Practical asymmetric synthesis of β-hydroxy γ-amino acids via complimentary aldol reactions

Article abstract of DOI:10.1016/j.tet.2011.06.043

Orthogonally protected chiral β-hydroxy-γ-amino acids can be accessed in >100 g quantities from readily available starting materials and reagents in three to four steps. These chiral synthons contain two adjacent stereocenters along with suitably protecte

Full text of DOI:10.1016/j.tet.2011.06.043

Tetrahedron 67 (2011) 6131e6137
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Practical asymmetric synthesis of
aldol reactions
b-hydroxy g-amino acids via complimentary
Bhaumik A. Pandya, Sivaraman Dandapani, Jeremy R. Duvall, Ann Rowley, Carol A. Mulrooney, Troy Ryba,
,
y
*
Michael Dombrowski, Marie Harton, Damian W. Young, Lisa A. Marcaurelle
Chemical Biology Platform, The Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02142, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 May 2011
Received in revised form 8 June 2011
Accepted 16 June 2011
Available online 22 June 2011
Orthogonally protected chiral
b-hydroxy-g-amino acids can be accessed in >100 g quantities from
readily available starting materials and reagents in three to four steps. These chiral synthons contain two
adjacent stereocenters along with suitably protected functional groups (O-TBS, N-Boc) for downstream
reactivity. Implementation of two existing aldol technologies allows rapid access to all possible stereo-
isomers of 1. The guiding principles during reaction optimization were reaction scalability and opera-
tional efficiency. Conversion of the amino acids to a variety of chiral building blocks in one to two steps
demonstrates their synthetic utility.
Keywords:
Aldol
Asymmetric
Stereochemistry
Ó 2011 Elsevier Ltd. All rights reserved.
g-Amino acid
Diversity-oriented
1. Introduction
Chiral b-hydroxy g-amino acids are a class of non-proteinogenic
amino acids present in many important biologically active natural
products1 (Fig. 1), including pepstatin,2 bistramide A,3 hapalosin,4
and the didemnins.5 Of particular interest to us was the utility of
b
-hydroxy g-amino acids for diversity-oriented synthesis (DOS) in
the context of developing new build/couple/pair pathways.6,7 In the
present study, we chose to focus on the synthesis of O-TBS-pro-
tected
b-hydroxy-g-amino acids 1a,b (Fig. 2), which are low in
molecular weight and contain handles for downstream chemistry.
Anticipating the need for substantial quantities of the four amino
acids for development of a number of DOS pathways, we selected
chemical transformations that were scalable, robust, and general in
scope. The enantioselective aldol8 reaction fits all three criteria.
2. Results and discussion
After examining the literature regarding the enantioselective
synthesis of chiral g
-amino acids,9 we settled on a chiral oxazoli-
dinone protocol pioneered by Evans for the synthesis of the 1,2-syn
Fig. 1. Examples of natural products containing b-hydroxy-g-amino acids.
* Corresponding author. E-mail address: lisa_marcaurelle@h3biomedicine.com
aldol10 products 1a and a norephedrine approach developed by
Abiko for the 1,2-anti aldol11 products 1b. The commercial avail-
ability of both antipodes of each chiral auxiliary (3a,b) in large
(L.A. Marcaurelle).
y
Present address: H3 Biomedicine Inc., 300 Technology Square, Cambridge, MA
02139, USA.
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.06.043

6132
B.A. Pandya et al. / Tetrahedron 67 (2011) 6131e6137
Having identified the critical variables for success of the aldol
reaction on one-gram scale we next turned our attention to max-
imizing material throughput. Increasing reaction concentration and
introducing the aldehyde neat, rather than as a solution, did not
diminish yield or selectivity. The temperature of aldehyde addition
could also be increased from ꢀ78 to 0 ꢁC, which allowed for shorter
reaction times without erosion of diastereoselectivity.19,20
Aware that the solvents and reagents used in both the aldol
reaction and hydrolytic removal of the auxiliary were compatible,
we contemplated if the two transformations could occur sequen-
tially in a single flask operation. If successful, we would be able to
avoid isolation of aldol adduct 4, which required aqueous workup
and silica gel chromatography.21 Our initial attempts were plagued
by sluggish hydrolysis reactions. We hypothesized that the im-
miscible solvent combination (PhMe/DCM/H2O) was sequestering
lithium peroxide from the substrate. Substituting methanol for
aqueous buffer, followed by the addition of a 2:1 THF/H2O2 solution
presumably increased the solubility of the nucleophile, thus
allowing for a more reasonable hydrolysis rate. The optimized
protocol (Scheme 2) provided hydroxy acid (ꢀ)-5a directly from
propionate 3a as a single isomer by chiral SFC in excellent yield
after aqueous workup.22 This one-pot procedure has been suc-
cessfully utilized on preparative scale to routinely access >90 g23
batches of either (ꢀ)-5a or (þ)-5a.
Fig. 2. Aldol approach to the full matrix of b-hydroxy-g-amino acids 1a,b.
quantities suggested that access to all stereoisomers of
-amino acid 1 should be possible.
Kato and co-workers had reported the preparation of amino
b-hydroxy-
g
substituted acetaldehyde 212 in two steps from relatively in-
expensive 2-methylaminoethanol. Though this protocol was facile
and was utilized for our preliminary studies, we replaced the
reported ParikheDoering oxidation with a Swern protocol (Scheme
1).13 The change in oxidation conditions produced a cleaner re-
action mixture from which the product could be isolated in 200 g
scale and the overall unit cost to produce 2 was also reduced.14
With access to substantial quantities of aldehyde 2 and auxilia-
ries, we proceeded with the development of the two aldol
protocols.
Bu2BOTf, Et3N, 2
O
O
OH
Me
1:1 Toluene:DCM, 0 °C
HO2C
N
N
O
Boc
Me
then THF/MeOH/H2O2;
LiOH
82-96%, d.r. 99:1
Me
Bn
(-)-5a
g-amino acid 5a.
(-)-3a
Scheme 2. One-pot preparation of 1,2-syn-
We next turned our attention to the preparation of 1,2-anti-g-
amino acids 5b. Many research programs have focused on the anti-
aldol reaction.24 Abiko and co-workers had demonstrated that nor-
ephedrine propionates 3b could be utilized with dicyclohexylboron
triflate to provide 1,2-anti aldol products in good diastereomeric
excess and yield. Aspiring toward the goals of high chemical effi-
ciency, selectivity, operational simplicity, and maximum material
throughput, we initiated our studies with the Abiko protocol.
A survey of various sources of dicyclohexylboron triflate for this
aldol reaction revealed the superiority of freshly prepared Lewis
acid25 over commercial supplies. The in-house prepared batch of
dicyclohexylboron triflate was also less expensive and could be
prepared in greater quantities (800 g scale) than was available from
commercial vendors.26 Optimization studies focused on the role of
solvent used to introduce the Lewis acid. Initially a solution of
dicyclohexylboron triflate in hexanes (1 M) was employed as
reported by Abiko.24d Further studies revealed dichloromethane as
a superior solvent for this reaction (Scheme 3). The anti-aldol re-
actions performed with a dichloromethane solution (1 M) of dicy-
clohexylboron triflate were faster, higher yielding, and more
consistent. Concerned that this enhanced reactivity of the Lewis
Scheme 1. Aldehyde preparation and initial syn-aldol results.
Seminal work by Evans and co-workers with propionated chiral
oxazolidinones has provided access to many 1,2-syn aldol products
in high diastereomeric, and ultimately, enantiomeric excess. Al-
though this procedure has been successfully utilized with a variety
of aldehydes, we initially encountered unpredictable results when
applying it to the reaction of aldehyde 2 and propionate 3a. In our
preliminary experiments, a solution of dibutylboron triflate in
dichloromethane (1.0 M) was employed, which resulted in variable
isolated yields (40e90%) of 4a. As noted by Evans15 and others,16
the purity of the Lewis acid directly impacts the chemical yield,
product purity, and diastereoselectivity. Examining other com-
mercial sources of the Lewis acid led to a solution of dibutylboron
triflate in toluene (1 M),17 which was more stable to prolonged
storage.18 Replacing dichloromethane with toluene as the reaction
solvent, however, led to slower reaction rates and lower yields.
After examining a variety of solvent combinations, we arrived at
a mixture of toluene and dichloromethane (1:1) as the optimal
solvent pair. This solvent combination, along with the more reliable
source of Lewis acid, provided more reproducible results and con-
sistently higher yields (88e96%).
Scheme 3. Synthesis of 1,2-anti-g-amino acids 5b.

B.A. Pandya et al. / Tetrahedron 67 (2011) 6131e6137
6133
acid in dichloromethane would be coupled with instability, we
studied the performance of aged solutions (>20 d) in the anti-se-
lective aldol reaction and we were pleased to observe no erosion of
yield or diastereoselectivity.
are orthogonally protected for rapid access to a variety of chemo-
types through appropriate functional group pairing strategies.
The hydrolysis of the ephedrine-based auxiliary was initially
carried out with lithium hydroxide to provide acid (þ)-5b con-
taminated with its C2-epimer (3e5%). Epimerization was sup-
pressed (<1e2%) by conducting the hydrolysis with sodium
hydroxide/hydrogen peroxide in a mixed tert-butanol/methanol
solvent system (Scheme 3). Attempts to perform these two trans-
formations sequentially in a single vessel, as was done in the syn-
aldol reaction, were unsuccessful. The rate of hydrolysis during
these experiments was too slow to be useful. Acceleration of the
reaction rate by increasing temperature or changing solvent mix-
tures was unsuccessful as they were plagued with lower di-
astereomeric excesses. Fortunately, the two-vessel anti-aldol
sequence was reliable and scalable. The chiral hydroxy acids (þ)-5b
and (ꢀ)-5b were obtained as colorless oils without need for silica
gel chromatography in >100 g quantities per batch.27
Protection of the secondary alcohol as the tert-butyldime-
thylsilyl ether for downstream applications was the final task of our
synthetic sequence (Scheme 4). Preliminary attempts utilized
classical conditions involving tert-butyldimethylsilyl chloride and
imidazole. These reactions were slow and unreliable on larger scale.
A rapid scan of other silylating agents revealed that tert-butyldi-
methylsilyl triflate28 as a superior reagent. The reaction was
allowed to proceed to a bis-silylated species (ester/ether) followed
by aqueous workup to remove residual triflic acid. Direct saponi-
fication of the silyl ester was accomplished with potassium car-
bonate in a binary mixture of THF/MeOH to provide amino acids
(1a,b) in good yield (83e99%). This procedure is general for all
stereoisomers, routinely providing >250 g of product per batch.
Scheme 5. Preparation of orthogonally protected chiral synthons.
3. Conclusion
The preparation of all possible stereoisomers of a versatile
b-
hydroxy -amino acid has been accomplished by two comple-
g
mentary aldol reactions. A one-pot protocol has been developed to
access the 1,2-syn diastereomeric class (1a) in high yield and en-
antiomeric excess. Significant quantities (>90 g) of each stereo-
isomer have been prepared in single batches. Elaboration of these
chiral acids to different orthogonally protected amines could be
achieved in short order. The application of these chiral building
blocks to a variety of build/couple/pair strategies for DOS has been
reported6,30 and is the focus of ongoing work.
TBSO
HO2C
Me
Me OTBS
CO2H
1) TBSOTf
(-)-5a
N
N
(+)-5a
Boc
Boc
2) K2CO3
99% yield
Me
Me
(+)-1a
(-)-1a
TBSO
Me
4. Experimental section
4.1. General procedure
Me OTBS
CO2H
1) TBSOTf
HO2C
N
N
(-)-5b
(+)-5b
Boc
Boc
2) K2CO3
83% yield
Me
Me
(+)-1b
(-)-1b
All oxygen and/or moisture-sensitive reactions were carried out
under N2 atmosphere in glassware that had been flame-dried under
vacuum (w0.5 mmHg) and purged with N2 prior touse. Unless noted
otherwise, reagents were introduced into the reaction vessels using
syringe and septum techniques under a positive flow of N2. Air- and/
or moisture-sensitive solids were transferred in a glove bag. Unless
otherwise noted, reactions were stirred with a TeflonÔ covered
magnet and carried out at room temperature (rt). Concentration
refers to the removal of solvent under reduced pressure using a ro-
tary evaporator. Silica gel flash column chromatography was per-
Scheme 4. Synthesis of g-amino acids 1a,b.
Confident in our ability to rapidly access large quantities of all
stereoisomers of -amino acid 1, we turned our attention to di-
g
versifying the carboxyl terminus. Converting the electrophilic car-
boxylate to a variety of masked amine or alcohol derivatives
expands the utility of the chiral synthon (Scheme 5). Amidation of
(þ)-1b with methylamine followed by carbonyl reduction with
borane methyl sulfide provided secondary amine 6 in two steps
(79% yield). Alternatively, Curtius rearrangement of the acid (ꢀ)-1a
provided protected amine 7 without stereochemical erosion in 79%
yield. Chemoselective reduction of (þ)-1a was accomplished via
the mixed anhydride to provide the alcohol, which was converted
to the corresponding tosylate and treated with tetra-n-buty-
lammonium azide to provide compound 8 in 60% overall yield. The
alcohol was also esterified with benzoyl chloride and pyridine to
provide the orthogonally protected substrate 929 in 70% yield from
the acid. Introduction of these chemotypes did not greatly increase
molecular weight or require lengthy synthetic sequences thus in-
creasing their utility for downstream activities. The linear tem-
plates 6e9 have two stereocenters and three functional groups that
ꢀ
formed using 60 A (230e400 mesh ASTM) silica gel as the stationary
phase on Teledyne ISCO Rf companion purification systems. Cerium
ammonium molybdate was used as the primary thin layer chro-
matography (TLC) staining reagent. 1H NMR spectra were collected
on either a Bruker 300 MHz spectrometeror a Varian Inova 500 MHz
spectrometer. All proton chemical shifts are reported in parts per
million (ppm) with the solvent reference as the internal standard
(CDCl3:
d 7.26 ppm). Data are reported as follows: chemical shift,
multiplicity (s¼singlet, d¼doublet, t¼triplet, q¼quartet, p¼pentet,
hex¼hextet, m¼multiplet, br¼broad), coupling constants (Hz), and
integration. 13C NMR (100 MHz) spectra were recorded with com-
plete proton decoupling. Chemical shifts are reported in ppm with

6134
B.A. Pandya et al. / Tetrahedron 67 (2011) 6131e6137
the solvent reference as the internal standard (CDCl3: 77.2 ppm).
Melting points were reported uncorrected. Compound purity was
determined by Waters Acquity HPLC analysis monitored at 210 nm.
High resolution exact mass spectrometry was determined by Bruker
Daltonics APEXIV 4.7 T Fourier Transform Ion Cyclotron Resonance
Mass Spectrometer. Enantiomeric ratios were determined by chiral
SFC. Elemental analyses were performed by Robertson Microlit
Laboratories, Inc. 29 Samson Ave. Madison, NJ 07940 and are
reported in percent abundance.
the organic layer was washed with aqueous NaOH (1.0 M, 1 L) and
brine (100 mL). The aqueous layer was back extracted with CH2Cl2
(2ꢂ100 mL) to remove the oxazolidinone. The combined aqueous
layers were cooled to 0 ꢁC, agitated with a magnetic stir bar and then
carefullyacidified with concentrated HCl(12 M)to pH4. Theaqueous
layer was extracted with EtOAc (3ꢂ600 mL). The combined organics
were dried over MgSO4 and concentrated to provide (2R,3R)-4-(tert-
butoxycarbonyl(methyl)amino)-3-hydroxy-2-methylbutanoic acid
(ꢀ)-5a (74.4 g, 301 mmol, 82% yield) as a colorless oil.31 TLC: Rf¼0.31
20
(10% MeOH in DCM). [
a
]
ꢀ21.6 (c 1.0, CHCl3). 1H NMR (500 MHz,
D
4.2. Detailed synthetic protocols
CDCl3, 60 ꢁC)
d
4.07 (dt, J¼10, 5 Hz, 1H), 3.41 (br s, 1H), 3.22 (d,
J¼15 Hz, 1H), 2.91 (s, 3H), 2.62 (ddd, J¼16, 10, 5 Hz, 1H), 1.45 (s, 9H),
4.2.1. tert-Butyl methyl(2-oxoethyl)carbamate (2). A flame-dried 3 L,
3-neck round bottom flask containing a mechanical stirrer (central
port), internal temperature probe and addition funnel was charged
with oxalyl chloride (176 mL, 2.01 mol) and CH2Cl2 (634 mL). The
flask was cooled to ꢀ70 ꢁC and DMSO (286 mL, 4.02 mol) was added
over 2.5 h at a rate that maintained an internal temperature below
ꢀ65 ꢁC. The mixture was then stirred for an additional 15 min, after
which tert-butyl 2-hydroxyethyl(methyl)carbamate12 (235 g,
1.34 mol) in CH2Cl2 (700 mL) was added over 1 h, followed by slow
addition of Et3N (841 mL, 6.04 mol) over 30 min. Both of these re-
actants were added at a rate that did not cause an increase in internal
temperature. After addition of the alcohol solution the reaction was
cloudy. Upon initial addition of Et3N the reaction became colorless/
clear however at the end the reaction was milky white. The reaction
was monitored by TLC (Hex/EtOAc 1:1) until the reaction was
deemed complete (2.5 h additional, ꢀ70 ꢁC). Saturated aqueous
sodium bicarbonate solution (500 mL) was then introduced to
quench the reaction at ꢀ78 ꢁC. (Note: Quenching is fairlyexothermic
and thus should be done slowly.) The reaction was warmed to rt and
the phases were separated. The combined organics were washed
with water, dried over MgSO4, and concentrated (upon concentra-
tion, some small amounts of precipitate (presumably Et3N/HCl salt)
were observed however this small amount did not impede distilla-
tion or effect final purity.) Distillation (87e89 ꢁC, 3 mmHg) provided
aldehyde 2 (200 g, 128 mmol) as a colorless oil, which matched all
data reported by Kato and co-workers.12
1.25 (d, J¼10 Hz, 3H). 13C NMR (125 MHz, CDCl3, 60 ꢁC)
d 178.0, 80.6,
71.3, 53.1, 43.1, 36.1, 28.6, 11.6. HRMS (ESI) calcd for C11H21NO5Na
[MþNa]þ: 270.1312. Found: 270.1312.
4.2.3. (2S,3S)-(þ)-5a. [
a
]
D
20 þ16.8 (c 1.0, CHCl3).
4.2.4. 1-Phenyl-2-(N,2,4,6-tetramethylphenylsulfonamido)propyl-4-
(tert-butoxycarbonyl(methyl)amino)-3-hydroxy-2-methylbutanoate
(4b). An oven dried, 3-L, 3-neck round bottom flask was equipped
with mechanical stirrer and temperature probe. Under a positive
flowof N2, the vessel was charged with (1R,2S)-1-phenyl-2-(N,2,4,6-
tetramethylphenylsulfonamido)
propyl
propionate
(109 g,
270 mmol) and CH2Cl2 (932 mL). The reaction was cooled to ꢀ78 ꢁC
with constant agitation at which point Et3N (112 mL, 810 mmol) was
added dropwise (over w10 min), maintaining an internal reaction
temperature no greater than ꢀ65 ꢁC. After 15 min of additional
stirring, a solution ofdicyclohexylboron triflate(1 M in CH2Cl2,176 g,
540 mmol) was added dropwise (over w30 min), maintaining an
internal reaction temperature below ꢀ67 ꢁC. The resulting yellow
enolate reaction solution was stirred at ꢀ78 ꢁC for 2 h additional. At
this point tert-butyl methyl(2-oxoethyl)carbamate (68.1 mL,
405 mmol) was added dropwise at a rate so as to maintain an in-
ternal temperature below ꢀ67 ꢁC (w15 min). The reaction mixture
was stirred at ꢀ78 ꢁC for 2 h and then was allowed to warm to 0 ꢁC
for 1 h. The reaction was quenched by the addition of MeOH (1.09 L)
and pH 7 buffer (130 mL). Next aqueous H2O2 (130 mL, 1.5 mol, 35%
by wt) was slowlyadded such that the internal reaction temperature
did not exceed 20 ꢁC. After the addition was completed, the mixture
was allowed to warm to ambient temperature where it was stirred
for 1 h. The resultant slurry was then concentrated in vacuo and the
resulting oil was partitioned between water (550 mL) and CH2Cl2
(500 mL). The aqueous layer was extracted with CH2Cl2 (4ꢂ300 mL)
and the combined organic layers were washed with water (100 mL)
followed by brine (100 mL). The organic layer was dried over an-
hydrous MgSO4 and the solvent was removed to yield 1-phenyl-2-
(N,2,4,6-tetramethylphenylsulfonamido)propyl-4-(tert-butoxycar-
bonyl(methyl)amino)-3-hydroxy-2-methylbutanoate as a yellow
oil. While the crude product was carried on to the next step without
further purification, an analytical sample was obtained by chroma-
tography on silica gel. (S,R,R,S)-(ꢀ)-4b: TLC: Rf¼0.34 (30% EtOAc in
4.2.2. (2R,3R)-4-(tert-Butoxy-carbonyl(methyl)amino)-3-hydroxy-2-
methylbutanoic acid (5a). A jacketed 5 L, 3-neck round bottom flask
was fitted with an overhead mechanical stirrer, internal temperature
probe, and recirculating chiller. Under a positive flow of N2, the re-
actor was charged with (R)-4-benzyl-3-propionyloxazolidin-2-one
3a (86.0 g, 367 mmol) followed by CH2Cl2 (835 mL) and toluene
(430 mL). The colorless solution was cooled to an internal tempera-
ture of ꢀ10 ꢁC and degassed with nitrogen for 30 min. Dibutylboron
triflate (405 mL, 405 mmol, 1 M in toluene) was added dropwise,
maintaining an internal temperature below 0 ꢁC. Next, triethylamine
(66.5 mL, 478 mmol) was added dropwise and the resulting enolate
solution was stirred at ꢀ5 ꢁC for 90 min. Afterward, tert-butyl
methyl(2-oxoethyl)carbamate 2 (68.0 mL, 404 mmol) was added
dropwise, keeping the internal temperature below 0 ꢁC. Upon com-
plete addition, the light yellow solution was stirred at ꢀ5 ꢁC for
90 min. The solution was cooled further to ꢀ10 ꢁC and quenched by
the slow addition of MeOH (428 mL) followed by a solution of THF/
H2O2 (1.23 L, 2:1) that changed the yellow homogenous solution to
a biphasic milky-white suspension. (Note: The initial rapid exotherm
induced by the peroxide addition can be minimized by initial drop-
wise addition until no further exotherm is observed.) The reaction
was stirred at ꢀ10 ꢁC for 90 min at which time both layers became
homogeneous. Solid lithium hydroxide (77.0 g, 1.84 mol) was then
added to the biphasic mixture and the mixture was allowed to warm
to ambient temperature over 12 h. Excess peroxides were reduced by
the careful addition of solid Na2SO3 and organic solvents were re-
moved in vacuo. The slurry was dissolved in dichloromethane and
hexanes). [a 20
]
D
ꢀ10.1 (c 1.0, CHCl3). 1H NMR (500 MHz, CDCl3, 60 ꢁC)
d
7.20 (d, J¼7.4 Hz, 2H), 7.05 (d, J¼7.5 Hz, 1H), 6.87 (s, 1H), 5.79 (d,
J¼5.3 Hz,1H), 4.07 (s, 1H), 3.90 (s, 1H), 3.30 (s, 2H), 2.90 (s, 3H), 2.78
(s, 3H), 2.68e2.56 (m, 1H), 2.45 (s, 6H), 2.29 (s, 3H), 1.45 (s, 9H), 1.31
(d, J¼6.8 Hz, 2H), 1.19 (d, J¼7.2 Hz, 1H). 13C NMR (125 MHz, CDCl3,
60 ꢁC)
d 173.8, 142.5, 140.6, 138.3, 132.9, 132.1, 128.6, 128.1, 126.5,
126.3, 80.2, 78.4, 73.1, 58.8, 55.9, 53.3, 47.3, 44.3, 36.3, 35.7, 28.6, 25.7,
24.2, 22.7, 20.9, 13.6, 12.3, 8.9. HRMS (ESI) calcd for C21H30N2O6Na
[MþNa]þ: 429.1996. Found: 429.2000.
20
4.2.5. (R,S,S,R)-(þ)-4b. [
a
]
þ6.42 (c 1.0, CHCl3).
D
4.2.6. (2R,2S)-4-(tert-Butoxycarbonyl(methyl)amino)-3-hydroxy-2-
methylbutanoic acid (5b). A 3-neck round bottom flask was

B.A. Pandya et al. / Tetrahedron 67 (2011) 6131e6137
6135
equipped with an overhead stirrer, an internal temperature probe
4.2.9. (2S,3S)-(þ)-1a. [
a
]
D
20 þ23.3 (c 0.9, CHCl3).
and an addition funnel. The vessel was charged with the crude 1-
phenyl-2-(N,2,4,6-tetramethylphenylsulfonamido)propyl-4-(tert-
butoxycarbonyl-(methyl)amino)-3-hydroxy-2-methyl-butanoate
(202 g, 350 mmol, 1.0 equiv) and 1:1 t-BuOH/MeOH (4.5 L) was
added and cooled to 0 ꢁC. A solution of H2O2 (35% in water, 184 mL,
2101 mmol, 6.0 equiv) was added via addition funnel, followed by
aqueous NaOH (1.0 M, 1051 mL, 1051 mmol, 3.0 equiv), which was
added at such a rate that the internal temperature did not rise above
10 ꢁC. The mixture was warmed to rt slowly and allowed to stir
overnight. Additional H2O2 (40 mL) and aqueous NaOH (200 mL)
solutions were added at 0 ꢁC to drive the reaction to completion and
the organic solvents were then removed in vacuo. The resulting
aqueous layer was diluted with water (500 mL) and extracted with
EtOAc (4ꢂ400 mL) to remove the auxiliary. The resulting aqueous
layer was then acidified with 6 M HCl to pH 4 and extracted with
EtOAc (5ꢂ500 mL). This second set of EtOAc extracts were com-
bined, dried (MgSO4), filtered, and concentrated. While the crude
product was carried on to the next step without further purification,
an analytical sample was obtained by chromatography on silica gel.
4.2.10. (2R,3S)-(ꢀ)-1b. Following the general reaction protocol
(2R,3S)-5b (58.7 g, 237 mmol, 1.0 equiv) was reacted with TBSOTf
(120 mL, 522 mmol, 2.2 equiv) and 2,6-lutidine (91 mL, 783 mmol,
3.3 equiv) in CH2Cl2 (950 mL), and worked up with aqueous K2CO3
(1.6 M, 325 mL, 522 mmol, 2.2 equiv) and MeOH (500 mL) in THF
(500 mL) to provide pure product (R,S)-1b (74.1 g, 83%) as a color-
20
less oil. (2R,3S)-(ꢀ)-1b: TLC: Rf¼0.67 (33% EtOAc in hexanes). [
a]
D
ꢀ3.2 (c 0.6, CHCl3). 1H NMR (500 MHz, CDCl3, 60 ꢁC)
d 4.17 (br s,1H),
3.35 (dd, J¼14.5, 6.0 Hz, 1H), 3.25 (br s, 1H), 2.90 (s, 3H), 2.66 (br s,
1H), 1.46 (s, 9H), 1.22 (d, J¼7.0 Hz, 1H), 0.91 (s, 9H), 0.11 (s, 3H), 0.10
(s, 3H). 13C NMR (125 MHz, CDCl3, 60 ꢁC)
d 176.8, 156.4, 80.3, 72.4,
52.9, 43.9, 36.7, 28.7, 26.0, 18.2, 12.8, ꢀ4.2, ꢀ4.7. HRMS (ESI) calcd
for C17H25NO5SiNa [MþNa]þ: 384.2177. Found: 384.2167.
4.2.11. (2S,3R)-(þ)-1b. [
a]
20 þ3.7 (c 1.0, CHCl3).
D
4.2.12. tert-Butyl (2R,3R)-2-(tert-butyldimethylsilyl)oxy-3-(methyl-
4-(methylamino)-butyl)(methyl)carbamate (6). To solution of
a
(2R,3S)-(þ)-5b: [
a
]
20 þ2.1 (c 1.0, CHCl3). 1H NMR (500 MHz, CDCl3,
(ꢀ)-(2R,3R)-4-(tert-butoxycarbonyl(methyl)amino)-3-(tert-butyldi-
methylsilyloxy)-2-methyl butanoic acid (ꢀ)-1a (4.49 g, 12.4 mmol),
and DIEA (6.5 mL, 37 mmol, 3.0 equiv) in CH2Cl2 (96 mL) was added
methylamine (7.45 mL, 14.9 mmol, 1.2 equiv). PyBop (6.46 g,
12.4 mmol,1.0 equiv) was added at once and the mixture was stirred
overnight. The reaction mixture was diluted with CH2Cl2 and satd
aqueous NH4Cl, the phases separated, and the organic phase was
dried (MgSO4), filtered, and concentrated. Purification was accom-
plished via silica gel chromatography to yield 11.7 g (94%) of tert-
butyl (2R,3S)-2-(tert-butyldimethylsilyl)oxy-3-methyl-4-(methyl-
amino)-4-(oxobutyl)(methyl)carbamate S1 as an oil. 1H NMR
D
60 ꢁC)
d
3.99 (s,1H), 3.91 (dd, J¼5.7,11.4 Hz,1H), 3.39 (m,1H), 2.95 (s,
0.5ꢂ3H), 2.93 (s, 0.5ꢂ3H), 2.59 (dd, J¼6.2, 12.0 Hz, 1H), 1.48 (s,
0.5ꢂ9H), 1.47 (s, 0.5ꢂ9H), 1.28 (d, J¼7.2 Hz, 3H). 13C NMR (125 MHz,
CDCl3, 60 ꢁC)
d 181.1, 158.2, 81.0, 72.6, 53.4, 43.8, 36.2, 28.7, 15.0.
HRMS (ESI) calcd for C11H21NO5Na [MþNa]þ: 270.1312. Found:
270.1312.
20
4.2.7. (2S,3R)-(ꢀ)-5b. [
a
]
ꢀ1.9 (c 1.0, CHCl3).
D
4.2.8. General reaction protocol for TBS protection. 4-(tert-Butox-
ycarbonyl(methyl)amino)-3-(tert-butyldimethylsilyloxy)-2-methyl
butanoic acid (1a). An oven dried, 5 L 3-neck round bottom flask
equipped with magnetic stirrer and internal temperature probe
was charged with 4-(tert-butoxycarbonyl (methyl)amino)-3-
hydroxy-2-methylbutanoic acid 5a (1.0 equiv), CH2Cl2 (concentra-
tion of 5a¼0.1 M and 2,6-lutidine (3.0e5.0 equiv)) under a positive
flow of N2. The reaction mixture was cooled to ꢀ78 ꢁC and tert-
butyldimethylsilyl trifluoromethanesulfonate (TBSOTf) (2.2e3.0
equiv) was added dropwise over 20 min. The reaction mixture was
stirred at ꢀ78 ꢁC for 1 h, quenched with aqueous satd NaHCO3, the
layers were separated, and the aqueous layer was extracted with
Et2O. The combined organic extracts were washed with aqueous
satd NH4Cl and brine, dried (MgSO4), filtered, and the solvent
evaporated. The residue was dissolved in MeOH and THF and
cooled to 0 ꢁC. An aqueous solution of K2CO3 (1.5e2.2 equiv) was
added and the mixture was stirred at 0 ꢁC for 1 h. The reaction
mixture was concentrated to remove volatile solvents and the
remaining aqueous layer was extracted with EtOAc. The organic
layer was washed with 1 N HCl, then dried over MgSO4, filtered,
and concentrated in vacuo to yield the crude product as a clear oil,
which was co-evaporated with toluene to remove excess TBSOH
and dried to provide the product 1a as a clear oil.
(500 MHz, CDCl3, 50 ꢁC)
d
6.69 (s, 0.5ꢂ1H), 6.38 (s, 0.5ꢂ1H), 4.01 (br s,
1H), 3.32 (dd, J¼6.5,14.2 Hz,1H), 3.20 (dd, J¼6.1,14.1 Hz,1H), 2.88 (s,
3H), 2.78 (d, J¼4.8 Hz, 3H), 2.41 (qd, J¼3.5, 7.2 Hz, 1H), 1.46 (s, 9H),
1.21 (d, J¼7.3 Hz, 3H), 0.92 (s, 9H), 0.12 (s, 3H), 0.11 (s, 3H). 13C NMR
(125 MHz, CDCl3, 50 ꢁC)
d 174.7,138.0, 80.0, 72.8, 53.7, 45.0, 36.8, 28.7,
26.2, 21.6, 18.2, 15.6, ꢀ4.1, ꢀ4.6.
To a chilled (0 ꢁC) solution of amide S1 (4.37 g,11.7 mmol) in THF
(100 mL) was added dropwise BH3/SMe2 (5.5 mL, 58.3 mmol,
5 equiv). The reaction mixture was warmed to rt then the flask was
fitted with a reflux condenser and the reaction mixture was heated
in a 65 ꢁC oil bath for 24 h. The mixture was cooled in an ice bath and
quenched with MeOH. The mixture was concentrated, the residue
was dissolved in MeOH (80 mL) and a satd aqueous solution of
Rochelle’s salt (50 mL) was added. The mixture was heated in a 90 ꢁC
oil bath for 48 h, then cooled to rt and concentrated. The residue was
diluted with EtOAc and water, the aqueous phase extracted with
EtOAc and the combined organics were washed with brine, dried
(MgSO4) and the solvent evaporated to yield tert-butyl (2R,3R)-2-
(tert-butyldimethylsilyl)oxy-3-(methyl-4-(methylamino)-butyl)(-
methyl)carbamate (6) as a colorless oil (3.55 g, 84%). 1H NMR
(500 MHz, DMSO, 120 ꢁC)
d
3.97 (dt, J¼3.9, 7.7 Hz, 1H), 3.28 (dd,
J¼4.4,14.1 Hz,1H), 3.10 (dd, J¼7.8,14.1 Hz,1H), 2.84 (s, 3H), 2.64 (dd,
J¼5.4,11.9 Hz,1H), 2.41 (dd, J¼7.9,11.9 Hz,1H), 2.36 (s, 3H),1.89e1.78
(m, 1H), 1.43 (s, 9H), 0.94 (d, J¼6.9 Hz, 3H), 0.91 (s, 9H), 0.08 (s, 3H),
Following the general reaction protocol (2R,3R)-5a (180 g,
728 mmol, 1.0 equiv) was reacted with TBSOTf (502 mL, 2.18 mol,
3.0 equiv) and 2,6-lutidine (424 mL, 3.64 mol, 5.0 equiv) in CH2Cl2
(3.5 L), and worked up with aqueous K2CO3 (151 g in 750 mL,
1090 mmol, 1.5 equiv) and MeOH (1475 mL) in THF (1475 mL) to
0.06 (s, 3H).13C NMR (125 MHz, CDCl3, 60 ꢁC)
d 156.4, 73.8, 72.9, 54.9,
54.0, 52.1, 37.0, 28.7, 26.1, 18.2, 14.6, 13.9, ꢀ4.4. HRMS (ESI) calcd for
C18H40N2O3Si [MþH]þ: 361.2886. Found: 361.2888.
provide pure product (2R,3R)-1a (260 g, 99%) as a clear oil. (2R,3R)-
20
(ꢀ)-1a: TLC: Rf¼0.70 (33% EtOAc in hexanes). [
a]
ꢀ29.1 (c 1.0,
4.2.13. tert-Butyl
((2S,3R)-3-((benzyloxy)carbonyl)amino-2-(tert-
D
1
CHCl3). H NMR (500 MHz, CDCl3, 60 ꢁC)
d
4.32e4.22 (m, 1H),
butyldimethylsilyl)oxy-butyl)(methyl)carbamate (7). To a solution of
4-(tert-butoxycarbonyl(methyl)amino)-3-(tert-butyldimethylsilyl-
oxy)-2-methyl butanoic acid (þ)-1a (1.15 g, 3.18 mmol) in toluene
(32 mL) were added Et3N (0.62 mL, 4.5 mmol) and DPPA (0.83 mL,
3.8 mmol). Themixturewasheatedto60ꢁCfor3 h, thenbenzylalcohol
(1.65 mL, 15.9 mmol) was added and the mixture heated to reflux
3.55e3.33 (m, 1H), 3.09 (dd, J¼6.7, 14.2 Hz, 1H), 2.89 (s, 3H),
2.69e2.41 (m,1H),1.47 (s, 9H),1.23 (d, J¼7.1 Hz, 3H), 0.90 (s, 9H), 0.08
(s, 3H), 0.07 (s, 3H). 13C NMR (125 MHz, CDCl3, 60 ꢁC)
d 179.3, 156.1,
80.2, 71.6, 53.0, 43.3, 36.4, 26.1, 18.2, 10.8, ꢀ4.30, ꢀ4.63. HRMS (ESI)
calcd for C17H25NO5SiNa [MþNa]þ: 384.2177. Found: 384.2173.

6136
B.A. Pandya et al. / Tetrahedron 67 (2011) 6131e6137
overnight. The mixture was cooled and concentrated and the residue
diluted with EtOAc, washed with H2O, dried (MgSO4), and the solvent
evaporated. Purification was accomplished with chromatography on
silica gel to provide tert-butyl ((2S,3R)-3-((benzyloxy)carbonyl)amino-
2-(tert-butyldimethylsilyl)oxy-butyl)(methyl)carbamate (7) as a clear
20 mmol). The reaction mixture was stirred overnight (16 h) then
diluted with CH2Cl2 and 0.1 N HCl. The phases were separated and
the aqueous was washed with CH2Cl2. The combined organics were
washed with 0.1 N HCl, H2O, brine, dried (Na2SO4), and the solvent
evaporated. Purification was accomplished via silica gel chroma-
tography (EtOAc/hexanes) to yield (2S,3S)-4-((tert-butoxycar-
bonyl)(methyl)amino)-3-((tert-butyldimethylsilyl)oxy)-2-methyl-
resin (1.18 g, 79%). [a 20
]
D
þ4.4 (c 1.0, CHCl3). 1H NMR (500 MHz, DMSO)
d
7.38e7.28 (m, 5H), 6.24 (br s, 1H), 5.17e4.92 (m, 2H), 4.02 (br s, 1H),
3.61 (br s,1H), 3.33 (dd, J¼5.9,14.3 Hz,1H), 3.08 (dd, J¼7.0,14.0 Hz,1H),
butyl benzoate (9) (1.24 g, 70%) as a colorless oil. [
a
]
20þ5.6 (c 1.0,
D
2.83 (s, 3H),1.43 (s, 9H),1.08 (d, J¼6.6 Hz, 3H), 0.90 (s, 9H), 0.06 (s, 3H),
CHCl3). 1H NMR (500 MHz, DMSO, 80 ꢁC)
d
7.97 (d, J¼7.5 Hz, 2H),
0.04 (s, 3H). 13C NMR (126 MHz, DMSO)
d
154.7, 154.4, 136.7, 127.4,
7.63 (t, J¼7.2 Hz, 1H), 7.50 (t, J¼7.5 Hz, 2H), 4.24 (d, J¼6.9 Hz, 2H),
4.15 (t, J¼6.0 Hz, 1H), 3.36 (dd, J¼6.4, 14.0 Hz, 1H), 3.19 (dd, J¼6.5,
14.0 Hz, 1H), 2.85 (s, 3H), 2.08 (dd, J¼6.7, 13.0 Hz, 1H), 1.41 (s, 9H),
1.00 (d, J¼6.9 Hz, 3H), 0.92 (s, 9H), 0.09 (s, 6H). 13C NMR (126 MHz,
127.0,126.8, 78.1, 71.7, 64.7, 49.0, 34.6, 27.5, 25.2,17.0,13.6, ꢀ5.4. HRMS
(ESI) calcd for C17H35NO5SiNa [MþNa]þ: 489.2761. Found: 489.2753.
4.2.14. tert-Butyl-((2S,3R)-4-azido-2-((tert-butyldimethylsilyl)oxy)-
3-methylbutyl)(methyl)carbamate (8). To a solution of 1a (500 mg,
1.25 mmol) in dry THF (14 mL) under N2 and chilled to 0 ꢁC was
added Et3N (0.23 mL, 1.7 mmol) followed by isobutyl chloroformate
(0.16 mL, 1.7 mmol). The resultant suspension was stirred at am-
bient temperature for 2 h, then cooled to 0 ꢁC and a solution of
NaBH4 (314 mg, 8.30 mmol) in water (6 mL) was added dropwise.
The mixture was stirred for 2 h, warming slowly to ambient tem-
perature. The reaction mixture was then diluted with water and the
aqueous phase was extracted with EtOAc. The combined organic
phases were washed with water, brine, dried (Na2SO4), and the
solvent was evaporated. To a solution of this alcohol (362 mg,
1.04 mmol) in dry CH2Cl2 (10 mL) under N2 and chilled to 0 ꢁC was
added p-toluenesulfonyl chloride (218 mg, 1.15 mmol) followed by
Et3N (0.44 mL, 3.1 mmol) then DMAP (13 mg, 0.10 mmol). The re-
action mixture was stirred for 16 h then was quenched with water,
the phases separated and the aqueous phase was washed with
CH2Cl2. The combined organic phases were washed with satd
aqueous NaHCO3 (2ꢂ), then satd aqueous NH4Cl (2ꢂ), water, brine,
dried (Na2SO4), and the solvent evaporated to provide S2, which
was carried on to the next step without further purification.
Tetrabutylammonium azide (567 mg, 1.99 mmol) was added to
a solution of tosylate S2 (500 mg, 0.997 mmol) in dry DMF (10 mL)
under nitrogen. The reaction mixture was stirred until LCeMS in-
dicated the disappearance of starting material. The reaction mixture
was diluted with water and EtOAc and the phases separated. The
aqueous phase was washed with EtOAc and the combined organics
were washed with water and brine, dried (Na2SO4) and the solvent
evaporated. Purification was accomplished via silica gel chroma-
tography (EtOAc/hexanes) to yield tert-Butyl-((2S,3R)-4-azido-2-
((tert-butyldimethylsilyl)oxy)-3-methylbutyl)(methyl)carbamate
DMSO, 80 ꢁC)
d 165.2, 154.5, 132.7, 129.6, 128.5, 128.2, 78.3, 69.2,
65.8, 51.4, 35.1, 27.7, 25.3,18.4,17.3, 9.8, ꢀ4.9, ꢀ5.5. HRMS (ESI) calcd
for C24H41NO5SiNa [MþNa]þ: 474.2652. Found: 474.2652.
Acknowledgements
This work was funded in part by the NIGMS-sponsored Center of
Excellence in Chemical Methodology and Library Development
(Broad Institute CMLD; P50 GM069721), as well as the NIH Geno-
mics Based Drug Discovery U54 grants Discovery Pipeline
RL1CA133834
(administratively
linked
to
NIH
grants
RL1HG004671, RL1GM084437, and UL1DE019585).
Supplementary data
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2011.06.043.
References and notes
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ꢂ
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D
1.0, CHCl3). 1H NMR (500 MHz, DMSO, 80 ꢁC)
d
3.99 (t, J¼5.2 Hz, 1H),
3.42e3.17 (m, 3H), 3.06 (dd, J¼6.1, 13.8 Hz, 1H), 2.82 (s, 3H), 1.78 (dd,
J¼6.6,11.9 Hz,1H),1.42 (s, 9H), 0.92 (d, J¼6.9 Hz, 3H), 0.89 (s, 9H), 0.10
(s, 3H), 0.08 (s, 3H). 13C NMR (126 MHz, DMSO)
d 154.4, 78.3, 69.8,
53.3, 51.2, 35.8, 35.1, 27.7, 25.3,17.2,11.0, ꢀ4.9, ꢀ5.4. HRMS (ESI) calcd
7. (a) Neilson, T. E.; Schreiber, S. L. Angew. Chem., Int. Ed. 2007, 74, 48e56; (b)
Uchida, T.; Rodriguez, M.; Schreiber, S. L. Org. Lett. 2009, 11, 1559e1562; (c)
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P.; Schreiber, S. L. Org. Lett. 2010, 12, 2822e2825.
for C17H36N4O3SiNa [MþNa]þ: 373.2635. Found: 373.2631.
4.2.15. (2S,3S)-4-((tert-Butoxycarbonyl)(methyl)amino)-3-((tert-bu-
tyldimethylsilyl)oxy)-2-methylbutyl benzoate (9). To a solution of
acid 1b (1.42 g, 3.93 mmol) in dry THF (20 mL) under N2 was added
Et3N (1.1 mL, 7.9 mmol) at 0 ꢁC followed by isobutyl chloroformate
(0.668 mL, 5.11 mmol). The resultant suspension was stirred at rt
for 2 h and then chilled to 0 ꢁC. A solution of NaBH4 (892 mg,
23.6 mmol) in H2O (17 mL) was added dropwise and the mixture
was stirred for 2 h, warming slowly to rt. The reaction mixture was
then diluted with H2O and the aqueous phase was extracted with
EtOAc. The combined organic phases were washed with H2O, brine,
dried (Na2SO4), and the solvent was evaporated to yield S3, which
was carried on crude to provide benzoate 9.
8. For reviews on recent developments on the aldol reaction, see (a) Schetter, B.;
Mahrwald, R. Angew. Chem., Int. Ed. 2006, 45, 7506e7525; (b) Palamo, C.;
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D.; Wong, C. H. Angew. Chem., Int. Ed. 2000, 39, 1352e1374; (d) Mahrwald, R.
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3099e3111; (c) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103,
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To a solution of crude alcohol S3 in dry CH2Cl2 (20 mL) under N2
was added pyridine (6.4 mL) then benzoyl chloride (2.3 mL,
14. Based on Aldrich prices for reagents.

B.A. Pandya et al. / Tetrahedron 67 (2011) 6131e6137
6137
15. Gage, J. R.; Evans, D. A. Org. Synth. 1993, 8, 339e344.
a contract research organization where it has been routinely performed on
>500 g scale.
16. Mickel, S. J.; Sedelmeier, G. H.; Niederer, D.; Daeffler, R.; Osmani, A.; Schreiner, K.;
Seeger-Weibel, M.; Berod, B.; Gamboni, R. Org. Process Res. Dev. 2004, 8, 92e100.
17. Available from BASF.
18. The solutions were stored on the bench in air-free containers without appre-
ciable change in concentration over 30 days. Molarity was assessed by No-D 1H
NMR Hoye, T.; Eklov, B. M.; Ryba, T. D.; Voloshin, M.; Yao, L. J. Org. Lett. 2004, 6,
953e956.
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19. No epimerization was detected by chiral SFC analysis of an aldol reaction that
was warmed to room temperature for 18 h then subjected to the hydrolysis
conditions.
26. Synthesis of 0.8 kg batches of the Lewis acid required scrupulously air-free
conditions as noted in Ref. 16.
27. Absolute stereochemical assignment for (ꢀ)-5b was confirmed by conversion to
20. At ꢀ78 ꢁC we observed freezing of the aldehyde upon contact with the solu-
tion. In contrast, when the addition is carried out at 0 ꢁC, the aldehyde quickly
dissolves with the aid of vigorous stirring.
the corresponding Mosher ester.
28. (a) Corey, E. J.; Cho, H.; Rucker, C.; Hua, D. H. Tetrahedron Lett. 1981, 22,
3455e3458; (b) The reagent was prepared in 0.5 kg batches according to the
Corey protocol.
29. We performed the selective deprotection of the silyl ether by means of TBAF,
while the benzoate is hydrolyzed by K2CO3/MeOH, and the selective de-
protection of the Boc group is accomplished by treatment with TBSOTf fol-
lowed by p-TsOH in DCM.
30. (a) Comer, E.; Liu, H.; Joliton, A.; Clabaut, A.; Johnson, C.; Akella, L. B.; Mar-
caurelle, L. A. Proc. Natl. Acad. Sci. U.S.A. 2011, 108, 6751e6756; (b) Gerard, B.;
Duvall, J. R.; Lowe, J. T.; Murillo, T.; Wei, J.; Akella, L. B.; Marcaurelle, L. A. ACS
Comb. Sci. 2011, ASAP.
31. Borane impurities, presumably from incomplete hydrolysis, have been ob-
served in large batches. They have been removed by trituration with cold
CH2Cl2. Typically the oil after workup is dissolved in CH2Cl2 (0.5 L) and stored in
a ꢀ20 ꢁC fridge. After 12 h at this temperature white precipitate was observed
and was removed from the sample by cold filtration. The sample was con-
centrated and analyzed by 1H NMR. If necessary, the process was repeated.
21. After aqueous workup the aldol adduct (ꢀ)-4a was isolated as a colorless oil
(>95% by HPLC), which could be carried forward to the subsequent hydrolysis.
Alternatively, silica gel chromatography provided the adduct as a white solid
from which we obtained single crystals for X-ray analysis. CCDC 828856 con-
tains the supplementary crystallographic data for (ꢀ)-4a. This data can be
obtained free of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
22. Absolute stereochemical assignment for (þ)-5a was confirmed by X-ray crys-
tallography. Purity was >95% by HPLC and er 99:1 by SFC. CCDC 828857 con-
tains the supplementary crystallographic data for (þ)-5a. This data can be
obtained free of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
23. The total volume of the reaction after the addition of all reagents and solvents
dictated the scale of the reaction. In house capabilities were initially limited to
a 5-L jacketed round bottom flask. We have since transferred this protocol to