Stereochemical Characterization of Polyketide Stereotriads Synthesized via Hydrogen-Mediated Asymmetric syn-Crotylation

Article abstract of DOI:10.1021/acs.joc.7b01820

The stereoselective access to stereotriads as important polyketide building blocks is reported on the basis of the Krische-type hydrogen-mediated syn-crotylation. The products were obtained with an extremely high diastereoselectivity (dr >99:1), and the n

Full text of DOI:10.1021/acs.joc.7b01820

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Note
Stereochemical Characterisation of Polyketide Stereotriads
Synthesized via Hydrogen Mediated Asymmetric Syn-Crotylation
Mathilde Pantin, Jonathan G Hubert, Tilo Söhnel, Margaret A. Brimble, and Daniel P. Furkert
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01820 • Publication Date (Web): 29 Sep 2017
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Stereochemical Characterisation of Polyketide Stereotriads Synthesized via
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Hydrogen Mediated Asymmetric Syn-Crotylation
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Mathilde Pantin, Jonathan G. Hubert,† Tilo Söhnel, Margaret A. Brimble* and Daniel P. Furkert*
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School of Chemical Sciences, The University of Auckland, 23 Symonds Street, Auckland 1010, New
Zealand
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Abstract
Stereoselective access to stereotriads important as polyketide building blocks is reported, based on
Krischeꢀtype hydrogen mediated synꢀcrotylation. The products were obtained with extremely high
diastereoselectivity (dr >99:1) and the newlyꢀformed syn stereocenters were controlled solely by the
chiral catalyst. Stereochemistry was assigned by crystallography and HPLC for both product
manifolds. This extension of the burgeoning transfer hydrogen methodology gives divergent
asymmetric access to anti,syn and syn,syn polyketide stereotriads from the same αꢀchiral starting
material and avoids potentially epimerisable aldehyde intermediates.
Asymmetric crotylation is an important transformation for the assembly of polyketides and
polyketide stereotriads in particular, and has historically been the focus of much synthetic
investigation.1 Seminal contributions from Brown2 and Roush3 (1 and 2, Scheme 1), and the work of
many others4 have led to the development of reliable enantioselective methods that have been proven
over decades of application in complex natural product synthesis and industrial settings. Despite this
strong record of success, these classical methods demonstrate a number of practical drawbacks,
including the requirement for preformed organometallic reagents, cryogenic temperatures, limitations
from mismatched substrate/reagent combinations and occasionally difficult work up and
chromatographic purification. As a result, ongoing studies have continued towards methods using
more convenient reagents and conditions, and possessing improved process characteristics. From
2011, the Leighton group has reported a series of enantioselective crotylation reagents (3, 4) based on
a substituted 1,2ꢀdiaminocyclohexyl auxiliary (Scheme 1).5,6 These crotylsilane reagents require
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operationally simple conditions and deliver crotylation products, including polyketide stereotriads 6-
9, in excellent dr with generally high yields. In many cases the chiral auxiliary may be recovered
during work up without chromatography, making these reagents advantageous for scaleꢀup and
process applications.
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Scheme 1. Established crotylation reagents (left) and application to asymmetric synthesis of
polyketide stereotriads 6-9 (right).5
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Recently, the Krische group has pursued a new synthetic paradigm in hydrogen mediated carbonꢀ
carbon bond formation, avoiding preformed organometallic reagents or carbonyl compounds.7 In
particular, methods for direct asymmetric antiꢀcrotylation of alcohols using allylic acetates (10) as
surrogates for crotylmetal regents (Scheme 2),8 and syn-crotylation of alcohols using 2ꢀ
phenyldimethylsilyl butadiene (13) have been developed.9 In the presence of an iridium or ruthenium
catalyst, respectively, and a chiral ligand based on SEGPHOS, the anti (11) or syn products (14) are
obtained in high yield with excellent enantioꢀ and diastereoselectivity. Although this chemistry and
other new methods have been applied to preparation of more complex extended polyketide arrays,
including C2 symmetric stereopentads,10,11 to our knowledge the stereochemical outcome of the
application of these crotylation methods to the synthesis of polyketide stereotriads (e.g. 6-9)12 has not
yet been systematically investigated.13 In the course of synthetic studies towards natural products
containing polyketide stereotriads we were interested to examine the practical utility of synꢀ
crotylation of αꢀchiral alcohols (15-17) in contrast to established methods requiring αꢀchiral
aldehydes. At the outset of these studies the stereochemical outcome in the presence of a preꢀexisting
αꢀchiral center was uncertain; in earlier studies of direct alcohol crotylation using butadiene, the
diastereoselectivity was found to be subject to unexpected controlling effects.14
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Scheme 2. Anti- (top) and syn-crotylation (bottom) of alcohols developed by Krische.7,8
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Table 1. Hydrogen mediated syn-crotylation αꢀchiral alcohols 15-17.
entry
alcohol
yield (%)a
product
dr
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9
35 (63b)c
27d,e
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26c,f
18
29c,g
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23
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22c
19
80
99.5:0.5
99.5:0.5
99.5:0.5
19
74 (82b)
64 (80b)
20a
20bh
Conditions: 13 (3 eq), (R)ꢀDMꢀSEGPHOS (5 mol%),
RuHCl(CO)(PPh3)3 (5 mol%), toluene, 95 °C, 48 h, sealed tube.
a
b
Isolated yield after chromatography on neutral alumina;
c
Based on recovered starting material; Anhydrous Na2SO4 (10
mol%) added; dAnhydrous Na2SO4 (20 mol%);
(R)ꢀDMꢀ
e
SEGPHOS (10 mol%), RuHCl(CO)(PPh3)3 (10 mol%) f 13 (1
eq); g 13 (6 eq); h (S)ꢀDMꢀSEGPHOS (5 mol%).
Our investigations commenced with application of the syn-crotylation conditions previously reported
by Krische to the αꢀchiral PMB ether 15 derived from the Roche ester,15 and vinyl silane 13,16 with
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the chiral ligand (R)ꢀDMꢀSEGPHOS, giving a single observable product diastereoisomer (18) in 35%
yield (62% brsm) (Table 1, Entry 1). Attempts to optimise this reaction by increasing the catalyst
and/or ligand loading (Table 1, Entry 2), by adjusting the stoichiometry of vinyl silane 13 (Table 1,
Entries 3 and 4) or by removing the sodium sulfate additive (Table 1, Entry 5) proved unsuccessful.
Suspecting that the suboptimal result might be due the protecting group, the reaction was repeated
using the corresponding TBS ether 16.17 A single product diastereoisomer (19) was again obtained, in
22% yield (Table 1, Entry 6), which increased to 80% yield upon removal of the sodium sulfate
additive (Table 1, entry 7). The steric demand of the protecting group proved unimportant as TBDPS
ether 1718 under identical conditions also afforded a single alcohol diastereomer 20a in 74% yield
(82% brsm) (Table 1, Entry 8). In order to examine the potential for matched/mismatched effects, the
reaction was finally repeated employing (S)ꢀDMꢀSEGPHOS (Table 1, Entry 9), affording alcohol 20b
as a single diastereoisomer in 64% yield (80% brsm).
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Scheme 3. SynꢀCrotylation of racemic αꢀchiral 17 with racꢀDMꢀSEGPHOS.19
To carefully establish the diastereoselectivity of the reaction, a racemic mixture of the racemic
anti,syn and syn,syn isomers (20a-d) was prepared as an HPLC standard (Scheme 3). This reaction
showed similar small diminution in yield for the allꢀsyn compounds also suggested in Table 1 (Entry
9). The anti,syn diastereoisomers (20a, 20c) were separable from syn,syn (20b, 20d) by
chromagraphy. Comparison of the chiral HPLC traces obtained for single diastereoisomers 20a and
20b to the racemic standards established excellent dr values of 99.5:0.5 for each compound.20 The
absolute stereochemistry of both 20a and 20b was unambiguously determined by Xꢀray
crystallography (see Supporting Information), following conversion to crystalline diols 21 and 22,
respectively (Scheme 4). To further exemplify the synthetic utility of these vinyl silanes, 21 was
readily converted to oxetane 23 in essentially quantitative yield (Scheme 5). The vinyl silane
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functionality could then be transformed to either the corresponding vinyl bromide 24, by a
brominationꢀdebromosilylation sequence in 91% yield,8,21 or alternatively the use of cobaltꢀmediated
conditions reported by Herzon22 afforded methyl ketone 25, again in nearly quantitative yield.
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Scheme 4. Synthesis of crystalline diols 21 and 22.
Scheme 5. Further synthetic elaboration of diol 21.
In summary, application of the hydrogen mediated syn-crotylation methodology developed by Krische
to αꢀsubstituted alcohols is reported. Polyketide stereotriads possessing anti,syn and syn,syn relative
stereochemistry were obtained in good yield, with nearly complete diastereoselectivity, as
unambiguously confirmed by chiral HPLC and Xꢀray crystallography. Enantioselective synthesis of
any of the four anti,syn and syn,syn stereotriads is therefore readily achievable by appropriate choice
of chiral pool starting material and chiral ligand. It might be expected that investigation of the
analogous anti-crotylation would reveal similar catalyst control, giving access to the remaining four
possible diastereoisomers.11b The stereochemical determination presented here is expected to facilitate
further application of hydrogen mediated crotylation methods to asymmetric polyketide synthesis, as a
complement to other wellꢀestablished preparative methods.
Experimental section
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General. All reactions were performed under a nitrogen or argon atmosphere in oven dried glassware.
Toluene was purified on alumina oxide activated basic Brockmann Grade 1, 58Ă, then dried over 4Ă
molecular sieves. Chromatography was carried out using 0.063ꢀ0.1 mm silica gel (Davisil® LC60A
40ꢀ63 Micron) or alumina oxide activated neutral Brockmann Grade 1, 58 Ă. Optical rotations were
measured on a Rudolph Research Analytical® ꢀ Autopol IV polarimeter. HRMS were recorded using
a Bruker® micrOTOFꢀQII mass spectrometer. NMR spectra were recorded at 21 °C in CDCl3 on a
Bruker® DRX400 spectrometer operating at 400 MHz for 1H nuclei and 100 MHz for 13C nuclei or on
a Bruker® Ascend 500 spectrometer operating at 500 MHz for 1H nuclei and 125 MHz for 13C nuclei.
Chemical shifts are reported in parts per million (ppm) from tetramethylsilane (δ = 0 ppm) and
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measured relatively to the solvent in which the sample was analysed (CDCl3 δ = 7.26 ppm for H
NMR and δ = 77.16 ppm for 13C NMR). Coupling constants (J) are reported in Hertz (Hz). 1H NMR
data is reported as chemical shift in ppm, followed by multiplicity (“s” singlet, “d” doublet, “dd”
doublet of doublet, “ddd” doublet of doublet of doublet, “t” triplet, “m” multiplet, “b” broad),
coupling constant where applicable, relative integral. 13C spectra are reported as chemical shift in ppm
followed by degree of hybridisation. Compounds 15,15 1617 and 1718 were prepared using literature
methods.
Vinyl silane 13. Dimethylphenylsilane (3.2 mL, 20.9 mmol, 1.0 equiv), 1,4ꢀdichloroꢀ2ꢀbutyne (2.0
mL, 20.9 mmol, 1.0 equiv) and chloroplatinic acid hexahydrate (2.2 mg, 4.20 ꢀmol, 0.02 mol%) were
stirred at rt for 18 h. Chromatography (hex/EtOAc, 49:1) afforded (E)ꢀ(1,4ꢀdichlorobutꢀ2ꢀenꢀ2ꢀ
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yl)dimethyl(phenyl)silane (3.48 g, 64 %) as a colorless liquid. H NMR (CDCl3, 400 MHz)
δ 7.57ꢀ
7.52 (m, 2 H), 7.41ꢀ7.37 (m, 3 H), 6.15 (t, J = 7.2 Hz, 1 H), 4.21 (d, J = 7.1 Hz, 2 H), 4.13 (s, 2 H),
0.48 (s, 6 H); 13C NMR (CDCl3, 100 MHz)
141.6, 140.9, 136.4, 134.2 (2), 129.7, 128.1 (2), 39.7,
δ
39.1, ꢀ2.9 (2); HRMS (ESI) m/z calcd for C12H16Cl2NaSi [(M+Na)+] 281.0291; found 281.0298; IR
νmax (neat) 2958, 1428, 1250, 700 cmꢀ1. To a solution of (E)ꢀ(1,4ꢀdichlorobutꢀ2ꢀenꢀ2ꢀ
yl)dimethyl(phenyl)silane (3.40 g, 13.1 mmol, 1.0 equiv) in EtOH (14 mL) at rt was added zinc dust
(1.71 g, 26.2 mmol, 2.0 equiv). The reaction mixture was stirred at 85 ºC for 4 h then filtered through
a pad of Celite®. The filtrate was washed with saturated aqueous NaHCO3 solution (10 mL) and the
organic layer dried over anhydrous Na2SO4 and concentrated in vacuo to afford 13 (2.25 g, 91 %) as a
colourless liquid. 1H NMR (CDCl3, 400 MHz)
10.7, 17.7 Hz, 1 H), 5.89 (d, J = 3.1 Hz, 1 H), 5.52 (d, J = 3.0 Hz, 1 H), 5.11 (d, J = 18.0 Hz, 1 H),
5.02 (d, J = 10.5 Hz, 1 H), 0.44 (s, 6 H); 13C NMR (CDCl3, 100 MHz)
147.8, 141.3, 138.4, 134.1
δ 7.55ꢀ7.51 (m, 2 H), 7.37ꢀ7.33 (m, 3 H), 6.48 (dd, J =
δ
(2), 130.6, 129.2, 127.9 (2), 116.8, ꢀ2.1 (2). Data were in agreement with literature values.23
General procedure for syn-crotylation. A solution of protected alcohol (1.0 equiv) and vinyl silane
13 (3.0 equiv) in degassed toluene (2 M) was added to a Schlenk flask containing RuHCl(CO)(PPh3)3
(0.05 equiv) and (R)ꢀ(DM)ꢀSegphos (0.05 equiv). The reaction mixture was stirred at 95 ºC for 48 h
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then concentrated in vacuo. Chromatography on neutral alumina (hexꢀEtOAc, 9:1) afforded the
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crotylation product and in some cases a small amount of the unreacted alcohol starting material.
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(2S)-Anti,syn-PMB vinyl silane 18. Obtained as a colorless oil (396 mg, 35 %) along with recovered
alcohol 15. (22 mg, 8 %). 1H NMR (CDCl3, 400 MHz)
δ 7.54ꢀ7.46 (m, 2 H), 7.37ꢀ7.29 (m, 3 H), 7.23ꢀ
7.17 (m, 2 H), 6.89ꢀ6.83 (m, 2 H), 5.75 (d, J = 2.6 Hz, 1 H), 5.51 (d, J = 2.5 Hz, 1 H), 4.39 (d, J = 11.9
Hz, 1 H), 4.34 (d, J = 11.6 Hz, 1 H), 3.81 (s, 3 H), 3.66ꢀ3.60 (m, 1 H), 3.30 (dd, J = 4.5, 9.0 Hz, 1 H),
3.26 (dd, J = 4.3, 9.0 Hz, 1 H), 2.50ꢀ2.40 (m, 1 H), 2.38 (d, J = 2.7 Hz, 1 H), 1.81ꢀ1.71 (m, 1 H), 1.03
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(d, J = 6.8 Hz, 3 H), 0.77 (d, J = 7.0 Hz, 3 H), 0.39 (s, 6 H); 13C NMR (CDCl3, 100 MHz)
δ 159.3,
154.3, 138.4, 134.1 (2), 130.5, 129.2 (2), 127.9 (3), 127.2, 113.9 (2), 76.3, 75.3, 73.1, 55.4, 42.9, 35.1,
17.9, 10.6, ꢀ2.0, ꢀ2.1; HRMS (ESI) m/z calcd for C24H34NaO3Si [(M+Na)+] 421.2169; found 421.2154;
IR ν
max (neat) 2962, 1719, 1249, 1109 cmꢀ1; [a]D21 ꢀ2.2 (c 1.05, CHCl3).
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(2S)-Anti,syn-TBS vinyl silane 19. Obtained as a colorless oil (86 mg, 80 %). H NMR (CDCl3, 400
MHz) 7.54ꢀ7.50 (m, 2 H), 7.36ꢀ7.32 (m, 3 H), 5.85 (dd, J = 1.4, 2.5 Hz, 1 H), 5.61 (d, J = 1.2 Hz, 1
δ
H), 3.60 (dd, J = 4.3, 9.9 Hz, 1 H), 3.44 (dd, J = 5.3, 9.8 Hz, 1 H), 3.36ꢀ3.32 (m, 1 H), 2.93 (d, J = 3.6
Hz, 1 H), 2.54ꢀ2.48 (m, 1 H), 1.69ꢀ1.59 (m, 1 H), 1.02 (d, J = 7.0 Hz, 3 H), 0.88 (s, 9 H), 0.75 (d, J =
7.0 Hz, 3 H), 0.41 (2 s, 6 H), 0.03 (2 s, 6 H); 13C NMR (CDCl3, 100 MHz)
δ 154.1, 138.4, 134.1 (2),
129.1, 127.9 (2), 127.1, 76.2, 67.2, 41.0, 37.1, 26.0 (3), 18.3, 14.1, 13.4, ꢀ2.1, ꢀ2.2, ꢀ5.4, ꢀ5.5; HRMS
(ESI) m/z calcd for C22H40NaO2Si2 [(M+Na)+] 415.2459; found 415.2443; IR νmax (neat) 2959, 1738,
1236, 1044 cmꢀ1; [a]D23 ꢀ3.2 (c 1.00, CHCl3)
(2S)-Anti,syn-TBDPS vinyl silane 20a. Obtained as a colorless oil (174 mg, 74 %) along with
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recovered alcohol 17 (15 mg, 10%). H NMR (CDCl3, 400 MHz)
δ 7.68ꢀ7.64 (m, 4 H), 7.51ꢀ7.35 (m,
8 H), 7.32ꢀ7.27 (m, 3 H), 5.83 (dd, J = 1.0, 2.3 Hz, 1 H), 5.60 (d, J = 2.6 Hz, 1 H), 3.69 (dd, J = 4.4,
10.1 Hz, 1 H), 3.51 (dd, J = 4.5, 10.0 Hz, 1 H), 3.46ꢀ3.39 (m, 1 H), 2.70 (d, J = 3.5 Hz, 1 H), 2.60ꢀ
2.49 (m, 1 H), 1.73ꢀ1.61 (m, 1 H), 1.04 (s, 9 H), 1.02 (d, J = 6.9 Hz, 3 H), 0.79 (d, J = 7.0 Hz, 3 H),
0.40 (s, 3 H), 0.39 (s, 3 H); 13C NMR (CDCl3, 100 MHz)
δ 154.0, 138.3, 135.8 (2), 134.1 (2), 133.5,
133.4, 129.8 (2), 129.1 (3), 127.9 (2), 127.8 (4), 127.2 , 75.3, 67.6, 40.8, 37.4, 27.0 (3), 19.3, 14.1,
12.8, ꢀ2.1, ꢀ2.2; HRMS (ESI) m/z calcd for C32H44NaO2Si2 [(M+Na)+] 539.2772; found 539.2762; IR
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νmax (neat) 2970, 1739, 1217, 1111 cmꢀ1; [a]D ꢀ3.7 (c 1.05, CHCl3). HPLC Daicel Chiralpak ADꢀH
column, nHexane/iPrOH: 99/1, 0.5 mL/min, 254 nm, tmajor = 8.0 min, tminor = 12.1 min, dr 99.5:0.5.
(2S)-Syn,syn-TBDPS vinyl silane 20b. Obtained as a colorless oil (100 mg, 64 %) along with
recovered alcohol 17 (15 mg, 20%). 1H NMR (CDCl3, 400 MHz)
δ 7.69ꢀ7.60 (m, 4 H), 7.53ꢀ7.35 (m,
8 H), 7.32ꢀ7.27 (m, 3 H), 5.74 (dd, J = 2.3, 2.4 Hz, 1 H), 5.49 (d, J = 2.9 Hz, 1 H), 3.76ꢀ3.68 (m, 1 H),
3.49 (dd, J = 4.6 Hz, J = 9.9 Hz, 1 H), 3.46 (dd, J = 4.2, 10.1 Hz, 1 H), 2.56 (d, J = 2.4 Hz, 1 H), 2.49ꢀ
2.39 (m, 1 H), 1.73ꢀ1.62 (m, 1 H), 1.06 (d, J = 6.8 Hz, 3 H), 1.05 (s, 9 H), 0.73 (d, J = 7.3 Hz, 3 H),
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0.40 (s, 3 H), 0.39 (s, 3 H); 13C NMR (CDCl3, 100 MHz)
δ
154.2, 138.3, 135.9 (2), 135.7 (2), 134.1
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(2), 133.4 , 133.2, 129.9 (2), 129.2, 127.9 (2), 127.9 (4), 127.2, 76.7, 69.4, 43.1, 36.6, 27.1 (3), 13.9,
19.3, 18.5, ꢀ2.0, ꢀ2.2; HRMS (ESI) m/z calcd for C32H44NaO2Si2 [(M+Na)+] 539.2772; found
539.2772; IR νmax (neat) 2970, 1739, 1217, 1111 cmꢀ1; [a]D ꢀ5.8 (c 0.80, CHCl3); HPLC Daicel
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Chiralpak ADꢀH column, nHexane/iPrOH: 99/1, 0.5 mL/min, 254 nm, tmajor = 11.1 min, tminor = 12.4
min, dr 99.5:0.5.
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(2S)-Anti,syn diol 21. To a solution of vinyl silane 20a (40 mg, 77 ꢀmol, 1.0 equiv) in THF (0.5 mL)
at rt was added TBAF (1 M in THF, 77 ꢀL, 77 ꢀmol, 1.0 equiv). After stirring at rt for 20 min, the
reaction mixture was quenched with sat aq NH4Cl solution and diluted with Et2O. The organic layer
was dried over anhydrous Na2SO4 then concentrated in vacuo. Chromatography (pet etherꢀEtOAc, 9:1
to 2:1) afforded 20a (21 mg, 98 %) as colorless crystals. 1H NMR (CDCl3, 400 MHz)
δ 7.51ꢀ7.46 (m,
2 H), 7.38ꢀ7.34 (m, 3 H), 5.84 (dd, J = 1.9, 1.6 Hz, 1 H), 5.71 (d, J = 2.3 Hz, 1 H), 3.57ꢀ3.48 (m, 1 H),
3.43 (dd, J = 7.8, 10.8 Hz, 1 H), 3.17 (dd, J = 2.4, 9.0 Hz, 1 H), 3.06 (d, J = 6.9 Hz, 1 H), 2.69ꢀ2.59
(m, 1 H), 1.94 (bs, 1 H), 1.69ꢀ1.59 (m, 1 H), 0.98 (d, J = 7.0 Hz, 3 H), 0.65 (d, J = 7.0 Hz, 3 H), 0.42
(s, 3 H), 0.41 (s, 3 H); 13C NMR (CDCl3, 100 MHz)
δ 153.9, 137.8, 134.0 (2), 129.5, 128.1 (2), 127.6,
77.3, 68.9, 39.8, 37.1, 13.4, 11.1, ꢀ2.4, ꢀ2.7; HRMS (ESI) m/z calcd for C16H26NaO2Si [(M+Na)+]
22
301.1594; found 301.1588; IR νmax (neat) 3365, 2959, 1737, 1248 cmꢀ1; [a]D ꢀ9.2 (c 0.42, CHCl3);
mp 20ꢀ22 ºC.
(2S)-Syn,syn diol 22. Using the same procedure as for 21 above, deprotection of 20b (98 mg, 190
ꢀmol) gave diol 22 (48 mg, 91 %) as colorless crystals. 1H NMR (CDCl3, 400 MHz)
δ 7.55ꢀ7.49 (m, 2
H), 7.39ꢀ7.31 (m, 3 H), 5.77 (dd, J = 0.9, 1.9 Hz, 1 H), 5.54 (d, J = 2.4 Hz, 1 H), 3.63 (dd, J = 2.9, 8.3
Hz, 1 H), 3.52ꢀ3.44 (m, 2 H), 2.52ꢀ2.40 (m, 1 H), 1.96 (bs, 1 H), 1.73ꢀ1.59 (m, 1 H), 1.04 (d, J = 6.8
Hz, 3 H), 0.76 (d, J = 7.1 Hz, 3 H), 0.42 (s, 3 H), 0.41 (s, 3 H); 13C NMR (CDCl3, 100 MHz)
138.2, 134.1 (2), 129.3, 128.0 (2), 127.3, 76.3, 67.8, 43.2, 36.5, 17.7, 9.8, ꢀ2.0, ꢀ2.2; HRMS (ESI) m/z
δ 154.1,
calcd for C16H26NaO2Si [(M+Na)+] 301.1594; found 301.1589; IR
νmax (neat) 3365, 2959, 1737, 1248
25
cmꢀ1; [a]D +19.8 (c 1.00, CHCl3); mp 80ꢀ82 ºC.
Oxetane 23. To a solution of diol 21 (57 mg, 0.21 mmol, 1.0 equiv) in CH2Cl2 (6 mL) at rt were added
triethylamine (55 ꢀL, 0.41 mmol, 2.0 equiv) and MsCl (16 ꢀL, 0.21 mmol, 1.0 equiv). After stirring
at rt for 16 h, KOtBu (173 mg, 1.72 mmol, 4.0 equiv) was added. The reaction mixture was stirred for
an additional 10 min then water was added. The organic layer was dried over anhydrous Na2SO4 then
concentrated in vacuo. Chromatography (pet etherꢀEtOAc, 95:5 to 9:1) afforded oxetane 23 (53 mg,
1
99 %) as a yellow oil. H NMR (CDCl3, 400 MHz)
δ 7.56ꢀ7.49 (m, 2 H), 7.40ꢀ7.30 (m, 3 H), 5.74ꢀ
5.68 (m, 1 H), 5.56ꢀ5.49 (m, 1 H), 4.38 (dd, J = 5.7, 8.1 Hz, 1 H), 4.26 (dd, J = 6.4, 8.8 Hz, 1 H), 4.09
(dd, J = 5.8, 7.0 Hz, 1 H), 2.63ꢀ2.52 (m, 1 H), 2.40ꢀ2.28 (m, 1 H), 1.05 (d, J = 6.8 Hz, 3 H), 0.99 (d, J
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= 6.7 Hz, 3 H), 0.42 (s, 3 H), 0.41 (s, 3 H); 13C NMR (CDCl3, 100 MHz)
δ 151.6, 137.9, 134.2 (2),
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129.2, 127.9 (2), 127.1, 92.9, 74.5, 44.6, 34.6, 18.4, 17.5, ꢀ2.7, ꢀ2.9; HRMS (ESI) m/z calcd for
21
C16H24NaOSi [(M+Na)+] 283.1489; found 283.1481; IR νmax (neat) 2959, 1249, 1110 cmꢀ1; [a]D
ꢀ
1.6 (c 0.50, CHCl3).
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Vinyl bromide 24. To a solution of oxetane 23 (421 mg, 1.62 mmol, 1.0 equiv) in CH2Cl2 (4.7 mL) at
0 ºC were added trimethylamine (262 ꢀL, 1.94 mmol, 1.2 equiv) and pyridinium tribromide (620 mg,
1.94 mmol, 1.2 equiv) and the reaction stirred at rt for 30 min. The above procedure was repeated
three times until complete by TLC then the reaction mixture was quenched with 4 % aq sodium
sulphite solution. The organic layer was dried over anhydrous Na2SO4 then concentrated in vacuo.
The crude product was dissolved in methanol (4.7 mL) and sodium methoxide (306 mg, 5.67 mmol,
3.5 equiv) was added. After 20 min stirring at rt, water was added and the organic layer dried over
anhydrous Na2SO4 and concentrated in vacuo. Chromatography (pet etherꢀEt2O, 95:5 to 9:1) afforded
the vinyl bromide 24 (302 mg, 91 %) as a colorless oil. 1H NMR (CDCl3, 400 MHz)
δ 5.71 (d, J = 1.5
Hz, 1 H), 5.49 (d, J = 1.5 Hz, 1 H), 4.55 (dd, J = 5.9, 8.3 Hz, 1 H), 4.29 (dd, J = 6.2, 8.5 Hz, 1 H),
4.22 (dd, J = 5.9, 6.8 Hz, 1 H), 2.81ꢀ2.63 (m, 2 H), 1.22 (d, J = 6.8 Hz, 3 H), 1.16 (d, J = 6.4 Hz, 3
H); 13C NMR (CDCl3, 100 MHz)
(CH), 18.2 (CH3), 15.4 (CH3); HRMS (ESI) m/z calcd for C8H13BrNaO [(M+Na)+] 227.0043; found
227.0049; IR
max (neat) 1739, 1217, 970, 758 cmꢀ1; [a]D23 +18.6 (c 1.00, CHCl3).
δ 135.0 (C), 117.9 (CH2), 91.2 (CH), 74.9 (CH2), 50.8 (CH), 34.5
ν
Ketone 25. A flask charged with oxetane 23 (200 mg, 0.75 mmol, 1.0 eq), Co(acac)2 (193 mg,
0.75 mmol, 1.0 eq), TBHP (94 ꢀL, 0.75 mmol, 1.0 eq) and triethylsilane (17 mg, 0.17 mmol, 0.1 eq)
in methanol (2 mL) was purged three times with oxygen. After stirring at room temperature for 16 h,
the reaction mixture was purged with nitrogen then concentrated in vacuo. Chromatography (pet
1
etherꢀEt2O, 7:3) afforded ketone 25 (106 mg, 99%) as a colourless oil. H NMR (CDCl3, 400 MHz)
δ
4.52 (dd, J = 8.2, 7.8 Hz, 1H), 4.46 (t, J = 6.8 Hz, 1H), 4.21 (dd, J = 6.7, 6.0 Hz, 1H), 2.97ꢀ2.88 (m,
1H), 2.84ꢀ2.72 (m, 1H), 2.19 (s, 3H), 1.22 (d, J = 6.8 Hz, 3H), 1.12 (d, J = 7.0 Hz, 3H); 13C NMR
(CDCl3, 100 MHz) 210.7, 90.2, 75.4, 52.7, 34.0, 30.2, 18.3, 11.8; HRMS (ESI) m/z calcd for
δ
C8H14NaO2 [(M+Na)+] 165.1886; found 165.1883; Rf 0.34 (Pet. Ether:Et2O 7:3); IR νmax (neat) 2933,
2161, 1710, 1455, cmꢀ1; [a]D21 ꢀ29.5 (c 1.60, CHCl3).
Acknowledgments
The authors thank Dr Tilo Söhnel and Tatiana Groutso (UoA) for assistance with X-ray
crystallography and The University of Auckland for the award of a UoA doctoral scholarship to JGH.
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Supporting Information. Copies of spectra for all compounds, chiral HPLC traces and Ortep
diagrams for 21 and 22.
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Author information
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* d.furkert@auckland.ac.nz, m.brimble@auckland.ac.nz
† Present Address ETH Zürich, Rämistrasse 101, 8092 Zürich, Suisse
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References
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(a) Hoffman, R. W. Angew. Chem., Int. Ed. 1987, 26, 489ꢀ594; (b) Hoffman, R. W.; Dahmann, G.; Andersen,
M. W, Synthesis 1994, 629ꢀ638; (c) Chemler, S. R.; Roush, W. R. J. Org. Chem. 1998, 63, 3800ꢀ3801.
2 Brown, H. C.; Ramachandran, P. V. J. Organomet. Chem. 1995, 500, 1ꢀ19.
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(a) Roush, W. R.; Palkowitz, A. D.; Ando, K. J. Am. Chem. Soc. 1990, 112, 6348ꢀ6359; (b) Roush, W. R.;
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For representative examples, see; (a) Hoppe, D.; Zschage, O. Angew. Chem., Int. Ed. 1989, 28, 69ꢀ71; (b)
Denmark, S. E.; Fu, J. J. Am. Chem. Soc. 2001, 123, 9488ꢀ9489; (c) Hu, T.; Takanaka. N.; Panek, J. S. J. Am.
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M.; Roush, W. R. J. Org. Chem. 2013, 78, 3ꢀ8.
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(a) Hackman, B. M.; Lombardi, P. J.; Leighton, J. L. Org. Lett. 2004, 6, 4375ꢀ4377; (b) Kim, H.; Ho, S.;
Leighton, J. L. J. Am. Chem. Soc. 2011, 133, 6517ꢀ6520.
6 Suen, L. M.; Steigerwald, M. L.; Leighton, J. L. Chem. Sci. 2013, 4, 2413ꢀ2417.
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(a) Shibahara, F.; Bower, J. F.; Krische, M. J. J. Am. Chem. Soc. 2008, 130, 6338ꢀ6339; (b) Zbieg, J. R.;
Yamaguchi, E.; McInturff, E. L.; Krische, M. J. Science 2012, 336, 324ꢀ327; (c) Feng, J.; Kaun, Z. A.;
Krische, M. J. Am. Chem. Soc. 2016, 138, 5467ꢀ5478; (d) Shin, I.; Hong, S.; Krische, M. J. Am. Chem. Soc.
2016, 138, 14246ꢀ14249; (e) Nguyen, K. D.; Park, B. Y.; Luong, T.; Sato, H.; Garza, V. J.; Krische, M. J.
Science 2016, 354 (6310), aah5133.
8 Kim, S.; Han, S. B.; Krische, M. J. J. Am. Chem. Soc. 2009, 131, 2514ꢀ2520.
9 Zbieg, J. R.; Moran, J.; Krische, M. J. J. Am. Chem. Soc. 2011, 133, 10582ꢀ10586.
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(a) Kotani, S.; Kai, K.; Sugihara, Nakajima, M. Org. Lett. 2017, 19, 3672ꢀ3675. (b) Chemler, S. R.; Roush,
W. R. J. Org. Chem. 1998, 63, 3800ꢀ3801.
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13 An example of an anti,anti stereotriad synthesis via Krische anti-crotylation has been reported, but the authors
made no comment on reaction stereochemistry; Oshita, J.; Noguchi, Y.; Watanabe, A.; Sennari, G.; Sato, S.;
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Hirose, T.; Oikawa, D.; Inahashi, Y.; Iwatsuki, M.; Ishiyama, A.; Omura, S. Tetrahedron Lett. 2016, 57, 357ꢀ
360. The compound in question had previously been prepared by the Roush group in their total synthesis of
bafilomycin A1; Scheidt, K. A.; Bannister, T. D.; Tasaka, A.; Wendt, M. D.; Savall, B. M.; Fegley, G. J.;
Roush, W. R. J. Am. Chem. Soc. 2001, 124, 6981ꢀ6990.
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14 McInturff, E. L.; Yamaguchi, E.; Krishce, M. J. J. Am. Chem. Soc. 2012, 134, 20628ꢀ20631.
15 Lentsch, C.; Furst, R.; Mulzer, J.; Rinner, U. Eur. J. Org. Chem. 2014, 919ꢀ923.
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17
Han, J.ꢀC.; Liu, L.ꢀJ.; Chang, Y.ꢀY.; Yue, G.ꢀZ.; Guo, J.; Zhou, L.ꢀY.; Li, C.ꢀC.; Yang, Z. J. Org. Chem.
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Pasqua, A. E.; Ferrari, F. D.; Hamman, C.;Liu, Y.; Crawford, J. J.; Marquez, R. J. Org. Chem. 2012, 77,
6989ꢀ6997.
19 An equimolar mixture of (R)ꢀ and (S)ꢀDMꢀSEGPHOS was used.
20 See Supporting Information for HPLC data.
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23 Pidiparthi, R.; Junker, C. S.; Welker, M. E.; Day, C. S.; Wright, M. W. J. Org. Chem. 2009, 74, 8290ꢀ8297.
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