Stereoselective palladium-catalyzed functionalization of homoallylic alcohols: A convenient synthesis of di- and trisubstituted isoxazolidines and β-amino-δ-hydroxy esters

Article abstract of DOI:10.1002/chem.201102716

Enantiopure, Boc-protected alkoxyamines 12 and 13, derived from the readily available homoallylic alcohols 4 via a reaction that involves either inversion or retention of configuration, undergo a diastereoselective Pd-catalyzed ring-closing carbonylative

Full text of DOI:10.1002/chem.201102716

FULL PAPER
DOI: 10.1002/chem.201102716
Stereoselective Palladium-Catalyzed Functionalization of Homoallylic
Alcohols: A Convenient Synthesis of Di- and Tri-Substituted Isoxazolidines
and b-Amino-d-Hydroxy Esters
Andrei V. Malkov,*[a, b] Maciej Barłꢀg,[a, c] Lucie Miller-Potuckꢁ,[a, d]
Mikhail A. Kabeshov,[a, b] Louis J. Farrugia,[a] and Pavel Kocˇovsky*[a]
´
Dedicated to Professor John E. McMurry on the occasion of his 70th birthday.
Abstract: Enantiopure, Boc-protected
alkoxyamines 12 and 13, derived from
the readily available homoallylic alco-
hols 4 via a reaction that involves
either inversion or retention of config-
uration, undergo a diastereoselective
Pd-catalyzed ring-closing carbonylative
amidation to produce isoxazolidines
16/17 (ꢁ50:1 diastereoisomer ratio
(d.r.)) that can be readily converted
into the N-Boc-protected esters of
b-amino-d-hydroxy acids and their
g-substituted homologues 37. The key
carbonylative cyclization proceeds
through an unusual syn addition of the
palladium and the nitrogen nucleophile
across the C=C bond (19!21), as re-
vealed by the reaction of 15, which af-
forded isoxazolidine 18 with high dia-
stereoselectivity.
Keywords: amidopalladation · ami-
no acids · carbonylation · palladi-
um · stereocontrol
Introduction
related reactions employing S, Se, Pd, Pt, Hg, Tl, Au, and
other electrophiles being the prime examples (Scheme 1,
(1)).[27] When metals, such as Pd[2,5] or Hg,[2,5,7] are employed
Carbon–carbon bond formation is traditionally regarded as
the ultimate goal of synthetic organic chemistry.[1] However,
a stereocontrolled functionalization through the construc-
tion of a carbon–heteroatom bond is of no less importance
and there are myriads of examples of its application in total
synthesis.[1,2] Thus, stereocontrolled electrophilic addition
across a C=C bond stands as a cornerstone of organic
chemistry,[2] with halolactonization, haloetherification, and
Scheme 1.
[a] Prof. Dr. A. V. Malkov, Dr. M. Barłꢀg, Dr. L. Miller-Potuckꢁ,
ˇ
´
Dr. M. A. Kabeshov, Dr. L. J. Farrugia, P. Kocovsky
Department of Chemistry, WestChem, University of Glasgow
Glasgow G12 8QQ (UK)
Fax : (+44)141-330-4888
E-mail: pavelk@chem.gla.ac.uk
as the electrophilic triggers of the reaction, the initially
formed organometallic product B can be utilized in a subse-
quent reaction that would allow the construction of a new
ꢀ
ꢀ
C C bond from the C M bond. The overall result would
[b] Prof. Dr. A. V. Malkov, Dr. M. A. Kabeshov
Present address: Department of Chemistry
Loughborough University
ꢀ
ꢀ
then be the formation of a C X and C C bond, where X is
introduced as a nucleophile, and the new carbon substituent
formally as an electrophile (C).[2,8–10]
Loughborough, Leics LE11 3TU (UK)
Fax : (+44)1509-22-3925
E-mail: a.malkov@lboro.ac.uk
In their seminal paper, Semmelhack and Bodurow[10] had
shown that olefinic alcohols can be readily cyclized in a ste-
reocontrolled manner by palladium(II) (Scheme 1, (1), Mn+
=Pd2+, X=O) in the presence of carbon monoxide and the
resulting organopalladium intermediate B would then un-
dergo carbonylation (with retention of configuration) to
produce the corresponding ester (M=CO2Me).[10–14] Sem-
melhack and co-workers had also developed a catalytic
cycle, in which the Pd0 resulting from the reaction is re-oxi-
dized by CuII,[10,11,15,16] in reminiscence of the Wacker pro-
cess.[17] The cyclization was formulated as an anti addition of
Pd2+ and the alkoxy group across the double bond
[c] Dr. M. Barłꢀg
Present address: College of Science
Texas A&M University at Qatar, P.O.Box 23874
Doha 23874 (Qatar)
[d] Dr. L. Miller-Potuckꢁ
Present address: AstraZeneca
Silk Road Business Park, Charter Way
Macclesfield, Cheshire, SK10 2NA (UK)
Supporting information for this article (including characterization
and NMR spectra for new compounds, chiral HPLC traces, and 19F
NMR spectra of the Mosher derivatives) is available on the WWW
under http://dx.doi.org/10.1002/chem.201102716.
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(Scheme 1, (1)),[10,11] which is in line, for example, with the
mechanism of the Bꢃckvall oxidation, where the initially
generated h4-PdII-complex of a conjugated diene is attacked
by a nucleophile from the face opposite to Pd.[16]
Herein, we report on a diastereoselective, palladium-cata-
lyzed ring-closing amidocarbonylation of the Boc-protected
ꢀ
homoallylic alkoxyamines A (XH=O NHBoc), derived
from enantiopure homoallylic alcohols, conversion of the
Aside from the anti mechanism (Scheme 1, (1)), the syn
addition (Scheme 1, (2)) can also operate in the Pd-cata-
lyzed reactions, especially in the absence of the strongly co-
ordinating ligand, such as carbon monoxide;[18] here, the hy-
droxyl can pre-coordinate the metal and steer its approach
to the C=C bond[19,20] in a similar way as, for example, in the
Sharpless epoxidation.[2c] Thus, Hayashi has demonstrated
the syn addition for the cyclopalladation of olefinic alcohols
and showed that the stereochemical outcome is strongly af-
fected by the chloride ion, either added (LiCl) or originating
from the oxidant (CuCl2): in the absence of Clꢀ, a clean syn
addition was observed, whereas addition of an excess of
LiCl to the reaction mixture (with para-benzoquinone as the
oxidant) reversed the mechanism to mainly anti addition.
The latter outcome was rationalized by the reduced propen-
sity of Pd to associate with the hydroxyl due to the strongly
bonded Clꢀ in its coordination sphere.[21] Stoltz and co-work-
ers have also documented the syn cyclopalladation of olefin-
ic alcohols but noted the anti pathway for analogous carbox-
ylic acids.[22] This dichotomy was tentatively attributed to
the combination of a number of factors, such as pKa differ-
ences, variation of nucleophilicity (OH vs. CO2H), and geo-
metrical constraints in the substrate molecules, illustrating
the sheer complexity of this problem.[22] Wolfe and co-work-
ers studied a Heck-type Pd-catalyzed cycloarylation of ole-
finic alcohols with aryl halides,[23] in which a strong base is
employed (that presumably deprotonates the hydroxyl,
making it prone to coordinate Pd) and found preferential
syn addition of the hydroxyl and the Ar–[Pd] species.[24,25]
Aminopalladation of ethylene with dimethylamine was
shown by ꢄkermark and co-workers to occur with anti ster-
eochemistry (in the presence of Clꢀ).[26] On the other hand,
Taniguchi found a syn mechanism for the intramolecular
amidation with an acetamido group [A, X=N(R)Ac], cata-
lyzed by (PhCN)2PdCl2.[27] Wolfe has developed an intramo-
lecular aminoarylation of olefinic amines (A, X=HNR)
with aryl halides (in the presence of a strong base) and de-
iniACTHUNGTERNNUtG ially formed isoxazolidines into the corresponding esters
of b-amino-d-hydroxy acids, and the stereochemistry of this
sequence.
Results and Discussion
In the past few years we and others have developed an
enantio- and diastereoselective allylation of aromatic and
a,b-unsaturated aldehydes 1a–f with allyl/crotyl trichlorosi-
lanes 2/3 to produce the homoallylic alcohols 4a–h
(Scheme 2).[33–38] The reaction is catalyzed by various chiral
Scheme 2.
Lewis basic pyridine N-oxides,[33–38] in particular METHOX
(5)[35] and QUINOX (9).[36] It is pertinent to note that
METHOX offers an interesting advantage in the case of
trans-crotyl silane 3: here, the required silane is prepared in
one step through the copper(I)-mediated coupling of Cl3SiH
with technical crotyl chloride,[39] which is an 87:13 mixture
of trans and cis isomers, and this ratio is reproduced in the
composition of the silane 3.[35,36] METHOX (5) exhibits
a strong kinetic preference for the trans-configured 3 (pre-
sumably resulting from the transition state TS1), so that
when excess of the latter reagent is used, only the trans is-
omer is consumed, and the resulting homoallylic alcohols 4
are obtained as pure anti-configured diastereoisomers in
high enantiopurity.[35,38e]
In contrast to 3, the cis-crotylsilane 6, obtained on the pal-
ladium(II)-catalyzed 1,4-hydrosilylation of butadiene with
Cl3SiH,[40] reacts best when QUINOX (8) is used as catalyst,
affording the syn-configured homoallylic alcohol 7g in high
enantio- and diastereoselectivity (Scheme 3).[36]
The portfolio of the available products based on this strat-
egy was further extended by us to the homoallylic alcohols,
such as 9, which arises from 4g (Scheme 4) in an unprece-
ACHTUNGTRENNUNGmonstrated the syn pathway (Scheme 1, (2)), assuming an
amine-palladium pre-coordination,[28] in analogy to the al-
koxyarylation.[24,25] Arylation of the related Boc-protected
olefinic amines (A, X=NHBoc, Boc=tert-butoxycarbonyl)
was also found to be dominated by the syn mechanism.[28b,29]
In fact, the groups of Wolfe[30] and Hartwig[31] have been
able to prepare the N-Pd complexes (D, X=NR) from the
corresponding amines through deprotonation with a strong
base, followed by treatment with PdII, and confirm the syn
mechanism with the aid of deuterium labeling. By contrast,
amidocarbonylation of an olefinic tosylurea derivative (A,
X=NCONHTs) with (AcO)2Pd, CuCl2, and CO, was report-
ed by Tamaru and Yoshida to proceed as a clean anti addi-
tion[32] in consonance with the Semmelhack findings for cy-
clative carbonylation of olefinic alcohols (in the presence of
CO).[10,11]
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Functionalization of Homoallylic Alcohols
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Scheme 3.
Scheme 4.
dented stereopurity through the oxonia-Cope rearrange-
ment.[41]
Along the lines discussed in the Introduction (Scheme 1),
Bates[42,43] and co-workers have shown that the simple Boc-
protected homoallylic alkoxyamine (ꢂ)-12a (i.e., lacking the
R2 substituent) readily undergoes a Pd-catalyzed ring-clos-
ing carbonylation, in which the nitrogen of the carbamate
group serves as an internal nucleophile. Aiming at the ex-
tension of this methodology to the crotyl series, we em-
barked on a detailed investigation, employing our readily
available homoallylic alcohols 4a–h, and 9 as starting model
compounds (Scheme 5); in this series, 4a was prepared
through the allylation catalyzed by DMF as a Lewis base
and was therefore racemic. The remaining members of this
set were scalemic, since they were obtained through the ally-
lation catalyzed by METHOX (5). The main goal was to
find out whether the stereochemical and functional group
manipulations were compatible with this ring-closing amido-
carbonylation, to what extent various combinations would
affect the stereoselectivity and yield, and what is the overall
stereochemistry of the addition across the C=C bond.
Scheme 5.
yields (Scheme 5 and Table 1). In all cases, except one
(Table 1, entry 2), the inversion of configuration was almost
perfect (with very little loss of the stereochemical integrity,
if any). However, the p-methoxy derivative 4b (96% en
AHCTUNGTREGaNNUN ntiomeric excess (ee)) produced the corresponding alkoxy-
amine 10b, which turned out to be almost racemic
(ca. 10% ee). This result represents a serious blow to the
general belief in the Mitsunobu reaction[47] as a reliable
means for clean inversion and will deserve further investiga-
tion.[48,49]
ACHTUNGTRENNUNGan-
The retention pathway (Scheme 5) is based on the con-
struction of the O N bond (i.e., without touching the chiral
ꢀ
center) through the reaction of the corresponding alkoxide
(generated in situ) with 3,3’-di-tert-butyloxaziridine, which
involves a nucleophilic substitution at the oxaziridine nitro-
gen.[44,45] According to this scenario, alcohols 4b, 4g, and 4h
were deprotonated with potassium hydride in the presence
of the potassium-specific 18-crown-6 ether and the resulting
alkoxides were allowed to react with 3,3’-di-tert-butyloxaziri-
dine to produce 11b (88%), 11g (65%), and 11h (33%).[50]
The inversion method, applied to the enantiopure homo-
allylic alcohol 9,[41] afforded alkoxyamine 14 (Scheme 5),
again with no appreciable loss of enantiopurity (Table 1,
entry 9).
It is pertinent to note that these two routes are stereo-
complementary (Scheme 5): thus, the anti-configured alco-
hols 4 afford the syn-configured alkoxyamines 10 on the
Mitsunobu inversion, whereas the oxaziridine route gives
rise to the anti products 11. On the other hand, starting with
the syn-configured alcohols, such as 7, the inversion pathway
Synthesis of alkoxyamines and their Boc derivatives: There
are essentially two methods available for the conversion of
ꢀ
an alcohol (R OH) into the corresponding alkoxyamine
ꢀ
(R ONH2): one involving the Mitsunobu inversion, in
[42b,44]
ꢀ
which a new C O bond is formed,
and one relying on
ꢀ
retention, in which the O N bond is constructed instead,
leaving the chiral center unaffected.[45,46] According to the
former approach, alcohols 4a–h were treated with N-hy-
droxyphthalimide (NHPI) in the presence of diisopropyl di-
azodicarboxylate (DIAD) and triphenylphosphine under the
standard Mitsunobu conditions[42b,44] and the resulting phtha-
limides were deprotected[42b,44] on reaction with hydrazine
hydrate to afford the required alkoxyamines 10a–h in good
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Table 1. Synthesis of alkoxyamines 10a–h and 14 from 4a–h and 9 via Mitsunobu in-
AcONa, PhCO2Na, or tetramethylguanidine, and so
on, precipitation of Pd-black was observed within
approximately 10 min, apparently as the result of
a stoichiometric oxidation of CO and/or MeOH at
the expense of PdII.[52] Finally, after much experi-
mentation, we were able to identify a 1:1 mixture of
methanol and methyl orthoacetate as the medium
of choice, with no additional base required.[12e,g,m]
Here, the apparent role of the orthoacetate is to
“mop up” the Brønsted acid generated during the
reaction; the latter process also produces MeOH,
which is present anyway, and one equivalent of the
innocuous AcOMe. Significantly, under these neu-
tral conditions, the reduction of PdII by CO/MeOH
was prevented, so that the desired carboamidation
could proceed.
The cyclization of 12a–f and 13b, that is, terminal
olefins lacking another substituent (R2 =H), pro-
ceeded with very high diastereoselectivity (24:1
to>50:1; Table 2, entries 1–6 and 9). The cycliza-
tion of their homologues with an additional methyl
(R2 =Me) exhibited dependence on the configura-
tion at this additional center. Thus, the syn-config-
ured alkoxycarbamates 12g and 12h produced the
less stereochemically pure syn,syn-isozaxolidines
16g and 16h (Table 2, entries 7 and 8), whereas the
anti-configured analogues 13g and 13h afforded the
version (Scheme 5).[a]
Entry Alcohol[b]
ee[c]
[%]
d.r.[d] alkoxyamine
Yield ee[f]
d.r.[g]
[%][e] [%]
1
2
3
4
5
6
7
8
9
(ꢂ)-4a
racemic n/a
(ꢂ)-10a
85
74
78
86
84
91
racemic n/a
(S)-(ꢀ)-4b
(S)-(ꢀ)-4c
(S)-(ꢀ)-4d
(S)-(ꢀ)-4e
(S)-(ꢀ)-4 f
96
95
91
92
94
n/a
n/a
n/a
n/a
n/a
55:1
35:1
n/a
(R)-(+)-10b
(R)-(+)-10c
(R)-(+)-10d
(R)-(+)-10e
(R)-(+)-10 f
ꢃ10
n/a
n/a
90
90
n/a
92
n/a
88
n/a
(1S,2S)-(ꢀ)-4g 95
G
95[h]
35:1[i]
28:1[j]
n/a
A
A
98[h]
90
[a] The reactions were carried on a 1 mmol scale. [b] The absolute configuration of the
starting alcohols 4 has either been established previously or is inferred by analogy,
based on the fact that the allylation of aromatic aldehydes catalyzed by
(+)-METHOX (5) is known to produce (S)-alcohols (see Refs. [33]–[36]); 4a in
entry 1 was prepared by the allylation catalyzed with DMF (instead with METHOX),
and was therefore, racemic. [c] The enantiomeric purity of the starting alcohols was es-
tablished by chiral HPLC, as reported previously (see Refs. [35] and [36]). [d] Estab-
lished by 1H NMR spectroscopy (or 19F NMR, where applicable). [e] Isolated product
yield after purification; note that conversions were practically quantitative. [f] The
enantiomeric purity was inferred from the 19F NMR spectra of the corresponding
Mosher derivatives. [g] Established by 1H NMR spectroscopy for 10g (by integrating
the signals of the benzylic protons of the crude products) and by 19F NMR spectrosco-
py for 10h. [h] The enantiomeric purity is assumed to be identical to that of the start-
ing material, as the second chiral center remained unchanged. [i] Increased to 55:1
purity by chromatography. [j] The conversion was ꢃ70%. The syn/anti ratio could not
be accurately established due to the overlap of the relevant signals in the 1H NMR
spectrum of the crude product with those of the unreacted starting material; the 28:1
ratio corresponds to the product after purification. [k] Previously obtained with up to
96% ee by using the same method (see Ref. [41]).
would produce anti-alkoxyamines 11, whereas retention
would furnish the syn-configured diastereoisomers 10. Natu-
rally, the absolute configuration in this exercise can be con-
trolled by the absolute configuration of the organocatalysts
5 and 8, which offers full stereo-complementarity.[51] It is
noteworthy that the stereopure p-MeO derivatives (e.g.,
10b or those with another chiral center), not available
through the Mitsunobu pathway, could thus be obtained in
ꢀ
all stereochemical combinations by construction of the N O
bond.
In the next step, Boc-derivatization of 10, 11, and 14 was
carried out under the standard Schotten-Bauman-type con-
ditions, using di-tert-butyl dicarbonate (Boc anhydride) and
NaOH in a two-phase system, and the model alkoxycarba-
mates 12, 13, and 15 were isolated in high yields (Scheme 5
and Scheme 6).
Ring-closing carbonylative amidation of the Boc-derivatized
homoallylic alkoxyamines: Treatment of the unsaturated al-
koxycarbamates 12a–h with methanol and carbon monoxide
at an atmospheric pressure in the presence of PdCl2 as cata-
lyst (10 mol%) and (AcO)2Cu (3 equiv) to reoxidize the pal-
ladium, was expected to result in the formation of isoxazoli-
dines 16a–h (Scheme 6 and Table 2). However, the first at-
tempts with just methanol as a solvent and reactant were
rather disappointing: thus, at 08C or at room temperature,
there was practically no reaction detected, whereas at 308C,
especially in the presence of a weak base, such as Et3N,
Scheme 6.
anti,anti-isoxazolidines 17g and 17h of high diastereoisomer-
ic purity (Table 2, entries 10 and 11). Homologue 15, with
a more sterically hindered disubstituted double bond, re-
quired a slightly higher temperature and an extended reac-
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Functionalization of Homoallylic Alcohols
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Table 2. Palladium-catalyzed ring-closing carbonylation of N-Boc pro-
upon its deprotonation (19; see below), followed by a syn
addition across the neighboring C=C bond, to generate the
palladium species 21, whose carbonylation (with retention
of configuration) gives rise to ester 18. The syn attack on
the opposite face of the double bond, as in 20, would gener-
ate a 1,3-strain, so that the corresponding Pd intermediate
22 is apparently not generated in any appreciable amount.
Moreover, the anti pathway (23!24) would give rise to yet
another diastereoisomer of 18, whose formation was not ob-
served.
The syn mechanism (Scheme 7) mirrors the findings by
the groups of Wolfe[28–30] and Hartwig[31] for the Pd-catalyzed
arylation of olefinic alcohols and amines with aryl halides
under basic conditions.[54] Wolfe[30b] also demonstrated the
syn addition by isotopic labeling for the Pd-catalyzed aryla-
tion of the Boc derivative 12a and its congeners, involving
N-deprotonation by tBuONa. Furthermore, the syn stereo-
chemistry is also compatible with the report by Taniguchi
et al.,[27] who studied the cyclopalladation of olefinic acet-
amides (see above). However, these reactions differ from
our system in one crucial point: we have studied carbonyla-
tion (i.e., reaction with CO) under neutral conditions.
Therefore, comparison with the Semmelhack cyclative car-
bonylation of olefinic alcohols,[10,11] and with the Tamaru–
Yoshida carbonylation of the olefinic tosylurea derivative
(A, X=NCONHTs),[32] which all prefer the anti pathway,
would be more appropriate. The syn pathway, observed for
the carbonylation of 15 under similar conditions, is thus
rather surprising. It may be attributed to the different
nature of the nitrogen, which in our case is part of an alk-
tected alkoxyamines 12, 13 and 15 (Scheme 6).[a]
Entry Alkene ee
[%]
d.r.
Isoxazolidine Yield d.r.[c]
[%][b]
1
2
3
4
5
6
7
8
12a
12b
12c
12d
12e
12 f
12g
12h
13b
13g
13h
15
racemic n/a
racemic n/a
16a
16b
16c
16d
16e
16 f
16g
93
80
76
93
73
96
69
60
78
71
66
55
>50:1
>50:1
90
90
92
88
95
98
96
95
98
90
n/a
n/a
n/a
n/a
55:1
20:1[d,e]
>50:1
25:1
>50:1
4.5:1[f,g]
5.7:1[g]
>35:1[f]
>20:1[f,g]
17:1[fh]
22:2:1[i]
28:1[h] 16h
9
n/a
17b
17g
17h
18
10
11
12
55:1
35:1
n/a
[a] The reactions were carried on a 1 mmol scale with 10 mol% of the
catalyst. [b] Isolated yield after purification; note that conversions were
1
practically quantitative. [c] Established for the crude product by H NMR
spectroscopy (by integrating the signals of benzylic protons). [d] The
19F NMR spectrum of the crude product showed a 16:1 ratio. [e] In-
creased to ꢄ40:1 by chromatography. [f] Increased to >50:1 by chroma-
tography. [g] In principle, three diastereoisomers could be formed here.
However, the third isomer could not be detected, presumably because its
concentration was below the detection limit of the NMR spectroscopy.
[h] Established by 19F NMR spectroscopy. [i] Increased to 40:2.5:1 by
chromatography.
tion time to produce 18 as an almost pure diastereoisomer
(Table 2, entry 12), whose configuration was established by
NMR spectroscopy and confirmed by X-ray crystallographic
analysis of the derivative 40, that is, after the removal of the
Boc group (see below).
AHCTUNGTREGoNNUN xyamine moiety, whose propensity to coordinate transition
Mechanistic considerations: The experiment involving car-
bamate 15 was of key importance for establishing the ste-
reochemistry of the Pd-catalyzed cyclization: here, the for-
mation of diastereoisomer 18 corresponds to a syn addition
((2) in Scheme 1) of Pd and the nitrogen across the C=C
bond. Apparently, the carbamate group is capable of coordi-
nating the PdII catalyst[53] (Scheme 7), possibly by nitrogen
metals can differ from that of the hydroxyl and carbamate-
type groups.
The actual mode of coordination of PdII to the N-Boc-alk-
AHCTUNGTREGoNNNU xyamine moiety is not clear. In principle, three models can
be considered, namely F (featured in 19 and 20 and in
Scheme 8 and Scheme 9), G, and H. Model F was chosen in
analogy with the work of Wolfe[28–30] and Hartwig[28–30] on
Boc-protected amines, which were first deprotonated by
ꢀ
a strong base. However, the N H of our N-Boc-alkoxya-
mines is likely to be more acidic than that in carbamates, so
that a strong base may not be required here. Model G rep-
resents a reversed role of the nitrogen and carbonyl oxygen
in chelation of Pd. The present data cannot shed light on
this dichotomy but it is pertinent to note that both models
are compatible with the experimentally observed syn addi-
tion. Finally, the third chelation mode H, assuming a five-
membered chelation through the two oxygens, is unlikely, as
it would move either the nitrogen or the palladium away
from the double bond, so that the cyclization could not be
Scheme 7.
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The alternative anti-addition mechanism (Scheme 9)
would produce the same cyclic derivatives as does the syn
pathway in the case of 12 and 13 (but not 15). Thus, the syn-
configured carbamate 12 could be predicted to give rise to
16 through 33 and 34 and, in a similar way, 13 would afford
17 via 35 and 36. However, the key experiment with carba-
mate 15 ruled out the anti mechanism (Scheme 6 and
Scheme 7), which can now be extrapolated to the terminal
olefins 12 and 13. Hence, the original mechanism, which
Bates formulated as the anti-addition,[42a] appears unlikely to
operate in light of the present experiments.
Examples of a synthetic utilization of the isoxazolidines:
ꢀ
The cleavage of the O N bond in the N-Boc-protected iso-
xazolidines 16 (Scheme 10) and in the related isoxazolidines
Scheme 8.
Scheme 9.
Scheme 10.
achieved. For the sake of simplicity, coordination of Pd to
the nitrogen is depicted in Scheme 7, Scheme 8, and
Scheme 9 but one should bear in mind that the actual mode
of coordination is likely to be more complex.
17 and 18, would open an interesting access to b-amino-d-
hydroxy acids, with an optional substituent (R2) at the g-po-
ꢀ
sition. Of the existing methods for the O N bond cleavage,
we chose one that uses Mo(CO)6,[43c–e,55] as this reagent ap-
pears to be tolerant to the N-Boc group and a number of
other functionalities. Indeed, on treatment with a stoichio-
metric amount of Mo(CO)6 at 908C (Scheme 10), the selec-
Similar mechanistic arguments can be applied to the re-
maining members of the series, that is, 12 and 13
(Scheme 8). Thus, carbamates 12 apparently prefer the path-
way involving the palladium complexes 25 and 26 to give
16; in analogy, carbamates 13 can be assumed to react via 29
and 30, giving rise to 17. In the case of the syn-configured
carbamates 12, the reactive intermediate 25 is more congest-
ed than the analogous species 29 arising from the anti-con-
figured carbamate 13, which can account for the clean for-
mation of one diastereoisomer in the latter instance (17)
and the less stereochemically homogeneous reaction in the
former 16 (compare entries 10 and 11 with 7 and 8 with in
Table 2). In the absence of the R2 substituent (i.e., R2 =H),
the diastereoselectivity was high in all instances (Table 2, en-
tries 1–6 and 9).
AHCTUNGTREGtNNUN ed N-Boc protected isoxazolidines 16a,16c,16 f, and 16g af-
forded the expected N-Boc-protected b-amino-d-hydroxy
esters 37a (78%), 37c (65%), 37 f (86%), and 37g (77%),
respectively. The latter products can actually serve as or-
thogonally protected tri-functional species, currently with
free OH, and protected amino and carboxyl groups; utiliza-
tion of these derivatives can be multifaceted, as they can be
envisioned to serve a number of purposes, for example, in
peptide chemistry, relying on selective reactivities of the in-
dividual groups. As an example, we have observed partial
lactonization of 37c during the workup of the reaction that
ꢀ
cleaved the O N bond in 16c, when a hot (rather than pre-
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Functionalization of Homoallylic Alcohols
FULL PAPER
cooled) reaction mixture was quenched with aqueous
NaHCO3, to afford d-lactone 39c (19%) as a by-product,
demonstrating the ease of this process. In an optimized
preparative experiment, racemic hydroxy ester 37a, ob-
tained from (ꢂ)-16a, was treated with DBU (5 mol%) at
room temperature for 4 h; under these conditions, lactone
(ꢂ)-39a was isolated in 88% yield.[56,57] Note that, in fact,
isoxazolidines 16–18 can also be utilized as orthogonally
protected surrogates of b-amino-d-hydroxy acids, offering
further versatility and protecting group compatibility of our
chemistry.
lar pattern but the diastereoselectivity was lower (4.5:1 to
5.7:1). In most cases, the crude products were purified by
flash chromatography to give a ratio of ꢄ50:1. These find-
ings can be regarded as a considerable extension of the
mosaic originally assembled by Bates and co-workers.[42–44]
The experiments carried out with carbamate 15 showed
that the initial addition of the nitrogen and the palladium
across the homoallylic double bond proceeds as a syn
attack, presumably via a species in which Pd is coordinated
to the carbamate group (15!19!21!18; Scheme 7), in
ꢀ
other words through insertion of the C=C bond into the N
Standard N-Boc deprotection of (ꢂ)-16a and (ꢀ)-18 re-
sulted in a clean formation of free isoxazolidines (ꢂ)-38
(90%) and (ꢀ)-40 (88%), respectively. X-ray crystallo-
graphic analysis of (ꢀ)-40 confirmed the relative configura-
tion at the three chiral centers (Figure 1), which was the key
issue for the mechanistic considerations (see above).
Pd bond. This mechanism stands in stark contrast to that of
the related carbonylative cyclization of olefinic alcohols and
the urea-type analogue of 12/13, which are known to pro-
ceed with anti stereochemistry.[10,11,32] In this respect, our
findings represent the first example of the syn cyclization in
the PdII-catalyzed carbonylation of heterosubstituted olefins
of type A (Scheme 1). On the other hand, the behavior of
our carbamates mirrors the mechanism of the cyclization of
olefinic alcohols, amines, and Boc-derivatized amines in the
Pd-catalyzed addition of aryl halides and related species,
which has been demonstrated to proceed with syn stereo-
chemistry.[28–31] Note, however, that free alkoxyamines 10,
11, and 14 do not undergo the Pd-catalyzed carbonylative
cyclization and have to be first converted into the corre-
sponding carbamates 12, 13, and 15, as shown here and by
Bates,[42–44] or into related derivatives, such as N-tosyl carba-
mates, ureas, and so on.[12m,59,60] Apparently, the catalytic re-
Figure 1. ORTEP diagram for (3R,5S,1’R)-(ꢀ)-40 showing the atom label-
ing scheme. Displacement are shown at 50% probability level. H atoms
are shown as spheres of arbitrary radius.
ꢀ
action requires rather more acidic N H, which is available
in carbamates, and related groups, but not in free amines.
The present method can be regarded as a complementary,
stereocontrolled approach to di- and tri-substituted isoxazo-
lidines, some of which can also be synthesized, for example,
by cycloaddition of nitrones[61] and other approaches[62,63]
but not always with the selectivity as high as reported here.
Furthermore, the Boc-protected isoxazolidines 16 can be
readily converted into the protected b-amino-d-hydroxy
esters and their g-substituted homologues, for example, 37,
Conclusion
Homoallylic alkoxyamines 10a–h and 14 were synthesized
from the corresponding homoallylic alcohols 4a–h and 9, re-
spectively, by using the Mitsunobu reaction with N-hydroxy-
ACHTUNGTRENNUNGphthalimide as the key reagent (Scheme 5). This transforma-
ꢀ
tion at the benzylic position proceeded with an almost pure
inversion of configuration, except for the p-methoxy deriva-
tive (4b), in which a practically complete racemization was
observed (Table 1). Additional alkoxyamines, namely 11b,
11g, and 11h, were obtained from alcohols 4b, 4g, and 4h
on reaction with 3,3-di-tert-butyl-oxaziridine, which proceeds
by cleavage of the N O bond (Scheme 10). In fact, isoxazo-
lidines 16 can be regarded as fully and orthogonally protect-
ed surrogates of b-amino-d-hydroxy acids: thus, the carboxyl
function of 16 can be envisaged to be deprotected by hy-
drolysis (whereas O and N remain protected). Conversely,
the Boc group can be removed and the resulting product 38/
40 could be functionalized at the nitrogen with an option of
a selective deprotection either at oxygen (by a subsequent
ꢀ
through O N bond formation, that is, with retention of the
original configuration of the alcohol (away from the chiral
center). The N-Boc-derivatives of the latter alkoxyamines,
namely 12, 13, and 15, have been shown to undergo a diaste-
reoselective Pd-catalyzed ring-closing carbonylative amida-
tion to produce isoxazolidines 16a–h, 17b, 17g, and 17h and
18, respectively (Scheme 6 and Table 2).[58] The N-Boc al-
koxyamines 12a–f lacking an additional substituent (R2 =H)
and their anti-configured congeners 13b, 13g, and 13h (R2 =
Me) exhibited high diastereoselectivity in favor of the for-
mation of the corresponding isoxazolidines 16a–f and 17b,
17g, and 17h (17:1 toꢄ50:1 diastereoisomer ratio (d.r.)).
The syn-configured derivatives 12g and 12h followed a simi-
ꢀ
cleavage of the O N bond) or at the carboxyl (by hydroly-
sis). Finally, cleavage of the N O bond in 16 gives the O-de-
ꢀ
protected product 37 with the two other functional groups
remaining to be orthogonally protected. Lactonization of
37a to produce 39a, as an example of yet another selective
transformation under very mild conditions, has also been
demonstrated (Scheme 10).
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P. Kocovsky, A. V. Malkov et al.
(100:0 to 90:10). The enantiomeric and diastereoisomeric purity was es-
tablished for both the crude product and the purified material.[70]
Experimental Section
Synthesis of alkoxyamines with retention of configuration (Method C).[45]
The respective alcohol (1.0 mmol), 18-crown-6 ether (0.2 mmol), and KH
(1.2 mmol), obtained by rinsing its oil suspension with hexane, were
General Methods: Optical rotations were recorded in CHCl3 at 258C
unless otherwise indicated with an error of < ꢂ0.1. The [a]D values are
given in 10ꢀ1 degcm2 gꢀ1. The NMR spectra were recorded for CDCl3 so-
ACHTUNGTRENNUNGluACHTUNGTRENNUNG
tions, 1H at 400 MHz, 13C at 100.6 MHz and 19F at 376 MHz with
added consecutively to 1,3-dimethyl-3,4,5,6-tetrahydro-2ACTHNUTRGENUGN(1H)-pyrimidi-
1
chloroform-d1 (d=77.0, 13C), tetramethylsilane (d=0.00, H) and trichlor-
none (DMPU; 1.5 mmol) and the mixture was stirred at room tempera-
ture for 1 h under Ar. The resulting mixture was then added dropwise to
a solution of 3,3-di-tert-butyl-oxaziridine (1.2 mmol) in DMPU (1.5 mL)
at ꢀ408C and the resulting mixture was stirred first at ꢀ408C, then
slowly allowed to warm to room temperature over a period 2 h (the reac-
tion starts at ca. ꢀ208C; if heated too fast, the mixture tends to overflow
from the flask). The reaction was quenched with brine (5 mL) and the
mixture was diluted with a mixture of ethyl acetate and petroleum ether
(1:1; 10 mL). The organic layer was separated and the aqueous layer was
extracted with an ethyl acetate-petroleum ether mixture (1:1; 3ꢇ15 mL).
The combined organic extracts were dried over Na2SO4 and the solvent
was removed in vacuum. The product was purified on a column of silica
gel (1.5ꢇ20 cm), using a gradient of petroleum ether and ethyl acetate as
eluent (100:0 to 90:10). The enantiomeric and diastereoisomeric purity
was established for both the crude product and the purified material.
Synthesis of N-Boc derivatives of alkoxyamines (Method D):[42a] A solu-
tion of the respective alkoxyamine (1.0 mmol) and (Boc)2O (2.0 mmol)
in CH2Cl2 (15 mL) was added to a solution of NaOH (2.0 mmol) in de-
ionized water (5 mL) and the resulting two-phase mixture was stirred at
room temperature for 24 h. The organic layer was separated and the
aqueous layer was extracted with CH2Cl2 (3ꢇ25 mL). The combined or-
ganic extracts were dried over Na2SO4 and the solvent was removed in
vacuum. The product was purified on a column of silica gel (1.5ꢇ20 cm)
using a gradient of petroleum ether and ethyl acetate as eluent (100:0 to
85:15).
1
ofluoromethane (d=0.00, H) as internal standards unless otherwise indi-
cated. The IR spectra were recorded for CHCl3 solutions. The mass spec-
tra (EI and/or CI) were measured on a dual sector mass spectrometer
using direct inlet and the lowest temperature enabling evaporation. All
reactions were performed under an atmosphere of dry, oxygen-free argon
in oven-dried glassware twice evacuated and filled with the argon. Sol-
vents and solutions were transferred by syringe-septum and cannula tech-
niques. Solvents for the reactions were of reagent grade and were dried;
acetonitrile was distilled immediately before use from calcium hydride,
THF was obtained from Pure-Solvꢅ Solvent Purification System (Inno-
vative Technology) and DMPU was dried with molecular sieves (4 ꢄ),
which were activated at 3008C. The enantiomeric purity was determined
by using chiral HPLC and GC techniques (for alcohols) and by 19F or
1H NMR measurements of Mosher derivatives (for O-alkoxyamines).[64]
The starting homoallylic alcohols were prepared previously: (ꢂ)-4a;[42b]
(S)-(ꢀ)-4b (96% ee);[35] and (S)-(ꢀ)-4c (95% ee). This sample has now
been obtained on the allylation reaction using (+)-5 as catalyst; previous-
ly, its enantiomer was prepared via the reaction catalyzed by (R)-
(+)-8;[36]] (S)-(ꢀ)-4e (92% ee; this sample has now been obtained on the
allylation reaction using (+)5 as catalyst; (1S,2S)-(ꢀ)-4g (95% ee by GC;
55:1 anti/syn by 1H NMR spectroscopy;[41] its enantiomer was also pre-
pared by us;[36] (R)-(+)-9 (92% ee)).[41,65] The alkoxyamine 10a and its
Boc derivative 12a were also prepared previously.[42b] Single crystal X-ray
diffraction data were collected at 100 K on Bruker APEX-II (lactone
39a) and Nonius KappaCCD (isoxazolidine 40) diffractometers using
MoKa radiation (0.71073 ꢄ). Data were merged and averaged using
SORTAV[66] and structures were solved using the programs SIR92[67] for
lactone 39a and SUPERFLIP[68] for isoxazolidine 40. Structures were re-
fined by full-matrix least-squares methods using the program SHELXL-
97.[69] General experimental syntheses are given below; full compound
characterization can be found in the Supporting Information.
Palladium-catalyzed cyclization/carbonylation (Method E):
A round-
bottom flask was charged with PdCl2 (0.1 mmol) and (AcO)2Cu·2H2O
(3.0 mmol) and flushed with CO. The flask was then connected to a CO
balloon (atmospheric pressure). Methyl orthoacetate (10 mL) was added
and the resulting solution was stirred at room temperature for 30 min. A
solution of the respective Boc-protected alkoxyamine (1.0 mmol) in
MeOH (10 mL)[71] was added in one portion and the mixture was stirred
at 408C until completion of the reaction (monitored by TLC), typically
48 h. The reaction was quenched with a saturated solution of NaHCO3
(5 mL), the mixture was diluted with deionized water (5 mL) and extract-
ed with ethyl acetate (4ꢇ10 mL). The combined organic phase was dried
over Na2SO4 and the solvent was evaporated in vacuum. The product
was purified by chromatography on a column of silica gel (1.5ꢇ10 cm)
using a gradient of petroleum ether and ethyl acetate as eluent (100:0 to
90:10). The diastereoisomeric purity was established for both the crude
product and the purified material.
Allylation and crotylation of aldehydes catalyzed by METHOX (Method
A): The respective allylic trichlorosilane (3 mmol) was added to a solution
of the respective aldehyde (1.5 mmol), Hꢆnig base (1.57 mL, 9 mmol),
and METHOX (28 mg, 0.075 mmol) in freshly distilled CH3CN (10 mL)
under argon at ꢀ408C. The reaction mixture was stirred at the corre-
sponding temperature for 24 h and monitored by TLC. The reaction was
quenched with a saturated aqueous solution of NaHCO3 and the mixture
was diluted with ethyl acetate (150 mL). The organic layer was separated
and the aqueous layer was extracted with ethyl acetate (2ꢇ100 mL). The
combined organic fractions were dried over Na2SO4 and the solvent was
removed in vacuum. The product was purified on a column of silica gel
(2.5ꢇ25 cm) using a gradient of petroleum ether and ethyl acetate as
eluent (100:0 to 85:15). The enantiomeric and diastereoisomeric purity
was established for both the crude product and the purified material.
Reduction of the cyclization products with Mo(CO)6 (Method F): A solu-
tion of the respective isoxazolidine (0.1 mmol) in a 9:1 mixture of
CH3CN and H2O (2.5 mL) was added to Mo(CO)6 (0.5 mmol) and the re-
sulting solution was heated to reflux (ꢃ908C) under argon for 2 h,
during which time the color had changed from white to black. The mix-
ture was then cooled to room temperature, filtered through Celite, which
was then washed with ether (3ꢇ5 mL), and the combined filtrate was
evaporated. The residue was purified by chromatography on a column of
silica gel (1ꢇ7 cm), using a gradient of petroleum ether and ethyl acetate
from 9:1 to 2:1.
Synthesis of alkoxyamines with inversion of configuration using the Mitsu-
nobu reaction (Method B): Triphenylphosphine (1.2 mmol) and N-hy-
droxy-phthalimide (1.2 mmol) were added to a solution of the respective
alcohol (1 mmol) in freshly distilled THF (10 mL) under argon at 08C
and the mixture was stirred for 2 min. Diisopropyl azodicarboxylate
(1.2 mmol) was then added dropwise over a period of 30 min and the re-
sulting solution was stirred at room temperature under argon for 2 h. Hy-
drazine hydrate (100% N2H4·H2O, 0.1 mL) was then added and the reac-
tion mixture was stirred at room temperature for 30 min. The reaction
was quenched with deionized water (5 mL) and the mixture was diluted
with a mixture of ethyl acetate and petroleum ether (1:1; 10 mL). The or-
ganic layer was separated and the aqueous layer was extracted with a mix-
ture of ethyl acetate and petroleum ether (1:1; 3ꢇ15 mL). The combined
organic extracts were dried over Na2SO4 and the solvents were removed
in vacuum. The product was purified on a column of silica gel (1.5ꢇ
20 cm) using a gradient of petroleum ether and ethyl acetate as eluent
Preparation of Mosher amides from N-Alkoxyamines (Method G).[64] (R)-
(+)-3,3,3-Trifluoro-2-methoxy-2-phenylpropionyl
chloride
(150 mg,
0.6 mmol), prepared in situ from (R)-(+)-a-methoxy-a-trifluoromethyl-
phenylacetic acid (99% ee from Sigma–Aldrich),[33f] was added to a solu-
tion of the alkoxyamine (0.5 mmol) and triethylamine (0.6 mmol) in
CH3CN (1 mL) and the reaction mixture was stirred at room temperature
for 1 h. The solvent was then removed in vacuo and the resulting oil was
dissolved in ether (20 mL). The ethereal solution was washed with 1m
HCl, saturated aqueous NaHCO3, and brine, dried (Na2SO4) and concen-
trated in vacuo to give an oil, which was analyzed by 19F and 1H NMR
techniques.
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Functionalization of Homoallylic Alcohols
FULL PAPER
J.-H. Choi, T. M. Frost, Angew. Chem. 2000, 112, 2382; Angew.
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Acknowledgements
We thank the EPSRC for grant No. EP/E011179/1, the University of
Glasgow for a fellowship to M.A.K., and the Erasmus Exchange Program
for supporting L.M.-P.
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ˇ
´
[5] P. Kocovsky, M. Pour, J. Org. Chem. 1990, 50, 5580 and references
cited therein.
[6] For examples in which neighboring-group participation in electro-
philic additions was utilized to alter the course of electrophilic addi-
tions to cyclic systems and thus attain unusual regio- and stereose-
lectivity, see: a) R. B. Woodward, F. E. Bader, H. Bickel, A. J. Frey,
R. W. Kierstead, Tetrahedron 1958, 2, 1; b) R. B. Woodward, J. Gos-
teli, I. Ernest, R. J. Friary, G. Nestler, H. Raman, R. Sitrin, C. Suter,
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´
J. K. Whitesell, J. Am. Chem. Soc. 1973, 95, 6853; c) P. Kocovsky, F.
ˇ
ˇ
´
Turecek, Tetrahedron Lett. 1981, 22, 2699; d) P. Kocovsky, I. Stiebor-
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´
´
ovꢁ, Tetrahedron Lett. 1989, 30, 4295; e) P. Kocovsky, I. Stary, J. Za-
ˇ
ˇ
ˇ ˇ
jꢈcek, F. Turecek, S. Vasꢈckovꢁ, J. Chem Soc. Perkin Trans 1 1988,
2297.
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b) A. B. Reitz, S. O. Nortey, B. E. Maryanoff, J. Org. Chem. 1987,
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Chem. 1991, 56, 240; d) P. Kocovsky, Organometallics 1993, 12, 1969;
ˇ
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´
ˇ
ˇ
e) P. Kocovsky, J. Srogl, A. Gogoll, V. Hanus, M. Polꢁsek, J. Chem.
Soc. Chem. Commun. 1992, 1086; f) P. Kocovsky, J. Srogl, M. Pour,
ˇ
ˇ
´
ˇ
´
A. Gogoll, J. Am. Chem. Soc. 1994, 116, 186; g) P. Kocovsky, J. M.
ˇ
´
Grech, W. L. Mitchell, J. Org. Chem. 1995, 60, 1482; h) P. Kocovsky,
J. M. Grech, W. L. Mitchell, Tetrahedron Lett. 1996, 37, 1125; i) P.
ˇ
ˇ
´
Kocovsky, V. Dunn, J. M. Grech, J. Srogl, W. L. Mitchell, Tetrahe-
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[14] Both 6(O)-exo-trig and 6(O)-endo-trig, as well as 5(O)-exo-trig pro-
cesses have been demonstrated (see Refs. [10–12]). For the modifi-
cation of the original Baldwin notation, see Ref. [5] and the follow-
ˇ
´
Org. Chem. 1985, 50, 2416; l) P. Kocovsky, V. Langer, A. Gogoll, J.
ˇ
ˇ
´
´
ˇ
ing: a) P. Kocovsky, V. Cerny, M. Synꢁckovꢁ, Collect. Czech. Chem.
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Chem. Soc. Chem. Commun. 1990, 1026; m) P. Kocovsky, R. S.
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Schwarz, L.; J.-H. Choi, T. M. Frost, Angew. Chem. 2000, 112, 2382;
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Commun. 1979, 44, 1483; b) P. Kocovsky, I. Stieborovꢁ, J. Chem.
Soc. Perkin Trans. 1 1987, 1969.
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P. Kocovsky, A. V. Malkov et al.
[15] Another popular reoxidation reagent is para-benzoquinone, particu-
larly in the Bꢃckvall oxidation of dienes (see Ref. [16]). For another
use of the latter stoichiometric oxidans in the transmetalation of or-
ganomercurials with PdII, followed by carbonylation (see Ref. [7h,i]).
[16] a) J.-E. Bꢃckvall, Acc. Chem. Res. 1983, 16, 335; b) J.-E. Bꢃckvall,
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ꢀ
Pure Appl. Chem. 1992, 64, 429; c) “C O and C N Bond Formation
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P. G. Andersson, J.-E. Bꢃckvall in Organopalladium Chemistry for
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[33] a) A. V. Malkov, M. Orsini, D. Pernazza, K. W. Muir, V. Langer, P.
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Meghani, P. Kocovsky, Org. Lett. 2002, 4, 1047; b) A. V. Malkov, M.
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Bell, M. Vassieu, V. Bugatti, P. Kocovsky, J. Mol. Catal. A 2003, 196,
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kenes via nucleopalladation, see: R. I. McDonald, G. Liu, S. S. Stahl,
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179; c) A. V. Malkov, M. Bell, M. Orsini, D. Pernazza, A. Massa, P.
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Herrmann, P. Meghani, P. Kocovsky, J. Org. Chem. 2003, 68, 9659;
ˇ
d) A. V. Malkov, M.-M. Westwater, A. Kadlcꢈkovꢁ, A. Gutnov, J.
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ˇ
ˇ
´
Hodacovꢁ, Z. Rankovic, M. Kotora, P. Kocovsky, Tetrahedron 2008,
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addition of an XPd OH species; see Refs. [17,18]
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´
64, 11335; e) A. V. Malkov, C. MacDonald, P. Kocovsky, Tetrahe-
dron: Asymmetry 2010, 21, 1173. For another application of pyridine
N-oxides as organocatalysts, see: f) A. V. Malkov, M. R. Gordon, S.
[20] For various modifications that allows pre-coordination of Pd to
´
ˇ
´
a substrate molecule, see, for example: a) I. Stary, P. Kocovsky, J.
´
ˇ
ˇ
´
Am. Chem. Soc. 1989, 111, 4981; b) I. Stary, J. Zajꢈcek, P. Kocovsky,
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Stoncius, J. Hussain, P. Kocovsky, Org. Lett. 2009, 11, 5390.
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Tetrahedron 1992, 48, 7229; c) C. N. Farthing, P. Kocovsky, J. Am.
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lent review on steering effects in general, see: p) A. H. Hoveyda,
D. A. Evans, G. C. Fu, Chem. Rev. 1993, 93, 1307. For a related pre-
ˇ
Starꢁ, L. Dufkovꢁ, S. Mitchell, I. Cꢈsarovꢁ, M. Kotora, Tetrahedron
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2006, 62, 968; g) R. Hrdina, A. Kadlcꢈkovꢁ, I. Valterovꢁ, J. Hoda-
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covꢁ, M. Kotora, Tetrahedron: Asymmetry 2006, 17, 3185; h) R.
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Hrdina, I. Valterovꢁ, J. Hodacovꢁ, I. Cꢈsarovꢁ, M. Kotora, Adv.
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Synth. Catal. 2007, 349, 822; i) R. Hrdina, M. Dracꢈnsky, I. Valter-
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ovꢁ, J. Hodacovꢁ, I. Cꢈsarovꢁ, M. Kotora, Adv. Synth. Catal. 2008,
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350, 1449; j) R. Hrdina, T. Boyd, I. Valterovꢁ, J. Hodacovꢁ, M.
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Kotora, Synlett 2008, 3141; k) A. Kadlcꢈkovꢁ, R. Hrdina, I. Valter-
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ˇ
Kadlcꢈkovꢁ, I. Valterovꢁ, L. Duchꢁckovꢁ, J. Roithovꢁ, M. Kotora,
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ˇ
Chem. Eur. J. 2010, 16, 9442; n) L. Duchꢁckovꢁ, A. Kadlcꢈkovꢁ, M.
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coordination of molybdenum, see the following: q) D. Dvorꢁk, I.
Kotora, J. Roithovꢁ, J. Am. Chem. Soc. 2010, 132, 12660; o) K.
´
ˇ
´
Stary, P. Kocovsky, J. Am. Chem. Soc. 1995, 117, 6130; r) A. V.
ˇ
Vlasanꢁ, R. Hrdina, I. Valterovꢁ, M. Kotora, Eur. J. Org. Chem.
ˇ
ˇ
´
Malkov, I. R. Baxendale, D. Dvorꢁk, D. J. Mansfield, P. Kocovsky, J.
2010, 6040. For an overview, see: p) M. Kotora, Pure Appl. Chem.
2010, 82, 1813.
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´
Org. Chem. 1999, 64, 2737; s) P. Kocovsky, A. V. Malkov, S. Vysko-
ˇ
cil, G. C. Lloyd-Jones, Pure Appl. Chem. 1999, 71, 1425; t) A. V.
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´
[35] a) A. V. Malkov, M. Bell, F. Castelluzzo, P. Kocovsky, Org. Lett.
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´
Malkov, P. Spoor, V. Vinader, P. Kocovsky, Tetrahedron Lett. 2001,
42, 509; u) G. C. Lloyd-Jones, S. W. Krska, D. L. Hughes, L. Gou-
ˇ
2005, 7, 3219; b) A. V. Malkov, M. Barłꢀg, Y. Jewkes, J. Mikusek, P.
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´
Kocovsky, J. Org. Chem. 2011, 76, 4800; c) A. V. Malkov, O. Kysilka,
ACHTUNGTRENNUNG
ˇ
ˇ
´
M. Edgar, A. Kadlcꢈkovꢁ, M. Kotora, P. Kocovsky, Chem. Eur. J.
2011, 17, 7162.
´
ˇ
´
Stary, V. Langer, P. Spoor, V. Vina
N
ˇ
´
[36] a) A. V. Malkov, L. Dufkovꢁ, L. Farrugia, P. Kocovsky, Angew.
Chem. 2003, 115, 3802; Angew. Chem. Int. Ed. 2003, 42, 3674;
b) A. V. Malkov, M. Bell, P. Ramꢈrez-Lꢀpez, L. Biedermannovꢁ, L.
2006, 12, 6910.
[21] T. Hayashi, K. Yamasaki, M. Mimura, Y. Uozumi, J. Am. Chem.
Soc. 2004, 126, 3036.
[22] R. M. Trend, Y. K. Ramtohul, B. M. Stoltz, J. Am. Chem. Soc. 2005,
127, 17778.
ˇ
ˇ
´
Rulꢈsek, L. Dufkovꢁ, M. Kotora, F. Zhu, P. Kocovsky, J. Am. Chem.
Soc. 2008, 130, 5341.
[37] For catalysis by chiral sulfoxides, see: a) A. Massa, A. V. Malkov, P.
[23] a) M. B. Hay, A. R. Hardin, J. P. Wolfe, J. Org. Chem. 2005, 70,
3099; b) M. B. Hay, J. P. Wolfe, Tetrahedron Lett. 2006, 47, 2793.
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b) M. B. Hay, J. P. Wolfe, J. Am. Chem. Soc. 2005, 127, 16468. For an
overview, see Ref. [13i].
ˇ
´
Kocovsky, A. Scettri, Tetrahedron Lett. 2003, 44, 7179. For an over-
view on catalysis by chiral phosphoramides, see: b) S. E. Denmark,
J. Fu, Chem. Rev. 2003, 103, 2763.
ˇ
´
[38] For reviews, see: a) A. V. Malkov, P. Kocovsky, Curr. Org. Chem.
ˇ
´
2003, 7, 1737; b) P. Kocovsky, A. V. Malkov, Izv. Akad. Nauk Ser.
[25] In fact, it can be speculated whether the coordination of the Pd to
the neighboring-group precedes the formation of the h2-complex
with the C=C bond, or whether two facially isomeric h2-complexes
are formed first and in the equilibrium the syn-stereoisomer (where
Pd is coordinated to the neighboring group) is consumed faster.
Khim. 2004, 1733; Russian Chem. Bull. Int. Ed. 2004, 59, 1806;
c) A. V. Malkov, P. Kocovsky, Eur. J. Org. Chem. 2007, 29;
d) “Chiral Lewis Bases as Catalysts”: P. Kocovsky, A. V. Malkov in
Enantioselective Organocatalysis—Reactions and Experimental Pro-
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Functionalization of Homoallylic Alcohols
FULL PAPER
cedures (Ed.: P. I. Dalko), Wiley-VCH, Weinheim, 2007, p. 255; e) P.
with no experimental evidence: K. G. Dongol, B. Y. Tay, Tetrahe-
dron Lett. 2006, 47, 927.
[55] For the original method, see: S. Cicchi, A. Goti, A. Brandi, A.
Guarna, F. De Sarlo, Tetrahedron Lett. 1990, 31, 3351.
ˇ
´
Kocovsky, A. V. Malkov, Pure Appl. Chem. 2008, 80, 953.
[39] For the method, see: K. Iseki, Y. Kuroki, M. Takahashi, S. Kishimo-
to, Y. Kobayashi, Tetrahedron 1997, 53, 3513.
[40] For the method, see: J. Tsuji, M. Hara, K. Ohno, Tetrahedron 1974,
30, 2143.
[56] Lactonization of hydroxy esters is typically carried out by treatment
with Brønsted or Lewis acids, or is catalyzed by enzymes (see
Ref. [57]). In our case (compound 37), the presence of the acid-sen-
sitive Boc group limited the choice of acidic conditions. Neverthe-
less, 10% of p-TsOH in toluene was sufficient to complete the reac-
tion and mild enough to avoid deprotection. However, partial epi-
merization at the benzylic center was observed, so that this method
was abandoned. The use of a strong mineral base, such as KOH, in
polar solvents or water resulted in the saponification of the ester
group. A stoichiometric amount of DBU (a strong, non-nucleophilic
base) in acetonitrile triggered a quantitative conversion to the de-
sired lactone 39a within minutes but this process was acompanied
by the formation of several byproducts. On the other hand, employ-
ing just 5 mol% of DBU in diluted reaction mixture (in MeCN) was
found to be an optimal protocol, as it resulted in a clean conversion
of 37a into lactone 39a in a few hours at room temperature. The X-
ray analysis of the final product confirmed the relative configuration
for the whole series of transformations.
ˇ
´
[41] A. V. Malkov, M. A. Kabeshov, M. Barłꢀg, P. Kocovsky, Chem. Eur.
J. 2009, 15, 1570.
[42] a) R. W. Bates, K. Sa-Ei, Org. Lett. 2002, 4, 4225; b) R. W. Bates, J.
Boonsombat, Org. Biomol. Chem. 2005, 3, 520; c) R. W. Bates, J.
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Cranwell, S. Winbush, Pure Appl. Chem. 2008, 80, 681. For a related,
gold(I)-catalyzed neighboring-group participation in the ring-closing
functionalization of Boc-protected ynamines, see: d) A. S. K.
Hashmi, R. Salathꢉ, W. Frey, Synlett 2007, 1763.
[43] For related reactions of allenes, using Ag+ and other metals as elec-
trophiles, see: a) R. W. Bates, J. A. Nemeth, R. H. Snell, Synthesis
2008, 1033; b) R. W. Bates, R. H. Snell, S. Winbush, Synlett 2008,
1042; c) R. W. Bates, Y. N. Lu, J. Org. Chem. 2009, 74, 9460;
d) R. W. Bates, C. J. Lim, Synlett 2010, 866; e) R. W. Bates, Y. N. Lu,
Org. Lett. 2010, 12, 3938.
[44] a) B. Janza, A. Studer, J. Org. Chem. 2005, 70, 6991; b) K. G.
Dongol, B. Y. Tay, K. Xiang, Synth. Commun. 2006, 36, 1247;
c) R. W. Bates, P. Song, Synthesis 2009, 655.
[57] For an effective and mild lactonization of hydroxy esters, see, for ex-
ample: a) H. Kuno, M. Shibagaki, K. Takahashi, I. Honda, H. Mat-
sushita, Chem. Lett. 1992, 571; b) J. Fujita, S. Watanabe, K. Suga, Y.
Higuchi, T. Sotoguchi, J. Org. Chem. 1984, 49, 1975; c) C. Bonini, P.
Pucci, R. Racioppi, L. Viggiani, Tetrahedron: Asymmetry 1992, 3,
[45] Retention by using 3,3’-di-tert-butyloxaziridine as the reagent: I. C.
Choong, J. A. Ellman, J. Org. Chem. 1999, 64, 6528.
[46] Retention by using N-Boc-3-trichloromethoxyaziridine as the re-
agent: a) O. F. Foot, D. W. Knight, Chem. Commun. 2000, 975. For
ˇ
ˇ
ˇ
29; d) D. Berkes, A. Kolarovic, R. Manduch, P. Baran, F. Povazanec,
Tetrahedron: Asymmetry 2005, 16, 1927; e) J. D. White, N. J. Green,
F. F. Fleming, Tetrahedron Lett. 1993, 34, 3515; f) A. Makita, T.
Nihira, Y. Yamada, Tetrahedron Lett. 1987, 28, 805. For lactonization
with DBU, see: g) J. J. Gaudino, C. S. Wilcox, Carbohydr. Res. 1990,
206, 233; h) Y. Yoshida, Y. Ukaji, S. Fujinami, K. Inomata, Chem.
Lett. 1998, 1023; i) Z. Yang, W. Zhou, Tetrahedron 1995, 51, 1429.
[58] Extension of this methodology to the realm of non-aromatic starting
materials was also briefly explored. Thus, the Mitsunobu reaction of
ꢀ
constructing the N N bond with the same reagent, see: b) J. Vidal,
J.-C. Hannachi, G. Hourdin, J.-C. Mulatier, A. Collet, Tetrahedron
Lett. 1998, 39, 8845.
[47] a) O. Mitsunobu, Y. Yamada, Bull. Chem. Soc. Japan 1967, 40, 2380;
b) O. Mitsunobu, Synthesis 1981, 1; c) D. L. Hughes, Org. React.
1992, 42, 335.
[48] Obviously, the p-methoxy group is a strong factor encouraging the
nucleophilic substitution in the benzylic position to swing from the
clean SN2 mechanism towards SN1. By contrast, the m-methoxy
group, as in 4 f (being actually slightly electron-withdrawing), does
not exhibit such a drastic effect on the Mitsunobu reaction (Table 1,
entry 6).
[49] We reasoned that the effect of the strongly donating p-MeO sub-
stituent effect could be mitigated by replacing the MeO with a less-
donating oxygen group, such as AcO. Indeed, the anti-configured p-
acetoxy derivative (4, R1 =4-AcOC6H4, R2 =Me, 96% ee, 28:1 d.r.)
underwent the Mitsunobu reaction with a practically clean inversion
of configuration to produce the corresponding syn-alkoxyamine
(25:1 d.r.). Details of this and other examples will be revealed in
due course.
[50] The reaction proved to be rather capricious and low conversions
were observed in some batches; it turned out that the system must
be rigorously dry.
[51] METHOX (+)-5 was synthesized in four steps from (+)-a-pinene
(see Ref. [35a]). Its enantiomer could be prepared in the same way
from (ꢀ)-a-pinene, which is also commercially available. QUINOX
(R)-(+)-8 was obtained from the racemate on a very efficient reso-
lution by (S)-(ꢀ)-BINOL (see Ref. [36]). The opposite enantiomer
was recovered from the mother liquor (Ref. [36]), and may also be
obtained by using (R)-(+)-BINOL for the resolution.
[52] The use of other solvents (iPrOH, THF, and CH3CN and their mix-
tures) instead of methanol proved fruitless.
[53] For the coordination of Pd to a carbonyl group, see, for example:
a) R. van Asselt, F. C. G. Gielens, R. E. Rꢆlke, K. Vrieze, C. J.
Elsevier, J. Am. Chem. Soc. 1994, 116, 977. For other stereodirecting
N-hydroxyphthalimide
with
PhCH=CHCH(OH)CH2CH=CH2
(88% ee), which in turn was obtained from the METHOX-catalyzed
allylation of cinnamaldehyde with allytrichlorosilane (Ref. [35b]),
followed by deprotection with hydrazine, produced an inseparable
2:1 mixture of the alkoxyamines corresponding to a direct substitu-
tion (SN2) and that arising by allylic rearrangement (SN2’), as re-
vealed by 1H NMR spectroscopy. The 19F NMR spectrum of the
Mosher derivatives, obtained from this mixture, showed ꢃ40% ee
for the former product, while the latter rearranged derivative was
practically racemic. Boc-derivatization of the latter mixture afforded
a 2:1 mixture, in which the desired “normal” product, that is,
PhCH=CHCHACHTNUGTRNEUNG(ONBoc)CH2CH=CH2 prevailed. Palladium-cata-
lyzed carbonylation of this mixture proceeded as expected, giving
rise to the corresponding isoxazolidine, as a result of the reaction of
the homoallylic double bond, whereas its allylic C=C bond remained
intact. The isomeric Boc derivative remained unreacted, which al-
lowed the isolation of the desired isoxazolidine. This promising che-
moselectivity demonstrated the wider applicability of this methodol-
ogy. The current bottle neck, that is, obtaining the desired alkoxy-
AHCTUNGTRENNaGUN mine, will be addressed in due course.
[59] Protected hydrazines, obtained from 4 via the Mitsunobu reaction
with dialkyl diazodicarboxylate (for the method, see: M. J. Di Gran-
di, J. W. Tilley, Tetrahedron Lett. 1996, 37, 4327), undergo analogous,
ring-closing amidocarbonylation to produce the pyrrazolidine ana-
logues of isoxazolidines 16; details of this new procedure will be dis-
closed in due course.
[60] a) For the Pd-catalyzed cyclization of N-tosyl carbamates in the ab-
sence of CO, see: F. Nahra, F. Liron, G. Prestat, C. Mealli, A. Mes-
saoudi, G. Poli, Chem. Eur. J. 2009, 15, 11078 and references cited
therein. For correction, see: b) F. Nahra, F. Liron, G. Prestat, C.
Mealli, A. Messaoudi, G. Poli, Chem. Eur. J. 2010, 16, 1414. In a simi-
lar way, our carbamate 15 undergoes an analogous cyclization in the
ˇ
´
effects of carbamate groups and discussion, see: b) P. Kocovsky, Tet-
ˇ
´
´
rahedron Lett. 1988, 29, 2475; c) P. Kocovsky, I. Stary, J. Org. Chem.
1990, 55, 3236. For other coordinating groups, see Ref. [20].
[54] In a cyclization reaction of racemic 10a with aryl iodides, carried
out in the presence of tBuONa and a catalytic amount of (dba)3Pd2/
dppe in refluxing toluene, Dongol also assumed the syn-addition but
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ˇ
´
P. Kocovsky, A. V. Malkov et al.
absence of CO, giving rise to the corresponding oxazolidine with
a pendant vinyl group; details will be communicated in due course.
[61] For selected examples of the synthesis of isoxazolidines by nitrone
cycloaddition, see, for example: a) X. Ding, K. Taniguchi, Y. Hama-
moto, K. Sada, S. Fujinami, Y. Ukaji, K. Inomata, Bull. Chem. Soc.
Jpn. 2006, 79, 1059; b) Y. Ukaji, K. Taniguchi, I. Sada, Chem. Lett.
1997, 547. For the synthesis of negamycin via nitrone addition, see:
c) H. Iida, K. Kasahara, C. Kibayashi, J. Am. Chem. Soc. 1986, 108,
4647; d) D. Socha, M. Jurczak, M. Chmielewski, Tetrahedron Lett.
1995, 36, 135. For the nitrone approach to monomorine, see: e) M.
Ito, C. Kibayashi, Tetrahedron Lett. 1990, 31, 5065; f) M. Ito, C. Ki-
bayashi, Tettrahedron 1991, 47, 9329; g) N. Morita, K. Fukui, J. Iri-
kuchi, H. Sato, Y. Takano, I. Okamoto, H. Ishibashi, O. Tamura, J.
Org. Chem. 2008, 73, 7146.
Mosher, J. Am. Chem. Soc. 1973, 95, 512; c) H. Iwagami M. Yatagai,
M. Nakazawa, H, Orita, Y. Honda, T. Ohnuki, T. Yukawa, Bull.
Chem. Soc. Jpn. 1991, 64, 175; d) For checking the enantiopurity of
the Mosher acid purchased from Aldrich, see Ref. [33f].
[65] J. Nokami, M. Ohga, H. Nakamoto, T. Matsubara, I. Hussain, K.
Kataoka, J. Am. Chem. Soc. 2001, 123, 9168.
[66] R. H. Blessing, J. Appl. Crystallogr. 1989, 22, 396.
[67] A. Altomare, G. Cascarano, C. Giacovazzo, A. Guagliardi, M. C.
Burla, G. Polidori, M. Camalli, J. Appl. Crystallogr. 1994, 27, 435.
[68] L. Palatinus, G. Chapuis, J. Appl. Crystallogr. 2007, 40, 786.
[69] G. M. Sheldrick, Acta Crystallogr. Sect. A 2008, 64, 112.
[70] For comparison, see Ref. [44] and the following: T. Ishikawa, M. Ka-
wakami, M. Fukui, A. Yamashita, J. Urano, S. Saito, J. Am. Chem.
Soc. 2001, 123, 7734.
[62] For the construction of isoxazolidines via the organocatalyzed intra-
molecular addition of an N-Boc-protected hydroxylamine moiety
across a conjugated double bond, see: Y. K. Chen, M. Yoshida,
D. W. C. MacMillan, J. Am. Chem. Soc. 2006, 128, 9328.
[63] For the IBX-mediated cyclization of N-acyl analogues of 12, see
Ref. [44].
[71] The minimum amount of the solvent for 1 mmol of the substrate is
5 mL of MeCACTHNURGTNEUNG(OMe)3 and 5 mL of MeOH, in which the reaction is
faster but less diastereoselective. Using 10 mL of each solvent gives
better yields and the anti product could not be detected in the
1H NMR spectrum of the crude product.
[64] Mosher acid: (R/S)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoic
acid. For the synthesis and utilization, see: a) J. A. Dale, D. L. Dull,
H. S. Mosher, J. Org. Chem. 1969, 34, 2543; b) J. A. Dale, H. S.
Received: August 30, 2011
Published online: && &&, 2012
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Functionalization of Homoallylic Alcohols
FULL PAPER
Stereocontrol
A. V. Malkov,* M. Barłꢀg,
L. Miller-Potuckꢁ, M. A. Kabeshov,
ˇ
´
L. J. Farrugia, P. Kocovsky* &&&& — &&&&
Syn-full cyclization! Enantiopure, Boc-
protected alkoxyamines undergo a dia-
stereoselective Pd-catalyzed ring-clos-
ing carbonylative amidation to pro-
duce isoxazolidines (ꢁ50:1 d.r.) that
can be readily converted into the N-
Boc-protected esters of b-amino-d-hy-
droxy acids and their g-substituted
homologues (see scheme). The key
carbonylative cyclization proceeds
through an unusual syn addition of the
palladium and the nitrogen nucleo-
phile across the C=C bond.
Stereoselective Palladium-Catalyzed
Functionalization of Homoallylic Alco-
hols: A Convenient Synthesis of Di-
and Tri-Substituted Isoxazolidines and
b-Amino-d-Hydroxy Esters
Chem. Eur. J. 2012, 00, 0 – 0
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www.chemeurj.org
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