80−5.93 (1 H, m), 6.87 (1 H, d, J = 7.7 Hz), 7.36 (1 H, d, J
= 8.0 Hz), 7.90 (1 H, s). 13C NMR (CDCl3, 75 MHz): δ −4.9, −4.7,
14.5, 15.7, 25.7 (3 C), 30.4, 41.5, 76.6, 82.6, 113.7, 115.6, 125.1, 127.6,
136.3, 139.5, 145.7, 160.3, 169.4. HRMS (ESI-TOF, arginine):
calculated for [M + H]+ = C20H31O4Si, 363.1991; found, 363.1992
(Δ = +0.1 mmu).
Epoxy alcohol 81e (1.50 g, 6.87 mmol, 1.0 equiv) was then oxidized
with Dess−Martin periodinane in the same way described above for
compound 81c to yield aldehyde 17b (1.12 g, 5.18 mmol, 75%) after
flash column chromatography on silica gel (petroleum ether/ethyl
acetate 30/1) as a colorless liquid. TLC: Rf = 0.28 (petroleum ether/
ethyl acetate 30/1). [α]D23 = +28.8 (c 1.0, CHCl3). H NMR (CDCl3,
1
300 MHz): δ 0.06 (3 H, s), 0.08 (3 H, s), 0.89 (9 H, s), 3.32−3.42 (2
H, m), 3.78 (1 H, dd, J = 12.2, 3.8 Hz), 3.99 (1 H, dd, J = 12.4, 2.2
Hz), 9.07 (1 H, d, J = 6.1 Hz). 13C NMR (CDCl3, 75 MHz): δ −5.5,
−5.5, 18.2, 25.7 (3 C), 56.1, 56.6, 61.3, 198.0. HRMS (EI-TOF):
calculated for [M]+ = C10H20O3Si, 216.1181; found, 216.1199 (Δ =
+1.8 mmu).
(E)-4-((tert-Butyldimethylsilyl)oxy)but-2-enal (58). A solution
of SO3·Py (3.15 g, 19.7 mmol, 2.0 equiv) in DMSO (10 mL) was
added to a solution of alcohol 81d (2.00 g, 9.88 mmol, 1.0 equiv) and
Et3N (4.1 mL, 29.6 mmol, 3.0 equiv) in CH2Cl2 (10 mL) at 0 °C.
After it was stirred at 0 °C for 4 h, the reaction mixture was added to a
mixture of brine (50 mL) at 0 °C and the aqueous layer was extracted
with DCM (3 × 30 mL). The combined organic layers were washed
with brine (20 mL), dried over MgSO4, and concentrated in vacuo.
Purification of the residue by flash column chromatography on silica
gel (petroleum ether/ethyl acetate 60/1) gave 58 (1.65 g, 8.24 mmol)
in 83% yield. TLC: Rf = 0.29 (petroleum ether/ethyl acetate 60/1). 1H
NMR (CDCl3, 300 MHz): δ 0.10 (6 H, s), 0.93 (9 H, s), 4.46 (2 H,
dd, J = 3.3, 2.2 Hz), 6.41 (1 H, ddt, J = 15.4, 8.0, 2.2, 2.2 Hz), 6.89 (1
(2R,3S)-3-(((4-Methoxybenzyl)oxy)methyl)oxirane-2-carbal-
dehyde (17a). To an ice-cooled suspension of NaH (60% dispersion
in mineral oil, 1.40 g, 35 mmol, 0.55 equiv) in DMF (25 mL) was
added dropwise a solution of (E)-but-2-en-1,4-diole 81 (5.60 g, 63.6
mmol, 1.0 equiv) in DMF (5 mL), and the resultant mixture was
stirred for 40 min. PMBCl (5.78 mL, 41.3 mmol, 0.65 equiv) was
added, and the mixture was stirred at 0 °C for 20 min before it was
warmed to room temperature. After the mixture was stirred at this
temperature for 14 h, EtOAc (100 mL) and H2O (100 mL) were
added, the mixture was extracted with 3 × 50 mL of EtOAc, and the
organic layers were dried over MgSO4, filtered, and concentrated
under reduced pressure. Flash column chromatography (petroleum
ether/ethyl acetate 15/1 to 9/1) furnished mono-PMB-protected 81a
(8.66 g, 41.6 mmol, 65%) as a colorless liquid.
To a flask containing freshly activated MS (4 Å) and CH2Cl2 (80
mL) was added L-(+)-diisopropyl tartrate (0.71 mL, 4.16 mmol, 0.1
equiv), and the mixture was cooled to −20 °C before Ti(O-i-Pr)4
(0.86 mL, 2.91 mmol, 0.07 equiv) and t-BuOOH (∼5.5 M in decane,
Q
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The Journal of Organic Chemistry
Article
H, dt, J = 15.4, 3.3 Hz), 9.61 (1 H, d, J = 8.0 Hz). 13C NMR (CDCl3,
75 MHz): δ −5.5 (2 C), 18.3, 25.8 (2 C), 62.2, 130.6, 156.5, 193.4.
HRMS (EI-TOF): calculated for [M]+ = C10H20O2Si, 200.1232;
found, 200.1254 (Δ = +2.2 mmu).
2-(Allyloxy)-6-((S)-((tert-butyldimethylsilyl)oxy)((2R,3S)-3-
(((4-methoxybenzyl)oxy)methyl)oxiran-2-yl)methyl)-N,N-diiso-
propyl-3-methylbenzamide (60). The procedure for asymmetric
ortholithiation of 37 was carried out with epoxy aldehyd 17a (322 mg,
1.45 mmol, 3.0 equiv), sulfoxide 45d (200 mg, 0.48 mmol, 1.0 equiv),
and tert-BuLi (1.7 M in pentane, 0.57 mL, 0.97 mmol, 2.0 equiv). After
flash column chromatography on silica gel (petroleum ether/ethyl
acetate 9/1 to 5/1) the corresponding epoxy alcohol 59 (149 mg, 0.30
mmol) was obtained in 62% as a colorless oil.
TBS protection of the generated alcohol 58a (170 mg, 0.35 mmol,
1.0 equiv) was then performed as described above for compound 59 to
yield bis-TBS-protected 58b (197 mg, 0.33 mmol) in 93% yield as a
colorless oil.
To an ice-cooled solution of bis-TBS-protected 58b (89 mg, 0.15
mmol, 1.0 equiv) in THF (5 mL) was added TBAF (1 M in THF, 165
μL, 0.16 mmol, 1.1 equiv). The mixture was stirred at this temperature
for 4 h before water (10 mL) was added, and the aqueous phase was
extracted with 3 × 15 mL of EtOAc. The combined organic layers
were dried over MgSO4 and concentrated in vacuo. Purification by
flash column chromatography on silica gel (petroleum ether/ethyl
acetate 9/1 to 5/1) afforded compound 63 (60.3 mg, 0.13 mmol) in
84% yield as a colorless oil. TLC: Rf = 0.49 (petroleum ether/ethyl
acetate 9/1). [α]2D3 = +38.6 (c 1.0, CHCl3). H NMR (CDCl3, 300
1
To an ice-cooled solution of 59 (111 mg, 0.23 mmol, 1.0 equiv) in
DMF (1 mL) were added 2,6-lutidine (103 μL, 0.89 mmol, 4.0 equiv)
and TBSOTf (102 μL, 0.45 mmol, 2.0 equiv). The resulting mixture
was stirred at 0 °C for 1 h and warmed to room temperature, and
stirring was continued for an additional 3 h. Subsequently, the reaction
was worked up with saturated aqueous NaHCO3 solution (10 mL)
and extracted with 3 × 15 mL of CH2Cl2. The combined organic layers
were dried over MgSO4 and concentrated in vacuo. Flash column
chromatography on silica gel (petroleum ether/ethyl acetate 9/1)
afforded 74% of silyl ether 60 (101 mg, 0.17 mmol) as a colorless oil.
TLC: Rf = 0.31 (petroleum ether/ethyl acetate 9/1). [α]2D3 = +89.3 (c
1.0, CHCl3). 1H NMR (CDCl3, 300 MHz): δ −0.11 (3 H, s), 0.09 (3
H, s), 0.85 (9 H, s), 1.06 (3 H, d, J = 6.6 Hz), 1.19 (3 H, d, J = 6.3
Hz), 1.57 (3 H, d, J = 6.7 Hz), 1.58 (3 H, d, J = 6.7 Hz), 2.28 (3 H, s),
2.85 (1 H, dd, J = 2.9, 1.8 Hz), 3.42−3.46 (2 H, m), 3.46−3.52 (1 H,
m), 3.57−3.66 (1 H, m), 3.67−3.76 (1 H, m), 3.80 (3 H, s), 4.25 (1 H,
ddt, J = 12.3, 5.5, 1.4, 1.4 Hz), 4.41−4.49 (2 H, m), 4.50−4.56 (1 H,
m), 4.83 (1 H, d, J = 2.8 Hz), 5.18 (1 H, dq, J = 10.5, 1.4 Hz), 5.35 (1
H, dq, J = 17.3, 1.7 Hz), 6.03 (1 H, ddt, J = 17.2, 10.6, 5.5, 5.5 Hz),
6.81−6.88 (2 H, m), 7.15−7.19 (2 H, m), 7.19−7.23 (2 H, m). 13C
NMR (CDCl3, 75 MHz): δ −5.4, −4.5, 16.0, 18.0, 20.3, 20.6, 20.9,
21.0, 25.8 (3 C), 45.9, 51.0, 53.8, 55.2, 59.1, 67.9, 69.6, 72.8, 74.7,
113.7 (2 C), 116.9, 123.3, 129.3 (2 C), 130.1, 130.8, 131.0, 131.8,
133.9, 137.3, 152.5, 159.2, 167.3. HRMS (ESI-TOF, arginine):
calculated for [M + H]+ = C35H54NO6Si, 612.3720; found, 612.3706
(Δ = −1.4 mmu).
2-(Allyloxy)-6-((2R,3R)-4-((tert-butyldimethylsilyl)oxy)-3-hy-
droxy-1-oxobutan-2-yl)-N,N-diisopropyl-3-methylbenzamide
(62). The procedure for asymmetric ortho lithiation of 37 was carried
out with epoxy aldehyde 17b (1.04 g, 4.81 mmol, 2.75 equiv),
sulfoxide 45d (723 mg, 1.75 mmol, 1.0 equiv), and tert-BuLi (1.7 M in
pentane, 2.57 mL, 4.38 mmol, 2.5 equiv). After flash column
chromatography on silica gel (petroleum ether/ethyl acetate 12/1 to
5/1) aldehyde 62 (662 mg, 1.35 mmol) was obtained in 78% as a
colorless oil. TLC: Rf = 0.44 (petroleum ether/ethyl acetate 9/1).
[α]2D3 = +56.2 (c 1.0, CHCl3). 1H NMR (CDCl3, 300 MHz): δ 0.03 (3
H, s), 0.04 (3 H, s), 0.87 (9 H, s), 1.07 (3 H, d, J = 6.6 Hz), 1.17 (3 H,
d, J = 6.6 Hz), 1.55 (3 H, d, J = 6.9 Hz), 1.55 (3 H, d, J = 6.8 Hz), 2.29
(3 H, s), 2.43 (1 H, d, J = 5.8 Hz), 3.20−3.25 (1 H, m), 3.50 (1 H, spt,
J = 6.8 Hz), 3.57−3.70 (2 H, m), 3.93 (1 H, dd, J = 12.2, 2.3 Hz), 4.29
(1 H, ddt, J = 12.2, 5.5, 1.4, 1.4 Hz), 4.48 (1 H, d, J = 5.2 Hz), 4.53 (1
H, ddt, J = 12.3, 5.5, 1.4, 1.4 Hz), 5.20 (1 H, dq, J = 10.5, 1.5 Hz), 5.37
(1 H, dq, J = 17.1, 1.7 Hz), 6.04 (1 H, ddt, J = 17.1, 10.6, 5.4, 5.4 Hz),
7.18−7.23 (1 H, m), 7.28 (1 H, d, J = 8.0 Hz), 9.09 (1 H, d, J = 6.1
Hz). 13C NMR (CDCl3, 75 MHz): δ −5.4 (2 C), 16.0, 18.3, 20.3, 20.5,
20.6, 25.8 (3 C), 32.3, 45.7, 51.3, 58.8, 62.5, 70.2, 74.6, 116.8, 122.3,
131.2, 131.4, 132.2, 133.9, 135.8, 152.6, 167.4, 198.1. HRMS (ESI-
TOF, arginine): calculated for [M + H]+ = C27H46NO5Si, 492.3145;
found, 492.3129 (Δ = −1.6 mmu).
MHz): δ −0.10 (3 H, s), 0.09 (3 H, s), 0.89 (9 H, s), 1.05 (3 H, d, J =
6.6 Hz), 1.19 (3 H, d, J = 6.6 Hz), 1.57 (3 H, d, J = 6.8 Hz), 1.59 (3 H,
d, J = 6.7 Hz), 2.26 (3 H, s), 3.48 (1 H, spt, J = 6.9 Hz), 3.59 (1 H, spt,
J = 6.6 Hz), 4.06−4.19 (2 H, m), 4.19−4.29 (1 H, m), 4.53 (1 H, ddt,
J = 12.3, 5.6, 1.4, 1.4 Hz), 5.18 (1 H, dd, J = 10.6, 1.5 Hz), 5.28 (1 H,
s), 5.35 (1 H, dq, J = 17.1, 1.7 Hz), 5.72−5.94 (2 H, m), 6.03 (1 H,
ddt, J = 17.2, 10.7, 5.5, 5.5 Hz), 7.15 (1 H, d, J = 7.8 Hz), 7.19 (1 H, d,
J = 7.9 Hz). 13C NMR (CDCl3, 75 MHz): δ −5.2, −4.8, 16.0, 18.2,
20.3, 20.6, 20.8, 21.1, 25.9 (3 C), 45.8, 50.8, 63.1, 69.9, 74.7, 116.8,
123.5, 128.1, 130.0, 130.9, 130.9, 134.0, 134.6, 139.5, 152.4, 167.4.
HRMS (ESI-TOF, arginine): calculated for [M + H]+ = C27H46NO4Si,
476.3196; found, 476.3194 (Δ = −0.2 mmu).
2-(Allyloxy)-6-((1S,2R,3R)-2-((tert-butyldimethylsilyl)oxy)-1-
hydroxy-3-methylpent-4-en-1-yl)-N,N-diisopropyl-3-methyl-
benzamide (66). The procedure described for the asymmetric
ortholithiation of 37 was carried out with aldehyde 35 (440 mg, 1.93
mmol, 1.0 equiv), sulfoxide 45d (1.57 g, 3.85 mmol, 2.0 equiv), and
tert-BuLi (1.7 M in pentane, 2.83 mL, 1.93 mmol, 2.5 equiv), yielding
after flash column chromatography on silica gel (petroleum ether/
ethyl acetate 9/1) 61% of the alcohol 66 (591 mg, 1.17 mmol) as a
colorless liquid. TLC: Rf = 0.26 (petroleum ether/ethyl acetate 9/1).
[α]2D3 = +63.2 (c 0.5, CHCl3). H NMR (CDCl3, 300 MHz): δ −0.46
1
(3 H, s), 0.10 (3 H, s), 0.77 (9 H, s), 1.06 (3 H, d, J = 6.6 Hz), 1.17 (3
H, d, J = 7.2 Hz), 1.22 (3 H, d, J = 6.6 Hz), 1.55 (3 H, d, J = 6.8 Hz),
1.56 (3 H, d, J = 6.9 Hz), 2.27 (3 H, s), 2.51 (1 H, br s), 2.72−2.85 (1
H, m), 3.51 (1 H, spt, J = 6.8 Hz), 3.75 (1 H, spt, J = 6.7 Hz), 4.21 (1
H, dd, J = 8.9, 2.1 Hz), 4.27 (1 H, dt, J = 5.4, 1.5 Hz), 4.43 (1 H, d, J =
9.1 Hz), 4.40−4.51 (1 H, m), 4.99−5.07 (1 H, m), 5.07−5.16 (1 H,
m), 5.20 (1 H, dq, J = 10.5, 1.4 Hz), 5.37 (1 H, dq, J = 17.2, 1.7 Hz),
5.95−6.12 (2 H, m), 7.14 (2 H, br s). 13C NMR (CDCl3, 75 MHz): δ
−4.5, −4.4, 15.9, 16.1, 18.5, 20.2, 20.3, 20.4, 20.8, 26.2 (3 C), 41.5,
45.8, 51.5, 72.7, 74.4, 76.6, 114.7, 116.9, 123.7, 130.5, 130.7, 133.4,
134.0, 138.4, 140.8, 152.6, 168.9. HRMS (ESI-TOF, arginine):
calculated for [M + H]+ = C29H50O4SiN, 504.3509; found, 504.3501
(Δ = −0.8 mmu).
2-(Allyloxy)-6-((1S,2R,3R)-1,2-dihydroxy-3-methylpent-4-en-
1-yl)-N,N-diisopropyl-3-methylbenzamide (67). To a solution of
TBS-protected alcohol 66 (250.0 mg, 496 μmol, 1.0 equiv) in DMF (3
mL) and H2O (89 μL, 4.96 mmol, 10 equiv) was added
tris(dimethylamino)sulfoniumdifluorotrimethyl silicate (TAS-F, 1.5
M in DMF, 1.65 mL, 2.48 mmol, 5.0 equiv). After it was stirred
overnight (14 h), the reaction mixture was then diluted with Et2O (5
mL) and washed with pH 7 buffer (3 × 5 mL). The aqueous layer was
extracted with 3 × 15 mL of Et2O, and the combined organic layers
were washed again with pH 7 buffer (5 mL), dried over MgSO4,
filtered, and concentrated in vacuo to afford 93% of 67 (179 mg, 459
μmol). TLC: Rf = 0.17 (petroleum ether/ethyl acetate 3/1). [α]D23
=
+16.7 (c 1.0, CHCl3). 1H NMR (CDCl3, 300 MHz): δ 1.04 (3 H, d, J
= 6.6 Hz), 1.14 (3 H, d, J = 7.2 Hz), 1.21 (3 H, d, J = 6.6 Hz), 1.55 (6
H, d, J = 6.9 Hz), 2.03 (1 H, br s), 2.28 (3 H, s), 2.73−2.92 (1 H, m),
3.43 (1 H, br s), 3.52 (1 H, spt, J = 6.9 Hz), 3.71 (1 H, spt, J = 6.6 Hz),
3.84−4.01 (1 H, m), 4.23−4.33 (1 H, m), 4.41 (1 H, d, J = 8.8 Hz),
4.44−4.55 (1 H, m), 5.06−5.18 (2 H, m), 5.18−5.25 (1 H, m), 5.32−
5.41 (1 H, m), 5.81−5.94 (1 H, m), 6.04 (1 H, ddt, J = 17.3, 10.6, 5.4
Hz), 7.21 (2 H, s). 13C NMR (CDCl3, 125 MHz): δ 16.0, 17.4, 20.1,
20.3, 20.4, 20.5, 39.0, 45.9, 51.7, 71.8, 74.5, 75.3, 116.3, 117.1, 122.5,
(R,E)-2-(Allyloxy)-6-(1-((tert-butyldimethylsilyl)oxy)-4-hy-
droxybut-2-en-1-yl)-N,N-diisopropyl-3-methylbenzamide (63).
The procedure for asymmetric ortho lithiation of 37 was carried out
with aldehyde 58 (350 mg, 1.75 mmol, 2.5 equiv), sulfoxide 45d (289
mg, 0.70 mmol, 1.0 equiv), and tert-BuLi (1.7 M in pentane, 0.82 mL,
1.40 mmol, 2.0 equiv). After flash column chromatography on silica gel
(petroleum ether/ethyl acetate 9/1 to 5/1) alcohol 58a (317 mg, 0.66
mmol) was obtained in 95% as a colorless oil.
R
DOI: 10.1021/acs.joc.5b02781
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131.1, 131.5, 133.8, 133.8, 137.6, 138.8, 152.8, 168.9. HRMS (ESI-
TOF, arginine): calculated for [M + H]+ = C23H36O4N, 390.2644;
found, 390.2661 (Δ = +1.5 mmu).
sulfoxide 45d (1.96 g, 4.73 mmol, 1.0 equiv) in dry THF (40 mL) at
−90 °C (acetone/liquid nitrogen). After 5 min the TES-protected
aldehyde 70 (2.0 g, 5.76 mmol, 1.85 equiv) in THF (5 mL) was added
dropwise within 4 min. The mixture was warmed to −78 °C and
stirred for 20 min at this temperature. Then an aqueous solution of
NH4Cl (40 mL) was added at −78 °C, and the mixture was warmed to
room temperature. Extraction with 3 × 30 mL of Et2O, drying over
MgSO4, and evaporation of the solvent gave a residue which was
purified by flash column chromatography on silica gel (petroleum
ether/ethyl acetate 15/1 to 9/1 to 5/1) to afford the ortho-lithiation
product 71 (1.69, 3.35 mmol) in 71% yield as a colorless oil. TLC: Rf
= 0.25 (petroleum ether/ethyl acetate 9/1). [α]2D3 = +61.4 (c 1.0,
CHCl3). 1H NMR (CDCl3, 300 MHz): δ 0.38−0.52 (6 H, m), 0.70−
0.86 (9 H, m), 1.06 (3 H, d, J = 6.6 Hz), 1.16 (3 H, d, J = 7.2 Hz), 1.22
(3 H, d, J = 6.6 Hz), 1.55 (3 H, d, J = 6.8 Hz), 1.56 (3 H, d, J = 6.3
Hz), 2.27 (3 H, s), 2.74−2.86 (1 H, m), 3.51 (1 H, spt, J = 6.8 Hz),
3.77 (1 H, spt, J = 6.6 Hz), 4.18 (1 H, dd, J = 9.2, 1.9 Hz), 4.22−4.31
(1 H, m), 4.40 (1 H, d, J = 9.2 Hz), 4.43−4.51 (1 H, m), 5.02 (1 H,
dd, J = 10.2, 2.1 Hz), 5.12 (1 H, dd, J = 17.4, 1.3 Hz), 5.20 (1 H, dd, J
= 10.5, 1.5 Hz), 5.37 (1 H, dd, J = 17.2, 1.7 Hz), 5.86−6.00 (1 H, m),
6.00−6.12 (1 H, m), 7.09−7.22 (2 H, m). 13C NMR (CDCl3, 125
MHz): δ 6.4 (3 C), 6.8 (3 C), 16.0, 17.4, 20.1, 20.3, 20.4, 20.5, 38.9,
46.0, 51.8, 71.7, 74.5, 75.2, 116.5, 117.1, 121.8, 122.4, 131.2, 131.6,
133.8, 137.5, 138.7, 152.8, 168.9. HRMS (ESI-TOF, arginine):
calculated for [M + H]+ = C29H50O4NSi, 504.3509; found, 504.3498
(Δ = −1.1 mmu).
2-(Allyloxy)-6-((5S,6R)-6-((R)-but-3-en-2-yl)-2,2,3,3,8,8,9,9-
octamethyl-4,7-dioxa-3,8-disiladecan-5-yl)-N,N-diisopropyl-3-
methylbenzamide (69). To a solution of alcohol 67 (170 mg, 463
μmol, 1.0 equiv) in dry CH2Cl2 (10 mL) were added 2,6-lutidine (136
μL, 1.18 mmol, 2.7 equiv) and, after cooling to −78 °C, TBSOTf (130
μL, 567 μmol, 1.3 equiv). The resulting mixture was stirred for 1.5 h at
−78 °C, for 1 h at −20 °C, and for 1 h at 0 °C before water (10 mL)
was added followed by extraction with 3 × 20 mL of CH2Cl2. The
combined organic layers were dried over MgSO4, filtered, and
concentrated in vacuo. Flash column chromatography on silica gel
(petroleum ether/ethyl acetate 15/1 to 9/1) afforded 53% of bis-silyl-
protected alcohol 69 (143 mg, 231 μmol) and 10% of the mono-silyl-
protected alcohol 68 (21.4 mg, 42.5 μmol) as a byproduct. TLC: Rf =
0.61 (petroleum ether/ethyl acetate 15/1). [α]2D3 = +16.7 (c 1.0,
1
CHCl3). H NMR (CDCl3, 300 MHz): δ −0.37 (3 H, s), 0.03 (3 H,
s), 0.10 (3 H, s), 0.11 (3 H, s), 0.81 (9 H, s), 0.84 (9 H, s), 1.09−1.19
(9 H, m), 1.56 (6 H, d, J = 6.7 Hz), 2.27 (3 H, s), 2.81 (1 H, quin, J =
7.5 Hz), 3.43−3.56 (1 H, m), 3.74−3.85 (2 H, m), 4.13−4.23 (1 H,
m), 4.49−4.58 (2 H, m), 4.97−5.07 (2 H, m), 5.17 (1 H, dd, J = 10.5,
1.7 Hz), 5.35 (1 H, dq, J = 17.2, 1.7 Hz), 5.89−6.13 (2 H, m), 7.06−
7.25 (2 H, m). 13C NMR (CDCl3, 75 MHz): δ −5.4, −5.1, −2.9, −2.2,
16.0, 18.0, 19.2, 20.3, 20.6, 20.6, 21.0, 21.6, 25.7 (3 C), 26.0 (3 C),
27.1, 45.7, 50.6, 74.5, 74.6, 77.2, 116.3, 116.6, 130.1, 130.4, 130.6,
134.2 (2 C), 138.7, 143.1, 152.9, 167.3. HRMS (ESI-TOF, arginine):
calculated for [M + H]+ = C35H64O4NSi2, 618.4373; found, 618.4363
(Δ = −1.0 mmu).
2-(Allyloxy)-6-((5S,6R)-6-((R)-but-3-en-2-yl)-8,8-diethyl-
2,2,3,3-tetramethyl-4,7-dioxa-3,8-disiladecan-5-yl)-N,N-diiso-
propyl-3-methylbenzamide (71a). The procedure described above
for the TBS protection of 69 was carried out with alcohol 71 (950 mg,
1.89 mmol, 1.0 equiv) and yielded after flash column chromatography
on silica gel (petroleum ether/ethyl acetate 50/1 to 15/1) 74% of the
TBS-protected aldehyde 71a (863 mg, 1.39 mmol) as a colorless oil.
TLC: Rf = 0.27 (petroleum ether/ethyl acetate 30/1). [α]2D3 = +13.0 (c
1.0, CHCl3). 1H NMR (CDCl3, 300 MHz): δ −0.36 (3 H, s), 0.11 (3
H, s), 0.22−0.48 (6 H, m), 0.75 (9 H, t, J = 7.9 Hz), 0.83 (9 H, s), 1.12
(3 H, d, J = 6.8 Hz), 1.14 (3 H, d, J = 7.1 Hz), 1.15 (3 H, d, J = 7.3
Hz), 1.55 (3 H, d, J = 6.8 Hz), 1.56 (3 H, d, J = 7.0 Hz), 2.26 (3 H, s),
2.80 (1 H, quin, J = 7.6 Hz), 3.49 (1 H, spt, J = 6.8 Hz), 3.79 (1 H, dd,
J = 8.9, 1.3 Hz), 3.80 (1 H, spt, J = 6.6 Hz), 4.18 (1 H, ddt, J = 12.4,
5.5, 1.5 Hz), 4.40 (1 H, d, J = 8.8 Hz), 4.55 (1 H, ddt, J = 12.4, 5.4, 1.4
Hz), 4.98−5.09 (2 H, m), 5.17 (1 H, dd, J = 10.5, 1.7 Hz), 5.36 (1 H,
dq, J = 17.2, 1.6 Hz), 5.87 (1 H, ddd, J = 17.3, 10.1, 9.1 Hz), 6.03 (1 H,
ddt, J = 17.2, 10.6, 5.4 Hz), 7.09 (1 H, d, J = 8.0 Hz), 7.14 (1 H, d, J =
8.0 Hz). 13C NMR (CDCl3, 75 MHz): δ −5.4, −5.1, 5.4, 6.8, 16.0,
18.0, 19.1, 19.9, 20.3, 20.5, 20.9, 25.9, 41.0, 45.7, 50.7, 71.3, 74.6, 81.0,
115.3, 116.5, 123.6, 129.9, 130.3, 133.7, 134.2, 138.8, 140.3, 152.7,
(2R,3R)-Ethyl 3-Methyl-2-((triethylsilyl)oxy)pent-4-enoate
(anti-33b). To an ice-cooled solution of the ester 33a (4.6 g, 29.1
mmol, 1.0 equiv) in dry CH2Cl2 (100 mL) were added 2,6-lutidine
(8.45 mL, 72.9 mmol, 2.5 equiv) and TESOTf (8.22 mL, 36.4 mmol,
1.25 equiv). The resulting mixture was stirred at room temperature for
3 h until TLC control indicated complete consumption of the starting
material. The reaction mixture was quenched with water (80 mL) and
extracted with 3 × 50 mL of CH2Cl2. The combined organic layers
were dried over MgSO4 and concentrated in vacuo. Flash column
chromatography on silica gel (petroleum ether/ethyl acetate 50/1 to
30/1) afforded 99% of silyl ether anti-33b (7.85 g, 28.8 mmol) as a
colorless liquid. TLC: Rf = 0.60 (petroleum ether/ethyl acetate 30/1).
[α]2D3 = +10.0 (c 1.0, CHCl3). 1H NMR (CDCl3, 300 MHz): δ 0.63 (6
H, m), 0.96 (9 H, t, J = 7.8 Hz), 1.06 (3 H, d, J = 7.0 Hz), 1.27 (3 H, t,
J = 7.2 Hz), 2.52−2.68 (1 H, m), 4.08 (1 H, d, J = 4.9 Hz), 4.17 (2 H,
qd, J = 7.0 Hz, 2.4 Hz), 4.95−5.08 (2 H, m), 5.73−5.93 (1 H, m). 13C
NMR (CDCl3, 75 MHz) δ 4.6 (3 C), 6.7 (3 C), 14.3, 16.4, 42.7, 60.5,
76.1, 115.3, 139.0, 172.8. HRMS (ESI-TOF, arginine): calculated for
[M + H]+ = C14H29O3Si, 273.1881; found, 273.1880 (Δ = −0.1 mmu).
(2R,3R)-3-Methyl-2-((triethylsilyl)oxy)pent-4-enal (70). The
procedure described below for DIBAl-H reduction of 34a was carried
out with 33b (1.70 g, 5.93 mmol, 1.0 equiv) and gave alcohol 33c
(1.43 g, 5.91 mmol) in nearly quantitative yield as a colorless liquid.
TLC: Rf = 0.41 (petroleum ether/ethyl acetate 9/1).
169.2. HRMS (ESI-TOF, arginine): calculated for [M + H]+
=
C35H64O4NSi2, 618.4368; found, 618.4374 (Δ = +0.6 mmu).
6-((1S,2R,3R)-1-((tert-Butyldimethylsilyl)oxy)-2-hydroxy-3-
methylpent-4-en-1-yl)-2-hydroxy-N,N-diisopropyl-3-methyl-
benzamide (41). Allyl ether 71a (450 mg, 0.72 mmol, 1.0 equiv) was
dissolved in dry MeOH (30 mL), followed by the addition of
[Pd(Ph3)4] (8.40 mg, 7.28 μmol, 1 mol %). After the mixture was
stirred for 10 min at room temperature, K2CO3 (302 mg, 2.18 mmol,
3.0 equiv) was added to the resulting yellow solution and stirring was
continued for 4 h until TLC control indicated complete consumption
of the starting material. Then the solvent was evaporated under
reduced pressure and the resulting slurry was resolved in water (50
mL), acidified with a solution of HCl (1 N) to pH 6, and extracted
with 3 × 20 mL of CH2Cl2. The combined organic layers were dried
over MgSO4 and concentrated in vacuo to afford phenol 71b (420 mg,
0.72 mmol) in quantitative yield as a pale yellow solid.
The procedure described above for the Swern oxidation of 35 was
carried out with alcohol 33c (1.17 g, 5.08 mmol, 1.0 equiv) and
yielded after flash column chromatography on silica gel (petroleum
ether/ethyl acetate 40/1 to 9/1) 82% of the TES-protected aldehyde
70 (948 mg, 4.15 mmol) as a colorless liquid. TLC: Rf = 0.46
(petroleum ether/ethyl acetate 30/1). [α]2D3 = +27.0 (c 1.0, CHCl3).
1H NMR (CDCl3, 300 MHz): δ 0.63 (6 H, q, J = 7.9 Hz), 0.97 (9 H, t,
J = 7.9 Hz), 1.10 (3 H, d, J = 6.9 Hz), 2.50−2.72 (1 H, m), 3.86 (1 H,
dd, J = 4.5, 2.2 Hz), 4.91−5.27 (2 H, m), 5.65−6.00 (1 H, m), 9.57 (1
H, d, J = 2.2 Hz). 13C NMR (CDCl3, 75 MHz): δ 4.8 (3 C), 6.7 (3 C),
16.0, 41.7, 80.9, 115.9, 138.3, 204.4. HRMS (ESI-TOF, arginine):
calculated for [M + Na]+ = C12H24O2SiNa, 251.1443; found, 251.1440
(Δ = −0.3 mmu).
TBS-TES-protected diol 71b (335 mg, 579 μmol, 1.0 equiv) was
dissolved in dry MeOH (20 mL) and treated with Pd on activated
charcoal (10% Pd, 123 mg, 115 μmol, 0.2 equiv). After 4 h TLC
indicated the cleavage of the TES group and the solvent was
evaporated under reduced pressure. The resulting residue was
dissolved in Et2O and filtered over a plug of Celite to afford in 99%
yield the TBS-protected alcohol 41 (266 mg, 573 μmol) as a colorless
2-(Allyloxy)-6-((1S,2R,3R)-1-hydroxy-3-methyl-2-
((triethylsilyl)oxy)pent-4-en-1-yl)-N,N-diisopropyl-3-methyl-
t
benzamide (71). A solution of BuLi (1.7 M in pentane, 3.90 mL,
6.63 mmol, 1.4 equiv) was added dropwise to a stirred solution of
S
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liquid, which was used in the microwave assisted amide cleavage
Hz, 1.4 Hz), 5.22−5.32 (2 H, m), 5.35−5.46 (2 H, m), 5.91−6.24 (2
H, m), 7.06 (1 H, dd, J = 7.6 Hz), 7.35 (1 H, d, J = 7.0 Hz), 7.67 (1 H,
d, J = 7.6 Hz). 13C NMR (CDCl3, 150 MHz): δ 16.3, 65.7, 75.0, 117.5,
118.5, 123.6, 125.0, 129.1, 132.2, 133.0, 133.9, 135.1, 157.1, 166.1.
HRMS (EI-TOF): calculated for [M]+ = C14H16O3, 232.1099; found,
232.1122 (Δ = +2.3 mmu).
without further purification. TLC: Rf = 0.12 (petroleum ether/ethyl
acetate 9/1). [α]2D3 = +17.0 (c 1.0, CHCl3). H NMR (CDCl3, 300
1
MHz): δ −0.34 (3 H, s), 0.02 (3 H, s), 0.92 (9 H, s), 1.07 (3 H, d, J =
6.0 Hz), 1.13 (3 H, d, J = 6.9 Hz), 1.28 (3 H, d, J = 6.3 Hz), 1.54 (3 H,
d, J = 6.9 Hz), 1.56 (1 H, br s), 1.57 (3 H, d, J = 6.9 Hz), 2.08 (3 H, s),
2.65 (1 H, quin, J = 7.3 Hz), 3.21 (1 H, d, J = 7.7 Hz), 3.52 (1 H, spt, J
= 6.5 Hz), 3.76 (1 H, spt, J = 6.5 Hz), 4.41 (1 H, d, J = 8.5 Hz), 5.00−
5.09 (2 H, m), 5.88−6.07 (1 H, m), 6.44 (1 H, br s), 7.03 (d, J = 8.00
Hz, 1 H), 7.06 (d, J = 7.90 Hz, 1 H). 13C NMR (CDCl3, 75 MHz): δ
−4.9, −3.7, 16.0, 17.9, 19.0, 20.4, 20.7, 21.1, 21.9, 25.7 (3 C), 40.7,
46.7, 51.0, 72.2, 80.8, 115.2, 118.7, 123.9, 131.2, 131.9, 139.9, 140.3,
149.3, 168.7. HRMS (ESI-TOF, arginine): calculated for [M + H]+ =
C26H46O4NSi, 464.3191; found, 464.3188 (Δ = −0.3 mmu).
2-(Allyloxy)-3-methylbenzoic Acid (73). To ester 29c (18.0 g,
77.5 mmol, 1.0 equiv) was added methanol (300 mL) followed by
aqueous sodium hydroxide (6 M, 78 mL, 465 mmol, 6.0 equiv), and
the mixture was heated under reflux for 4 h. The solvent was then
removed under reduced pressure to leave a dense white residue. This
was dissolved in water (150 mL), and the solution was acidified to pH
3 with aqueous sulfuric acid (2 N) and extracted with 3 × 100 mL of
Et2O. The combined organic extracts were washed with water (100
mL), dried with MgSO4, and concentrated under reduced pressure to
provide the product 73 as a white solid in quantitative yield (14.9 g,
(3R,4S)-3-((R)-but-3-en-2-yl)-4-((tert-butyldimethylsilyl)oxy)-
8-hydroxy-7-methylisochroman-1-one (anti,anti-42). Com-
pound 71b (439 mg, 759 μmol, 1.0 equiv) was dissolved in dry
toluene (6 mL) and placed in a septum-sealed microwave vessel, and
acetic acid (99.9%, 0.97 mL, 30 equiv) was added. The resulting
mixture was heated to 150 °C in a microwave reactor (ca. 60 W
continuous power) for 3.5 h. Then the solvent was removed under
reduced pressure and the residue was purified by flash column
chromatography on silica gel (petroleum ether/ethyl acetate 30/1) to
yield 86% of the TBS-protected hydroxyisochromanone anti,anti-42
(237 mg, 654 μmol) as a colorless oil. TLC: Rf = 0.33 (petroleum
1
77.5 mmol). TLC: Rf = 0.42 (petroleum ether/ethyl acetate 9/1). H
NMR (CDCl3, 300 MHz): δ 2.39 (3 H, s), 4.53 (2 H, dt, J = 5.9 Hz,
1.2 Hz), 5.39 (1 H, dd, J = 10.6 Hz, 1.1 Hz), 5.48 (1 H, dq, J = 17.2,
1.3 Hz), 6.15 (1 H, ddt, J = 16.9 Hz, 10.6 Hz, 6.0 Hz), 7.19 (1 H, dd, J
= 7.7 Hz), 7.46 (1 H, m), 7.96 (1 H, d, J = 7.8 Hz), 10.71 (1 H, br s).
13C NMR (CDCl3, 75 MHz): δ 16.1, 75.8, 120.0, 122.7, 124.8, 130.5,
131.9, 131.9, 136.8, 156.4, 167.1. HRMS (EI-TOF): calculated for
[M]+ = C11H12O3, 192.0786; found, 192.0795 (Δ = +0.8 mmu). Mp:
52−54 °C.
1
ether/ethyl acetate 30/1). [α]2D3 = +69.1 (c 1.0, CHCl3). H NMR
Isopropylpropan-3-olamine (74a). To a solution of 3-amino-1-
propanol (9.90 mL, 133 mmol, 1.0 equiv) in ethanol (250 mL) was
added acetone (14.9 mL, 200 mmol, 1.5 equiv). The reaction mixture
was stirred overnight at room temperature and cooled to 0 °C. Sodium
borohydride (7.60 g, 200 mmol, 1.5 equiv) was added slowly under a
gentle flow of argon, with the temperature of the mixture kept at 4 °C.
The reaction mixture was stirred at 5 °C for an additional 2 h before
the mixture was quenched with cold H2O (50 mL), diluted with DCM
(25 mL), and filtered. The solvents were removed in vacuo, and the
aqueous residue was extracted with EtO2 (3 × 60 mL). The combined
organic layers were dried over MgSO4 and filtered. After evaporation
of the solvents the product was obtained as a colorless liquid (9.80 g,
83.8 mmol, 63%). The crude product 74a was used without further
(CDCl3, 600 MHz): δ 0.00 (3 H, s), 0.14 (3 H, s), 0.87 (9 H, s), 1.08
(3 H, d, J = 6.9 Hz), 2.28 (3 H, s), 2.41 (1 H, sxt, J = 6.8 Hz), 4.40 (1
H, dd, J = 7.2, 3.6 Hz), 4.73 (1 H, d, J = 3.6 Hz), 5.03 (1 H, d, J = 17.2
Hz), 5.08 (1 H, d, J = 10.4 Hz), 5.83 (1 H, ddd, J = 17.4, 10.2, 7.5 Hz),
6.73 (1 H, d, J = 7.5 Hz), 7.35 (1 H, d, J = 7.5 Hz), 11.28 (1 H, s). 13C
NMR (CDCl3, 151 MHz): δ −4.3, −4.2, 15.7, 17.0, 18.1, 25.7 (3 C),
39.1, 66.7, 88.0, 106.8, 116.5, 117.2, 127.0, 136.8, 137.4, 137.9, 160.0,
168.5 HRMS (ESI-TOF, arginine): calculated for [M + H]+
=
C20H31O4Si, 363.1986; found, 363.2000 (Δ = +1.4 mmu).
(3R,4S)-3-((R)-But-3-en-2-yl)-4,8-bis((tert-butyldimethylsilyl)-
oxy)-7-methylisochroman-1-one (72). To an ice-cooled solution
of isochromanone anti,anti-42 (150 mg, 398 μmol, 1.0 equiv) in dry
CH2Cl2 (3 mL) were added NEt3 (131 μL, 1.63 mmol, 4.0 equiv) and
TBSOTf (186 μL, 0.82 mmol, 2.0 equiv). The resulting mixture was
stirred at room temperature overnight (15 h, and then water (10 mL)
was added followed by extraction with 3 × 5 mL of CH2Cl2. The
combined organic layers were dried over MgSO4 and concentrated in
vacuo. Flash column chromatography on silica gel (petroleum ether/
ethyl acetate 60/1 to 30/1) afforded 97% of bis-silyl ether 72 (185 mg,
385 μmol) as a colorless liquid. TLC: Rf = 0.29 (petroleum ether/ethyl
1
purification. TLC: Rf = 0.14 (cyclohexane/2% H2N(i-Pr)). H NMR
(CDCl3, 400 MHz): δ 1.07 (dd, J = 6.3 Hz, 6H), 1.69 (pent, J = 5.8
Hz, 2H), 2.80 (sept, J = 6.3 Hz, 1H), 2.87 (t, J = 5.8 Hz, 2H), 3.12 (br
s, 2H), 3.80 (t, J = 5.8 Hz, 2H). 13C NMR (CDCl3, 75 MHz): δ 22.9,
31.3, 47.3, 49.1, 64.4. HRMS (ESI-TOF, arginine): calculated for [M +
H]+ = C6H16NO, 118.1232; found, 118.1226 (Δ = −0.6 mmu).
3-(t-Butyldimethylsilyloxy)propaneisopropylamine (74). To
a stirred solution of 74a (1.00 g, 8.50 mmol, 1.0 equiv) and TBSCl
(1.80 mL, 9.40 mmol, 1.1 equiv) in DCM (15 mL) was added NEt3
(3.10 mL, 22.1 mmol, 2.6 equiv). The reaction mixture was stirred for
12 h at room temperature. The resulting solution was quenched with
H2O (15 mL), and the organic phase was washed with a saturated
aqueous NaCl solution (15 mL), dried over MgSO4, and filtered. The
solvent was removed in vacuo, and the resulting oil was purified by
flash column chromatography (silica gel, cyclohexane/2% H2N(i-Pr))
yielding 74 as a colorless oil (1.30 g, 5.80 mmol, 68%). TLC: Rf = 0.62
acetate 30/1). [α]2D3 = +55.2 (c 1.0, CHCl3). H NMR (CDCl3, 300
1
MHz): δ 0.02 (3 H, s), 0.14 (3 H, s), 0.15 (3 H, s), 0.17 (3 H, s), 0.88
(9 H, s), 1.04 (9 H, s), 1.08 (3 H, d, J = 7.0 Hz), 2.27 (3 H, s), 2.34−
2.48 (1 H, m), 4.20 (1 H, dd, J = 7.1, 4.7 Hz), 4.70 (1 H, d, J = 4.8
Hz), 5.01−5.13 (2 H, m), 5.97 (1 H, ddd, J = 17.3, 10.5, 7.1 Hz), 6.87
(1 H, d, J = 7.7 Hz), 7.34 (1 H, d, J = 7.9 Hz). 13C NMR (CDCl3, 75
MHz): δ −4.2, −4.1, −3.5, −3.4, 17.1, 17.6, 18.1, 18.6, 25.7 (3 C),
26.0 (3 C), 38.2, 67.6, 86.2, 115.9, 116.1, 119.1, 131.6, 135.6, 138.5,
139.4, 154.7, 161.8. HRMS (ESI-TOF, arginine): calculated for [M +
H]+ = C26H45O4Si2, 477.2851; found, 477.2855 (Δ = +0.4 mmu).
Allyl 2-(Allyloxy)-3-methylbenzoate (29c). 3-Methylsalicylic
acid (29; 12.0 g, 78.8 mmol) was dissolved in DMF (160 mL) and
cooled to 0 °C, and NaH (60% in mineral oil, 7.57 g, 189 mmol, 2.4
equiv) was added in three portions over a period of 20 min. The
reaction mixture was stirred at this temperature for 1.5 h before allyl
bromide (18.8 mL, 236 mmol, 3.0 equiv) was added dropwise. After
complete conversion of the starting material (1.5 h), water (200 mL)
and Et2O (100 mL) were added. The organic layer was separated, and
the aqueous layer was extracted with 3 × 150 mL of Et2O. The
combined organic phases were washed with brine (2 × 100 mL) and
were dried over MgSO4, filtered, and evaporated to give a yellow liquid
of crude 29c in quantitative yield (18.3 g, 78.9 mmol). TLC: Rf = 0.62
(petroleum ether/ethyl acetate 15/1). 1H NMR (CDCl3, 300 MHz): δ
2.32 (3 H, s), 4.45 (2 H, dt, J = 5.6 Hz, 1.4 Hz), 4.81 (2 H, dt, J = 5.8
1
(cyclohexane/2% H2N(i-Pr)). H NMR (CDCl3, 300 MHz): δ 0.04
(s, 6H), 0.88 (s, 9H), 1.09 (d, J = 6.3 Hz, 6H), 1.74 (tt, J = 7.0, 6.0 Hz,
2H), 2.73 (t, J = 7.0 Hz, 2H), 2.85 (sept, J = 6.3 Hz, 1H), 3.69 (t, J =
6.0 Hz, 2 H). 13C NMR (CDCl3, 75 MHz): δ −5.2, −3.4, 11.5, 18.4,
22.6, 25.8, 26.1, 32.7, 44.8, 46.4, 49.1, 62.0. HR/MS (ESI-TOF,
arginine): calculated for [M + H]+ = C12H30NOSi, 232.2097; found,
232.2091 (Δ = −0.6 mmu).
N,N-3-(t-Butyldimethylsilyloxy)propaneisopropyl-3-methyl-
2-propanoxybenzamide (75). To a stirred solution of acid 73 (1.25
g, 6.50 mmol, 1.0 equiv), amine 74 (1.50 g, 6.50 mmol, 1.0 equiv), and
Na2CO3 (3.40 g, 32.4 mmol, 5.0 equiv) in THF (60 mL) were added
NEt3 (4.50 mL, 32.4 mmol, 5.0 equiv) and DEPBT (2.50 g, 8.36
mmol, 1.3 equiv). The reaction mixture was stirred for 12 h at room
temperature before a saturated aqueous Na2CO3 solution (50 mL) and
Et2O (50 mL) were added, forming a white suspension. The white
precipitate was solved by addition of H2O, and the organic layer was
T
DOI: 10.1021/acs.joc.5b02781
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
separated. The aqueous layer was extracted with EA (3 × 30 mL), and
the combined organic layers were dried over MgSO4. After filtration
and concentration in vacuo the product was purified by flash column
chromatography (silica gel, cyclohexane/2% H2N(i-Pr)) to afford 73a
as a pale yellow oil (1.80 g, 4.44 mmol, 68%). TLC: Rf = 0.31
(cyclohexane/ethyl acetate 5/1)
aqueous layer was extracted with Et2O (3 × 50 mL), and the
combined organic layers were dried over MgSO4. After removal of the
solvents in vacuo the alcohol 77 was obtained as a pale yellow oil in
quantitative yield (91.3 mg, 0.22 mmol, 99%). The product was
obtained as a mixture of rotamers (11/1). The product was used
without further purifications. TLC: Rf = (cyclohexane/ethyl acetate 3/
1).
To a slurry of 10% Pd/C (76.0 mg, 0.07 mmol, 0.15 equiv) in DCM
(20 mL) was carefully added a solution of 73a (200 mg, 0.49 mol, 1.0
equiv) in MeOH (25 mL) in a fashion such that the Pd/C was
constantly covered with solvent. The reaction vessel was evacuated and
filled with H2 (1 atm) five times before it was stirred under H2 for 30
min. Then the reaction mixture was filtered over a plug of silica gel
topped with Celite and washed with DCM in a fashion such that the
Pd/C would not go dry, before all of the MeOH was removed. After
removal of the solvents in vacuo the product was obtained as a pale
yellow oil (198 mg, 0.49 mmol, 99%). The product 75 was obtained as
a mixture of rotamers (1.5/1) and used without further purification.
To a stirred solution of alcohol 77 (75.0 mg, 0.19 mmol, 1.0 equiv)
in THF (1 mL) was added 2-nitrophenylselenium cyanate (43.1 mg,
0.19 mmol, 1.0 equiv), and the dark red solution was cooled to 0 °C.
Then PBu3 (46.9 μL, 0.19 mmol, 1.0 equiv) was added and the
reaction mixture was stirred at 0 °C for 3 h until the color of the
solution lightened. The reaction was quenched with a saturated
aqueous NH4Cl solution (1 mL), and the aqueous layer was extracted
with ethyl acetate (3 × 2 mL). The combined organic layers were
dried over Na2SO4 and filtered, and the solvents were removed in
vacuo. The crude mixture was resolved in THF (1 mL) and cooled to
0 °C. Then 35% aqueous hydrogen peroxide (23.0 μL, 0.29 mmol, 1.5
equiv) was added, and the reaction mixture was warmed to room
temperature and stirred for 2 h. The reaction mixture was quenched
with a saturated aqueous NaHSO4 solution (1 mL), and the aqueous
layer was extracted with ethyl acetate (3 × 2 mL). The combined
organic layers were washed with H2O (5 mL) and saturated aqueous
NaCl solution (5 mL), dried over MgSO4, and filtered. The solvents
were removed in vacuo, and the product was purified by flash column
chromatography (n-pentane/Et2O 10/1) to yield a pale yellow oil of
78 (41.9 mg, 0.10 mmol, 55%). The product was obtained as a mixture
1
TLC: Rf = 0.31 (cyclohexane/ethyl acetate 5/1). H NMR (CDCl3,
400 MHz): δ −0.08 (s, 6H)#, 0.08 (s, 6H), 0.80 (s, 9H)#, 0.92 (s, 9H),
0.99 (t, J = 7.4 Hz, 3H), 1.02 (d, J = 6.5 Hz, 3H), 1.20 (d, J = 6.7 Hz,
3H), 1.25 (d, J = 6.7 Hz, 3H)#, 1.28 (d, J = 6.9 Hz, 3H)#, 1.73 (sxt, J =
7.1 Hz, 2H), 1.84−1.95 (m, 1H), 1.98−2.10 (m, 1H)*, 2.68 (s, 3H)#,
2.28 (s, 3H), 3.29−3.38 (m, 1H), 3.43−3.54 (m, 1H), 3.65−3.80 (m,
3H), 3.88−3.94 (m, 1H), 6.97−7.05 (m, 2H), 7.13−7.17 (m, 1H). 13C
NMR (CDCl3, 100 MHz): δ −5.4#, −5.2#, −5.2, −5.2, 10.7, 16.1#,
16.4, 18.3#, 18.4, 20.5#, 20.7#, 21.1, 21.3, 23.7#, 23.8, 26.0#, 26.1, 32.3,
34.2#, 38.2, 42.1#, 46.0#, 50.5, 53.6#, 60.9, 61.0#, 61.5, 75.6, 75.7#, 77.4#,
118.1#, 124.0#, 124.0, 125.0#, 125.2, 125.6, 131.5, 131.6#, 131.7, 132.1,
132.5#, 133.2#, 153.1#, 153.6, 169.6, 170.2#. HR/MS (ESI-TOF,
arginine): calculated for [M + Na]+ = C23H41NO3SiNa, 430.2753;
found, 430.2748 (Δ = −0.5 mmu).
1
of rotamers (1.7/1). TLC: Rf = 0.13 (n-pentane/Et2O). H NMR
(CDCl3, 400 MHz): δ 0.98 (t, J = 7.4 Hz, 3H), 1.00 (t, J = 7.4 Hz,
3H)#, 1.15 (d, J = 6.6 Hz, 3H), 1.20 (d, J = 6.7 Hz, 3H), 1.29 (d, J =
7.0 Hz, 3H)#, 1.32 (d, J = 6.9 Hz, 3H)#, 1.72 (m, 2H), 2.21 (s, 3H)#,
2.23 (s, 3H), 3.61−3.69 (m, 2H + 1H#), 3.72−3.80 (m, 2H + 1H#),
3.89−3.95 (m, 1H), 4.00 (ddt, J = 15.5, 6.5, 1.6 Hz, 1H), 4.11 (ddt, J =
15.3, 5.7, 1.6 Hz, 1H), 4.72 (sept, J = 6.9 Hz, 1H)#, 4.87 (ddt, J = 17.1,
1.5 Hz, 1.5 Hz, 1H)#, 4.95 (ddt, J = 10.1, 1.5 Hz, 1.5 Hz, 1H)#, 5.15
(ddt, J = 10.3, 1.5 Hz, 1.5 Hz, 1H), 5.32 (ddt, J = 17.3, 1.5 Hz, 1.5 Hz,
1H), 5.79−5.89 (m, 1H)#, 6.05−6.15 (m, 1H), 6.85 (d, J = 8.1 Hz,
1H)#, 6.87 (d, J = 8.1 Hz, 1H), 7.41 (d, J = 8.1 Hz, 1H)#, 7.44 (d, J =
8.1 Hz, 1H). 13C NMR (CDCl3, 100 MHz): δ 10.6, 15.4#, 16.0, 20.2#,
20.4#, 21.5, 21.7, 23.6, 29.8#, 30.5#, 43.3, 46.4#, 48.5#, 51.1, 66.0#, 75.9,
89.7, 90.2#, 116.5, 116.8#, 132.1, 132.2#, 132.6, 134.5, 134.6#, 135.6,
136.1, 137.8#, 154.3#, 154.5, 168.5, 168.8#. HR/MS (ESI-TOF,
arginine): calculated for [M + Na]+ = C17H24INO2Na, 424.0750;
found, 424.0744 (Δ = −0.6 mmu).
N,N-3-(t-Butyldimethylsilyloxy)propaneisopropyl-6-iodo-3-
methyl-2-propanoxybenzamide (76). To a stirred solution of 75
(204 mg, 0.50 mmol, 1.0 equiv) and TMEDA (90.0 μL, 0.60 mmol,
1.2 equiv) in THF (5 mL) at −78 °C was added sec-BuLi (1.4 M in n-
hexane, 430 μL, 0.60 mmol, 1.2 equiv) dropwise, and the reaction
mixture was stirred for 30 min at that temperature. Then a solution of
iodine (152 mg, 0.60 mmol, 1.2 equiv) in THF (5 mL) was added
dropwise, with the temperature kept below 70 °C. The reaction
mixture was stirred for an additional 1 h before it was quenched with a
saturated aqueous Na2S2O3 solution (10 mL) at that temperature. The
organic layer was separated, and the aqueous layer was washed with
Et2O (3 × 10 mL). The combined organic layers were washed with
H2O (25 mL) and a saturated aqueous NaCl solution (25 mL) before
it was dried over MgSO4. After filtration and removal of the solvents in
vacuo the resulting oil was purified by flash column chromatography
(silica gel, cyclohexane/ethyl acetate 10/1) to afford a pale yellow oil
(144 mg, 0.27 mmol, 54%). The iodide 76 was obtained as a mixture
of rotamers (2.5/1). TLC: Rf = 0.18 (cyclohexane/ethyl acetate 10/1).
1H NMR (CDCl3, 400 MHz): δ −0.06 (s, 3H)#, 0.08 (s, 3H), 0.80 (s,
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b02781.
■
S
1H and 13C NMR spectra and crystallographic data and
thermal ellipsoid plots for 41, 54, 57, 67, and 72 (PDF)
X-ray crystallographic data for 41, 54, 57, 67, and 72
(CIF)
9H)#, 0.92 (s, 9H), 0.97−1.01 (m, 3H), 1.15 (d, J = 6.6 Hz, 3H), 1.22
(d, J = 6.7 Hz, 3H), 1.31 (d, J = 6.7 Hz, 3H)#, 1.33 (d, 6.7 Hz, 3H)#,
1.68−1.73 (m, 2H), 1.94−2.04 (m, 1H), 2.06−2.16 (m, 1H), 2.21 (s,
3H)#, 2.23 (s, 3H), 2.99−3.07 (m, 2H)#, 3.11−3.19 (m, 2H)#, 3.34−
3.43 (m, 1H), 3.44−3.51 (m, 1H), 3.59 (sept, J = 6.7 Hz), 3.71−3.80
(m, 2H), 3.89−3.97 (m, 1H). 4.73 (sept, J = 6.7 Hz, 1H)#, 6.85 (d, J =
8.1 Hz, 1H)#, 6.86 (d, J = 8.0 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H)#, 7.44
(d, J = 8.1 Hz, 1H). 13C NMR (CDCl3, 100 MHz): δ −5.4#, −5.3#,
−5.2, −5.2, 10.6, 15.4#, 16.1, 16.1#, 18.3#, 18.4, 20.2#, 20.5#, 21.3, 21.5,
23.6#, 23.6, 25.5#, 26.0#, 26.1, 26.1, 31.9, 33.4#, 38.3, 42.7#, 46.4#, 51.0,
61.1#, 61.5, 66.0, 75.9, 76.0#, 77.4, 89.8, 90.4#, 132.1, 132.1#, 132.5,
132.5#, 134.5#, 134.6, 138.1, 138.1#, 154.3#, 154.5, 168.6, 168.9#. HR/
AUTHOR INFORMATION
Corresponding Author
*E-mail for D.M.: dirk.menche@uni-bonn.de.
■
Present Address
§(S.E.) MRC Laboratory of Molecular Biology, Francis Crick
Avenue, CB2 0QH Cambridge, U.K.
MS (ESI-TOF, arginine): calculated for [M
C23H40INO3SiNa, 556.1720; found, 556.1714 (Δ = −0.6 mmu).
+ =
Na]+
Notes
N-Allyl-6-iodo-N-isopropyl-3-methyl-2-propoxybenzamide
(78). To a stirred solution of 76 (115 mg, 0.22 mmol, 1.0 equiv) in
MeOH (3.5 mL) was added CSA (14.0 mg, 60 μmol, 0.3 equiv), and
the mixture was stirred for 30 min. Then the mixture was diluted with
EA (35 mL) and washed with a saturated aqueous NaHCO3 solution
(2 × 35 mL) and a saturated aqueous NaCl solution (35 mL). The
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Generous financial support by the Fond der Chemischen
Industrie (fellowship to S.E.) and the DFG (SFB 813) are most
U
DOI: 10.1021/acs.joc.5b02781
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(20) (a) Essig, S.; Bretzke, S.; Muller, R.; Menche, D. J. Am. Chem.
̈
gratefully acknowledged. We thank Dr. Frank Rominger for the
performance of X-ray structure analyses, Jan Hartmann for
exploratory studies and Dipl.-Chem. Florian Wolf for the
development of the synthetic route for the aza-isochromanone
precursor during his diploma thesis.
Soc. 2012, 134, 19362−19365. (b) Essig, S.; Schmalzbauer, B.; Bretzke,
S.; Scherer, O.; Koeberle, A.; Werz, O.; Muller, R.; Menche, D. J. Org.
̈
Chem. 2016, DOI: 10.1021/acs.joc.5b02844.
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