Asymmetric syntheses of APTO and AETD: The β-amino acid fragments within microsclerodermins C, D, and e

Article abstract of DOI:10.1021/jo302731m

Efficient asymmetric syntheses of APTO and AETD, the highly functionalized β-amino acid fragments within microsclerodermins C, D, and E, are reported. The conjugate addition of lithium (R)-N-benzyl-N-(α-methylbenzyl)amide to tert-butyl (E,E)-7-(triisopropylsilyloxy)hepta-2,4-dienoate and in situ enolate oxidation with (-)-camphorsulfonyloxaziridine, diastereoselective dihydroxylation of a 2,3-syn-γ,δ-unsaturated-α-hydroxy-β- amino ester derivative under Donohoe conditions, and a Julia-Kocienski olefination were used as the key steps.

Full text of DOI:10.1021/jo302731m

Article
pubs.acs.org/joc
Asymmetric Syntheses of APTO and AETD: the β‑Amino Acid
Fragments within Microsclerodermins C, D, and E
Stephen G. Davies,* Ai M. Fletcher, Emma M. Foster, James A. Lee, Paul M. Roberts,
and James E. Thomson
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA, U.K.
S
* Supporting Information
ABSTRACT: Efficient asymmetric syntheses of APTO and AETD, the highly functionalized β-
amino acid fragments within microsclerodermins C, D, and E, are reported. The conjugate
addition of lithium (R)-N-benzyl-N-(α-methylbenzyl)amide to tert-butyl (E,E)-7-
(triisopropylsilyloxy)hepta-2,4-dienoate and in situ enolate oxidation with (−)-camphorsulfony-
loxaziridine, diastereoselective dihydroxylation of a 2,3-syn-γ,δ-unsaturated-α-hydroxy-β-amino
ester derivative under Donohoe conditions, and a Julia−Kocien
steps.
́
INTRODUCTION
■
Microsclerodermins A−I are a family of nine cyclic hexapeptide
natural products, isolated from marine sponges of the
Microscleroderma and Theonella genera native to the waters
off New Caledonia and the Philippines.1 All nine of these
compounds exhibit antifungal activity against Candida albicans
in a paper disk diffusion assay,1 and microsclerodermins F−I
have also been shown to display moderate cytotoxicity against
the HCT-116 cell line.1b The structures of microsclerodermins
A−I were elucidated by a combination of spectroscopic
methods and chemical degradation studies. All the members
of this family contain a 23-membered ring constructed of six
amino acid residues; three amino acid residues are common to
all members of the microsclerodermin family viz. glycine,
sarcosine (N-methylglycine) and (R)-4-amino-3-hydroxybutyric
acid (GABOB). In each case the three remaining amino acids
comprise a substituted tryptophan residue, a 4-aminopyrrolidin-
2-one-5-acetic acid residue, and a 2,4,5-trihydroxy substituted
β-amino acid residue, with considerable variation in their
substitution across the microsclerodermin family. In each case
the identity of the 2,4,5-trihydroxy substituted β-amino acid
residue was identified by a combination of evidence, including
1H NMR NOE data, derivatization of the 4,5-dihydroxy unit to
the corresponding trans-configured acetonide, and degradation
to give (S,S)-3-hydroxyaspartic acid via oxidative cleavage of the
4,5-dihydroxy unit followed by hydrolysis of the resultant
peptide. Microsclerodermin C 1 and microsclerodermin D 2,
for example, both contain the common β-amino acid residue
(2S,3R,4S,5S,E)-3-amino-8-phenyl-2,4,5-trihydroxyoct-7-enoic
acid (APTO), and microsclerodermin E 3 contains a
(2S,3R,4S,5S,E,E)-3-amino-10-(4′-ethoxyphenyl)-2,4,5-trihy-
droxydeca-7,9-dienoic acid (AETD) residue (Figure 1).
Figure 1. The structures of microsclerodermins C, D, and E 1−3.
date, only one member of the microsclerodermin family has
been synthesized: in 2003 Zhu and Ma reported a total
synthesis of microsclerodermin E 3,2 employing an enantio-
specific synthesis of a protected AETD−GABOB dipeptide
The potent biological activity of the microsclerodermins has
made them attractive targets for total syntheses. However, to
Received: December 17, 2012
Published: February 4, 2013
© 2013 American Chemical Society
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fragment from δ-gluconolactone. Since then, several other
reports have described syntheses of the 2,4,5-trihydroxy
substituted β-amino acid fragments within microsclerodermins
A−I in protected form.3 Shioiri et al. reported an
enantiospecific synthesis of (2S,3R,4S,5S,6S,E)-3-amino-12-
(4′-methoxyphenyl)-6-methyl-2,4,5-trihydroxydodec-11-enoic
acid (AMMTD), the β-amino acid component within both
microsclerodermins A and B, from methyl (R)-3-O-tert-
butyldiphenylsiloxy-2-methylpropionate,4 Chandrasekhar and
Sultana have also reported an enantiospecific synthesis of
AMMTD from (S)-citronellol,5 and Burnett and Williams have
reported studies toward (2S,3R,4S,5S,6S,E,E,E)-3-amino-6-
methyl-12-phenyl-2,4,5-trihydroxydodeca-7,9,11-trienoic acid
(AMPTD), the core β-amino acid component within micro-
sclerodermins F and G.6 However, of all the β-amino acid
components within microsclerodermins A−I, (2S,3R,4S,5S,E)-
3-amino-8-phenyl-2,4,5-trihydroxyoct-7-enoic acid (APTO),
the β-amino acid component within both microsclerodermins
C 1 and D 2, has received the most interest from synthetic
chemists. In 2007 McLeod et al. reported an asymmetric
synthesis of APTO in protected form,7 and as a Wittig
olefination was used in the final step, their route was also
applied to the synthesis of (2S,3R,4S,5S,E,E)-3-amino-10-(4′-
ethoxyphenyl)-2,4,5-trihydroxydeca-7,9-dienoic acid (AETD),
the β-amino acid component within microsclerodermin E 3,
also in protected form. More recently, Aitken et al.8 have
reported syntheses of protected forms of APTO and AETD
from a 2-deoxy-D-ribose derivative,9 and this was followed by a
report by Dodd et al. in which APTO was produced from
L‑gulose.10
Previous investigations from our laboratory have demon-
strated that the conjugate addition of enantiopure secondary
lithium amides (derived from α-methylbenzylamines) to α,β-
unsaturated esters represents a general and efficient synthetic
protocol for the synthesis of β-amino esters and their
derivatives.11 This methodology has found numerous applica-
tions, including the total syntheses of natural products,12
molecular recognition phenomena13 and resolution protocols,14
and has been reviewed.15 We have recently extended the utility
of this methodology to encompass the synthesis of amino
sugars.16 For example, conjugate addition of lithium (R)-N-
benzyl-N-(α-methylbenzyl)amide 5 to tert-butyl sorbate 4
followed by in situ oxidation of the resultant enolate with
(−)-camphorsulfonyloxaziridine [(−)-CSO] 6 gave α-hydroxy-
β-amino ester 7 in 68% yield as a single diastereoisomer (>99:1
dr). Subsequent syn-dihydroxylation of the C−C double bond
within 7 upon treatment with the OsO4/TMEDA complex
(Donohoe conditions)17 gave amino triol 8 in 81% yield and
>99:1 dr. Alternatively, oxidation of 7 with OsO4/NMO
(Upjohn conditions)18 produced antipodal diastereoselectivity,
giving amino triol 9 as a single diastereoisomer (>99:1 dr).
Subsequent elaboration of 9 gave the target 3,6-dideoxy-3-
amino sugar 10 as a mixture of protected pyranose and
furanose anomers (Scheme 1). As part of our ongoing research
program in this area we became interested in the application of
this methodology for the preparation of the 2,4,5-trihydroxy
substituted β-amino acid fragments within the microscler-
odermins, and we report herein our full investigations
concerning the total asymmetric syntheses of APTO and
AETD.
Scheme 1
RESULTS AND DISCUSSION
■
We envisaged that 2,3-syn-γ,δ-unsaturated-α-hydroxy-β-amino
ester 13 would be a useful substrate for the synthesis of APTO
(in the first instance) as it could be accessed from 2,3-anti-α-
hydroxy-β-amino ester 12 via epimerization at the C(2)-
position; in turn, 12 can be produced from 11 using our
diastereoselective aminohydroxylation protocol.15,19,20 Two
alternative strategies for the elaboration of 2,3-syn-γ,δ-
unsaturated-α-hydroxy-β-amino ester 13 were investigated. In
the first of these two approaches, diastereoselective dihydrox-
ylation of 13 would be followed by subsequent introduction of
the styryl unit using the (protected) ζ-hydroxyl group within 14
as a synthetic handle (Route A, Figure 2). The second approach
would involve olefination of 13 followed by regioselective
dihydroxylation of γ,δ,ζ,η-diunsaturated-α-hydroxy-β-amino
ester 16 (Route B, Figure 2). As we have already established
that remarkable diastereoselectivity can be achieved upon
dihydroxylation of acyclic γ,δ-unsaturated-α-hydroxy-β-amino
Figure 2. Proposed strategies to access APTO.
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esters,16 we sought to develop a reliable olefination procedure
to install the required styryl moiety and therefore investigated
“Route B” first.
followed by the addition of benzaldehyde, gave 25 in 66% yield
and >99:1 dr. An oxidation/diastereoselective reduction
sequence was then used to invert the configuration of the
C(2)-stereogenic center within 25: oxidation of 25 under
Swern conditions, followed by immediate reduction of the
intermediate ketone 28 with NaBH4 gave 2,3-syn-α-hydroxy-β-
amino ester 29 as a single diastereoisomer (>99:1 dr), which
was isolated in 25% yield after purification (Scheme 3).
We have previously employed O-TIPS protection of ω-
hydroxyl groups to good effect in the lithium amide conjugate
addition reaction,12a,b so this protecting group was selected for
our proposed syntheses of APTO and AETD. The requisite
α,β-unsaturated ester 20 was prepared via a three step
procedure from 3-butyn-1-ol 17: initially, protection of the
hydroxyl group within 17 was achieved upon treatment with
TIPSCl in the presence of DMAP and imidazole, which gave 18
in 92% isolated yield. Subsequent reduction of 18 with
DIBAL‑H and Cp2ZrCl2,21 followed by treatment with I2
gave vinyl iodide 19 (3J1,2 = 14.4 Hz) in 79% yield as a single
diastereoisomer (>99:1 dr). Heck coupling22 of 19 with tert-
butyl acrylate then gave α,β-unsaturated ester 20 in 89% yield
and >99:1 dr (Scheme 2). The (E,E)-configuration within 20
Scheme 3
1
3
was confirmed by H NMR J coupling constant analysis (3J2,3
3
= 15.4 Hz; J4,5 = 15.4 Hz).
Scheme 2
Conjugate addition of lithium (R)-N-benzyl-N-(α-
methylbenzyl)amide 5 to α,β-unsaturated ester 20 followed
by oxidation of the intermediate lithium (Z)-β-amino enolate23
with (−)-CSO 6 produced β-amino ester 21 as a single
diastereoisomer (>99:1 dr), which was isolated in 72% yield
and >99:1 dr after chromatographic purification. The stereo-
chemical outcome of this transformation was initially assigned
by reference to the well-established transition state mnemonic
developed by us to rationalize the diastereoselectivity observed
upon conjugate addition of lithium amides derived from α-
methylbenzylamines,24 and by analogy to the outcome of our
aminohydroxylation protocol.15,19,20 Subsequent treatment of
21 with TBAF gave 22 in 90% yield and >99:1 dr. The relative
configuration within 22 was unambiguously assigned via single
crystal X-ray diffraction analysis,25 with the absolute (R,R,R,E)-
configuration within 22 following from the known (R)-
configuration of the N-α-methylbenzyl stereocenter; this
analysis therefore also allowed the absolute configuration
within 21 to be assigned unambiguously. Two potential routes
to install the desired styryl moiety were then investigated. In
the first instance, Appel reaction of 22 produced the
corresponding iodide 23 in 85% yield, which was then
converted to phosphonium iodide salt 24 in quantitative
yield. Unfortunately all attempts at Wittig reaction of the ylid
derived from 24 with benzaldehyde were unsuccessful.
Attention then turned to our alternative strategy via a Julia−
Unfortunately, attempted regioselective dihydroxylation of the
C(4)−C(5) double bonds within both 25 and 29 under
Donohoe conditions produced complex mixtures of products
consistent with preferential oxidation of the styryl units,
although it was not possible to isolate any of the products
from these reactions.
With a reliable procedure for the installation of the styryl unit
established, our attention turned toward our alternative
synthetic strategy in which the chemo- and diastereoselective
oxidation of the C−C double bond within 2,3-syn-α-hydroxy-β-
amino ester 31 would be followed by olefination. Oxidation of
the C(2)-hydroxyl functionality within 2,3-anti-α-hydroxy-β-
amino ester 21 under Swern conditions followed by immediate
reduction of the intermediate ketone 30 upon treatment with
NaBH4 gave 2,3-syn-α-hydroxy-β-amino ester 31 as a single
́
Kocienski olefination with benzaldehyde. Thus, Mitsunobu
reaction of 22 with 1-phenyl-1H-tetrazole-5-thiol (PTSH) gave
26 in 82% yield. Oxidation of 26 to the corresponding sulfone
27 was achieved upon treatment with ammonium molybdate
tetrahydrate and H2O2, which gave 27 in 58% yield. Julia−
́
Kocienski olefination, upon deprotonation of 27 with KHMDS
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diastereoisomer (>99:1 dr). After purification of the crude
reaction mixture, 31 was isolated in 67% yield (from 21) and
>99:1 dr. On the basis of our previous observations concerning
the chemo- and diastereoselective oxidation of the correspond-
ing tert-butyl 2-hydroxy-3-aminohex-4-enoates,16,26 we antici-
pated that syn-dihydroxylation of 31 under Donohoe conditions
(using the OsO4/TMEDA complex)17 would install the correct
stereochemistry for syntheses of both APTO and AETD.
Indeed, dihydroxylation of α-hydroxy-β-amino ester 31 under
Donohoe conditions17 gave a single osmate ester-TMEDA
complex 32, which after treatment with trishydroxymethyl-
phosphine,27 gave lactone 33 in 53% yield (from 31) and >99:1
dr (Scheme 4). The relative configuration within 33 was
(>99:1 dr) in each case. Further optimization of the reaction
conditions revealed that treatment of the 80:20 mixture of 39
and 38 with DMP and TsOH in acetone at rt for 24 h produced
40 exclusively, which was isolated in 19% yield (from 35) and
>99:1 dr (Scheme 5). The relative configuration within 40 was
Scheme 5
1
initially established by H NMR NOE analysis and was later
confirmed by single crystal X-ray diffraction analysis of a
derivative.
Scheme 4
Hydrogenolytic deprotection of 33 in the presence of Boc2O
gave 34 in 69% yield, and subsequent O-silyl deprotection of 34
upon treatment with TBAF produced 35 in only 19% isolated
yield. An improved yield of 35 was obtained upon O-silyl
deprotection of 33 followed by hydrogenolysis: desilylation of
33 with either TBAF or HF·pyridine gave 36 in 46 or 88%
yield, respectively, and then hydrogenolysis of 36 in the
presence of Pd/C and Boc2O gave 35 in quantitative yield.28
Mitsunobu reaction of 35 with PTSH gave the corresponding
sulfide 37 in 100% conversion, although attempted reaction of
36 under identical conditions was not successful. Sulfide 37
could not be separated from the resultant Ph3PO residues, so
the mixture of 37 and Ph3PO was therefore treated with
ammonium molybdate tetrahydrate to give sulfone 38 in 100%
conversion. Upon attempted chromatographic purification of
the crude reaction mixture on silica (using a mixture of
CH2Cl2/MeOH as the eluent), an 80:20 mixture of ester 39
and lactone 38 was isolated. Treatment of this mixture with 2,2-
dimethoxypropane (DMP) and BF3·OEt2 in acetone produced
a 74:26 mixture of 40 and 41, respectively. Upon purification of
this mixture, 40 was isolated in 8% yield (from 35), and 41 was
isolated in 5% yield (from 35), as single diastereoisomers
a
Isolated yields from 35
unambiguously assigned via single crystal X-ray diffraction
analysis,25 and the determination of a Flack x parameter29 of
0.17(5) for the crystal structure of 40 allowed the absolute
(S,S,S,S)-configuration within 40 (and therefore the absolute
configurations within 21−39 and 41) to be determined,
thereby confirming the sense of diastereofacial selectivity
observed upon oxidation of 31 under Donohoe conditions.17
Repetition of this process, followed by treatment of sulfone
38 with DMP and TsOH in acetone (i.e., omitting the
attempted purification of 38), gave 40 as the sole reaction
product. Upon chromatographic purification of the crude
reaction mixture, 40 was isolated as a single diastereoisomer
(>99:1 dr) in 30% overall yield for the three step procedure
from 35 (Scheme 6).
Olefination of 40 produced 42 as a single diastereoisomer
(>99:1 dr), which was isolated in 79% yield and >99:1 dr after
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Analogous reaction of 40 with (E)-3-(4′-ethoxyphenyl)-
acrylaldehyde 44 (which was prepared in 82% yield and >99:1
dr via Heck coupling of 4-iodophenetole with acrolein diethyl
acetal, followed by hydrolysis of the resultant acetal),30
produced 45 in >99:1 dr. After chromatographic purification
of the crude reaction mixture, 45 was isolated in 23% yield and
>99:1 dr (Scheme 7). Again, single crystal X-ray diffraction
analysis of 4525 and the determination of a Flack x parameter29
of 0.11(6) for the crystal structure of 45 allowed the assigned
absolute (S,S,S,S,E,E)-configuration within 45 to be confirmed.
This route therefore constitutes a synthesis of a protected form
of AETD in 14 steps and 1.0% overall yield from commercially
available starting materials.
Scheme 6
CONCLUSION
■
purification (Scheme 7), concluding the synthesis of a
protected derivative of APTO in 14 steps and 3.4% overall
yield from commercially available starting materials. Further-
more, the relative configuration within 42 was unambiguously
assigned via single crystal X-ray diffraction analysis,25 and the
determination of a Flack x parameter29 of −0.08(9) for the
crystal structure of 42 allowed the assigned absolute (S,S,S,S,E)-
configuration within 42 to be confirmed. In order to correlate
our synthesis with that of McLeod et al.,7 treatment of 42 with
BF3·OEt2 and DMP gave 66% conversion to 43 (i.e., the final
product in McLeod’s synthesis of the APTO fragment). After
purification, 43 was isolated in 37% yield and >99:1 dr; the
spectroscopic data for this sample of 43 were found to be
consistent with those reported previously.7 This route
produced 43 in superior yield when compared with the
In conclusion, the asymmetric syntheses of APTO and AETD,
the β-amino acid fragments within microsclerodermins C, D,
and E, were achieved using the conjugate addition of lithium
(R)-N-benzyl-N-(α-methylbenzyl)amide to tert-butyl (E,E)-7-
(triisopropylsilyloxy)hepta-2,4-dienoate and in situ enolate
oxidation with (−)-camphorsulfonyloxaziridine, diastereoselec-
tive dihydroxylation of a 2,3-syn-γ,δ-unsaturated-α-hydroxy-β-
amino ester derivative under Donohoe conditions, and a Julia−
́
Kocienski olefination as the key steps. Overall, APTO and
AETD (in protected form) were produced in 3.4 and 1.0%
yield, respectively, in 14 steps from commercially available
starting materials in each case.
EXPERIMENTAL SECTION
■
General Experimental Details. All reactions involving organo-
metallic or other moisture-sensitive reagents were carried out under a
nitrogen atmosphere using standard vacuum line techniques and
glassware that was flame-dried and cooled under nitrogen before use.
Solvents were dried according to the procedure outlined by Grubbs
and co-workers.31 BuLi was purchased as a solution in hexanes and
titrated against diphenylacetic acid before use. All other reagents were
used as supplied without prior purification. Organic layers were dried
́
Julia−Kocienski olefination of 41, which proceeded in only
28% conversion, giving 43 in 16% yield in addition to returning
starting material 41, which was isolated in 31% yield. While a
shorter enantiospecific route to an alternative protected form of
APTO has previously been reported,8 the yield of 42 obtained
via this strategy is comparable with that of 43 obtained by
McLeod et al.7 in their asymmetric synthesis.
Scheme 7
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over MgSO4. Thin layer chromatography was performed on aluminum
plates coated with 60 F254 silica. Plates were visualized using UV light
(254 nm), 1% aq KMnO4 or Dragendorff′s reagent. Flash column
chromatography was performed on Kieselgel 60 silica. Melting points
are uncorrected. Specific rotations are reported in 10−1 deg cm2 g−1
and concentrations in g/100 mL. IR spectra were recorded using an
ATR module. Selected characteristic peaks are reported in cm−1. NMR
spectra were recorded in the deuterated solvent stated. Spectra were
recorded at rt unless otherwise stated. The field was locked by external
referencing to the relevant deuteron resonance. When the
diastereotopic methyl groups of acetonide functionalities could not
be unambiguously assigned, the descriptor MeCMe was employed.
41.2 mmol) in THF (180 mL) at −78 °C, and stirring was continued
at −78 °C for 30 min. A solution of 20 (7.30 g, 20.6 mmol, >99:1 dr)
in THF (180 mL) was then added via cannula, and the reaction
mixture was stirred at −78 °C for 2 h. (−)-CSO 6 (9.44 g, 41.2 mmol)
was then added, the reaction mixture was allowed to warm to rt over
12 h, and then satd aq NH4Cl (20 mL) was added, and the resultant
mixture was concentrated in vacuo. The residue was partitioned
between Et2O (150 mL) and H2O (150 mL), and the aqueous layer
was extracted with Et2O (3 × 100 mL). The combined organic extracts
were washed sequentially with 10% aq citric acid (300 mL), satd aq
NaHCO3 (300 mL) and brine (300 mL) and then dried and
concentrated in vacuo to give 21 in >99:1 dr. Purification via flash
column chromatography (eluent 30−40 °C petrol/Et2O, 10:1) gave
21 as a pale yellow oil (10.3 g, 72%, >99:1 dr): [α]2D5 −41.2 (c 1.0 in
CHCl3); νmax (ATR) 3505 (O−H), 2941, 2866 (C−H), 1724 (CO)
, 1602 (CC); δH (400 MHz, CDCl3) 1.05−1.10 (21H, m,
Si(CHMe2)3), 1.33 (9H, s, CMe3), 1.37 (3H, d, J 6.8, C(α)Me),
2.29 (2H, app q, J 6.7, C(6)H2), 2.93 (1H, d, J 5.6, OH), 3.55 (1H, dd,
J 9.1, 2.7, C(3)H), 3.71 (2H, t, J 6.7, C(7)H2), 3.77 (1H, d, J 14.3,
NCHAHBPh), 3.97 (1H, d, J 14.3, NCHAHBPh), 4.08 (1H, dd, J 5.6,
2.7, C(2)H), 4.23 (1H, q, J 6.8, C(α)H), 5.60 (1H, dt, J 15.6, 6.7, C(5)
H), 5.75 (1H, dd, J 15.6, 9.1, C(4)H), 7.18−7.43 (10H, m, Ph); δC
(100 MHz, CDCl3) 12.0 (Si(CHMe2)3), 14.8 (C(α)Me), 18.1
(Si(CHMe2)3), 27.9 (CMe3), 36.5 (C(6)), 51.4 (NCH2Ph), 56.8
(C(α)), 63.0 (C(3)), 63.1 (C(7)), 74.5 (C(2)), 81.9 (CMe3), 126.6,
126.7 (p-Ph), 127.0 (C(4)), 128.0, 128.0, 128.2, 128.5 (o,m-Ph), 131.7
(C(5)), 141.6, 144.2 (i-Ph), 172.7 (C(1)); m/z (ESI+) 582 ([M + H]+,
100%); HRMS (ESI+) C35H56NO4Si+ ([M + H]+) requires 582.3973;
found 582.3972.
1
1
1H−1H COSY, H−13C HMQC, and H−13C HMBC analyses were
used to establish atom connectivity. Accurate mass measurements were
run on a TOF spectrometer internally calibrated with polyalanine.
4-Triisopropylsilyloxy-but-1-yne 18. Imidazole (14.6 g, 214
mmol), DMAP (350 mg, 2.85 mmol) and TIPSCl (15.3 mL, 71.3
mmol) were sequentially added to a solution of 17 (5.00 g, 71.3
mmol) in CH2Cl2 (500 mL) at rt, and the resultant solution was
stirred at rt for 16 h. The reaction mixture was then concentrated in
vacuo. The residue was dissolved in Et2O (500 mL), and the resultant
solution was washed with 1.0 M aq HCl (250 mL) and then dried and
concentrated in vacuo. Purification via flash column chromatography
(eluent 30−40 °C petrol) gave 18 as a colorless oil (14.8 g, 92%):32 δH
(400 MHz, CDCl3) 1.01−1.14 (21H, m, Si(CHMe2)3), 1.97 (1H, t, J
2.6, C(1)H), 2.45 (2H, td, J 7.3, 2.6, C(3)H2), 3.83 (2H, t, J 7.3,
C(4)H2).
(E)-1-Iodo-4-(triisopropylsilyloxy)but-1-ene 19. DIBAL-H
(1.0 M in THF, 9.72 mL, 9.72 mmol) was added to a solution of
Cp2ZrCl2 (2.84 g, 9.72 mmol) in THF (50 mL) at 0 °C. The reaction
mixture was stirred at 0 °C for 30 min, and then a solution of 18 (2.00
g, 8.83 mmol) in THF (12 mL) was added via cannula. The reaction
mixture was allowed to warm to rt, and stirring was continued until a
homogeneous solution resulted (ca. 30 min). The reaction mixture
was then cooled to −78 °C, and a solution of I2 (2.91 g, 11.4 mmol) in
THF (38 mL) was added via cannula. The reaction mixture was stirred
at −78 °C for 1 h, and then 1.0 M aq HCl (40 mL) was added, and the
resultant mixture was extracted with Et2O (2 × 40 mL). The
combined organic extracts were washed sequentially with satd aq
Na2S2O3 (40 mL) and satd aq NaHCO3 (40 mL) and then dried and
concentrated in vacuo. The residue was passed through a short plug of
silica gel (eluent 40−60 °C petrol/Et2O, 200:1) and then concentrated
in vacuo to give 19 as a pale yellow oil (2.46 g, 79%, >99:1 dr):33 δH
(400 MHz, CDCl3) 1.02−1.14 (21H, m, Si(CHMe2)3), 2.30 (2H, m,
C(3)H2), 3.73 (2H, t, J 6.5, C(4)H2), 6.09 (1H, d, J 14.4, C(1)H),
6.58 (1H, dt, J 14.4, 7.2, C(2)H).
tert-Butyl (E,E)-7-(triisopropylsilyloxy)hepta-2,4-dienoate
20. Pd(OAc)2 (68 mg, 0.30 mmol) was added to a solution of 19
(2.13 g, 6.01 mmol, >99:1 dr), tert-butyl acrylate (1.74 mL, 11.9
mmol), Ag2CO3 (1.82 g, 6.61 mmol) and Et3N (1.72 mL, 12.3 mmol)
in CH2Cl2 (30 mL) at rt, and the resultant mixture was stirred at rt for
16 h. Satd aq NaHCO3 (15 mL) was then added, and the resultant
mixture was extracted with Et2O (3 × 20 mL). The combined organic
extracts were then dried and concentrated in vacuo. Purification via
flash column chromatography (eluent 30−40 °C petrol/Et2O, 40:1)
gave 20 as a pale yellow oil (1.90 g, 89%, >99:1 dr): νmax (ATR) 2943,
2867 (C−H), 1710 (CO), 1645, 1618 (CC); δH (400 MHz,
CDCl3) 1.02−1.09 (21H, m, Si(CHMe2)3), 1.49 (9H, s, CMe3), 2.40
(2H, app q, J 6.5, C(6)H2), 3.76 (2H, t, J 6.5, C(7)H2), 5.73 (1H, d, J
15.4, C(2)H), 6.13 (1H, dt, J 15.4, 6.5, C(5)H), 6.22 (1H, dd, J 15.4,
10.3, C(4)H), 7.16 (1H, dd, J 15.4, 10.3, C(3)H); δC (125 MHz,
CDCl3) 10.2 (Si(CHMe2)3), 16.2 (Si(CHMe2)3), 26.4 (CMe3), 34.9
(C(6)), 60.7 (C(7)), 78.3 (CMe3), 119.8 (C(2)), 128.2 (C(4)), 138.4
(C(5)), 142.0 (C(3)), 164.9 (C(1)); m/z (ESI+) 377 ([M + Na]+,
100%); HRMS (ESI+) C20H38NaO3Si+ ([M + Na]+) requires
377.2482; found 377.2470.
tert-Butyl (R,R,R,E)-2,7-dihydroxy-3-[N-benzyl-N-(α-methyl-
benzyl)amino]hept-4-enoate 22. TBAF (1.0 M in THF, 15.0
mL, 15.0 mmol) was added dropwise to a stirred solution of 21 (1.74
g, 2.99 mmol, >99:1 dr) in THF (50 mL) at rt, and the resultant
mixture was stirred at rt for 16 h. The reaction mixture was diluted
with Et2O (50 mL) and washed with H2O (50 mL). The aqueous layer
was extracted with Et2O (3 × 50 mL), and the combined organic
extracts were dried and concentrated in vacuo. Purification via flash
column chromatography (eluent 30−40 °C petrol/Et2O, 1:1) gave 22
as a white crystalline solid (1.15 g, 90%, >99:1 dr): mp 61−65 °C;
[α]2D5 −53.8 (c 1.0 in CHCl3); νmax (ATR) 3474, 3318 (O−H), 3064,
3027, 2983, 2968, 2931, 2882 (C−H), 1730 (CO); δH (400 MHz,
CDCl3) 1.35 (9H, s, CMe3), 1.39 (3H, d, J 6.8, C(α)Me), 2.05 (1H, br
s, C(7)OH), 2.24−2.39 (2H, m, C(6)H2), 3.01 (1H, br s, C(2)OH),
3.52−3.60 (2H, m, C(3)H, C(7)HA), 3.61−3.69 (1H, m, C(7)HB),
3.85 (1H, d, J 14.4, NCHAHBPh), 4.04 (1H, d, J 14.4, NCHAHBPh),
4.17 (1H, app s, C(2)H), 4.24 (1H, q, J 6.8, C(α)H), 5.47 (1H, dt, J
15.4, 7.4, C(5)H), 5.85 (1H, dd, J 15.4, 9.4, C(4)H), 7.20−7.46 (10H,
m, Ph); δC (100 MHz, CDCl3) 14.9 (C(α)Me), 27.9 (CMe3), 36.1
(C(6)), 51.4 (NCH2Ph), 56.9 (C(α)), 61.4 (C(7)), 63.0 (C(3)), 74.8
(C(2)), 82.2 (CMe3), 126.7, 126.8 (p-Ph), 127.0, 128.1, 128.2, 128.4
(o,m-Ph), 129.2 (C(4)), 130.6 (C(5)), 141.4, 144.0 (i-Ph), 173.3
(C(1)); m/z (ESI+) 426 ([M + H]+, 100%); HRMS (ESI+)
+
C26H36NO4 ([M + H]+) requires 426.2639; found 426.2640.
tert-Butyl (R,R,R,E)-2-hydroxy-3-[N-benzyl-N-(α-methyl-
benzyl)amino]-7-iodohept-4-enoate 23. PPh3 (89 mg, 0.34
mmol) and imidazole (29 mg, 0.42 mmol) were added to a solution
of 22 (120 mg, 0.28 mmol, >99:1 dr) in PhMe and MeCN (v/v 4:1,
3.42 mL). I2 (86 mg, 0.34 mmol) was then added, and the resultant
mixture was heated to 60 °C for 1 h. The reaction mixture was allowed
to cool to rt and diluted with Et2O (5 mL), and then the resultant
solution was washed sequentially with satd aq Na2S2O3 (10 mL), H2O
(10 mL) and brine (10 mL). The organic layer was then dried and
concentrated in vacuo. Purification via flash column chromatography
(eluent 30−40 °C petrol/Et2O, 10:1) gave 23 as a colorless oil (129
mg, 85%, >99:1 dr): [α]D25 −55.5 (c 1.0 in CHCl3); νmax (ATR) 3499
(O−H), 3061, 3027, 2976, 2933 (C−H), 1722 (CO); δH (400
MHz, CDCl3) 1.36 (9H, s, CMe3), 1.42 (3H, d, J 6.8, C(α)Me), 2.56−
2.71 (2H, m, C(6)H2), 2.94 (1H, br s, OH), 3.16 (1H, dt, J 14.8, 7.2,
C(7)HA), 3.18 (1H, dt, J 14.8, 7.2, C(7)HB), 3.61 (1H, dd, J 9.1, 2.3,
C(3)H), 3.85 (1H, d, J 14.5, NCHAHBPh), 4.02 (1H, d, J 14.5,
tert-Butyl (R,R,R,E)-2-hydroxy-3-[N-benzyl-N-(α-methyl-
benzyl)amino]-7-(triisopropylsilyloxy)hept-4-enoate 21. BuLi
(2.45 M in THF, 16.3 mL, 39.9 mmol) was added dropwise to a
stirred solution of (R)-N-benzyl-N-(α-methylbenzyl)amine (8.70 g,
2505
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NCHAHBPh), 4.14 (1H, d, J 2.3, C(2)H), 4.28 (1H, q, J 6.8, C(α)H),
5.49 (1H, dt, J 15.4, 6.8, C(5)H), 5.83 (1H, dd, J 15.4, 9.1, C(4)H),
7.20−7.47 (10H, m, Ph); δC (100 MHz, CDCl3) 5.0 (C(7)), 15.3
(C(α)Me), 28.0 (CMe3), 36.5 (C(6)), 51.4 (NCH2Ph), 56.9 (C(α)),
62.7 (C(3)), 74.4 (C(2)), 82.1 (CMe3), 126.7, 126.7 (p-Ph), 128.0,
128.1, 128.2, 128.4 (o,m-Ph), 128.5 (C(4)), 132.7 (C(5)), 141.4, 144.2
(i-Ph), 172.7 (C(1)); m/z (ESI+) 536 ([M + H]+, 100%); HRMS
(ESI+) C26H35INO3+ ([M + H]+) requires 536.1656; found 536.1667.
{tert-Butyl (R,R,R,E)-2-hydroxy-3-[N-benzyl-N-(α-methyl-
benzyl)amino]hept-4-en-7-yl}triphenylphosphonium iodide
24. PPh3 (43 mg, 0.16 mmol) was added to a solution of 23 (88
mg, 0.16 mmol, >99:1 dr) in MeCN (4 mL) at rt, and the resultant
mixture was heated at reflux for 48 h. The reaction mixture was then
concentrated in vacuo to give 24 as a pale yellow solid (131 mg, quant,
>99:1 dr): mp 73−77 °C; [α]2D5 −47.3 (c 1.0 in CHCl3); νmax (ATR)
3324 (O−H), 3057, 3027, 2976, 2932, 2872 (C−H), 1730 (CO);
δH (400 MHz, CDCl3) 1.31 (9H, s, CMe3), 1.33 (3H, d, J 6.8,
C(α)Me), 2.32−2.44 (2H, m, C(6)H2), 2.96 (1H, br s, OH), 3.50−
3.68 (3H, m, C(3)H, C(7)H2), 3.82 (1H, d, J 14.9, NCHAHBPh), 3.88
(1H, d, J 14.9, NCHAHBPh), 4.05 (1H, app s, C(2)H), 4.10 (1H, q, J
6.8, C(α)H), 5.69 (1H, dd, J 15.4, 8.8, C(4)H), 5.86 (1H, dt, J 15.4,
6.6, C(5)H), 7.09−7.82 (25H, m, Ph); δC (100 MHz, CDCl3)
[selected peaks] 16.2 (C(α)Me), 22.6 (C(7)), 25.7 (C(6)), 28.0
(CMe3), 51.4 (NCH2Ph), 57.5 (C(α)), 62.3 (C(3)), 73.4 (C(2)), 82.3
(CMe3), 172.6 (C(1)); m/z (ESI+) 670 ([M]+, 100%); HRMS (ESI+)
C44H49NO3P+ ([M]+) requires 670.3445; found 670.3453.
9.0, C(4)H), 7.17−7.59 (15H, m, Ph); δC (125 MHz, CDCl3) 15.1
(C(α)Me), 27.9 (CMe3), 32.0 (C(6)), 32.8 (C(7)), 51.3 (NCH2Ph),
56.8 (C(α)), 62.6 (C(3)), 74.4 (C(2)), 82.1 (CMe3), 123.8, 127.9,
128.1, 128.2, 128.3, 129.8 (o,m-Ph), 126.7, 126.7, 130.1 (p-Ph), 129.1
(C(4)), 130.9 (C(5)), 133.6, 141.3, 144.0 (i-Ph), 154.2 (C(5′)), 172.6
(C(1)); m/z (ESI+) 608 ([M + Na]+, 100%); HRMS (ESI+)
C33H39N5NaO3S+ ([M + Na]+) requires 608.2666; found 608.2664.
tert-Butyl (R,R,R,E)-2-hydroxy-3-[N-benzyl-N-(α-methyl-
benzyl)amino]-7-(1′-phenyl-1H-tetrazol-5′-ylsulfonyl)hept-4-
enoate 27. (NH4)6Mo7O24·4H2O (48 mg, 0.04 mmol) was dissolved
in 30% aq H2O2 (0.33 mL, 2.89 mmol) at 0 °C, and the resultant
solution was added dropwise to a solution of 26 (113 mg, 0.19 mmol,
>99:1 dr) in EtOH (3 mL) at 0 °C. The resultant suspension was
allowed to warm to rt, stirred at rt for 16 h, and then added to brine
(10 mL). The reaction mixture was then extracted with EtOAc (3 × 20
mL), and the combined organic extracts were dried and concentrated
in vacuo. Purification via flash column chromatography (eluent 30−40
°C petrol/Et2O, 2:1) gave 27 as a pale yellow oil (69 mg, 58%, >99:1
dr): [α]2D5 −46.9 (c 1.0 in CHCl3); νmax (ATR) 3507 (O−H), 3062,
3028, 2977, 2934 (C−H), 1722 (CO), 1345, 1150 (SO); δH
(400 MHz, CDCl3) 1.35 (9H, s, CMe3), 1.37 (3H, d, J 6.8, C(α)Me),
2.65−2.80 (2H, m, C(6)H2), 2.93 (1H, br s, OH), 3.61 (1H, dd, J 9.1,
2.3, C(3)H), 3.72−3.78 (2H, m, C(7)H2), 3.86 (1H, d, J 14.7,
NCHAHBPh), 3.98 (1H, d, J 14.7, NCHAHBPh), 4.15 (1H, app s,
C(2)H), 4.23 (1H, q, J 6.8, C(α)H), 5.56 (1H, dt, J 15.4, 6.8, C(5)H),
5.89 (1H, dd, J 15.4, 9.1, C(4)H), 7.20−7.73 (15H, m, Ph); δC (100
MHz, CDCl3) 15.7 (C(α)Me), 25.3 (C(6)), 28.0 (CMe3), 51.3
(NCH2Ph), 55.4 (C(7)), 57.0 (C(α)), 62.3 (C(3)), 74.2 (C(2)), 82.3
(CMe3), 125.0, 127.9, 128.1, 128.3, 128.3, 129.8 (o,m-Ph), 126.7,
126.8, 131.5 (p-Ph), 127.9 (C(5)), 130.1 (C(4)), 133.0, 141.4, 143.8
(i-Ph), 153.4 (C(5′)), 172.6 (C(1)); m/z (ESI+) 640 ([M + Na]+,
100%); HRMS (ESI+) C33H39N5NaO5S+ ([M + Na]+) requires
640.2564; found 640.2546.
tert-Butyl (2S,3R,αR,E,E)-2-hydroxy-3-[N-benzyl-N-(α-
methylbenzyl)amino]-8-phenylocta-4,7-dienoate 29. Step 1.
DMSO (0.43 mL, 6.82 mmol) was added dropwise to a stirred
solution of (COCl)2 (51 μL, 0.60 mmol) in CH2Cl2 (2 mL) at −78
°C, and the resultant mixture was stirred at −78 °C for 5 min. A
solution of 25 (150 mg, 0.30 mmol, >99:1 dr) in CH2Cl2 (2 mL) was
then added via cannula, and the reaction mixture was stirred at −78 °C
for 30 min. Et3N (0.17 mL, 1.20 mmol) was then added, and stirring
was continued at −78 °C for a further 10 min. The reaction mixture
was allowed to warm to rt over 20 min. H2O (20 mL) was added, and
the reaction mixture was extracted with CH2Cl2 (3 × 50 mL). The
combined organic extracts were then dried and concentrated in vacuo
to give 28 as a yellow oil (175 mg, >99:1 dr): m/z (ESI+) 496
([M + H]+, 100%).
Step 2. The residue of 28 (175 mg, >99:1 dr) was dissolved in
MeOH (6 mL), and the resultant solution was cooled to −20 °C.
NaBH4 (11 mg, 0.30 mmol) was then added, and the reaction mixture
was stirred at −20 °C for 2 h. The reaction mixture was then allowed
to warm to rt and concentrated in vacuo. The residue was partitioned
between H2O (30 mL) and Et2O (30 mL), and the aqueous layer was
extracted with Et2O (3 × 50 mL). The combined organic extracts were
then dried and concentrated in vacuo to give 29 in >99:1 dr.
Purification via flash column chromatography (gradient elution, 20:1
→ 10:1 30−40 °C petrol/Et2O) gave 29 as a pale yellow oil (37 mg,
25% from 25, >99:1 dr): [α]2D5 −37.5 (c 1.0 in CHCl3); νmax (ATR)
3387 (O−H), 3027, 2977, 2932 (C−H), 1736 (CO), 1585 (CC)
; δH (500 MHz, CDCl3) 1.36 (9H, s, CMe3), 1.48 (3H, d, J 6.9,
C(α)Me), 2.98−3.03 (2H, m, C(6)H2), 3.37−3.44 (1H, m, C(3)H),
3.68 (1H, d, J 13.6, NCHAHBPh), 3.88 (1H, d, J 13.6, NCHAHBPh),
3.90 (1H, d, J 9.1, C(2)H), 4.12 (1H, q, J 6.9, C(α)H), 5.65−5.75
(2H, m, C(4)H, C(5)H), 6.22 (1H, dt, J 15.8, 6.8, C(7)H), 6.46 (1H,
d, J 15.8, C(8)H), 7.21−7.39 (15H, m, Ph); δC (125 MHz, CDCl3)
14.8 (C(α)Me), 27.9 (CMe3), 36.0 (C(6)), 50.2 (NCH2Ph), 56.5
(C(α)), 62.6 (C(3)), 71.8 (C(2)), 81.3 (CMe3), 126.8 (C(4)), 127.2,
127.2, 127.3 (p-Ph), 127.5 (C(7)), 126.0, 127.8, 128.4, 128.5, 128.5,
129.0 (o,m-Ph), 131.3 (C(8)), 133.9 (C(5)), 137.4, 139.4, 143.2 (i-
tert-Butyl (R,R,R,E,E)-2-hydroxy-3-[N-benzyl-N-(α-methyl-
benzyl)amino]-8-phenylocta-4,7-dienoate 25. KHMDS (0.5 M
in PhMe, 0.47 mL, 0.24 mmol) was added dropwise to a solution of 27
(66 mg, 0.11 mmol, >99:1 dr) and PhCHO (13 μL, 0.13 mmol) in
THF (2.5 mL) at −78 °C, and the resultant mixture was stirred at −78
°C for 30 min. H2O (2 mL) was then added, and the reaction mixture
was allowed to warm to rt. The aqueous layer was then extracted with
Et2O (3 × 10 mL), and the combined organic extracts were washed
sequentially with satd aq NH4Cl (20 mL) and brine (20 mL) and then
dried and concentrated in vacuo to give 25 in >99:1 dr. Purification via
flash column chromatography (eluent 30−40 °C petrol/Et2O, 10:1)
gave 25 as a pale yellow oil (35 mg, 66%, >99:1 dr): [α]2D5 −49.6 (c 1.0
in CHCl3); νmax (ATR) 3499 (O−H), 3083, 3066, 3026, 2977, 2933,
2824 (C−H), 1722 (CO), 1600 (CC); δH (500 MHz, CDCl3)
1.33 (9H, s, CMe3), 1.40 (3H, d, J 6.8, C(α)Me), 2.96 (2H, app t, J 6.6,
C(6)H2), 3.61 (1H, dd, J 9.1, 2.5, C(3)H), 3.83 (1H, d, J 14.5,
NCHAHBPh), 3.99 (1H, d, J 14.5, NCHAHBPh), 4.14 (1H, d, J 2.5,
C(2)H), 4.26 (1H, q, J 6.8, C(α)H), 5.58 (1H, dt, J 15.5, 6.6, C(5)H),
5.79 (1H, dd, J 15.5, 9.1, C(4)H), 6.17 (1H, dt, J 15.9, 6.6, C(7)H),
6.41 (1H, d, J 15.9, C(8)H), 7.18−7.45 (15H, m, Ph); δC (125 MHz,
CDCl3) 15.1 (C(α)Me), 27.9 (CMe3), 36.0 (C(6)), 51.4 (NCH2Ph),
56.9 (C(α)), 62.9 (C(3)), 74.5 (C(2)), 82.0 (CMe3), 126.6, 126.7,
127.0 (p-Ph), 127.0 (C(4)), 126.0, 127.9, 128.0, 128.2, 128.4, 128.5
(o,m-Ph), 128.1 (C(7)), 130.9 (C(8)), 132.4 (C(5)), 137.5, 141.5,
144.1 (i-Ph), 172.7 (C(1)); m/z (ESI+) 498 ([M + H]+, 100%);
+
HRMS (ESI+) C33H40NO3 ([M + H]+) requires 498.3003; found
498.3011.
tert-Butyl (R,R,R,E)-2-hydroxy-3-[N-benzyl-N-(α-methyl-
benzyl)amino]-7-(1′-phenyl-1H-tetrazol-5′-ylthio)hept-4-
enoate 26. DEAD (48 μL, 0.31 mmol) was added dropwise to a
solution of 22 (100 mg, 0.23 mmol, >99:1 dr), PTSH (50 mg, 0.28
mmol) and PPh3 (74 mg, 0.28 mmol) in THF (2 mL) at 0 °C, and the
resultant mixture was allowed to warm to rt over 16 h. EtOAc (10 mL)
was then added, and the reaction mixture was washed sequentially with
brine (10 mL) and H2O (10 mL) and then dried and concentrated in
vacuo. Purification via flash column chromatography (eluent 30−40
°C petrol/Et2O, 2:1) gave 26 as a colorless oil (113 mg, 82%, >99:1
dr): [α]2D5 −53.2 (c 1.0 in CHCl3); νmax (ATR) 3493 (O−H), 3061,
3027, 2976, 2933 (C−H), 1722 (CO); δH (500 MHz, CDCl3) 1.31
(9H, s, CMe3), 1.32 (3H, d, J 6.9, C(α)Me), 2.59 (2H, app q, J 7.1,
C(6)H2), 2.87 (1H, d, J 4.4, OH), 3.45 (2H, t, J 7.1, C(7)H2), 3.57
(1H, dd, J 9.0, 2.2, C(3)H), 3.77 (1H, d, J 14.5, NCHAHBPh), 3.96
(1H, d, J 14.5, NCHAHBPh), 4.10 (1H, app br s, C(2)H), 4.21 (1H, q,
J 6.9, C(α)H), 5.54 (1H, dt, J 15.5, 7.1, C(5)H), 5.82 (1H, dd, J 15.5,
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Ph), 171.4 (C(1)); m/z (ESI+) 498 ([M + H]+, 100%); HRMS (ESI+)
(10H, m, Ph); δC (125 MHz, CDCl3) 11.7 (Si(CHMe2)3), 17.9
(Si(CHMe2)3), 18.1 (C(α)Me), 35.2 (C(6)), 50.0 (NCH2Ph), 60.1
(C(α)), 62.3 (C(7)), 64.1 (C(3)), 68.8 (C(2)), 69.1 (C(5)), 82.7
(C(4)), 127.2, 127.5 (p-Ph), 127.9, 128.0, 128.4, 128.6 (o,m-Ph),
140.2, 142.8 (i-Ph), 175.7 (C(1)); m/z (ESI+) 564 ([M + Na]+,
100%); HRMS (ESI+) C31H47NNaO5Si+ ([M + Na]+) requires
564.3116; found 564.3115.
+
C33H40NO3 ([M + H]+) requires 498.3003; found 498.3007.
tert-Butyl (2S,3R,αR,E)-2-hydroxy-3-[N-benzyl-N-(α-methyl-
benzyl)amino]-7-(triisopropylsilyloxy)hept-4-enoate 31. Step
1. DMSO (1.22 mL, 17.2 mmol) was added dropwise to a stirred
solution of (COCl)2 (0.15 mL, 1.72 mmol) in CH2Cl2 (6 mL) at −78
°C, and the resultant mixture was stirred at −78 °C for 5 min. A
solution of 21 (500 mg, 0.86 mmol, >99:1 dr) in CH2Cl2 (6 mL) was
then added via cannula, and the reaction mixture was stirred at −78 °C
for 30 min. Et3N (0.45 mL, 3.43 mmol) was then added, and stirring
was continued at −78 °C for a further 10 min. The reaction mixture
was allowed to warm to rt over 20 min. H2O (20 mL) was added, and
the reaction mixture was extracted with CH2Cl2 (3 × 50 mL). The
combined organic extracts were then dried and concentrated in vacuo
to give 30 as a yellow oil (570 mg, >99:1 dr): δH (400 MHz, CDCl3)
1.04−1.09 (21H, m, Si(CHMe2)3), 1.39 (3H, d, J 6.8, C(α)Me), 1.46
(9H, s, CMe3), 2.32 (2H, app q, J 6.6, C(6)H2), 3.70 (2H, t, J 6.6,
C(7)H2), 3.81 (1H, d, J 14.6, NCHAHBPh), 3.88 (1H, d, J 14.6,
NCHAHBPh), 4.02 (1H, q, J 6.8, C(α)H), 4.60 (1H, d, J 8.1, C(3)H),
5.66 (1H, dt, J 15.9, 6.6, C(5)H), 5.75 (1H, dd, J 15.9, 8.1, C(4)H),
7.20−7.37 (10H, m, Ph); m/z (ESI+) 580 ([M + H]+, 100%).
Step 2. The residue of 30 (570 mg, >99:1 dr) was dissolved in
MeOH (6 mL), and the resultant solution was cooled to −20 °C.
NaBH4 (33 mg, 0.86 mmol) was added portionwise, and the reaction
mixture was then stirred at −20 °C for 2 h. The reaction mixture was
then allowed to warm to rt and concentrated in vacuo. The residue
was partitioned between H2O (30 mL) and Et2O (30 mL), and the
aqueous layer was extracted with Et2O (3 × 50 mL). The combined
organic extracts were then dried and concentrated in vacuo to give 31
in >99:1 dr. Purification via flash column chromatography (gradient
elution, 20:1 → 10:1 30−40 °C petrol/Et2O) gave 31 as a pale yellow
oil (333 mg, 67% from 21, >99:1 dr): [α]2D5 −49.6 (c 1.0 in CHCl3);
νmax (ATR) 3439 (O−H), 3087, 3062, 3028, 2942, 2892, 2866 (C−H)
, 1733 (CO), 1630 (CC); δH (400 MHz, CDCl3) 1.08−1.15
(21H, m, Si(CHMe2)3), 1.36 (9H, s, CMe3), 1.47 (3H, d, J 6.8,
C(α)Me), 2.30−2.40 (2H, m, C(6)H2), 3.33−3.40 (1H, m, C(3)H),
3.66 (1H, d, J 13.3, NCHAHBPh), 3.75−3.81 (3H, m, C(7)H2, OH),
3.86 (1H, d, J 13.3, NCHAHBPh), 3.88 (1H, d, J 6.6, C(2)H), 4.11
(1H, q, J 6.8, C(α)H), 5.63−5.75 (2H, m, C(4)H, C(5)H), 7.20−7.36
(10H, m, Ph); δC (100 MHz, CDCl3) 12.0 (Si(CHMe2)3), 14.7
(C(α)Me), 18.0 (Si(CHMe2)3), 27.9 (CMe3), 36.6 (C(6)), 50.1
(NCH2Ph), 56.5 (C(α)), 62.6 (C(3)), 62.9 (C(7)), 71.8 (C(2)), 81.1
(CMe3), 127.2 (C(4)), 127.2, 127.2 (p-Ph), 127.8, 128.4, 128.5, 129.1
(o,m-Ph), 133.3 (C(5)), 139.5, 143.3 (i-Ph), 171.5 (C(1)); m/z (ESI+)
582 ([M + H]+, 100%); HRMS (ESI+) C35H56NO4Si+ ([M + H]+)
requires 582.3973; found 582.3969.
(S,S,S,S)-2,5-Dihydroxy-3-(N-tert-butoxycarbonylamino)-7-
(triisopropylsilyloxy)-4-heptylolactone 34. Pd/C (50% w/w of
substrate, 204 mg) was added to a stirred solution of 33 (408 mg,
0.753 mmol, >99:1 dr) and Boc2O (181 mg, 0.829 mmol) in MeOH
(10 mL) at rt. The resultant mixture was degassed and saturated with
H2 and then left to stir under an atmosphere of H2 (1 atm) for 18 h.
The reaction mixture was then filtered through a short plug of Celite
(eluent MeOH), and the filtrate was concentrated in vacuo.
Purification via flash column chromatography (gradient elution, 3:1
→ 2:1 30−40 °C petrol/EtOAc) gave 34 as a colorless oil (232 mg,
69%, >99:1 dr): [α]D25 +10.9 (c 1.0 in CHCl3); νmax (ATR) 3366
(O−H), 2943, 2867 (C−H), 1782, 1689 (CO); δH (500 MHz,
CDCl3) 1.01−1.15 (21H, m, (Si(CHMe2)3), 1.45 (9H, s, CMe3),
1.70−1.80 (1H, m, C(6)HA), 1.90−2.01 (1H, m, C(6)HB), 3.91−4.04
(2H, m, C(7)H2), 4.05−4.18 (2H, m, C(3)H, C(5)H), 4.23−4.29
(1H, m, C(4)H), 4.51 (1H, d, J 7.6, C(2)H), 4.69 (1H, br s, OH), 5.47
(1H, br s, NH); δC (125 MHz, CDCl3) 11.7 (Si(CHMe2)3), 17.9
(Si(CHMe2)3), 28.2 (CMe3), 33.5 (C(6)), 56.4 (C(3)), 61.8 (C(7)),
69.6 (C(5)), 72.7 (C(2)), 81.1 (CMe3), 81.3 (C(4)), 156.4 (NCO),
173.6 (C(1)); m/z (ESI+) 470 ([M + Na]+, 100%); HRMS (ESI+)
C21H41NNaO7Si+ ([M + Na]+) requires 470.2545; found 470.2531.
(S,S,S,S)-2,5,7-Trihydroxy-3-(N-tert-butoxycarbonylamino)-
4-heptylolactone 35. Method A (from 34). TBAF (1.0 M in THF,
0.32 mL, 0.32 mmol) was added dropwise to a stirred solution of 34
(121 mg, 0.27 mmol, >99:1 dr) in THF (4 mL) at rt, and the resultant
mixture was stirred at rt for 1 h. The reaction mixture was then diluted
with Et2O (10 mL) and washed with H2O (10 mL). The aqueous layer
was extracted with Et2O (3 × 10 mL), and the combined organic
extracts were dried and concentrated in vacuo. Purification via flash
column chromatography (eluent EtOAc) gave 35 as a colorless oil (15
mg, 19%, >99:1 dr):28 [α]D25 +21.8 (c 1.0 in MeOH); νmax (ATR) 3347
(O−H), 2977, 2934 (C−H), 1778, 1689 (CO); δH (500 MHz,
MeOH-d4) 1.48 (9H, s, CMe3), 1.72−1.92 (2H, m, C(6)H2), 3.70−
3.77 (2H, m, C(7)H2), 3.86−3.92 (1H, m, C(5)H), 4.10 (1H, dd, J
9.6, 2.2, C(4)H), 4.27 (1H, app t, J 9.6, C(3)H), 4.49 (1H, d, J 9.6,
C(2)H); δC (125 MHz, MeOH-d4) 28.7 (CMe3), 37.0 (C(6)), 56.6
(C(3)), 59.6 (C(7)), 66.8 (C(5)), 72.9 (C(2)), 80.9 (CMe3), 82.9
(C(4)), 158.0 (NCO), 176.1 (C(1)); m/z (ESI+) 314 ([M + Na]+,
+
100%); HRMS (ESI+) C12H21NNaO7 ([M + Na]+) requires
314.1210; found 314.1213.
(2S,3S,4S,5S,αR)-2,5-Dihydroxy-3-[N-benzyl-N-(α-methyl-
benzyl)amino]-7-(triisopropylsilyloxy)-4-heptylolactone 33.
Step 1. OsO4 (265 mg, 1.04 mmol) was added to a stirred solution
of 31 (552 mg, 0.95 mmol, >99:1 dr) and TMEDA (0.21 mL, 1.34
mmol) in CH2Cl2 (40 mL) at −78 °C, and the resultant mixture was
stirred at −78 °C for 1 h. The reaction mixture was allowed to warm
to rt over 15 min and was then concentrated in vacuo. The residue was
then passed through a short plug of silica gel (eluent CH2Cl2/MeOH,
20:1) and concentrated in vacuo.
Method B (from 36). Pd/C (50% w/w of substrate, 258 mg) was
added to a stirred solution of 36 (516 mg, 1.34 mmol, >99:1 dr), and
Boc2O (321 mg, 1.47 mmol) in MeOH (10 mL) at rt. The resultant
mixture was degassed, saturated with H2, and then left to stir under an
atmosphere of H2 (1 atm) for 18 h. The reaction mixture was then
filtered through a short plug of Celite (eluent MeOH), and the filtrate
was concentrated in vacuo to give 35 as a yellow oil (390 mg, quant,
>99:1 dr).
Step 2. The residue was dissolved in CH2Cl2 (150 mL), and then
P(CH2OH)3 (5.89 g, 47.5 mmol)34 and Et3N (2.64 mL, 19.0 mmol)
were added sequentially. The reaction mixture was stirred at rt for 5
min, and then SiO2 (∼2.0 g) was added. The resultant mixture was
stirred at rt for 48 h and then concentrated in vacuo. Purification via
flash column chromatography (eluent 30−40 °C petrol/EtOAc, 3:1)
gave 33 as a colorless oil (272 mg, 53%, >99:1 dr): [α]2D5 +36.6 (c 1.0
in CHCl3); νmax (ATR) 3454 (O−H), 3086, 3062, 3030, 2942, 2891,
2866 (C−H), 1770 (CO); δH (500 MHz, CDCl3) 1.07−1.14 (21H,
m, (Si(CHMe2)3), 1.47 (3H, d, J 6.9, C(α)Me), 1.56−1.63 (1H, m,
C(6)HA), 1.91−2.00 (1H, m, C(6)HB), 2.92 (1H, d, J 6.3, C(2)OH),
3.45 (1H, d, J 3.8, C(5)OH), 3.79 (1H, d, J 14.8, NCHAHBPh), 3.83
(1H, d, J 14.8, NCHAHBPh), 3.89−3.95 (3H, m, C(3)H, C(4)H,
C(7)HA), 3.99−4.04 (1H, m, C(7)HB), 4.09 (1H, q, J 6.9, C(α)H),
4.13−4.18 (1H, m, C(5)H), 4.28−4.33 (1H, m, C(2)H), 7.21−7.46
(2S,3S,4S,5S,αR)-2,5,7-Trihydroxy-3-[N-benzyl-N-(α-methyl-
benzyl)amino]-4-heptylolactone 36. Method A. TBAF (1.0 M in
THF, 0.20 mL, 0.20 mmol) was added dropwise to a stirred solution
of 33 (92 mg, 0.17 mmol, >99:1 dr) in THF (4 mL) at rt, and the
resultant mixture was stirred at rt for 1 h. The reaction mixture was
then diluted with Et2O (10 mL) and washed with H2O (10 mL). The
aqueous layer was extracted with Et2O (3 × 10 mL), and the
combined organic extracts were dried and concentrated in vacuo.
Purification via flash column chromatography (eluent 30−40 °C
petrol/EtOAc, 1:2) gave 36 as a pale yellow oil (30 mg, 46%, >99:1
dr): [α]2D5 +22.7 (c 1.0 in CHCl3); νmax (ATR) 3362 (O−H), 2933
(C−H), 1769 (CO); δH (500 MHz, C6D6) 1.29−1.34 (1H, m,
C(6)HA), 1.35 (3H, d, J 6.9, C(α)Me), 1.63−1.71 (2H, m, C(6)HB,
C(7)OH), 2.55 (1H, d, J 6.3, C(5)OH), 2.78 (1H, d, J 4.9, C(2)OH),
3.32−3.39 (1H, m, C(7)HA), 3.41−3.48 (1H, m, C(7)HB), 3.57 (1H,
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d, J 15.1, NCHAHBPh), 3.61 (1H, d, J 15.1, NCHAHBPh), 3.70 (1H,
dd, J 8.1, 1.4, C(4)H), 3.98−4.03 (1H, m, C(5)H), 4.04 (1H, app t, J
8.1, C(3)H), 4.09 (1H, q, J 6.9, C(α)H), 4.32 (1H, dd, J 8.1, 4.9, C(2)
H), 7.10−7.49 (10H, m, Ph); δC (125 MHz, C6D6) [selected peaks]
19.0 (C(α)Me), 35.5 (C(6)), 50.1 (NCH2Ph), 60.7 (C(7)), 61.4
(C(α)), 64.9 (C(3)), 68.5 (C(5)), 68.8 (C(2)), 81.3 (C(4)), 141.4,
143.8 (i-Ph), 175.2 (C(1)); m/z (ESI+) 408 ([M + Na]+, 100%);
HRMS (ESI+) C22H27NNaO5+ ([M + Na]+) requires 408.1781; found
408.1769.
Method B. HF·pyridine solution (70%, 1.27 mL, 49.3 mmol) was
added dropwise to a stirred solution of 33 (922 mg, 1.70 mmol, >99:1
dr) in THF (6 mL) at 0 °C. The resultant solution was allowed to
warm to rt, stirred at rt for 16 h, and then neutralized by the dropwise
addition of satd aq NaHCO3 (∼50 mL). The reaction mixture was
extracted with EtOAc (3 × 100 mL), and the combined organic
extracts were then dried and concentrated in vacuo. The residue was
passed through a short plug of silica gel (eluent 30−40 °C petrol/
EtOAc, 1:2) and concentrated in vacuo to give 36 as a pale yellow oil
(579 mg, 88%, >99:1 dr).
Data for mixture: mp 177−181 °C; νmax (ATR) 3514, 3415, 3385
(N−H, O−H), 2985, 2953, 2913 (C−H), 1740, 1668 (CO), 1332,
1151 (SO); m/z (ESI+) 538 ([M(39) + Na]+, 100%), 506 ([M(38)
+ Na]+, 100%); HRMS (ESI+) C20H28N5Na2O9S+ ([M(39) − H +
2Na]+) requires 560.1398; found 560.1383; HRMS (ESI+)
C19H25N5NaO8S+ ([M(38) + Na]+) requires 506.1316; found
506.1308.
Methyl (S,S,S,S)-2,4,5-trihydroxy-3-(N-tert-butoxycarbonyla-
mino)-4,5-O-isopropylidine-7-[N(1′)-phenyl-1H-tetrazol-5′-
ylsulfonyl]heptanoate 40 and (5S,4R,1′S,2′S)-2,2-Dimethyl-
N(3)-(tert-butoxycarbonyl)-4-(1′,2′-dihydroxy-1′,2′-O-isopro-
pylidene-4′-{[N(1″)-phenyl-1H-tetrazol-5″-yl]sulfonyl}but-1′-
yl)-5-methoxycarbonyloxazolidine 41. Method A. PPTS (5 mg,
cat.) was added to a solution of an 80:20 mixture of 39 and 38 (50
mg) in acetone (2.5 mL) at rt. The resultant mixture was then heated
at reflux for 24 h. The reaction mixture was allowed to cool to rt,
NaHCO3 was then added until pH 7 was achieved, and the reaction
mixture was filtered and concentrated in vacuo to give an 83:17
mixture of 40 and 41. Purification via flash column chromatography
(gradient elution, 5:1 → 2:1 30−40 °C petrol/EtOAc) gave 41 as a
colorless oil (7 mg, 3% from 35, >99:1 dr):35 [α]D25 −5.7 (c 0.6 in
CHCl3); νmax (ATR) 2984, 2938 (C−H), 1740, 1691 (CO), 1369,
1153 (SO); δH (500 MHz, CDCl3) 1.40 (6H, app s, 2 × MeCMe),
1.47 (9H, s, CMe3), 1.56 (3H, s, MeCMe), 1.60 (3H, s, MeCMe),
2.11−2.21 (1H, m, C(3′)HA), 2.23−2.34 (1H, m, C(3′)HB), 3.78−
3.92 (2H, m, C(1′)H, C(4′)HA), 3.80 (3H, s, OMe), 3.96−4.06 (1H,
m, C(4′)HB), 4.23−4.32 (1H, m, C(2′)H), 4.49 (1H, app br s,
C(4)H), 4.72 (1H, app br s, C(5)H), 7.57−7.75 (5H, m, Ph); δC (125
MHz, CDCl3) 26.0 (C(3′)), 26.9, 27.2, 27.2, 27.3 (4 × MeCMe), 28.3
(CMe3), 52.6 (OMe), 53.3 (C(4′)), 61.4 (C(4)), 75.0 (C(5)), 76.4
(C(2′)), 80.3 (C(1′)), 81.4 (CMe3), 96.5 (C(2)), 109.4 (MeCMe),
125.1, 129.7 (o,m-Ph), 131.5 (p-Ph), 133.0 (i-Ph), 152.3 (NCO), 154.4
(C(5″)), 171.8 (CO2Me); m/z (ESI+) 618 ([M + Na]+, 100%);
HRMS (ESI+) C26H37N5NaO9S+ ([M + Na]+) requires 618.2204;
found 618.2181. Further elution gave 40 as a white solid (20 mg, 11%
from 35, >99:1 dr): mp 143−146 °C; [α]2D5 −3.0 (c 1.0 in CHCl3);
νmax (ATR) 3388 (O−H, N−H), 2984, 2936 (C−H), 1741, 1712
(CO), 1341, 1156 (SO); δH (400 MHz, CDCl3) 1.40 (9H, s,
CMe3), 1.42 (6H, app s, 2 × MeCMe), 2.11−2.21 (1H, m, C(6)HA),
2.27−2.36 (1H, m, C(6)HB), 3.11 (1H, br s, OH), 3.77 (1H, dd, J 9.6,
7.0, C(4)H), 3.78−3.84 (1H, m, C(7)HA), 3.81 (3H, s, OMe), 3.98
(1H, app ddd, J 15.3, 11.5, 4.4, C(7)HB), 4.16−4.22 (2H, m, C(3)H,
C(5)H), 4.57 (1H, app br s, C(2)H), 4.91 (1H, d, J 10.1, NH), 7.58−
7.72 (5H, m, Ph); δC (125 MHz, CDCl3) 26.9 (C(6)), 27.0, 27.3 (2 ×
MeCMe), 28.1 (CMe3), 53.0 (C(7)), 53.0 (OMe), 55.2 (C(5)), 69.8
(C(2)), 77.4 (C(3)), 78.7 (C(4)), 80.5 (CMe3), 109.8 (MeCMe),
125.0, 129.7 (o,m-Ph), 131.5 (p-Ph), 133.0 (i-Ph), 153.3 (C(5′)), 155.2
(NCO), 173.8 (C(1)); m/z (ESI+) 578 ([M + Na]+, 100%); HRMS
(ESI+) C23H33N5NaO9S+ ([M + Na]+) requires 578.1891; found
578.1894.
Method B. BF3 (1.0 M in Et2O, ∼2 drops) was added dropwise to a
solution of an 80:20 mixture of 39 and 38 (30 mg) and DMP (0.4
mL) in acetone (2.0 mL) at rt until a permanent color change from
colorless to dark orange was observed. The resultant mixture was
stirred at rt for 18 h. Et3N (∼0.1 mL) was added until pH 7 was
achieved, and the reaction mixture was then concentrated in vacuo
gave a 74:26 mixture of 40 and 41. Purification via flash column
chromatography (gradient elution, 5:1 → 2:1 30−40 °C petrol/
EtOAc) gave 41 as a colorless oil (6 mg, 5% from 35, >99:1 dr) and 40
as a white solid (9 mg, 8% from 35, >99:1 dr).
Method C. TsOH·H2O (6 mg, cat.) was added to a solution of an
80:20 mixture of 39 and 38 (32 mg) in acetone (2.8 mL) and DMP
(0.2 mL) at rt, and the resultant solution was then heated at 40 °C for
24 h. The reaction mixture was allowed to cool to rt, and solid
Na2CO3 was then added until pH 7 was achieved. The resultant
mixture was then filtered and concentrated in vacuo to give an 80:20
mixture of 40 and 41. Purification via flash column chromatography
(gradient elution, 5:1 → 2:1 30−40 °C petrol/EtOAc) gave 41 as a
colorless oil (7 mg, 6% from 35, >99:1 dr). Further elution gave 40 as
a white solid (24 mg, 21% from 35, >99:1 dr).
(S,S,S,S)-2,5-Dihydroxy-3-(N-tert-butoxycarbonylamino)-7-
(1′-phenyl-1H-tetrazol-5′-ylthio)-4-heptylolactone 37. DEAD
(98 μL, 0.62 mmol) was added dropwise to a solution of 35 (140
mg, 0.48 mmol, >99:1 dr), PTSH (103 mg, 0.58 mmol) and PPh3
(151 mg, 0.58 mmol) in THF (6 mL) at 0 °C, and the resultant
mixture was allowed to warm to rt over 16 h. EtOAc (10 mL) was then
added, and the reaction mixture was washed sequentially with brine
(10 mL) and H2O (10 mL) and then dried and concentrated in vacuo.
Purification via flash column chromatography (gradient elution, 10:1
→ 2:1 30−40 °C petrol/acetone) gave a sample of 37 contaminated
with Ph3PO (258 mg): δH (400 MHz, MeOH-d4) [selected peaks]
1.41 (9H, s, CMe3), 2.03−2.18 (2H, m, C(6)H2), 3.40−3.51 (1H, m,
C(7)HA), 3.55−3.65 (1H, m, C(7)HB), 3.86−3.94 (1H, m, C(5)H),
4.10−4.16 (1H, m, C(4)H), 4.33 (1H, app t, J 9.8, C(3)H), 4.55 (1H,
d, J 9.8, C(2)H); δC (100 MHz, MeOH-d4) [selected peaks] 27.8
(CMe3), 30.0 (C(6)), 33.0 (C(7)), 55.7 (C(3)), 67.5 (C(5)), 71.9
(C(2)), 79.9 (CMe3), 81.7 (C(4)), 155.0 (C(5′)), 156.9 (NCO), 174.9
(C(1)); m/z (ESI+) 474 ([M + Na]+, 100%); HRMS (ESI+)
C19H25N5NaO6S+ ([M + Na]+) requires 474.1418; found 474.1405.
(S,S,S,S)-2,5-Dihydroxy-3-(N-tert-butoxycarbonylamino)-7-
[N(1′)-phenyl-1H-tetrazol-5′-ylsulfonyl]-4-heptylolactone 38
and Methyl (2S,3R,4S,5S)-2,4,5-trihydroxy-3-(N-tert-butoxycar-
bonylamino)-7-[N(1′)-phenyl-1H-tetrazol-5′-ylsulfonyl]heptan-
oate 39. (NH4)6Mo7O24·4H2O (60 mg, 0.05 mmol) was dissolved in
30% aq H2O2 (0.42 mL, 3.65 mmol) at 0 °C, and the resultant
solution was added dropwise to a solution of 37 (258 mg,
contaminated with Ph3PO) in EtOH (4.5 mL) at 0 °C. The
resultant suspension was allowed to warm to rt, stirred at rt for 16 h,
and then added to brine (10 mL). The resultant mixture was then
extracted with EtOAc (3 × 20 mL), and the combined organic extracts
were dried and concentrated in vacuo to give 38. Purification via flash
column chromatography (eluent CH2Cl2/MeOH, 50:1) gave an 80:20
mixture of 39 and 38 as a white solid (67 mg). Data for 39: δH (500
MHz, DMSO-d6) 1.35 (9H, s, CMe3), 1.76−1.84 (1H, m, C(6)HA),
1.93−2.03 (1H, m, C(6)HB), 3.26−3.32 (1H, m, C(2)H), 3.50−3.56
(1H, m, C(5)H), 3.58 (3H, s, OMe), 3.75−3.82 (2H, m, C(7)H2),
3.91 (1H, app td, J 10.0, 1.6, C(3)H), 4.40 (1H, d, J 7.3, C(5)OH),
4.43 (1H, dd, J 7.6, 1.6, C(4)H), 4.91 (1H, d, J 8.2, C(2)OH), 5.11
(1H, d, J 7.6, C(4)OH), 6.29 (1H, d, J 10.0, NH), 7.63−7.79 (5H, m,
Ph); δC (125 MHz, DMSO-d6) 26.3 (C(6)), 28.1 (CMe3), 51.4
(OMe), 53.5 (C(7)), 54.3 (C(3)), 67.2 (C(5)), 68.9 (C(4)), 70.1
(C(2)), 78.1 (CMe3), 126.4, 129.4 (o,m-Ph), 131.5 (p-Ph), 133.0
(C(5′)), 153.3 (i-Ph), 155.3 (NCO), 174.0 (C(1)). Data for 38: δH
(500 MHz, DMSO-d6) [selected peaks] 1.39 (9H, s, CMe3), 1.89−
2.04 (2H, m, C(6)H2), 3.18 (1H, d, J 5.0, C(2)OH), 3.60−3.67 (1H,
m, C(5)H), 3.75−3.82 (1H, m, C(7)HA), 3.84−3.92 (1H, m, C(7)HB)
, 3.99 (1H, dd, J 8.8, 2.2, C(4)H), 4.10−4.18 (1H, m, C(2)H), 4.36
(1H, dd, J 9.6, 7.2, C(3)H), 5.39 (1H, d, J 7.3, C(5)OH), 6.18 (1H, d,
J 7.2, NH); δC (125 MHz, DMSO-d6) [selected peaks] 25.8 (C(6)),
28.2 (CMe3), 53.0 (C(7)), 54.6 (C(2)), 65.9 (C(5)), 71.0 (C(3)), 78.4
(CMe3), 80.8 (C(4)), 153.3 (C(5′)), 155.1 (NCO), 174.2 (C(1)).
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Method D. TsOH·H2O (7 mg, cat.) was added to a solution of an
80:20 mixture of 39 and 38 (36 mg) in acetone (2.8 mL) and DMP
(0.2 mL) at rt. The resultant solution was then stirred at rt for 24 h,
and then solid Na2CO3 was added until pH 7 was achieved. The
resultant mixture was then filtered and concentrated in vacuo to give
40 in >99:1 dr. Purification via flash column chromatography (gradient
elution, 5:1 → 2:1 30−40 °C petrol/EtOAc) gave 40 as a white solid
(24 mg, 19% from 35, >99:1 dr).
resultant mixture was stirred at −78 °C for 30 min. H2O (1 mL) was
then added, and the reaction mixture was allowed to warm to rt. The
aqueous layer was extracted with EtOAc (3 × 5 mL), and the
combined organic extracts were dried and concentrated in vacuo to
give a 28:72 mixture of 43 and 41. Purification via flash column
chromatography (gradient elution 20:1 → 5:1 30−40 °C petrol/
EtOAc) gave 43 as a yellow oil (2 mg, 16%, >99:1 dr).7 Further
elution gave 41 as a colorless oil (5 mg, 31%, >99:1 dr).
Method E. TsOH·H2O (7 mg, cat.) was added to a solution of 38
(34 mg, >99:1 dr) in acetone (2.8 mL) and DMP (0.2 mL) at rt. The
resultant solution was then stirred at rt for 24 h, and then solid
Na2CO3 was added until pH 7 was achieved. The resultant mixture
was then filtered and concentrated in vacuo to give 40 in >99:1 dr.
Purification via flash column chromatography (gradient elution, 5:1 →
2:1 30−40 °C petrol/EtOAc) gave 40 as a white solid (20 mg, 30%
from 35, >99:1 dr).
(E)-3-(4′-Ethoxyphenyl)acrylaldehyde 44. 4-Iodophenetole
(120 mg, 0.48 mmol) was dissolved in DMF (2 mL) at rt, and then
acrolein diethyl acetal (0.22 mL, 1.45 mmol), Bu4NOAc (292 mg, 0.97
mmol), K2CO3 (100 mg, 0.73 mmol), KCl (36 mg, 0.48 mmol) and
Pd(OAc)2 (3.3 mg, 0.01 mmol) were sequentially added. The reaction
vessel was evacuated, placed under an atmosphere of N2, and then
heated at 90 °C for 18 h. The reaction mixture was allowed to cool to
rt, and then 2.0 M aq HCl (7 mL) was added dropwise, and the
resultant mixture was stirred at rt for 10 min. The reaction mixture was
diluted with Et2O (50 mL) and washed with H2O (3 × 50 mL), and
then the organic layer was dried and concentrated in vacuo.
Purification via flash column chromatography (gradient elution 40:1
→ 10:1 30−40 °C petrol/EtOAc) gave 44 as a yellow solid (70 mg,
82%, >99:1 dr): mp 50−52 °C; νmax (ATR) 1673 (CO), 1600
(CC); δH (400 MHz, CDCl3) 1.45 (3H, t, J 7.0, CH2CH3), 4.10
(2H, q, J 7.0, CH2CH3), 6.62 (1H, dd, J 15.9, 7.9, C(2)H), 6.94 (2H,
d, J 8.7, C(3′)H, C(5′)H), 7.43 (1H, d, J 15.9, C(3)H), 7.52 (2H, d, J
8.7, C(2′)H, C(6′)H), 9.66 (1H, d, J 7.9, C(1)H); δC (100 MHz,
CDCl3) 14.7 (CH2CH3), 63.7 (CH2CH3), 115.0 (C(3′), C(5′)), 126.4
(C(2)), 126.6 (C(1′)), 130.4 (C(2′), C(6′)), 152.9 (C(3)), 161.6
(C(4′)), 193.8 (C(1)); m/z (FI+) 176 ([M]+, 100%); HRMS (FI+)
Methyl (S,S,S,S,E)-2,4,5-trihydroxy-3-(N-tert-butoxycarbonyl-
amino)-4,5-O-isopropylidine-8-phenylocta-7-enoate 42.
KHMDS (0.5 M in PhMe, 0.70 mL, 0.35 mmol) was added dropwise
to a solution of 40 (61 mg, 0.11 mmol, >99:1 dr) and PhCHO (36 μL,
0.13 mmol) in THF (2.2 mL) at −78 °C, and the resultant mixture
was stirred at −78 °C for 30 min. H2O (1 mL) was added, and the
reaction mixture was allowed to warm to rt. The aqueous layer was
then extracted with EtOAc (3 × 5 mL), and the combined organic
extracts were dried and concentrated in vacuo to give 42 in >99:1 dr.
Purification via flash column chromatography (gradient elution 10:1
→ 3:1 30−40 °C petrol/EtOAc) gave 42 as a white solid (38 mg, 79%,
>99:1 dr): mp 131−135 °C; [α]2D5 −7.9 (c 0.4 in CHCl3); νmax (ATR)
3437, 3360 (N−H, O−H), 3027, 2983, 2935 (C−H), 1741, 1716
(CO); δH (400 MHz, CDCl3) 1.42 (9H, s, CMe3), 1.45 (6H, app s,
2 × MeCMe), 2.44−2.53 (1H, m, C(6)HA), 2.53−2.61 (1H, m,
C(6)HB), 3.18 (1H, d, J 3.5, OH), 3.77−3.84 (1H, m, C(4)H), 3.79
(3H, s, OMe), 4.16−4.25 (2H, m, C(3)H, C(5)H), 4.59 (1H, app s,
C(2)H), 4.88 (1H, d, J 10.1, NH), 6.24 (1H, dt, J 15.8, 7.3, C(7)H),
6.46 (1H, d, J 15.8, C(8)H), 7.18−7.39 (5H, m, Ph); δC (100 MHz,
CDCl3) 27.2, 27.5 (2 × MeCMe), 28.2 (CMe3), 37.7 (C(6)), 52.9
(OMe), 55.3 (C(5)), 69.9 (C(2)), 78.4 (C(4)), 79.5 (C(3)), 80.1
(CMe3), 109.4 (MeCMe), 125.6 (C(7)), 126.2, 128.5 (o,m-Ph), 127.2
(p-Ph), 132.6 (C(8)), 137.3 (i-Ph), 155.0 (NCO), 174.0 (C(1)); m/z
(ESI+) 458 ([M + Na]+, 100%); HRMS (ESI+) C23H33NNaO7+ ([M +
Na]+) requires 458.2149; found 458.2135.
+
C11H12O2 ([M]+) requires 176.0832; found 176.0841.
Methyl (S,S,S,S,E,E)-2,4,5-trihydroxy-3-(N-tert-butoxycarbo-
nylamino)-4,5-O-isopropylidine-10-(4′-ethoxyphenyl)deca-
7,9-dienoate 45. KHMDS (0.5 M in PhMe, 1.89 mL, 0.94 mmol)
was added dropwise to a solution of 40 (164 mg, 0.30 mmol, >99:1
dr) and 44 (166 mg, 0.94 mmol, >99:1 dr) in THF (30 mL) at −78
°C, and the resultant mixture was stirred at −78 °C for 30 min. H2O
(5 mL) was added, and the reaction mixture was allowed to warm to
rt. The aqueous layer was then extracted with EtOAc (3 × 20 mL),
and the combined organic extracts were dried and concentrated in
vacuo to give 45 in >99:1 dr. Purification via flash column
chromatography (gradient elution 7:1 → 5:1 30−40 °C petrol/
EtOAc) gave 45 as a yellow solid (35 mg, 23%, >99:1 dr): mp 116−
120 °C; [α]2D5 −11.1 (c 1.0 in CHCl3); νmax (ATR) 3364 (N−H,
O−H), 2982, 2934 (C−H), 1741, 1716 (CO), 1604, 1510 (CC);
δH (400 MHz, CDCl3) 1.37−1.50 (18H, m, CMe3, 2 × MeCMe,
CH2CH3), 2.35−2.45 (1H, m, C(6)HA), 2.45−2.54 (1H, m, C(6)HB),
3.17 (1H, br s, OH), 3.76 (1H, dd, J 9.5, 6.5, C(4)H), 3.80 (3H, s,
OMe), 4.03 (2H, q, J 7.1, CH2CH3), 4.13−4.21 (2H, m, C(3)H,
C(5)H), 4.58 (1H, app s, C(2)H), 4.85 (1H, d, J 10.4, NH), 5.76 (1H,
dt, J 15.0, 7.5, C(7)H), 6.24 (1H, dd, J 15.0, 10.5, C(8)H), 6.41 (1H,
d, J 15.5, C(10)H), 6.63 (1H, dd, J 15.5, 10.5, C(9)H), 6.83 (2H, d, J
8.7, C(3′)H, C(5′)H), 7.30 (2H, d, J 8.7, C(2′)H, C(6′)H); δC (100
MHz, CDCl3) 14.8 (CH2CH3), 27.1, 27.5 (2 × MeCMe), 28.2
(CMe3), 37.5 (C(6)), 52.9 (OMe), 55.3 (C(3)), 63.4 (CH2CH3), 70.0
(C(2)), 78.4 (C(4)), 79.5 (C(5)), 80.0 (CMe3), 109.3 (MeCMe),
114.6 (C(3′), C(5′)), 126.8 (C(9)), 127.4 (C(2′), C(6′)), 128.6
(C(7)), 130.0 (C(1′)), 130.8 (C(10)), 133.4 (C(8)), 155.0 (NCO),
158.4 (C(4′)), 174.0 (C(1)); m/z (ESI+) 528 ([M + Na]+, 100%);
HRMS (ESI+) C27H39NNaO8+ ([M + Na]+) requires 528.2568; found
528.2564.
(5S,4R,1′S,2′S,E)-2,2-Dimethyl-N(3)-(tert-butoxycarbonyl)-4-
(1′,2′-dihydroxy-1′,2′-O-isopropylidene-5′-phenylpent-4′-en-
1′-yl)-5-methoxycarbonyloxazolidine 43. Method A (from 42). A
solution of 42 (37 mg, 0.08 mmol, >99:1 dr) in acetone (2.9 mL) and
DMP (0.58 mL) was stirred at rt, and BF3 (1.0 M in Et2O, ∼3 drops)
was added dropwise until a permanent color change from colorless to
dark orange was observed. The resultant mixture was then stirred at rt
for 24 h. Et3N (∼5 drops) was then added until pH 7 was achieved,
and the reaction mixture was concentrated in vacuo to give a 66:34
mixture of 43 and 42. Purification via flash column chromatography
(gradient elution 20:1 → 10:1 30−40 °C petrol/EtOAc) gave 43 as a
pale yellow oil (15 mg, 37%, >99:1 dr):35 [α]D25 −0.4 (c 1.0 in
CH2Cl2); {lit.7 [α]D21 −3.1 (c 3.8 in CH2Cl2)}; [α]2D5 −2.3 (c 1.0 in
CHCl3); νmax (ATR) 2983, 2936 (C−H), 1740, 1697 (CO); δH
(250 MHz, CDCl3, 327 K) 1.43 (6H, s, 2 × MeCMe), 1.52 (9H, s,
CMe3), 1.58 (3H, s, MeCMe), 1.63 (3H, s, MeCMe), 2.40−2.66 (2H,
m, C(3′)H2), 3.76 (3H, s, OMe), 4.02 (1H, dd, J 7.9, 5.5, C(1′)H),
4.12−4.23 (1H, m, C(2′)H), 4.45−4.53 (1H, m, C(4)H), 4.73 (1H, d,
J 2.1, C(5)H), 6.29 (1H, dt, J 15.8, 7.0, C(4′)H), 6.51 (1H, d, J 15.8,
C(5′)H), 7.16−7.39 (5H, m, Ph); δC (62.5 MHz, CDCl3, 327 K) 27.2,
27.2, 27.4, 27.7 (4 × MeCMe), 28.5 (CMe3), 36.5 (C(3′)), 52.3
(OMe), 61.3 (C(4)), 75.2, 78.3, 80.0 (C(5), C(1′), C(2′)), 80.9
(CMe3), 96.7 (C(2)), 109.0 (MeCMe), 125.5 (C(4′)), 126.2, 128.5
(o,m-Ph), 127.2 (p-Ph), 132.9 (C(5′)), 137.6 (i-Ph), 151.8 (NCO),
172.1 (CO2Me); m/z (ESI+) 498 ([M + Na]+, 100%); HRMS (ESI+)
ASSOCIATED CONTENT
■
S
* Supporting Information
Copies of 1H and 13C NMR spectra, and crystallographic
information files (for structures CCDC 907676−907679). This
material is available free of charge via the Internet at http://
pubs.acs.org.
+
C26H37NNaO7 ([M + Na]+) requires 498.2462; found 498.2464.
Method B (from 41). KHMDS (0.5 M in PhMe, 64 μL, 32.2 μmol)
was added dropwise to a solution of 41 (16 mg, 26.9 μmol, >99:1 dr)
and PhCHO (3.5 μL, 32.2 μmol) in THF (0.6 mL) at −78 °C, and the
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dx.doi.org/10.1021/jo302731m | J. Org. Chem. 2013, 78, 2500−2510

The Journal of Organic Chemistry
Article
(22) Wovkulich, P. M.; Shankaran, K.; Kiegiel, J.; Uskokovic,
Org. Chem. 1993, 58, 832.
(23) Davies, S. G.; Foster, E. M.; McIntosh, C. R.; Roberts, P. M.;
Rosser, T. E.; Smith, A. D.; Thomson, J. E. Tetrahedron: Asymmetry
2011, 22, 1035.
́
M. R. J.
AUTHOR INFORMATION
Corresponding Author
*E-mail: steve.davies@chem.ox.ac.uk.
Notes
■
(24) Costello, J. F.; Davies, S. G.; Ichihara, O. Tetrahedron:
Asymmetry 1994, 5, 1999.
The authors declare no competing financial interest.
(25) Crystallographic data (excluding structure factors) have been
deposited with the Cambridge Crystallographic Data Centre as
supplementary publication numbers CCDC 907676 (22), 907677
(40), 907678 (42) and 907679 (45).
(26) Analogous reaction of the 2,3-syn-configured substrates
produced antipodal diastereoselectivity.
(27) In comparable systems, treatment of osmate ester-TMEDA
complexes with trishydroxymethylphosphine gives superior yields to
those obtained upon treatment with ethylenediamine.
(28) As lactone 35 was found to be susceptible to decomposition it
was necessary to prepare fresh samples to be used immediately in
subsequent reactions.
(29) (a) Flack, H. D. Acta Crystallogr., Sect. A 1983, 39, 876.
(b) Flack, H. D.; Bernardinelli, G. Acta Crystallogr., Sect. A 1999, 55,
908. (c) Flack, H. D.; Bernardinelli, G. J. Appl. Crystallogr. 2000, 33,
1143.
(30) Battistuzzi, G.; Cacchi, S.; Fabrizi, G. Org. Lett. 2003, 5, 777.
(31) Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.;
Timmers, F. J. Organometallics 1996, 15, 1518.
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(35) The peaks in the 1H and 13C NMR spectra of both 41 and 43 in
CDCl3 at rt were found to be broad because of the rotameric nature of
these compounds.
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