Multistereocenter-Containing Cyclopentanoids from Ynamides via Oxazolidinone-Controlled Nazarov Cyclization

Article abstract of DOI:10.1021/acs.joc.7b00082

Achieving ready-enantioselective access to multistereocenter-containing cyclopentyl rings is an area of great significance to organic synthesis. In this work, we describe a general protocol for accessing multistereocenter-containing cyclopentanoids from simple N-alkynyloxazolidinones (Ox-ynamides). This protocol involves conversion of Ox-ynamides into Ox-activated divinyl and aryl vinyl ketones that undergo facile Nazarov cyclization with excellent chemo-, regio-, and stereocontrol. The Ox auxiliary directs all aspects of reactivity and selectivity, both in the electrocyclization and in the subsequent transformations of the resulting oxyallyl intermediate. Stereoinduction in the electrocyclization results from a "coupled-torque" mechanism in which rotation of the Ox group, driven by increasing orbital overlap of the nitrogen lone pair with the incipient oxyallyl cation, is coupled with the rotation of the termini of the pentadienyl cation, favoring a particular direction of conrotatory ring closure (torquoselectivity). The associated lone-pair stabilization of the transition state by Ox promotes cyclization of traditionally resistant substrates, broadening the scope of this asymmetric Nazarov cyclization. The Ox group also facilitates the stereo- and regioselective incorporation of nucleophiles (Nu) and dienes, giving more complex, multistereocenter containing cyclopentanoids. Finally, the Ox group is readily removed and recovered or can be converted into other amine functionalities.

Full text of DOI:10.1021/acs.joc.7b00082

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Article
Multi-Stereocenter-Containing Cyclopentanoids from
Ynamides via Oxazolidinone Controlled Nazarov Cyclization
Narasimhulu Manchala, Hanson Yeu Leuk Law, Daniel Jarrah Kerr, Rohan Volpe,
Romain J Lepage, Jonathan M White, Elizabeth H. Krenske, and Bernard L. Flynn
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 16 May 2017
Downloaded from http://pubs.acs.org on May 17, 2017
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MultiꢀStereocenterꢀContaining Cyclopentanoids from Ynamides via Oxazolidinone Controlled
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Nazarov Cyclization.
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Narasimhulu Manchala,† Hanson Y. L. Law,† Daniel J. Kerr,† Rohan Volpe,† Romain J. Lepage,§,^ Jonathan
M. White,‡ Elizabeth H. Krenske,§ Bernard L. Flynn†*
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†Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade,
Parkville, VIC 3052, Australia; ‡Bio21 Institute, School of Chemistry, University of Melbourne, Parkville,
VIC 3010, Australia. §School of Chemistry and Molecular Biosciences, The University of Queensland,
Brisbane, QLD 4072, Australia.
Email: bernard.flynn@monash.edu
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ABSTRACT
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Achieving ready enantioselective access to multiꢀstereocenter containing cyclopentyl rings is an area of
great significance to organic synthesis. In this work we describe a general protocol for accessing multiꢀ
stereocenter containing cyclopentanoids from simple Nꢀalkynyloxazolidinones (Oxꢀynamides). This
protocol involves conversion of Oxꢀynamides into Oxꢀactivated divinyl and aryl vinyl ketones that undergo
facile Nazarov cyclization with excellent chemoꢀ, regioꢀ and stereocontrol. The Ox auxiliary directs all
aspects of reactivity and selectivity, both the electrocyclization and in the subsequent transformations of the
resulting oxyallyl intermediate. Stereoinduction in the electrocyclization results from a “coupledꢀtorque”
mechanism where rotation of the Ox group, driven by increasing orbital overlap of the nitrogen lone pair
with the incipient oxyallyl cation, is coupled with the rotation of the termini of the pentadienyl cation,
favoring a particular direction of conrotatory ring closure (torquoselectivity). The associated loneꢀpair
stabilization of the transition state by Ox promotes cyclization of traditionally resistant substrates,
broadening the scope of this asymmetric Nazarov cyclization. The Ox group also facilitates the stereoꢀ and
regioselective incorporation of nucleophiles (Nu) and dienes, giving more complex, multiꢀstereocenter
containing cyclopentanoid. Finally, the Ox group is readily removed and recovered or can be converted into
other amine functionalities.
INTRODUCTION
Versatile methods for accessing cyclopentyl rings are highly desirable given the preponderance of
cyclopentyl rings in bioactive natural products and the potential utility of cyclopentyl rings as sp3ꢀrich
scaffolds in de novo drug design and compoundꢀlibrary screening.1,2 Nazarov cyclizations of divinyl and
aryl vinyl ketones 1 to give cyclopentenones and indenones 3 have attracted considerable attention as the
basis for developing general methods for the enantioselective synthesis of cyclopentyl rings, which, if
suitably controlled, could rival or even surpass the versatility that the Diels–Alder reaction holds for the
synthesis of cyclohexyl rings (Scheme 1).3,4 The Nazarov cyclization is potentially enriched by the number
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of ways in which the reaction pathway can be terminated through the cationic intermediate 2. Depending on
the substitution pattern and the presence of suitable additives, cation 2 may undergo αꢀproton elimination to
give 3, [1,2]ꢀsigmatropic shift to give 4,5 nucleophilic trapping to give 5,6 (4+3)ꢀcycloaddition to give 67 or a
cationic reaction cascade to generate a polycycle (not shown). 8 In order to effectively harness this
extraordinary potential of the Nazarov reaction in multiꢀstereocenter (sp3ꢀrich) scaffold synthesis, a number
of challenges need to be overcome:9 (i) concise stereoselective access to a structurally diverse array of
substrates 1; (ii) a capacity to cyclize conventionally resistant substrates; (iii) chemoselective control over
the competing outcomes 3ꢀ6; (iv) regiochemical control over the doubleꢀbond placement in 3/4 and of the
Nu in 5; and (v) control of relative and absolute stereochemistry in 3ꢀ6. Herein, we describe our studies
towards the identification of a masterꢀcontrol group X that can be readily incorporated into substrates 1X
from simple alkynes 7X and which is highly effective in addressing the various chemoꢀ, regioꢀ, and
stereoselectivity issues confronting the Nazarov reaction (Scheme 1).10 These studies have identified Evans’
oxazolidinone (Ox) as an excellent control element X (X = Ox) that promotes Nazarov cyclization of
resistant substrates by stabilizing the charge redistribution (δ+) in the transition state of the conversion of
pentadienyl cation 8X to (oxy)allylic cation 2X. The Ox auxiliary has a strong influence on the
torquoselectivty of the Nazarov reaction, resulting in essentially complete diastereoselectivity across a broad
range of substrates. The charge stabilization afforded in 2X by X = Ox strongly infuences its fate. It tends to
favor regioselective proton elimination from 2X, relative to [1,2]ꢀshifts, and facilitates the regioꢀ and
stereoselective trapping of 2X by nucleophiles and dienes. The Ox group is readily removed and recovered
or can be further diversified by conversion into other amine functionalities.
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Divergent outcome from the Nazarov reaction:
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H
R
O
Nu
acid
(A)
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OA
R/H
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R
R/H
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H
7
2
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diene-
trapping
H+-elimn
O
Nu-
trapping
1,2-shift
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O
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Nu
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Nu
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3
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Chemo-, regio- and stereoselectivity issues
This work:
O
OA
X
R
R
X
R
X
A
multiple, concise
stereoselective
methods
R
R
R
R
R
8X
R
7X
1X
X promotes
cyclization and
controls
X = master control element
O
X = Ox =
torquoselectivity
N
O
R
R'
OA
X controls regio- and
diastereoselectivity
R
X
3X, 5X and 6X
(single isomers)
X= Ox can be removed or
converted into amino groups
R
R
R
2X
Scheme 1: Use of a masterꢀcontrol element X to achieve regioꢀ,
diastereoꢀ and enantioselective control in the Nazarov reaction
RESULTS AND DISCUSSION
Identification of suitable control elements X: Since both electronꢀwithdrawing and electronꢀdonating groups
X in 1X have been proposed to be effective in promoting the Nazarov reaction, we examined both as chiral
activating groups X.11 The chiral sulfoxide (X = Sox) was employed as a chiral electronꢀwithdrawing group
while Oppolzer’s camphorsultam (X = Cs) and several Evans’ oxazolidinones (X = Ox) were employed as
chiral electronꢀdonating groups (Scheme 2). Ready access to aryl vinyl and divinyl ketones bearing X
groups was achieved using a reductiveꢀcoupling protocol (Scheme 2).12 This involves initial Pdꢀmediated
hydrostannylation of the alkyne 7 followed by in situ crossꢀcoupling to an acid chloride: 7 → 9 + 10 → 11.
A series of alkynes 7 bearing different groups X and Ra were intially coupled to tigloyl chloride 10 (Rb = Rc
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= Me) for a preliminary evaluation of their synthetic utility in the formation of divinyl ketones 11 and for
their capacity to induce torquoselectivity in the Nazarov cyclization to give 12 (Scheme 2 and Table 1). The
regioselectivity of the hydrostannylation step in the reductiveꢀcoupling varied for the different alkynes 7.
The αꢀdirecting effect of the Xꢀgroup dominated in all cases where Ra = alkyl, giving exclusively the desired
regioiosmer 9. However, since aryl groups are also αꢀdirecting groups in the Pdꢀmediated hydrostannylation
of aryl alkynes, the capacity of X to favor 9 over 9' in cases where Ra = aryl became an additional
consideration in identifying preferred X groups. The order of the regioselectivity (ratio of 9:9') for the
different X groups in the hydrostannylation of 7X (Ra = Ar) was found to be OxPh2 ~ OxiPr (~9:1) > OxBn
(~5:1) > OxPh (~3:1) >> Cs (~2:3).13 The modest regioselectivities seen in the hydrostannylation of 7c (X =
Cs) (2:3) and 7e (X = OxPh) (3:1) account for the lower yields achieved in their reductiveꢀcouplings with
tigloyl chloride: 11c (15%) and 11e (51%), respectively (Table 1).
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Scheme 2: Synthesis of various Xꢀsubstituted divinyl ketones and their Nazarov cyclization products.
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Table 1: Evaluation of Control Elements X
3
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entry
Ra
11, yielda
12, yield (dr)b
7
X
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nPr
11a, 79%
no reaction
7a
7b
7c
7d
7e
7f
Sox
nꢀpentyl 11b, 68%
Ph 11c, 15%
nꢀpentyl 11d, 91%
12b, 80% (> 20:1)
12c, 99% (> 20:1)
12d, 99% (> 20:1)
12e, 75% (> 20:1)
12f, 85% (>20:1)
12g, 80% (> 20:1)
12h, 98% (> 20:1)
12i, 84% (> 20:1)
Cs
Cs
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OxPh
OxPh
OxBn
OxiPr
OxPh2
OxPh2
Ph
Ph
Ph
11e, 51%
11f, 67%
11g, 83%
7g
7h
7i
nꢀpentyl 11h, 93%
Ph 11i, 78%
a 11aꢀi were formed by reductiveꢀcoupling with tigloyl choride 10 (Rb = Rc = Me)
b
see Scheme 2). All reactions were performed using MeSO3H (10 equivalents) in
CH2Cl2 at 0 ˚C–rt.
The Nazarov cyclizations of 11aꢀi were undertaken using MeSO3H (10 equivalents = 1 M in CH2Cl2, 0 ˚C–
rt) (Table 1). During the course of these studies, SalomꢀRoig and Sun reported the Nazarov cyclizations of
some aryl vinyl and divinyl ketones bearing a chiral sulfoxide (Sox).4d,e These cyclizations require the
involvement other electronꢀrich substituents in order to offset the electronꢀwithdrawing nature of the
sulfoxide.4d,e In the case of sulfoxide 11a, which does not bear such an electronꢀdonating group, no
cyclization was observed under the conditions used in this study (1 M MeSO3H in CH2Cl2, rt, 24 h). By
contrast, the chiral electronꢀdonating Cs and Ox activated systems all cyclized efficiently (75ꢀ99% yield)
with excellent diastereoselectivity favoring the C4βꢀstereochemistry [diastereomeric ratio (dr) > 20:1 (no
1
C4αꢀdiastereomer observable by H NMR)]. While the substrate activation of 11bꢀi by Ox and Cs is
sufficient to enable cyclizations to be conducted at much lower temperatures (<0 ˚C) with catalytic amounts
of acid (3 mol%), the higher acid concentrations (1 M) and sustained reaction at rt (24 h) were necessary to
facilitate the epimerization at C5 to give exclusively the thermodynamically favored C4,C5ꢀtrans isomer.
Much to our satisfaction, the cyclizations of divinyl ketones 11bꢀi produced only one doubleꢀbond
regioisomer 12bꢀi, favoring placement of the doubleꢀbond distal to the auxiliary X. Xꢀray crystal structure
analysis of 12c, 12e and a number of other products (12j and 23, see below) confirmed the C4βꢀ
stereochemistry and all other isomers have also been assigned this stereochemistry.10,13 In light of their
superior utility in the reductive coupling protocol and their high levels of regioꢀ and stereocontrol in the
Nazarov reaction, Ox groups emerged as the preferred control elements X in the further development of this
protocol.
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Substituent variation in the Ox-controlled Nazarov cyclization: A series of other divinyl and aryl vinyl
ketones 11jꢀaa containing Ox groups were accessed using either the reductiveꢀcoupling (Scheme 2) or a
carbonylative crossꢀcoupling protocol and were subjected to the Nazarov cyclization (Scheme 3 and Table 2;
see legend for method of synthesis). Generally speaking, the reductiveꢀcoupling protocol worked well in all
cases where it was applied (Table 2), except for those involving 2,3ꢀdimethylcinnamoylchloride (Table 2
entries 7 and 8), which suffer from the increased steric hindrance asociated with the cisꢀmethyl group. As a
complement to hydrostannylation of 7, the regioꢀ and stereoselective hydrobromination of ynamides 7e,h,i
to give 13aꢀc (99ꢀ100% yield) using TMSBr and MeOH in dichloromethane afforded access to Nazarov
substrates 11 via carbonylative crossꢀcoupling (Scheme 3). Carbonylative Stille coupling of 13b with 14 to
give 11l (88%) was achieved using Pd(dppf)Cl2 and copper 2ꢀthiophenecarboxylate (CuTC) in THF under 1
atm of CO(g).14 Hydrostannylation of the arylalkyne 15 to give 16 (75%), followed by carbonylative Stille
crossꢀcoupling of 16 with 13b and 13c gave 11m (80%) and 11n (73%), respectively, demonstrating a
convergent synthesis of divinyl ketones 11 from two alkyne substrates (Scheme 2). While initial attempts to
couple 13a to arylboronic acids under standard, aqueous, carbonylative SuzukiꢀMiyaura conditions led only
to the carboxylation of 13a (not shown), we identified an alternative set of anhydrous conditions that could
be performed at room temperature under just 1 atm of CO(g) using organotrifluoroboronate salts, CsF and
Pd(dppf)Cl2 in THF to give exclusively the coupled products 11x (95%) and 11y (72%).15
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Scheme 3: Carbonylative coupling approaches to Oxꢀsubstituted divinyl ketones.
Table 2: Nazarov Cyclizations of Divinyl and Aryl Vinyl Ketones
entry 7 + 10 → 11, yielda
12, yield (dr)c,d
entry 7 + 10 →11, yielda
12, yield (dr)c,d
1
10
11j, 95%
11s, 86%
12j, 84%
12s, 97%
2
11
11t, 67%
11k, 60%
12t, 81%
12u, 92%
12k, 99%
12l, 85%
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11l, 88%b
11u, 75%
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11m, 80% b
11v, 82%
12v, 76%
12m, 100%
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11n, 73% b
11o, 68%
11w, 79%
12n 92%
12w, 94%
12x, 97%
12y, 82%e
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O
O
O
N
S
Complex mixture
15
16
Ph
Ph
11x, 95% b
11y, 72% b
7
8
9
11p, 43%
11q, not isol.
11r, 87%
12p, 99%
17
18
12q, 45% from 7h
11z 61%
12z, 79%
O
O
O
N
O
Ph
iPr
12aa, 25%f
11aa, 78%
12r, 90%
a Unless otherwise stated, divinyl and and aryl vinyl ketones were formed by reductiveꢀcoupling (see
Scheme 2). b Formed by carbonylative coupling (see Scheme 3). c Unless otherwise stated, all reactions were
performed using MeSO3H (2ꢀ10 equivalents) in dichloromethane, 1,2ꢀdichloroethane or toluene at rt or
heating, depending on substrate (see Supporting Information for details). dUnless otherwise stated, all
reactions proceeded with dr >20:1, with no other diastereomer observable by 1H NMR. e Formed as a
mixture of C5 epimers each with dr = 18:1. f Cyclized using 2 equivalents of TfOH in dichloromethane at 40
˚C.
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Nazarov cyclizations of divinyl ketones and aryl vinyl ketones depticted in Table 2 proceeded smoothly,
except for 11o, which gave a complex mixture of products (entry 6). Surprisingly, Nazarov cyclization of
the same substrate, 11o, in the presence of furan gave a good yield of furanꢀtrapped product (see below),
indicating that the Nazarov cyclization itself is facile but the product (or oxyallyl cation) are subject to
further reaction under these conditions. As in the examples reported above in Table 1, the Ox group favors
the C4βꢀstereochemistry (dr > 20:1) and the C4,5ꢀtransꢀstereochemistry. The modest overall yield of 12q
(45% from ynamide 7h) is associated with a low yield in the reductiveꢀcoupling step. In this case 11q was
not isolated but the crude reaction mixture resulting from reductiveꢀcoupling of 7h and 2,3ꢀ
dimethylcinnamoylchloride was treated directly with MeSO3H. Again, as in the earlier examples, the
regiochemical placement of the double bond in cyclopentenones 12jꢀq is always to the distal side of the ring
with respect to Ox (Table 1, entries 1ꢀ8).
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While the cyclizations of divinyl ketones were generally quite rapid, proceeding at < 0 ˚C, cyclizations of
some aryl vinyl ketones were usually slower with some examples requiring moderate heating (40ꢀ80 ˚C).
Importantly, the necessity to heat these Nazarov cyclizations had little effect on the level of chiral induction
which remained high in all cases (dr > 20:1). For example, the cyclization of the phenyl vinyl ketone 11v,
which required 10 equivalents of MeSO3H in refluxing chloroform (65 ˚C) still afforded 12v in 76% yield
and dr > 20:1. Furanꢀ2ꢀyl vinyl ketones are well known to be resistant to Nazarov cyclization16 and the
cyclization of 11y to 12y (82%) and 11z to 12z (79%), the former at rt, are indicative of the powerful
activating capacity of Ox in promoting the Nazarov reaction (Table 2 entries 16 and 17). While all other
products could be isolated as a single C4,5ꢀtrans product after C5ꢀepimerization, 12y was resistant to C5ꢀ
epimerization and attempts to achieve this through more forcing reaction conditions led to some C4
epimerization and loss of overall stereoinduction. Accordingly, 12y was isolated as a mixture of C5ꢀepimers.
This inability to equilibrate 12y to a single C5ꢀepimer is of no consequence where the OxPh group is
subsequently cleaved from the epimeric mixture to give a single product (see below).
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Nazarov cyclization of isopropyl substituted furanyl vinyl ketone 11aa was sluggish and required
treatment with triflic acid (2 equivalents) in refluxing 1,2ꢀdichloroethane (80 ˚C) to give 12aa in low yield
(25%) (Table 2, entry 18). Presumably the combination of the furan ring and a sterically hindering iPr group
combine to retard cyclization. This outcome stands in contrast to the corresponding pyrrole 11w, which
cyclized efficiently to 12w (94%) upon treatment with 10 equivalents of MeSO3H in refluxing
dichloromethane (40 ˚C). The resistance of furanꢀ2ꢀyl vinyl ketones to cyclization most likely arises from
conflation of several factors (eq 1): (i) disruption of furan aromaticity; (ii) a significant reduction in charge
stabilization (delocalization) in progression of 19 to the transition state TSA (eq 1); and accumulating strain
in TSA due to a widened bond angle (θ~144˚). These effects are less pronounced in equivalent pyrrolꢀ2ꢀyl
and thiophenꢀ2ꢀyl systems since the disruption in aromaticity is less in the case of the pyrrole and bondꢀ
angle strain is less in the case of the thiophene due to the large size of the sulfur atom. Presumably, the
presence of the C5 Ox substituent (πꢀelectronꢀdonor) in the furanꢀ2ꢀyl vinyl ketones 11y and 11z
compensates to some extent for these unfavorable features by increasing charge stabilization in TSA. In
general, the Nazarov cyclization of a divinyl (or aryl vinyl) ketone has the effect of concentrating the
positive charge as shown in Scheme 4. The positive charge is initially delocalized across the oxygen and
fiveꢀcarbons (resonance contributors A–D) but upon electrocyclization the charge is delocalized across a
threeꢀcarbon system (resonance contributors E and F). An electronꢀdonating substituent, such as OxPh, at
the C5 position introduces the additional resonance contributor G. Calculations on the model system shown
in Scheme 4 indicate that upon cyclization, about +0.1 e of positive charge is transferred onto the
oxazolidinone as it comes into resonance with the oxyallyl cation.13 The cyclization transition state (D →
E) also derives stabilization from the incipient resonance stabilization by X = OxPh. In the model system,
the OxPh substituent is calculated to lower the electrocyclization barrier by approximately 5 kcal/mol.13
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Scheme 4: Chargeꢀstabilization by X = EDG = Ox
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We have previously examined the strong preference for the C4βꢀstereochemistry in the Oxꢀpromoted
Nazarov cyclization using density functional theory (DFT).17 DFT calculations revealed that stereoinduction
by Ox follows a unique "coupledꢀtorque" mechanism. There are two lowꢀlying transition states for the
cyclization, wherein the Ox group adopts opposing conformations (TSB and TSC, Scheme 5). In both
transition states, the Ox group exists at a relatively oblique angle (~40˚) with respect to the pentadienyl
cation and, as the reaction proceeds further along the reaction coordinate, the Ox rotates (blue arrows)
increasing orbital overlap of the electronꢀloneꢀpair on nitrogen with the emerging allylic πꢀcation in
intermediates 20 and 21. In each case, TSB → 20 and TSC → 21, the sense of rotation of Ox is the same:
clockwise. This unidirectional rotation by Ox minimizes steric clashing between the Ox Rꢀgroup and the
semiꢀplanar pentadienyl cation. In turn, steric interactions between Ox and Ra determine the
torquoselectivity of the conrotatory ring closure. The termini of the divinyl ketone rotate anticlockwise (red
arrows), as this is the direction that minimizes clashing between Ra and the Oxꢀcarbonyl (in TSB) or Ra and
the OxꢀCHR group (in TSC). Both cases lead to the same stereochemical outcome: the formation of the C4β
stereoisomer.
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Scheme 5: “Coupledꢀtorque” mechanism of chiral induction in the Oxꢀpromoted Nazarov cyclization.
DFT calculations also explained the regioselectivity of the doubleꢀbond placement in the Oxꢀactivated
Nazarov cyclization (Scheme 6).17 The double bond is consistently delivered to the distal side of the
cyclopentenone ring with respect to Ox (12dꢀq). DFT calculations predicted that the intramolecularly Hꢀ
bonded species 21 is the preferred conformation of the intermediate oxyallyl cation (Scheme 5). Assuming
that the proton is transferred to another molecule acting as a base B (B = solvent, counter ion, substrate or
product molecule), the calculations indicated that the preference for Ha, Hb or Hcꢀelimination (IꢀIII
respectively) is likely to result from a combination of thermodynamic and kinetic effects (Scheme 6).
Kinetically, I and II are both favored over III, but thermodynamically IIꢀIII are favored over I. The strong
preference for II observed experimentally can be rationalized as resulting from a rapid equilibration of the
kinetically accessible isomers I and II through reversible formation of 21, favoring II thermodynamically,
under conditions where III is kinetically inaccessible.
To further explore the kinetic barriers to doubleꢀbond isomerisation, we treated 12d with a large
concentration of MeSO3H (5 M / 30 equivalents) for an extended period (Scheme 7). Under these conditions
a small amount of the thermodynamic doubleꢀbond isomer 22 was detected by NMR after 7 days.18 DFT
calculations reveal that the relatively high barrier to Haꢀabstraction arises from the steric effects imposed by
the Ox substituent in 21, which blocks access to Ha by the base B (Scheme 6). Abstraction of Ha requires
that the Ox group adopt a higher energy conformation involving loss of Hꢀbonding, i.e. 21d → 20d (Scheme
7). The necessity to form the enol 12d' in order to reꢀaccess the allylic cation 21d is also likely to contribute
to the low rate of equilibration of 12d and 22. Double bond isomerization of 12p was also studied (Scheme
7). In this case, reformation of the allylic cation 21p is more facile due to the higher electron denisty in the
double bond in 12p. Nonetheless, its conversion to the thermodynamically preferred isomer 23 was still very
slow, being notable only after 16 h and complete after 4 days. By contrast, Nazarov cyclization of 11p to
12p is complete in < 5 min under these conditions. 23 was obtained as a 10:1 mixture of C2 Meꢀepimers,
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favoring the C2αꢀepimer as determined by Xꢀray crystallography.13 The experimental studies Scheme 7 are
consistant with our earlier theoretical studies (Scheme 6)17 demonstrating significant kinetic barriers to Haꢀ
abstraction during the Nazarov reaction, which are responsible for the regioselectivity favoring I/II over III.
These barriers are important, because although the Oxꢀpromoted Nazarov cyclization to form
cyclopentenones is very fast (usually complete within minutes), the epimerization at C5 is slower, requiring
up to 1ꢀ2 h in the presence of 3ꢀ10 equivalents (0.3ꢀ1.0 M) of MeSO3H. Thus, the low barrier for the
conversion I → II, the thermodynamic preference for II relative to I, and the significant thermodynamic
difficulty associated with formation of III ensure that Nazarov cyclization of 11Ox to 12Ox can be achieved
under conditions that enable thermodynamic equilibration of the Ox group to the lower energy transꢀisomer
II without competing doubleꢀbond isomerisation of II to III. Of additional significance is that no [1,2]ꢀ
sigmatropic shifts were observed in these Nazarov cyclizations, even in cases where the group adjacent to
the oxyallyl cation has a relatively high migratory aptitude, such as the Me and Ph groups attached to the
quaternary center in 12p and 12q. This is attributed to the Oxꢀstabilization of the allylic cation, disfavoring
the formation of higher energy cations via [1,2]ꢀmigration. This further underscores the masterꢀcontrol role
played by the Ox auxiliary in ensuring a predictable, chemoselective outcome.
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Scheme 6: Oxꢀdirected regioselective placement of the doubleꢀbond.17
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Scheme 7: Thermodynamic doubleꢀbond isomerisation of 12d and 12o
Oxyallyl Cation Trapping: One of the most significant innovations in the Nazarov cyclization has been the
effective trapping of the intermediate oxyallyl cations with a range of nucleophiles and dienes.5ꢀ7 We have
investigated the utility of the Oxꢀpromoted Nazarov cyclization for the regioꢀ and stereoselective
incorporation of nucleophiles and dienes [alkylation, arylation, or (4+3)ꢀcycloaddition] (Scheme 8). Nazarov
cyclizations of 11k and 11m in the presence of Nꢀmethyl indole and of 11l and 11o in the presence of furan
gave exclusively the trapped products 24 (93%), 25 (77%), 26 (75%) and 27 (65%), respectively.19 West and
coworkers have previously shown that the use of AlMe3 as a Lewis acid in the Nazarov cyclization results in
oxyallyl cation trapping through methyl transfer from aluminium.6d Cyclization of 11m with AlMe3 afforded
a modest yield of the trapped material 28 (35%), which was isolated as the kinetically favored cisꢀisomer,
plus a significant amount of the cyclopentenone cis-12m. The Oxꢀgroup plays a key role in the
regioselectivity of these intermolecular trapping reactions, favoring a 1,4ꢀtype addition to the α,βꢀ
unsaturated Oxꢀiminum ion 2Ox (Scheme 7 box). At first glance, the stereochemistry of Nu incorporation
might appear to be attributed to steric interations between Nu and the neighbouring αꢀRb group of 2Ox;
however, computational studies of the furanꢀtrapping suggest that the stereoselectivity depends on CH–π
interactions (see below). Trapping of 11l with 1,3ꢀbutadiene produced the (4+3)ꢀcycloadduct 29 in modest
yield (32%). Lastly, intramolecular trapping of a tethered arene was achieved upon treatment of 30
(accessed in 76% yield by reductiveꢀcoupling)13 with BF3.THF to give 31 (88%). These trapping reactions
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have enabled four new continguous stereocenters to be generated enantioselectively, including chiral
quaternary stereocenters.
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Scheme 8: Oxyallyl trapping of nucleophilies and dienes
The trapping of furan in 26 and 27 by a Friedel–Crafts reaction rather than a (4+3)ꢀcycloaddition is in
contrast to previous studies, which have suggested that stabilized oxyallyl cations arising from Nazarov
cyclizations are biased towards asynchronous (4+3)ꢀcycloadditions with furans, whereas less stabilized,
more electrophilic, oxyallyl cations prefer to undergo nucleophilic trapping.7d It also contrasts with other
studies on the reactions of furans with acyclic Oxꢀstabilized oxyallyl intermediates, which led to (4+3)
cycloadducts.20 To gain a better understanding of the factors controlling the chemoꢀ and stereoselectivity of
the trapping of furans in the Oxꢀcontrolled Nazarov reaction, we performed DFT calculations. Computations
with M06ꢀ2X21 were performed on the reaction of furan with oxyallyl intermediate 2o (X = OxPh2, A =
BF3) which leads to 27 (Figure 1). The computations show that the transition states for addition of furan to
the top and bottom faces of 2o (TSD and TSE, respectively) differ in energy by 1.0 kcal/mol (ꢀꢀG‡)
favoring addition to the top (β) face.13 Although the molecular conformations of TSD and TSE resemble
those of (4+3)ꢀcycloaddition transition states,20c,d the products contain only one C–C bond, i.e. the bond
between furan and C2 of oxyallyl 2o. The interaction between furan and C5 of 2o in the TS is stabilizing but
does not lead to bond formation. This result is similar to that reported by West et al.7d in their DFT studies
on nonꢀstabilized oxallyl cations. Computations predict that ring closure of the C2(β)–furanꢀtrapped
intermediate via formation of a bond to C5, which would lead to a (4+3)ꢀcycloadduct, has a barrier (ꢀG‡) of
21.3 kcal/mol, which is 5.7 kcal/mol higher than the barrier for the first C–C bondꢀforming step (15.6
kcal/mol, TSD) (see the Supporting Information). This provides the opportunity for the initially formed
furanꢀtrapped intermediate to undergo deprotonation leading to 27, rather than ring closure leading to the
(4+3)ꢀcycloadduct. The stereoselectivity of the addition of furan to 2o can be traced to CH–π interactions
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occurring within the transition states. The TS for addition to the β face (TSD) contains a CH–π interaction
between furan and OxPh2 whereas the TS for addition to the bottom face (TSE) contains a CH–π interaction
between furan and the C3ꢀPh group of 2o. The phenyl rings involved in these CH–π interactions are
highlighted in blue in Figure 1. In TSD, H3 of the furan lies 2.79 Å from the center of the nearby Ph ring of
OxPh2, while in TSE, H2 of the furan lies 3.04 Å from the center of the nearby Ph ring of 2o. The stronger
CH–π interaction in TSD explains the lower energy of TSD, which leads to the preference for the formation
of the C4β product. Related CH–π interactions have previously been observed in both nucleophilic and
cycloaddition pathways of oxyallyl trapping,7d,20c including the aforementioned (4+3)ꢀcycloadditions of
furans to acyclic Oxꢀstabilized oxyallyl cations.20a
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Figure 1: Transition states for addition of furan (highlighted in gold) to the α or β face of oxyallyl
intermediate 2o (X = OxPh2, A = BF3), computed with M06ꢀ2X/6ꢀ311+G(d,p)ꢀSMD(CH2Cl2)//M06ꢀ2X/6ꢀ
31G(d). Distances in Å. Energies (kcal/mol) are reported with respect to 2o plus furan.
Auxiliary cleavage: The Ox group can be cleaved using either lithium naphthalenide (LiNp) or SmI2 as
demonstrated for a sample set of Nazarov cyclization products 12, 24, and 31 giving the 32ꢀ38 in good
yields (78ꢀ96%) (Scheme 9). If desired, the cleaved Ox group can be recovered from these reactions for
recycling, adding to the atom efficiency of the protocol. The diphenyloxazolidinone OxPh2 also serves as a
masked amine, which can be revealed upon Pd/C hydrogenation (Scheme 9). 22 Since the Nazarov
cyclization products contain a ketone, it proved necessary to perform these hydrogenations in the presence
of an electrophile (Boc2O or CH3CHO) in order to avoid the formation of dimers and oligomers through
reductiveꢀamination reactions. Accordingly, a sample set of OxPh2ꢀcontaining Nazarov products 12, 25 and
31 was converted to a series of substituted amines 39ꢀ44 (52ꢀ78%). In the case of 12h and 12i, the doubleꢀ
bond was also stereoselectively hydrogentated to give 39 (75%) and 40, respectively. Isolation of 40 proved
difficult as the product was prone to decomposition during chromatography; however, diastereoselective
reduction of the ketone with NaBH4 gave the more stable alcohol 41, which was isolated in 78% yield from
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12i. The stereochemistry of 41 was assigned by NOESY NMR, revealing that the stereoselective delivery of
the hydrogen from hydrogenation (Pd/C, H2) and the hydride from NaBH4 had occurred from the bottom
face. Hydrogenation of 12s to give 44 (76%) is presumed to involve stereoselective hydrogenation of the
enol tautomer of 12s to give a hydroxyl group, followed by hydrogenation of OxPh2. This explanation is
supported by the observation that both the pure transꢀisomer 12s (formed under conditions of
thermodynamic control) and a mixture of cisꢀand transꢀ12s (formed under conditions of kinetic control) both
gave the same product, 44, upon hydrogenation. The stereochemistry of 44 is tentatively assigned as all cis,
assuming that delivery of the hydrogen to the enol occurs from the face opposite the C4ꢀPh group.
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Scheme 9: Oxꢀgroup removal or elaboration
CONCLUSION
The stereoselective syn-hydrostannylation and syn-hydrobromination of readily accessible ynamides 7, in
conjunction with palladiumꢀmediated coupling techniques (in particular reductiveꢀcoupling and
carbonylativeꢀcoupling), provides concise, stereoselective access to a range of aryl vinyl and divinyl ketones
11. The Ox group has emerged as a highly effective, multiꢀfunctional, masterꢀcontrol element in the
Nazarov cyclization, enabling access to a broad range of cyclopentanoid structures with high levels of
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chemoꢀ, regioꢀ and stereoselectivity. The capacity of the Ox group to alleviate the otherwise unfavorable
chargeꢀconcentrating effect of the Nazarov cyclization (8X → 2X, Scheme 1) through nitrogen loneꢀpair
donation in 2Ox, enables it to be effectively employed in the cyclization of traditionally resistant substrates,
such as furanꢀ2ꢀyl vinyl ketones (19 → TSA, eq 1). The Ox in the oxyallyl intermediate 2Ox also plays a
critical role in controlling the regioselectivity of doubleꢀbond formation or nucleophilic trapping, and in
avoiding competing [1,2]ꢀsigmatropic shifts. The Oxꢀgroups can be reductively cleaved from the products
and recycled or, in the case of OxPh2, converted into other amine functionalities by hydrogenation (Scheme
9). In short, the Oxꢀcontrolled Nazarov cyclization represents a broadly applicable method for the synthesis
of enantiopure, multiꢀstereocenter containing cyclopentanoids from readily accessible Oxꢀynamides.
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EXPERIMENTAL
General: All experiments were performed under an anhydrous atmosphere of nitrogen in flameꢀdried
glassware except as indicated. Melting points were recorded with an electrothermal melting point apparatus.
Proton (1H) and carbon (13C) NMR spectra were recorded at 400 MHz for proton and 100 MHz for carbon
nuclei. All NMR spectra were recorded in (D)chloroform (CDCl3) at 30 °C. The protonicities of the carbon
atoms observed in the carbon NMR were determined using Jꢀmodulated spinꢀecho (jmod) experiments.
Highꢀresolution mass spectra (HRMS) were recorded on a time of flight mass spectrometer fitted with either
an electrospray (ESI) or atmospheric pressure ionization (APCI) ion source. Tetrahydrofuran (THF) and
dichloromethane (DCM), were purified using a commercial Solvent Purification System. Analytical and
preparative TLC were conducted on aluminium backed 0.2 mm thick silica gel 60 GF254 plates and the
chromatograms were visualized under a 254 nm U.V. lamp and/or by treatment with a reagent solution
[phosphomolybdic acid / 95% ethanol (4g: 100mL) dip] or anisaldehyde dip (214 mL EtOH, 8 mL H2SO4,
AcOH 2.4 mL, anisaldehyde 5.9 mL) followed by heating. Flash column chromatography was performed
using silica 40 ꢀ 63 micron. The synthesis and spectral data of the following compounds has been previously
reported: 7d,e,g,j,10 7l,23 11d,e,g,j,k,p,vꢀz,10 11u,23 12d,e,g,j,k,p,vꢀz,10 12u,23 13a,10 16,10 24,10 and 32ꢀ3810.
General Method A, Copper(II) Catalyzed Ynamide Formation:
Using a modification of the procedure previously described.24 A mixture of camphorsultam or oxazolidinone
(NHꢀsubstrate) (1.0 equivalent), ground K2CO3 (2.0 equivalents), ground CuSO4.H2O (0.1 equivalents),
1,10ꢀphenanthroline (0.2 equivalents) and bromoalkyne (1.2 equivalents) in toluene (1 M in NHꢀsubstrate)
1
was heated at 90 °C until H NMR (aliquot) indicated complete consumption of the NHꢀsubstrate, typically
24ꢀ48 h. After this time the reaction was cooled to rt, filtered through Celite (rinsing with EtOAc),
concentrated under reduced pressure and chromatographed.
General Method B, ReductiveꢀCoupling:
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To a stirred solution of alkyne 7 (1.0 equivalent) and Pd(PPh3)4 (3ꢀ5 mol%) in dichloromethane (0.1 ꢀ 0.2 M,
relative to 7) at 0 °C was added Bu3SnH (1.05 equivalents) dropwise over 2 minutes. The solution was then
warmed to RT over 0.5 h and to it were added sequentially the acid chloride 10 (1.0 ꢀ 1.2 equivalents) and
copper(I) thiophenecarboxylate (CuTC) or CuCl (10 mol%). The reaction mixture was stirred until TLC
revealed complete consumption of the intermediate vinylstannane (2ꢀ16 h, typically run overnight). The
solvent was removed under reduced pressure and the residue dissolved in Et2O (or EtOAc for solubility). KF
solution (20% w/v, aq.) was added and the resultant mixture stirred for 1ꢀ2 h. The liquid phases were
separated (some solid particulate matter may remain suspended in the organic phase, presumably Bu3SnF,
which is removed upon later filtration) and the aqueous phase was reꢀextracted twice with Et2O (or EtOAc).
The combined organic extracts were dried over MgSO4, concentrated under reduced pressure and the crude
product purified by flash chromatography.
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General Method C, Nazarov Reaction:
MeSO3H (10 equivalents) was added to a stirred solution of divinyl or aryl vinyl ketone 11 in
dichloromethane (0.1ꢀ0.2 M) at 0 °C, the reaction mixture was then allowed to warm to rt over 1 h. After
this time the reaction was monitored by TLC until completion then quenched by careful addition saturated
NaHCO3 aq. solution. The mixture was transferred to a separatory funnel and the phases separated. The
aqueous phase was extracted twice with dichloromethane, the combined organic phases were dried over
MgSO4 and concentrated under reduced pressure. Where necessary, the crude compounds were purified by
flash chromatography.
General Method D, Reductive Cleavage of Ox:
Lithium naphthalenide solution (0.7ꢀ1.0 M, ~2 equivalents, freshly prepared from addition of lithium metal
into a solution naphthalene in THF) was added dropwise to a stirred solution of Oxꢀcyclopentanoid (1.0
equilavent) in THF (0.05ꢀ0.1 M) at ꢀ78 °C until the dark color persisted. The reaction was quenched at ꢀ78
°C by addition of saturated aqueous NH4Cl solution. After warming to rt the reaction mixture was
partitioned between Et2O and H2O and the aqueous phase was reꢀextracted with Et2O. The combined organic
extracts were washed with brine, dried over MgSO4, concentrated under reduced pressure and purified by
flash chromatography.
General Method E, Hydrogenation of OxPh2:
Triethylamine (3 drops) and the desired electrophile (Boc anhydride or acetaldehyde) (5 equivalents) was
added to a solution of OxPh2ꢀcyclopentanoid (1 equivalent) in EtOAc or THF (0.1 M in cyclopentanoid)
and Pd/C (10%) (1:1 weight ratio with cyclopentanoid). The reaction mixture was evacuated and backꢀfilled
with hydrogen three times and stirred at rt for 2 days. After this time the reaction filtered through Celite
(rinsing with EtOAc), concentrated under reduced pressure and chromatographed.
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1
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(3a
S,6
R
,7aR
)ꢀ1ꢀ(Heptꢀ1ꢀynꢀ1ꢀyl)ꢀ8,8ꢀdimethylhexahydroꢀ1
H
ꢀ3a,6ꢀmethanobenzo[
c
]isothiazole
2,2ꢀ
3
4
dioxide (7b)
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7
8
Prepared according to General Method A using (1S)ꢀ(−)ꢀ2,10ꢀcamphorsultam (754 mg, 3.5 mmol), 1ꢀbromoꢀ
1ꢀheptyne (674 mg, 3.85 mmol), CuSO4.H2O (62 mg, 0.35 mmol), 1,10ꢀphenanthroline (126 mg, 0.70
mmol) and K2CO3 (967 mg, 7.0 mmol) in toluene (3.5 mL). Flash chromatography (silica gel, 12:88
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EtOAc/hexanes) gave the title compound 7bꢀCS as a thick oil (939 mg, 87%). H NMR (400 MHz, CDCl3)
δ 3.51 (dd, J = 7.8, 4.2 Hz, 1H), 3.21 (s, 2H), 2.29 (t, J = 6.9 Hz, 2H), 2.18 (mc, 1H), 1.95ꢀ1.82 (m, 3H),
1.74 (dd, J = 13.5, 8.1 Hz, 1H), 1.52 (pent., J = 7.2 Hz, 2H), 1.42 (mc, 1H), 1.47ꢀ1.25 (m, 5H), 1.10 (s, 3H),
0.93 (s, 3H), 0.89 (t, J = 6.9 Hz, 3H). This NMR spectra is consistent with that previously reported.25
(3a
S,6
R
,7aR
)ꢀ8,8ꢀDimethylꢀ1ꢀ(phenylethynyl)hexahydroꢀ1
H
ꢀ3a,6ꢀmethanobenzo[
c
]isothiazole
2,2ꢀ
dioxide (7c)
Prepared according to General Method A using (1S)ꢀ(−)ꢀ2,10ꢀcamphorsultam (754 mg, 3.5 mmol), 1ꢀbromoꢀ
2ꢀphenylethyne (697 mg, 3.85 mmol, from phenylacetylene), CuSO4.H2O (62 mg, 0.35 mmol), 1,10ꢀ
phenanthroline (126 mg, 0.70 mmol) and K2CO3 (967 mg, 7.0 mmol) in toluene (3.5 mL). Flash
chromatography (silica gel, 15:85 EtOAc/hexanes) gave the title compound 7c as a lowꢀmelting solid (991
1
mg, 90%). Η ΝΜΡ (400 MHz, CDCl3) δ 7.40 (δ, J = 3.9 Ηz, 2Η), 7.27 (s, 3Η), 3.64 (δδ, J = 7.8, 3.9 Ηz,
1Η), 3.27 (s, 2Η), 2.24 (d, J = 12.9 Ηz, 1Η), 1.95ꢀ1.72 (m, 4Η), 1.42 (mc, 1Η), 1.26 (mc, 1Η), 1.12 (s, 3Η),
0.91 (s, 3Η). 13C NMR (75 MHz, CDCl3) δ 131.7 (CH), 128.3 (CH), 128.0 (CH), 122.8 (C), 77.1 (C), 72.7
(C), 67.3 (CH), 51.3 (C), 49.9 (CH2), 48.0 (C), 44.5 (CH), 34.5 (CH2), 31.6 (CH2), 27.1 (CH2), 20.3 (CH3),
20.0 (CH3). This NMR spectra is consistent with that previously reported.25
(S)ꢀ4ꢀBenzylꢀ3ꢀ(phenylethynyl)oxazolidinꢀ2ꢀone (7f)
Prepared according to General Method A (S)ꢀ4ꢀbenzyloxazolidinꢀ2ꢀone (1.42 g, 8.00 mmol), 1ꢀbromoꢀ2ꢀ
phenylethyne (1.73 g, 9.56 mmol, from phenylacetylene), CuSO4.H2O (142 mg, 0.80 mmol), 1,10ꢀ
phenanthroline (288 mg, 1.60 mmol) and K2CO3 (2.21 g, 16.0 mmol) in toluene (8 mL). Flash
chromatography (silica gel, 2:49:49 Et2O/DCM /hexanes) gave the title compound 7f as a white solid (1.82
g, 82%) 1H NMR (400 MHz, CDCl3) δ 7.46 (mc, 2H), 7.39ꢀ7.22 (m, 8H), 4.42ꢀ4.31 (m, 2H), 4.18 (mc, 1H),
3.30 (dd, J = 14.0, 3.7 Hz, 1H), 3.02 (mc, 1H). This NMR spectra is consistent with that previously
reported.26
(4
S,5
R
)ꢀ3ꢀ(Heptꢀ1ꢀynꢀ1ꢀyl)ꢀ4,5ꢀdiphenyloxazolidinꢀ2ꢀone (7h)
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Prepared according to General Method A (4S,5R)ꢀ4,5ꢀdiphenyloxazolidinꢀ2ꢀone (1.0 g, 4.18 mmol), 1ꢀ
bromoheptyne (0.946 g, 5.44 mmol, from 1ꢀheptyne), CuSO4.H2O (66.7 mg, 0.418 mmol), 1,10ꢀ
phenanthroline (150.8 mg, 0.837 mmol) and K2CO3 (1.154 g, 8.362 mmol) in toluene (5 mL). Flash
chromatography (silica gel, 2:48:48 Et2O/DCM/hexanes) gave the title compound as a thick oil (1.142 g,
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2
3
4
5
6
7
1
82%). H NMR (400 MHz, CDCl3) δ 7.18 – 7.04 (m, 6H), 6.98 – 6.83 (m, 4H), 5.91 (d, J = 8.2 Hz, 1H),
8
9
5.29 (d, J = 8.2 Hz, 1H), 2.18 (t, J = 7.0 Hz, 2H), 1.43 – 1.30 (m, 2H), 1.22 – 1.09 (m, 4H), 0.79 (t, J = 6.9
Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 156.7, 133.6, 133.0, 128.6, 128.44, 128.2, 128.1, 127.6, 126.2,
80.7, 72.56, 69.6, 67.2, 30.8, 28.32, 22.1, 18.4, 134.0. HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for
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+
C22H24NO2 : 334.1802. Found: 334.1804.
(4S,5R)ꢀ4,5ꢀDiphenylꢀ3ꢀ(phenylethynyl)oxazolidinꢀ2ꢀone (7i)
Prepared according to General Method A (4S,5R)ꢀ4,5ꢀdiphenyloxazolidinꢀ2ꢀone (3 g, 12.552 mmol), 1ꢀ
bromoꢀ2ꢀphenylethyne (2.83 g, 15.64 mmol), CuSO4.H2O (200 mg, 1.29 mmol), 1,10ꢀphenanthroline (452
mg, 2.51 mmol) and K2CO3 (3.46 g, 25.07 mmol) in toluene (15 mL). Flash chromatography (silica gel,
2:48:48 Et2O/DCM/hexanes) gave the title compound as a white solid (3.80 g, 90%). MP = 158.2ꢀ162.3. 1H
NMR (400 MHz, CDCl3) δ 7.26 (dddd, J = 7.4, 5.8, 4.0, 1.5 Hz, 5H), 7.14 (ddd, J = 9.6, 5.2, 2.0 Hz, 6H),
13
6.96 (dt, J = 7.6, 3.0 Hz, 4H), 5.99 (d, J = 8.1 Hz, 1H), 5.44 (d, J = 8.1 Hz, 1H). C NMR (101 MHz,
CDCl3) δ 156.0, 133.4, 132.8, 131.7, 128.8, 128.6, 128.4, 128.3, 128.2, 128.2, 127.6, 126.2, 122.2, 81.1,
+
78.6, 72.5, 67.4. HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C23H18NO2 : 340.1332. Found: 340.1335.
(S)ꢀ4ꢀIsopropylꢀ3ꢀ[(4ꢀmethoxyphenyl)ethynyl]oxazolidinꢀ2ꢀone (7k)
Prepared according to General Method A (S)ꢀ4ꢀisopropyloxazolidinꢀ2ꢀone (1.21 g, 9.39 mmol), 1ꢀ
(bromoethynyl)ꢀ4ꢀmethoxybenzene (2.08 g, 9.86 mmol), CuSO4.H2O (167 mg, 0.94 mmol), 1,10ꢀ
phenanthroline (339 mg, 1.88 mmol) and K2CO3 (2.60 g, 18.8 mmol) in toluene (9.4 mL). Flash
chromatography (silica gel, 3:49:48 Et2O/DCM/hexanes) gave the title compound 7k as a white solid (1.48
g, 61%). MP = 121ꢀ123 ˚C. 1H NMR (400 MHz, CDCl3) δ 7.38 (d, J = 8.9 Hz, 2H), 6.83 (d, J = 8.9 Hz, 2H),
4.41 (t, J = 9.0 Hz, 1H), 4.19 (dd, J = 9.0, 5.8 Hz, 1H), 4.03 (ddd, J = 8.8, 5.8, 4.1 Hz, 1H), 3.81 (s, 3H),
2.29 (septet.d, J = 6.9, 4.1 Hz, 1H), 1.03 (d, J = 6.9 Hz, 3H), 1.02 (d, J = 6.9 Hz, 3H). 13C NMR (100 MHz,
CDCl3) δ 159.5 (C), 156.0 (C), 133.1 (CH), 114.1 (C), 113.7 (CH), 77.0 (C), 71.7 (C), 64.7 (CH2), 61.9
(CH), 55.1 (CH3), 29.1 (CH), 17.0 (CH3), 15.1 (CH3). HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for
+
C15H18NO3 : 260.1281. Found: 260.1278.
(4
S,5
R
)ꢀ3ꢀ((E
)ꢀ1ꢀbromoꢀ2ꢀphenylvinyl)ꢀ4,5ꢀdiphenyloxazolidinꢀ2ꢀone (13b):
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Prepared as for 13a above: TMSꢀBr (221.29 mg, 1.445 mmol), MeOH (0.058 mL, 1.445 mmol), (4S,5R)ꢀ
4,5ꢀdiphenylꢀ3ꢀ(phenylethynyl)oxazolidinꢀ2ꢀone 7i (500 mg, 1.474 mmol) in DCM (10 mL), gave 13b 99%
(610 mg, 100%) as white solid. Mp 138.6ꢀ142.8. IR: 1H NMR (400 MHz, CDCl3) δ 7.37 (d, J = 2.8 Hz, 5H),
7.14 – 7.01 (m, 4H), 6.95 (s, 1H), 6.86 (dd, J = 10.9, 4.7 Hz, 4H), 6.44 (d, J = 7.3 Hz, 2H), 5.80 (d, J = 8.4
Hz, 1H), 5.42 (d, J = 8.4 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 156.7, 136.9, 134.3, 134.3, 131.7, 128.9,
128.8, 128.6, 128.6, 128.5, 128.4, 128.0, 127.9, 126.1, 116.7, 80.2, 67.3. HRMS (APCIꢀTOF) m/z: [M+H]+
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+
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Calcd for C23H19BrNO2 : 420.0594. Found: 420.0588.
(4S,5R)ꢀ3ꢀ((E)ꢀ1ꢀbromoheptꢀ1ꢀenꢀ1ꢀyl)ꢀ4,5ꢀdiphenyloxazolidinꢀ2ꢀone (13c):
Prepared as for 13a above: TMSꢀBr (150.03 mg, 0.98 mmol), MeOH (0.0395 mL, 0.98 mmol), 7h (333 mg,
1
1 mmol) in DCM (7 mL) gave 13c (410 mg, 100%) as a thick oil: Η ΝΜR (400 MHz, CDCl3) δ 7.22 –
7.00 (m, 6Η), 6.95 (dd, J = 6.3, 2.8 Hz, 2Η), 6.89 – 6.76 (m, 2Η), 5.96 – 5.81 (m, 2Η), 5.45 (d, J = 8.6 Hz
1Η), 2.29 – 1.91 (m, 2Η), 1.51 – 1.03 (m, 6Η), 0.88 (t, J = 7.0 Ηz, 3Η). 13C NMR (101 MHz, CDCl3) δ
172.80, 153.9, 134.7, 133.0, 128.5, 128.4, 128.23, 128.1, 126.6, 126.2, 80.39, 62.8, 35.8, 31.636, 28.8, 24.3,
22.6, 14.1. HRMS (APCIꢀTOF) m/z: [M+H]+ Calcd for C22H25NO2Br+: 414.1063. Found 414.1063.
(2E,5Z)ꢀ3ꢀMethylꢀ5ꢀ[(S)ꢀpꢀtolylsulfinyl]nonaꢀ2,5ꢀdienꢀ4ꢀone (11a)
Prepared according to General Method B using alkynyl sulfoxide 7a27 (103 mg, 0.500 mmol), Pd(PPh3)4 (16
mg, 0.014 mmol), Bu3SnH (140 ꢁL, 0.500 mmol), tigloyl chloride (0.50 mmol) and CuCl (40 mg, 0.40
mmol) in THF (3.5 mL). Flash chromatography (silica gel, 84:16 hexane / EtOAc) yielded the title
1
compound 11a as a discoloured oil (114 mg, 79%). H NMR (300 MHz, CDCl3) δ 7.39 (d, J = 8.1 Hz, 2H),
7.23 (d, J = 8.1 Hz, 2H), 6.60 (t, J = 7.7 Hz, 1H), 6.42 (q, J = 7.1 Hz, 1H), 2.37 (s, 3H), 2.14 (app. q, Japp
=
7.4 Hz, 2H), 1.75 (d, J = 7.1 Hz, 3H), 1.62 (s, 3H), 1.49 (app. sext, Japp = 7.3 Hz, 2H), 0.91 (t, J = 7.4 Hz,
3H). 13C NMR (JMOD, 75 MHz, CDCl3) δ 193.5 (C), 145.4 (C), 144.8 (CH), 141.9 (C), 139.08 (C), 139.07
(C), 137.6 (CH), 129.7 (CH), 125.1 (CH), 31.7 (CH2), 22.0 (CH2), 21.4 (CH3), 15.0 (CH3), 13.7 (CH3), 10.3
(CH3). LRMS m/z (%): 313.2 (40, M+Na+), 291.2 (100, MH+). IR (cmꢀ1): 2959, 2929, 1632, 1242, 1083,
1055, 809. HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C17H22NaO2S+: 313.1238. Found: 313.1235.
(2
E,5Z)ꢀ5ꢀ[(3aS,6R,7aR)ꢀ8,8ꢀDimethylꢀ2,2ꢀdioxidohexahydroꢀ1Hꢀ3a,6ꢀmethanobenzo[c]isothiazolꢀ1ꢀ
yl]ꢀ3ꢀmethylundecaꢀ2,5ꢀdienꢀ4ꢀone (11b)
Prepared according to General Method B using ynamide 7b (464 mg, 1.5 mmol), DCM (15 mL), Pd(PPh3)4
(87 mg, 0.075 mmol), Bu3SnH (0.42 mL, 1.58 mmol), tigloyl chloride (181 µL, 1.65 mmol) and CuTC (29
mg, 0.15 mmol). Flash chromatography (silica gel, 12:88 EtOAc/hexanes) gave the title compound as a low
1
melting solid (404 mg, 68%. H NMR (400 MHz, CDCl3) δ 6.42 (mc, 1H), 6.28 (dd, J = 8.8, 6.4 Hz, 1H),
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3.86 (dd, J = 7.8, 4.2 Hz, 1H), 3.16 (s, 2H), 2.44 (mc, 1H), 2.32 (mc, 1H), 1.83ꢀ1.74 (m, 10H), 1.54 (dd, J =
12.0, 8.0 Hz, 1H), 1.45ꢀ1.35 (m, 2H), 1.32ꢀ1.17 (m, 6H), 1.15 (s, 3H), 0.87 (s, 3H), 0.80 (t, J = 7.0 Hz, 3H).
13C NMR (100 MHz, CDCl3) δ 195.0 (C), 147.4 (CH), 139.7 (CH), 137.7 (C), 129.4 (C), 64.9 (CH), 49.83
(C), 49.76 (CH2), 47.3 (C), 44.5 (CH), 35.1 (CH2), 32.2 (CH2), 31.4 (CH2), 28.6 (CH2), 28.5 (CH2), 26.6
(CH2), 22.1 (CH2), 20.5 (CH3), 19.9 (CH3), 14.5 (CH3), 13.7 (CH3), 11.9 (CH3). HRMS (ESIꢀTOF) m/z:
[M+H]+ Calcd for C22H36NO3S+: 394.2410. Found: 394.2412.
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(1
Z,4E)ꢀ2ꢀ[(3aS,6R,7aR)ꢀ8,8ꢀDimethylꢀ2,2ꢀdioxidohexahydroꢀ1Hꢀ3a,6ꢀmethanobenzo[c]isothiazolꢀ1ꢀ
yl]ꢀ4ꢀmethylꢀ1ꢀphenylhexaꢀ1,4ꢀdienꢀ3ꢀone (11c)
Prepared according to General Method B using ynamide 7c (473 mg, 1.5 mmol), DCM (15 mL), Pd(PPh3)4
(87 mg, 0.075 mmol), Bu3SnH (0.420 mL, 1.58 mmol), tigloyl chloride (181 µL, 1.65 mmol) and CuTC (29
mg, 0.15 mmol). Flash chromatography (silica gel, hexanes/toluene/EtOAc) gave the title compound 11c as
a white solid (91.2 mg, 15%). Mp 143ꢀ146 °C. 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 4.0 Hz, 2H), 7.40ꢀ
7.28 (m, 3H), 6.90 (s, 1H), 6.88 (q, J = 7.2 Hz, 1H), 3.70 (br. s, 1H), 3.19 (s, 1H), 1.89 (s, 3H), 1.87 (d, J =
7.2 Hz, 3H), 1.85ꢀ1.55 (m, 4H), 1.33 (mc, 1H), 1.15 (s, 3H), 1.05ꢀ0.90 (m, 3H), 0.86 (s, 3H). 13C NMR (100
MHz, CDCl3) δ 196.0 (C), 143.4 (CH), 137.9 (C), 133.1 (C), 129.7 (C), 129.4 (CH), 128.9 (CH), 127.9 (CH,
2C), 65.6 (CH, broad), 50.6 (C), 49.8 (CH2), 47.5 (C), 44.3 (CH), 35.0 (CH2), 32.7 (CH2), 26.6 (CH2), 20.4
(CH3), 20.3 (CH3), 15.0 (CH3), 11.7 (CH3). HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C23H30NO3S+:
400.1941. Found: 400.1944.
(S)ꢀ4ꢀBenzylꢀ3ꢀ[(1Z,4E)ꢀ4ꢀmethylꢀ3ꢀoxoꢀ1ꢀphenylhexaꢀ1,4ꢀdienꢀ2ꢀyl]oxazolidinꢀ2ꢀone (11f)
Prepared according to General Method B using ynamide 7f (418 mg, 1.51 mmol), DCM (10 mL), Pd(PPh3)4
(52 mg, 0.045 mmol), Bu3SnH (0.43 mL, 1.58 mmol), tigloyl chloride (144 µL, 1.31 mmol) and CuTC (29
mg, 0.15 mmol). Flash chromatography (silica gel, 17:82:1 EtOAc/hexanes/Et3N) gave the title compound
1
11f as a white solid (366 mg, 67%). MP = 130ꢀ132 °C. H NMR (400 MHz, CDCl3) δ 7.53 (mc, 2H), 7.48ꢀ
7.38 (m, 3H), 7.19ꢀ7.12 (m, 3H), 7.00 (s, 1H), 6.77 (mc, 2H), 6.66 (qq, J = 6.9, 1.3 Hz, 1H), 4.25 (mc, 1H),
4.17ꢀ4.06 (m, 2H), 2.81 (dd, J = 13.6, 4.5 Hz, 1H), 2.65 (dd, J = 13.6, 9.5 Hz, 1H), 1.94 (mc, J < 1.3 Hz,
3H), 1.88 (dq, J = 6.9, 1.0 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ194.2 (C), 156.8 (C), 140.9 (CH), 137.0
(C), 135.63 (C), 135.56 (CH), 133.2 (C), 132.4 (C), 129.7 (CH), 129.3 (CH), 128.8 (CH), 128.7 (CH), 128.6
(CH), 126.8 (CH), 68.4 (CH2), 56.2 (CH), 38.4 (CH2), 14.7 (CH3), 12.3 (CH3). HRMS (ESIꢀTOF) m/z:
[M+H]+ Calcd for C23H24NO3 : 362.1751. Found: 362.1758.
+
(4
S,5
R
)ꢀ3ꢀ((2E
,5
Z)ꢀ3ꢀMethylꢀ4ꢀoxoundecaꢀ2,5ꢀdienꢀ5ꢀyl)ꢀ4,5ꢀdiphenyloxazolidinꢀ2ꢀone (11h)
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Prepared according to General Method B using ynamide 7h (1.00 g, 3.003 mmol), DCM (30 mL), Pd(PPh3)4
(173 mg, 5 mol%), Bu3SnH (0.848 mL, 3.15 mmol), tigloyl chloride (395 µL, 3.609 mmol) and CuTC
(57.26 mg, 0.3 mmol). Flash chromatography (silica gel, 12:88 EtOAc/hexanes) gave the title compound
11h as a thick oil. (1.158 g, 93%). 1H NMR (400 MHz, CDCl3) δ 7.19 – 6.92 (m, 8H), 6.80 – 6.70 (m, 2H),
6.23 (dd, J = 8.9, 5.6 Hz, 1H), 5.93 (d, J = 8.7 Hz, 1H), 5.68 (qd, J = 6.9, 1.4 Hz, 1H), 5.53 (d, J = 8.7 Hz,
1H), 2.47 – 2.17 (m, 2H), 1.76 – 1.68 (m, 3H), 1.61 (dd, J = 6.9, 1.1 Hz, 3H), 1.52 – 1.38 (m, 1H), 1.36 –
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1.16 (m, 5H), 0.88 (t, J = 6.9 Hz, 3H). C NMR (101 MHz, CDCl3) δ 194.0, 156.2, 144.8, 138.5, 137.1,
135.4, 134.2, 132.7, 128.7, 128.5, 128.1, 128.0, 126.1, 79.8, 64.7, 31.9, 29.1, 28.0, 22.5, 14.5, 14.1, 12.4.
+
HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C27H32NO3 : 418.2377. Found: 418.2381.
(4S,5R)ꢀ3ꢀ((1Z,4E)ꢀ4ꢀMethylꢀ3ꢀoxoꢀ1ꢀphenylhexaꢀ1,4ꢀdienꢀ2ꢀyl)ꢀ4,5ꢀdiphenyloxazolidinꢀ2ꢀone (11i)
Prepared according to General Method B using ynamide 7i (678 mg, 2.5 mmol), DCM (20 mL), Pd(PPh3)4
(115.55 mg, 0.1 mmol), Bu3SnH (0.565 mL, 2.1 mmol), tigloyl chloride (241 µL, 2.193 mmol) and CuTC
(38.13 mg, 0.2 mmol). Flash chromatography (silica gel, 19:81 EtOAc/hexanes) gave the title compound 11i
as a low melting solid. 424.191 (658 mg, 78%). MP = 65.6ꢀ67.5. IR: NMR (400 MHz, CDCl3) δ 7.42 – 7.30
(m, 5H), 7.15 – 7.10 (m, 3H), 6.98 (ddd, J = 9.7, 4.0, 1.5 Hz, 3H), 6.84 (dd, J = 13.5, 6.0 Hz, 3H), 6.53 (dd,
J = 8.2, 1.0 Hz, 2H), 6.35 (qd, J = 6.9, 1.3 Hz, 1H), 5.83 (d, J = 8.8 Hz, 1H), 5.41 (d, J = 8.7 Hz, 1H), 1.87 –
1.85 (m, 3H), 1.76 (dd, J = 6.9, 1.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 193.91, 156.77, 140.57, 137.36,
135.8, 135.3, 133.6, 132.9, 132.2, 129.5, 129.5, 128.7, 128.6, 128.2, 128.1, 127.869, 127.6, 126.3, 80.4,
+
65.0, 14.8, 12.5. HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C28H26NO3 : 424.1907. Found: 424.1910.
Tributyl(cyclohexꢀ1ꢀenꢀ1ꢀyl)stannane (14)
tꢀBuLi (1.31 M in pentane, 5.7 mL, 7.45 mmol) was added slowly to a solution of 1ꢀbromocyclohexꢀ1ꢀene
(0.42 mL, 3.726 mmol) and anhydrous THF (6.2 mL) at −78 ˚C and the reaction stirred for 1 h at −78 °C.
Bu3SnCl (1.1 mL, 3.912 mmol) was slowly added and the reaction allowed to warm to rt and stir for 18 h.
K2CO3 aq. (10% w/v, 12 mL) was added to the reaction and the mixture extracted with Et2O (2 x 12 mL),
washed with H2O (2 x 12 mL) and brine (2 x 12 mL) then dried over MgSO4 and concentrated under
1
reduced pressure yielding tributyl(cyclohexꢀ1ꢀenꢀ1ꢀyl)stannane as colourless liquid (1.33 g, 96%). H NMR
(401 MHz, CDCl3) δ 5.79 (m, 1H), 2.20 – 2.10 (m, 2H), 2.09 – 1.99 (m, 2H), 1.66 – 1.57 (m, 4H), 1.53 –
1.42 (m, 6H), 1.37 – 1.25 (m, 6H), 0.92 – 0.81 (m, 15H).28
(4
S,5
R
)ꢀ3ꢀ((Z
)ꢀ3ꢀ(Cyclohexꢀ1ꢀenꢀ1ꢀyl)ꢀ3ꢀoxoꢀ1ꢀphenylpropꢀ1ꢀenꢀ2ꢀyl)ꢀ4,5ꢀdiphenyloxazolidinꢀ2ꢀone
(11l)
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Bromoenamide 13b (461.6 mg, 1.10 mmol), cyclohexenyl stannane 14 (530 mg, 1.4277 mmol), Pd(dppf)Cl2
(44.8 mg, 0.0549 mmol), CuTC (20.9 mg, 0.11 mmol) and anhydrous THF (11 mL) were added to flamed
dried round bottom flask. Reaction was evacuated and backfilled with CO(g) for 3 times then heat to 50 oC
overnight. Reaction was then diluted with water (15 mL) and extracted with EtOAc (2 x 15 mL), wash with
water (2 x 15 mL) and brine (2 x 15mL), dried over MgSO4, and concentrated under reduced pressure. Flash
chromatography (NEt3 treated silica gel, 15:85 EtOAc/hexanes) yielded the title compound 11l as an off
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white syrup (432.3 mg, 88%). H NMR (400 MHz, CDCl3) δ7.40ꢀ7.38 (m, 3H), 7.32ꢀ7.29 (m, 2H), 7.11ꢀ
7.09 (m, 3H), 6.98ꢀ6.94 (m, 3H), 6.84ꢀ6.81 (m, 3H), 6.56ꢀ6.54 (m, 1H), 6.52 (dd, J= 8.17, 0.97 Hz, 2H),
5.82 (d, J= 8.77Hz 1H), 5.39 (d, J= 8.75Hz 1H), 2.57ꢀ2.51 (m, 1H), 2.17ꢀ2.03 (m, 3H), 1.68ꢀ1.57 (m, 4H).
13C NMR (101 MHz, CDCl3) δ193.1, 156.8, 143.19, 138.6, 135.6, 135.3, 133.7, 132.8, 132.2, 129.5, 129.4,
128.7, 128.6, 128.2, 128.1, 127.9, 127.6, 126.3, 80.5, 65.0, 26.1, 24.1, 22.0, 21.6. HRMS (ESIꢀTOF) m/z:
+
[M+H]+ Calcd for C30H27NO3 : 450.2064. Found 450.2058.
(4
S,5R)ꢀ3ꢀ((1Z,4E)ꢀ4ꢀ(4ꢀMethoxyphenyl)ꢀ3ꢀoxoꢀ1ꢀphenyloctaꢀ1,4ꢀdienꢀ2ꢀyl)ꢀ4,5ꢀdiphenyloxazolidinꢀ2ꢀ
one (11m)
To a solution of bromoenamide 13b (700 mg, 1.67 mmol) in THF (20 mL), the vinyl stannane 16 (1012 mg,
2.171 mmol) was added along with CuTC (31.9 mg, 0.167 mmol) and Pd(dppf)Cl2 (68.2 mg, 0.083 mmol).
o
The reaction was heated for 15 h at 50 C under an atmosphere of CO (g) (balloon) after which time TLC
revealed complete consumption of 13b. The reaction mixture was diluted with water and extracted with
EtOAc, dried over MgSO4, evaporated in vacuo and chromatographed (silica gel, 30% EtOAc in hexane)
1
giving the product as a yellow solid (728 mg, 80.2%). MP = 114.8ꢀ118.2. H NMR (400 MHz, CDCl3) δ
7.45 – 7.28 (m, 5H), 7.10 (dd, J = 8.4, 4.8 Hz, 4H), 7.05 – 6.92 (m, 5H), 6.91 – 6.74 (m, 4H), 6.50 (d, J =
7.2 Hz, 2H), 6.30 (t, J = 7.5 Hz, 1H), 5.85 (d, J = 8.7 Hz, 1H), 5.55 (d, J = 8.7 Hz, 1H), 3.78 (s, 3H), 2.16
13
(ddd, J = 14.7, 7.3, 1.5 Hz, 2H), 1.37 (h, J = 7.4 Hz, 2H), 0.83 (t, J = 7.4 Hz, 3H). C NMR (101 MHz,
CDCl3) δ 193.0, 158.9, 157.2, 143.8, 140.4, 139.6, 135.2, 133.3, 133.0, 133.0, 130.6, 129.8, 129.6, 128.6,
128.5, 128.3, 128.2, 128.0, 127.8, 127.7, 126.2, 113.7, 80.2, 65.3, 55.2, 31.5, 22.4, 13.9. HRMS (ESIꢀTOF)
+
m/z: [M+H]+ Calcd for C36H34NO4 : 544.2482. Found: 544.2486.
(4S,5R)ꢀ3ꢀ((4E,7Z)ꢀ5ꢀ(4ꢀMethoxyphenyl)ꢀ6ꢀoxotridecaꢀ4,7ꢀdienꢀ7ꢀyl)ꢀ4,5ꢀdiphenyloxazolidinꢀ2ꢀone
(11n) Prepared according to the procedure described for 11m: bromoenamide 13c (400 mg, 0.969 mmol),
vinyl stannane 16 (587 mg, 1.26 mmol), CuTC (18.4 mg, 0.10 mmol), Pd(dppf)Cl2 (40 mg, 0.48 mmol) and
THF (10 mL). Flash chromatography (silica gel, 30% EtOAc in hexane) gave the product 11n as a thick oil
1
(380 mg, 73.1%). H NMR (400 MHz, CDCl3) δ 7.21 – 6.90 (m, 8H), 6.73 (dt, J = 20.9, 6.5 Hz, 6H), 6.37
(dd, J = 9.4, 4.9 Hz, 1H), 5.98 – 5.83 (m, 2H), 5.77 (d, J = 8.7 Hz, 1H), 3.75 (s, 3H), 2.45 – 2.30 (m, 1H),
2.20 (tt, J = 14.7, 7.3 Hz, 1H), 2.05 (q, J = 7.5 Hz, 2H), 1.38 – 0.93 (m, 8H), 0.81 (dt, J = 12.3, 7.3 Hz, 6H).
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13C NMR (101 MHz, CDCl3) δ 207.4, 192.9, 158.82 156.40 147.7, 142.45 140.40, 135.46134.3, 133.4,
130.4, 128.8, 128.5, 128.3, 128.1, 128.0, 128.0, 126.0, 113.7, 79.8, 64.6, 55.2, 31.7, 31.3, 30.7, 30.5, 30.3,
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+
30.1, 29.9, 29.18, 27.9, 22.57, 22.4, 14.0, 13.9. HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C35H40NO4 :
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538.2952. Found: 538.2956.
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(4S,5R)ꢀ3ꢀ((1Z,4E)ꢀ3ꢀOxoꢀ1,5ꢀdiphenylpentaꢀ1,4ꢀdienꢀ2ꢀyl)ꢀ4,5ꢀdiphenyloxazolidinꢀ2ꢀone (11o)
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Prepared according to General Method B using ynamide 7i (300 mg, 0.884 mmol), Pd(PPh3)4 (30.6 mg,
0.027 mmol), Bu3SnH (0.23 mL, 0.884 mmol), cinnamoyl chloride (147.3 mg, 0.884 mmol), CuTC (10.1
mg, 0.0530 mmol) DCM (4.4 mL). Flash chromatography (silica gel, 15:85 EtOAc / hexanes) yielded 11o as
1
yellow oil (284.2 mg, 68%). H NMR (401 MHz, CDCl3) δ 7.72 (d, J = 15.7 Hz, 1H), 7.56 (dd, J = 6.7, 2.8
Hz, 2H), 7.47 – 7.37 (m, 9H), 7.21 (d, J = 15.7 Hz, 1H), 7.15 – 7.08 (m, 3H), 7.01 – 6.94 (m, 3H), 6.81 (t, J
= 7.8 Hz, 2H), 6.46 (d, J = 7.2 Hz, 2H), 5.88 (d, J = 8.7 Hz, 1H), 5.46 (d, J = 8.7 Hz, 1H). 13C NMR (101
MHz, CDCl3) δ 186.8, 157.5, 145.3, 137.9, 135.2, 134.7, 134.3, 133.4, 132.8, 130.7, 130.0, 129.6, 129.0,
128.7, 128.7, 128.6, 128.3, 128.1, 127.9, 127.7, 126.2, 121.4, 80.5, 65.6. HRMS (ESIꢀTOF) m/z: [M+H]+
+
Calcd for C32H26NO3 : 472.1907. Found 472.1907.
(S,Z)ꢀ3ꢀ[1ꢀ(3ꢀMethoxyphenyl)ꢀ1ꢀoxooctꢀ2ꢀenꢀ2ꢀyl]ꢀ4ꢀphenyloxazolidinꢀ2ꢀone (11r)
Prepared according to General Method B using ynamide 7d (515 mg, 2.0 mmol), DCM (10 mL), Pd(PPh3)4
(116 mg, 0.10 mmol), Bu3SnH (0.56 mL, 2.1 mmol), 3ꢀmethoxybenzoyl chloride (310 µL, 2.2 mmol) and
CuTC (38.2 mg, 0.10 mmol). Flash chromatography (silica gel, 18:82 EtOAc/hexanes) gave the title
1
compound as a thick oil (687 mg, 87%). H NMR (400 MHz, CDCl3) δ 7.38ꢀ7.27 (m, 5H), 7.23 (t, J = 7.8
Hz, 1H), 7.02 (ddd, J = 8.3, 2.7, 0.9 Hz, 1H), 6.87ꢀ6.83 (m, 2H), 6.36 (dd, J = 8.8, 5.6 Hz, 1H), 5.28 (tapp., J
= 8.8 Hz, 1H), 4.78 (tapp., J = 8.8 Hz, 1H), 4.38 (tapp., J = 9.0 Hz, 1H), 3.74 (s, 3H), 2.34 (mc, 1H), 2.20 (mc,
13
1H), 1.37 (mc, 1H), 1.30ꢀ1.10 (m, 5H), 0.86 (t, J = 7.0 Hz, 3H). C NMR (100 MHz, CDCl3) δ 191.7 (C),
159.0 (C), 155.7 (C), 148.6 (CH), 138.6 (C), 136.6 (C), 132.5 (C), 128.93 (CH), 128.89 (CH), 128.7 (CH),
127.6 (CH), 121.1 (CH), 118.4 (CH), 113.1 (CH), 69.7 (CH2), 59.7 (CH), 54.9 (CH3), 31.3 (CH2), 28.8
+
(CH2), 27.5 (CH2), 22.0 (CH2), 13.6 (CH3). HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C24H28NO4 :
394.2013. Found: 394.2011.
(4S,5R)ꢀ3ꢀ[(Z)ꢀ3ꢀ(3ꢀMethoxyphenyl)ꢀ3ꢀoxoꢀ1ꢀphenylpropꢀ1ꢀenꢀ2ꢀyl]ꢀ4,5ꢀdiphenyloxazolidinꢀ2ꢀone (11s)
Prepared according to General Method B using ynamide 7i (577 mg, 1.70 mmol), DCM (15 mL), Pd(PPh3)4
(98 mg, 0.085 mmol), Bu3SnH (0.50 mL, 1.79 mmol), 3ꢀmethoxybenzoyl chloride (225 µL, 1.60 mmol) and
CuTC (32 mg, 0.17 mmol). Flash chromatography (silica gel, 21:79 EtOAc/hexanes) gave the title
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compound 11s as a thick gum (610 mg, 75%). H NMR (400MHz, CDCl3) δ 7.46ꢀ7.38 (m, 5H), 7.30ꢀ7.23
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(m, 1H), 7.18ꢀ7.12 (m, 5H), 7.09ꢀ7.00 (m, 4H), 6.99 (s, 1H), 6.92ꢀ6.83 (m, 2H), 6.57 (dd, J = 8.2, 1.0 Hz,
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2
13
2H), 5.91 (d, J = 8.7 Hz, 1H), 5.57 (d, J = 8.7 Hz, 1H), 3.77 (s, 3H). C NMR (100 MHz, CDCl3) δ 192.2
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(C), 159.4 (C), 156.8 (C), 139.8 (CH), 138.7 (C), 135.1 (C), 133.1 (C), 132.7 (C), 132.4 (C), 129.9 (CH),
129.6 (CH), 129.2 (CH), 128.6 (CH), 128.5 (CH), 128.3 (CH), 128.0 (CH), 127.8 (CH), 127.6 (CH), 126.1
(CH), 122.3 (CH), 119.0 (CH), 113.7 (CH), 80.3 (CH), 65.1 (CH), 55.4 (CH3). HRMS (ESIꢀTOF) m/z:
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[M+H]+ Calcd for C31H26NO4 : 476.1856. Found: 476.1852.
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(S,Z)ꢀ3ꢀ[3ꢀ(3,5ꢀDimethoxyphenyl)ꢀ1ꢀ(4ꢀmethoxyphenyl)ꢀ3ꢀoxopropꢀ1ꢀenꢀ2ꢀyl]ꢀ4ꢀisopropyloxazolidinꢀ2ꢀ
one (11t)
Prepared according to General Method B using ynamide 7k (324 mg, 1.25 mmol), DCM (12 mL), Pd(PPh3)4
(72 mg, 0.063 mmol), Bu3SnH (0.37 mL, 1.31 mmol), 3,5ꢀdimethoxybenzoyl chloride (231 mg, 1.15 mmol)
and CuTC (24 mg, 0.13 mmol). Flash chromatography (silica gel, 27:73 EtOAc/hexanes) gave the title
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compound 11t as a yellow gum (358 mg, 67%). H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 8.7 Hz, 2H),
7.32 (s, 1H), 6.91 (d, J = 8.7 Hz, 2H), 6.90 (d, J = 2.3 Hz, 2H), 6.65 (t, J = 2.3 Hz, 1H), 4.47 (t, J = 8.7 Hz,
1H), 4.21 (dd, J = 8.5, 7.3 Hz, 1H), 3.92 (ddd, J = 8.8, 7.3, 5.7 Hz, 1H), 3.84 (s, 3H), 3.82 (s, 6H), 1.82
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(septet.d, J = 6.9, 5.7 Hz, 1H), 0.87 (d, J = 6.9 Hz, 3H), 0.85 (d, J = 6.9 Hz, 3H). C NMR (100 MHz,
CDCl3) δ 192.4 (C), 161.5 (C), 160.6 (C), 157.6 (C), 142.3 (CH), 139.7 (C), 132.4 (CH), 131.3 (C), 125.3
(C), 114.3 (CH), 107.2 (CH), 104.4 (CH), 65.8 (CH2), 61.4 (CH), 55.6 (CH3), 55.3 (CH3), 30.9 (CH), 18.7
+
(CH3), 16.8 (CH3). HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C24H28NO6 : 426.1911. Found: 426.1913.
(4S,5R)ꢀ5ꢀ((3aS,6R,7aR)ꢀ8,8ꢀDimethylꢀ2,2ꢀdioxidotetrahydroꢀ3Hꢀ3a,6ꢀmethanobenzo[c]isothiazolꢀ
1(4H)ꢀyl)ꢀ2,3ꢀdimethylꢀ4ꢀpentylcyclopentꢀ2ꢀenꢀ1ꢀone (12b)
Prepared according to General Method C using 11b (5.9 mg, 0.015 mmol) in DCM (1.5 mL) with MeSO3H
(0.1 M in DCM, 1.5 mL, 0.15 mmol), warmed to rt and stirred overnight. Preparative TLC (silica gel, 15:85
EtOAc/hexanes) gave the title compound as an oil (4.7 mg, 80%). 1H NMR (400 MHz, CDCl3) δ 3.79 (dd, J
= 7.8, 4.6 Hz, 1H), 3.57 (d, J = 3.2 Hz, 1H), 3.23ꢀ3.12 (m, 3H), 2.01 (s, 3H), 1.93ꢀ1.78 (m, 5H), 1.71 (d, J =
0.8 Hz, 3H), 1.54ꢀ1.43 (m, 3H), 1.38ꢀ1.13 (m, 7H), 1.21 (s, 3H), 0.91 (s, 3H), 0.87 (t, J = 6.8 Hz, 3H). 13C
NMR (100 MHz, CDCl3) δ 205.4 (C), 171.1 (C), 135.9 (C), 64.8 (CH), 59.0 (CH), 50.1 (CH2), 49.7 (C),
47.6 (C), 44.9 (CH), 43.5 (CH), 35.0 (CH2), 32.5 (CH2), 32.0 (CH2), 30.5 (CH2), 26.8 (CH2), 25.2 (CH2),
22.5 (CH2), 20.3 (CH3), 20.1 (CH3), 15.2 (CH3), 14.0 (CH3), 8.2 (CH3). HRMS (ESIꢀTOF) m/z: [M+H]+
Calcd for C22H36NO3S+: 394.2410. Found: 394.2412.
5ꢀ[(3a
S,6R,7aR)ꢀ8,8ꢀDimethylꢀ2,2ꢀdioxidohexahydroꢀ1Hꢀ3a,6ꢀmethanobenzo[c]isothiazolꢀ1ꢀyl]ꢀ2,3ꢀ
dimethylꢀ4ꢀphenylcyclopentꢀ2ꢀenone (12c)
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Prepared according to General Method C using 11c (87 mg, 0.217 mmol) in DCM (2.2 mL) with MeSO3H
(140 µL, 2.17 mmol) and stirred at rt for 24h. The crude product was of good purity (86 mg, 99%), further
purification by flash chromatography (silica gel, 6:94 EtOAc/hexanes) gave cleaner product but with
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significant loss of mass (54 mg, 63%). MP = 102ꢀ104 °C, H NMR (400 MHz, CDCl3) δ 7.32 (t, J = 7.2 Hz,
2H), 7.26 (t, J = 7.4 Hz, 1H), 7.13 (d, J = 7.6 Hz, 2H), 4.35 (br. s, 1H), 3.89 (dd, J = 7.6, 4.8 Hz, 1H), 3.65
(d, J = 3.2 Hz, 1H), 3.19 (s, 2H), 1.87 (s, 3H), 1.85ꢀ1.80 (m, 4H), 1.78 (mc, 1H), 1.63 (mc, 1H), 1.52ꢀ1.43
(m, 2H), 1.30ꢀ1.20 (m, 2H), 1.11 (s, 3H), 0.90 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 205.2 (C), 169.5 (C),
139.8 (C), 136.7 (C), 128.9 (CH), 127.8 (CH), 127.3 (CH), 65.1 (CH), 63.9 (CH), 50.7 (CH), 50.4 (CH2),
49.9 (C), 47.5 (C), 44.8 (CH), 35.0 (CH2), 32.3 (CH2), 26.7 (CH2), 20.3 (CH3), 20.0 (CH3), 15.7 (CH3), 8.4
(CH3). HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C23H30NO3S+: 400.1941. Found: 400.1948.
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(S)ꢀ4ꢀBenzylꢀ3ꢀ[(1R,5S)ꢀ3,4ꢀdimethylꢀ2ꢀoxoꢀ5ꢀphenylcyclopentꢀ3ꢀenꢀ1ꢀyl]oxazolidinꢀ2ꢀone (12f)
Prepared according to General Method C using 11f (50 mg, 0.138 mmol) in DCM (1.4 mL) with MeSO3H
(90 µL, 1.38 mmol), warmed to rt and stirred for 3 d. Trituration with 4:1 hexanes/Et2O gave the title
compound as a white solid (42.5 mg, 85%). Xꢀray crystal structure obtained from a crystal grown in an
evaporating DCM crystallization. MP = 240ꢀ242 °C 1H NMR (400 MHz, CDCl3) δ 7.38 (mc, 2H), 7.30 (mc,
1H), 7.23ꢀ7.13 (m, 5H), 6.87 (mc, 2H), 4.34ꢀ4.16 (m, 3H), 3.97 (dd, J = 8.2, 6.7 Hz, 1H), 3.63 (d, J = 4.2 Hz,
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1H), 2.44 (dd, J = 13.8, 4.4 Hz, 1H), 2.32 (dd, J = 13.8, 9.1 Hz, 1H), 1.84 (s, 6H). C NMR (100 MHz,
CDCl3) δ 202.8 (C), 168.5 (C), 157.3 (C), 139.7 (C), 136.0 (C), 135.0 (C), 129.1 (CH), 128.7 (CH), 128.6
(CH), 127.9 (CH), 127.6 (CH), 126.9 (CH), 67.6 (CH2), 66.4 (CH), 58.5 (CH), 53.0 (CH), 39.7 (CH2), 15.4
+
(CH3), 8.4 (CH3). HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C23H24NO3 : 362.1751. Found: 362.1746.
(4
S,5
R
)ꢀ3ꢀ((1R
,5
S)ꢀ3,4ꢀdimethylꢀ2ꢀoxoꢀ5ꢀpentylcyclopentꢀ3ꢀenꢀ1ꢀyl)ꢀ4,5ꢀdiphenyloxazolidinꢀ2ꢀone
(12h)
Prepared according to General Method C using 11h (400 mg, 0.959 mmol) in DCM (9.5 mL) with MeSO3H
(621 µL, 9.59 mmol), warmed to rt and stirred for overnight. Flash chromatography (silicagel, 15% EtOAc
1
in hexane) gave the title compound as yellow solid (391.2 mg, 98%). MP = 125.7ꢀ127.2. IR: H NMR (400
MHz, CDCl3) δ 7.18 – 7.02 (m, 6H), 7.03 – 6.86 (m, 4H), 5.95 (d, J = 8.8 Hz, 1H), 5.49 (d, J = 8.8 Hz, 1H),
3.41 (d, J = 1.2 Hz, 1H), 3.25 (d, J = 3.7 Hz, 1H), 1.94 (s, 3H), 1.67 (d, J = 1.0 Hz, 3H), 1.46 – 1.21 (m,
13
3H), 1.11 – 0.90 (m, 4H), 0.74 (t, J = 7.1 Hz, 4H). C NMR (101 MHz, CDCl3) δ 193.91, 156.77, 140.57,
137.36, 135.80, 135.3, 133.6, 132.9, 132.2, 129.5, 129.4, 128.6, 128.5, 128.2, 128.0, 127.8, 127.6, 126.2,
+
80.4, 64.9, 14.7, 12.4. HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C27H32NO3 : 418.2377. Found: 418.2382.
(4
S,5
R
)ꢀ3ꢀ((1R
,5
S)ꢀ3,4ꢀdimethylꢀ2ꢀoxoꢀ5ꢀphenylcyclopentꢀ3ꢀenꢀ1ꢀyl)ꢀ4,5ꢀdiphenyloxazolidinꢀ2ꢀone (12i)
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The Journal of Organic Chemistry
Prepared according to General Method C using 11i (200 mg, 0.4728 mmol) in DCM (5 mL) with MeSO3H
1
2
(306 µL, 4.728 mmol), warmed to rt and stirred 2 d. Flash chromatography (silicagel, 20% EtOAc in
3
4
1
hexane) gave the title compound as clear resin (196 mg, 98%). H NMR (400 MHz, CDCl3) δ 7.22 – 7.15
5
6
7
8
(m, 3H), 7.09 – 7.02 (m, 3H), 6.96 (dd, J = 6.6, 2.9 Hz, 2H), 6.86 (ddd, J = 8.6, 6.7, 4.2 Hz, 3H), 6.64 (t, J =
7.6 Hz, 2H), 6.41 (d, J = 7.2 Hz, 2H), 5.85 (d, J = 8.7 Hz, 1H), 5.58 (d, J = 8.7 Hz, 1H), 4.64 – 4.55 (m, 1H),
3.36 (d, J = 4.4 Hz, 1H), 1.81 (d, J = 2.8 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 204.0, 169.2, 158.1, 139.8,
136.0, 135.1, 133.1, 129.0, 128.2, 128.1, 128.0, 128.0, 127.9 (2C), 127.5, 126.2, 79.9, 67.8, 66.8, 52.6, 15.6,
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
+
8.6. HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C28H26NO3 : 424.1907. Found: 424.1913.
(4
S,5
R
)ꢀ3ꢀ((2R
,3
S
)ꢀ1ꢀOxoꢀ3ꢀpentylꢀ2,3,4,5,6,7ꢀhexahydroꢀ1Hꢀindenꢀ2ꢀyl)ꢀ4,5ꢀdiphenyloxazolidinꢀ2ꢀone
(12l)
Prepared according to General Method C using 11l (87.0 mg, 0.194 mmol) DCM (1.9 mL), MeSO3H (0.13
mL, 1.94 mmol), at rt for 48 h. Flash chromatography (silica gel, 20:80 EtOAc / hexanes) gave 12l as pale
1
yellow oil (73.7 mg, 85%). H NMR (401 MHz, CDCl3) δ 7.21 – 7.17 (m, 3H), 7.07 – 7.03 (m, 3H), 6.97ꢀ
6.95 (m, 2H), 6.90 – 6.82 (m, 3H), 6.64 (t, J = 7.6 Hz, 2H), 6.41 (d, J = 7.2 Hz, 2H), 5.85 (d, J = 8.7 Hz,
1H), 5.57 (d, J = 8.7 Hz, 1H), 4.64 (d, J = 1.6 Hz, 1H), 3.38 (d, J = 4.3 Hz, 1H), 2.39 – 1.90 (m, 4H), 1.74 –
1.57 (m, 4H). 13C NMR (101 MHz, CDCl3) δ 203.0, 172.4, 185.1, 139.5, 138.0, 135.1, 133.1, 128.9, 128.1,
128.0, 127.9, 127.8, 127.3, 126.1, 79.7, 67.7, 67.1, 51.5, 26.3, 22.2, 21.4, 20.1. HRMS (ESIꢀTOF) m/z:
+
[M+H]+ Calcd for C30H27NO3 : 450.2064, found 450.207.
(4S,5R)ꢀ3ꢀ((1R,5S)ꢀ3ꢀ(4ꢀmethoxyphenyl)ꢀ2ꢀoxoꢀ5ꢀphenylꢀ4ꢀpropylcyclopentꢀ3ꢀenꢀ1ꢀyl)ꢀ4,5ꢀ
diphenyloxazolidinꢀ2ꢀone (12m)
Prepared according to General Method C using 11m (350 mg, 0.644 mmol) in DCM (6 mL) with MeSO3H
(417 µL, 6.44 mmol), heated to 50 oC for 2d. Flash chromatography (silicagel, 20% EtOAc in hexane) gave
1
the title compound as an oil (346 mg, 100%, including 7% of the minor cisꢀisomer). H NMR (400 MHz,
CDCl3) δ 7.25 (dd, J = 16.6, 5.3 Hz, 5H), 7.08 (dd, J = 6.1, 3.3 Hz, 5H), 6.95 (d, J = 8.8 Hz, 2H), 6.92 –
6.85 (m, 3H), 6.67 (t, J = 7.6 Hz, 2H), 6.44 (d, J = 7.1 Hz, 2H), 5.85 (d, J = 8.7 Hz, 1H), 5.61 (d, J = 8.6 Hz,
1H), 3.83 (s, 3H), 3.50 (d, J = 4.5 Hz, 1H), 2.64 – 2.51 (m, 1H), 2.10 – 1.97 (m, 1H), 1.44 (ddd, J = 22.3,
15.8, 7.4 Hz, 2H), 0.80 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 202.7, 173.4, 159.4, 158.2, 139.9,
139.8, 135.1, 133.1, 130.5, 129.1, 128.3, 128.2, 128.3, 128.2, 127.9, 127.9, 127.5, 126.2, 123.7, 113.9, 79.9,
67.6, 67.2, 55.4, 50.1, 31.3, 20.7, 13.9. HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C36H34NO4 : 544.2482;
+
Found: 544.2486.
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