Synthesis of the C1-C16 fragment of ionomycin using a neutral (η3-allyl)iron complex

Article abstract of DOI:10.1039/b606262h

Key steps in the synthesis of the C1-C16 polyketide fragment of ionomycin were the nucleophilic addition of an organocuprate to a neutral (η³-allyl)iron complex and the construction of a β-diketone moiety by the Rh-catalysed rearrangement of an

Full text of DOI:10.1039/b606262h

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Synthesis of the C1–C16 fragment of ionomycin using a neutral (g3-allyl)iron
complex
John P. Cooksey, Philip J. Kocienski,* Ying-fa Li, Stefan Schunk and Thomas N. Snaddon
Received 3rd May 2006, Accepted 7th July 2006
First published as an Advance Article on the web 31st July 2006
DOI: 10.1039/b606262h
Key steps in the synthesis of the C1–C16 polyketide fragment of ionomycin were the nucleophilic
addition of an organocuprate to a neutral (g3-allyl)iron complex and the construction of a b-diketone
moiety by the Rh-catalysed rearrangement of an a-diazo-b-hydroxyketone.
In the following account we first describe the synthesis of the
C1–C9 fragment 3, then the synthesis of the C10–C16 fragment 4
Ionomycin (1, Scheme 1) is a doubly charged ionophore antibiotic
and finally their union via the Pellicciari protocol to generate the
Introduction
that forms neutral hexacoordinate complexes with calcium and
b-diketone moiety.
other divalent cations owing to the presence of a carboxylate
ion at C1 and an unusual b-diketone at C9 and C11.1,2 Total
Synthesis of the C1–C9 fragment 3
syntheses of ionomycin from the groups of Evans,3 Hanessian4
and Lautens5 have been described as well as syntheses of various
fragments.6–17 We now report a synthesis of the C1–C16 fragment
2 which features the use of functionalised planar chiral neutral
g3-allyliron complex to install the carboxyl terminus and control
the stereochemistry at C4 in a single operation. Such complexes
have not been used previously in natural product synthesis.
We recently reported two syntheses of the C1–C9 fragment
9, a precursor to 3, in which the key step was the addition
of alkylmetal reagents to planar chiral cationic (g3-allyl)metal
complexes (Scheme 2).18 The first approach entailed the addition
of organocopper(I) reagent 5 to the (g3-allyl)molybdenum complex
719 to give the adduct 9 in 37% yield. In the second approach, the
zinc cuprate 6 added to the (g3-allyl)iron complex 820 to give the
adduct 9 in 30% yield. In both cases nucleophilic attack occurred
regioselectively at C4 anti to the metal in accord with precedent19–22
but variations in time, temperature, solvent and metal failed to
improve the mediocre yields.23
Scheme 2
The one parameter we neglected in the previous optimisation
study was the reactivity of the (g3-allyl)metal complex and to
that end we examined functionalised neutral (g3-allyl)Fe(CO)2NO
complexes as electrophiles. Nakanishi and co-workers had pre-
viously made three key observations that were pertinent to
our study (Scheme 3). Firstly, the diastereosiomeric mixture
of allylic bromides 10 reacted with tetrabutylammonium tri-
carbonylnitrosylferrate (TBAFe) to give a chromatographically
separable mixture of diastereoisomeric complexes (2R,4S)-11 and
Scheme 1
School of Chemistry, Leeds University, Leeds, UK LS2 9JT
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after oxidative demetallation. The disappointing dr suggested that
either (a) the formation of (2R,4S)-14 by reaction of enantiopure
(R)-tosylate 13 with TBAFe did not proceed with clean inversion
or (b) the reaction of the cuprate 17 with enantiopure (2R,4S)-14
did not proceed with clean attack anti to the metal. Unfortunately
we were unable to distinguish between these two prognoses because
Nakanishi never disclosed the [a]D of tosylate 13 and the assay of
26
optical purity of 14 based on the chiral shift reagent Eu(hfc)3
was precluded by extreme line broadening.
In order to address the stereochemical issues outlined above, we
required an (g3-allyl)iron complex whose stereochemical integrity
was assured by an internal reference; therefore, we prepared
(2R,4S)-11 as shown in Scheme 5. A Horner–Wadsworth–
Emmons reaction of the aldehyde (R)-18 with the phosphonate
19 gave the enamide 20 in 58% yield. After cleavage of the TBS
ether group, the alcohol 21 was activated as its mesylate ester 22
because preparation of the corresponding tosylate using Ts2O and
DMAP was slow and messy. By contrast the mesylate formed
quickly with MsCl and triethylamine and it was more stable.
Reaction of mesylate 22 with TBAFe in an 8 : 1 mixture of
toluene and dichloromethane at 0 ◦C gave diastereoisomeric (g3-
allyl)iron complexes 11 in 50% yield. The dr (4 : 1) was ascertained
1
by integration of the C2H signals in the H NMR spectrum of
the mixture (see the experimental data).24 The red, air-sensitive
complexes 11 were separable with difficulty by column chromatog-
raphy but the major diastereoisomer was more easily obtained by
crystallisation from pentane. Reaction of pure (2R,4S)-11 with
lithium dibutylcuprate gave a 74% yield of a single adduct 23
whose structure and stereochemistry was determined by X-ray
crystallography. Thus the reaction of a carbonyl-functionalised
neutral (g3-allyl)iron complex with organocuprates appears to
Scheme 3
(2S,4R)-11 and the absolute configuration of the complex (2R,4S)-
11 was secured by X-ray crystallography.24 Secondly, soft carbon
nucleophiles such as malonates reacted with complex (2R,4S)-11
regioselectively at C4 anti to the iron.25 Thirdly, the scalemic (S)-
allylic tosylate 13 reacted with TBAFe under mild conditions to
give the (g3-allyl)iron complex (2R,4S)-14 with clean inversion of
configuration.26 Taken together these observations suggested that
the neutral (g3-allyl)iron complexes could offer a convenient and
readily accessible alternative to the cationic complexes shown in
Scheme 2 provided the complexes reacted with suitable alkylmetal
reagents.
The requisite alkylmetal reagent was prepared as shown
in Scheme 4. The readily available meso-2,4-dimethylglutaric
anhydride27,28 was converted to the scalemic iodoalkane 16 in
5 easy, scalable steps. Halogen–metal exchange29,30 afforded an
organolithium reagent that was transmetallated to the organocop-
per(I) reagent 5 but it failed to react with (2R,4S)-14. However, the
corresponding organocuprate 17 added to (2R,4S)-14 to give an
inseparable mixture of (4S)-9 and (4R)-9 (dr = 4 : 1) in 57% yield
Scheme 4
Scheme 5
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be both highly regioselective and stereospecific with nucleophilic
attack occurring anti to the metal.
The foregoing experiments indicate that the formation of
diastereoisomers (4S)- and (4R)-9 from the reaction depicted in
Scheme 4 was due to reaction of cuprate 17 with a 4 : 1 mixture of
(2R,4S)-14 and (2S,4R)-14, the mixture being generated during
the reaction of TBAFe with tosylate (R)-13 (Scheme 6). The
stereochemistry can be rationalised in terms of the competition
between the SN2 and SN2ꢀ pathways (syn and anti) leading to the
g1-allyl intermediates (S)-24, (S)-25 and (R)-25 which expel CO
to form the enantiomeric (g3-allyl)iron complexes 14.31 Precedent
from the Nakanishi group26 indicated that in nonpolar solvents
such as toluene, (2R,4S)-14 should have predominated (er = 97 :
3) whereas our results (er = 4 : 1) are less impressive.
Scheme 7
an authentic sample prepared by a stereochemically unambiguous
route.18
Synthesis of the C10–C16 fragment 4
Three syntheses of the C10–C16 fragment were accomplished
based on (1) a classical resolution, (2) the use of a chiral auxiliary
and (3) a catalytic asymmetric process. The first route (Scheme 8)
began with methanolysis of meso-2,4-dimethylglutaric anhydride
(15) followed by resolution of the resultant carboxylic acid with
(+)-a-methylbenzylamine.34,35 The scalemic acid 29 was converted
Scheme 6
Proof that neutral (g3-allyl)iron complexes react with
organocuprates efficiently and with high anti stereoselectivity as
detailed above paved the way for a satisfactory conclusion to
the synthesis of the C1–C9 fragment 3 (Scheme 7). Reaction of
cuprate 17 (2 equiv.) with (2R,4S)-11 in Et2O–THF at −78 ◦C
followed by oxidative demetallation gave the adduct 26 as a single
diastereoisomer in 51% yield. Hydrogenation of the enamide 26
gave the saturated amide 27 in quantitative yield but hydrolysis
of the secondary amide was problematic. It was inert towards
N-nitrosation thereby precluding cleavage via the N-nitrosamide
using the procedure of Mori.32 Base hydrolysis of the amide using
5 M KOH in MeOH at reflux for 2 d resulted in decomposition
of the starting material. A 3-step procedure of Grieco33 was
successful. Formation of the N-Boc derivative 28 followed by base
hydrolysis using 1 M LiOH and methylation of the resulting acid
using trimethylsilyldiazomethane gave 3 in 68% yield from 27. The
structure and stereochemistry of 3 was proved by comparison of
the 1H and 13C NMR spectra (500 and 125 MHz, respectively) with
Scheme 8
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to the a-diazoketone 30 which underwent a Wolff rearrangement
on treatment with silver(I) oxide at 0 ◦C to give the carboxylic
acid 31. Selective reduction of the carboxylic acid with borane
dimethylsulfane complex generated the alcohol 32 (44% overall
yield from 29) whereupon four simple transformations were used
to obtain the target a-diazoketone 4. The first route benefits from
easy scalability for all steps, except the Wolff rearrangement, and
the low cost of the reagents.
In the second route (Scheme 9) both stereogenic centres were
generated by sequential alkylation of the lithium enolate derived
from (1S,2S)-(+)-pseudoephedrine propionamide (35) according
to the procedure of Myers.36–38 Both alkylation reactions proceeded
with high diastereoselectivity (dr = 98 : 2) and gave the alcohol
39 in 48% overall yield. Oxidation of 38 by the procedure of
Sharpless and co-workers39 gave carboxylic acid 33 which is an
intermediate in route 1 described above. Route 2 is short and highly
stereoselective but (1S,2S)-(+)-pseudoephedrine propionamide is
expensive.
Scheme 10
derivative 42 with vinyl bromide in the presence of 5 mol% of
Pd(0) to give the alkene 43 contaminated by the TBDPS ether
of 3-methylbutanol (ca. 10 mol%). This mixture underwent a
second ZACA reaction to give a diastereoisomeric mixture of
alcohols (dr = 2.3 : 1) in 51% overall yield from 37. Although
the desired (2R,4S)-diastereoisomer 39 was the major product, it
was difficult to separate from its (2S,4S)-diastereoisomer and so
further optimisation of the ZACA route was abandoned.
Union of fragments 3 and 4 to give the C1–C16 fragment 2
In their total syntheses of ionomycin, Evans,3 Hanessian4 and
Lautens5 generated the b-diketone moiety spanning C9–C11 by
consecutive aldol and oxidation reactions. We exploited a protocol
devised by Pellicciari and co-workers50 whereby LDA was added
to a mixture of aldehyde 44 and a-diazoketone 4 at −78 ◦C
(Scheme 11). The metallated a-diazoketone 46, generated in situ,
added to the aldehyde to form the b-hydroxy-a-diazoketone 47
which was then treated with Rh2(OAc)4 (1 mol%). The resultant
carbene inserted into the adjacent C–H bond to generate the C1–
C16 fragment 2 in 60% overall yield as a single diastereoisomer.
In conclusion, we have shown that functionalised neutral (g3-
allyl)iron complex (2R,4S)-11 reacts with organocuprate nucle-
ophiles regioselectively anti to the iron. Thus, a major limitation
to the use of the related ester-functionalised cationic (g3-allyl)-iron
and -molybdenum complexes 7 and 8, their inefficient reaction
with alkylmetal nucleophiles,18 has been addressed. But, there is a
weevil in the wheat: the synthesis of the neutral complex (2R,4S)-
11 from scalemic allylic mesylate 22 is stereoselective and proceeds
mainly by inversion but there is significant contribution from a
Scheme 9
The third and final route (Scheme 10) is in principle the most
attractive because it exploits the Negishi–Kondakov zirconium-
catalysed asymmetric carboalumination (ZACA) of terminal
alkenes40,41 to create the two stereogenic centres. The reaction
is a rare example of an asymmetric catalytic carbometallation
process and its prowess has been amply demonstrated in syntheses
of polypropionates17,42–45 and terpenoids.46,47 We began with the
known48 methylalumination of the alkene 40 catalysed by 0.5 mol%
of bis[(−)-1-neomenthylindenyl)zirconium dichloride (41).49 After
oxidation of the intermediate alane, the alcohol 36 was obtained
in 74% yield and the Mosher ester revealed an er = 88 :
12. Attempts to displace the tosylate derived from 36 using
vinylmagnesium bromide and dilithium tetrachlorocuprate failed
but the corresponding iodoalkane 37 reacted slowly (44 h) at r.t.
in the presence of one equivalent of dilithium tetrachlorocuprate
to give the desired alkene 43 in <40% yield. A faster and more
efficient route entailed a Negishi coupling43 of the organozinc
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Infrared spectra were recorded neat on NaCl plates, details are
reported as mmax in cm−1, followed by an intensity descriptor: s =
strong, m = medium, w = weak, br = broad. Magnetic resonance
spectra were recorded on Bruker 300 and 500 MHz spectrometers
in the solvents specified and the chemical shifts (d) reported in
ppm relative to the residual signals of chloroform (dH = 7.27,
dC = 77.2) or benzene dH = 7.37, dC = 128.4). Coupling constants
(J) are reported in Hz with multiplicities described using the
following abbreviations: s = singlet, d = doublet, t = triplet,
q = quartet, quint = quintet, sext = sextet, sept = septet, m =
multiplet and signal assignments based on COSY and HMQC
correlation experiments. In the 13C NMR spectra, multiplicities
and signal assignments were elucidated using DEPT 135 and
HMBC correlation experiments. Mass spectra are reported as
values in atomic mass units followed by the peak intensity relative
to the base peak (100%). Specific optical rotations were recorded
◦
at ambient temperature (22 3 C) on an AA 1000 polarimeter
reported in 10−1deg m−2g−1.
(2S,4R)-5-(tert-Butyldiphenylsilyloxy)-1-iodo-2,4-
dimethylpentane (16)
tert-Butyldiphenylsilyl chloride (1.8 g, 6.5 mmol) in CH2Cl2 (3 mL)
was added to a solution of (2S,4R)-5-iodo-2,4-dimethylpentan-1-
ol18 (1.6 g, 6.5 mmol), imidazole (575 mg, 8.5 mmol) and DMAP
(24 mg, 0.2 mmol) in CH2Cl2 (7 mL) and the resulting suspension
was stirred at r.t. for 1 h. H2O (10 mL) was added to the reaction
mixture and the layers were separated. The aqueous layer extracted
with CH2Cl2 (2 × 10 mL). The combined organic layers were dried
(Na2SO4), filtered and concentrated in vacuo to give a colourless
oil. Purification by column chromatography [SiO2, hexanes] gave
the title compound 16 (3.1 g, 6.45 mmol, 99%) as a colourless oil:
[a]D = −8.0 (c = 1.0, CHCl3). 1H NMR (500 MHz, CDCl3): d =
7.68 (4H, d, J 6.8, Ph), 7.46–7.38 (6H, m, Ph), 3.51 (1H, dd, J
9.8, 5.6, C1HAHB), 3.45 (1H, dd, J 9.8, 6.0, C1HAHB), 3.24 (1H,
dd, J 9.6, 3.6, C5HAHB), 3.09 (1H, dd, J 9.6, 5.8, C5HAHB), 1.72
(1H, apparent oct, J 6.4, C2H), 1.53–1.46 (1H, m, C4H), 1.47
(1H, ddd, J 7.3, 6.6, 5.5, C3HAHB), 1.08 (9H, s, (CH3)3Si), 1.01
(1H, ddd, J 7.3, 6.6, 5.5, C3HAHB), 0.96 (3H, d, J 6.4, C2CH3),
0.95 (3H, d, J 6.8, C4CH3). 13C NMR (75 MHz, CDCl3): d =
135.8 (4C, Ph), 134.1 (2C, Ph), 129.7 (2C, Ph), 127.8 (4C, Ph), 68.9
(C1H2), 40.5 (C3H2), 33.3 (C4H), 32.0 (C2H), 27.1 ((CH3)3CSi),
21.6 (C4CH3), 19.5 ((CH3)3CSi), 18.3 (C5H2), 17.5 (C2CH3). IR
(neat, NaCl plates): m = 3070 s, 2958 s, 2929 s, 1472 m, 1427 m,
1389 m, 1378 m, 1194 m, 1111 s cm−1. LRMS (ES mode) m/z =
481 [MH+, 10%], 225 (100). HRMS (ES mode): m/z = 481.1441
[MH+, 10%]; calculated for C23H34IOSi [MH+]: m/z = 481.1424.
Anal. calcd for C23H33IOSi: C, 57.49; H, 6.92. Found: C, 57.6; H,
6.95.
Scheme 11
pathway that proceeds by retention even in non-polar solvents—
contrary to the report of Nakanishi and co-workers.24 In the
present case this vexation was inconsequential because the major
complex could be obtained by crystallisation but extrapolation
to other systems may be more difficult. Therefore, the synthetic
potential of neutral (g3-allyl)iron electrophiles will only be realised
in full when the issue of their synthesis is resolved. A further
markworthy feature of our approach to the C1–C16 fragment
2 of ionomycin is the use of the Pellicciari protocol50 for the
construction of the b-diketone moiety.
Experimental
All reactions requiring anhydrous conditions were conducted
under a nitrogen atmosphere in flame-dried glassware. Where
appropriate, solvents and reagents were dried by standard meth-
ods, i.e., distillation from the usual drying agent under a nitrogen
atmosphere prior to use: THF and Et2O from sodium benzophe-
none ketyl; CH2Cl2, DME, MeCN, PhH and PhMe from CaH2.
Reactions were magnetically stirred and monitored by TLC using
0.25 mm E. Merck pre-coated silica gel plates and visualized
with UV light followed by phosphomolybdic acid. All organic
extracts were dried over Na2SO4 and concentrated in vacuo using
a Bu¨chi rotary evaporator. Yields refer to chromatographically
and spectroscopically pure products unless stated otherwise.
(1ꢀS)-Diethyl 2-oxo-2-(1ꢀ-phenylethylamino)ethylphosphonate (19)
DMAP (4.9 g, 40 mmol) then EDCI·HCl (7.7 g, 40.0 mmol)
were added to a colourless solution of diethylphosphonoacetic
acid (3.2 mL, 20 mmol) and (S)-a-methylbenzylamine (2.6 mL,
20.0 mmol) in CH2Cl2 (500 mL) at r.t. The resulting colourless
solution was strirred at r.t. for 2 h. HCl (1 M, 500 mL) was added
to the reaction mixture and the layers separated. The organic
layer washed with HCl (1 M, 500 mL), then brine (500 mL),
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dried (Na2SO4), filtered and concentrated in vacuo to give the
title compound 19 (5.7 g, 18.9 mmol, 94%) as a colourless oil:
[a]D −48.4 (c = 1.0, CHCl3). 1H NMR (500 MHz, CDCl3):
d = 7.36–7.29 (4H, m, Ph), 7.26–7.21 (1H, m, Ph), 7.14 (1H,
broad s, NH), 5.11 (1H, apparent quint, J 7.3, C1ꢀH), 4.14 (2H,
overlapping dq, J 15.0, 7.3, OCH2CH3), 4.02 (2H, overlapping
dq, J 15.0, 7.3, OCH2CH3), 2.86 (1H, dd, J 20.9, 15.4, C2HAHB),
2.81 (1H, overlapping dd, J 20.5, 15.4, C2HAHB), 1.49 (3H, d, J
6.8, C1ꢀCH3), 1.34 (3H, t, J 7.3, OCH2CH3), 1.22 (3H, t, J 7.3,
(1 : 5)] followed by recrystallisation from hexanes gave the title
compound 21 (0.9 g, 4.1 mmol, 98%) as a colourless solid: mp 76–
77 ◦C; [a]D −159 (c = 0.5, CHCl3). 1H NMR (500 MHz, CDCl3):
d = 7.35–7.30 (4H, m, Ph), 7.28–7.24 (1H, m, Ph), 6.82 (1H, dd,
J 15.2, 4.5, C3H), 6.10 (1H, broad s, NH), 5.96 (1H, dd, J 15.2,
1.7, C2H), 5.18 (1H, apparent quint, J 7.5, C1ꢀH), 4.40 (1H, m,
C4H), 2.53 (broad s, OH), 1.51 (3H, d, J 6.8, C1ꢀCH3), 1.28 (3H,
d, J 6.6, C5H3). 13C NMR (75 MHz, CDCl3): d = 165.1 (C1),
147.5 (C3H), 143.3 (Ph), 128.8 (2C, Ph), 127.6 (Ph), 126.4 (2C,
Ph), 121.9 (C2H), 67.3 (C4H), 49.0 (C1ꢀH), 23.0 (C1ꢀCH3), 21.8
(C5H3). IR (neat): m = 3469 s, 1658 s, 1633 s cm−1. LRMS (ES
mode): m/z = 220 [MH+, 100%]. Anal. calcd for C13H17NO2: C,
71.21; H, 7.81; N, 6.39. Found: C, 71.25; H, 7.75; N, 6.4.
OCH2CH3). 13C NMR (75 MHz, CDCl3): d = 163.0 (C O), 143.1
=
(Ph), 128.5 (2C, Ph), 128.4 (Ph), 127.1 (Ph), 126.0 (3C, Ph), 62.6
(2C, 2J (31P-13C) = 6.9, OCH2CH3), 49.1 (C1ꢀH), 35.0 (d, 1J (31P–
3
13C) 131.0, C2H2), 22.0 (C1ꢀCH3), 16.2 (2C, t, J (31P–13C) 6.9,
OCH2CH3). IR (neat): m = 3280 s, 3064 s, 2981 s, 2932 s, 1651 s,
1552 s 1245 s cm−1. LRMS (ES mode): m/z = 300 [MH+, 100%],
197 (30), 196 (75), 179 (65), 168 (20).
(2E,1ꢀS,4R)-4-(Methanesulfonyloxy)pent-2-enoic acid
(1ꢀ-phenylethyl) amide (22)
MsCl (0.35 mL, 4.6 mmol) was added dropwise to a colourless
solution of the alcohol 21 (1.0 g, 4.6 mmol), Et3N (0.63 mL,
4.6 mmol) and CH2Cl2 (65 mL) at 0 ◦C. The resulting clear,
colourless solution was stirred at 0 ◦C for 1 h. The reaction
was quenched with NaHCO3 (saturated aqueous, 60 mL), the
layers separated and the aqueous layer extracted with CH2Cl2
(2 × 60 mL). The combined organic layers were washed with HCl
(1 M, 60 mL, chilled using an ice-water bath), dried (Na2SO4),
filtered and concentrated in vacuo to give the title compound 22
(1.4 g, 4.6 mmol, 100%) as a colourless solid that was used with no
further purification. 1H NMR (500 MHz, CDCl3): d = 7.31–7.24
(4H, m, Ph), 7.23–7.18 (1H, m, Ph), 6.73 (1H, dd, J 15.4, 5.6,
C3H), 6.01 (1H, d, J 15.4, C2H), 6.59 (1H, broad s, NH), 5.27
(1H, apparent quint, J 6.4, C4H), 5.12 (1H, apparent quint, J 7.3,
C1ꢀH), 2.93 (3H, s, OSO2CH3), 1.46 (3H, d, J 7.3, C1ꢀCH3), 1.45
(3H, d, J 6.4, C5CH3). 13C NMR (75 MHz, CDCl3): d = 163.6
(C1), 142.9 (Ph), 140.6 (C3H), 128.9 (2C, Ph), 127.7 (Ph), 126.4
(2C, Ph), 126.4 (Ph), 125.1 (C2H), 77.3 (C4H), 49.3 (C1ꢀH), 39.1
(OSO2CH3), 21.8 (C1ꢀCH3), 21.4 (C5CH3). IR (neat): m = 3332
br, 1671 s, 1630 s, 1531 s, 1445 s, 1338 s cm−1. LRMS (ES mode):
m/z = 320 [MNa+, 80%], 298 [MH+, 95], 265 (40), 236 (20), 224
(35), 202 (100).
(2E,1ꢀS,4R)-4-(tert-Butyldimethylsilyloxy)pent-2-enoic acid
(1ꢀ-phenylethyl) amide (20)
Phosphonate 19 (2.9 g, 9.6 mmol) in THF (19 mL) was added
via a cannula to a suspension of NaH (60% dispersion in mineral
oil, 385 mg, 9.6 mmol) in THF (19 mL) at 0 ◦C. The resulting
white suspension was stirred at r.t. for 2 h. The aldehyde (R)-1851
(1.7 g, 9.2 mmol) in THF (10 mL + 3 mL rinse) was added via a
cannula and the resulting suspension was stirred at r.t. for 18 h. The
reaction was quenched with pre-mixed NH4Cl (saturated aqueous,
25 mL) and brine (25 mL), the layers separated and the aqueous
layer extracted with Et2O (3 × 50 mL). The combined organic
layers were dried (Na2SO4), filtered and concentrated in vacuo to
give a yellow oil. Purification by column chromatography [SiO2,
hexanes–Et2O (3 : 1)] followed by recrystallisation from hexanes
gave the title compound 20 (1.7 g, 5.4 mmol, 58%) as colourless
needles: mp 70–72 ◦C; [a]D −91.8 (c = 1.0, CHCl3). H NMR
1
(500 MHz, CDCl3): d = 7.28 (4H, m, Ph), 7.23–7.17 (1H, m, Ph),
6.78 (1H, dd, J 15.0, 3.9, C3H), 5.87 (1H, d, J 15.0, C2H), 5.63
(1H, broad s, NH), 5.15 (1H, apparent quint, J 7.3, C1ꢀH), 4.42–
4.36 (1H, m, C4H), 1.45 (3H, d, J 6.8, C1ꢀCH3), 1.17 (3H, d, J 6.4,
C5H3), 0.84 (9H, s, (CH3)3CSi), 0.00 (6H, s, (CH3)2Si). 13C NMR
(75 MHz, CDCl3): d = 165.1 (C1), 148.4 (C3H), 143.3 (Ph), 128.8
(Ph), 127.6 (2C, Ph), 126.5 (2C, Ph), 120.9 (C2H), 67.9 (C4H),
48.9 (C1ꢀH), 26.0 ((CH3)3CSi), 23.9 (C1ꢀCH3), 21.8 (C5H3), 18.4
((CH3)3CSi), −4.7 ((CH3)2Si). IR (neat): m = 1668 s, 1633 s cm−1.
LRMS (ES mode): m/z = 334 [MH+, 100%], 230 (20), 213 (65)
202 (35). Anal. calcd for C19H31NO2Si: C, 68.5; H, 9.15; N, 4.3.
Found: C, 68.5; H, 9.15; N 4.2.
Neutral iron complex (2R,4S)-11
Mesylate 22 (221 mg, 0.74 mmol) in CH2Cl2 (0.4 mL) was added in
one portion to tetrabutylammonium tricarbonylnitrosylferrate52
(TBAFe, 306 mg, 0.74 mmol) in PhMe (3.5 mL) at 0 ◦C. The
resulting red–orange mixture was stirred at 0 ◦C for 1 h and at
r.t. for a further 18 h. The reaction mixture was passed rapidly
through a SiO2 column under N2 eluting with degassed CH2Cl2,
the 2 characteristic red bands were collected and concentrated in
vacuo to give a mixture of the title compounds (2R,4S)-11 and
(2S,4R)-11 (128 mg, 0.37 mmol, 50%, dr = 4 : 1) as a red oily
solid. Recrystallisation of the mixture from pentane (ca. 15 mL)
gave (2R,4S)-11 (86 mg) as a red solid: mp 130 ◦C (dec.); [a]D −132
(c = 0.2, CHCl3). 1H NMR (300 MHz, CDCl3): d = 7.42–7.28 (5H,
m, Ph), 5.96 (1H, broad d, J 7.7, NH), 5.27 (1H, apparent quint, J
6.9, C1ꢀH), 5.04 (1H, dd, J 12.0, 10.2, C3H), 4.22 (1H, overlapping
dq, J 12.3, 6.2, C4H), 3.59 (1H, d, J 10.2, C2H), 2.01 (3H, d, J 6.1,
C5H3), 1.59 (3H, d, J 6.7, C1ꢀCH3). 13C NMR (75 MHz, CDCl3):
d = 217.9 (CO), 217.4 (CO), 170.1 (C1), 143.3 (Ph), 128.8 (2C, Ph),
(2E,1ꢀS,4R)-4-Hydroxypent-2-enoic acid (1ꢀ-phenylethyl) amide
(21)
Concentrated HCl (1 mL) was added dropwise to a solution of
silyl ether 20 (1.4 g, 4.2 mmol) in i-PrOH (20 mL) at 0 ◦C and
the resulting colourless solution stirred at r.t. for 18 h. Solid
NaHCO3 was added portionwise until no further gas evolution
was observed. H2O (10 mL) and CH2Cl2 (10 mL) was added,
the layers separated and the aqueous layer extracted with CH2Cl2
(3 × 10 mL). The combined organic layers were dried (Na2SO4),
filtered and concentrated in vacuo to give a clear, colourless oil.
Purification by column chromatography [SiO2, hexanes–EtOAc
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127.5 (Ph), 126.5 (2C, Ph), 96.8 (C4H), 77.0 (C3H), 60.5 (C2H),
49.4 (C1ꢀH), 21.8 (C1ꢀCH3), 19.8 (C5H3). IR (solid): m = 3277 s,
3076 s, 3029 s, 2979 s, 2023 s, 1964 s, 1731 s, 1634 s, 1555 s cm−1.
LRMS (ES mode): m/z = 345 [MH+, 5%], 330 (90), 300 (95), 289
(50), 259 (5), 242 (100).
The mother liquors were concentrated in vacuo to give enriched
(2S,4R)-11 (42 mg) as a red oil. The dr was assigned from the 1H
NMR spectra by integration of the signals for the C2H at dH
=
3.59 (d, J 10.2) for (2R,4S)-11 and 3.57 (d, J 10.2) for (2S,4R)-11.24
(2E,1ꢀS,4S)-4-Methyl-N-(1ꢀ-phenylethyl)oct-2-enamide (23)
A solution of CuBr·SMe2 (215 mg, 1.05 mmol) in diisopropylsul-
fane (1 mL + 0.9 mL rinse) at 0 ◦C was added in one portion to
n-BuLi (1.57 M in hexanes, 1.33 mL, 2.09 mmol) in Et2O (21 mL) at
−78 ◦C and the resulting red–brown solution was stirred at −78 ◦C
for 1 h. The reaction mixture was allowed to warm to −50 ◦C for
Fig. 1 X-Ray structure of amide 23. The ellipsoid probabilities are 50%.
◦
30 min then recooled to −78 C. Complex (2R,4S)-11 (180 mg,
N8 was positioned in a planar configuration and the distance N8-
0.52 mmol) in THF (8.8 mL) at −50 ◦C was added dropwise
to the reaction mixture at −78 ◦C and the resulting red-brown
suspension stirred at −78 ◦C for 4 h and allowed to warm to r.t.
slowly (16 h) forming a dark brown suspension. The reaction was
quenched with pre-mixed NH4OH (10 mL) and NH4Cl (saturated
aqueous, 10 mL) at r.t. and O2 was bubbled through the reaction
mixture for 1 h. The layers were separated and the aqueous layer
extracted with Et2O (3 × 20 mL). The combined organic layers
were dried (Na2SO4), filtered and concentrated in vacuo to give a
yellow–orange oil. Purification by column chromatography [SiO2,
hexanes–Et2O (2 : 1)] followed by recrystallisation from hexanes
gave the title compound 23 (100 mg, 0.4 mmol, 74%) as colourless
˚
H8 refined to 0.85(3) A. All Uiso(H) values were constrained to
be 1.2 times Ueq of the parent atom. In the absence of significant
anomalous scattering effects, the absolute stereochemistry could
not be determined from the X-ray data and Friedel pairs were
merged. The model was assigned on the basis of the known (S)-
configuration of the phenethylamine.
(2E,1ꢀS,4S,6S,8S,)-9-(tert-Butyldiphenylsilyloxy)-4,6,8-
trimethyl-N-(1ꢀ-phenylethyl)non-2-enamide (26)
t-BuLi (1.65 M in pentane, 4.0 mL, 6.6 mmol) was added dropwise
to a solution of iodoalkane 16 (1.6 g, 3.3 mmol) in Et2O (35 mL) at
−78 ◦C and the resulting suspension stirred at −78 ◦C for 1 h. The
mixture was allowed to warm to r.t. slowly (1 h) and the pale yellow
solution then re-cooled to −78 ◦C. CuBr·SMe2 (340 mg, 1.7 mmol)
in diisopropylsulfane (2.5 mL◦, 0.5 mL rinse) was added rapidly to
the reaction mixture at −78 C, the resulting yellow suspension
needles: mp 87–88 ◦C; [a]D −84.0 (c = 0.5, CHCl3). H NMR
1
(500 MHz, CDCl3): d = 7.38–7.32 (4H, m, Ph), 7.30–7.24 (1H,
m, Ph), 6.77 (1H, dd, J 15.2, 7.7, C3H), 5.71 (1H, d, J 15.2,
C2H), 5.67 (1H, broad d, J 7.1, NH), 5.22 (1H, apparent quint,
J 7.5, C1ꢀH), 2.25 (1H, apparent sept, J 7.1, C4H), 1.53 (3H,
d, J 6.8, C1ꢀCH3), 1.41–1.20 (6H, m, C5H2/C6H2/C7H2), 1.04
(3H, d, J 6.6, C4CH3), 0.88 (3H, t, J 6.6, C8H3). 13C NMR
(75 MHz, CDCl3): d = 165.4 (C1), 150.8 (C3H), 143.4 (Ph),
128.8 (2C, Ph), 127.5 (Ph), 126.5 (2C, Ph), 121.9 (C2H), 48.8
(C1ꢀH), 36.5 (C4H), 36.0 (C5H2), 29.6 (C6H2), 22.9 (C7H2), 21.8
(C1ꢀCH3), 19.8 (C4CH3), 14.8 (C8H3). IR (neat): m = 3282 s, 1666 s,
1623 s cm−1. LRMS (ES mode): m/z = 282 [MNa+, 10%], 260
[MH+, 100]. HRMS (ES mode): m/z calculated for C17H26NO
[MH+]: 260.2014; found: 260.2008. Anal. calcd for C17H25NO: C,
78.72; H, 9.71; N, 5.40. Found: C, 78.60; H, 9.55; N, 5.35.
◦
stirred at −78 C for 1 h. The mixture was allowed to warm to
◦
−50 C for 30 min forming a pale yellow–orange suspension of
◦
the cuprate 17, and then recooled to −78 C. Complex (2R,4S)-
11 (285 mg, 0.8 mmol) in THF (12 mL, 2 mL rinse) was added
dropwise to the reaction mixture at −78 ◦C. The resulting orange–
brown suspension was stirred at −78 ◦C for 4 h and allowed
to warm to r.t. slowly (24 h) to give a dark brown suspension.
The reaction was quenched with a solution composed of NH4OH
(25 mL) and NH4Cl (saturated aqueous, 25 mL) at r.t. whereupon
O2 was bubbled through the reaction mixture for 2 h. The layers
were separated and the aqueous layer extracted with Et2O (3 ×
50 mL). The combined organic layers were dried (Na2SO4), filtered
and concentrated in vacuo to give a yellow–orange oil. Purification
by column chromatography [SiO2, hexanes–Et2O (5 : 1 → 3 : 1 →
2 : 1)] gave the title compound 26 (235 mg, 0.42 mmol, 51%) as
a pale red oil: [a]D −42.9 (c = 0.5, CHCl3). 1H NMR (500 MHz,
CDCl3): d = 7.68–7.64 (4H, m, Ph), 7.43–7.31 (10H, m, Ph), 7.29–
7.25 (1H, m, Ph), 6.78 (1H, dd, J 15.2, 7.5, C3H), 5.64 (1H,
dd, J 15.2, 1.1, C2H), 5.56 (1H, broad d, J 7.7, NH), 5.21 (1H,
apparent quint, J 7.7, C1ꢀH), 3.49 (1H, dd, J 9.8, 5.1, C9HAHB),
3.41 (1H, dd, J 9.8, 6.2, C9HAHB), 2.34 (1H, m, C4H), 1.71 (1H,
apparent oct, J 6.6, C8H), 1.56–1.46 (1H, m, C6H), 1.52 (3H, d,
J 7.1, C1ꢀCH3), 1.36 (1H, dt, J 13.7, 6.7, C7HAHB), 1.23 (1H,
ddd, J 13.6, 8.9, 5.2, C5HAHB), 1.12 (1H, ddd, J 13.6, 8.9, 5.2,
A single crystal X-ray analysis defined the relative stereochem-
istry of the amide 23 (Fig. 1). C17H25NO, monoclinic, space group
˚
˚
˚
P21, a = 11.2621(11) A, b = 5.2062(5) A, c = 14.3092(14) A, V =
792.83(13) A , Z = 2, qcalc = 1.087 Mg m−3, l = 0.066 mm−1,
3
˚
crystal size: 0.38 × 0.15 × 0.10 mm, data collection range: 2.80 ≤
h ≤ 25.99◦, 33635 measured reflections, final R(wR) values: 0.0319,
(0.0818) for 1743 independent data and 178 parameters [I > 2r(I)],
−3
˚
largest residual peak and hole: 0.301, −0.145 e A .†
Hydrogen atoms were positioned geometrically with the follow-
˚
˚
ing carbon–hydrogen distances: aromatic, 0.95 A; olefinic, 0.95 A;
˚
˚
˚
methyl, 0.98 A; methylene, 0.99 A; methine, 1.00 A. H8 attached to
† CCDC reference number 606362. For crystallographic data in CIF
format see DOI: 10.1039/b606262h
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C5HAHB), 1.05 (9H, s, (CH3)3CSi), 0.98 (3H, d, J 6.8, C4CH3),
0.96–0.86 (1H, m, C7HAHB), 0.92 (3H, d, J 6.6, C8CH3), 0.81 (3H,
d, J 6.3, C6CH3). 13C NMR (75 MHz, CDCl3): d = 165.4 (C1),
151.4 (C2H), 143.3 (Ph), 135.8 (4C, Ph), 134.3 (Ph), 134.2 (Ph),
129.7 (2C, Ph), 128.9 (2C, Ph), 127.8 (4C, Ph), 127.6 (Ph), 126.5
(2C, Ph), 121.3 (C2H), 69.1 (C9H2), 48.9 (C1ꢀH), 43.6 (C5H2), 41.8
(C7H2), 33.8 (C4H), 33.3 (C8H), 27.9 (C6H), 27.1 ((CH3)3CSi),
21.8 (C4CH3), 20.4 (C6CH3), 19.5 ((CH3)3CSi), 19.1 (C1ꢀCH3),
17.9 (C8CH3). IR (neat): m = 3266 br, 1665 m, 1626 s cm−1. LRMS
(ES mode): m/z = 578 [MNa+, 65%], 556 [M+, 30], 479 (80),
478 (100). HRMS (ES mode): m/z calculated for C36H49NO2NaSi
[MNa+]: 578.3430; found: 578.3419.
and concentrated in vacuo to give the crude N-Boc amide 28 (and
Boc2O) as a yellow oil which was used with no further purification.
LiOH (1 M solution, 0.38 mL, 0.38 mmol) was added to the
crude N-Boc amide 28 in THF (1 mL) and the resulting yellow
mixture heated under reflux for 4 h. The THF was removed in vacuo
and the aqueous solution poured into a stirred solution of HCl
(1 M, 10 mL) and Et2O (10 mL). The layers were separated and
the aqueous layer extracted with Et2O (2 × 10 mL). The combined
organic layers were dried (Na2SO4), filtered and concentrated in
vacuo. The residue was dissolved in PhH (3 mL) and MeOH (1 mL)
◦
at 0 C whereupon TMSCHN2 (2 M solution in Et2O, 0.66 mL,
1.3 mmol) was added dropwise. The resulting yellow solution was
stirred at 0 ◦C for 2 h and concentrated in vacuo. The residue was
purified by column chromatography [SiO2, hexanes–Et2O (10 : 1)]
to give the title compound 3 (42 mg, 0.1 mmol, 68% over 3 steps)
(2E,1ꢀS,4R,6S,8S)-9-(tert-Butyldiphenylsilyloxy)-4,6,8-trimethyl-
N-(1ꢀ-phenylethyl)nonanamide (27)
1
as a colourless oil. The H and 13C NMR data recorded at 500
A mixture of 26 (225 mg, 0.4 mmol) and Pd(OH)2 (20% on
activated charcoal, 10 mg) in MeOH (8 mL) at r.t. was stirred
under an atmosphere of hydrogen for 24 h. The reaction mixture
was filtered through a celite pad washing the black residue with
MeOH (10 mL) and CH2Cl2 (30 mL) and the filtrate concentrated
in vacuo. The residue was purified by column chromatography
[SiO2, hexanes–Et2O (1 : 1)] to give the title compound 27 (229 mg,
0.4 mmol, 100%) as a colourless oil: [a]D −6.2 (c = 0.5, CHCl3).
1H NMR (500 MHz, CDCl3): d = 7.72–7.67 (4H, m, Ph), 7.47–
7.33 (10H, m, Ph), 7.31–7.27 (1H, m, Ph), 5.63 (1H, broad s,
NH), 5.18 (1H, apparent quint, J 6.6, C1ꢀH), 3.52 (1H, dd, J 9.9,
5.5, C9HAHB), 3.44 (1H, dd, J 9.9, 6.4, C9HAHB), 2.22 (2H, m,
C2H2), 1.75 (1H, apparent oct, J 6.6, C8H), 1.51 (3H, d, J 6.8,
C1ꢀCH3), 1.62–1.47 (3H, m, C4H/C6H/C3HAHB), 1.31 (1H, dt,
J 13.7, 6.8, C7HAHB), 1.08 (9H, s, (CH3)3CSi), 1.12–1.05 (1H,
m, C5HAHB), 0.95 (3H, d, J 6.6, C8CH3), 1.02–0.91 (3H, m,
C3HAHB/C5HAHB/C7HAHB), 0.85 (3H, d, J 6.2, C4CH3), 0.80
(3H, d, J 6.6, C6CH3). 13C NMR (75 MHz, CDCl3): d = 172.5
(C1), 143.4 (Ph), 135.8 (4C, Ph), 134.3 (2C, Ph), 129.7 (2C, Ph),
128.9 (2C, Ph), 127.8 (4C, Ph), 127.5 (Ph), 126.4 (2C, Ph), 69.2
(C9H2), 48.7 (C1ꢀH), 44.3 (C5H2), 42.3 (C7H2), 34.9 (C2H2), 34.1
(C3H2), 33.2 (C8H), 30.1 (C4H), 27.6 (C6H), 27.1 ((CH3)3CSi),
21.9 (C1ꢀCH3), 20.2 (C6CH3), 19.5 ((CH3)3CSi), 19.1 (C4CH3),
17.7 (C8CH3). IR (neat): m = 3282 br, 1639 s cm−1. LRMS (ES
mode): m/z = 580 [MNa+, 55%], 558 [MH+, 100], 481 (98), 480
(100). HRMS (ES mode): m/z calculated for C36H52NO2Si [MH+]:
558.3767; found 558.3782.
and 125 MHz, respectively, were identical to those obtained on a
sample of 3 prepared by an unambiguous route.18
(2R,4S)-6-Hydroxy-2,4-dimethylhexanoate (32)
Oxalyl chloride (0.75 mL, 8.7 mmol) was added dropwise to a
solution of (2R,4S)-2,4-dimethylpentanedioic acid monomethyl
ester 29 (500 mg, 2.9 mmol) in PhH (1 mL) at 0 ◦C and the resulting
solution stirred at 0 ◦C for 4 h [gas evolution was observed].
The reaction mixture was concentrated in vacuo to give the acid
chloride (1782 s, 1736 s cm−1) as a colourless oil that was used with
no further purification.
The acid chloride in PhH (2 mL) was added dropwise to a so-
lution of diazomethane [prepared from Diazald (2.0 g, 9.3 mmol)
in Et2O (45 mL)] at 0 ◦C and the resulting yellow solution stirred
at 0 ◦C for 2 h. The reaction mixture was concentrated in vacuo to
give the a-diazoketone 30 (2106 s, 1732 s cm−1) as an orange oil
that was used in the next step with no further purification.
The a-diazoketone 30 in dioxane (10 mL) was added dropwise
to a suspension of Ag2O (672 mg, 2.9 mmol) and Na2S2O3·5H2O
◦
(720 mg, 2.9 mmol) in H2O (15 mL) at 0 C [gas evolution was
◦
observed]. The resulting dark suspension was stirred at 0 C for
20 min and the reaction quenched with HCl (1 M, 30 mL). The
reaction mixture was filtered, the layers separated, and the aqueous
layer extracted with CH2Cl2 (3 × 30 mL). The combined organic
layers were dried (Na2SO4), filtered and concentrated in vacuo to
give the acid 31 (1737 s, 1710 s cm−1) as a yellow oil that was used
in the next step with no further purification.
BH3·SMe2 (2.0 M in THF, 1.6 mL, 3.2 mmol) was added
dropwise to a solution of the acid 31 in THF (10 mL) at −20 ◦C
and the resulting solution stirred at −20 ◦C for 1 h and allowed to
warm slowly to r.t. over 18 h. H2O (10 mL) and EtOAc (10 mL)
was added to the reaction mixture, the layers separated and the
aqueous layer extracted with EtOAc (3 × 10 mL). The combined
organic layers were dried (Na2SO4), filtered and concentrated in
vacuo. The residue was purified by column chromatography [SiO2,
hexanes–Et2O (1 : 1)] to give the title compound 32 (219 mg,
1.3 mmol, 44% over 4 steps) as a colourless oil: [a]D −28.9 (c = 2.5,
CHCl3). 1H NMR (500 MHz, CDCl3): d = 3.68 (1H, dt, J 10.7, 6.4,
C6HAHB), 3.69–3.63 (1H, m, C6HAHB), 3.68 (3H, s, OCH3), 2.62–
2.54 (1H, m, C2H), 1.77 (1H, m, C3HAHB), 1.63 (1H, broad s, OH),
1.61–1.52 (1H, m, C4H), 1.55–1.49 (1H, m, C5HAHB), 1.46–1.39
(1H, m, C5HAHB), 1.16 (3H, d, J 7.3, C6CH3), 1.18–1.11 (1H, m,
Methyl [4R,6S,8S]-9-(tert-Butyldiphenylsilyloxy)-4,6,8-
trimethylnonanoate (3)
LHMDS (2.0 M in THF, 0.14 mL, 0.14 mmol) was added dropwise
to 27 (70 mg, 0.13 mmol) in THF (3 mL) at −10 ◦C and the
resulting pale yellow solution stirred at −5 ◦C for 30 min. Boc2O
(82 mg, 0.38 mmol) in THF (1 mL, 0.4 mL rinse) was added to the
reaction mixture and the resulting yellow solution stirred at r.t. for
30 min. DMAP (3 mg, 0.025 mmol) in THF (0.3 mL) was added
to the reaction mixture at r.t. and the resulting yellow suspension
◦
stirred at r.t. for 1 h, then heated at 45 C for 3 h. The reaction
was quenched with NH4Cl (saturated aqueous, 5 mL) and Et2O
(5 mL), the layers separated and the aqueous layer extracted with
Et2O (2 × 10 mL). The combined organic layers were washed
with H2O (10 mL) and brine (10 mL), dried (Na2SO4), filtered
3332 | Org. Biomol. Chem., 2006, 4, 3325–3336
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C3HAHB), 0.93 (3H, J 6.4, C4CH3). 13C NMR (75 MHz, CDCl3):
d = 177.8 (C1), 60.9 (C6H2), 52.0 (OCH3), 41.0 (C5H2), 39.9
(C3H2), 37.5 (C6H), 27.8 (C4H), 20.0 (C6CH3), 18.4 (C4CH3).
IR (neat): m = 3420 br, 1736 s cm−1. LRMS (ES mode): m/z = 197
[MNa+, 80%], 175 [MH+, 95]. Anal. calcd for C9H18O3: C, 62.04;
H, 10.41. Found: C, 61.80; H, 10.60.
(R)-4-(tert-Butyldiphenylsilyloxy)-2-methylbutan-1-ol (36)
n-BuLi (1.58 M in hexanes, 12.6 mL, 19.5 mmol, 4.0 equiv.)
was added dropwise to a suspension of LiCl (2.62 g, 0.062 mol,
12.7 equiv.) and diisopropylamine (2.95 mL, 20.9 mmol,
4.3 equiv.) in THF (13.5 mL) at −78 ◦C. The resulting suspension
was stirred at −78 ◦C for 10 ◦min and 0 ◦C for 10 min. The
suspension was cooled to −78 C and propionamide 34 (2.26 g,
10.2 mmol, 2.1 equiv.) in THF (31 mL) added dropwise at a rate
sufficient to maintain the reaction temperature below −70 ◦C. The
Conversion of 32 to 33
TBDPSCl (302 mg, 1.1 mmol) in CH2Cl2 (1.5 mL) was added
to a solution of alcohol 32 (188 mg, 1.08 mmol)), imidazole
(88 mg, 1.3 mmol) and DMAP (13 mg, 0.11 mmol) in CH2Cl2
(2 mL). The reaction was stirred at r.t. for 5 h whereupon CH2Cl2
(15 mL) and H2O (5 mL) was added and the layers separated.
The aqueous layer was extracted with CH2Cl2 (2 × 5 mL). The
combined organic layers were washed with H2O (10 mL), dried
(Na2SO4), filtered and concentrated in vacuo. The residue was
dissolved in THF (3 mL) to which was added methanolic LiOH
(3.0 M, 2.0 mL) and the mixture stirred at ambient temperature
until TLC indicated complete consumption of starting material
(ca. 2 h). The reaction mixture was poured into iced 0.1 M HCl
(10 mL) and the product extracted into CH2Cl2 (3 × 10 mL). The
combined organic layers were washed with H2O (5 mL), dried
(Na2SO4), filtered and concentrated in vacuo. The residue was
purified by column chromatography [SiO2 Et2O–hexanes (1 : 3)] to
give carboxylic acid 33 (409 mg, 1.03 mmol, 95%) as a colourless
oil. The spectroscopic data were identical to those recorded on a
sample of 33 prepared by a different route (see below).
◦
◦
reaction was stirred at −78 C for 1 h, 0 C for 15 min and r.t.
for 5 min. The reaction was cooled to 0 ◦C and 1-iodo-2-(tert-
butyldiphenylsilyloxy)ethane53 (1.5 g, 3.32 mmol, 1.0 equiv.) in
◦
THF (1.4 mL) added. The reaction was stirred at 0 C for 14 h,
slowly warming to r.t. Thereafter, the reaction was quenched by
the dropwise addition of saturated aqueous NH4Cl (30 mL). The
layers were separated and the aqueous layer extracted with Et2O
(3 × 30 mL). The combined organic layers were dried (Na2SO4),
filtered and concentrated in vacuo. The residue was purified by
column chromatography [SiO2, Et2O–hexanes (1 : 3)] to give the
amide 35 (2.56 g) as a colourless oil that was used directly in the
next step.
n-BuLi (1.58 M in hexanes, 12.0 mL, 19.0 mmol, 3.9 equiv.)
was added dropwise to a solution of diisopropylamine (2.9 mL,
20.45 mmol, 4.2 equiv.) in THF (22 mL) at −78 ◦C. The reaction
◦
◦
was stirred at −78 C for 10 min and 0 C for 10 min. Borane–
ammonia complex (0.6 g, 19.5 mmol, 4.0 equiv.) was added in one
portion and the resulting suspension stirred at 0 ◦C for 10 min
and r.t. for 15 min. The crude amide 35 (2.56 g) in THF (12.0 mL,
2.5 mL wash) was added dropwise at 0 ◦C. The resulting colourless
solution was warmed to r.t. and stirred for 2 h. The reaction was
cooled to 0 ◦C and HCl (2 M, 20 mL) added dropwise. The solution
was stirred at r.t. for 30 min. The layers were separated and the
aqueous layer extracted with Et2O (4 × 30 mL). The combined
organic layers were washed with HCl (2 M, 20 mL), NaOH
(2 M, 20 mL) and brine (20 mL) before being dried (Na2SO4),
filtered and concentrated in vacuo. The residue was purified by
column chromatography [SiO2, Et2O–hexanes (1 : 4)] to give the
title compound 36 (1.46 g, 4.27 mmol, 87%) as a colourless oil:
(3R,5S)-7-(tert-Butyldiphenylsilyloxy)-1-diazo-3,5-
dimethylheptan-2-one (4)
Oxalyl chloride (35 lL, 0.4 mmol, 1.6 equiv) was added to
a solution of 33 (100 mg, 0.25 mmol, 1.0 equiv.) in CH2Cl2
(1 mL). The reaction was stirred at r.t. for 2 min before cooling
◦
to 0 C. DMF (1 drop) was added and immediate effervescence
occurred. The reaction was stirred at 0 ◦C until effervescence had
ceased (2 h). The resulting pale yellow solution was concentrated
in vacuo giving a yellow oil that was dissolved in MeCN–THF (1 :
1, 2 mL). The resulting pale yellow solution was added dropwise
to a solution of diazomethane [prepared from Diazald (1.5 g,
7.0 mmol) in Et2O (22 mL)] at 0 ◦C. The reaction was stirred for 1 h.
Thereafter, nitrogen was bubbled through the solution for 30 min
at 0 ◦C to give a colourless solution. The solution was concentrated
in vacuo. The residue was purified by column chromatography
[SiO2, Et2O–hexanes (1 : 5)] to give the title compound 4 (87 mg,
0.21 mmol, 82%) as a yellow oil: [a]2D4 −20.95 (c = 0.21, CHCl3).
1H NMR (500 MHz, CDCl3): d = 7.67 (4H, dd, J 7.8 and 1.4),
7.45–7.38 (6H, m), 5.12 (1H, s, C1H) 3.75–3.66 (2H, m, C16H2),
2.47–2.44 (1H, m, C12H), 1.72–1.57 (3H, m, C14H/C15H2), 1.34–
1.28 (1H, m, C13HAHB), 1.20–1.14 (1H, m, C13HAHB), 1.10 (3H,
d, J 6.89, C12HCH3), 1.06 (9H, s, C(CH3)3), 0.86 (3H, d, J 6.45,
◦
1
[a]D +4.5 (c = 1.2, Et2O, 20 C). H NMR, 13C NMR and IR
spectroscopic data agree with those reported.54 The er of alcohol
1
36 (98 : 2) was established by H and 19F NMR spectroscopic
analysis of the corresponding Mosher ester derivative which was
prepared as follows:
Alcohol 36 (15 mg, 44 lmol, 1.0 equiv.) in CH2Cl2 (1 mL)
was added dropwise to a stirred solution of (R)-3,3,3-trifluoro-
2-methoxy-2-phenylpropanoic acid (15 mg, 62 lmol, 1.4 equiv.),
DCC (13 mg, 62 lmol, 1.4 equiv.) and DMAP (1 mg, 6.2 lmol,
0.1 equiv.) in CH2Cl2 (4 mL). The reaction was stirred at r.t.
for 5 h whereupon TLC analysis showed remaining 36. DCC
(13 mg, 62 lmol, 1.4 equiv.) and (R)-3,3,3-trifluoro-2-methoxy-
2-phenylpropanoic acid (15 mg, 62 lmol, 1.4 equiv.) were added
and the reaction stirred for a further 16 h whereupon TLC analysis
showed complete consumption of 36. Thereafter, the mixture was
filtered and the filtrate washed with water (2 × 2 mL). The organic
layer was dried (MgSO4), filtered and concentrated in vacuo. The
residue was purified by column chromatography [SiO2, Et2O–
petrol (1 : 4)] giving the Mosher ester of 36 (21 mg, 40 lmol, 83%)
as a pale yellow oil: 1H NMR (500 MHz, CDCl3, major isomer):
C14HCH3). 13C NMR (300 MHz, CDCl3): d = 199.3 (C2, C O),
=
135.7 (4CH), 134.1 (2C), 129.7 (2CH), 127.8 (4CH), 62.0 (C16H2),
41.7 (C12H2), 39.6 (C14H2) 27.5 (C13H), 27.0 (3C, C(CH3)3),
19.9 (C14CH3), 19.4 (C, C(CH3)3), 18.0 (C12CH3). IR (neat): m =
2101 s, 1645 s cm−1. LRMS (ES mode): m/z = 396.3 [(M–N2 +
2H)+, 45%], 395.2 (M–N2 + H). HRMS (ES mode): m/z calcd for
C25H35O2Si: 395.2406; found: 395.2412 [M–N2].
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d = 7.66 (4H, dd, J 6.5 and 1.5), 7.52 (2H, m, ArH), 7.45–7.37
(9H, m and ArH), 4.29 (1H, dd, J 10.7 and 5.4, C13HAHB), 4.11
(1H, dd, J 10.7 and 6.5, C13HAHB), 3.74–3.66 (2H, m, C16H),
3.55 (3H, d, J 1.1, OCH3), 2.12 (1H, m, C14H), 1.71–1.64 (1H, m,
C15HAHB), 1.43–1.35 (1H, m, C15HAHB), 1.05 (9H, s, C(CH3)3),
0.91 (3H, d, J 6.7, C14CH3). 13C NMR (300 MHz, CDCl3, major
isomer): d = 166.8 (CO2R), 135.7 (CH), 133.9 (C), 132.5 (C), 129.8
(CH), 129.76 (CH), 128.6 (CH), 127.9 (CH), 127.5 (CH), 71.5
(C13H2), 61.6 (C16H2), 55.6 (OCH3), 35.9 (C15H2), 29.6 (C14H),
27.0 (C(CH3)3), 19.3 (C(CH3)3), 16.8 (C14CH3). A signal for the
CF3 group was not detected. 19F NMR (470 MHz, CDCl3): d =
−71.993 (major); −72.017 (minor). IR (neat): m = 2923 s, 1749 s,
1169 s, 1111 s cm−1. HRMS (ES mode) m/z = found: 581.2295
[MNa+, 80%]. C31H37O4F3NaSi requires: 581.2311.
portion and the resulting suspension stirred at 0 ◦C for 10 min and
r.t. for 15 min. The amide 38 (1.18 g) in THF (9 mL, 1 mL wash)
was added dropwise at 0 ◦C. The resulting colourless solution
was warmed to r.t. and stirred for 2 h. The reaction was cooled
to 0 ◦C and HCl (2 M, 20 mL) added dropwise. The solution
was stirred at r.t. for 30 min. The layers were separated and the
aqueous layer extracted with Et2O (4 × 30 mL). The combined
organic layers were washed with HCl (2 M, 20 mL), NaOH (2 M,
20 mL) and brine (20 mL) before being dried (Na2SO4), filtered
and concentrated in vacuo. The residue was purified by column
chromatography [SiO2, Et2O–hexanes (1 : 5)] to give the title
compound 39 (0.75 g, 1.95 mmol, 59%, single diastereoisomer) as
a colourless oil. This compound has been prepared previously,55
1
but no spectroscopic data was reported. H NMR (500 MHz,
CDCl3): d = 7.68 (4H, dd, J 7.8 and 1.3), 7.45–7.38 (6H, m),
3.76–3.66 (2H, m, C6H2), 3.51–3.49 (1H, m, C11HAHB), 3.39–3.36
(1H, m, C11HAHB), 1.77–1.61 (3H, m, C12H/C14H/C15HAHB),
1.32–1.24 (2H, m, C13HAHB/C15HAHB), 1.24 (1H, broad s, OH),
1.06 (9H, s, C(CH3)3), 0.97–0.90 (1H, m, C13HAHB), 0.92 (3H,
d, J 6.7, C4HCH3), 0.85 (3H, d, J 6.6, C12CH3). 13C NMR
(300 MHz, CDCl3): 135.8 (4C), 134.2 (2C), 129.7 (4C), 127.8
(4C), 68.6 (C1H2), 62.1 (C16H2), 41.2 (C13H2), 39.3 (C15H2),
33.2 (C12H), 27.0 (3C, C(CH3)3), 26.8 (C14H), 20.6 (C12HCH3),
19.4 (C(CH3)3), 17.3 (C14HCH3). IR (neat): m = 3368 br s, 1111 s,
701 s cm−1. LRMS (ES mode): m/z = 385 (M+H, 20%). HRMS (ES
mode): m/z calcd for C24H36O2NaSi: 407.2382; found: 407.2373
[MNa]. Anal. calcd for C24H36O2Si: C, 74.94; H, 9.43. Found: C,
75.0; H, 9.5.
(R)-4-Iodo-3-methyl-(tert-butyldiphenylsilyloxy)-butane (37)
Iodine (1.3 g, 3.8 mmol, 1.0 equiv.) was added in one portion
to a colourless solution of PPh3 (1.3 g, 4.94 mmol, 1.3 equiv.)
and imidazole (0.67 g, 9.9 mmol, 2.6 equiv.) in CH2Cl2 (20 mL).
The reaction was stirred at r.t. for 10 min giving a red–orange
suspension. Alcohol 36 (1.3 g, 3.8 mmol, 1.0 equiv.) in CH2Cl2
(11 mL) was added dropwise and the reaction stirred at r.t. for
2 h. The reaction mixture was washed with saturated aqueous
Na2S2O3 (2 × 20 mL). The organic layer was dried (MgSO4),
filtered and concentrated in vacuo. The residue was purified by
column chromatography [SiO2, Et2O–hexanes (1 : 9)] to give the
title compound 37 (1.61 g, 3.56 mmol, 93%) as a colourless oil: [a]D22
−0.6 (c = 1.3, Et2O); lit.54 [a]D22 − 0.50 (c = 1.2, Et2O). 1H NMR,
13C NMR and IR spectroscopic data agree with those reported.54
(2R,4S)-6-(tert-Butyldiphenylsilyloxy)-2,4-dimethylhexanoic acid
(33)
(2R,4S)-6-(tert-Butyldiphenylsilyloxy)-2,4-dimethylhexan-1-ol
(39)
RuCl3·nH2O (17 mg) was added in one portion to a solution of 39
(0.62 g, 1.6 mmol, 1.0 equiv.) and NaIO4 (1.21 g, 5.6 mmol, 3.5
equiv.) in CCl4 (3.9 mL), MeCN (3.9 mL) and H2O (6.2 mL). The
reaction was stirred vigorously at r.t. for 3.5 h. Thereafter, Et2O
(5 mL) and H2O (5 mL) were added and the layers separated. The
organic layer was extracted with Et2O (5 × 5 mL). The combined
organic layers were dried (Na2SO4), filtered and concentrated in
vacuo. The green residue was purified by column chromatography
[SiO2 Et2O–hexanes (1 : 3)] to give the title compound 33 (0.57 g,
1.43 mmol, 89%) as a colourless oil: 1H NMR (500 MHz, CDCl3):
d = 7.67 (4H, dd, J 7.8 and 1.5), 7.44–7.37 (6H, m), 3.74–3.65
(2H, m, C16H2), 2.58–2.54 (1H, m, C12H), 1.74–1.67 (2H, m,
C13HAHB/C14H), 1.64–1.57 (1H, m, C15HAHB), 1.36–1.29 (1H,
m, C15HAHB), 1.23–1.16 (1H, m, C13HAHB), 1.17 (3H, d, J 6.91,
C14HCH3), 1.04 (9H, s, C(CH3)3), 0.86 (3H, d, J 6.4, C12HCH3).
13C NMR (300 MHz, CDCl3): 135.8 (4CH), 134.2 (2C), 129.7
(4CH), 127.8 (4CH), 61.9 (C16H2), 41.4 (C13H2), 39.6 (C15H2),
37.2 (C12H), 27.5 (C14H), 27.0 (C(CH3)3), 19.7 (C12HCH3), 19.3
n-BuLi (1.6 M in hexanes, 8.3 mL, 13.3 mmol, 4.0 equiv.) was
added dropwise to a suspension of LiCl (1.79 g, 42.2 mmol, 12.7
equiv.) and diisoprop◦ylamine (2.0 mL, 14.3 mmol, 4.3 equiv.) in
THF (9 mL) at −78 C. The resulting suspension was stirred at
−78 ◦C for 10 min and 0 ◦C for 10 min. The suspension was
cooled to −78 ◦C and N-[(1S,2S)-1-hydroxy-1-phenylpropan-2-
yl]-N-methylpropionamide 34 (1.54 g, 7.0 mmol, 2.1 equiv.) in
THF (21 mL) added dropwise at a rate sufficient to maintain the
◦
reaction temperature below −70 C. The reaction was stirred at
◦
◦
−78 C for 1 h, 0 C for 15 min and r.t. for 5 min. The reaction
was cooled to 0 ◦C and iodoalkane 37 (1.5 g, 3.3 mmol, 1.0 equiv.)
in THF (1.4 mL) added dropwise. The reaction was stirred at
0 ◦C for 14 h, slowly warming to r.t. Thereafter, the reaction was
quenched by the dropwise addition of saturated aqueous NH4Cl
(30 mL). The layers were separated and the aqueous layer extracted
with Et2O (3 × 30 mL). The combined organic layers were dried
(Na2SO4), filtered and concentrated in vacuo. The residue was
purified by column chromatography [SiO2, Et2O–hexanes (1 : 3)]
to give the amide 38 (1.18 g) as a colourless oil that was used
directly in the next step.
=
(C(CH3)3), 17.2 (C14HCH3). (C O, not visible). IR (neat): m =
3300–2200 m br, 1706 s, 1111 s cm−1. LRMS (ES mode): m/z =
421.3 (MNa+, 80%), 381.3 (67), 261.2 (100). HRMS (ES mode):
m/z calcd for C24H34O3NaSi: 421.2175; found: 421.2195 [MNa].
n-BuLi (1.6 M in hexanes, 8.1 mL, 13.0 mmol, 3.9 equiv.)
was added dropwise to a solution of diisopropylamine (2.0 mL,
bis[(−)-1-Neomenthylindenyl)zirconium dichloride (41)
◦
13.9 mmol, 4.2 equiv.) in THF (15 mL) at −78 C. The reaction
◦
◦
was stirred at −78 C for 10 min and 0 C for 10 min. Borane–
The title compound was prepared by
a modification of
ammonia complex (0.41 g, 13.3 mmol, 4.0 equiv.) was added in one
the procedure by Erker and co-workers.49 n-BuLi (1.58 M
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in hexanes, 7.37 mL, 11.65 mmol, 2.0 equiv.) was added
dropwise to a solution of (+)-3-[1ꢀS,2ꢀS,5ꢀR)-2ꢀ-isopropyl-5ꢀ-
methylcyclohexyl]indene (2.96 g, 11.65 mmol, 2.0 equiv.) in THF
(80 mL) at 0 ◦C. The reaction was stirred at r.t. for 2.5 h. The
solution was cooled to −40 ◦C and transferred by cannula to a
flask containing a suspension of ZrCl4(thf)2 (2.20 g, 5.82 mmol,
1.0 equiv.) in PhMe (30 mL) at −78 ◦C. The reaction mixture
was gradually warmed to r.t. (over 4 h) and stirred for a further
16 h whereupon a bright yellow suspension was obtained. The
solvent was removed in vacuo (vacuum quenched with N2) giving
a yellow–orange solid. The solid was washed with pentane (40 mL)
and treated with CH2Cl2 (80 mL) under a nitrogen atmosphere.
After stirring at r.t. for 2 h the precipitate was removed by filtration
through a celite pad (under nitrogen). The yellow–orange filtrate
was concentrated to saturation (solvent removal by distillation)
and set in the freezer for 16 h. The mother liquor was removed via
cannula and the crystals washed at −78 ◦C with CH2Cl2 (5 mL).
After removal of the washings the crystals were dried under a
stream of nitrogen for 2 h. The title compound (0.6 g, 0.9 mmol,
15%) was obtained as bright yellow needles (2 crops): mp 140–
and H2O (31 lL, 1.77 mmol, 1.0 equiv.) added dropwise with
vigorous stirring. The reaction was warmed to r.t. (over 2 h)
whereupon a dark orange–red solution was obtained. The solution
was cooled to −20 ◦C and crude 43 in CH2Cl2 (1.0 mL) added
◦
dropwise. The reaction was stirred at −20 C for 4 h and r.t. for
15 h. The reaction was cooled to 0 ◦C and O2 bubbled through for
3 h. The solution was washed with NaOH (2 M, 2 × 5 mL) and
brine (5 mL), dried (MgSO4), filtered, and concentrated in vacuo.
The residue was purified by column chromatography [SiO2, Et2O–
hexanes (1 : 5)] to give the title compound 39 (348 mg, 0.9 mmol,
51%, dr 2.3 : 1) as a colourless oil. The dr of 39 varied between
2.2 : 1 to 3.7 : 1 and we were unable to identify an experimental
procedure that gave consistent results.
The identity of the major product 39 and the dr was determined
by comparison of the 13C and 1H NMR spectroscopic data
recorded on the mixture with those recorded for the pure isomer
prepared as described above.
Methyl [4R,6S,8S]-9-hydroxy-4,6,8-trimethylnonanoate (44)
◦
◦
TBAF·3H2O (61 mg, 0.23 mmol) was added in one portion to
silyl ether 3 (100 mg, 0.2 mmol) in THF (1.0 mL) at r.t. and the
resulting pale yellow solution was stirred at r.t. for 3 h. H2O (2 mL)
was added, the layers separated and the aqueous layer extracted
with Et2O (2 × 2 mL). The combined organic layers were dried
(Na2SO4), filtered and concentrated in vacuo to give a colourless
oil. Purification by column chromatography [SiO2, hexanes–Et2O
(5 : 1) → (1 : 3)] gave the title compound 44 (49 mg, 0.2 mmol,
100%) as a colourless oil. [a]D −20.1 (c = 1.0, CHCl3); lit.5 [a]D
−37.0 (c = 1.0, CHCl3), Lit.16 [a]D −22.6 (c = 1.0, CHCl3), Lit.17
[a]D −26.8 (c = 1.0, CHCl3). Spectroscopic data are in accordance
with those reported.5,16,17
141.5 C; lit.49 mp 146 C; [a]D22 −67 (c = 0.1, PhCH3); lit.49 [a]2D2
−77 (c = 0.23, PhCH3). 1H NMR, 13C NMR and IR spectroscopic
data agree with those reported. 49
(R)-4-(tert-Butyldiphenylsilyloxy)-2-methyl-butan-1-ol (36) via
carboalumination
Alcohol 36, prepared on a 1.0 mmol scale (74%) from 4-
(tert-butyldiphenylsilyloxy)-but-3-ene48 according to literature
procedure,54 gave NMR and IR spectroscopic data that agree with
those reported.54 [a]D22 +4 (c = 1.5, Et2O). The er of 36 (88 : 12) was
ascertained by integration of the 19F signals of the Mosher ester
derivative prepared as described above.
Methyl (4R,6S,8S)-4,6,8-trimethyl-9-oxononanoate (47)
The aldehyde 45, prepared on a 0.44 mmol scale (75% yield from
44) according to a literature procedure,5 gave spectroscopic data
in accordance with those reported.5,16,17 [a]D = −10.1 (c = 1.0,
CHCl3); lit.5 [a]D = −9.0 (c = 1.0, CHCl3).
(2R,4S)-6-(tert-Butyldiphenylsilyloxy)-2,4-dimethylhexan-1-ol
(39) via carboalumination
t-BuLi (1.63 M in pentane, 2.17 mL, 3.54 mmol, 2.0 equiv.) was
added dropwise to a solution of iodoalkane 37 (0.8 g, 1.77 mmol,
◦
1.0 equiv.) in Et2O (1.7 mL) at −78 C. The mixture was stirred
Methyl (4R,6S,8S,12R,14S,Z)-16-(tert-butyldiphenylsilyloxy)-
at −78 ◦C for 40 min whereupon ZnBr2 (0.26 g, 1.15 mmol, 0.65
equiv.) in THF (17 mL) was added dropwise. The mixture was
stirred at −78 ◦C for 30 min and 0 ◦C for 10 min. A solution
of freshly prepared Pd(PPh3)4 (0.104 g, 0.09 mmol, 5 mol%) in
a 4 M solution of vinyl bromide in THF (1.77 mL, 4.0 equiv.)
was added via syringe at 0 ◦C. The mixture was allowed to warm
gradually to r.t. over 15 h whereupon H2O (5 mL) was added
and the resultant mixture filtered through celite. The layers of the
filtrate were separated and the aqueous phase extracted with Et2O
(3 × 5 mL). The combined organic layers were washed with brine
(5 mL), dried (MgSO4), filtered and concentrated in vacuo. The
residue, consisting of an inseparable mixture of 43 and the tert-
butyldiphenylsilyl ether of 3-methylbutanol, was passed through
a short column of silica gel eluting with hexanes. Evaporation of
the solvent gave a colourless oil that was used immediately in the
next step.
11-hydroxy-4,6,8,12,14-pentamethyl-9-oxohexadec-10-enoate (2)
n-BuLi (1.6 M in hexanes, 0.11 mL, 0.17 mmol, 1.0 equiv.)
was added dropwise to a solution of diisopropylamine (27 lL,
0.19 mmol, 1.1 equiv.) in THF (0.16 mL) at −78 ◦C. The reaction
was stirred at −78 ◦C for 10 min and 0 ◦C for 10 min. The solution
was cooled to −20 ◦C and added dropwise to a pale yellow solution
of a-diazoketone 4 (70 mg, 0.17 mmol, 1.0 equiv.) and aldehyde 45
(39 mg, 0.17 mmol, 1.0 equiv.) in THF (0.25 mL) at −78 ◦C. The
resulting red–orange solution was stirred at −78 ◦C for 1 h before
being quenched by dropwise addition of AcOH–Et2O (1 : 5,
1.5 mL). The resulting pale yellow solution was warmed to r.t. and
water (1 mL) added. The layers were separated and the organic
layer washed with NaHCO3 (saturated aqueous, 2 × 1 mL) and
brine (1 mL), dried (MgSO4), filtered and concentrated in vacuo.
The residue was purified by column chromatography [SiO2, Et2O–
hexanes (1 : 5)] to give the a-diazo-b-hydroxy carbonyl compound
47 (80 mg) as a yellow oil and recovered 4 (15 mg, 0.036 mmol). The
yellow oil was dissolved in DME (0.5 mL) whereupon Rh2(OAc)4
Neat AlMe3 (0.51 mL, 5.31 mmol, 3.0 equiv.) was added to a
solution of (−)-41 (6.0 mg, 0.088 mmol, 0.5 mol%) in CH2Cl2
(7 mL). The resulting homogenous solution was cooled to −50 ◦C
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(1 mg, 2 lmol, 0.01 equiv.) was added. The resultant emerald
green solution was stirred at r.t. for 100 min. The reaction mixture
was filtered through a pad of celite eluting with hexanes (10 mL).
The filtrate was concentrated in vacuo. The residue was purified
by column chromatography [SiO2, Et2O–hexanes (1 : 5)] to give
the title compound 2 (64 mg, 0.10 mmol, 60%) as a colourless
14 H. von der Emde, A. Langels, M. Noltemeyer and R. Bru¨ckner,
Tetrahedron Lett., 1994, 35, 7609.
15 A. M. Montana, F. Garcia and P. M. Grima, Tetrahedron, 1999, 55,
5483.
16 C. Spino and M. Allan, Can. J. Chem., 2004, 82, 177.
17 T. Novak, Z. Tan, B. Liang and E. Negishi, J. Am. Chem. Soc., 2005,
127, 2838.
18 J. Cooksey, P. J. Kocienski and Y.-f. Li, Collect. Czech. Chem. Commun.,
2005, 70, 1653.
19 J. W. Faller and D. Linebarrier, Organometallics, 1988, 7, 1670.
20 D. Enders, U. Frank, P. Fey, B. Jandeleit and B. B. Lohray,
J. Organomet. Chem., 1996, 519, 147.
21 J. W. Faller and C. Lambert, Tetrahedron, 1985, 41, 5755.
22 D. Enders, B. Jandeleit, S. von Berg, G. Raabe and J. Runsink,
Organometallics, 2001, 20, 4312.
23 By contrast, ArCu reagents add to complexes 7 and 8 in 68–72% yield:
R. Chow, P. J. Kocienski, A. Kuhl, J.-Y. LeBrazidec, K. Muir and P.
Fish, J. Chem. Soc., Perkin Trans. 1, 2001, 2344.
24 S. Nakanishi, H. Yamaguchi, K. Okamoto and T. Takata, Tetrahedron:
Asymmetry, 1996, 7, 2219.
1
oil: [a]2D5 −9.4 (c = 0.17, CHCl3). H NMR (500 MHz, CDCl3):
15.74 (1H, s, OH), 7.67 (4H, d, J 7.7), 7.45–7.36 (6H, m), 5.46
(1H, s, C10H), 3.76–3.60 (2H, m, C16H2), 3.67 (3H, s, CO2Me),
2.45–2.38 (2H, m, C8H/C12H), 2.35–2.25 (2H, m, C2H2), 1.69–
1.41 (9H, m, C3H2/C4H/C6H/C7H2/C13H2/C15HAHB), 1.36–
1.28 (1H, m, C15HAHB), 1.20–1.09 (2H, m, C5H2), 1.13–1.11
(6H, overlapping 2 × d, J 6.8 each, C8CH3/C12CH3), 1.05
(9H, s, (SiC(CH3)3), 0.92–0.81 (1H, m, C14H), 0.86–0.81 (9H,
overlapping 3 × d, J 6.3, 6.4 and 6.5, C4CH3/C6CH3/C14CH3).
13C NMR (300 MHz, CDCl3): 199.1, 198.6 (C9/C11), 174.6 (C1),
135.7 (4CH), 134.22 (2C), 129.7 (2CH), 127.8 (4CH), 97.2 (C10H),
62.0 (C16H2), 51.7 (CO2CH3), 44.4 (C5H2), 42.5 (C15H2), 41.8
(C13H2), 40.3, 40.1 (C8H/C12H), 39.7 (C7H2), 32.9 (C2H2), 32.0
(C3H2), 29.8, 28.0, 27.5 (C4H/C6H/C14H), 27.0 (SiC(CH3)3),
19.9, 19.6, 19.1 (C4CH3/C6CH3/C14CH3), 19.3 (SiC(CH3)3),
18.5 (2C, C8CH3/C12CH3). IR (neat): m = 2929 s, 1741 s, 1603
br s, 1111 s, 702 s cm−1. LRMS (ES mode): m/z = 645.5 [(MNa)+,
55%], 546.4 (70), 545.4 (80), 468.4 (60), 467.4 (100). HRMS (ES
mode): m/z calcd for C38H58O5NaSi: 645.3951; found: 645.3964
(MNa). Anal. calcd for C38H58O5Si: C, 73.27; H, 9.38. Found: C,
73.25; H, 9.5.
25 H. Yamaguchi, S. Nakanishi, K. Okamoto and T. Takata, SYNLETT,
1997, 722.
26 H. Yamaguchi, S. Nakanishi and T. Takata, J. Organomet. Chem., 1998,
554, 167.
27 P. F. Wiley, K. Gerzon, E. H. Flynn, M. V. Sigal, Jr., O. Weaver, U. C.
Quarck, R. R. Chauvette and R. Monahan, J. Am. Chem. Soc., 1957,
79, 6062.
28 N. L. Allinger, J. Am. Chem. Soc., 1959, 81, 232.
29 W. F. Bailey and E. R. Punzalan, J. Org. Chem., 1990, 55, 5404.
30 E. Negishi, D. R. Swanson and C. J. Rousset, J. Org. Chem., 1990, 55,
5406.
31 There is no evidence to exclude a competing SN1 mechanism but it
has been ignored here because the carbonyl group should destabilise a
positive charge.
32 T. Tashiro, K. Akasaka, H. Ohrui, E. Fattorusso and K. Mori,
Eur. J. Org. Chem., 2002, 3659.
33 D. L. Flynn, R. E. Zelle and P. A. Grieco, J. Org. Chem, 1983, 48, 2424.
34 J. A. Robinson and U. C. Dyer, J. Chem. Soc., Perkin Trans. 1, 1988,
53.
Acknowledgements
We thank the EPSRC for financial support; the Deutsche
Forschungsgemeinschaft for a fellowship (SS) and the Society for
Chemical Industry for a Gray Scholarship (TNS). We also thank
Professor Ei-ichi Negishi for valuable advice. Expert analytical
services were provided by Simon Barrett (NMR), Tanya Marinko-
Covell (MS), Colin Kilner (X-ray) and James Titchmarsh (HPLC).
35 R. W. Hoffmann, H. J. Zeiss, W. Ladner and S. Tabche, Chem. Ber.,
1982, 115, 2357.
36 A. G. Myers, B. H. Yang, H. Chen, L. McKinstry, D. J. Kopecky and
J. L. Gleason, J. Am. Chem. Soc., 1997, 119, 6496.
37 A. G. Myers and B. H. Yang, Org. Synth., 2000, 77, 22.
38 A. G. Myers, B. H. Yang and H. Chen, Org. Synth., 2000, 77, 29.
39 P. H. J. Carlsen, T. Katsuki, V. S. Martin and K. B. Sharpless, J. Org.
Chem., 1981, 46, 3936.
40 D. Y. Kondakov and E. Negishi, J. Am. Chem. Soc., 1995, 117, 10771.
41 E. Negishi and Z. Tan, Top. Organomet. Chem., 2005, 8, 139.
42 X. Zeng, F. Zeng and E. Negishi, Org. Lett., 2004, 6, 3245.
43 Z. Tan and E. Negishi, Angew. Chem., Int. Ed., 2004, 43, 2911.
44 E. Negishi, Z. Tan, B. Liang and T. Novak, Proc. Natl. Acad. Sci.
U. S. A., 2004, 101, 5782.
References
1 W. C. Liu, D. Smith-Slusarchyk, G. Astle, W. H. Trejo, W. E. Brown
and E. J. Meyers, J. Antibiot., 1978, 31, 815.
2 B. K. Toeplitz, A. I. Cohen, P. T. Funke, W. L. Parker and J. Z.
Gougatas, J. Am. Chem. Soc., 1979, 101, 3344.
3 D. A. Evans, R. L. Dow, T. L. Shih, J. M. Takacs and R. Zahler, J. Am.
Chem. Soc., 1990, 112, 5290.
4 S. Hanessian, N. G. Cooke, B. DeHoff and Y. Sakito, J. Am. Chem.
Soc., 1990, 112, 5276.
5 M. Lautens, J. T. Colucci, S. Hiebert, N. D. Smith and G. Bouchain,
Org. Lett., 2002, 4, 1879.
6 P. G. M. Wuts, R. D’Costa and W. Butler, J. Org. Chem., 1984, 49,
2582.
7 S. L. Schreiber and Z. Wang, J. Am. Chem. Soc., 1985, 107, 5303.
8 C. Spino and L. Weiler, Tetrahedron Lett., 1987, 28, 731.
9 K. P. Shelly and L. Weiler, Can. J. Chem., 1988, 66, 1359.
10 D. A. Nicoll-Griffith and L. Weiler, Tetrahedron, 1991, 47, 2733.
11 M. J. Taschner and Q. Z. Chen, Bioorg. Med. Chem. Lett., 1991, 1, 535.
12 Y. Guindon, C. Yoakim, V. Gorys, W. W. Ogilvie, D. Delorme, J.
Renaud, G. Robinson, J. F. Lavalle´e, A. Slassi, G. Jung, J. Rancourt,
K. Durkin and D. Liotta, J. Org. Chem., 1994, 59, 1166.
13 T. Q. Hu and L. Weiler, Can. J. Chem., 1994, 72, 1500.
45 M. Magnin-Lachaux, Z. Tan, B. Liang and E. Negishi, Org. Lett., 2004,
6, 1425.
46 S. Q. Huo, J. C. Shi and E. Negishi, Angew. Chem., Int. Ed., 2002, 41,
2141.
47 S. Q. Huo and E. Negishi, Org. Lett., 2001, 3, 3253.
48 S. Ribe, R. K. Kondru, D. N. Beratan and P. Wipf, J. Am. Chem. Soc.,
2000, 122, 4608.
49 G. Erker, M. Aulbach, M. Knickmeier, D. Wingbermuhle, C. Kruger,
M. Nolte and S. Werner, J. Am. Chem. Soc., 1993, 115, 4590.
50 R. Pellicciari, R. Fringuelli, E. Sisani and M. Curini, J. Chem. Soc.,
Perkin Trans. 1, 1981, 2566.
¨
¨
51 J. A. Marshall and S. Xie, J. Org. Chem, 1995, 60, 7230.
52 K. Itoh, S. Nakanishi and Y. Otsuji, J. Organomet. Chem., 1994, 473,
215.
53 L. A. Paquette, A. M. Doherty and C. M. Rayner, J. Am. Chem. Soc.,
1992, 114, 3910.
54 P. Wipf and S. Ribe, Org. Lett., 2000, 2, 1713.
55 S. Hanessian and P. J. Murray, Can. J. Chem., 1986, 64, 2231.
3336 | Org. Biomol. Chem., 2006, 4, 3325–3336
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