Stereoselective Synthesis of Baulamycin A

Article abstract of DOI:10.1021/acs.joc.9b03443

New structural classes of antibiotics are rare, structurally novel broad-spectrum antibiotics exceptionally so. The recently discovered baulamycins constitute a remarkable example of these highly prized compounds and, as such, have attracted considerable attention in the form of both synthetic efforts and biological studies. For the first time, we report a gram-scale preparation of the common carbon framework of the baulamycin family, as well as the total synthesis of its most potent member, baulamycin A. Our approach employs highly stereoselective, catalyst-controlled asymmetric conjugate additions to thioesters to set key stereocenters, as well as the first reported use of "dry ozonolysis" to reveal a masked carboxylic acid in the total synthesis of a natural product.

Full text of DOI:10.1021/acs.joc.9b03443

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Article
Stereoselective Synthesis of Baulamycin A
Jonathan R. Thielman, David H. Sherman, and Robert M. Williams
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b03443 • Publication Date (Web): 23 Jan 2020
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Page 1 of 15
The Journal of Organic Chemistry
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Stereoselective Synthesis of Baulamycin A
Jonathan R. Thielman,† David H. Sherman,‡* and Robert M. Williams†°*
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†Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523, USA;
° University of Colorado Cancer Center, Aurora, CO 80045, USA
‡ Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, USA; 3University of Colorado Cancer Center,
Aurora, CO 80045, USA
KEYWORDS GO HERE
ABSTRACT: New structural classes of antibiotics are rare, structurally-novel broad-spectrum antibiotics exceptionally so. The
recently discovered baulamycins constitute a remarkable example of these highly-prized compounds and, as such, have attracted
considerable attention in the form of both synthetic efforts and biological studies. For the first time, we report a gram-scale preparation
of the common carbon framework of the baulamycin family, as well as the total synthesis of its most potent member, baulamycin A.
Our approach employs highly-stereoselective, catalyst-controlled asymmetric conjugate additions to thioesters to set key
stereocenters, as well as the first reported use of “dry ozonolysis” to reveal a masked carboxylic acid in the total synthesis of a natural
product.
INTRODUCTION
additional mode of action.7 Finally, the unusual structure of the
baulamycin scaffold holds promise, as it remains distinct from
all previously-reported classes of antimicrobials. In the face of
ever-growing resistance to known structural manifolds, this
characteristic was particularly alluring.
The worldwide appearance of drug- and multidrug-resistant
pathogens is widely recognized as a serious threat to public
health.1-4 Thus, our interest was strongly piqued when Sherman
and coworkers published a report detailing unusual broad-
spectrum antibiotic activity in the newly-identified natural
products baulamycins A (1) and B (2) (Fig. 1).5 These natural
products represent an entirely new molecular scaffold of natural
antibiotics and present a compelling opportunity to identify new
biochemical targets for the development of new antimicrobial
agents.
With the above in mind, we set about designing a scalable
synthetic route to the baulamycins that would give access to
both the natural products as well as designed derivatives, with
the hope of further interrogating the underlying biological mode
of action. In the course of our initial synthetic investigations,
the relative stereochemistry of the natural products was revised
and their absolute stereochemistry assigned in Aggarwal and
co-workers’ seminal total synthesis of 1 and 28, an achievement
paralleled by the concurrent work of Sengupta et al in their
synthesis of the antipode of the natural product9, and of
Guchhait et al in their synthesis of the proposed structure.10
OH OH OH
O
3'
9
7
5
14
12
8
6
4
HO
2
1'
13
11
10
Me
Me
Me Me Me
R
5'
15
19
20
21
16
OH
Our strategic synthetic analysis partitioned the baulamycin
scaffold into left-hand side (LHS) and right-hand side (RHS)
moieties, disconnecting at the C11 – C12 carbon-carbon bond
(Scheme 1). Initial work in our group toward the proposed
structure of the baulamycins envisioned a coupling of the LHS
and RHS fragments by way of a diastereoselective aldol
reaction. When extensive optimization of these efforts failed to
produce the required diastereoselectivity, our attention turned
to alternate methods of accessing late-stage key intermediate 3.
We imagined obtaining this β-hydroxy ketone from a
diastereoselective formal hydration of enone 4, which in turn
would be accessed by Horner-Wadsworth-Emmons coupling of
key RHS intermediate 6 with β-keto phosphonate 5.
1
2
: baulamycin A, R = Me
: baulamycin B, R = H
Figure 1. Structure of baulamycins A and B.
These partially-deoxygenated polyketides were isolated in
low yield with substantial difficulty from Streptomyces
tempisquensis, making them ideal targets for total synthesis. At
the time of their isolation, intriguing questions about the
baulamycins’ biological mode of action drew our attention.
Identified during a high-throughput screen for inhibitors of
enzymes involved in siderophore biosynthesis, the baulamycins
were initially proposed to target microbial iron acquisition, a
validated but under-exploited target.6 At the same time, lack of
potentiation by iron deprivation in whole-cell assays suggested
the possibility of other cellular targets.5 Our interest in these
questions was only amplified when, during the course of our
own investigations, elegant work by Wuest and coworkers
raised the possibility of membrane disruption as an alternate or
Finally, we envisioned 5 arising from a diastereoselective
aldol reaction between known11 thiazolidinethione 23 and
protected 3,5-dihydroxybenzaldehyde 22. The optimal
approach to 6 appeared – at first glance – less obvious. A
number
polydeoxypropionates, employing both iterative and non-
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The Journal of Organic Chemistry
Page 2 of 15
iterative strategies with varying degrees of generality and complete regioselectivity. Protection of the alcohol as the
target-specificity.12-14 We ruled out approaches relying upon the
purchase of expensive chiral, non-racemic starting materials as
infeasible; methods requiring the synthesis of complex catalysts
were also deemed undesirable. Ultimately, we settled upon the
asymmetric conjugate addition of Grignard reagents to α,β-
unsaturated thioesters developed by Feringa and coworkers as
the most tractable path toward 6 and similar structures.15
methyl carbonate proceeded accordingly, setting the stage for
the oxidation of the terminal arene to unveil carboxylic acid 15.
1
2
3
4
5
6
7
8
Our initial work toward the proposed structure of the
baulamycins relied upon Sharpless’ well-known adaption of the
ruthenium tetroxide oxidation of arenes to access compounds
like 15 from aromatic precursors.18 This approach, while indeed
successful, nonetheless suffered from a variety of drawbacks
including complicated purifications and modest yields (~50%,
despite optimization). In pursuit of alternate conditions that
would alleviate what, at the time, was a major supply problem
in our sequence, we noted with interest the application of so-
called “dry ozonolysis” in the oxidation of arenes to carboxylic
acids and other oxygenated species.19-20 Once a topic of active
research, these conditions – consisting in the adsorption of
substrate onto silica followed by exposure to gaseous O3 at
cryogenic temperatures – have seen little use in the last twenty
years, despite extensive prior documentation.21 Pleasingly,
application of these conditions to 14 gave 15 as the sole product
in quantitative yield on a multi-gram scale, re-emphasizing the
synthetic utility of this neglected reaction.
baulamycins
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TBSO
O
OH
O
MOMO
OMe
N
Me
Me Me Me Me
OMOM
TBSO
Me
3
O
O
MOMO
OMe
N
Me
Me
Me Me Me Me
With scalable access to 15 in hand, we proceeded with the
installation of the third methyl-bearing stereogenic center.
Construction of N-acyloxazolidinone 16 followed by alkylation
under Evans’ conditions22 gave trimethylated oxazolidinone 17
as a single diastereomer. With the last stereogenic center of the
right-hand side of the baulamycins in place, hydrolysis23,
Weinreb amide formation, and deprotection24 gave alcohol 20
in good overall yield. Finally, it was determined that the
oxidation of 20 with Dess-Martin periodinane provided 6 in
optimal yields; however, 6, being relatively unstable, was not
isolated but rather used immediately in the next step.
OMOM
O
4
TBSO
O
O
O
OMe
MOMO
P
OMe
OMe
H
N
+
Me Me Me Me
Me
Me
6
MOMO
5
Scheme 1. Retrosynthetic analysis based on Horner-
Wadsworth-Emmons coupling of left- and right-hand sides.
Turning to the left-hand side of the baulamycin scaffold, we
first developed a scalable route to aldehyde 22 from 3,5-
dihydroxybenzoic acid, giving decagram quantities of 22 in
three steps (Scheme 3). As we had hoped, coupling with
thiazolidinethione 23 under Evans’ conditions gave the TMS-
protected aldol, which was immediately deprotected without
RESULTS
Wittig coupling of known16 phosphonium ylide 7 (Scheme 2,
prepared on >100 g scale in three steps from bromoacetic acid)
with inexpensive ($0.02/mol) hydrocinnamaldehyde gave
unsaturated thioester 9. Pleasingly, when treated with
methylmagnesium bromide in the presence of catalytic CuBr
and (R,S)-Josiphos, 9 smoothly gave β-methyl thioester 10 in
good yield and with excellent enantioselectivity. Reduction of
the thioester with DIBAL-H at -65 °C proceeded rapidly and
quantitatively17, and Wittig olefination of the resulting aldehyde
gave homologated thioester 11 in excellent overall yield and
diastereoselectivity. A second asymmetric conjugate addition
under Feringa’s conditions gave 12 with excellent
diastereoselectivity; subsequent reduction and Wittig
olefination yielded hydrocarbon 13, which was easily purified
by elution from silica with neat pentane. Our attempts at
hydroboration-oxidation reminded us of the subtleties of
apparently-simple reaction manifolds. Initial attempts to
employ 9-BBN as the borylating agent were foiled by
incomplete separation of 1,5-cyclooctanediol from our alcohol
product. The reaction with borane-THF, while surprisingly
regioselective and free of reagent-derived impurities, was
hindered by competing protodeboronation of the generated
trialkylboranes during the oxidative workup, giving up to 32%
yield of the alkane. In the end, disiamylborane proved most
effective, giving the desired alcohol in quantitative yields with
purification in excellent yield giving 24 as
a single
diastereomer. TBS-protection followed by half-reduction with
DIBAL-H25 gave the aldehyde, which could be transformed to
the β-ketophosphonate in excellent yield over two steps, giving
5 in an overall yield of 40% from commercial material.
With efficient access to both left- and right-hand sides of the
baulamycin scaffold in hand, we turned our attention to the
coupling of 5 and 6 to give key enone intermediate 26.
Pleasingly, application of Paterson’s barium hydroxide-
mediated Horner-Wadsworth-Emmons conditions26 to
equimolar quantities of 5 and freshly-prepared 6 gave 26 in
good yield on a gram scale. With access to ample quantities of
the common carbon skeleton of the baulamycins effectively
secured, we turned our attention to the task of developing
conditions for the diastereoselective formal hydration of 26 to
give β-hydroxy ketone 27.
Our intuitions that this transformation might prove
challenging were validated over the course of an extended
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The Journal of Organic Chemistry
H
1
2
3
4
i) (R,S)-Josiphos, 1.7 mol %,
CuBrSMe2, 1.4 mol%
ii) MeMgBr, 1.2 eq, -78 °C
O
Me
O
O
1. DIBAL-H
2. Ph3PCH(CO)SEt
O
8
SEt
SEt
Ph3P
87%, two steps
Wittig dr = 17:1
86% yield
dr = 6:1
83% yield
93% ee
SEt
9
7
10
5
6
7
8
Me Me
i) (R,S)-Josiphos, 1.7 mol %,
CuBr•SMe2, 1.4 mol%
ii) MeMgBr, 1.2 eq, -78 °C
Me Me
O
1. DIBAL-H
2. Me=PPh3
92%, two steps
Me
O
SEt
SEt
13
84%
dr > 20:1
12
11
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
Me Me
Me Me
1. disiamyl borane; NaOH, H2O2
2. methyl chloroformate, pyridine
O
OMe
HO
O
OMe
O3 • SiO2
99%
81%, two steps
O
O
O
15
14
O
O
O
OCOOMe
OCOOMe
O
O
OCOOMe O
O
NH
Bn
Et3N, LiCl,
pivaloyl chloride
LiOOH
NaHMDS, MeI
N
N
O
O
OH
97%
81%
dr > 20 : 1
Me
Bn
Me Me
Me Me
17
72%
Me
Me Me
Bn
16
18
PyBOP,
i-Pr2NEt,
MeNH(OMe)
82%
O
O
N
OCOOMe
OH
O
O
H
OMe
OMe
Dess-Martin
periodinane
K2CO3
Me
N
N
82%
Me Me
Me Me Me
Me Me
19
Me
(83%)
Me OMe
Me Me
6
20
[gram scale]
Scheme 2. Synthesis of key RHS intermediate 6.
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60
campaign to identify conditions for the diastereoselective
formation of 27. long list of seemingly-promising
transformations, including catalyst-directed epoxidations,
hydroperoxidations, dihydroxylations and borylations, as well
as a variety of substrate-controlled conditions, were surveyed
with little initial success.
Finally, it was discovered that conditions27 employing Cu(I)-
catalyzed β-borylation with B2(pin)2 in the presence of (R,S)-
Josiphos followed by oxidation with sodium perborate gave 11-
epi-27 in excellent yield and 17:1 d.r. Invigorated, we attempted
the β-borylation of 26 with (S,R)-Josiphos, which
indeed gave 27 as the major diastereomer in reasonable yield
and with modest selectivity after oxidation (Scheme 4). At this
juncture, exhaustive efforts to identify conditions leading to
improved diastereoselectivity were not undertaken; purification
of 27 by flash chromatography provided the required amounts
of diastereomerically pure material.
A
With appreciable quantities of 27 in hand, we now turned our
attention the final stereocenter in the baulamycin scaffold, the
C13 hydroxyl. Ultimately, it was found that syn-reduction of 27
was best effected by BH3•DMS at -20 °C, giving diol 28 in near-
quantitative yields as a 4:1 mixture with its C13-epimer.
O
S
OMOM
O
S
O
OH
O
2
1. MgBr2 • Et2O, TMSCl, Et3N,
2. TFA
MOMO
1. MOMCl, Hünig's base
2. DIBAL-H
H
HO
S
N
N
OH
S
+
89%
over two steps
3. MnO2
Me
Me
Bn
OMOM
Bn
68%
21
OMOM
Me
24
OH
over three steps
Me
22
23
TBSO
O
TBSO
O
O
P
1. H3C(P=O)(OCH3)2, n-BuLi
2. Dess-Martin periodinane
1. TBSOTf, 2,6-lutidine
2. DIBAL-H
MOMO
MOMO
OMe
OMe
H
Me
73%
, two steps
90%
, two steps
Me
Me
5
25
OMOM
Me
OMOM
TBSO
O
O
6
1.0 eq
MOMO
OMe
0.8 eq Ba(OH)2
N
70%
20
, two steps from
dr > 20 : 1
Me
Me
Me Me Me Me
26
OMOM
[gram scale]
Scheme 3. Synthesis of key LHS intermediate 5 and coupling with LHS aldehyde 6.
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1
2
3
4
1. CuCl, (S,R)-Josiphos,
NaOt-Bu, MeOH, B2(pin)2
2. NaBO3 • 4H2O
TBSO
O
O
TBSO
O
OH
O
MOMO
OMe
MOMO
OMe
N
N
80%
23%
Me
Me
Me Me Me Me
(both diastereomers, dr = 3:1)
(after chromatography, dr > 20:1)
Me
Me
Me Me Me Me
26
27
OMOM
OMOM
5
6
7
8
9
TBSO
OH OH
O
p-TsOH, Na2SO4
MOMO
Me
acetone
BH3 • DMS
N
94%
(combined yield)
67%, 29
95%
Me
Me
Me Me Me OMe
pure
dr
= 4 : 1
28
OMOM
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
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32
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50
51
52
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60
Me Me
OH OH OH
O
TBSO
O
O
O
N
HO
1. EtMgBr
2. HCl, THF/MeOH
MOMO
Me
Me
Me
Me Me Me Me
Me
Me
Me Me Me OMe
51%
(two steps)
OH
29
1
OMOM
Scheme 4. Completion of the synthesis of baulamycin A.
These isomers could be readily separated by protection as the
acetonides followed by selective hydrolysis of the anti-
acetonide with p-TsOH in dry DCM at 0 °C.28 Subsequent
Weinreb ketone synthesis proceeded uneventfully, and global
deprotection furnished baulamycin A in good overall yield.
Reactions conducted in flame- or oven-dried glassware were
conducted with anhydrous solvents and reagents. In these cases,
toluene, THF, DMF, diethyl ether, dichloromethane,
acetonitrile, DMSO, pyridine, benzene, methanol, triethylamine
and diisopropylamine were sparged with argon then dried by
passage through a Glass Contour solvent purification system.
Anhydrous n-pentane, hexanes and tert-butyl methyl ether were
obtained by drying over 4 Å molecular sieves (20% w/w) for at
least 12 hours prior to use. Acetone was dried over 3 Å
molecular sieves (20 % w/w) overnight then used immediately
to prevent re-equilibration to a higher water content through
self-condensation29. Concentrations of acids, bases, and
hydrogen peroxide refer to aqueous solutions except where
otherwise noted.
CONCLUSION
In summary, we report here a gram-scale preparation of the
common carbon scaffold of the baulamycins, as well as the total
synthesis of the archetypal member of this family of natural
products. Further investigations into the biological activity and
additional direct biochemical targets of the baulamycins in
human pathogenic bacterial will be reported in due course.
EXPERIMENTAL
General Considerations. The use of flame- or oven-dried
glassware, inert atmosphere and other specific elements of air-
free technique are explicitly noted and described in detail for
each experimental procedure in which they were used. The use
of dried glassware or inert atmosphere should not be assumed
for reactions which do not explicitly describe their use.
Except when stated otherwise, reactants and reagents were
obtained commercially and used without further purification.
The terms freshly distilled and freshly purified, when used
without citing an alternative reference, refer to purification
according to the procedures described in standard reference
works30,31 or references contained therein.
Where used below, the term high vacuum refers to a vacuum
measured at approximately 0.10 – 0.05 mm Hg. The term purge
is used to refer to the evacuation of an experimental apparatus
by high vacuum and subsequent back-filling with a specified
inert gas at least three times. The term sparge indicates that a
gas was vigorously bubbled through a solvent, typically from a
stainless steel needle positioned with its tip at the lowest point
of the vessel. The term oven-dried refers to an apparatus which
has been kept at a temperature of 120 °C overnight; the term
flame-dried refers to glassware placed under high vacuum and
heated with a propane torch until frosting of glass components
was no longer observed, then cooled under positive pressure of
a dry inert gas. Freeze-pump-thaw degassed denotes that the
material thus described has been placed in a Schlenk flask
sealed with a fresh rubber septum, connected to high vacuum
by a sidearm equipped with a closed stopcock, magnetically
stirred at -196 °C until frozen, exposed to high vacuum by
opening of the stopcock for at least 3 minutes, resealed by
closing of the stopcock, thawed, and thus treated a total of three
times.
Flash chromatography was performed on “Standard Grade”
60 Å porosity, 230-400 mesh silica gel from Sorbent
Technologies. Analytical and preparative TLC were conducted
on glass-backed plates precoated (0.21 – 0.27 mm) with Merck
Silica Gel 60 F254. Preparative TLC was conducted by loading
10 mgs or less of sample onto 20 cm x 20 cm plates. In the case
of analytical TLC, unless otherwise noted, compounds were
visualized by 254 nm UV light or by immersion in Seebach’s
stain32 followed by heating in a stream of hot air until the plate
evolved a uniform blue color.
1H and 13C NMR spectra were acquired at various field
strengths as indicated using Varian and Bruker spectrometers.
1H NMR spectra were referenced internally to residual
undeuterated solvents (CHCl3 σ = 7.26 ppm, CH3OH σ = 3.31
ppm, DMSO, σ = 2.50 ppm, CH3CN σ = 1.94 ppm, H2O σ =
4.79 ppm, C6H6 σ = 2.50 ppm, acetone σ = 2.05 ppm). 13C NMR
spectra were referenced internally to the solvent (CHCl3 σ =
77.0 ppm, CH3OH σ = 49.0 ppm).
Infrared spectra were recorded on a Nicolet iS5 or Nicolet
iS50 FT-IR spectrometer. Mass spectra were obtained on
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various TOF or QTOF spectrometers. Optical rotations were
measured using a Rudolf Research Autopol III polarimeter
operating at 589 nm at room temperature, typically 25 °C.
128.3, 126.2, 34.3, 33.9, 23.1, 14.8. Characterization agreed
with that previously reported in the literature36.
1
2
S-ethyl (R)-3-methyl-5-phenylpentanethioate (10). An
argon-purged, 250-mL round-bottom flask equipped with a
magnetic stir bar as charged with CuBr·Me2S (0.065 g, 0.32
mmol, 0.014 eq) and (R,SP)-Josiphos ethanol adduct (0.247 g,
0.390 mmol, 0.017 eq), followed by tert-butyl methyl ether (125
mL). The resulting orange solution was stirred at r.t. for 30 min,
then cooled to -78 °C. To this solution was added
methylmagnesium bromide (9.1 mL of a 3.0 M solution in Et2O,
27.0 mmol, 1.2 eq); 9 (5.00 g, 23 mmol, 1.00 eq) was then added
as a solution in tert-butyl methyl ether (33 mL) over 1.5 hrs via
syringe pump. The reaction mixture was allowed to stir for 14
hrs at -78 °C, at which time TLC showed complete consumption
of starting material. MeOH (8 mL) was added at -78 °C and the
mixture allowed to warm to room temperature; saturated
aqueous NH4Cl was then added and the biphasic mixture stirred
30 min. The layers were separated and the aqueous layer
extracted with a 1:1 mixture of DCM / Et2O (3 x 100 mL). The
combined organics were dried over MgSO4 and concentrated
under reduced pressure to give a brown oil. Purification by flash
chromatography on silica gel (250 g) eluting with 49:1 pentane
/ Et2O gave 10 (4.49 g, 83%, 93% e.e.) as a colorless oil.
Enantiomeric excess was determined by reduction to the
alcohol with LAH (3.00 eq) followed by HPLC analysis on a
chiral column using the following conditions: column =
Chiralpak IB, eluent = 97:3 hexanes/iso-propanol, flow = 1.0
mL/min; tR = 12.55 min (R), 13.51 min (S). Absolute
configuration was established by conversion to the known37
S-ethyl 2-(triphenyl-λ5-phosphanylidene)ethanethioate
(7). Following the previously described procedure34, a 2-L
round-bottom flask containing a magnetically-stirred solution
of bromoacetic acid (50.0 g, 360 mmol, 1.00 eq) in DCM (700
mL) was charged with ethanethiol (34.6 mL, 468 mmol, 1.3 eq)
and 4-dimethylaminopyridine (4.40 g, 36.0 mmol, 0.10 eq) at 0
°C. N,N-dicyclohexylcarbodiimide (77.94 g, 378 mmol, 1.05 eq)
was then added portionwise, and the addition funnel rinsed with
DCM (50 mL). The resulting thick white slurry was stirred 20
hrs, at which point the reaction mixture was filtered through
Celite® and the filter cake washed with DCM (4 x 200 mL). The
filtrate was concentrated under reduced pressure to give the
crude thioester as a tan oil with particulate inclusions. This
material was taken up in benzene (500 mL) and charged to a
1-L Erlenmeyer flask, to which triphenylphosphine (99.15 g,
378 mmol, 1.05 eq) was added. The reaction mixture was
allowed to sit for four days with periodic agitation, at which
point the mixture was filtered to reveal a white solid which was
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5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
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60
washed with toluene (2
x
100 mL) to give the
triphenylphosphonium bromide salt as free-flowing crystalline
powder. This solid was taken up in DCM (500 mL) and charged
to a 3-L round-bottom flask containing a 10% w/w solution of
Na2CO3 (500 mL). The reaction vessel was then equipped with
a mechanical stirring apparatus and the biphasic mixture stirred
for 6 hrs, evolving a yellow color. The layers were separated
and the aqueous phase extracted with DCM (3 x 500 mL); the
combined organics were dried over Na2SO4 and concentrated
1
aldehyde 30 in the next step. H NMR (400 MHz, CDCl3): δ
7.31 – 7.25 (m, 3H), 7.21 – 7.15 (m, 3H), 2.88 (q, J = 7.4 Hz,
2H), 2.72 – 2.54 (m, 3H), 2.41 (dd, J = 14.5, 8.0 Hz, 1H), 2.16
– 2.02 (m, 1H), 1.74 – 1.62 (m, 1H), 1.57 – 1.46 (m, 1H), 1.25
(t, J = 7.4 Hz, 3H), 1.01 (d, J = 6.7 Hz, 3H). 13C{1H} NMR (101
MHz, CDCl3) δ 199.0, 142.3, 128.3, 128.3, 125.7, 51.2, 38.4,
33.2, 30.8, 23.3, 19.5, 14.8. IR (neat): 3026, 2930, 1685, 1454
cm-1. [α]25D = +6.5° (c 0.83, CH2Cl2). HRMS (ESI): calc’d for
C14H21OS [M + H]+ 237.1308, found 237.1310.
under reduced pressure to give
a light yellow solid.
Precipitation from DCM with pentane (2:1 pentane / DCM) and
filtration, followed by repeated concentration and precipitation
of the mother liquor as above, afforded 7 (108 g, 82% over three
1
steps) as a free-flowing, white crystalline powder. H NMR
(300 MHz, CDCl3) δ 7.69 – 7.51 (m, 9H), 7.51 – 7.41 (m, 6H),
3.66 (d, J = 22.5 Hz, 1H), 2.84 (q, J = 7.4 Hz, 2H), 1.25 (t, J =
7.4 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 180.5, 133.0
(d, J = 10.3 Hz), 132.2 (d, J = 2.9 Hz), 128.9 (d, J = 12.5 Hz),
126.8 (d, J = 90.9 Hz), 46.9 (d, J = 109.7 Hz), 23.1 (d, J = 2.4
Hz), 16.3. 31P NMR (162 MHz, CDCl3) δ 13.5. IR (neat) 1578,
1336, 1085, 871, 691, 501 cm-1. HRMS (ESI): calc'd for
(R)-3-methyl-5-phenylpentanal (30). A 1-L flame-dried
round bottom containing 10 (8.05 g, 34.1 mmol, 1.00 eq) and
equipped with a magnetic stir bar was capped with a rubber
septum, purged with argon and charged with DCM (340 mL) to
give a colorless, magnetically-stirred solution which was then
cooled to -65 °C. DIBAL-H (35.8 mL of a 1.0 M solution in
hexanes) was added slowly, and the resulting colorless solution
stirred 50 minutes, at which time TLC showed complete
consumption of starting material. MeOH (3 mL) was added at -
65 °C and the solution stirred 10 min; the solution was then
allowed to warm to rt. Saturated aqueous Rochelle’s salt was
added and the resulting biphasic mixture stirred until two clear
phases were obtained; layers were then separated and the
aqueous phase extracted with DCM. The organics were
combined, dried over Na2SO4, decanted and concentrated under
reduced pressure to reveal 30 (6.01 g, 100%) as a colorless oil.
C22H21OPS [M
+
H]+ 365.1124, found 365.1122.
Characterization was in accordance with that previously
reported35.
S-ethyl (E)-5-phenylpent-2-enethioate (9).The procedure
described in the literature36 was adapted as follows: to a 1-L
round-bottom flask containing a magnetically-stirred solution
of hydrocinnamaldehyde (5.56 mL, 42 mmol, 1.0 eq) in DCM
(200 mL) was added 7 (20.00 g, 55 mmol, 1.3 eq). The resulting
solution was stirred 22 hrs at room temperature, at which time
TLC showed complete consumption of starting material. The
reaction mixture was concentrated under reduced pressure and
the residue repeatedly extracted under sonication with pentane
(4 x 100 mL). The combined washings were then purified by
flash chromatography on silica gel (300 g) eluting with 49:1
Characterization agreed with that previously reported37: [α]25
D
= +22.8° (c 1.0, CH2Cl2); lit. [α]25 = +22.9°(c 1, CH2Cl2). H
1
D
NMR (400 MHz, CDCl3) δ 9.75 (t, J = 2.4 Hz, 1H), 7.31 – 7.26
(m, 3H), 7.21 - 7.15 (m, 3H), 2.73 – 2.55 (m, 2H), 2.45 (ddd, J
= 16.1, 5.7, 2.0 Hz, 1H), 2.28 (ddd, J = 16.1, 7.9, 2.6 Hz, 1H),
2.18 – 2.04 (m, 1H), 1.74 – 1.62 (m, 1H), 1.62 – 1.50 (m, 1H),
1.04 (d, J = 6.7 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ
202.7, 142.1, 128.4, 128.3, 125.8, 51.0, 38.6, 33.3, 27.8, 19.8.
1
pentane / Et2O to give 9 (7.93 g, 86%) as a colorless oil. H
NMR (400 MHz, CDCl3) δ 7.30 (apparent t, J = 7.4 Hz, 2H),
7.24 – 7.15 (m, 3H), 6.92 (dt, J = 15.5, 6.8 Hz, 1H), 6.12 (dt, J
= 15.5, 1.5 Hz, 1H), 2.94 (q, J = 7.4 Hz, 2H), 2.78 (t, J = 7.6
Hz, 2H), 2.56 – 2.47 (m, 2H), 1.28 (t, J = 7.4 Hz, 3H). 13C{1H}
NMR (101 MHz, CDCl3) δ 190.0, 143.9 140.6, 129.1, 128.5,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 15
S-ethyl (R,E)-5-methyl-7-phenylhept-2-enethioate (11).
To 1-L round bottom flask containing colorless,
at -65 °C. The resulting colorless solution was stirred an
1
2
3
4
5
6
7
8
a
a
additional 10 min, after which time TLC showed no starting
material remaining. Methanol (4 mL) was added at -65 °C and
the solution stirred until gas evolution ceased. The reaction
solution was then allowed to warm to r.t. and saturated aqueous
Rochelle’s salt was added; the resulting mixture was then stirred
until two clear phases were obtained. Layers were separated and
the aqueous phase extracted with DCM (2 x 150 mL). The
organics were then combined, dried over Na2SO4, decanted and
concentrated under reduced pressure to reveal the pure product
(4.68 g, 96%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ
9.74 (s, 1H), 7.31 – 7.25 (m, 2H), 7.21 – 7.14 (m, 3H), 2.68
(ddd, J = 13.6, 10.3, 5.5 Hz, 1H), 2.55 (ddd, J = 13.7, 10.1, 6.1
Hz, 1H), 2.44 – 2.31 (m, 1H), 2.23 – 2.09 (m, 2H), 1.73 – 1.61
(m, 1H), 1.60 – 1.48 (m, 1H), 1.47 – 1.37 (m, 1H), 1.37 – 1.23
(m, 1H), 1.11 (dt, J = 13.7, 7.0 Hz, 1H), 1.00 – 0.89 (m, 6H).
13C{1H} NMR (101 MHz, CDCl3) δ 202.9, 142.8, 128.3, 125.6,
50.9, 44.6, 38.5, 33.2, 29.7, 25.6, 20.5, 19.9. [α]25D = +15.3° (c
1.17, CHCl3). IR (neat): 2914 (alkane C-H stretch), 1722 (C=O
stretch) cm-1. HRMS (ESI): calc’d for C15H22NaO [M + Na]+
241.1563, found 241.1552.
magnetically-stirred solution of 30 (6.01 g, 34.1 mmol, 1.00 eq)
in CHCl3 (340 mL) was added 7 (24.84 g, 68.2 mmol, 2.00 eq),
giving a pale gold solution which was brought to reflux and
1
stirred 12 hrs, at which time H NMR of a reaction aliquot
showed no aldehyde signal. The reaction solution was allowed
to cool to r.t., then concentrated onto silica (50 g) and purified
by flash chromatography on silica gel (400 g) eluting with 98:2
pentane / ether to give 11 (6.41 g, 72%) as a colorless oil. The
Z-isomer of 11 was also isolated as a colorless oil; integration
9
1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
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30
31
32
33
34
35
36
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55
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59
60
of the corresponding signals in the H NMR spectrum of the
1
crude reaction mixture indicate a d.r. of 17:1. H NMR (400
MHz, CDCl3) δ 7.32 – 7.24 (m, 2H), 7.22 – 7.14 (m, 3H), 6.86
(dt, J = 15.2, 7.5 Hz, 1H), 6.10 (apparent d, J = 15.4 Hz, 1H),
2.94 (q, J = 7.4 Hz, 2H), 2.72 – 2.53 (m, 2H), 2.31 – 2.19 (m,
1H), 2.13 – 2.01 (m, 1H), 1.76 – 1.60 (m, 2H), 1.57 – 1.41 (m,
1H), 1.28 (d, J = 7.5 Hz, 3H), 0.97 (d, J = 6.4 Hz, 3H). 13C{1H}
NMR (101 MHz, CDCl3) δ 190.0, 143.8, 142.3, 129.9, 128.34,
128.30, 125.7, 39.5, 38.4, 33.4, 32.2, 23.0, 19.5, 14.8. IR (neat):
3026, 2927, 1668, 1631, 1453 cm-1. [α]25 = +6.6° (c 0.37,
D
CHCl3). HRMS (ESI): calc’d for C16H23OS [M + H]+ 263.1464,
((3R,5S)-3,5-dimethyloct-7-en-1-yl)benzene (13). To a
500-mL, flame-dried, argon-purged round bottom flask
containing a magnetically stirred suspension of freshly-dried
methyltriphenylphosphonium bromide (9.17 g, 25.7 mmol, 1.20
eq, dried by heating at 100 °C under high vacuum for 2 hrs) in
THF (105 mL) was added n-butyllithium (9.4 mL of a 2.5 M
solution in hexanes, 23.5 mmol, 1.10 eq) at 0 °C; an orange
color evolved and most of the solid dissolved. The reaction
mixture was brought to r.t. and stirred for 1 hr, at which time 31
(4.68 g, 21.4 mmol, 1.00 eq) was added as a solution in THF
(40 mL + 3 x 10 mL washes). The resulting cloudy orange
reaction suspension was stirred 40 min, at which time TLC
showed complete consumption of starting material. Saturated
aqueous NH4Cl, Et2O and water were added and stirred to give
a colorless, biphasic mixture. The aqueous phase was separated,
extracted with Et2O (2 x 200 mL); the organics were then
combined, dried over MgSO4, filtered and concentrated under
reduced pressure to give a colorless oil. Passage of this crude
material through a plug of SiO2 eluting with pentane gave pure
13 (4.30 g, 93%) as a colorless oil. 1H NMR (400 MHz, CDCl3)
δ 7.32 – 7.23 (m, 2H), 7.23 – 7.12 (m, 3H), 5.85 – 5.68 (m, 1H),
5.05 – 4.91 (m, 2H), 2.66 (ddd, J = 13.6, 10.4, 5.4 Hz, 1H), 2.54
(ddd, J = 13.6, 10.4, 5.8 Hz, 1H), 2.10 – 2.01 (m, 1H), 1.88 –
1.78 (m, 1H), 1.70 – 1.49 (m, 3H), 1.45 – 1.21 (m, 3H), 1.00
(dd, J = 13.8, 6.9 Hz, 1H), 0.94 (d, J = 6.5 Hz, 3H), 0.84 (d, J =
6.6 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 143.1, 137.5,
128.3, 128.3, 125.5, 115.6, 44.3, 41.2, 38.7, 33.3, 30.1, 29.8,
found 263.1470.
S-ethyl
(3R,5R)-3,5-dimethyl-7-phenylheptanethioate
(12). To a flame-dried, argon-purged 500-mL round bottom
flask were added CuBr•DMS (0.070 g, 0.341 mmol, 1.4 mol %)
and (R,SP)-Josiphos (0.266 g, 0.415 mmol, 1.7 mol %); the flask
sealed with a rubber septum and tert-butyl methyl ether (100
mL) was added to give an orange solution. This solution was
stirred 10 min, then cooled to -78 °C and stirred a further 15
min. Methylmagnesium bromide (9.8 mL of a 3.0 M solution in
Et2O, 29.3 mmol, 1.20 eq) was then added dropwise, giving a
yellow solution. 11 (6.39 g, 24.4 mmol, 1.00 eq) was then added
dropwise via syringe pump as a solution in tert-butyl methyl
ether (25 mL) over 2 hrs. The resulting solution was stirred 16
hrs, at which time TLC showed complete consumption of
starting material. The reaction was quenched with methanol (~3
mL) at -78 °C to give an opaque yellow-white suspension which
was stirred 5 min, then allowed to come to r.t. Et2O and
saturated aqueous NH4Cl were added, the mixture stirred, water
added and the layers separated. The aqueous phase was then
extracted with Et2O (2 x 200 mL), the organics combined, dried
over MgSO4, filtered and concentrated under reduced pressure
to reveal an orange oil (6.80 g). This crude material was
adsorbed onto silica, loaded onto a column containing silica gel
(170 g), and purified by flash chromatography eluting with 98:2
pentane/ether to reveal the product as a colorless oil (5.73 g,
84%). 1H NMR (400 MHz, CDCl3) δ 7.31 – 7.23 (m, 2H), 7.22
– 7.13 (m, 3H), 2.87 (q, J = 7.4 Hz, 2H), 2.73 – 2.61 (m, 1H),
2.61 – 2.46 (m, 2H), 2.29 (dd, J = 14.4, 8.3 Hz, 1H), 2.21 – 2.06
(m, 1H), 1.74 – 1.59 (m, 1H), 1.59 – 1.48 (m, 1H), 1.45 – 1.36
(m, 1H), 1.36 – 1.28 (m, 1H), 1.24 (t, J = 7.4 Hz, 3H), 1.06 (dt,
J = 13.6, 7.3 Hz, 1H), 0.95 (d, J = 6.5 Hz, 3H), 0.91 (d, J = 6.6
Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 199.3, 142.9,
128.3, 128.3, 125.6, 51.3, 44.3, 38.4, 33.2, 29.7, 28.6, 23.3,
20.2, 20.0. [α]25 = +9.86° (c 0.77, CHCl3). HRMS (ESI):
D
calc’d for C16H25 [M + H]+ 217.1951, found 217.1964.
(4S,6R)-4,6-dimethyl-8-phenyloctan-1-ol (32). A 2-necked,
250-mL round bottom flask was outfitted with a pressure-
equalized dropping funnel and magnetic stir bar, then sealed
with rubber septa. The entire apparatus was then flame dried
under high vacuum and purged with argon. The round bottom
flask was charged with BH3•THF (40.4 mL of a 1.0 M solution
in THF, 40.4 mmol, 1.10 eq), and 2-methyl-2-butene (9.40 mL,
88.8 mmol, 2.42 eq) was added via the dropping funnel as a
solution in THF (20 mL) over 30 min at 0 °C. The colorless
reaction solution was then stirred 2.5 hrs, at which time 13 (7.94
g, 36.7 mmol, 1.00 eq) was added as a solution in THF (20 mL
+ 2 x 5 mL washes). The resulting solution was allowed to
gradually come to r.t. over 1 hr, then stirred an additional 1 hr.
20.1, 20.0, 14.8. . [α]25 = +4.56° (c 1.54, CHCl3). IR (neat):
D
2928 (alkane C-H stretch), 1686 (C=O stretch) cm-1. HRMS
(ESI): calc’d for C17H27OS [M + H]+ 279.1777, found 279.1777.
(3R,5R)-3,5-dimethyl-7-phenylheptanal (31). To a 2000-
mL, flame-dried, argon-purged round bottom flask containing a
magnetically stirred, colorless solution of 12 (6.21 g, 22.3
mmol, 1.00 eq) was added DIBAL-H (33.4 mL of a 1.0 M
solution in toluene, 33.4 mmol, 1.50 eq) dropwise over 15 min
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Page 7 of 15
The Journal of Organic Chemistry
TLC indicated complete consumption of starting material. The introduced through the cap such that its tip was positioned in
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4
5
6
7
8
reaction vessel was cooled to 0 °C and aqueous sodium
hydroxide (13.93 mL of a 3 M solution, 41.8 mmol, 1.14 eq)
was added portionwise, with an initial evolution of gas. The
reaction mixture evolved a cloudy, opaque appearance. The
reaction vessel was then equipped with an internal thermometer
and 30% aqueous hydrogen peroxide (w/w) (13.93 mL) was
then added very slowly, keeping the reaction temperature below
20 °C. The resulting cloudy mixture was stirred 2 hrs, then
water and Et2O were added and the resulting layers separated.
The pH of the aqueous phase was adjusted to 7.5 with saturated
aqueous NH4Cl, then the aqueous phase was extracted with
Et2O (3 x 120 mL) and the organics combined, dried over
MgSO4, filtered and concentrated under reduced pressure to
reveal 32 (8.63 g, 100%) as a colorless oil. 1H NMR (400 MHz,
CDCl3) δ 7.32 – 7.23 (m, 2H), 7.22 – 7.13 (m, 3H), 3.69 – 3.56
(m, 2H), 2.67 (ddd, J = 13.6, 10.5, 5.4 Hz, 1H), 2.54 (ddd, J =
13.6, 10.4, 5.9 Hz, 1H), 1.72 – 1.45 (m, 4H), 1.45 – 1.23 (m,
3H), 1.23 – 1.04 (m, 2H), 1.00 (dt, J = 13.9, 7.2 Hz, 1H), 0.93
(d, J = 6.5 Hz, 3H), 0.85 (d, J = 6.6 Hz, 3H). 13C{1H} NMR
(101 MHz, CDCl3) δ 143.1, 128.3, 128.3, 125.5, 63.4, 44.8,
38.7, 33.3, 32.7, 30.2, 29.9, 29.8, 20.2, 20.1. [α]25D = +10.6° (c
1.45, CHCl3). HRMS (ESI): calc’d for C16H30NO [M + NH4]+
252.2322, found 252.2317.
the headspace of the flask; this needle would serve as a point of
efflux. A stream of ozone in oxygen (OREC ozone generator,
high-purity oxygen as input) was introduced into the flask
through the longer needle and the flask cooled to -78 °C with
magnetic stirring. After approximately 2 hrs, the silica obtained
a pale blue coloration; the flask was uncapped and allowed to
warm to r.t. The reaction was monitored by TLC on aliquots of
the silica extracted with ethyl acetate; after three cycles of
ozone saturation at -78 °C followed by warming to r.t., TLC
indicated the complete consumption of starting material. The
room-temperature silica was loaded into a glass column and
eluted with two column volumes of ethyl acetate; the combined
ethyl acetate washings were then concentrated under reduced
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
pressure to give pure 15 (6.22 g, 100%) as a colorless oil. H
NMR (400 MHz, CDCl3) δ 10.38 (br. s, 1H), 4.12 (t, J = 6.7,
2H), 3.78 (s, 3H), 2.45 – 2.25 (m, 2H), 1.79 – 1.46 (m, 5H), 1.45
– 1.30 (m, 2H), 1.29 – 1.18 (m, 1H), 1.18 – 1.05 (m, 1H), 1.05
– 0.93 (m, 1H), 0.92 – 0.80 (m, 6H). 13C{1H} NMR (101 MHz,
CDCl3) δ 179.8, 155.9, 68.5, 54.6, 44.5, 32.6, 31.5, 31.2, 29.7,
29.5, 26.1, 19.9, 19.8. [α]25 = +1.6° (c 4.2, CHCl3). HRMS
D
+
(ESI): calc’d for C13H24NaO5 [M + Na]+ 283.1516, found
283.1523.
(4S,6R)-9-((R)-4-benzyl-2-oxooxazolidin-3-yl)-4,6-
(4S,6R)-4,6-dimethyl-8-phenyloctyl methyl carbonate
(14). To a 500-mL round bottom flask purged with argon,
sealed with a rubber septum, and containing a magnetically
stirred, colorless solution of 32 (8.60 g, 36.7 mmol, 1.00 eq),
pyridine (3.84 mL, 47.7 mmol, 1.30 eq) and 4-
dimethylaminopyridine (0.090 g, 0.734 mmol, 2 mol %) in
DCM (75 mL) was added methyl chloroformate (3.69 mL, 47.7
mmol, 1.30 eq) dropwise over 5 min. A pale pink color evolved,
dimethyl-9-oxononyl methyl carbonate (16). To a 50-mL
flame-dried, argon-purged round bottom flask equipped with a
magnetic stir bar and capped with a rubber septum was added
15 (0.250 g, 0.96 mmol, 1.00 eq) as a solution in THF (1.5 mL,
including washes) followed by triethylamine (0.33 mL, 2.40
mmol, 2.50 eq) and pivaloyl chloride (0.12 mL, 0.960 mmol,
1.00 eq) at 0 °C. A white precipitant formed and the resulting
suspension was stirred 1 hr, then (S)-4-benzyl-2-oxazolidinone
(0.170 g, 0.96 mmol, 1.00 eq) and lithium chloride (0.061 g,
1.44 mmol, 1.50 eq). The resulting mixture was stirred 24 hrs,
then saturated aqueous ammonium chloride was added, the
resulting mixture stirred, layers separated and the aqueous layer
extracted with Et2O. The organics were combined, dried over
Na2SO4, decanted and concentrated under reduced pressure to
reveal a brown oil. This crude material was purified by flash
chromatography on silica gel (25 g) eluting first with 9:1
hexanes/ethyl acetate followed by 3:2 hexanes/ethyl acetate
gave 16 (0.30 g, 72%) as a colorless oil. 1H NMR (400 MHz,
CDCl3) δ 7.38 – 7.25 (m, 3H), 7.23 – 7.17 (m, 2H), 4.66 (ddt, J
= 10.3, 6.8, 3.2 Hz, 1H), 4.23 – 4.14 (m, 2H), 4.11 (t, J = 6.8
Hz, 2H), 3.76 (s, 3H), 3.29 (dd, J = 13.3, 3.4 Hz, 1H), 2.98 (ddd,
J = 15.8, 9.9, 5.5 Hz, 1H), 2.87 (ddd, J = 16.4, 9.8, 5.9 Hz, 1H),
2.74 (dd, J = 13.3, 9.7 Hz, 1H), 1.78 – 1.49 (m, 5H), 1.48 – 1.32
(m, 2H), 1.26 (dt, J = 13.6, 6.9 Hz, 1H), 1.18 – 1.07 (m, 1H),
1.01 (dt, J = 14.0, 7.2 Hz, 1H), 0.94 – 0.83 (m, 6H). 13C{1H}
NMR (101 MHz, CDCl3) δ 173.6, 155.9, 153.4, 135.3, 129.4,
128.9, 127.3, 68.5, 66.1, 55.2, 54.6, 44.7, 37.9, 33.2, 32.6, 30.9,
1
and the reaction solution was stirred 3 hrs, at which time H
NMR of a reaction aliquot confirms the absence of starting
material. Saturated aqueous NH4Cl and water were added and
the biphasic mixture stirred until two clear, distinct phases were
obtained. The layers were separated and the aqueous phase
extracted with DCM (2 x 120 mL); the organics were then
combined, dried over Na2SO4, decanted and concentrated under
reduced pressure to reveal 9.85 g colorless oil. This crude
material was adsorbed onto SiO2 and loaded onto a column of
silica gel (300 g). Flash chromatography eluting with 95:5
hexanes / ethyl acetate gave 14 (8.60 g, 80%) as a colorless oil.
1H NMR (400 MHz, CDCl3) δ 7.32 – 7.22 (m, 2H), 7.18 (m,
3H), 4.11 (t, J = 6.8, 2H), 3.78 (s, 3H), 2.66 (ddd, J = 13.6, 10.5,
5.4 Hz, 1H), 2.54 (ddd, J = 13.6, 10.4, 5.9 Hz, 1H), 1.77 – 1.46
(m, 5H), 1.44 – 1.22 (m, 3H), 1.12 (m, 1H), 1.00 (dt, J = 13.9,
7.2 Hz, 1H), 0.93 (d, J = 6.5 Hz, 3H), 0.84 (d, J = 6.6 Hz, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 155.9, 143.1, 128.3, 128.2,
125.5, 68.6, 54.6, 44.8, 38.6, 33.3, 32.6, 29.8, 29.8, 26.1, 20.2,
20.0. [α]25D = +5.6° (c 0.34, CHCl3). IR (neat): 2955 (alkane C-
H stretch), 1747 (carbonate C=O stretch) cm-1. HRMS (ESI):
calc’d for C18H32NO3 [M + NH4]+ 310.2377, found 310.2383.
(4R,6S)-9-((methoxycarbonyl)oxy)-4,6-dimethylnonanoic
acid (15). Carbonate 14 (7.00 g, 23.9 mmol) was dissolved in
DCM; silica (175 g, 7.3 g/mmol 14) was then added and the
DCM removed under reduced pressure to give a free-flowing
white powder. This powder was charged to a 1000-mL round
bottom flask equipped with a magnetic stir bar. The flask was
sealed with a plastic cap and a stainless steel needle was
introduced through the cap in such a way that the tip of the
needle rested at the bottom of the flask below the surface of the
silica. A second needle of slightly-narrower gauge was
29.7, 29.6, 26.1, 19.9. [α]25 = +39.5° (c 0.24, CHCl3). IR
D
(neat): 2956 (alkane C-H stretch), 1779 (C=O stretch), 1745
(C=O stretch), 1698 (C=O stretch) cm-1. HRMS (ESI): calc’d
for C23H34NO6 [M + H]+ 420.2381, found 420.2383.
(4S,6S,8S)-9-((R)-4-benzyl-2-oxooxazolidin-3-yl)-4,6,8-
trimethyl-9-oxononyl methyl carbonate (17). To a 500-mL
argon-purged round bottom flask capped with a rubber septum
and containing a magnetically-stirred colorless solution of 16
(5.00 g, 11.9 mmol, 1.00 eq) in THF (90 mL) was added sodium
hexamethyldisilazide (14.3 mL of a 1.0 M solution in THF, 14.3
mmol, 1.20 eq) dropwise at -78°C. The resulting pale brown
solution was stirred 1 hr, at which time methyl iodide (1.85 mL,
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29.8 mmol, 2.50 eq) was added dropwise. The resulting solution hydrochloride (1.19 g, 12.2 mmol, 1.35 eq) was added and the
1
2
3
4
5
6
7
8
was then stirred 4.5 hrs, at which time TLC indicated complete
consumption of starting material. Saturated aqueous NH4Cl,
water, Et2O and saturated aqueous Na2S2O3 were added and the
mixture allowed to warm to r.t. with stirring overnight. The
layers were separated and the aqueous phase extracted with
Et2O (2 x 100 mL); the organics were then combined, dried over
Na2SO4, decanted and concentrated under reduced pressure to
reveal a dark yellow oil. Flash chromatography on silica gel
(250 g) eluting first with 9:1 hexanes / ethyl acetate followed
by 3:1 hexanes / ethyl acetate gave 17 (4.66 g, 81%) as a
reaction solution stirred an additional 1.5 hrs. At this time, TLC
indicated complete consumption of starting material. The
reaction solution was charged to a separatory funnel and rinsed
with 1N HCl (1 x 30 mL), water (1 x 30 mL), saturated aqueous
NaHCO3 (1 x 30 mL), dried over Na2SO4, decanted and
concentrated under reduced pressure to give a glassy solid. This
crude material was dissolved in DCM, adsorbed onto SiO2 (35
g); subsequent purification by flash chromatography on silica
gel (250 g) eluting with 3:1 hexanes / ethyl acetate gave 19 (2.24
g, 82%) as a colorless, low-viscosity oil. 1H NMR (400 MHz,
CDCl3) δ 4.11 (t, J = 6.8 Hz, 2H), 3.77 (s, 3H), 3.70 (s, 3H),
3.18 (s, 3H), 3.01 (s, 1H), 1.79 (ddd, J = 13.9, 9.6, 4.7 Hz, 1H),
1.74 – 1.66 (m, 1H), 1.66 – 1.50 (m, 2H), 1.50 – 1.40 (m, 1H),
1.40 – 1.29 (m, 1H), 1.24 – 1.15 (m, 1H), 1.15 – 1.06 (m, 4H),
1.04 – 0.89 (m, 2H), 0.87 (d, J = 4.2 Hz, 3H), 0.85 (d, J = 4.2
Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 155.9, 68.6, 61.4,
54.6, 45.2, 41.1, 32.7, 32.6, 29.6, 28.1, 26.2, 20.6, 19.9, 18.5.
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1
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12
13
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16
17
18
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25
26
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colorless oil. H NMR (400 MHz, CDCl3) δ 7.36 – 7.24 (m,
3H), 7.22 (d, J = 6.7, 2H), 4.69 (ddt, J = 10.3, 7.4, 3.1 Hz, 1H),
4.25 – 4.15 (m, 2H), 4.13 (t, J = 6.7 Hz, 2H), 3.94 – 3.83 (m,
1H), 3.77 (s, 3H), 3.25 (dd, J = 13.4, 3.3 Hz, 1H), 2.77 (dd, J =
13.4, 9.6 Hz, 1H), 1.90 (ddd, J = 13.7, 9.3, 4.7 Hz, 1H), 1.80 –
1.67 (m, 1H), 1.67 – 1.52 (m, 2H), 1.52 – 1.41 (m, 1H), 1.41 –
1.31 (m, 1H), 1.30 – 1.18 (m, 4H), 1.18 – 1.01 (m, 2H), 1.01 –
0.92 (m, 1H), 0.88 (d, J = 6.6 Hz, 3H), 0.85 (d, J = 6.5 Hz, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 177.2, 155.8, 152.9, 68.5,
65.9, 55.1, 54.5, 45.0, 40.5, 37.7, 35.2, 32.5, 29.6, 28.0, 26.0,
[α]25 = +16.1° (c 0.27, CHCl3). IR (neat): 2956 (alkane C-H
D
stretch), 1747 (C=O stretch), 1662 (C=O stretch) cm-1. HRMS
(ESI): calc’d for C16H32NO5 [M + H]+ 318.2275, found
318.2272.
20.4, 19.9, 18.6. [α]25 = +46.1° (c 0.20, CHCl3). IR (neat):
D
2956 (alkane C-H stretch), 1778 (C=O stretch), 1746 (C=O
stretch), 1695 (C=O stretch) cm-1. HRMS (ESI): calc’d for
C24H36NO6 [M + H]+ 434.2537, found 434.2532.
(2S,4S,6S)-9-hydroxy-N-methoxy-N,2,4,6-
tetramethylnonanamide (20). To an argon-purged 500-mL
round bottom flask equipped with a magnetic stir bar, sealed
with a rubber septum and containing 19 (2.17 g, 6.84 mmol,
1.00 eq) was added 1% (w/w) K2CO3 in methanol (60 mL). The
resulting colorless solution was stirred 1 hr, at which time
1H NMR of a reaction aliquot appeared to indicate the complete
consumption of starting material. The reaction solution was
diluted with Et2O and washed with water. These washings were
then back-extracted twice with Et2O and the combined organics
dried over Na2SO4, decanted and concentrated under reduced
pressure to reveal a colorless oil with included water. This
material was dissolved in DCM, re-dried over Na2SO4, decanted
and concentrated under reduced pressure to give a colorless oil.
Despite the apparent lack of starting material in the reaction
mixture, flash chromatography on silica gel (150 g) gave both
starting material (0.52 g) and product (1.22 g, 69%) as colorless
oils. The recovered starting material was re-subjected to the
conditions described above (13 mL 1% (w/w) K2CO3 in
methanol for 2 hrs); workup without chromatography gave
additional pure product (0.22 g) which was combined with the
previously-obtained material to give 20 (1.46 g, 82%) as a
colorless oil. 1H NMR (400 MHz, CDCl3) δ 3.70 (s, 3H), 3.68
– 3.56 (m, 2H), 3.18 (s, 3H), 3.02 (s, 1H), 1.80 (ddd, J = 13.8,
9.6, 4.4 Hz, 1H), 1.67 – 1.40 (m, 4H), 1.40 – 1.29 (m, 2H), 1.26
– 1.16 (m, 1H), 1.16 – 1.06 (m, 4H), 1.06 – 0.90 (m, 2H), 0.87
(d, J = 4.1 Hz, 3H), 0.86 (d, J = 4.1 Hz, 3H). 13C{1H} NMR
(101 MHz, CDCl3) δ 63.4, 61.5, 45.3, 41.3, 32.7, 32.5, 32.4,
(2S,4S,6S)-9-((methoxycarbonyl)oxy)-2,4,6-
trimethylnonanoic acid (18). To a 500-mL round bottom flask
containing a magnetically stirred colorless solution of 17 (4.19
g, 9.67 mmol, 1.00 eq) in THF (100 mL) was added a solution
of lithium hydroxide monohydrate (0.811 g, 19.3 mmol, 2.00
eq) and 30% (w/w) hydrogen peroxide (7.83 mL, 77.3 mmol,
8.00 eq) in water (25 mL + 25 mL of washings) at 0 °C. Gas
evolution was noted; the walls of the flask were then rinsed with
an additional 50 mL THF and the resulting cloudy, colorless
mixture was stirred 45 min, at which time TLC indicated the
complete consumption of starting material. Na2S2O3 (8.00 eq)
dissolved in water was added, followed by saturated aqueous
NH4Cl as well as solid NH4Cl to give a biphasic mixture of
approximately neutral pH. Et2O was added, layers were
separated and the aqueous phase extracted with ethyl acetate (3
x 300 mL). The organics were combined, dried over Na2SO4,
decanted and concentrated under reduced pressure to reveal a
colorless oil. Flash chromatography on silica gel (250 g) eluting
with 13:5 hexanes / ethyl acetate + 1% (v/v) AcOH gave 18
1
(2.58 g, 97%) colorless oil. H NMR (400 MHz, CDCl3) δ
10.61 (s, 1H), 4.12 (t, J = 6.8 Hz, 2H), 3.78 (s, 3H), 2.67 – 2.49
(m, 1H), 1.79 – 1.46 (m, 5H), 1.41 – 1.29 (m, 1H), 1.24 – 1.02
(m, 6H), 0.97 (dt, J = 14.0, 7.2 Hz, 1H), 0.89 (d, J = 6.5 Hz,
3H), 0.85 (d, J = 6.5 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3)
δ 182.8, 155.9, 68.5, 54.6, 45.0, 40.9, 37.2, 32.7, 29.6, 28.1,
26.1, 20.3, 19.7, 18.1. [α]25 = +12.9° (c 0.57, CHCl3). IR
30.0, 29.8, 28.3, 20.5, 20.1, 18.5. [α]25 = +28.5° (c 0.22,
D
D
(neat): 2956 (alkane C-H stretch), 1747 (C=O stretch), 1704
(C=O stretch) cm-1. HRMS (ESI): calc’d for C14H27O6 [M + H]+
275.1853, found 275.1858.
CHCl3). IR (neat): 2931 (alkane C-H stretch), 1643 (C=O
stretch) cm-1. HRMS (ESI): calc’d for C14H30NO3 [M + H]+
260.2220, found 260.2193.
(4S,6S,8S)-9-(methoxy(methyl)amino)-4,6,8-trimethyl-9-
oxononyl methyl carbonate (19). To an argon-flushed, 500-
mL round bottom flask containing a magnetically stirred
colorless solution of 18 (2.48 g, 9.04 mmol, 1.00 eq) in DCM
Methoxymethyl 3,5-bis(methoxymethoxy)benzoate (21).
To a 500-mL, flame-dried three neck round bottom flask
equipped with a magnetic stir bar and pressure-equalized
dropping funnel was added 3,5-dihydroxybenzoic acid (10.63
g, 69.0 mmol, 1.00 eq); the flask was then sealed with rubber
septa and purged with argon. DCM (80 mL) was added,
followed by Hünig’s base (72.11 mL, 414 mmol, 6.00 eq). The
resulting off-white suspension was then cooled to 0 °C with
stirring and methoxymethyl chloride (25.00 g, 311 mmol, 4.5
(20
mL)
was
added
(benzotriazol-1-
yloxy)tripyrrolidinophosphonium hexafluorophosphate (4.94 g,
9.49 mmol, 1.05 eq) and diisopropylethylamine (3.85 mL, 22.1
mmol, 2.45 eq). The resulting near-colorless solution was
stirred 10 min, at which time N,O-dimethylhydroxylamine
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The Journal of Organic Chemistry
eq) was added dropwise (dropping funnel) over 1.5 hrs with
of months. 1H NMR (400 MHz, CDCl3) δ 9.91 (s, 1H), 7.21 (d,
1
2
3
4
5
6
7
8
some evolution of white gas. The resulting opaque, dark brown
solution was allowed to come to r.t. and stirred 23 hrs, at which
time TLC appeared to show complete consumption of starting
material. Saturated aqueous NaHCO3 was added and the
biphasic mixture stirred until color had lightened considerably.
Layers were then separated and the aqueous phase extracted
with DCM (2 x 150 mL). Organics were combined and back-
extracted with aqueous KOH (1 N, 2 x 250 mL), washed with
brine, and dried over Na2SO4, then decanted and concentrated
under reduced pressure to reveal the product as a brown oil
(17.84 g) which was used directly in the next step without
further purification. Pure 21 could be obtained as a colorless oil
by purification by flash chromatography on silica gel eluting
with 3:1 hexanes / ethyl acetate. 1H NMR (300 MHz, CDCl3) δ
7.40 (d, J = 2.3 Hz, 2H), 6.95 (t, J = 2.3 Hz, 1H), 5.47 (s, 2H),
5.20 (s, 4H), 3.54 (s, 3H), 3.49 (s, 6H). 13C{1H} NMR (101
MHz, CDCl3) δ 165.5, 158.1, 131.9, 110.9, 109.9, 94.5, 91.1,
57.8, 56.1. IR (neat): 2956 (C-H stretch), 1723 (C=O stretch),
1595 (C=C stretch) cm-1. HRMS (ESI): calc’d for C13H19O7 [M
+H]+ 287.1125, found 287.1116.
J = 2.3 Hz, 2H), 6.98 (t, J = 2.3 Hz, 1H), 5.21 (s, 4H), 3.49 (s,
6H). 13C{1H} NMR (101 MHz, CDCl3) δ 191.6, 158.7, 138.5,
111.1, 110.4, 94.5, 56.2. IR (neat): 2904 (C-H stretch), 2827
(aldehyde C-H stretch), 1700 (C=O stretch), 1593 cm-1. HRMS
(ESI): calc’d for C11H15O5 [M + H]+ 227.0910, found 227.0912.
(R)-1-((R)-4-benzyl-2-thioxothiazolidin-3-yl)-2-((S)-(3,5-
bis(methoxymethoxy)phenyl)(hydroxy)methyl)-4-
methylpentan-1-one (24). To a 500-mL round bottom flask
containing
freshly-prepared38
(R)-1-(4-benzyl-2-
9
thioxothiazolidin-3-yl)-4-methylpentan-1-one (3.43 g, 11.2
mmol, 1.00 eq) was added MgBr2•Et2O (0.434 g, 1.68 mmol,
15 mol %). The flask was equipped with a magnetic stir bar,
sealed with a rubber septum and purged with argon. Ethyl
acetate (10 mL) was then added, followed by 22 (2.53 g, 11.2
mmol, 1.00 eq) as a solution in ethyl acetate (5 mL + 3 mL
washings). Triethylamine (3.12 mL, 22.4 mmol, 2.00 eq) and
trimethylsilyl chloride (2.13 mL, 16.8 mmol, 1.50 eq) were then
added to give a pale yellow opaque suspension. The reaction
mixture was stirred 43 hrs, at which time TLC indicated
complete consumption of starting material. The reaction
mixture was filtered through a plug of silica gel, eluting with
Et2O. The filtrate was then concentrated under reduced pressure
into a 500-mL round bottom flask to give the crude
trimethylsilyl ether as a viscous, yellow oil. This material was
dried under high vacuum overnight; the flask was then charged
with a magnetic stir bar, sealed with a rubber septum and purged
with argon. DCM (100 mL) was added to give a yellow
solution, then trifluoroacetic acid (1.72 mL, 22.4 mmol, 2.00
eq) was added dropwise over 5 min. The resulting solution was
stirred 1.5 hrs; saturated aqueous NaHCO3 was then added and
the resulting biphasic mixture stirred until gas evolution had
ceased. The layers were separated and the aqueous phase
extracted with DCM (2 x 100 mL); the organics were then
combined, dried over Na2SO4, decanted, and concentrated
under reduced pressure onto SiO2 (25 g). This silica-adsorbed
material was then loaded onto a silica gel (250 g) column and
purified by flash chromatography eluting with 9:1 hexanes /
ethyl acetate followed by 7:3 hexanes / ethyl acetate to give 24
(5.31 g, 89%) as a light yellow amorphous solid after azeotropic
drying with heptane and drying on high vacuum. 1H NMR (400
MHz, CDCl3) δ 7.35 – 7.28 (m, 2H), 7.28 – 7.18 (m, 3H), 6.65
(d, J = 2.2 Hz, 2H), 6.56 (t, J = 2.3 Hz, 1H), 5.22 – 5.14 (m,
3H), 5.06 (d, J = 6.8 Hz, 2H), 4.86 (dt, J = 8.3, 4.1 Hz, 1H),
4.80 (td, J = 6.7, 3.3 Hz, 1H), 3.34 (s, 6H), 3.27 (d, J = 9.1 Hz,
1H), 3.10 (dd, J = 13.2, 3.8 Hz, 1H), 2.89 (dd, J = 13.2, 10.7
Hz, 1H), 2.70 (dd, J = 11.3, 6.8 Hz, 1H), 2.61 (d, J = 11.3 Hz,
1H), 1.96 – 1.83 (m, 1H), 1.79 (t, J = 7.1 Hz, 2H), 1.00 (d, J =
6.5 Hz, 3H), 0.96 (d, J = 6.5 Hz, 3H). 13C{1H} NMR (101 MHz,
CDCl3) δ 202.0, 177.1, 158.3, 145.5, 136.4, 129.4, 128.8, 127.2,
106.0, 103.9, 94.3, 74.2, 68.8, 56.0, 48.1, 37.8, 36.5, 31.9, 25.7,
23.7, 22.2. [α]25D = -200° (c 0.24, CHCl3). IR (neat): 3491 (O-
H stretch), 2952 (alkane C-H stretch), 1667 (C=O stretch) cm-1.
HRMS (ESI): calc’d for C27H35NNaO6S2 [M + Na]+ 556.1798,
found 556.1821.
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(3,5-bis(methoxymethoxy)phenyl)methanol (33). A flame-
dried 1000-mL round bottom flask equipped with a magnetic
stir bar, purged with argon and containing crude 21 (14.53 g,
50.8 mmol, 1.00 eq) was sealed with a rubber septum and
charged with DCM (100 mL) to give a pale yellow stirred
solution. The reaction vessel was cooled to -78 °C and DIBAL-
H (100 mL of a 1.0 M solution in hexanes, 100 mmol, 1.97 eq)
was added over 15 minutes via cannula. The yellow reaction
solution was stirred an additional 5 minutes, at which time TLC
showed complete consumption of starting material. Excess
MeOH was added at -78 °C; once gas evolution had ceased, the
reaction mixture was allowed to warm somewhat and saturated
aqueous Rochelle’s salt was added. The biphasic mixture was
allowed to warm to r.t. and stirred overnight, at which time
layers were separated. The aqueous phase was extracted with
diethyl ether (3 x 150 mL); organics were combined, dried over
Na2SO4, decanted and concentrated under reduced pressure to
reveal the crude product (12.04 g) as a viscous, yellow oil which
was used directly in the next step without further purification.
Pure 33 could be obtained as a colorless oil after purification by
flash chromatography on silica gel eluting with 98:2
1
DCM/MeOH. H NMR (400 MHz, CDCl3) δ 6.72 (d, J = 2.3
Hz, 2H), 6.66 (t, J = 2.3 Hz, 1H), 5.16 (s, 4H), 4.64 (s, 2H), 3.48
(s, 6H), 1.68 (s, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ 158.4,
143.5, 107.9, 104.0, 94.4, 65.1, 56.0. IR (neat): 3401 (br, O-H
stretch), 2902 (C-H stretch), 1596 cm-1. HRMS (ESI): calc’d
for C13H19O7 [M +H]+ 287.1125, found 287.1116.
3,5-bis(methoxymethoxy)benzaldehyde (22). To a 1000-
mL round bottom flask containing a magnetically-stirred
solution of crude 33 (12.04 g) in DCM (200 mL) was added
activated manganese dioxide (88.33 g, 1.02 mol). The walls of
the flask were rinsed with DCM (2 x 25 mL) and the black
suspension cooled with an ice bath until the reaction was no
longer exothermic. The reaction was then brought to r.t. and
stirred 21 hrs, at which time TLC showed complete
consumption of starting material. The reaction mixture was
filtered through Celite and the filter cake thoroughly washed
with DCM and the combined filtrates concentrated under
(R)-2-((S)-(3,5-bis(methoxymethoxy)phenyl)((tert-
butyldimethylsilyl)oxy)methyl)-4-methylpentanal (25). A
500-mL flame-dried round bottom flask charged with 24 (5.31
g, 9.95 mmol, 1.00 eq) was equipped with a magnetic stir bar,
sealed with a rubber septum and purged with argon. DCM (80
mL) was added to give a yellow solution, then 2,6-lutidine (2.32
mL, 19.9 mmol, 2.00 eq) was added at 0 °C, followed by tert-
butyldimethylsilyl triflate (3.43 mL, 14.9 mmol, 1.50 eq)
reduced pressure to reveal 9.40
g yellow oil. Flash
chromatography on silica gel (330 g) eluting with 85:15
hexanes/ethyl acetate gave 22 (9.16 g, 59% over three steps) as
a colorless oil that solidified on standing at -30 °C over a period
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dropwise. The cooling bath was then removed and the yellow
crude β-hydroxyphosphonate as a yellow oil. 1H NMR indicated
1
reaction solution allowed to warm towards ambient temperature
over 20 min, at which time TLC indicated the complete
consumption of starting material. Saturated aqueous NaHCO3
and water were added and the biphasic mixture stirred; the
layers were then separated and the aqueous phase extracted with
Et2O (2 x 100 mL). The combined organics were then rinsed
with 1 N HCl (1 x 200 mL), water (1 x 200 mL), saturated
aqueous NaHCO3 (1 x 200 mL) and dried over Na2SO4. The
organics were then decanted and concentrated under reduced
pressure to reveal a viscous yellow oil that contained residual
2,6-lutidine. This crude material was then redissolved in Et2O
(200 mL), re-washed with 1 N HCl (2 x 100 mL), rinsed with
water (1 x 150 mL) and saturated aqueous NaHCO3 (1 x 150
mL), then dried over MgSO4. Filtration and concentration under
reduced pressure followed by stirring under high vacuum
overnight gave the crude TBS ether as a viscous yellow oil. This
material was then charged to a flame-dried 500-mL round
bottom flask equipped with a magnetic stir bar; the flask was
sealed with a rubber septum and purged with argon. DCM (100
mL) was added to give a stirred rich yellow solution. DIBAL-
H (19.5 mL of a 1.0 M solution in hexanes, 19.5 mmol, 2.00 eq)
was then added dropwise at -78 °C over 30 min to give a near-
colorless solution. This solution was then immediately
quenched with saturated aqueous Rochelle’s salt at -78 °C; the
resulting heterogeneous mixture was then allowed to warm to
r.t. with stirring and stirred an additional 2 hrs to give two clear
phases. The layers were separated and the aqueous phase
extracted with DCM (2 x 100 mL). The organics were
combined, dried over Na2SO4, decanted and concentrated under
reduced pressure to give a yellow oil. Flash chromatography on
silica gel (250 g) eluting with 9:1 hexanes / ethyl acetate gave
25 (3.18 g, 73%) as a colorless oil. Characterization agreed with
that recently reported39. 1H NMR (400 MHz, CDCl3) δ 9.70 (d,
J = 3.8 Hz, 1H), 6.65 (d, J = 2.3 Hz, 2H), 6.63 (d, J = 2.2 Hz,
1H), 5.14 (s, 4H), 4.73 (d, J = 6.7 Hz, 1H), 3.46 (s, 6H), 2.69 –
2.58 (m, 1H), 1.62 – 1.51 (m, 1H), 1.46 (dt, J = 13.5, 6.5 Hz,
1H), 1.04 (ddd, J = 13.6, 8.7, 4.7 Hz, 1H), 0.85 (s, 9H), 0.83 (d,
J = 6.5 Hz, 3H), 0.78 (d, J = 6.5 Hz, 3H), 0.01 (s, 3H), -0.20 (s,
3H). 13C{1H} NMR (101 MHz, CDCl3) δ 204.3, 158.1, 145.0,
108.1, 104.1, 94.5, 75.8, 58.1, 55.9, 35.1, 25.7, 25.6, 23.1, 21.8,
18.0, -4.6, -5.2.
an inconsequential 1:1 mixture of diastereomers at C-13. This
crude material was then charged to a 2000-mL round bottom
flask equipped with a magnetic stir bar; the flask was charged
with DCM (65 mL) to give a pale yellow solution. Dess-Martin
periodinane (4.60 g, 10.8 mmol, 1.50 eq) was then added to the
reaction flask against a stream of argon; the reaction vessel was
capped with a rubber septum and the opaque white reaction
suspension stirred 30 min, at which time TLC indicated
complete consumption of starting material. The reaction was
quenched with saturated aqueous NaHCO3 and saturated
aqueous Na2S2O3 and the resulting the biphasic mixture stirred.
Water and solid Na2S2O3 were then added portionwise with
shaking until two clear phases were obtained. Layers were then
separated and the aqueous phase extracted twice with Et2O. The
organics were combined, rinsed with water (1x) and brine (1x),
then dried over Na2SO4, decanted and concentrated under
reduced pressure to reveal a milky, off-white oil. This crude
material was then purified by flash chromatography on silica
gel (250 g) eluting with ethyl acetate to give 5 (3.65 g, 90%) as
a colorless oil. 1H NMR (400 MHz, CDCl3) δ 6.65 (d, J = 2.2
Hz, 2H), 6.62 (t, J = 2.2 Hz, 1H), 5.15 (s, 4H), 4.50 (d, J = 8.5
Hz, 1H), 3.79 (dd, J = 11.2, 9.4 Hz, 6H), 3.46 (s, 6H), 3.35 (dd,
J = 20.9, 15.1 Hz, 1H), 3.21 – 3.05 (m, 2H), 1.65 – 1.54 (m,
1H), 1.34 – 1.21 (m, 1H), 0.81 (s, 9H), 0.77 (d, J = 6.6 Hz, 3H),
0.70 (d, J = 6.5 Hz, 3H), -0.05 (s, 3H), -0.25 (s, 3H). 13C{1H}
NMR (101 MHz, CDCl3) δ 205.1, 158.0, 145.1, 108.5, 104.3,
94.4, 78.5, 58.7, 55.9, 52.8 (d, J = 6.4 Hz), 52.7 (d, J = 6.3 Hz),
43.6 (d, J = 133 Hz), 37.7, 25.7, 25.4, 23.5, 21.6, 18.0, -4.8, -
5.3. [α]25D = -79.5° (c 0.38, CDCl3). IR (neat): 2954 (alkane C-
H stretch), 1712 (C=O stretch) cm-1. HRMS (ESI): calc’d for
C26H47NaO9PSi [M + Na]+ 585.2619, found 585.2601.
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(2S,4S,6S,12R,E)-12-((S)-(3,5-
bis(methoxymethoxy)phenyl)((tert-
butyldimethylsilyl)oxy)methyl)-N-methoxy-N,2,4,6,14-
pentamethyl-11-oxopentadec-9-enamide (26). To a 500-mL
flame-dried, argon-purged round bottom flask containing a
magnetically stirred colorless solution of 20 (0.620 g, 2.39
mmol, 1.00 eq) in DCM (24 mL) was added Dess-Martin
periodinane (1.52 g, 3.59 mmol, 1.50 eq). The flask was sealed
with a rubber septum and the reaction mixture stirred; most of
the solid dissolved to give a slightly cloudy, colorless mixture
which was stirred 18 min, at which time TLC showed no
starting material. Ethanol (0.07 mL, 1.20 mmol, 0.50 eq) was
added to quench any excess periodinane, and the resulting
mixture was stirred an additional 30 min. All volatiles were then
evaporated under reduced pressure to leave a white residue
which was sonicated with 1:1 hexanes / ethyl acetate. The
resulting suspension was then passed through a plug of silica
gel, eluting with 1:1 hexanes / ethyl acetate. The combined
eluent was concentrated under reduced pressure into a 100-mL
round bottom flask to reveal the crude aldehyde as a colorless
oil. This flask was then charged with a magnetic stir bar and
THF (12 mL) to give a colorless stirred solution. Barium
hydroxide octahydrate (0.603 g, 1.91 mmol, 0.80 eq) which had
been pre-treated at 120 °C for 2 hrs was added at room
temperature. The reaction flask was sealed with a rubber septum
and a wide-bore stainless steel needle inserted through the
septum such that the needle reached the bottom of the flask. A
vigorous stream of argon was bubbled through the white
reaction suspension, vented by way of a second needle piercing
the rubber septum which in turn was exhausted through a
mineral oil bubbler. The reaction was thus stirred 25 min, at
dimethyl ((R)-3-((S)-(3,5-bis(methoxymethoxy)phenyl)
((tert-butyldimethylsilyl)oxy)methyl)-5-methyl-2-
oxohexyl)phosphonate (5). To a 500-mL flame-dried, argon-
purged round bottom flask containing a colorless, magnetically
stirred solution of dimethyl methylphosphonate (2.39 mL, 22.0
mmol, 3.05 eq) in THF (35 mL) was added n-BuLi (8.64 mL of
a 2.5 M solution in hexanes, 21.6 mmol, 3.00 eq) dropwise over
8 min at -78 °C; approximately halfway through this addition
the reaction solution became opaque as a fine white suspension
appeared to form. This suspension was stirred 1.5 hrs, at which
time 25 (3.18 g, 7.22 mmol, 1.00 eq) was added dropwise over
25 min as a solution in THF (20 mL + 25 mL washings). The
reaction mixture was then stirred an additional 10 min, at which
time TLC showed complete consumption of 25. The reaction
was quenched via the addition of saturated aqueous NH4Cl and
Et2O at -78 °C; the biphasic mixture was stirred as it was
allowed to come to r.t. gradually. Water and additional Et2O
were added to obtain two clear phases; the layers were then
separated and the aqueous phase extracted with Et2O (2 x 150
mL). The organics were then combined, dried over Na2SO4,
filtered and concentrated under reduced pressure to reveal the
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The Journal of Organic Chemistry
which time 5 (1.34 g, 2.39 mmol, 1.00 eq) was added as a The mixed boronate ester isomers were charged to a 20-mL
1
solution in THF (12 mL), followed by water (0.3 mL). The
opaque white reaction mixture was stirred 1.5 hrs, during which
time the reaction mixture obtained a gel-like consistency and
TLC indicated complete consumption of the aldehyde starting
material. The reaction mixture was partitioned between
saturated aqueous NaHCO3 and Et2O; the aqueous phase was
then diluted with water, the layers separated, and the aqueous
phase extracted with additional Et2O (3 x 25 mL). The organics
were then combined, rinsed with brine, dried over MgSO4,
filtered and concentrated under reduced pressure to reveal 1.51
g pale yellow oil. Flash chromatography on silica gel eluting
with 1:1 hexanes/ethyl acetate gave a viscous, colorless oil.
Azeotropic drying with DCM followed by heptane gave 26
(1.17 g, 70% over two steps) as a colorless oil. 1H NMR (400
MHz, CDCl3) δ 6.89 (dt, J = 15.6, 6.9 Hz, 1H), 6.67 (d, J = 2.3
Hz, 2H), 6.62 (t, J = 2.2 Hz, 1H), 6.28 (d, J = 15.6 Hz, 1H), 5.15
(s, 4H), 4.58 (d, J = 9.2 Hz, 1H), 3.71 (s, 3H), 3.47 (s, 6H), 3.19
(s, 3H), 3.18 – 3.10 (m, 1H), 3.02 (s, 1H), 2.35 – 2.11 (m, 2H),
1.80 (ddd, J = 13.8, 9.4, 4.7 Hz, 1H), 1.66 – 1.41 (m, 4H), 1.35
– 1.17 (m, 3H), 1.11 (d, J = 6.9 Hz, 3H), 1.07 – 0.93 (m, 2H),
0.90 (d, J = 3.0 Hz, 3H), 0.88 (d, J = 2.9 Hz, 3H), 0.75 (s, 9H),
0.72 (app. d, J = 6.6 Hz, 4H), 0.69 (d, J = 6.6 Hz, 3H), -0.11 (s,
3H), -0.31 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 203.7,
157.9, 147.5, 145.8, 131.9, 108.7, 104.0, 94.5, 78.4 61.4, 55.9,
55.6, 45.1, 41.1, 38.4, 35.3, 32.6, 30.1, 29.7, 28.1, 25.7, 25.6,
glass vial equipped with a magnetic stir bar, and THF (3 mL)
was added to give a colorless solution. Sodium perborate
tetrahydrate (0.412 g, 2.68 mmol, 5.00 eq) was added, followed
by water (3 mL). The resulting brown mixture was stirred 13
hrs, at which time the reaction mixture was partitioned between
water and EtOAc to obtain two phases. The layers were
separated and the aqueous phase extracted with Et2O (3 x 7 mL).
The organics were then combined, dried over Na2SO4, decanted
and concentrated under reduced pressure to reveal a yellow oil.
This crude material was then purified by flash chromatography
on silica (50 g) gel eluting with 4:1 hexanes / ethyl acetate to
give recovered starting material (0.113 g) and pure 27 (0.077 g)
as colorless oils; additional product contaminated with 11-epi-
27 was also isolated as a colorless oil. The recovered starting
material was then oxidized as follows: to a colorless,
magnetically stirred solution of recovered starting material in
THF (5 mL) was added a freshly-prepared homogenous
solution of sodium perborate tetrahydrate (0.105 g, 0.687 mmol,
5.00 eq) in water (5 mL). The resulting opaque colorless
mixture was then stirred 15 hrs, at which time TLC indicated
complete consumption of starting material. The reaction was
then worked up in a manner directly analogous to that described
above, giving a colorless oil which was then combined with the
impure product obtained above to give a colorless oil (0.250 g).
A second round of flash chromatography on silica (25 g) gel
again eluting with 4:1 hexanes / ethyl acetate yielded further
pure product (0.027 g), which was combined with that obtained
above, giving pure 27 (0.094 g, 23% over two steps) as a
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23.7, 21.5, 20.5, 19.9, 18.5, 18.0, -4.8, -5.5. [α]25 = -40.2° (c
D
0.84, CHCl3). IR (neat): 2926 (alkane C-H stretch), 1665 (C=O
stretch) cm-1. HRMS (ESI): calc’d for C38H68NO8Si [M + H]+
694.4709, found 694.4701.
(2S,4S,6S,9S,12R)-12-((S)-(3,5-
bis(methoxymethoxy)phenyl)((tert-
1
colorless oil. H NMR (400 MHz, CDCl3) δ 6.70 – 6.62 (m,
3H), 5.18 (s, 4H), 4.61 (d, J = 9.0 Hz, 1H), 4.09 – 3.98 (m, 1H),
3.73 (s, 3H), 3.49 (s, 6H), 3.40 (s, 1H), 3.21 (s, 3H), 3.04 (s,
1H), 2.96 (ddd, J = 10.5, 8.9, 3.7 Hz, 1H), 2.75 – 2.68 (m, 2H),
1.82 (ddd, J = 13.7, 9.1, 4.9 Hz, 1H), 1.65 – 1.44 (m, 5H), 1.44
– 1.32 (m, 2H), 1.32 – 1.19 (m, 3H), 1.14 (d, J = 6.8 Hz, 3H),
1.09 – 0.94 (m, 2H), 0.91 (d, J = 7.4 Hz, 3H), 0.89 (d, J = 7.4
Hz, 3H), 0.83 (s, 9H), 0.78 (d, J = 6.6 Hz, 3H), 0.76 (d, J = 6.5
Hz, 3H), -0.02 (s, 3H), -0.24 (s, 3H). 13C{1H} NMR (101 MHz,
CDCl3) δ 216.2, 158.0, 145.1, 108.6, 104.2, 94.4, 78.1, 67.7,
61.4, 58.8, 55.9, 51.9, 45.3, 41.1, 38.2, 33.8, 32.6, 32.4, 29.8,
28.1, 25.8, 25.8, 23.7, 21.5, 20.7, 20.0, 18.4, 18.0, -4.8, -5.2.
butyldimethylsilyl)oxy)methyl)-9-hydroxy-N-methoxy-
N,2,4,6,14-pentamethyl-11-oxopentadecanamide (27).
A
flame-dried 2-dram vial equipped with a magnetic stir bar was
charged with copper(I) chloride (6.8 mgs, 0.0687 mmol, 12 mol
%) and (S,RP)-Josiphos ethanol adduct (0.132 g, 0.173 mmol,
36 mol %), sealed with a rubber septum, and purged with argon.
To this vial was then added dry, degassed toluene (1 mL) to give
a dark orange, homogenous solution (henceforth “Solution A”).
Solution A was stirred 30 min, then sodium tert-butoxide (0.05
mL of a 2.0 M solution in degassed THF, 0.0864 mmol, 18 mol
%) was added. Meanwhile, a flame-dried 25-mL round bottom
flask was charged with 26 (0.400 g, 0.576 mmol, 1.00 eq),
bis(pinacolato)diboron (0.249 g, 0.979 mmol, 1.70 eq) and a
magnetic stir bar, then sealed with a rubber septum and purged
with argon. Dry, degassed toluene (3 mL) was then added to
this flask, yielding a colorless, homogenous solution. To this
solution was then added 0.83 mL of Solution A (a volume such
that the reaction vessel contained 10 mol % CuCl and 30 mol %
(S,R)-Josiphos), yielding a bright orange homogenous reaction
solution which was stirred 19 hrs, at which time 1H NMR of an
aliquot indicated complete consumption of starting material.
The reaction was quenched by the addition of saturated aqueous
NH4Cl and water. The layers were then separated and the
aqueous phase extracted with EtOAc (2 x 10 mL). The organics
were combined, dried over Na2SO4, decanted and concentrated
under reduced pressure to give a viscous orange oil. This crude
material was then purified by flash chromatography on silica
gel (50 g) eluting with 4:1 hexanes/ethyl acetate to give the
boronate ester as a pale yellow oil; 1H NMR analysis showed a
3:1 mixture of C-11 epimers which were carried on to the next
step without further purification.
[α]25 = -13.2 ° (c 1.1, CHCl3). IR (neat): 3447 (alcohol O-H
D
stretch), 1701 (ketone C=O stretch), 1663 (amide C=O stretch)
cm-1. HRMS (ESI): calc’d for C38H69ClNO9Si [M + Cl]-
746.4436, found 746.4421.
(2S,4S,6S,9S,11S,12S)-12-((S)-(3,5-
bis(methoxymethoxy)phenyl)((tert-
butyldimethylsilyl)oxy)methyl)-9,11-dihydroxy-N-
methoxy-N,2,4,6,14-pentamethylpentadecanamide (28). To
a 20-mL glass scintillation vial containing 28 (0.093 g, 0.131
mol, 1.00 eq) and equipped with a magnetic stir bar was added
anhydrous THF (1.5 mL) to give a colorless solution. The vial
was blown out with argon, capped with a rubber septum and
cooled to -30 °C. BH3•DMS (27 μL, 0.287 mmol, 2.20 eq) was
then added via syringe through the rubber septum and the
resulting solution stirred 14 hrs, at which time TLC indicated
complete consumption of starting material. Saturated aqueous
NaHCO3 (0.75 mL) and 30% (w/w) H2O2 (0.70 mL) were added
sequentially, with gas evolution observed upon the initial
addition of base. The resulting mixture was stirred 15 min, then
Et2O and water were added and the biphasic mixture sonicated
to give two clear phases. The layers were separated and the
aqueous phase extracted with Et2O (2 x 10 mL); the organics
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The Journal of Organic Chemistry
Page 12 of 15
were then combined, dried over Na2SO4, decanted and J = 13.7, 9.0, 4.9 Hz, 1H), 1.59 – 1.42 (m, 5H), 1.38 (s, 3H),
1
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4
5
6
7
8
concentrated under reduced pressure to reveal the product
(0.090 g, 96%) as a colorless oil was used in the subsequent step
without further purification. 1H NMR showed a 3:1 mixture of
28 and 13-epi-28; epimers were separated in the subsequent
1.34 (s, 3H), 1.34 – 1.15 (m, 5H), 1.10 (apparent d, J = 6.8 Hz,
5H), 1.01 (ddd, J = 13.6, 8.4, 5.2 Hz, 1H), 0.98 – 0.89 (m, 1H),
0.88 (s, 9H), 0.87 – 0.82 (m, 6H), 0.81 (d, J = 6.5 Hz, 3H), 0.77
(d, J = 6.5 Hz, 3H), 0.01 (s, 3H), -0.21 (s, 3H). 13C{1H} NMR
(101 MHz, CDCl3) δ 157.6, 146.3, 108.7, 103.3, 98.1, 94.5,
74.7, 69.2, 69.0, 61.4, 55.9, 48.4, 45.1, 41.1, 34.9, 34.0, 33.6,
32.6, 32.5, 31.9, 30.2, 28.1, 26.1, 25.8, 23.2, 22.5, 20.7, 20.0,
19.8, 18.4, 18.1, -4.7, -5.1. [α]25D = -12.8° (c 0.95, CHCl3). IR
(neat): 2952 (alkane C-H stretch), 1669 (C=O stretch) cm-1.
HRMS (ESI): calc’d for C41H79N2O9Si [M + NH4]+ 771.5549,
found 771.5594.
1
step. H NMR (400 MHz, CDCl3) Major (syn) isomer: δ 6.66
(d, J = 2.3 Hz, 2H), 6.61 – 6.57 (m, 1H), 5.14 (s, 4H), 4.63 (d,
J = 5.6 Hz, 1H), 3.97 (dd, J = 9.5, 5.1 Hz, 1H), 3.75 (br s, 1H),
3.70 (s, 3H), 3.46 (s, 6H), 3.18 (s, 3H), 3.01 (br s, 1H), 1.83 –
1.71 (m, 4H), 1.59 – 1.14 (m, 12H), 1.10 (d, J = 6.7 Hz, 3H),
1.07 – 0.95 (m, 1H), 0.90 (s, 9H), 0.89 – 0.82 (m, 9H), 0.75 (d,
J = 6.5 Hz, 3H), 0.04 (s, 3H), -0.20 (s, 3H). Minor (anti) isomer:
δ 6.74 – 6.52 (m, 3H), 5.14 (s, 4H), 4.82 (d, J = 3.5 Hz, 1H),
4.24 (d, J = 10.3 Hz, 1H), 3.76 (br s, 1H), 3.69 (s, 3H), 3.47 (s,
6H), 3.17 (s, 3H), 3.00 (br s, 1H), 1.85 – 1.10 (m, 16H), 1.09 (d,
J = 6.7 Hz, 3H), 1.00 (m, 2H), 0.92 (s, 9H), 0.91 – 0.82 (m, 9H),
0.80 (d, J = 6.5 Hz, 3H), 0.08 (s, 3H), -0.17 (s, 3H). 13C{1H}
NMR (101 MHz, CDCl3) Major (syn) isomer: δ 157.9, 146.5,
108.3, 103.6, 94.4, 74.6, 73.6, 61.4, 55.9, 49.5, 45.2, 41.2, 39.7,
36.1, 35.3, 32.7, 32.2, 29.9, 28.2, 25.8, 23.0, 22.3, 20.7, 20.0,
18.4, 18.1, -4.5, -5.2. Minor (anti) isomer: δ 158.0, 145.9, 107.9,
103.7, 94.5, 78.0, 69.3, 67.3, 61.4, 56.0, 55.9, 47.7, 45.1, 41.2,
40.4, 34.5, 34.3, 32.7, 29.8, 28.2, 25.9, 25.7, 23.4, 22.0, 20.6,
20.0, 18.4, 18.0, -4.5, -5.3. HRMS (ESI): calc’d for
C38H71NNaO9Si [M + Na]+ 736.4790, found 736.4848.
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Baulamcyin A (1). A 2-dram vial equipped with a magnetic
stir bar and containing 29 (29.9 mgs, 0.0396 mmol, 1.00 eq)
was sealed with a rubber septum, purged with argon and
charged with Et2O (2 mL) to give a colorless solution. Ethyl
magnesium bromide (0.13 mL of a 3.0 M solution in diethyl
ether, 0.396 mmol, 10.0 eq) was added dropwise at room
temperature, and the resulting solution was stirred 19 hrs, at
which time the reaction mixture was cooled to 0 °C and
saturated aqueous NH4Cl was added dropwise until gas
evolution ceased. Water and additional diethyl ether were added
and the resulting biphasic mixture stirred until two clear phases
were obtained. The layers were then separated and the aqueous
phase extracted with diethyl ether (3 x 10 mL). The organics
were combined, dried over Na2SO4, decanted and concentrated
under reduced pressure to reveal the ethyl ketone (23.1 mg) as
a colorless oil. A portion of this material was then deprotected
as follows: a 20-mL glass vial equipped with a magnetic stir bar
crude was charged with crude ethyl ketone (20.4 mg, 0.0282
mmol, 1.00 eq) followed by THF (1 mL) and methanol (1 mL)
to give a colorless solution. 2 N HCl (1 mL) was then added
dropwise to give an opaque white mixture which clarified upon
stirring. The reaction solution was stirred 36 hrs, then quenched
by the slow, portionwise addition of solid NaHCO3 until gas
evolution ceased and the pH of the reaction approached
neutrality. EtOAc and water were added to give two clear
phases, which were then separated. The aqueous phase was then
extracted with EtOAc (4 x 10 mL). The organics were
combined, dried over Na2SO4, decanted and concentrated under
reduced pressure to reveal a colorless oil. This crude residue
was dissolved in EtOAc and purified by PTLC eluting with 1:1
heptane / ethyl acetate to reveal baulamycin A (8.9 mgs, 51%
over two steps) as a colorless oil. Characterization matched that
(2S,4S,6S)-8-((4S,6S)-6-((1S,2S)-1-(3,5-
bis(methoxymethoxy)phenyl)-1-((tert-
butyldimethylsilyl)oxy)-4-methylpentan-2-yl)-2,2-
dimethyl-1,3-dioxan-4-yl)-N-methoxy-N,2,4,6-
tetramethyloctanamide (29). To a 20-mL glass scintillation
vial equipped with a magnetic stir bar and containing 28 and
13-epi-28 (0.051 g, 0.0714 mmol, 1.00 eq, 3:1 ratio of epimers)
was added dry acetone (2 mL) to give a colorless solution.
Sodium sulfate (0.101 g, 0.714 mmol, 10.0 eq) was added,
followed by p-TsOH (1.2 mgs, delivered as 0.1 mL of a freshly-
prepared solution of 12 mgs p-TsOH in 1 mL dry acetone,
0.00714 mmol, 10 mol %) to give a colorless suspension. This
reaction mixture was then stirred 1 hr, at which time TLC
indicated complete consumption of starting material. The
reaction was quenched with saturated aqueous NaHCO3 (12
drops) to obtain a near-neutral mixture which was then
partitioned between EtOAc (7 mL) and water (5 mL). The
resulting layers were separated and the aqueous phase extracted
with EtOAc (3 x 10 mL). The organics were then combined,
dried over Na2SO4, decanted and concentrated under reduced
pressure to reveal a colorless oil (0.051 g, 94%). This crude
residue was then dissolved in anhydrous DCM (3.5 mL) and
transferred to a 20-mL glass scintillation vial containing a
magnetic stir bar. The vial was blown out with argon, capped
with a rubber septum and cooled to 0 °C, at which time p-TsOH
(0.6 mgs, delivered as 0.1 mL of a freshly-prepared solution of
5.8 mgs p-TsOH in 1 mL dry DCM, 0.00338 mmol, 5 mol %)
was added. This colorless solution was then stirred 4 hr 15 min,
at which time the solution was quenched with Et3N (5 drops)
and concentrated under reduced pressure to give 29 together
with 13-epi-28 as a pale yellow oil. This crude material was
then dissolved in DCM and loaded directly onto a silica gel (2.5
g) plug, which was eluted with several plug volumes of 7:3
hexanes / ethyl acetate, giving pure 29 (0.036 g, 67%) as a
colorless oil. 1H NMR (400 MHz, CDCl3) δ 6.66 (d, J = 2.3 Hz,
2H), 6.58 (t, J = 2.2 Hz, 1H), 5.18 – 5.09 (m, 4H), 4.73 (d, J =
5.5 Hz, 1H), 3.96 – 3.83 (m, 1H), 3.70 (apparent s, 4H), 3.46 (s,
6H), 3.18 (s, 3H), 3.01 (s, 1H), 1.89 – 1.82 (m, 1H), 1.78 (ddd,
1
previously reported in the literature in all respects. H NMR
(400 MHz, methanol-d4) δ 6.33 (d, J = 2.2 Hz, 2H), 6.15 (t, J =
2.2 Hz, 1H), 4.47 (d, J = 6.8 Hz, 1H), 4.00 (dt, J = 10.0, 3.4 Hz,
1H), 3.74 – 3.64 (m, 1H), 2.75 (dqd, J = 9.1, 6.9, 5.0 Hz, 1H),
2.64 – 2.242 (m, 2H), 1.88 (m, 1H), 1.78 (m, 1H), 1.72 (m, 1H),
1.61 – 1.46 (m, 2H), 1.46 – 1.27 (m, 5H), 1.27 – 1.13 (m, 4H),
1.06 (d, J = 6.9 Hz, 3H), 1.02 (t, J = 7.3 Hz, 3H), 0.99 – 0.90
(m, 2H), 0.89 (d, J = 6.5 Hz, 3H), 0.86 (d, J = 6.6 Hz, 3H), 0.83
(d, J = 6.6 Hz, 3H), 0.77 (d, J = 6.5 Hz, 3H). 13C{1H} NMR
(101 MHz, methanol-d4) δ 218.6, 159.3, 148.3, 106.3, 102.2,
76.9, 73.7, 72.9, 48.8, 46.6, 45.0, 42.0, 41.0, 37.6, 35.7, 35.4,
33.4, 31.2, 29.5, 26.9, 23.6, 22.8, 20.9, 20.6, 18.2, 8.1. [α]25
=
D
-15.3° (c 0.65, CH3OH). HRMS (ESI): calc’d for C28H49O6
[M + H]+ 481.3524, found 481.3529.
ASSOCIATED CONTENT
Supporting Information.
Copies of 1H and 13C NMR spectra for newly-reported compounds.
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(16) Keck, G. E.; Boden, E. P.; Mabury, S. A. A useful Wittig
reagent for the stereoselective synthesis of trans-alpha,beta.-
unsaturated thiol esters. J. Org. Chem. 1985, 50 (5), 709-710.
(17) Reduction under Fukuyama’s conditions40 was also
quantitative.
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This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
*Robert M. Williams: robert.williams@colostate.edu
*David H. Sherman: davidhs@umich.edu
ACKNOWLEDGEMENT
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We are grateful to the National Institutes of Health R35
GM118101, and the Hans W. Vahlteich Professorship (to D.H.S.),
and CA070375 (to R.M.W. and D.H.S.), and Colorado State
University for supporting this work.
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Insert Table of Contents artwork here
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Me Me
Me Me
"dry ozonolysis"
gram scale
>95% yield
HO
OCOOMe
OCOOMe
O
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OH OH OH
O
• N-acyl oxazolidinone alkylation
• Asymmetric conjugate addition
• Asymmetric -borylation
• syn-selective BH3-DMS reduction
• Evans thiazolidinethione aldol
HO
Me
Me
Me Me Me Me
baulamycin A
OH
broad spectrum antibiotic
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