A scalable, Nonenzymatic synthesis of highly stereopure difunctional C4 secondary methyl linchpin synthons

Article abstract of DOI:10.1021/jo5025392

In response to the continuing widespread use of heterodifunctional C₄ secondary methyl building blocks in asymmetric synthesis, we have developed a mole-scale, two-step synthesis of a 1:1 mixture of the diastereomers of 3-bromo-2-methyl-1-propyl camphorsulfonate (casylate). One isomer (2S) has been crystallized to >99:1 dr in ～25% yield. Equilibration of the mother liquor (enriched in 2R) to a 1:1 mixture and recrystallization significantly raises the overall yield of 2S. Applications of 2S include chemoselective Grignard coupling, enabling the very short synthesis of highly stereopure long-chain natural products containing remote, methyl-bearing stereogenic centers [e.g., (R)-tuberculostearic acid], with complete control of configuration. Also, Ag-mediated, completely chemoselective Br displacement from 2S leads to a range of >99:1 er difunctional synthons. Both applications incorporate concurrent recovery of CasO. The enantiomer of 2S can be made from commercial (1R)-10-CasOH.

Full text of DOI:10.1021/jo5025392

Article
pubs.acs.org/joc
A Scalable, Nonenzymatic Synthesis of Highly Stereopure
Difunctional C4 Secondary Methyl Linchpin Synthons
Shekar Mekala and Roger C. Hahn*
Department of Chemistry, Syracuse University, Syracuse, New York 13244-4100, United States
S
* Supporting Information
ABSTRACT: In response to the continuing widespread use of heterodifunctional C4 secondary methyl building blocks in
asymmetric synthesis, we have developed a mole-scale, two-step synthesis of a 1:1 mixture of the diastereomers of 3-bromo-2-
methyl-1-propyl camphorsulfonate (casylate). One isomer (2S) has been crystallized to >99:1 dr in ∼25% yield. Equilibration of
the mother liquor (enriched in 2R) to a 1:1 mixture and recrystallization significantly raises the overall yield of 2S. Applications
of 2S include chemoselective Grignard coupling, enabling the very short synthesis of highly stereopure long-chain natural
products containing remote, methyl-bearing stereogenic centers [e.g., (R)-tuberculostearic acid], with complete control of
configuration. Also, Ag-mediated, completely chemoselective Br displacement from 2S leads to a range of >99:1 er difunctional
synthons. Both applications incorporate concurrent recovery of CasO. The enantiomer of 2S can be made from commercial (1R)-
10-CasOH.
blocks at a very high level of stereoisomeric purity. In the context
of the difunctional C4 framework, 3-X-2-methyl-1-propyl
casylates10 (X = Cl/Br/I) were attractive because the two
isomers are diastereomers, with different melting points and
solubilities, making feasible separation by crystallization. Further,
the nucleofugality of both halides and sulfonates could lead to
chiral synthons conveniently usable for further elaboration. The
bromalkyl casylate pair 2R and 2S, with a critical similarity in Br/
OCas nucleofugality (see below) and a 30° mp difference,11 was
chosen for further study. To obtain pure 2R and 2S for
spectroscopic comparison and for seeding, commercially
available (R)- and (S)-3-bromo-2-methyl-1-propanol were
camphorsulfonated in standard fashion.
INTRODUCTION
■
Much effort has focused on preparation and use of chiral
secondary methyl synthons. Among the most versatile of these
are difunctional C4 secondary methyl building blocks (Figure 1).
Roche esters (methyl 3-hydroxy-2-methylpropionates; non-
crystallizable) have been widely applied to the synthesis of
biologically active compounds. There are many routes to their
preparation,1−4 but none has achieved a greater ee than the
products from microbe-mediated (formal) β-hydroxylation of
isobutyric acid.5 Other commonly used C4 chiral synthons are
products of desymmetrization of very cheap 2-methyl-1,3-
propanediol or its diesters.1 Many have sought convenient,
scalable procedures to convert this diol to high er synthons. Trost
et al.6 have discussed advantages and disadvantages of enzymatic
desymmetrizations and those mediated by nonenzymatic
catalysts and chiral auxiliaries. Their chiral catalyst provided a
desymmetrized 2-methyl-1,3-diol building block in 90% ee.
However, large-scale preparation of >99% stereopure C4 chiral
building blocks of the type described here remains rare.7,8
Our approach to difunctional C4 secondary methyl building
blocks was inspired by the observation that many alkyl
camphorsulfonates (casylates)9 are crystalline. Crystallization
remains a superior and often essential avenue to chiral building
RESULTS AND DISCUSSION
■
The quest for a large-scale route to pure 2S started with the
scalable, quaternary salt-catalyzed bromide−chloride exchange12
of commercially available racemic 1-bromo-2-methyl-3-chloro-
propane and 1-bromobutane, to provide dibromide 1 (Scheme 1,
eq 1). This exchange and all others herein are thermoneutral and
Received: November 6, 2014
© XXXX American Chemical Society
A
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Figure 1. Some chiral C4 difunctional building blocks.
Scheme 1. Preparation of 2R and 2S
Figure 2. Partial spectra of (a) ∼1:1 2S/2R, (b) >99:1 2S/2R, and (c) 2R prepared from 2S.
scalable and need no solvent; the mixtures are homogeneous at
exchange temperatures.
In the conversion of dibromide 1 to a 2R/2S mixture by n-
Bu4NBr-catalyzed Br−OCas exchange (Scheme 1, eq 3), methyl
or ethyl casylate (Me/EtOCas) was used as the covalent casylate
source. Transfer of casylate to the C4 manifold was driven to
completion by distilling out low-boiling Me/EtBr. Casylate
displaces bromide more readily than do the arenesulfonates
previously studied;14 this superiority has not been quantitated.
Me/EtOCass was made directly from camphorsulfonic acid
(conveniently on a one-mole scale) by modification of the
reported Arbuzov reaction of TsOH with trialkyl phosphites
(Scheme 1, eq 2).13 Running the reaction neat shortened the
time to 2 h and removed the need for solvent handling.
B
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The exchange (eq 3) was performed with 3 equiv of 1 (6 equiv of
Br vs OCas), to minimize the percentage of dicasylate 3 at
equilibrium. The equilibrated product mixture, as determined by
the disappearance of Me/EtBr (which removes 1 equiv of Br),
included excess 1, a 1:1 mixture of 2R and 2S, and 3; the mole
ratio of total bromide to total casylate was approximately 5:1,
thereby affording 1, (2R+2S), and 3 in the approximate
(statistically predicted for Br (x) and OCas (y) by x2 + 2xy +
y2) molar proportions 25:10:1. Unreacted dibromide 1 was
distilled out at reduced pressure, to avoid increasing the
proportion of dicasylate 3 by concurrent reversible CasO−Br
exchange. The residue was taken up in Et2O, and the catalyst,
now n-Bu4NOCass (4, reusable for the same reaction), was
separated by H2O extraction. The 2R + 2S mixture was easily
separated from 3 by silica gel chromatography, but could be left
in the mixture with minimal effect on subsequent crystallization.
Seeding a MeOH solution of the 2R + 2S mixture (and 1−2%
residual dibromide 1) with pure 2S afforded ∼85:15 dr 2S
crystals; the mother liquor contained a 22:78 2S/2R mixture.
Subsequent recrystallizations of the ∼85:15 dr material from
Et2O (preferably via evaporative concentration vs controlled
cooling) afforded ∼25% of >99:1 dr 2S. In the range 95:5 2S/2R
to 5:95 2S/2R, ratios were assayed by 400-MHz 1H NMR, by a
resolved pair of doublets (δ 3.025 and 3.015, respectively)
produced by the diastereogenic geminal protons at C10 of the
camphor moiety; the other pair of doublets (δ 3.63) is
unresolved. Above 95:5 2S/2R, samples were assayed using the
ddd’s for the methylene protons adjacent to the OCas group.
These are nearly identically centered in the two isomer spectra (δ
4.26), but the outside peaks for 2R are baseline separated (δ 4.32
and 4.19) from all other peaks and discernible up to >99:1 dr.
Spectroscopic comparisons of (a) ∼1:1 2S/2R, (b) >99:1 dr 2S/
2R, and (c) 2R prepared from 2S provide qualitative evidence of
the high dr of 2S (Figure 2).15 The equally stereopure
enantiomer of 2S (ent-2S) can be prepared via the same
protocol, from commercially available (1R)-10-camphorsulfonic
acid.
crystallization differs from a “crystallization-induced asymmetric
transformation”, in that isomer interconversion and crystal-
lization are not concurrent.16 The observed 2S/2R equilibration
appears to be the first example of diastereomer interconversion
mediated by concurrent reversible SN2 reactions at two
nonstereogenic centers.
With >100 g of >99:1 dr 2S in hand, we turned to the critical
question of chemoselectivity17,18 in using this chiral synthon.
Reaction of 2S with a range of nucleophiles revealed a 9:1 or
greater preference for bromide displacement, but direct OCas
displacement by Nu−, along with attack on OCas by in situ
generated Br−, appreciably degraded the chemical and optical
purity of the products. A solution to this problem was found in
the known halophilicity of Ag+ and insolubility of AgBr, which
enabled a nearly quantitative, completely selective silver-
assisted19,20 conversion of 2S to the nitrate ester 5R (Scheme
3, eq 4). Zinc in acetic acid21,22 selectively reduced 5R to alcohol
Scheme 3. Preparation of 5R, 6R, and 7a/7b
6R (Scheme 3, eq 5), which was reacted with n-Bu4NCl/Br to
give haloalkanol 7a or 7b and n-Bu4NOCass (Scheme 3, eq 6).
The clean, high-yielding conversion of 2S or ent-2S to 6R or
ent-6R opens access to other >99:1 er difunctional building
blocks1 by chemoselective nucleophilic displacement of OCas
from 6R/ent-6R by an array of nucleophiles (e.g., CN−,
To improve the 25% yield, we used the reversibility of casylate−
bromide exchange to obtain additional pure 2S from 2R and/or
dicasylate 3. A mixture of dibromide 1, 2S/2R mixture (∼25:75),
3, and catalyst, under exchange conditions (Scheme 2),
equilibrated (to nearly 1:1 diastereomers) in 4 h.
Recrystallization as before gave an improved (∼50%) yield of
2S, based on the overall amount of Et/MeOCass. Repetitions of
the equilibration−crystallization cycle in this manner can further
increase the yield, but efficiency increases will depend on
improved separation in the crystallization steps. Equilibration−
−
−
(RO2C)2CH−, I−, N3 , ArS−, ArSO2 . RNH2). However, widely
used 7b and ent-7b (or their protected counterparts) and rarely
used 7a and ent-7a are considered keys, because their formation
by reaction of 6R/ent-6R with n-Bu4NBr/Cl simultaneously puts
OCas most efficiently into reusable form. The building blocks
mentioned above often have been prepared from the
corresponding Roche esters and desymmetrization products of
2-methyl-1,3-diol,1 and 7b and ent-7b are commercially
available, but very expensive. The present method provides
another avenue to these highly pure synthons, but differs from
other methods in having the options of increasing the dr of 2S (or
its enantiomer) by recrystallization, and conveniently tracking
the diastereomeric purity of 2S to a very high level by 1H NMR.
The presence of the OCass auxiliary in 5R and 6R similarly
Scheme 2. Equilibration of 2R and 2S
1
enables H NMR confirmation of their very high dr’s (isomer
signals not detected). Alcohols 7/ent-7 (or protected deriva-
tives) in which X = CN are of particular interest as one form of a
heterodifunctional isoprenoid building block.15,23,24 Also, many
uses of alcohols 7/ent-7 in which X = I have been reported.25,26
The success of the 2S to 7 sequence moved us to consider a
second approach to increasing the yield of purified 2S. After
converting very cheap 2-methyl-1,3-diol to racemic 7b on a large
scale,27 we made a 1:1 mixture of 2S/2R by direct
camphorsulfonation of the alcohol, thus avoiding the presence
C
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Scheme 4. Inversion of 2R and 2S
of dibromide 1, Me/EtOCas, dicasylate 3, and n-Bu4NOCas (4).
We planned to crystallize this mixture as before and subject the
anticipated ∼25:75 2S/2R mother liquor to the sequence seen in
Scheme 3, eqs 4−6. The established chemoselectivity of this
sequence would deliver 25:75 7b/ent-7b, which could be
camphorsulfonated to 75:25 2S/2R, thereby completing an
overall inversion of 2R and 2S (Scheme 4).
Recovery and reuse of expensive ingredients (Ag and OCas) in
the conversion of 2S to 7 reduces cost and waste. In the Ag+-
assisted displacement of Br, 1.5 equiv of AgNO3 were used; the
excess was completely recovered. AgBr also was quantitatively
recovered and reduced by Zn0 to Ag0 (Scheme 5, eq 7).29 The n-
Bu4NOCass byproduct from conversion of 6R to 7, along with
excess n-Bu4NX, reacted with Me2SO4 to give MeX (distilled
out) and recyclable MeOCass (Scheme 5, eq 8).30
However, crystallization of the 1:1 2S/2R mixture, containing
no dibromide 1, dicasylate 3, or n-Bu4NOCas (4) gave a
disappointing yield of 85:15 2S/2R crystals and a disappointing
composition (36:64 2S/2R) of the mother liquor (ML). ML
crystallization (MeOH), seeding with 2S, gave crystals enriched
in 2R (30:70 2S/2R) (see Experimental Section). Only after
many more crystallizations was a 25% yield of >99:1 dr 2S
obtained. This experience and previous crystallization experi-
ments raised the suspicion that the 2S/2R system is susceptible
to nucleation inhibition,28 particularly of 2R, by the presence of
one or more impurities. When another 36:64 2S/2R solution in
MeOH with 2 mol % added dibromide was seeded with 2S and
cooled, crystallization was much slower, but gave 81:19 2S/2R
material. The presence of “impurities” thus can account for the
superior selectivity obtained in crystallization of 1:1 2S/2R
mixtures obtained from Br−OCas exchange, which contain small
amounts of dibromide. Although kinetic recrystallizations of
<40:60 2S/2R mixtures (seeding with 2R) can afford <25:75
material suitable for inversion, the process is not efficient, making
the inversion protocol less appealing. Also, repeated crystal-
lizations from MeOH increase the appearance of substrate
solvolysis products. On the other hand, recrystallizations of the
initial 85:15 2S/2R crystals proceed well in Et2O, with no
substrate degradation. We compared the merits and drawbacks of
the two protocols. Catalyzed equilibration avoids use of HBr,
CasCl, and AgNO3 and a reduction step, but incurs some loss/
degradation of material and is limited to a 1:1 2S/2R mixture in
starting the recycle process. The inversion protocol can provide
>75:25 2S/2R to start the second crystallization sequence, but
the recycle process, starting with the AgNO3 reaction, is longer
and lower yielding. Overall, optimized catalyzed equilibration is
deemed the better protocol.
Scheme 5. Recycling Ag and OCas
A second chemoselective reaction of 2S/ent-2S, which does
not require use of Ag+, also has been uncovered. In 2000, Cahiez
et al.31 reported that bromoalkanes bearing other functional
groups (Cl, ArSO3, CN, OH, CO2H, CO2R, and CH2COR), in
the presence of catalytic Li2CuCl4 and additive NMP, chemo-
selectively couple with organomagnesium reagents at the Br site
in excellent yields [85−90% except for the bromoalkyl
arenesulfonate (55%)] (eq 9). These results, in which
arenesulfonates were
RMgCl + Br(CH2)nFG ⎯⎯⎯T⎯⎯H⎯⎯F⎯,⎯⎯N⎯⎯M⎯⎯P⎯→ R(CH2)nFG
Li2CuCl4 cat., rt
(1.05 equiv)
(9)
less reactive than bromides, and ketones were tolerated, moved
us to test the procedure with 2S. Indeed, coupling with
CH3(CH2)6MgBr (1.1 equiv) proceeded cleanly to give alkyl
casylate 8 in 81% yield (unoptimized). With a high-yield
conversion of alkyl casylate to alkyl bromide/chloride (and
concurrent initiation of casylate reuse) already in hand, this
chemoselective reaction further enhances the versatility of 2S/
ent-2S as a chiral linchpin,32 as shown in a five-step formal
synthesis of (R)-tuberculostearic acid (11) (Scheme 6), a
component of a major phospholipid from M. tuberculosis,
recently synthesized in five steps and 95:5 er.33 Coupling of
bromide 9 (made from 8 in >95% yield) with the Grignard of
D
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Scheme 6. Formal Synthesis of (R)-Tuberculostearic Acid (11)
300/400 MHz (1H spectra) and 75/100 MHz (13C spectra). Chemical
shifts (δ, ppm) were referenced to the residual CHCl3 signal (δ 7.26
ppm for 1H NMR and δ 77.00 ppm for 13C NMR). Each resonance was
given with chemical shifts in ppm; multiplicities were given as s (singlet),
d (doublet), t (triplet), q (quartet), dd (doublet of a doublet), m
(multiplet), b (broad) if signals were overlapped. Signals are assigned
where significant. Elemental analyses were obtained on an elemental
analyzer with a thermal conductivity detector and 2 M GC column at 50
°C. High resolution mass spectra were obtained using an FTICR-MS
instrtument. Optical rotations were measured in a given solvent on a
dual wavelength (589/546 nm) automatic polarimeter with a 1 dm cell.
Values are reported as specific rotations: [α]D, T, concn c in solvent (g/
100 mL). Anhydrous THF was obtained from a solvent purification
system. Acetone and CH2Cl2 were dried (24 h) over activated 4 Å
molecular sieves. Unless otherwise indicated, all reactions were
conducted in oven- (140 °C) or flame-dried glassware, using distilled
and degassed solvents under a positive pressure of dry Ar with standard
Schlenk techniques. Air-sensitive reagents were stored in a glovebox
containing dry Ar. Stainless steel syringes or cannulas (oven-dried at 140
°C and cooled under Ar) were used to transfer air- and moisture-
sensitive liquids. Workups and purifications were carried out with
reagent grade commercial solvents.
THP-protected 8-bromo-1-octanol gave ether 10, convertible in
two known steps to 11.34,35 The demonstrated diastereomeric
purity of 8 (1H NMR) can be can be taken as evidence for the
enantiomeric purity of 11.
This sequence demonstrates that 2S (or ent-2S) can be
conveniently and efficiently used in a scalable, nonenzymatic
linchpin process to place a methyl branch, with either
configuration in >99:1 er, at any desired position in a long-
chain, sparsely functionalized hydrocarbon structure. Such
compounds, many containing more than one methyl branch,
abound in the world of insect (and other animal) communica-
tions. Because of the difficulty in determining the absolute
configurations of such branches in biologically active substances,
there is a need for simple ways to make all stereoisomers of these
compounds.36−38 Future work will explore those ways, as well as
other uses of 7.39,40
CONCLUSION
■
A protocol has been developed that converts racemic 1-bromo-3-
chloro-2-methylpropane or racemic 3-bromo-2-methyl-1-prop-
anol to a difunctional C4 chiral building block (2S) in >99:1 dr
(or greater if desired). A bromide−casylate exchange process has
been developed that, because of its reversibility and the Cs
symmetry of the C4 skeleton, also provides a way to increase the
yield of 2S at the expense of 2R. Chemoselective reactions of 2S
can afford a range of >99:1 er difunctional chiral synthons and
concurrently release the casylate auxiliary for reuse. Chemo-
selective organometallic coupling of the bromide in 2S has been
shown to lead to highly efficient, enantioselective installation of
remote, methyl-bearing secondary chiral centers in (e.g.) long-
chain hydrocarbons, again with concurrent release of casylate.
The concept introduced here, of placing an easily installed and
easily removed chiral sulfonate into a chiral/prochiral manifold
to create separable/crystallizable diastereomers, will be pursued
further. Efforts will continue to improve crystallization efficiency
and to remove silver from the process.
Warning: Many of these compounds are known or suspected to be
toxic and/or carcinogenic.
1. Starting Materials for Bromide−Camphorsulfonate Ex-
change. 1.1. 1,3-Dibromo-2-methylpropane (1); Chloride−Bromide
Exchange. A mixture of 1-bromo-3-chloro-2-methylpropane (686 g,
4.00 mol), 1-bromobutane (1654 g, 12 mol), and n-Bu4NBr (26.8 g, 0.08
mol, 0.5 mol %) was heated in a 2 L, three-neck flask with a magnetic
stirrer, immersion thermometer, and 30 cm fractionating column (glass
helices). Distillation of 1-chlorobutane (1 atm) was continued for 23 h.
The pot solution was further fractionated at ∼100 mm; bromobutane
(bp 60 °C) was removed until the pot reached 82 °C. The washed, dried,
and filtered residue was fractionally distilled [bp 33 °C @ 3 mm (same
column)] to give >99% pure 1 (745 g, 86%). 1H NMR and 13C NMR
data matched literature values.41 1H NMR (400 MHz, CDCl3): δ 3.53−
3.43 (m, 4H), 2.23−2.12 (m, 1H), 1.15 (d, J = 6.8 Hz, 3H); 13C NMR
(100 MHz, CDCl3): δ 37.6, 36.9, and 17.8.
1.2. Ethyl (1S)-Camphor-10-sulfonate [Ethyl (1S) Casylate;
EtOCass] (12). (1S)-Camphor-10-sulfonic acid (116 g, 0.50 mol,
predried at 80 °C in vacuo) and triethyl phosphite (97 g, 0.58 mol)
were swirled together until homogeneous (moderate exotherm) and
then heated for 2 h at 50 °C. 1H NMR analysis indicated 100%
conversion to EtOCass (no CH3 singlets for the acid at δ 1.06, 0.96).
After kugelrohr removal of volatiles (76 °C/0.03 mmHg), the residue
was crystallized (MeOH) to afford 126 g (96%) of 12, mp 42.1−42.7 °C
(lit42 mp 46 °C). 1H NMR (400 MHz, CDCl3): δ 4.44−4.30 (m, 2H),
3.60 (d, J = 15.1 Hz, 1H), 2.98 (d, J = 15.1 Hz, 1H), 2.56−2.35 (m, 2H),
2.13 (t, J = 4.6 Hz, 1H), 1.96 (d, J = 18.5 Hz, 1H), 1.66 (m, 1H), 1.45 (m,
EXPERIMENTAL SECTION
■
General Experimental Methods. Melting points were measured
on a standard apparatus and are uncorrected. Analytical TLC was
performed on POLYGRAM Sil G/UV254 and visualized under a 254 nm
UV lamp and/or stained using alkaline aq KMnO4 or 2,4-DNP in aq
H2SO4−EtOH. Column chromatography was performed with silica gel,
60 Å, 40−63 μm. 1H and 13C NMR spectra were recorded in CDCl3 at
E
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1H), 1.41 (t, J = 7.0 Hz, 3H), 1.12 (s, 3H), 0.89 (s, 3H); 13C NMR (100
MHz, CDCl3): δ 214.5, 66.8, 57.9, 47.9, 46.7, 42.7, 42.5, 26.8, 24.82,
19.8, 19.7, 15.0.
cleanly separated (1:1 2R + 2S) from dicasylate 3. Crystallization of 3
afforded pure material, mp 89−91 °C; 1H NMR δ 4.32 (dd, J = 5.0, 9.9
Hz, 1H), 4.27 (overlapping dd’s, 2H), 4.21 (dd, J = 6.6, 9.9 Hz, 1H), 3.61
(d, J = 15.1 Hz, 1H), 3.04 (d, J = 15.1 Hz, 1H), 1.10 (s, 3H), 1.09 (d, J =
8.0 Hz, 1H), 0.88 (s, 3H), + other camphor moiety signals. 13C NMR
(100 MHz, CDCl3): δ 214.3, 70.3, 70.2, 57.9, 48.1, 46.9, 46.8, 42.8, 42.5,
33.4, 26.9, 24.9, 19.7, 19.6, and 13.1. Anal. Calcd for C24H32O8S2: C,
55.57; H, 7.38. Found: C, 55.79; H, 7.07.
2.2. Equilibration of a 2R-Enriched Mixture of 2S and 2R. A
36:64 mixture of 2S/2R (77.85 g, 0.212 mol), dicasylate 3 (12.67 g,
0.0244 mol), and dibromide 1 (145 g, 0.67 mol) was heated with n-
Bu4N+CassO− (4, 28.1 g, 0.059 mol = ∼3 mol % of total functional
groups). After 4 h @120 °C (bath temp), the mixture (now 49:51 2S/
2R) was cooled, and Et2O (300 mL) and H2O (150 mL) were added.
The organic layer was washed with H2O (3 × 50 mL; combined with the
first aq layer) and satd aq NaCl (50 mL) and dried over Na2SO4−
MgSO4. Silica gel (15 g) was added, and the solution was pressure
filtered through 1 in of SiO2. Et2O was distilled off, followed by
kugelrohr distillation at reduced pressure to give 139 g (97%) of nearly
pure 1. The residue (82.5 g) was taken up in Et2O−hexanes (50 mL
40:60) and chromatographed on silica gel. Elution with Et2O−hexanes
(25:75 v/v, then 100% Et2O) in 21 500 mL fractions gave 73.4 g of
colorless, ∼1:1 2S + 2R (93% yield), followed by 9.0 g of dicasylate 3
(96% yield); overall recovery was 95%.
1.3. Pure (2′R)- and (2′S)-1′-(3′-Bromo-2′-methylpropyl) (1S)-10-
Camphorsulfonate (Casylates 2R and 2S). Each of the precursor
bromoalkanols was converted via the same general procedure to the
corresponding (1S)-casylate as described for 2S: To a 0 °C solution of
(S)-3-bromo-2-methyl-1-propanol (306 mg, 2.0 mmol) in pyridine (0.5
mL) was added a solution of freshly crystallized (1S)-casyl chloride (525
mg, 2.10 mmol) in pyridine (0.5 mL); crystals (pyr·HCl) formed within
5 min. After overnight refrigeration, CH2Cl2 (10 mL) was added, and
the solution was washed with H2O (1 × 25 mL), 2 N HCl (1 × 25 mL),
and 10% aq NaHCO3 (1 × 25 mL), dried (over MgSO4), and filtered.
The filtrate was stripped of solvent and heated to 90 °C at 1 mmHg to
remove unreacted alcohol. The residue (573 mg, 78%), on addition of a
few drops of MeOH, crystallized instantly to give pure 2S: mp 57−59
°C; 1H NMR (300 MHz, CDCl3): δ 4.30−4.21 (m, 2H), 3.62 (d, J = 15
Hz, 1H), 3.52−3.42 (m, 2H), 3.025 (d, J = 15.1 Hz, 1H), 2.53−2.35 (m,
2H), 2.32−2.24 (m, 1H), 2.13 (t, J = 6.0 Hz, 1H), 2.10−2.00 (m, 1H),
1.96 (d, J = 18.5 Hz, 1H), 1.73−1.63 (m, 1H), 1.49−1.42 (m, 1H), 1.12
(s, 3H), 1.11 (d, J = 6.9 Hz, 3H), 0.89 (s, 3H). 13C NMR (75 MHz,
CDCl3): δ 213.5, 71.1, 57.1, 47.2, 46.0, 41.9, 41.7, 35.0, 34.2, 26.1, 24.1,
18.9, 18.9, and 14.6. Anal. Calcd for C14H23BrO4S: C, 45.78; H, 6.31.
Found: C, 46.11; H, 6.31; [α]25D +39.4 (c 5.2, CHCl3).
A MeOH solution of 2R crystallized on cooling (0 to −20 °C) and
remained crystalline on cold filtration and rapid removal of residual
solvent in vacuo: mp 27−31 °C; 1H NMR (400 MHz, CDCl3): δ 4.32−
4.19 (m, 2H), 3.62 (d, J = 15.1 Hz, 1H), 3.51−3.43 (m, 2H), 3.015 (d, J
= 15.1 Hz, 1H), 2.53−2.35 (m, 2H), 2.32−2.24 (m, 1H), 2.13 (t, J = 6.0
Hz, 1H), 2.10−2.00 (m, 1H), 1.96 (d, J = 18.5 Hz, 1H), 1.73−1.65 (m,
1H), 1.49−1.42 (m, 1H), 1.11 (s, 3H), 1.10 (d, J = 6.7 Hz, 3H), 0.88 (s,
3H). 13C NMR (100 MHz, CDCl3): δ 214.3, 71.8, 57.8, 48.0, 46.7, 42.6,
42.4, 35.9, 34.9, 26.8, 24.8, 19.7, 19.6, 15.3. Anal. Calcd for
3. Crystallization of (1:1 2R + 2S). 3a. From a Mixture
Containing Residual Dibromide. A 1:1 mixture of 2S/2R (166 g)
containing residual C4 dibromide was dissolved in MeOH (340 mL;
∼2:1 v/w). The cooled mixture (6 °C) was seeded with pure 2S and left
for 15 h and then cooled to −5 °C for 13 h. The mother liquor (ML) was
removed; crystals were washed with cold Et2O (50 mL) and air-dried to
give 68.6 g of an 87:13 2S/2R mixture (1H NMR analysis). Et2O
washings (44:56) weighed 6.0 g, and ML (25:75) weighed 91.3 g
(calcd). The 87:13 crystals (68.6 g) were recrystallized from Et2O (135
mL) as before to give 55.2 g of ∼96:4 2S/2R and 13.4 g of 45:55 2S/2R
ML. The cooled 25:75 ML deposited 7.9 g of 70:30 crystals, leaving 83.4
g of 22:78 ML, which was saved for re-equilibration. Combined 44:56
washings (6.0 g) and 45:55 ML (13.4 g) were crystallized from MeOH
(38 mL) as before to give 7.7 g of 73:27 crystals and 11.7 g of 24:76 ML
(saved). Combined 70:30 crystals (7.9 g) and 73:27 crystals (7.7 g) were
crystallized from Et2O (25 mL) to give 10.3 g of 86:14 crystals and 5.3 g
of 32:68 ML (saved). Crystallization of 10.3 g of 86:14 crystals from
Et2O (20 mL) gave 8.8 g of 95:5 crystals and 1.5 g of 66:34 ML.
Combined 96:4 crystals (55.2 g) and 95:5 crystals (8.8 g) were
crystallized from Et2O (125 mL) to give 55.3 g of 99.7:0.3 dr crystals
(calcd) and 8.7 g of ∼80:20 ML. Access to a 400 MHz NMR instrument
later enabled an improved 2S/2R dr assay, which showed the “99.7:0.3”
dr to be closer to 99:1; one more crystallization (88% 2S recovery) gave
48.7 g (29%) of >99:1 dr 2S/2R.
3b. From a Mixture Containing No Dibromide 1, Me/EtOCas, or C4
Dicasylate 3. A 0 °C 1:1 mixture of 2S/2R (168 g) in MeOH (340 mL)
was seeded with pure 2S. After 15 h. the cold mixture was suction
filtered, and the crystals were washed with cold Et2O (50 mL) and air-
dried to give 47.5 g of 85:15 2S/2R. Mother liquor (120 g of 36:64 2S/
2R) recrystallization as above (240 mL of MeOH, seeding with 2S) gave
48 g of 30:70 2S/2R crystals and 72 g of 42:58 ML. Many
recrystallizations gave a 25% yield of >99:1 dr 2S.
4. Preparation of 5R, 6R, and 7a/7b. 4.1. (2′R)-1′-(3′-Nitrato-2′-
methylpropyl) (1S)-10-Camphorsulfonate (5R).19 To a solution of
bromocasylate 2S (8.0 g, 21.8 mmol) in dry CH3CN (10 mL) was added
AgNO3 (5.53 g, 32.7 mmol, 1.5 equiv). After the solution refluxed for 5 h
and cooled, the solid (AgBr, 4.0 g, 99%) was filtered off and washed with
Et2O (3 × 20 mL) and H2O (3 × 20 mL). The separated aqueous layer
was extracted with Et2O, and the combined organic layers were dried
over anhyd MgSO4 and filtered, with subsequent removal of solvent in
vacuo to give 5R (7.5 g, 99%) as a colorless liquid. 1H NMR (400 MHz,
CDCl3): δ 4.48−4.40 (m, 2H), 4.28−4.21 (m, 2H), 3.59 (d, J = 15.0 Hz,
1H), 3.00 (d, J = 15.0 Hz, 1H), 2.49−2.33 (m, 3H), 2.13 (t, J = 4.4 Hz,
1H), 2.11−2.00 (m, 1H), 1.96 (d, J = 18.5 Hz, 1H), 1.70−1.63 (m, 1H),
1.49−1.42 (m, 1H), 1.11 (d, J = 7.0 Hz, 3H), 1.10 (s, 3H), 0.87 (s, 3H).
13C NMR (100 MHz, CDCl3): δ 214.4, 73.4, 70.5, 57.9, 48.1, 46.9, 42.7,
C14H23BrO4S: C, 45.78; H, 6.31. Found: C, 45.91; H, 6.18; [α]26
D
+25.8 (c 4.85, CHCl3).
1.4. Tetra-n-butylammonium Casylate (n-Bu4N+CassO−; 4). This
salt, isolable from Br-OCas exchange reactions by H2O extraction, was
prepared independently: n-Bu4N+Br− (3.22 g, 10.0 mmol), MeOCass
(2.71 g, 11.0 mmol), and CH2Cl2 (a few drops) were mixed in a test tube
and heated (oil bath, 77−80 °C) until gas evolution ceased (∼15 min).
The mixture solidified on cooling; it was crushed in Et2O, filtered,
washed with Et2O (2 × 15 mL), and dried to yield 4.62 g (97.5%) of 4
1
(crystals, mp 139−141 °C) containing no detectable MeOCass. H
NMR (400 MHz, CDCl3): (Many peak positions vary 0.05 ppm in the
presence of other compounds) δ 3.40 (d, J = 15.1 Hz, 1H), 3.26 (broad
m, 8H), 2.91 (d, J = 15.1 Hz, 1H; diagnostic peak in bromide-casylate
exchange mixtures), 2.71−2.62 (m, 1H), 2.32 (br dt, 1H), 2.03 (br t,
1H), 2.02−1.96 (m, 1H), 1.88 (d, 18.5 Hz, 1H), 1.70−1.60 (m, 9H),
1.44 (sext, 8H), 1.41−1.32 (m, 1H), 1.11 (s, 3H), 1.00 (t, 12H), 0.84 (s,
3H). 13C NMR (100 MHz, CDCl3): δ 216.5, 58.3, 58.2, 47.6, 47.0, 42.6,
42.4, 26.7, 24.3, 23.6, 19.7, 19.5, 19.4, and 13.4. n-Bu4N+CassO− is very
soluble in H2O, MeOH, EtOH, CH2Cl2, and CHCl3; it is insoluble in
ether, and can be recrystallized from dry EtOAc.
2.1. Conversion of Dibromide 1 to a 1:1 Mixture of Casylates
2R and 2S, and Dicasylate 3. EtOCass (12; 260.4 g, 1.00 mol),
dibromide 1 (648 g, 3.00 mol), and n-Bu4N+Br− (12.9 g, 0.04 mol, 1 mol
%) were mixed in a 1L, 3-neck flask fitted with a N2 bubbler insert,
thermometer, and a vigreux column with a distillation head. At 90 °C
(oil bath heating, N2 bubbling), the mixture became homogeneous. At
1
126−127 °C (pot), EtBr distilled out steadily. After 2.5 h, H NMR
analysis indicated >95% disappearance of EtOCass; the collected
distillate contained no dibromide. Kugelrohr removal of 1 (451 g) (oven
54−62 °C/7.5 to 0.05 mmHg) left 348 g (94.5% of the calculated
weight) of clear, pale tan oil consisting of 2R, 2S, 3, and n-
Bu4N+OCassO− (4). The residue was taken up in sufficient Et2O
(∼300 mL) to make the solution less dense than H2O, and extracted
with H2O (3 × 100 mL). Combined extracts were stripped of H2O to
give a near quantitative yield of 4. The Et2O phase was concentrated and
taken up in Et2O-hexanes (25:75 v/v). Silica gel flash column
chromatography, eluting with 25:75 and then 50:50 Et2O-hexanes,
F
DOI: 10.1021/jo5025392
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The Journal of Organic Chemistry
Article
−
42.5, 31.9, 26.9, 24.9, 19.7, 19.6, and 13.4. Anal. Calcd for C14H23NO7S:
Me2SO4, and small amounts of n-Bu4N+ (δ 1.02 t) and MeOSO3 .
Multiple Et2O extractions of the aq phase afforded more MeOCass and
traces of the ionic impurities, but no Me2SO4. Aq NaHCO3 (50 mL) was
added to the initial Et2O phase, and the mixture was stirred vigorously
until Me2SO4 was gone. Combined Et2O solutions were washed with
H2O and dried over MgSO4. Filtration and solvent removal yielded 17.9
g (89%) of colorless crystals of MeOCass, mp 60−61 °C (lit42 mp 61
°C). 1H NMR (400 MHz, CDCl3): δ 3.95 (s, 3H), 3.60 (d, J = 15.1 Hz,
1H), 2.98 (d, J = 15.1 Hz, 1H), 2.51−2.36 (m, 2H), 2.12 (t, J = 4.4 Hz,
1H), 2.10−2.01 (m, 1H), 1.95 (d, J = 18.5 Hz, 1H), 1.70−1.63 (m, 1H),
1.47−1.41 (m, 1H), 1.11 (s, 1H), and 0.88 (s, 1H). 13C NMR (100
MHz, CDCl3): δ 214.5, 57.8, 56.1, 48.0, 46.0, 42.7, 42.5, 26.8, 24.8, 19.7,
and 19.6.
24
C, 48.13; H, 6.63; N, 4.01. Found: C, 48.09; H, 6.87; N, 4.27; [α]D
+36.6 (c 5, CHCl3).
:
4.2. (2′R)-1′-(3′-Hydroxy-2′-methylpropyl) (1S)-10-Camphor-
sulfonate (6R).21 To a vigorously stirred, 10 °C (ice bath) solution of
nitratoalkyl casylate 5R (30.9 g, 88.4 mmol) and acetic acid (168 mL)
was added Zn powder (17.4 g, 265 mmol, 1.6 equiv) at a rate to maintain
the temperature. The stirred contents were allowed to warm to room
temperature (8 h) and then diluted with EtOAc (250 mL), and the solid
was filtered off. The two-phase filtrate was neutralized with saturated
NaHCO3, and the organic layer was washed with H2O (3 × 150 mL) and
saturated aq NaCl, dried over anhyd Na2SO4, and filtered; the solvent
was then removed in vacuo. The residue was purified by silica gel flash
chromatography (hexanes/Et2O 3:1 v/v) to give hydroxyalkyl casylate
6. Direct Application of 2S: Formal Synthesis of (R)-
Tuberculostearic Acid (11). 6.1. (2′R)-2′-Methyldecyl (1S)-10-
Camphorsulfonate (8)31. To a stirred solution of 2S (2.0 g, 5.44
mmol) and Li2CuCl4 [24 mg, 0.16 mmol (0.1 M in THF, 3 mol %)],
THF (5 mL), and NMP (N-methyl-2-pyrrolidone, 2.2 g, 21.8 mmol)
was added n-heptylmagnesium bromide (1.2 equiv of 1.3 M solution in
THF, 6.53 mmol), dropwise at 20 °C. After being stirred for 1 h, the
reaction mixture was cooled to −10 °C and quenched with 1 N HCl (25
mL). The aq layer was extracted with pentane (3 × 15 mL), and the
combined organic layers were washed with 1 N HCl (15 mL) and H2O
(3 × 20 mL) and dried over anhyd MgSO4. Filtration and concentration
in vacuo gave a colorless oil, which was purified by silica gel column
chromatography, eluting with ether/pentane (0:1 and 1:10) to give alkyl
casylate 8 (1.71 g, 81%) as a colorless oil. 1H NMR (400 MHz, CDCl3):
δ 4.17 (dd, J = 9.4, 5.6 Hz, 1H), 4.03 (dd, J = 9.4, 6.8 Hz, 1H), 3.60 (d, J =
15.0 Hz, 1H), 2.98 (d, J = 15.0 Hz, 1H), 2.55−2.36 (m, 2H), 2.12 (t, J =
4.4 Hz, 2H), 2.09−2.01 (m, 1H), 1.95 (d, J = 18.4 Hz, 1H), 1.89−1.81
(m, 1H), 1.68−1.61 (m, 1H), 1.47−1.25 (m, 16H), 1.12 (s, 3H), 0.97
(d, J = 6.7 Hz, 3H), and 0.89−0.86 (m, 6H). 1H signals for the
diastereomer of 11 (δ 4.17−4.03) were not detected. 13C NMR (100
MHz, CDCl3): δ 214.5, 75.0, 57.9, 47.9, 46.5, 42.7, 42.5, 33.1, 32.8, 31.8,
29.7, 29.5, 29.2, 26.8, 26.6, 24.9, 22.6, 19.8, 19.7, 16.5, and 14.1. HRMS
(ESI) Calcd for C21H38O4S ([M + Na]+): 409.2383. Found: 409.2382.
[α]D20 +30.85 (c 1.6, CHCl3).
1
6R (23.8 g, 88%) as a colorless oil. H NMR (400 MHz, CDCl3): δ
4.32−4.27 (m, 2H), 3.67−3.51 (m, 2H), 3.59 (d, J = 15.1 Hz, 1H), 2.99
(d, J = 15.1 Hz, 1H), 2.51−2.32 (m, 2H), 2.11 (t, J = 2.4 Hz, 1H), 2.10−
2.01 (m, 2H), 1.95 (d, J = 18.5 Hz, 1H), 1.95 (s, 1H (OH)), 1.7−1.65
(m, 1H), 1.47−1.41 (m, 1H), 1.10 (s, 3H), 0.99 (d, J = 7.0 Hz, 3H), and
0.87 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 214.9, 71.9, 63.5, 58.0,
48.1, 46.6, 42.7, 42.5, 35.7, 26.8, 24.9, 19.7, 19.7, and 13.1. HRMS (ESI)
Calcd for C14H24O5S ([M + Na]+): 327.123666. Found: 327.123670;
[α]D21 +4.0 (c 5.8, CHCl3).
4.3. (2R)-3-Chloro-2-methyl-1-propanol (7a). To a 500 mL round
bottom (rb) flask were added 6R (23.5 g, 77.2 mmol), dry n-Bu4NCl
(32.2 g, 116 mmol; 1.5 equiv), and dry DCE (50 mL). After 16 h at
reflux, DCE was distilled out. Et2O (100 mL) was added to the cooled
liquid and stirred for 15 min. The colorless solid precipitate (n-
Bu4NOCass + excess n-Bu4NCl) was filtered off, and the filtrate was
concentrated in vacuo. Kugelrohr distillation (20 °C/2 mmHg) gave 7a
1
(8.3 g, 93%) as a colorless oil. H and 13C NMR spectra matched
literature data.43 1H NMR (300 MHz, CDCl3): δ 3.66−3.54 (m, 4H),
2.11−2.00 (m, 1H), 1.47 (br s, 1H), 1.02 (d, J = 6.8 Hz, 3H). 13C NMR
(75 MHz, CDCl3): δ 64.7, 47.6, 37.7, and 14.4; [α]D22 −14.5 (c 0.65,
CHCl3) (lit.43 [α]DRT −14.6 (c 4.13, EtOH).
4.4. (2R)-3-Bromo-2-methyl-1-propanol (7b). A mixture of 6R (0.5
g, 1.64 mmol) and dry n-Bu4NBr (0.795 g, 2.46 mmol; 1.5 equiv) was
heated until it was liquid (10 min). Acetone (2 mL) was added, and the
mixture was refluxed for 5 h. Acetone was evaporated, and Et2O (10 mL)
was added and stirred until a colorless solid formed (10 min). The ppt
was filtered off, and the filtrate was concentrated in vacuo. The residue
was chromatographed (silica gel) with Et2O/hexanes (3:1) to give 7b
(0.24 g, 96%) as a colorless oil. 1H and 13C NMR spectra matched those
of a commercial sample.44 1H NMR (300 MHz, CDCl3): δ 3.68−3.56
(m, 2H), 3.54−3.47 (m, 2H), 2.11−1.98 (m, 1H), 1.50 (br s, 1H), 1.05
(d, J = 6.8 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 65.4, 37.6, 37.3, and
15.4; [α]D21 −6.2 (c 2.01, CHCl3) (lit.44 [α]D25 −6.6 (c 2, CHCl3).
5. Recycling Procedures. 5.1. Recovery of Silver.29 AgBr (88.5 g,
0.47 mol) and Zn powder (61.45 g, 0.94 mol) were thoroughly mixed in
a 1 L beaker. Contents were cooled (ice/water), and 1 M aq HCl (500
mL) was added slowly, with stirring. The wet solid was transferred onto
a filter funnel, and the liquid was drained off. Then 5 M aq HCl (4 × 250
mL) was added portionwise with stirring, until bubbling ceased. The
gray solid was washed thoroughly with H2O and vacuum-dried to give
pure Ag0 (∼50.2 g, ∼99%) as a gray-brown powder.
6.2. (R)-1-Bromo-2-methyldecane (9). A mixture of alkyl casylate 8
(1.50 g, 3.96 mmol) and n-Bu4N+Br− (1.91 g, 5.94 mmol) was heated to
90 °C for 4 h (neat; liquefied). Et2O (20 mL) was added to the cooled
mixture; stirring (10 min) caused formation of a white precipitate. This
was filtered off, the solid was washed with Et2O (10 mL), and the filtrate
was concentrated in vacuo to give a colorless liquid, which was
chromatographed on silica gel (pentane elution) to provide 9 (0.9 g,
98%) as a colorless liquid. H and 13C NMR spectral values matched
1
literature data.45 1H NMR (400 MHz, CDCl3): δ 3.39 (dd, J = 9.8, 4.9
Hz, 1H), 3.32 (dd, J = 9.8, 6.2 Hz, 1H), 1.82−1.74 (m, 1H), 1.46−1.26
(m, 13H), 1.0 (d, J = 6.6 Hz, 3H) and 0.88 (t, J = 6.6 Hz, 3H). 13C NMR
(100 MHz, CDCl3): δ 41.6, 35.2, 34.9, 31.9, 29.7, 29.5, 29.3, 26.9, 22.7,
18.8, and 14.1. [α]D20 −0.33 (c 0.9, CHCl3) [lit.46 [α]D −0.31 (neat).
6.3. (R)-10-Methyloctadecyl-1-tetrahydropyranyl Ether (10).34
The Grignard (8.0 mmol, 1.9 equiv by titration) freshly prepared
from the THP ether of 8-bromo-1-octanol34 was added dropwise, at 20
°C, to a stirred solution of bromoalkane 9 (1.0 g, 4.25 mmol), Li2CuCl4
(1.27 mL of 0.1 M solution in THF, 3 mol %), THF (5 mL), and NMP
(2.05 mL, 21.3 mmol). After being stirred for 1 h more, the reaction
mixture was cooled to 0−5 °C and quenched with ice cold aq NH4Cl (25
mL). The separated aqueous layer was extracted with EtOAc (3 × 30
mL). Combined organic layers were washed with H2O (3 × 30 mL) and
brine (3 × 25 mL), dried over anhyd MgSO4, filtered, and concentrated
in vacuo. The colorless residue was purified by silica gel column
chromatography, eluting with Et2O/hexanes (0 → 5 → 10% Et2O) to
give ether 10 (1.46 g, 93%) as a colorless liquid. 1H NMR (400 MHz,
CDCl3): δ 4.58−4.56 (m, 1H), 3.90−3.84 (m, 1H), 3.75−3.70 (m, 1H),
3.52−3.47 (m, 1H), 3.41−3.35 (m, 1H), 1.87−1.79 (m, 1H), 1.75−1.68
(m, 1H), 1.62−1.49 (m, 9H), 1.36−1.19 (m, 24H), 1.08−1.03 (m, 2H),
and 0.89−0.82 (overlapped d and t, 6H). 13C NMR (100 MHz, CDCl3):
δ 98.8, 67.7, 62.3, 37.1, 32.7, 31.9, 31.8, 30.8, 30.0, 30.0, 29.7, 29.7, 29.6,
29.6, 29.5, 29.4, 29.3, 29.2, 27.0, 26.2, 25.5, 22.7, 22.6, 19.7, 19.7, 14.1,
5.2. Recovery of Camphorsulfonate (as MeOCass).30 Freshly
distilled Me2SO4 (10.0 mL, ∼25% excess) was slowly dripped into n-
Bu4N+CassO− (4, 38.6 g, 81.5 mmol, in a 500 mL, three-neck rb flask
containing a magnetic stirring bar and fitted with a gas (N2) inlet, a
pressure-equalizing dropping funnel, and a takeoff condenser. The solid
salt dissolved in the path of the liquid, and the bottom material liquefied
sufficiently to allow the stirring bar to move. The bath (oil) was heated
to 55 °C; the solid gradually dissolved and became a colorless, nearly
homogeneous solution as the bath temperature reached 63 °C. After 2 h
@68 °C (bath), 1H NMR analysis showed singlets for Me2SO4,
−
MeOCass, and MeOSO3 at δ 3.98, 3.97, and 3.71, respectively; no
signal was present for the OCass ion. The colorless mixture remained
liquid on cooling overnight. Et2O (50 mL) and H2O (100 mL) were
added, and the whole was swirled until two clear phases appeared. NMR
analysis of the Et2O phase revealed mostly MeOCass, appreciable
G
DOI: 10.1021/jo5025392
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The Journal of Organic Chemistry
Article
and 14.1. HRMS (ESI) Calcd for C24H48O2([M + Na]+): 391.3547.
(19) Ferris, A. F.; McLean, K. W.; Marks, I. G.; Emmons, W. D. J. Am.
Chem. Soc. 1953, 75, 4078.
Found: 391.3546. [α]D21 +4.48 (c 0.24 in CHCl3).
(20) Tertiary or benzylic bromides react with AgNO3 in H2O−acetone
to give good yields of the corresponding alcohols: (a) Hayashi, T.;
Hayashizaki, K.; Kiyoi, T.; Ito, Y. J. Am. Chem. Soc. 1988, 110, 8153−
8156. (b) Easton, C. J.; Hutton, C. A.; Wui Tan, E.; Tiekink, E. R. T.
Tetrahedron Lett. 1990, 31, 7059−7062. With 2S, in our hands, this
method gave a mixture of alcohol and nitrate.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(21) Dewar, J.; Fort, G. J. Chem. Soc. 1944, 496−499.
(22) High-yield catalytic hydrogenolysis of nitrate esters also has been
reported: Kuhn, L. P. J. Am. Chem. Soc. 1946, 68, 1761−1762.
(23) Khumsubdee, S.; Zhou, H.; Burgess, K. J. Org. Chem. 2013, 78,
11948−11955.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: rchahn@syr.edu.
Notes
(24) Marshall, J. A.; Andersen, M. W. J. Org. Chem. 1992, 57, 5851−
5856.
The authors declare no competing financial interest.
(25) Liang, B.; Novak, T.; Tan, Z.; Negishi, E. J. Am. Chem. Soc. 2006,
128, 2770−2771.
ACKNOWLEDGMENTS
(26) Xu, S.; Lee, C.-T.; Wang, G.; Negishi, E. Chem.Asian J. 2013, 8,
1829−1835.
■
We thank the Hahn Gift Fund and the Syracuse University
Department of Chemistry for financial support. We also thank
Professors John Chisholm, Daniel Clark, Karin Ruhlandt, and
Nancy Totah of this department for use of selected
instrumentation. Dr. Frank Cook is thanked for some early
experiments. This paper is dedicated to the memory of Professor
Donald C. Dittmer.
(27) Chong, J. M.; Heuft, M. A.; Rabbat, P. J. Org. Chem. 2000, 65,
5837−5838.
(28) Leeman, M.; Brasile, G.; Gelens, E.; Vries, T.; Kaptein, B.;
Kellogg, R. Angew. Chem., Int. Ed. 2008, 47, 1287−1290.
(29) Cucciolito, M. E.; Flores, G.; Vitagliano, A. Organometallics 2004,
23, 15−17.
(30) Brandstrom, A. Preparative Ion Pair Extraction, an Introduction to
̈
̈
Theory and Practice, 2nd ed.; Apotekarsocieteten/Hassle Lakemedel:
̈
̈
Stockholm, 1976, Ch. VIII, pp 143−144.
(31) Cahiez, G.; Chaboche, C.; Jezequel, M. Tetrahedron 2000, 56,
2733−2737.
REFERENCES
■
́
́
(1) Banfi, L.; Guanti, G. Synthesis 1993, 1029−1056.
(2) Nunez-Rico, J. L.; Etayo, P.; Fernan
́
dez-Per
́
ez, H.; Vidal-Ferran, A.
́
̃
(32) Chen, M. Z.; Gutierrez, O.; Smith, A. B., III. Angew. Chem., Int. Ed.
2014, 53, 1279−1282.
Adv. Synth. Catal. 2012, 354, 3025−3035.
(3) Qiu, M.; Wang, D.-Y.; Hu, X.-P.; Huang, J.-D.; Yu, S. B.; Deng, J.;
Duan, Z.-C.; Zheng, Z. Tetrahedron:Asymmetry 2009, 20, 210−213.
(4) Asymmetric bioreduction of methyl 2-hydroxymethylacrylate and
derivatives has been reported, but appears not to be easily scaled up:
Stueckler, C.; Winkler, C. K.; Bonnekessel, B.; Faber, K. Adv. Synth.
Catal. 2010, 352, 2663−2666.
(33) Fodran, P.; Minnaard, A. J. Org. Biomol. Chem. 2013, 11, 6919−
6928.
(34) Liu, X.; Stocker, B. L.; Seeberger, P. H. J. Am. Chem. Soc. 2006,
128, 3638−3648.
(35) Dyer, B. S.; Jones, J. D.; Ainge, G. D.; Denis, M.; Larsen, D. S.;
Painter, G. F. J. Org. Chem. 2007, 72, 3282−3288.
(36) Bello, J. E.; Millar, J. C. Tetrahedron: Asymmetry 2013, 24, 822−
826.
(5) Goodhue, C. T.; Schaeffer, J. R. Biotechnol. Bioeng. 1971, 203−214.
(6) Trost, B. M.; Malhotra, S.; Mino, T.; Rajapaksa, N. S. Chem.Eur.
J. 2008, 14, 7648−7657.
(7) Enzymatic synthesis of 5.9 g of >99% ee (R)-3-hydroxy-2-
methylpropyl acetate has been reported: Bhuniya, R.; Nanda, S.
Tetrahedron 2013, 69, 1153−1165. The % ee was based on an [α]D
comparison.
(37) Svensson, G. P.; Gunduz, E. A.; Sjoberg, N.; Hedenstrom, E.;
Lassance, J.-M.; Wang, H.-L.; Lofstedt, C.; Anderbrant, O. J. Chem. Ecol.
̈
̈
̈
̈
̈
2014, 40, 387−395.
(38) Wyatt, T. D. J. Comp. Physiol. A 2010, 196, 685−700.
(39) Cahiez, G.; Alexis, A.; Normant, J. F. Tetrahedron Lett. 1978, 19,
́
(8) Guduguntla, S.; Fananas-Mastral, M.; Feringa, B. J. Org. Chem.
̃
3013−3014.
2013, 78, 8274−8280.
(40) Najera, C.; Yus, M.; Seebach, D. Helv. Chim. Acta 1984, 67, 289−
(9) McManus, S. P.; Roberts, F. E.; Lam, D. H.; Hovanes, B. J. Org.
Chem. 1982, 47, 4386−4388. See also: Eliel, E. L.; Wilen, S. H.
Stereochemistry of Organic Compounds; Wiley: New York, 1994; p 389.
(10) Most of this work was done with (1S)-10-camphorsulfonates; in
identifying compounds by number, the camphor chirality descriptor
sometimes is omitted to minimize confusion.
300.
́
(41) Westerbeek, A.; van Leeuwen, J. G. E.; Szymanski, W.; Feringa, B.
L.; Janssen, D. B. Tetrahedron 2012, 68, 7645−7650.
(42) Patterson, T. S.; Loudon, J. D. J. Chem. Soc. 1932, 1725−1744.
(43) Gaucher, A.; Ollivier, J.; Marguerite, J.; Paugam, R.; Salaun, J. Can.
̈
J. Chem. 1994, 72, 1312−1327.
(11) 2R has mp 27−31 °C; 2S has mp 57−59 °C. Jacques, J.; Collet, A.;
Wilen, S. H. Enantiomers, Racemates, and Resolutions; Wiley: New York,
1981; p 342.
(44) Aldrich Handbook of Fine Chemicals 2012−2014; p 500.
(45) Maki, E. C.; Rodstein, J.; Millar, J. C.; Barbour, K. S.; Hanks, L. M.;
Barbour, J. D. J. Chem. Ecol. 2011, 37, 714−716.
(12) Hahn, R. C. J. Org. Chem. 1988, 53, 1331−1333.
(13) (a) Nitta, Y.; Arakawa, Y.; Ueyama, N. Chem. Pharm. Bull. 1986,
34, 2710−2718. (b) A similar, less thorough, independent study
appeared one year later: Karaman, R.; Leader, H.; Goldblum, A.; Breuer,
E. Chem. Ind. (London) 1987, 24, 857−858.
(14) Hahn, R. C.; Tompkins, J. J. Org. Chem. 1988, 53, 5783−5785.
(15) Compare (e.g.): Cao, J.; Perlmutter, P. Org. Lett. 2013, 15, 4327−
4329.
(46) Hogberg, H.-E.; Hedenstrom, E.; Wassgren, A.-B.; Hjalmarsson,
̈
̈
M.; Bergstrom, G.; Lofqvist, J.; Norin, T. Tetrahedron 1990, 46, 3007−
̈
̈
3018.
NOTE ADDED AFTER ASAP PUBLICATION
Scheme 4 was corrected on January 15, 2015.
■
(16) Jacques, J.; Collet, A.; Wilen, S. H. Enantiomers, Racemates, and
Resolutions; Wiley: New York, 1981; pp 369−377.
(17) Afagh, N. A.; Yudin, A. K. Angew. Chem., Int. Ed. 2010, 49, 262−
310 and references therein.
(18) Shenvi, R. A.; O’Malley, D. P.; Baran, P. S. Acc. Chem. Res. 2009,
42, 530−541.
H
DOI: 10.1021/jo5025392
J. Org. Chem. XXXX, XXX, XXX−XXX