Oxazolidinones and 2,5-Dihydrofurans via Zinc-Catalyzed Regioselective Allenylation Reactions of l -α-Amino Aldehydes

Article abstract of DOI:10.1021/acs.joc.7b00969

The simultaneous control of diastereoselectivity and regioselectivity in Zn-catalyzed allenylation reactions of N-protected l-α-amino aldehydes is reported. A reversal in diastereoselectivity could be realized by variation of the α-amino aldehyde protecti

Full text of DOI:10.1021/acs.joc.7b00969

Article
Oxazolidinones and 2,5-Dihydrofurans via Zinc-Catalyzed
Regioselective Allenylation Reactions of L-#-Amino Aldehydes
Farzad Zamani, Stephen G. Pyne, and Christopher J. T. Hyland
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 30 May 2017
Downloaded from http://pubs.acs.org on June 1, 2017
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Oxazolidinones and 2,5ꢀDihydrofurans via ZincꢀCatalyzed
Regioselective Allenylation Reactions of LꢀαꢀAmino Aldehydes
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Farzad Zamani, Stephen G. Pyne* and Christopher J. T. Hyland*
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School of Chemistry, University of Wollongong, Wollongong, New South Wales, 2522,
Australia
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[*Corresponding authors: emails: spyne@uowmail.edu.au, chrhyl@uow.edu.au]
Abstract
The simultaneous control of diastereoselectivity and regioselectivity in Znꢀ
catalyzed allenylation reactions of Nꢀprotected ꢀαꢀamino aldehydes is reported. A
L
reversal in diastereoselectivity could be realized by variation of the ɑꢀamino aldehyde
protecting groups. A range of 1ꢀallenylꢀ2ꢀamino alcohols were obtained with
excellent regioselectivity and converted to oxazolidinones and dihydrofurans. Many
of which could be isolated as single diastereoisomers and without significant erosion
of ee, making this a practical catalytic synthesis of highly functionalized heterocycles.
Introduction
Allenyl and propargyl boronates have emerged as key reagents for catalyzed
allenylation and propargylation reactions of carbonyls and imines, providing rapid
synthesis of allenes and alkynes with pendant heteroatoms via C–C bond formation.1
Allenes are valuable intermediates for targetꢀoriented synthesis and methodology
development because they can undergo a vast array of transformations and have high
levels of structural diversity.1e Allenes bearing pendant heteroatoms, such as N or O,
are particularly important due to the ability of these heteroatoms to engage in
cyclization reactions with the reactive allene moiety – typically under the catalysis of
πꢀphilic transition metals.2 Furthermore, a number of natural products and
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pharmaceuticals feature allenes with pendant heteroatoms.3
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A powerful route to allenes with a pendant O has been developed by Fandrick
et al. who have demonstrated that Et2Zn catalyzes the regioselective allenylation of
various achiral aldehydes and ketones with allenylboronic acid pinacol ester 1
(Scheme 1a).4a This seminal study indicated that this was a kinetically controlled
process, where addition of a catalytically generated propargyl zinc intermediate to the
carbonyl electrophile competes with equilibration of the propargyl and allenyl
intermediates. They also demonstrated that a regiochemical switch to the more typical
homopropargyl alcohols was possible when the reaction was run at room temperature
and under thermodynamic control.4b More recently, Kobayashi showed that a
Zn(HMDS)2ꢀcatalyst process with allenylboronic acid 2,2ꢀdimethylꢀ1,3ꢀpropanediol
ester 1ʹ could also give either the allenyl or homopropargyl alcohols from the same
starting materials by using kinetic or thermodynamic reaction control, respectively
(Scheme 1a).5 Despite these reports, methods to prepare allenes with multiple pendant
heteroatoms are extremely rare6 and mostly limited to systems containing only
oxygen, rather than both O and N; furthermore, the methods that do exist are not
catalytic.7 Combining both O and N reactive elements in a single allenic substrate
would allow the synthesis of highly functionalized heterocycles with multiple
heteroatoms. However, the potential route to these compounds via catalytic
allenylation of αꢀamino aldehydes8 (A, Scheme 1b) has not been developed; although
the preparation of propargyl amino alcohols by the stoichiometric addition of
propargylzinc species to αꢀamino aldehydes has been established.9 Such a method
would be challenging due to the requirement for concurrent control of both
regioselectivity and diastereoselectivity – something that has not been achieved to
date. Herein, we report a simultaneous control of diastereoselectivity and
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regioselectivity in the Et2Znꢀcatalyzed allenylation reactions of chiral αꢀamino
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aldehydes with allenylboronic acid pinacol ester 1.
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Scheme 1. (a) Previous methods for the preparing allenylcarbinols from
allenylboronic reagents 1 and 1ʹ using zinc catalysts; (b) current study.
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The resulting allenic products are direct precursors to 2,5ꢀdihydrofurans with a
pendant N (25, Scheme 1b) and allenyloxazolidinones (23, Scheme 1b), which are
two key heterocycles in a diverse array of biologically active structures, fragrance
compounds, antirheumatics and antidiabetics.10,11 Diastereoselective methods to
prepare oxazolidinones with pendant unsaturated moieties are severely limited,12 and
while the preparation of 2,5ꢀdihydrofurans by Auꢀcatalyzed cyclisation of allenes is
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well known, the same method to 2,5ꢀdihydrofurans with pendant N are unknown – the
only other routes involve long nonꢀgeneral multiꢀstep synthesis.13
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Results and Discussion
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The L
ꢀalanineꢀderived NꢀBoc protected αꢀamino aldehyde 2a8 was first chosen
for investigation of these reactions using diethylzinc as a catalyst under the reaction
conditions shown in Table 1. We chose to focus on diethylzinc as it is a commercially
available and mild reagent unlikely to cause racemization of the αꢀamino aldehyde
starting materials. When the reaction of allenyl boronate 1 and the aldehyde 2a was
conducted in toluene in the absence of Et2Zn (entry 1), a slow background reaction
was observed to give only propargyl amino alcohol 16a, in low yield and with low
diastereoselectivity. The addition of 5 mol% of the Et2Zn catalyst resulted in a more
rapid reaction to give the allene 9a with almost complete control of allenyl to
propargyl regioselectivity, but with modest syn diastereoselectivity (entry 2).
Switching to the more polar solvent THF resulted in the reversal of regioselectivity to
favour the propargyl product 16a, but with almost no diastereoselectivity (entry 3).
The reaction also proceeded in CH2Cl2 but with modest regioselectivity (entry 4). An
increase in the amount of catalyst from 5 mol% to 10 mol% in toluene improved the
yield significantly from 77% (entry 2) to 92% (entry 5), with moderate
diastereoselectivity. In an attempt to improve the diastereoselectivity, the reaction was
conducted at −40 °C (entry 6), but no reaction was observed.
At this point alternate protecting groups on the nitrogen were investigated in
an attempt to further control the diastereoselectivity. The NꢀTs and NꢀFmoc alanals 3
and 4 (entries 7 and 8) did not undergo the desired allenylation/propargylation
reaction, while NꢀTr alanal 5 (entry 9) provided the corresponding 1ꢀallenylꢀ2ꢀamino
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alcohol in high yield and regioselectivity – however, the diastereoselectivity was
poor. After testing a range of singly Nꢀprotected αꢀamino alanals, N,Nꢀdiprotected αꢀ
amino alanals were investigated to see if a switch in diastereoselectivity was possible
by virtue of increased steric bulk at the nitrogen of these substrates (entries 10ꢀ12).14
The reaction of the NꢀBn, NꢀBoc alanal 6a proved the most rewarding giving the
allenyl product 13 with good regioselectivity (89:11) and high diastereoselectivity (dr
=19:1 anti:syn).
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Table 1. Optimization of reaction conditionsa
Cat.
(mol %)
Yieldb %
(al:pr)c
drc
(syn:anti)
Entry
1
NR1R2
Sol.
NHBoc
PhMe
0
12 (0:100)
2.6:1
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3
4
5
6
7
8
9
10
11
NHBoc
NHBoc
NHBoc
NHBoc
NHBocd
NHTs
PhMe
THF
5
5
5
10
10
10
10
10
10
10
77 (97:3)
60 (5:95)
38 (71:29)
92 (93:7)
0
2.6:1
1.1:1
2:1
2.6:1
0
CH2Cl2
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
0e
0
0
NHFmoc
NHTr
0f
82 (84:16)
96 (89:11)
54i (94:6)
50i (94:6)
1.3:1
1:19h
1:1.5
NBnBocg
NBnTsg
g
12
NBn2
PhMe
10
1:1.3
aReaction conditions: 1 (1.10 equiv.), Et2Zn, solvent, 0 oC, 18 h.
bIsolated yield of allene and propargyl products.
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cRegioselectivity of determined by H NMR analysis of the
crude reaction product – stereochemistry of propargyl products
not determined. dThe reaction was carried out at ꢀ40 oC.
f
g
eDecomposition of SM. Recovery of SM. 1.3 equiv. of 1 was
h
1
used. Determined by H NMR analysis of NꢀBoc deprotected
crude RM. Lowering of the catalyst loading for this substrate
i
resulted in incomplete conversion. Isolated yield for the major
allene diastereoisomer.
The anti and syn configurations assigned to 9a and 13a, respectively, were
1
based on H NMR analysis, including the nOe interactions between H4, H5 and the
CH3 group in the corresponding oxazolidinones 23a and 24 (Scheme 2) and the
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magnitudes of J4,5 couplings (J4,5 = 6.0 Hz for 23a and J4,5 = 7.2 Hz for 24) which
were also consistent with these assignments.6a It is proposed that the syn
diastereoisomer is likely formed via a Cram−chelateꢀlike model, where interaction
between the aldehyde and the NꢀH drives the direction of nucleophilic attack.
(Scheme 2a).14e,f Conversely, switching to the aldehyde having a more steric bulky,
doubly protected, nitrogen favors Felkin−Ahn control as Hꢀbonding is no longer
possible (Scheme 2b).14aꢀd That the dr for the uncatalyzed reaction (Table 1, entry 1) is
identical to the catalyzed provides further support for this Hꢀbond model, rather than
Zn playing a role in chelation.
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Scheme 2. Determination of relative configuration of the allenyl products.
While only a moderate diastereoselectivity was observed for the allenylation of NꢀBoc
protected αꢀamino aldehyde 2a, the reactions are highly regioselective. Furthermore,
the levels of diastereoselectivity observed in Table 2 are comparable to the recently
reported crossꢀbenzoin condensation using NꢀBoc protected αꢀamino aldehydes.14d,e
We found that baseꢀinduced conversion to the allenyl oxazolidinones 23 provides a
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convenient method for producing regioꢀ and diastereomerically enriched products (up
to >98:2 for the majority of cases) after chromatographic purification for the removal
of the minor diastereomer.
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Table 2. Reaction scope of 5ꢀallenyl
oxazolidinonesa
1ꢀallenylꢀ2ꢀaminoalcoholsb,c
5ꢀallenyl oxazolidinoneb,c
aReaction conditions: (i) 1 (1.1 equiv.), Et2Zn (10 mol%),
toluene, 0 oC, 18 h; (ii) NaH (2 equiv.), THF, r.t, 1.5 h.
bIsolated yield, with dr measured on purified oxazolidinone
after chromatographic purification. cRegioselectivity and dr
d
estimated by 1H NMR analysis of purified 9. Isolated yield of
e
the single major diastereomer. ee was determined by 1H NMR
analysis
of
the
resulting
diastereomeric
(S)ꢀ
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camphorsulfonamide derivatives (see SI).
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These structures are more convenient building blocks than the precursor Nꢀ
protected aminoꢀalcohols as their NMR spectra are more clearly defined due to the
absence of rotamers and they have a rigid stereodefined oxazolidinone unit combined
with a reactive allene moiety. This is the first example of oxazolidinones bearing a
reactive C5 allenyl side chain along with the free NH,15 which suggests they should be
powerful synthetic intermediates for the synthesis of biological active compounds.
Therefore, the optimized reaction conditions for the Znꢀcatalyzed allenylation
reactions were performed for other chiral NꢀBoc αꢀamino aldehydes having different
aryl and aliphatic side chains, before conversion to the corresponding allenyl
oxazolidinone (Table 2). These reactions afforded the syn 1ꢀallenylꢀ2ꢀamino alcohols
9aꢀ9f with high regioselectivities and generally provided high yields (70ꢀ92%) and
moderate to high diastereoselectivities (2.3:1−9:1 syn/anti). For the aliphatic R
substituents, the dr improved as the size of the R group of 2 increased from Me (2a)
to iꢀPr (2d). The 1ꢀallenylꢀ2ꢀamino alcohol products underwent baseꢀinduced
cyclisations to give 5ꢀallenyloxazolidinones 23aꢀ23f which could be isolated in yields
of 50ꢀ74% – in the majority of cases (23aꢀc and 23f) these were obtained as single
diastereomers, after separation of the major diasteromer using column
chromatography, thus providing practical access to these intriguing heterocycles.12,15
We next explored the substrate scope of the allenylation reaction of the NꢀBn,
NꢀBoc aldehydes 6. The NMR spectra for the direct allenylation products are
complicated by the presence of a mixture of rotamers, diastereoisomers and
regioisomers, therefore dihydrofurans 25 were targeted as the final desired products.16
Consequently, following allenylation of aldehydes 6aꢀg under the optimized
conditions, a sequential Au(I)ꢀcatalyzed cyclization17 and NꢀBoc deprotection was
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carried out on the crude reaction mixture to give dihydrofurans 25 in good threeꢀstep
yields (Table 3). In three cases, the products (25a, 25d and 25f) could be obtained as
single diastereoisomers after purification by column chromatography and the others in
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good to modest dr. The dr as estimated by the H NMR of the crude dihydrofurans
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(25) is essentially the same as the purified material, expect for 25f, which showed a dr
of 4.9:1 in the crude reaction mixture, indicating the minor diastereomer had been
removed during purification. This method is advantageous for two reasons, firstly the
dihydrofurans are medicinally important skeletons and secondly, the direct NꢀBoc
deprotection of allene products 13 resulted in formation of an unstable product.18
Despite the importance of these structures, we are unaware of any general methods to
prepare 2,5ꢀdihydrofurans with a pendant nitrogen atom – let alone in a stereodefined
fashion. The NꢀBoc protected prolineꢀderived amino aldehyde 6g performed well in
the reaction to give 13g, and then the corresponding cyclized material 25g. The
corresponding deprotected derivative proved unstable, which is consistent with
previous reports.19
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Table
3.
Reaction
scope
of
2,5ꢀ
dihydrofuransa,b,c
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aReaction conditions: (i) 1 (1.3 equiv.), Et2Zn (10 mol%), PhMe, 0
oC, 18 h; (ii) AuPPh3NTf2 (10 mol%), DCE, 60 oC, 8 h; (iii)
TMSCl (5 equiv.), MeOH, r.t, overnight. bIsolated yields over
c
three steps without any intermediate purification. dr determined
by 1H NMR analysis of purified 25. dThe NꢀBoc deprotected
e
product could not be obtained due to instability. Isolated yield
from two steps.
All the αꢀamino aldehydes utilized in this study were enantiomerically
enriched and obtained from naturally occurring Lꢀαꢀamino acids and are generally
known for their propensity to racemization.8 Therefore, the enantioretention of
representative reactions from Tables 2 and Table 3 were investigated and gratifyingly,
no erosion of enantiopurity was observed in any case. The ees of diastereomerically
enriched oxazolidinones 23aꢀc and 23f were determined by preparation of their (S)ꢀ
camphorsulfonyl derivatives according to the previously reported method20 (see SI).
The ees of 23a (ee 96%) and 23c (ee 86%) were identical to those of their precursor
aldehydes 2a (ee 96%)8 and 2c (ee 86%), which indicates little or no erosion of the
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enantiomeric purities of the aldehydes during the reaction steps (aldehyde ee from
chiral HPLC analysis of the corresponding alcohol, see SI). However, this method
was not suitable for the 2,5ꢀdihydrofuran products 25 due to instability of the
corresponding camphorsulfonyl derivative. Therefore, the ee of the precursor
aldehyde 6a (ee 91%) was determined by chiral HPLC (see SI), which was identical
to that of its derived dihydrofuran 25a (ee 91%, from chiral HPLC analysis, see SI).
The proposed mechanism for these allenylation reactions is shown in Scheme
3 and is consistent with the proposal of Fandrick and coꢀworkers.4 Transmetallation
between 1 and Et2Zn gives the reactive propargylic Zn species B, which under the
kinetic control conditions of the reaction reacts in an SE2ʹ fashion with the αꢀamino
aldehyde under Felkin−Ahn or Cram−chelationꢀlike control to give Zn alkoxide C.
The reaction remains catalytic in Zn as the alkoxide can undergo BꢀtoꢀZn exchange
with 1 to regenerate the propargyl zinc species B.
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Scheme 3. Proposed catalytic cycle for the Znꢀcatalyzed allenylation reactions
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It is also possible that Et2Zn is regenerated by reaction of the alkoxide C with
EtBpin generated in the initial transmetallation. Isomerisation of propargylic Zn
species B to the thermodynamically more stable allene species D under our reaction
conditions is clearly facilitated by more polar solvents, such as THF (entry 3 of Table
1).
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In conclusion, we have developed the first examples of simultaneous control
of diastereoselectivity and regioselectivity in Znꢀcatalyzed allenylation reactions of Nꢀ
protected
Lꢀαꢀamino aldehydes. These reactions proceed with high regiochemical
control to favor the allenic products. Felkin−Ahn control is observed in the presence
of sterically hindered groups on nitrogen, while Cram−chelation like control is
observed for singly protected αꢀamino aldehydes. Furthermore, the products of these
allenylation reactions undergo intramolecular cyclization to obtain novel 5ꢀallenyl
oxazolidinones and 2,5ꢀdihydrofurans. Many of these heterocyclic compounds could
be obtained as single diastereomers in high ee after simple column chromatography,
making this a practical method for preparing these highly functionalized and useful
chiral scaffolds. Work is currently underway to investigate the reactivity of the
allenyloxazoldinone products.
Experimental Section
General Methods. Commercial reagents were purchased and used as received
without any purification. Dry reaction solvents were passed through activated alumina
columns to obtain dryness before being stored under nitrogen over 4Å molecular
sieves. All reactions using air/moisture sensitive reagents were performed in ovenꢀ
dried glassware, under an atmosphere of nitrogen quipped with a stir bar. Reactions
were monitored by thinꢀlayer chromatography (TLC) on aluminum backed silica gel
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sheets, visualizing with UVꢀlight (254 nm) fluorescence quenching, followed by
staining of the plates with potassium permanganate stain. Column chromatography
used for compound purification was performed using preꢀpacked flash grade silica gel
9
1
(40ꢀ75 nm) as the stationary phase. H NMR and 13C{1H} NMR spectra were
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1
recorded either at 300, 400 and 500 MHz H NMR or at 75, 100 and 125 MHz 13C
NMR. All H NMR and 13C{1H} NMR were recorded in deuterated chloroform
1
(CDCl3) containing 0.1% (v/v) tetramethylsilane (TMS). Abbreviations used in the
description of resonances are: singlet (s), doublet (d), triplet (t), quartet (q), doublet of
doublets (dd), broad (br) and multiplet (m). All coupling constants (J) were measured
in hertz (Hz). NMR chemical shift abbreviations were reported in parts per millions
1
(ppm) from tetramethylsilane (TMS) and were corrected to 0.00 ppm (TMS) for H
NMR and 77.00 ppm (CDCl3 centre line) for 13C NMR. The αꢀamino amino methyl
ester hydrochlorides were prepared from commercially available amino acids using
previously reported literature procedures (citations to these compounds are provided
in the experimental below).
Synthesis of singly Nꢀprotectedꢀamino Aldehydes
The Nꢀprotected αꢀamino aldehydes 2a,21a 2c,21b 2d,21c 2e,21d 321e, 421f and 521g are
known and were prepared by the previously reported methods.
Methyl (S)ꢀtertꢀbutyl(1ꢀoxopentanꢀ2ꢀyl)carbamate (2b).
Methyl 2ꢀ((tertꢀbutoxycarbonyl)amino)pentanoate S1. To a solution of methyl
2ꢀaminopentanoate hydrochloride22a (1.00 g, 5.96 mmol) in dry dichloromethane (15
mL) at 0 °C, was added triethylamine ((0.94 mL, 6.55 mmol, 1.1 equiv.), followed by
diꢀtertꢀbutyl dicarbonate (1.56 g, 7.16 mmol, 1.2 equiv.). Stirring was continued for 1
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h at 0 °C, and then overnight at room temperature. The reaction mixture was then
quenched by the addition of saturated aqueous NaHCO3(aq) solution and the separated
organic layer washed with brine solution and dried over Na2SO4. Purification by flash
column chromatography (EtOAc/hexane 3:7) yielded methyl 2ꢀ((tertꢀ
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butoxycarbonyl)amino)pentanoate S1 as a colorless oil (1.29 g, 93% yield). H NMR
matched that reported previously, but other characterization data has not been
published so is included here.23 Rf (Et2O/hexane 2:8) = 0.42. ꢁ = +84.6 (c 2
ꢀ ꢂꢄꢄ
ꢃ
CHCl3). 13C{1H} NMR (125 MHz, CDCl3) δ 13.5, 18.5, 28.1, 34.6, 52.0, 53.1, 79.5,
155.3, 173.4. IR (νmax/cmꢀ1) 3370 (w), 2963 (m), 2934 (m), 1743 (s), 1713 (s), 1507
(s), 1365 (s), 1249 (s), 1159 (s), 1011 (m), 779 (m). HRMS (ESIꢀTOF) m/z calcd for
C11H21NO4Na [M + Na]+ 254.1368, found 254.1361.
Methyl (S)ꢀtertꢀbutyl(1ꢀoxopentanꢀ2ꢀyl)carbamate (2b). To a solution of
methyl 2ꢀ((tertꢀbutoxycarbonyl)amino)pentanoate S1 (0.19 g, 0.82 mmol) in dry
toluene (2 mL) at −78 °C, was added dropwise diisobutylaluminum hydride (5.5 M in
nꢀhexane, 0.30 mL, 1.64 mmol, 2 equiv.) over a period of 45 min. The mixture was
stirred at the same temperature for 1.5 h, and then quenched by the addition of
precooled methanol. The reaction mixture was allowed to warm to room temperature,
ice (1 g) was added with heavy agitation, the mixture filtered and the filtrate was
extracted with chloroform. The organic layer was washed with brine solution, dried
over Na2SO4 and concentrated under reduced pressure to 2b as a colorless oil which
was used without further purification (0.149 g, 91% yield). The data matched that
previously reported.24
(S)ꢀtertꢀButyl 3ꢀ(2ꢀ((tertꢀbutoxycarbonyl)amino)ꢀ3ꢀoxopropyl)ꢀ1Hꢀindoleꢀ
1ꢀcarboxylate (2f).
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tertꢀButyl
3ꢀ(2ꢀ((tertꢀbutoxycarbonyl)amino)ꢀ3ꢀmethoxyꢀ3ꢀoxopropyl)ꢀ1Hꢀ
5
6
indoleꢀ1ꢀcarboxylate S2. Triethylamine (0.56 mL, 3.92 mmol, 1.0 equiv.) was added
7
8
dropwise to a stirred solution of methyl tryptophanate hydrochloride22b (1.00 g, 3.92
9
o
mmol) in THF (15 mL) at 0 C. Then, diꢀtertꢀbutyl dicarbonate (1.71 g, 7.85 mmol,
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2.0 equiv.) and 4ꢀ(dimethylamino)pyridine (0.72 g, 5.88 mmol, 1.5 equiv.) were
added and the mixture was stirred overnight at room temperature. The reaction
mixture was concentrated under reduced pressure, and the tertꢀbutyl 3ꢀ(2ꢀ((tertꢀ
butoxycarbonyl)amino)ꢀ3ꢀmethoxyꢀ3ꢀoxopropyl)ꢀ1Hꢀindoleꢀ1ꢀcarboxylate S2 was
obtained after flash column chromatography (EtOAc/hexane 3:7). Colorless oil (1.59
g, 97%). The data recorded matched that previously reported.25
(S)ꢀtertꢀButyl 3ꢀ(2ꢀ((tertꢀbutoxycarbonyl)amino)ꢀ3ꢀoxopropyl)ꢀ1Hꢀindoleꢀ1ꢀ
carboxylate (2f). The title compound 2f was obtained following the same procedure
used for 2b with tertꢀbutyl 3ꢀ(2ꢀ((tertꢀbutoxycarbonyl)amino)ꢀ3ꢀmethoxyꢀ3ꢀ
oxopropyl)ꢀ1Hꢀindoleꢀ1ꢀcarboxylate S2 (0.11 g, 0.26 mmol) and diisobutylaluminum
hydride (5.7 M in nꢀhexane, 0.10 mL, 0.57 mmol, 2.2 equiv.) in toluene (1 mL).
1
ꢀ ꢂꢄꢄ
Colorless gummy oil (0.064 g, 99% yield). ꢁ = +53.5 (c 3.2 CHCl3). H NMR
ꢃ
(500 MHz, CDCl3) δ 1.44 (s, 9H, C(CH3)3), 1.66 (s, 9H, C(CH3)3), 3.22 (br s, 2H,
CH2Ph), 4.48 (br s, 1H, CH), 5.22 (br s, 1H, NH), 7.25 (br s, 1H, CHAr), 7.32 (br s,
1H, CHAr), 7.43 (br s, 1H, CHAr), 7.54 (br s, 1H, CHAr), 8.13 (br s, 1H, CHAr), 9.65 (s,
1H, CHO). 13C{1H} NMR (125 MHz, CDCl3) δ 25.0, 28.2, 28.3, 59.6, 80.2, 83.8,
114.8, 115.3, 119.0, 122.7, 124.2, 124.7, 130.2, 135.5, 149.5, 155.4, 199.5. IR
(νmax/cmꢀ1) 3371 (w), 2979 (m), 2361 (w), 1730 (s), 1700 (s), 1507 (s), 1452 (s), 1367
(s), 1253 (s), 1154 (s), 1086 (s), 856 (m), 766 (s), 744 (s). HRMS (ESIꢀTOF) m/z
calcd for C21H28N2O5Na [M + Na]+ 411.1896, found 411.1878.
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Preparation of doubly protected αꢀamino esters and aldehydes
The NꢀBn,NꢀBoc αꢀamino aldehyde 6e26 and the NꢀBoc αꢀamino prolinal 6g27,
NꢀBn,NꢀTs αꢀamino alaninal 728 and N,Nꢀdibenzylꢀαꢀamino alaninal 829 are known
and were prepared by the previously reported methods. The remaining NꢀBn,NꢀBoc αꢀ
amino aldehydes were prepared as described below. The starting materials methyl
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tosylꢀ
L
ꢀalaninate21e, (S)ꢀtertꢀbutyl benzyl(1ꢀhydroxypropanꢀ2ꢀyl)carbamate30a, (S)ꢀ
31a
methyl Nꢀbenzyl valinate
and (S)ꢀ2ꢀ(benzylamino)ꢀ3ꢀmethylbutanꢀ1ꢀol31b were
prepared as previously described.
tertꢀButyl benzyl(1ꢀoxopropanꢀ2ꢀyl)carbamate 6a.
To a stirred solution of tertꢀbutyl benzyl(1ꢀhydroxypropanꢀ2ꢀyl)carbamate30a (0.42 g,
1.58 mmol) in CH2Cl2 (30 mL) at 0 °C, was added saturated aqueous NaHCO3
solution (15 mL), KBr (0.18 g, 1.58 mmol, 1.0 equiv.) and TEMPO (12.35 mg, 0.079
mmol, 0.05 equiv.). NaOCl (3.79 mL, 1.89 mmol, 1.2 equiv.) was then added with a
syringe pump over 30 min. The reaction was stirred for another 15 min at 0 °C. Then,
the reaction mixture was quenched with saturated aqueous Na2S2O3 solution (15 mL)
and extracted into CH2Cl2 (3×10 mL). The combined organic layers were dried
(Na2SO4) and concentrated under reduced pressure to afford the aldehyde 6a, which
was utilized for the next step without purification. Colorless oil (0.38 g, 91%). The ee
was determined by chiral HPLC analysis of the corresponding alcohol (obtained by
NaBH4 reduction of a small quantity of the unpurified aldehyde) using a Phenomenex
Lux iꢀCelluloseꢀ5 column; hexane/isopropanol (95:5); flow rate = 0.5 mL/min; 210
nm; tmajor = 23.29 min, tminor = 25.15 min, 91% ee. The data matches that
previously reported.30b
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(S)ꢀtertꢀButyl benzyl(1ꢀoxopentanꢀ2ꢀyl)carbamate (6b).
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Methyl 2ꢀ(benzylamino)pentanoate S3. To a stirred suspension of Lꢀnorvaline
9
methyl ester hydrochloride22a (1.30 g, 7.75 mmol) and benzyl bromide (0.90 mL, 7.75
mmol, 1.0 equiv.) in acetonitrile (20 mL), was added potassium carbonate (2.14 g,
15.50 mmol, 2.0 equiv.) and the mixture was stirred overnight at room temperature.
The reaction mixture was washed with saturated aqueous NH4Cl solution (30 mL) and
water (30 mL), dried (MgSO4), concentrated under reduced pressure and purified by
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flash column chromatography (Et
2
O/hexane 1:9) to obtain the Nꢀbenzylated product
ꢀ ꢂꢄꢄ
S3. Colorless oil (1.25 g, 73%). Rf (Et2O/hexane 1:9) = 0.16. ꢁ = −35.4 (c 5.5
ꢃ
1
CHCl3). H NMR (300 MHz, CDCl3) δ 0.88 (t, 3H, J = 7.2 Hz, CH3), 1.33ꢀ1.43 (m,
2H, CH2), 1.57ꢀ1.64 (m, 2H, CH2), 1.79 (s, 1H, NH), 3.26 (t, 1H, J = 6.6 Hz, CH),
3.61 (d, 1H, J = 13.2 Hz, CHPh), 3.67 (s, 3H, CH3), 3.80 (d, 1H, J = 12.9 Hz, CHPh),
7.22ꢀ7.31 (m, 5H, 5CHAr). 13C{1H} NMR (125 MHz, CDCl3) δ 13.8, 19.0, 35.7, 51.5,
52.1, 60.5, 126.9, 128.2, 128.3, 139.9, 176.0. IR (νmax/cmꢀ1) 3735 (m), 3031 (w), 2957
(m), 1734 (s), 1456 (m), 1339 (m), 1267 (m), 976 (m), 732 (m), 698 (s). HRMS (ESIꢀ
TOF) m/z calcd for C13H20NO2 [M + H]+ 222.1494, found 222.1492.
Methyl 2ꢀ(benzyl(tertꢀbutoxycarbonyl)amino)pentanoate S4. Triethylamine
(2.58 mL, 9.02 mmol, 2.0 equiv.) was added dropwise to a stirred solution of S3 (1.00
g, 4.51 mmol) and diꢀtertꢀbutyl dicarbonate (Boc2O, 1.47 g, 6.77 mmol, 1.5 equiv.) in
dry dichloromethane (10 mL), and the reaction mixture was stirred for 24 h at room
temperature. The reaction was washed with aqueous solution of HCl (1M) (15 mL),
dried (Na2SO4), and concentrated under reduced pressure. Purification was carried out
by flash column chromatography (Et
2
O/hexane 1:9) to yield the NꢀBn,NꢀBoc αꢀamino
ꢀ ꢂꢄꢄ
ester S6. Colorless oil (0.89 g, 62%). Rf (Et2O/hexane 1:9) = 0.23. ꢁ = −50.4 (c
ꢃ
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9.5 CHCl3). H NMR (300 MHz, CDCl3) (mixture of rotamers) δ 0.79 (br s, 3H,
CH3), 1.24 (br s, 2H, CH2), 1.40 (br s, 4.2H, C(CH3)3), 1.45 (br s, 4.8H, C(CH3)3),
1.62ꢀ1.75 (m, 1H, CH), 1.84ꢀ1.94 (m, 1H, CH), 3.55 (s, 3H, CH3), 3.90ꢀ4.80 (m, 3H,
CH2Ph, CH), 7.19ꢀ7.28 (m, 5H, 5CHAr). 13C{1H} NMR (75 MHz, CDCl3) (mixture of
rotamers, minor rotamer indicated by asterisk) δ 13.5, 19.5, 28.1, 31.6, 32.3*, 32.4,
49.4, 50.7*, 51.5, 58.5, 59.1*, 80.2, 126.8, 127.1, 128.0, 128.3, 138.0, 138.9*, 155.6,
172.1. IR (νmax/cmꢀ1) 3031 (w), 2961 (m), 2875 (w), 1739 (s), 1700 (s), 1452 (s), 1319
(m), 1248 (m), 1163 (m), 979 (m), 862 (m), 734 (m), 699 (s). HRMS (ESIꢀTOF) m/z
calcd for C18H27NO4Na [M + Na]+ 344.1838, found 344.1833.
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tertꢀButyl benzyl(1ꢀhydroxypentanꢀ2ꢀyl)carbamate S5. To a solution of lithium
aluminum hydride (1 M solution in THF, 4.98 mL, 4.98 mmol, 2.0 equiv.) at 0 °C,
was added dropwise methyl 2ꢀ(benzyl(tertꢀbutoxycarbonyl)amino) pentanoate S4
(0.80 g, 2.49 mmol) in THF (3 mL) and the mixture was stirred at the same
temperature for 30 min. The reaction was quenched with water (1 mL), filtered, and
concentrated under reduced pressure. The crude product was purified by flash column
chromatography (EtOAc/hexane 4:6) to obtain the corresponding αꢀamino alcohol
ꢀ ꢂꢄꢄ
product S5 as a colorless oil (0.60 g, 82%). Rf (EtOAc/hexane 4:6) = 0.61. ꢁ
=
ꢃ
1
+16.3 (c 4.6 CHCl3). H NMR (500 MHz, CDCl3) (mixture of rotamers) δ 0.84 (br s,
3H, CH3), 1.26 (br s, 2H, CH2), 1.37 (br s, 7H, C(CH3)3, CH), 1.49 (br s, 4H,
C(CH3)3, CH), 3.40ꢀ3.60 (m, 3H), 3.84ꢀ3.86 (m, 1H, CH), 4.21ꢀ4.70 (m, 2H, CH2Ph),
7.21ꢀ7.27 (m, 5H, 5CHAr). 13C{1H} NMR (125 MHz, CDCl3) (mixture of rotamers,
minor rotamer indicated by asterisk) δ 13.9, 19.7, 28.3, 30.9, 31.7*, 48.2*, 49.3, 59.2,
64.1, 80.1, 126.9, 127.6, 128.3, 139.6, 156.9. IR (νmax/cmꢀ1) 3446 (m), 2959 (m), 2930
(m), 2873 (m), 1665 (s), 1465 (m), 1410 (s), 1341 (m), 1243 (m), 1166 (s), 1053 (w),
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701 (s). HRMS (ESIꢀTOF) m/z calcd for C17H27NO3Na [M + Na]+ 316.1889, found
316.1891.
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tertꢀButyl benzyl(1ꢀoxopentanꢀ2ꢀyl)carbamate 6b. Swern oxidation of methyl
tertꢀbutyl benzyl(1ꢀhydroxypentanꢀ2ꢀyl)carbamate S5 (0.59 g, 2.01 mmol) was
carried out with oxalyl chloride (0.37 mL, 4.02 mmol, 2 equiv.), DMSO (0.61 mL,
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8.04 mmol, 4 equiv.) and Et
−78 °C. The reaction mixture was quenched with saturated aqueous NaHCO
(5 mL) and extracted into CH Cl (3×3 mL). The combined organic layers were
washed with brine solution (10 mL), dried (Na SO ) and concentrated under reduced
3
N 4.56 mL, 32.17 mmol, 16 equiv.) in CH
2Cl
2
(5 mL) at
3
solution
2
2
2
4
pressure to yield 6b as a colorless oil (0.50 g, 85%), which was used in the
allenylation reaction without further purification. (Caution! This reaction is carried
out at −78 °C as it has been reported that oxalyl chloride and dimethyl sulfoxide can
react explosively at room temperature. Furthermore, this procedure should be carried
out in a fumehood since a dimethyl sulfide is an odorous byꢀproduct of the reaction).32
1
ꢀ ꢂꢄꢄ
Rf (EtOAc/hexane 1:9) = 0.43. ꢁ = −92.3 (c 7.0 CHCl3). H NMR (300 MHz,
ꢃ
CDCl3) (mixture of rotamers) δ 0.89 (t, 3H, J = 7.2 Hz, CH3), 1.34ꢀ1.41 (m, 2H,
CH2), 1.45 (br s, 9H, C(CH3)3), 1.49ꢀ1.80 (m, 1H, CH), 1.89ꢀ1.99 (m, 1H, CH), 3.45
(br s, 0.6H, CH), 3.76 (br s, 0.4H, CH), 4.11ꢀ4.22 (m, 1H, CHPh), 4.70 (br d, 0.4H, J
= 15.0 Hz, CHPh), 4.98 (br d, 0.6H, J = 15.0 Hz, CHPh), 7.26ꢀ7.35 (m, 5H, 5CHAr),
9.35 (br s, 0.6H, CHO), 9.44 (br s, 0.4H, CHO). 13C{1H} NMR (75 MHz, CDCl3)
(mixture of rotamers, minor rotamer indicated by asterisk) δ 13.8, 19.5, 28.1, 29.2*,
30.4, 51.4*, 51.8, 65.5, 80.9*, 81.3, 127.6, 128.3, 128.6, 137.7, 138.1*, 155.1, 199.5.
IR (νmax/cmꢀ1) 2965 (m), 2933 (m), 2876 (w), 1739 (s), 1692 (s), 1452 (s), 1405 (s),
1365 (s), 1249 (s), 1180 (s), 1002 (m), 864 (m), 735 (s), 699 (s). HRMS (ESIꢀTOF)
m/z calcd for C17H25NO3Na [M + Na]+ 314.1732, found 314.1741.
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tertꢀButyl benzyl(4ꢀmethylꢀ1ꢀoxopentanꢀ2ꢀyl)carbamate (6c)
Methyl Nꢀbenzyl leucinate S6. To a stirred suspension of
Lꢀmethyl leucinate
9
hydrochloride33 (1.0 g, 5.50 mmol) and benzyl bromide (0.7 mL, 6.05 mmol, 1.1
equiv.) in acetonitrile (20 mL), was added potassium carbonate (1.52 g, 11 mmol, 2
equiv.) and the mixture was stirred overnight at room temperature. The reaction
mixture was washed with saturated aqueous NH4Cl solution (20 mL) and water (20
mL), dried (MgSO4), concentrated under reduced pressure and purified by flash
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column chromatography (Et O/hexane 1:9) to obtain the Nꢀbenzylated product S6.
2
Light yellow oil (0.996 g, 77%). Data matches that reported previously.34
Methyl NꢀbenzylꢀNꢀ(tertꢀbutoxycarbonyl) leucinate S7. Triethylamine (0.81
mL, 2.75 mmol, 1.1 equiv.) was added dropwise to a stirred solution of S6 (1.00 g,
4.51 mmol) and diꢀtertꢀbutyl dicarbonate (Boc2O, 0.67 g, 3.1 mmol, 1.24 equiv.) in
dry dichloromethane (5 mL), and the reaction mixture was stirred for 24 h at room
temperature. The reaction was washed with aqueous solution of HCl (1M) (5 mL),
dried (Na2SO4), and concentrated under reduced pressure. Purification was carried out
by flash column chromatography (Et O/hexane 1:9) to yield the NꢀBn,NꢀBoc αꢀamino
2
ester S7. Colorless oil (0.59 g, 70%). Data matches that previously reported.35
tertꢀButyl benzyl(4ꢀmethylꢀ1ꢀoxopentanꢀ2ꢀyl)carbamate 6c. To a solution of
S9 (0.58 g, 1.74 mmol) in dry diethyl ether (3 mL) at −78 °C, was added dropwise
diisobutylaluminum hydride (5.0 M in nꢀhexane, 0.70 mL, 3.49 mmol, 2 equiv.) over
45 min. The mixture was stirred at the same temperature for 1 h, and was quenched
with methanol (1 mL). The reaction mixture was allowed to warm to room
temperature, followed by adding water (2 mL). The crude mixture was filtered
through a sintered glass funnel and the filtrate was washed with brine (20 mL). The
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organic layer was dried (Na2SO4) and concentrated under reduced pressure to yield
the desired aldehyde. Colorless oil (0.35 g, 65%). Data matches that previously
reported.14d
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tertꢀButyl benzyl(3ꢀmethylꢀ1ꢀoxobutanꢀ2ꢀyl)carbamate (6d)
(S)ꢀMethyl NꢀbenzylꢀNꢀ(tertꢀbutoxycarbonyl) valinate S8. Triethylamine (3.32
mL, 11.56 mmol, 2 equiv.) was added dropwise to a stirred solution of (S)ꢀmethyl Nꢀ
benzyl valinate31a (1.28 g, 5.78 mmol) and diꢀtertꢀbutyl dicarbonate (Boc2O, 2.14 g,
9.82 mmol, 1.7 equiv.) in dry dichloromethane (15 mL), and the reaction mixture was
stirred for 24 h at room temperature. The reaction was washed with aqueous solution
of HCl (1M) (15 mL), dried (Na2SO4), and concentrated under reduced pressure.
Purification was carried out by flash column chromatography (Et O/hexane 1:9) to
2
yield the NꢀBn,NꢀBoc αꢀamino ester S8. Colorless oil (1.18 g, 63%). Data matches
that previously reported.31b S8 was then converted into (S)ꢀ2ꢀ(benzylamino)ꢀ3ꢀ
methylbutanꢀ1ꢀol as previously reported for use in the next step.31b
(S)ꢀtertꢀButylbenzyl(3ꢀmethylꢀ1ꢀoxobutanꢀ2ꢀyl)carbamate 6d. Swern oxidation
of (S)ꢀ2ꢀ(Benzylamino)ꢀ3ꢀmethylbutanꢀ1ꢀol31b (0.73 g, 2.48 mmol) was carried out
with oxalyl chloride (0.46 mL, 4.96 mmol, 2 equiv.), DMSO (0.75 mL, 9.94 mmol, 4
equiv.) and Et3N (5.63 mL, 39.68 mmol, 16 equiv.) in CH2Cl2 (5 mL) at −78 °C. The
reaction mixture was quenched with saturated aqueous NaHCO3 solution (5 mL) and
extracted into CH2Cl2 (3×3 mL). The combined organic layers were washed with
brine solution (10 mL), dried (Na
2
SO ) and concentrated under reduced pressure to
4
yield 6d as a colorless oil (0.558 g, 77%), which was used in the allenylation reaction
without further purification. Data matches that reported previously.31b
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(S)ꢀtertꢀButyl 3ꢀ(2ꢀ(benzyl(tertꢀbutoxycarbonyl)amino)ꢀ3ꢀoxopropyl)ꢀ1Hꢀindoleꢀ
1ꢀcarboxylate (6f)
7
8
9
Methyl benzylꢀLꢀtryptophanate S9. Methyl tryptophanate hydrochloride22b (3.60 g,
14.13 mmol) was neutralized into the free base by dissolving in diethyl ether (20 mL)
followed by treating with saturated aqueous K2CO3 solution (20 mL). The organic
layer was dried (Na2SO4) and concentrated under reduced pressure to obtain a light
yellow oil. To a stirred suspension of neutralized tryptophan methyl ester and MgSO4
(2.70 g) in dichloromethane (40 mL), was added benzaldehyde (1.43 mL, 14.13
mmol, 1 equiv.) and the mixture was stirred for 5 h at room temperature. The
resulting imine compound was dissolved in dry methanol (30 mL) and NaBH4 (0.58 g,
15.54 mmol, 1.1 equiv.) was added slowly at 0 °C. The solvent was evaporated after 1
h at 0 °C. Then the mixture was washed by NH4OH (5%, 20 mL), extracted by ethyl
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acetate and dried (Na2SO4). Methyl benzylꢀLꢀtryptophanate S9 was obtained after
flash column chromatography (EtOAc/hexane 2:8) as a colorless gummy oil (3.12 g,
72%). Data matches that reported previously.22b
Methyl
NαꢀbenzylꢀNαꢀ(tertꢀbutoxycarbonyl)ꢀLꢀtryptophanate
S10.
Triethylamine (2.85 mL, 9.92 mmol, 2 equiv.) was added dropwise to a stirred
solution of methyl benzylꢀLꢀtryptophanate S10 (1.53 g, 4.96 mmol) and diꢀtertꢀbutyl
dicarbonate (1.02 g, 4.71 mmol, 0.95 equiv.) in dry dichloromethane (20 mL), and
was stirred for 24 h at room temperature. The crude reaction mixture was
concentrated under reduced pressure. Then title compound S10 was obtained after
flash column chromatography (EtOAc/hexane 2:8). Colorless gummy oil (1.37 g,
67%). Data matches that reported previously.22b
tertꢀButyl
(S)ꢀ3ꢀ(2ꢀ(benzyl(tertꢀbutoxycarbonyl)amino)ꢀ3ꢀmethoxyꢀ3ꢀ
oxopropyl)ꢀ1Hꢀindoleꢀ1ꢀcarboxylate S11. To a stirred solution of methyl Nαꢀbenzylꢀ
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Nαꢀ(tertꢀbutoxycarbonyl)ꢀ
Lꢀtryptophanate S10 (1.07 g, 2.62 mmol) and diꢀtertꢀbutyl
5
6
7
8
dicarbonate (0.85 g, 3.93 mmol, 1.5 equiv.) in dichloromethane (15 mL), was added
4ꢀ(dimethylamino)pyridine (0.063 g, 0.52 mmol, 0.2 equiv.) and the mixture was
stirred overnight at room temperature. The reaction mixture was diluted with EtOAc
(10 mL) and washed with water (30 mL) and saturated aqueous NaHCO3 solution (30
mL) and brine (30 mL). The organic layer was dried (Na2SO4) and the filtrate was
concentrated under reduced pressure. The title compound S11 was obtained after flash
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column chromatography (EtOAc/hexane 2:9) as a colorless gummy oil (1.15 g, 86%).
1
ꢀ ꢂꢄꢄ
Rf (EtOAc/hexane 2:9) = 0.48. ꢁ = −67.2 (c 1.0 CHCl3). H NMR (300 MHz,
ꢃ
CDCl3) (mixture of rotamers) δ 1.48 (s, 9H, 3CH3), 1.65 (s, 9H, 3CH3), 3.10ꢀ3.39 (m,
2H, CH2), 3.62 (s, 3H, CH3), 4.15ꢀ4.39 (m, 3H, CH2, CH), 7.01ꢀ7.42 (m, 9H, 9CHAr),
8.11 (br d, 1H, J = 6.9 Hz, CHAr). 13C NMR (75 MHz, CDCl3) (mixture of rotamers,
minor rotamer indicated by asterisk) δ 24.9*, 25.9, 28.2*, 28.3, 51.8*, 52.0, 59.6,
59.8*, 80.5*, 80.8, 83.2*, 83.4, 115.2, 115.3*, 116.5, 116.7*, 118.5, 118.7, 118.9*,
122.4, 124.00*, 124.09, 124.4, 124.3*, 126.9, 127.0, 127.1*, 127.6*, 127.9, 128.1*,
128.3, 128.5, 130.2*, 130.5, 135.4, 137.2, 137.6*, 149.5, 155.2, 171.4, 174.9*. IR
(νmax/cmꢀ1) = 2976 (m), 2931 (m), 2357 (w), 2167 (w), 1732 (s), 1695 (s), 1452 (s),
1365 (s), 1253 (s), 1155 (s), 1083 (s), 1016 (m), 858 (m), 742 (s), 698 (s). HRMS
(ESI) m/z calcd for C29H36N2O6Na [M + Na]+ 531.2471, found 531.2492.
tertꢀButyl (S)ꢀ3ꢀ(2ꢀ(Nꢀbenzylformamido)ꢀ3ꢀmethoxyꢀ3ꢀoxopropyl)ꢀ1Hꢀindoleꢀ
1ꢀcarboxylate
6f.
To
a
solution
of
tertꢀbutyl
3ꢀ(2ꢀ(benzyl(tertꢀ
butoxycarbonyl)amino)ꢀ3ꢀmethoxyꢀ3ꢀoxopropyl)ꢀ1Hꢀindoleꢀ1ꢀcarboxylate S11 (0.55
g, 1.08 mmol) in diethyl ether (3 mL) at −78 oC, was added dropwise
diisobutylaluminum hydride (5.4 M in nꢀhexane, 0.40 mL, 2.16 mmol, 2 equiv.). The
mixture was stirred at the same temperature for 1 h, and was quenched with methanol
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(1 mL). The reaction mixture was allowed to warm to room temperature, followed by
adding water (2 mL). The crude mixture was filtered and the filtrate was washed with
brine solution (20 mL). The organic layer was dried (Na2SO4) and concentrated under
reduced pressure to yield the desired aldehyde 6f. Light orange oil (0.398 g, 77%). Rf
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1
ꢀ ꢂꢄꢄ
(EtOAc/hexane 2:8) = 0.63. ꢁ
= −113.5 (c 9.8 CHCl3). H NMR (500 MHz,
ꢃ
CDCl3) (mixture of rotamers) δ 1.49 (s, 9H, C(CH3)3), 1.67 (s, 9H, C(CH3)3), 3.04ꢀ
3.09 (m, 0.5H, CH), 3.29ꢀ3.31 (m, 0.5H, CH), 3.37ꢀ3.42 (m, 1H, CH), 3.52 (t, 1H, J =
16.0 Hz, CH), 3.76ꢀ3.77 (m, 1H, CHPh), 4.50 (d, 0.5H, J = 15.0 Hz, CHPh), 4.76 (d,
0.5H, J = 15.0 Hz, CHPh), 7.00 (br s, 2H, 2CHAr), 7.19ꢀ7.24 (m, 4H, 4CHAr), 7.31ꢀ
7.41 (m, 3H, 3CHAr), 8.16 (br s, 1H, CHAr), 9.42 (s, 0.5H, CHO), 9.53 (0.5H, CHO).
13C{1H} NMR (125 MHz, CDCl3) (mixture of rotamers, minor rotamer indicated by
asterisk) δ 22.7, 23.8*, 28.2, 28.3*, 52.0, 52.7*, 65.3, 66.0*, 81.2*, 81.8, 83.5*, 83.6,
115.4*, 115.5, 116.4, 116.7*, 118.5, 118.7*, 122.64, 122.69*, 124.2*, 124.3*, 124.5,
124.6, 127.6*, 127.75, 127.78*, 128.4, 128.63, 128.65*, 130.1, 130.4*, 135.6, 137.3,
137.5*, 149.5, 154.8, 155.3*, 198.6, 199.0*. IR (νmax/cmꢀ1) 2978 (m), 2814 (w), 2364
(w), 2163 (w), 1730 (s), 1733 (s), 1683 (s), 1452 (s), 1365 (s), 1308 (m), 1251 (s),
1154 (s), 1085 (s), 976 (m), 856 (s), 743 (s), 700 (s). HRMS (ESIꢀTOF) m/z calcd for
C28H33N2O5 [M − H]+ 477.2389, found 477.2382.
(S)ꢀMethyl NꢀbenzylꢀNꢀtosyl alaninate S12. The aldehyde 8 was prepared as
previously reported29 but a modified synthesis of the ester starting material required
for its synthesis was employed. Potassium carbonate (2.37 g, 17.32 mmol, 2 equiv.)
was added to a stirred solution of methyl tosylꢀL
ꢀalaninate21e (2.23 g, 8.66 mmol) and
benzyl bromide (1.50 mL, 13.00 mmol, 1.5 equiv.) in acetonitrile (30 mL), and was
stirred overnight at room temperature. The reaction mixture was washed with
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saturated aqueous NH4Cl solution (50 mL) and water (50 mL), dried (MgSO4),
concentrated under reduced pressure and purified by flash column chromatography
7
8
(EtOAc/hexane 3:7) to obtain the methyl NꢀbenzylꢀNꢀtosylꢀalaninate S13. Colorless
9
1
ꢀ ꢂꢄꢄ
oil (2.74 g, 88%). Rf (EtOAc/hexane 3:7) = 0.54. ꢁ = −42.5 (c 2.5 CHCl3). H
ꢃ
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NMR (500 MHz, CDCl3) δ 1.26ꢀ1.28 (m, 3H, CH3), 2.42 (br s, 3H, CH3), 3.42 (br s,
3H, CH3), 4.42 (br d, 1H, J = 14.5 Hz, CHPh), 4.55 (br d, 1H, J = 16.0 Hz, CHPh),
4.61ꢀ4.63 (m, 1H, CH), 7.23ꢀ7.32 (m, 7H, 7CHAr), 7.71 (br d, 2H, J = 5.5 Hz, 2CHAr).
13C{1H} NMR (125 MHz, CDCl3) δ 16.4, 21.5, 49.1, 52.0, 55.0, 127.4, 127.5, 128.0,
128.3, 129.5, 137.1, 137.3, 143.4, 171.6. IR (νmax/cmꢀ1) 2950 (w), 1742 (s), 1456 (m),
1339 (s), 1152 (s), 1089 (m), 845 (m), 725 (s), 655 (s). HRMS (ESIꢀTOF) m/z calcd
for C18H21NO4NaS [M + Na]+ 370.1089, found 370.1073.
General Procedure A. Allenylation of Chiral NꢀBoc αꢀAmino Aldehydes and
Subsequent BaseꢀCatalyzed Cyclization. To a solution of allenylboronic acid
pinacol ester 1 (1.1 equiv.) and the amino aldehydes 2aꢀ2f in toluene at 0 °C, was
added Et2Zn (1 M in toluene, 10 mol%) under nitrogen. The suspension was then
stirred at 0 °C for 18 h. The reaction mixture was quenched with saturated aqueous
NH4Cl solution, and washed with saturated aqueous NaHCO3 solution (15 mL) and
water (10 mL). The organic layer was dried (Na2SO4), concentrated under reduced
pressure and purified by flash column chromatography (EtOAc/hexane) to afford the
allenyl amino alcohol products 9aꢀ9f. To a solution of the allenyl product in dry THF
was added sodium hydride (60% in mineral oil, 2.0 equiv.) at 0 °C and the reaction
mixture was stirred at room temperature for 90 min. The reaction mixture was
quenched by saturated aqueous NH4Cl solution, washed with water (10 mL), dried
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(MgSO4), and then purified by flash column chromatography (acetone/nꢀpentane) to
afford the corresponding oxazolidinone products 23aꢀ23f.
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tertꢀButyl ((2S,3S)ꢀ3ꢀhydroxyhexaꢀ4,5ꢀdienꢀ2ꢀyl)carbamate (9a). The title
compound 9a was obtained after flash column chromatography (EtOAc/hexane 3:7)
as a 2.6:1 mixture of syn and anti diasteresomers following the general procedure A
using tertꢀbutyl (1ꢀoxopropanꢀ2ꢀyl)carbamate 2a (0.06 g, 0.34 mmol), allenylboronic
acid pinacol ester 1 (69.0 ꢁL, 0.37 mmol, 1.1 equiv.) and Et2Zn (1 M in toluene, 35.7
ꢁL, 0.034 mmol, 10 mol%) in dry toluene (1 mL). Yellow oil (0.067 g, 92%). Rf
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1
(EtOAc/hexane 3:7) = 0.36. H NMR (500 MHz, CDCl3) (mixture of two allene
diastereomers, relative integrations given for each diastereomer) δ 1.12 (d, 3H, J = 6.5
Hz, CH3, minor isomer), 1.19 (d, 3H, J = 7.0 Hz, CH3, major isomer), 1.44 (s, 9H,
C(CH3)3, for each isomer), 2.87 (br s, 1H, OH, major isomer), 3.17 (br s, 1H, OH,
minor isomer), 3.71ꢀ3.75 (m, 1H, CH, major isomer), 3.75ꢀ3.82 (m, 1H, CH, minor
isomer), 4.09 (br s, 1H, CH, major isomer), 4.23 (br s, 1H, CH, minor isomer), 4.86ꢀ
4.90 (m, 2H, CH2=C=, for each isomer), 5.16ꢀ5.28 (m, 1H, CH=C=, for each isomer).
13C{1H} NMR (125 MHz, CDCl3) (mixture of two allene diastereomers, minor
indicated by asterisk) δ 18.8, 19.9, 20.1, 28.3, 29.8, 30.0*, 60.4, 60.8*, 69.3, 69.4*,
76.8, 79.1, 79.2*, 90.7*, 93.0, 156.6, 156.7*, 207.4, 207.9*. IR (νmax/cmꢀ1) 3378 (w),
2976 (w), 1955 (w), 1683 (s), 1506 (m), 1365 (m), 1257 (m), 1162 (s), 1051 (s), 1024
(s). HRMS (ESIꢀTOF) m/z calcd for C11H18NO3 [M − H]+ 212.1287, found 212.1289.
(4S,5S)ꢀ4ꢀMethylꢀ5ꢀ(propaꢀ1,2ꢀdienꢀ1ꢀyl)oxazolidinꢀ2ꢀone (23a). The title
compound 23a was obtained as a single diastereomer following the general procedure
A using 9a (0.060 g, 0.28 mmol) and sodium hydride (60% in mineral oil, 18.81 mg,
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0.56 mmol, 2.0 equiv.) in THF (1 mL). Colorless oil (0.024 g, 61%). Rf (2%
1
ꢀ ꢂꢄꢄ
CH2Cl2/Et2O) = 0.52. ꢁ = −30.3 (c 1.2 CHCl3). H NMR (500 MHz, CDCl3) δ
ꢃ
7
8
1.28 (d, 3H, J = 6.0 Hz, CH3), 3.75ꢀ3.80 (m, 1H, CH), 4.55 (t, 1H, J = 6.5, 7.0 Hz,
9
CH), 4.93ꢀ5.00 (m, 2H, CH2=C=), 5.32 (q, 1H, J = 7.0 Hz, CH=C=), 6.02 (br s, 1H,
NH). 13C{1H} NMR (125 MHz, CDCl3) δ 20.0, 54.0, 78.6, 81.6, 89.0, 158.9, 209.2.
IR (νmax/cmꢀ1) 3272 (m), 2926 (w), 1955 (w), 1739 (s), 1378 (m), 1003 (s), 942 (s),
855 (s), 770 (m). HRMS (ESIꢀTOF) m/z calcd for C7H9NO2Na [M + Na]+ 162.0531,
found 162.0537.
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tertꢀButyl ((4S,5S)ꢀ5ꢀhydroxyoctaꢀ6,7ꢀdienꢀ4ꢀyl)carbamate (9b). The title
compound 9b was obtained after flash column chromatography (EtOAc/hexane 2:8)
as a 5.2:1 mixture of syn and anti diastereomers following the general procedure A
using tertꢀbutyl(1ꢀoxopentanꢀ2ꢀyl)carbamate 2b (0.149 g, 0.74 mmol), allenylboronic
acid pinacol ester 1 (155.6 ꢁL, 0.81 mmol, 1.1 equiv.) and Et2Zn (1 M in toluene,
79.17 ꢁL, 0.074 mmol, 10 mol%) in dry toluene (2 mL). Colorless oil (0.145 g,
1
81%). Rf (EtOAc/hexane 2:8) = 0.45. H NMR (500 MHz, CDCl3) (mixture of two
allene diastereomers, relative integrations given for each diastereomer) δ 0.92 (t, 3H,
J = 7.0 Hz, CH3, for each isomer), 1.31ꢀ1.40 (m, 3H, CH and CH2, for each isomer),
1.43 (s, 9H, C(CH3)3, for each isomer), 1.50ꢀ1.56 (m, H, CH, for each isomer), 3.00
(br s, 1H, OH, minor isomer), 3.17 (br s, 1H, OH, major isomer), 3.59 (br s, 1H, CH,
major isomer), 3.70ꢀ3.73 (m, 1H, CH, minor isomer), 4.16 (br s, 1H, CH, major
isomer), 4.23 (br s, 1H, CH, minor isomer), 4.85ꢀ4.90 (m, 2H, CH2=C=, major
isomer), 4.94ꢀ4.96 (m, 2H, CH2=C=, minor isomer), 5.18ꢀ5.27 (m, 1H, CH=C=, for
each isomer). 13C{1H} NMR (125 MHz, CDCl3) (mixture of two allene
diastereomers, minor indicated by asterisk) δ 13.9, 19.3, 28.3, 34.0, 34.2*, 54.9,
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55.2*, 70.2*, 71.4, 77.3, 79.2, 79.4*, 90.5*, 92.3, 156.4, 156.5*, 207.6. IR (νmax/cmꢀ1)
3380 (m), 2959 (m), 1955 (m), 1683 (s), 1506 (s), 1365 (s), 1248 (s), 1166 (s), 1055
(s), 1018 (s), 843 (s). HRMS (ESIꢀTOF) m/z calcd for C13H23NO3Na [M + Na]+
264.1576, found 264.1573.
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(4S,5S)ꢀ5ꢀ(Propaꢀ1,2ꢀdienꢀ1ꢀyl)ꢀ4ꢀpropyloxazolidinꢀ2ꢀone (23b). The title
compound 23b was obtained as s single diastereomer after column chromatography
(acetone/nꢀpentane 2:8) following the general procedure A using 9b (0.067 g, 0.28
mmol) and sodium hydride (60% in mineral oil, 18.81 mg, 0.56 mmol, 2.0 equiv.) in
ꢀ ꢂꢄꢄ
THF (1 mL). Colorless oil (0.026 g, 55%). Rf (acetone/nꢀpentane 2:8) = 0.45. ꢁ
=
ꢃ
1
−24.9 (c 1.3 CHCl3). H NMR (500 MHz, CDCl3) δ 0.95 (t, 3H, J = 7.0, 7.5 Hz,
CH3), 1.32ꢀ1.43 (m, 2H, CH2), 1.54ꢀ1.57 (m, 2H, CH2), 3.67 (q, 1H, J = 6.5 Hz, CH),
4.62ꢀ4.65 (m, 1H, CH), 4.96ꢀ4.99 (m, 2H, CH2=C=), 5.34 (q, 1H, J = 6.5, 7.0 Hz,
CH=C=), 6.51 (br s, 1H, NH). 13C{1H} NMR (125 MHz, CDCl3) δ 73.7, 78.6, 96.7,
117.8, 138.4, 140.0, 149.4, 219.0, 268.8. IR (νmax/cmꢀ1) 3266 (m), 2959 (m), 2932
(m), 1955 (m), 1742 (s), 1387 (s), 1239 (s), 1239 (s), 978 (s), 852 (s), 767 (s). HRMS
(ESIꢀTOF) m/z calcd for C9H12NO2 [M − H]+ 166.0862, found 166.0870.
tertꢀButyl ((4S,5S)ꢀ5ꢀhydroxyꢀ2ꢀmethyloctaꢀ6,7ꢀdienꢀ4ꢀyl)carbamate (9c).
The title compound 9c was obtained after flash column chromatography
(EtOAc/hexane 2:8) as a 5.7:1 mixture of syn and anti diastereomers following the
general procedure A using tertꢀbutyl (4ꢀmethylꢀ1ꢀoxopentanꢀ2ꢀyl)carbamate 2c (0.18
g, 0.83 mmol), allenylboronic acid pinacol ester 1 (176.56 ꢁL, 0.92 mmol, 1.1 equiv.)
and Et2Zn (1 M in toluene, 88.80 ꢁL, 0.083 mmol, 10 mol%) in dry toluene (2 mL).
White solid (0.172 g, 81%). Mp = 38ꢀ40 °C. Rf (EtOAc/hexane 2:8) = 0.37. 1H NMR
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The Journal of Organic Chemistry
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(500 MHz, CDCl3) (mixture of two allene diastereomers, relative integrations given
for each diastereomer) δ 0.92 (d, 6H, J = 6.0 Hz, 2CH3, for each isomer), 1.27ꢀ1.39
(m, 1H, CH, for each isomer), 1.43 (s, 9H, C(CH3)3, for each isomer), 1.65ꢀ1.68 (m,
2H, CH2, for each isomer), 3.11 (br s, 1H, OH, major isomer), 2.95 (br s, 1H, OH,
minor isomer), 3.68 (br s, 1H, CH, major isomer), 3.70ꢀ3.80 (br s, 1H, CH, minor
isomer), 4.12 (br s, 1H, CH, major isomer), 4.22 (br s, 1H, CH, minor isomer), 4.79ꢀ
4.90 (m, 2H, CH2=C=, for each isomer), 5.18ꢀ5.20 (m, 1H, CH=C=, minor isomer),
5.25ꢀ5.27 (m, 1H, CH=C=, major isomer). 13C{1H} NMR (125 MHz, CDCl3)
(mixture of two allene diastereomers, minor indicated by asterisk) δ 22.0*, 23.2, 24.8,
28.3, 40.8, 41.3*, 53.2, 53.9*, 71.7, 72.5*, 76.8, 79.2, 79.7*, 91.2*, 92.3, 156.3,
156.5*, 207.6. IR (νmax/cmꢀ1) 3361 (m), 2956 (m), 1955 (m), 1682 (s), 1504 (s), 1365
(s), 1248 (s), 1166 (s), 1047 (s), 843 (s). HRMS (ESIꢀTOF) m/z calcd for
C14H25NO3Na [M + Na]+ 278.1732, found 278.1720.
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(4S,5S)ꢀ4ꢀIsobutylꢀ5ꢀ(propaꢀ1,2ꢀdienꢀ1ꢀyl)oxazolidinꢀ2ꢀone (23c). The title
compound 23c was obtained as s single diastereomer after column chromatography
(acetone/nꢀpentane 2:8) following the general procedure A using 9c (0.05 g, 0.195
mmol) and sodium hydride (60% in mineral oil, 18.81 mg, 0.39 mmol, 2.0 equiv.) in
ꢀ ꢂꢄꢄ
THF (1 mL). Colorless oil (0.021 g, 58%). Rf (acetone/nꢀpentane 2:8) = 0.30. ꢁ
=
ꢃ
1
−32.6 (c 1 CHCl3). H NMR (500 MHz, CDCl3) δ 0.91ꢀ0.93 (m, 6H, 2CH3), 1.38ꢀ
1.43 (m, 1H, CH), 1.48ꢀ1.53 (m, 1H, CH), 1.61ꢀ1.68 (m, 1H, CH), 3.70ꢀ3.74 (m, 1H,
CH), 4.58ꢀ4.61 (m, 1H, CH), 4.93ꢀ5.00 (m, 2H, CH2=C=), 5.33 (q, 1H, J = 6.5 Hz,
CH=C=), 6.28 (br s, 1H, NH). 13C{1H} NMR (125 MHz, CDCl3) δ 22.2, 23.1, 25.2,
44.1, 56.5, 78.6, 80.5, 89.5, 159.1, 209.1. IR (νmax/cmꢀ1) 3256 (m), 2962 (m), 1956
(w), 1742 (s), 1387 (m), 1228 (m), 993 (m), 852 (m), 734 (m). HRMS (ESIꢀTOF) m/z
calcd for C10H15NO2Na [M + Na]+ 204.0995, found 204.0996.
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