Widely applicable synthesis of enantiomerically pure tertiary alkyl-containing 1-alkanols by zirconium-catalyzed asymmetric carboalumination of alkenes and palladium- or copper-catalyzed cross-coupling

Article abstract of DOI:10.1002/asia.201300311

A highly enantioselective and widely applicable method for the synthesis of various chiral 2-alkyl-1-alkanols, especially those of feeble chirality, has been developed. It consists of zirconium-catalyzed asymmetric carboalumination of alkenes (ZACA), lipase-catalyzed acetylation, and palladium- or copper-catalyzed cross-coupling. By virtue of the high selectivity factor (E) associated with iodine, either (S)- or (R)-enantiomer of 3-iodo-2-alkyl-1- alkanols (1), prepared by ZACA reaction of allyl alcohol, can be readily purified to the level of ≥99 % ee by lipase-catalyzed acetylation. A variety of chiral tertiary alkyl-containing alcohols, including those that have been otherwise difficult to prepare, can now be synthesized in high enantiomeric purity by Pd- or Cu-catalyzed cross-coupling of (S)-1 or (R)-2 for introduction of various primary, secondary, and tertiary carbon groups with retention of all carbon skeletal features. These chiral tertiary alkyl-containing alcohols can be further converted into the corresponding acids with full retention of the stereochemistry. The synthetic utility of this method has been demonstrated in the highly enantioselective (≥99 % ee) and efficient syntheses of (R)-2-methyl-1-butanol and (R)- and (S)-arundic acids. Look, mom, one hand! 2-Alkyl-1-alkanols of feeble chirality have been synthesized by a sequence of zirconium-catalyzed asymmetric carboalumination of alkenes (ZACA), lipase-catalyzed acetylation, and Pd- or Cu-catalyzed cross-coupling in high enantiomeric purity of ≥99 % ee. The synthetic utility of this method has been demonstrated in highly enantioselective and efficient syntheses of (R)-2-methyl-1-butanol, (R)- and (S)-arundic acids. Copyright

Full text of DOI:10.1002/asia.201300311

FULL PAPER
DOI: 10.1002/asia.201300311
Widely Applicable Synthesis of Enantiomerically Pure Tertiary Alkyl-
Containing 1-Alkanols by Zirconium-Catalyzed Asymmetric
Carboalumination of Alkenes and Palladium- or Copper-Catalyzed Cross-
Coupling
Shiqing Xu, Ching-Tien Lee, Guangwei Wang, and Ei-ichi Negishi*[a]
Abstract:
A
highly enantioselective
by ZACA reaction of allyl alcohol, can
be readily purified to the level of
ꢁ99% ee by lipase-catalyzed acetyla-
tion. A variety of chiral tertiary alkyl-
containing alcohols, including those
that have been otherwise difficult to
prepare, can now be synthesized in
high enantiomeric purity by Pd- or Cu-
catalyzed cross-coupling of (S)-1 or
(R)-2 for introduction of various pri-
mary, secondary, and tertiary carbon
groups with retention of all carbon
skeletal features. These chiral tertiary
alkyl-containing alcohols can be further
converted into the corresponding acids
with full retention of the stereochemis-
try. The synthetic utility of this method
has been demonstrated in the highly
enantioselective (ꢁ99% ee) and effi-
cient syntheses of (R)-2-methyl-1-buta-
nol and (R)- and (S)-arundic acids.
and widely applicable method for the
synthesis of various chiral 2-alkyl-1-al-
kanols, especially those of feeble chir-
ality, has been developed. It consists of
zirconium-catalyzed asymmetric car-
boalumination of alkenes (ZACA),
lipase-catalyzed acetylation, and palla-
dium- or copper-catalyzed cross-cou-
pling. By virtue of the high selectivity
factor (E) associated with iodine,
either (S)- or (R)-enantiomer of 3-
iodo-2-alkyl-1-alkanols (1), prepared
Keywords: asymmetric synthesis ·
cross-coupling · enzyme catalysis ·
homogeneous catalysis
Introduction
boalumination of alkenes (ZACA) and lipase-catalyzed ace-
tylation.[5b] In all of the examples reported in our previous
papers,[5b,g,6] b-chiral 1-alcohols of at least 98% ee were pre-
Recent major advances in the synthesis of chiral tertiary
alkyl-containing compounds including a large number of
those with biologically and medicinally important properties,
for example, isoprenoids, deoxypolypropionates, and
others,[1] have been made through the development of cata-
lytic asymmetric alkene hydrogenation,[2] epoxidation,[3] car-
boalumination,[4] and so on. Those that have been synthe-
sized by our group include vitamin E,[5a] vitamin K,[5a,b] si-
phonarienolone,[5c]
4,6,8,10,16,18-hexamethyldocosane,[5d]
(+)-scyphostatin,[5e,f] and (ꢀ)-spongidepsin[5g] (Figure 1).
These target compounds containing two or more asymmetric
carbon atoms have been synthesized with high stereoiso-
meric purity, even if each stereogeneric process is of less
than satisfactory stereoselectivity (<98%) by exploitation
of the statistical enantiomeric amplification principle
(Table 1).
An efficient route to compounds containing a single ste-
reogenic carbon center has also been developed by us
through the synergy of zirconium-catalyzed asymmetric car-
Figure 1. Some naturally occurring chiral tertiary alkyl groups of biologi-
cal and medicinal importance.
Table 1. Statistical enantiomeric amplification.
ee of each Overall ee [%]
stereogenic
center [%]
[a] Dr. S. Xu, Dr. C.-T. Lee, Dr. G. Wang, Prof.Dr. E.-i. Negishi
H. C. Brown Laboratories of Chemistry
Purdue University
Two stereogenic
centers
Three stereogenic
centers
Four stereogenic
centers
560 Oval Drive, West Lafayette, IN 47907-2084 (USA)
Fax : (+1)765-494-0239
E-mail: negishi@purdue.edu
90
80
70
99.4
97.6
94.0
ca. 100
99.7
ca. 100
ca. 100
99.8
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201300311.
98.9
1
&
&
Chem. Asian J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
These are not the final page numbers! ÞÞ

www.chemasianj.org
Ei-ichi Negishi et al.
pared by the ZACA reaction of 1-alkenes (R1CH=CH2) to
produce the final b-chiral 1-alcohols (R1R2CHCH2OH) of
mostly 70–85% ee, which were then enantiomerically puri-
fied to the level of at least 98% ee by resorting to sufficient-
ly high selectivity factors (E)[7] associated with the R1 or R2
group of the desired compounds R1R2CHCH2OH containing
proximal p bonds or heterofunctional groups. However, in
cases where 1) the initial enantiomeric excess of the crude
product is low, 2) the two carbon groups R1 and R2 are
structurally similar, and/or 3) the selectivity factors (E) are
not sufficiently high, enantiomeric purification of the ob-
tained crude products, that is, R1R2CHCH2OH, can be diffi-
cult and synthetically impractical, representing a major defi-
ciency to be overcome. Consider, for example, the prepara-
tion of (R)- and (S)-2-methyl-1-butanol. Whereas the (S)-
isomer is commercially available at relatively low cost as
a ꢁ98% isomerically pure compound,[8] the (R)-isomer is
not. In fact, a number of research groups have reported the
syntheses of (R)-2-methyl-1-butanol.[9–12] One frequently em-
ployed route is to convert isomerically pure and commer-
cially available methyl (S)-3-hydroxy-2-methylpropionate
into (R)-2-methyl-1-butanol, typically in several steps.[9]
While the enantiomeric purity of (R)-2-methyl-1-butanol
thus obtained is satisfactory (ꢁ98% ee), this method re-
quires rather expensive (S)-3-hydroxy-2-methylpropionate,
which seriously compromises the practical value of this
strategy.[10] Brown developed an asymmetric hydroboration–
one-carbon homologation–reduction–oxidation route[11] to
provide (R)-2-methyl-1-butanol efficiently and selectively
(ꢁ99% ee). However, the entire process is non-catalytic, re-
quiring stoichiometric quantities of chiral reagents. More-
over, its scope, as reported, is limited to the use of symmet-
rically substituted alkenes, such as cis-2-butene, to avoid the
formation of regioisomeric mixtures. Lipase-catalyzed acety-
lation of enantiomeric mixtures of (R)- and (S)-2-methyl-1-
butanols has also been reported.[12] Due to the low E factor,
(R)-2-methyl-1-butanol of only 90% ee was obtained in
a disappointingly low recovery of 30% after multiple rounds
of lipase-catalyzed acetylation of a racemic mixture.
Scheme 1. Strategy for the synthesis of feebly chiral 2-alkyl-1-alkanols.
R3CH2 =R1; R1 and R2CH2 are structurally similar.
Results and Discussion
Asymmetric Synthesis of (R)- and (S)-3-Iodo-2-Alkyl-1-
Alkanols (1)
We began our study by asymmetric synthesis of (R)- and
(S)-3-iodo-2-alkyl-1-alkanols (1) via ZACA reaction of allyl
alcohol. Compounds (S)- and (R)-1a were prepared in 80%
and 81% yields by treatment of allyl alcohol with Me3Al
(2.5 equiv), methylaluminoxane (MAO, 1 equiv), and
[(+)-(NMI)2ZrCl2] or [(ꢀ)-(NMI)2ZrCl2] (5 mol%) in
[14]
CH2Cl2, followed by iodinolysis with I2.[4f] Their enantio-
meric purities were 82% ee and 84% ee, respectively
(Table 2, entries 1 and 2). Similarly, the ZACA reaction of
allyl alcohol with Et3Al or nPr3Al was also performed. In
Table 2. Asymmetric synthesis of (R)- and (S)-3-iodo-2-alkyl-1-alkanols
(1).
Entry
R
Protocol[a]
Product
Yield [%][b]
Purity of 1
ee [%][c]
We report herein a widely applicable and highly enantio-
selective (ꢁ99% ee) method for the synthesis of various
chiral 2-alkyl-1-alkanols, including those that have been oth-
erwise very difficult to prepare, by exploitation of 1) gener-
ally facile purification of ICH2CH(R)CH2OH (1) to the
level of ꢁ99% ee owing to the high E factor associated with
iodine[4f] proximal to the chiral center and 2) full retention
(>99%) of all carbon skeletal features of (S)-1 or (R)-2 in
palladium- or copper-catalyzed cross-coupling reactions,[4h,13]
which eliminates the limitations discussed above. The de-
sired chiral 2-alkyl-1-alkanols of ꢁ99% ee, even in cases
where R1 and R2CH2 lacking any proximal p bonds or heter-
ofunctional groups are structurally similar, have been readi-
ly prepared by substituting iodine with various primary, sec-
ondary, and tertiary carbon groups via Pd- or Cu-catalyzed
cross-coupling of (S)-1 or (R)-2 without epimerization
(Scheme 1).
1
2
3
4
5
6
Me
Me
Et
Et
nPr
nPr
I
II
III
IV
III
IV
(S)-1a
(R)-1a
(S)-1b
(R)-1b
(S)-1c
(R)-1c
80
81
60
62
59
60
82
84
87
88
82
80
[a] Protocol I: i) Me3Al (2.5 equiv), MAO (1 equiv), 5 mol%
[(+)-(NMI)2ZrCl2] ii) I2 (2.5 equiv), THF. Protocol II: i) Me3Al
(2.5 equiv), MAO (1 equiv), 5 mol% [(ꢀ)-(NMI)2ZrCl2] ii) I2 (2.5 equiv),
THF. Protocol III: i) R3Al (3.0 equiv), IBAO (1 equiv), 5 mol%
[(+)-(NMI)2ZrCl2] ii) I2 (6 equiv), Et2O. Protocol IV: i) R3Al (3.0 equiv),
IBAO (1 equiv), 5 mol% [(ꢀ)-(NMI)2ZrCl2] ii) I2 (6 equiv), Et2O.
[b] Yield of isolated product. [c] Enantiomeric excess determined by
1H NMR spectroscopic analysis of Mosher esters.
&
&
2
Chem. Asian J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

www.chemasianj.org
Ei-ichi Negishi et al.
these reactions, however, isobutylaluminoxane (IBAO) was
used in place of MAO, and after iodinolysis with I2, (S)-1b,
(R)-1b, (S)-1c, and (R)-1c of enantiomeric purities ranging
from 80–88% ee were obtained in 59–62% yields (Table 2,
entries 3–6).
and 3). The (S)-1b of ꢁ99% ee was obtained in 60% recov-
ery yield by using Amano AK (Table 3, entry 4).
Five commercially available lipases were tested for enan-
tiomeric purification of (S)-1c (Table 3, entries 5–10).
Amano AK proved to be the most satisfactory reagent for
the purification of (S)-1c, producing (S)-1c of ꢁ99% ee in
58% recovery yield (Table 3, entry 7). Amano PS lipase was
effective in providing (S)-1c of 92% ee in 74% recovery
yield (Table 3, entry 8). However, lipase from porcine pan-
creas (PPL), lipase from Rhizomucor miehei, and lipase
from Candida rugosa were disappointingly ineffective in se-
lective acetylation of (S)-1c (Table 3, entries 5, 9, and 10).
Thus, (S)-1a, (S)-1b, and (S)-1c are now readily obtaina-
ble as enantiomerically pure compounds of ꢁ99% ee in
50%, 36%, and 34% yields over two steps from allyl alco-
hol in a highly enantioselective, efficient, and satisfactory
manner.
Lipase-Catalyzed Acetylation of (S)- and (R)-3-Iodo-2-
Alkyl-1-Alkanols (1)
Amano PS lipase from Pseudomonas cepacia (Amano PS,
purchase from Aldrich) or Amano AK lipase from Pseudo-
monas fluorescens (Amano AK, purchase from Aldrich) was
generally satisfactory for purification of (S)- and (R)-3-iodo-
2-alkyl-1-alkanols (1). Compound (S)-1a of ꢁ99% ee was
prepared in 63% recovery by using Amano PS (Table 3,
entry 1). In the purification of (S)-1b, Amano AK and
Amano PS were comparatively effective (Table 3, entries 2
The results of lipase-cata-
lyzed purification of (R)-1 are
summarized in Table 4. Com-
Table 3. Lipase-catalyzed acetylation of (S)-1.
pound (R)-2a of ꢁ99% ee was
prepared in 60% yield by
using Amano PS (Table 4,
entry 1), while (R)-2b of
ꢁ99% ee was obtained in
52% yield from a 94/6 mixture
(88% ee) of (R)-1b and (S)-1b
(Table 4, entry 2). We were
further pleased to find that
(R)-2b of ꢁ99% ee was also
obtained by two rounds of
lipase-catalyzed purification in
62% overall yield. Thus, (R)-
2b of 96% ee was obtained in
81% yield (Table 4, entry 4).
Hydrolysis of acetate (R)-2b
(96% ee) without isolation,
followed by the second round
of lipase-catalyzed acetylation,
provided (R)-2b of ꢁ99% ee
(Table 4, entry 5).
Entry Substrate Initial purity of Lipase
Conversion [%][a] Recovery of Purity of
(S)-1 ee [%]
(S)-1 [%]
(S)-1 ee [%][b]
1
2
3
4
5
6
7
8
9
(S)-1a
(S)-1b
(S)-1b
(S)-1b
(S)-1c
(S)-1c
(S)-1c
(S)-1c
(S)-1c
82
87
87
87
82
82
82
82
82
Amano PS
Amano PS
Amano AK
Amano AK
PPL
Amano AK
Amano AK
Amano PS
lipase from
Rhizomucor Miehei
lipase from
Candida rugosa
33
23
22
37
62
24
39
22
63
63
72
74
60
35
74
58
74
34
ꢁ99
96
96
ꢁ99
85
94
ꢁ99
92
80
10
(S)-1c
82
37
59
83
[a] Conversion determined by 1H NMR spectroscopy. [b] Enantiomeric excess determined by 1H NMR spec-
troscopic analysis of Mosher esters.
Table 4. Lipase-catalyzed acetylation of (R)-1.
Similarly, the acetate of (R)-
1c of ꢁ99% ee was obtained
in 50% yield from a 90/10 mix-
ture (80% ee) of (R)-1c and
(S)-1c (Table 4, entry 6). Com-
pound (R)-2c of ꢁ99% ee was
also obtained by two rounds of
lipase-catalyzed purification in
60% overall yield (Table 4, en-
tries 8 and 9). As summarized
in Table 4, (R)-2a, (R)-2b, and
(R)-2c were all readily purified
to ꢁ99% ee in 49%, 38%,
and 36% overall yields from
allyl alcohol.
Entry
Substrate
Initial purity
of (R)-1 ee [%]
Lipase
Conversion [%][b]
Yield of
(R)-2 [%]
Purity of
(R)-2 ee [%][e]
1
2
3
4
5
6
7
8
9
(R)-1a
(R)-1b
(R)-1b
(R)-1b
(R)-1b
(R)-1c
(R)-1c
(R)-1c
(R)-1c
84
88
88
88
96
80
80
80
94
Amano PS
Amano PS
Amano PS
Amano PS
62
56
67
84
82
53
63
82
83
60
52
64
ꢁ99
ꢁ99
98
81
96
Amano PS
62[c]
50
ꢁ99
ꢁ99
98
94
ꢁ99
Amano AK[a]
Amano AK[a]
Amano AK[a]
Amano AK[a]
60
79
60[d]
[a] Toluene was used in place of THF. [b] Conversion determined by 1H NMR spectroscopy. [c] Overall yield
in two rounds of lipase-catalyzed purification (entries 4+5). [d] Overall yield in two rounds of lipase-catalyzed
purification (entries 8+9). [e] Enantiomeric excess determined by 1H NMR spectroscopic analysis of Mosher
esters.
3
&
&
Chem. Asian J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
These are not the final page numbers! ÞÞ

www.chemasianj.org
Ei-ichi Negishi et al.
Synthesis of (S)- and (R)-Chiral Tertiary Alkyl-Containing
Alcohols
With six key intermediates, that is, (S)-1a, (S)-1b, (S)-1c,
(R)-2a, (R)-2b, and (R)-2c of ꢁ99% ee in hand, our atten-
tion was then focused on establishing the feasibility of syn-
thesizing feebly chiral 2-alkyl-1-alkanols of high enantiomer-
ic purity by their Pd- or Cu-catalyzed cross-coupling reac-
tions. The cross-coupling reaction of (S)-1a with methylmag-
nesium bromide (3 equiv) in the presence of 1 mol% of
[13]
Li2CuCl4 gave (R)-2-methyl-1-butanol (3) of ꢁ99% ee in
77% yield. Thus, we have developed a highly selective and
efficient route to the synthesis of (R)-2-methyl-1-butanol (3,
ꢁ99% ee) in 39% yield from allyl alcohol over three steps
via ZACA, lipase-catalyzed acetylation, and Cu-catalyzed
cross-coupling.
Treatment of (S)-1a with TBSCl followed by Negishi cou-
pling[4h] catalyzed by 5 mol% [Pd
ACTHUNTRGNEUNG(DPEphos)Cl2] with vinyl
bromide and subsequent desilylation with tetrabutylammo-
nium fluoride (TBAF), provided (R)-4 in 85% yield over
three steps (Scheme 2). Synthesis of (S)-5 was achieved in
Scheme 3. Synthesis of chiral tertiary alkyl-containing 1-alcohols from
ꢂ
(S)-1b and (R)-2b. [a] LiAlH4 (1.5 equiv). [b] CuCl2 (5 mol%), PhC
ꢂ
CMe (15 mol%), RMgCl (3.3 equiv). [c] i) CuCl2 (5 mol%), PhC CMe
(15 mol%), RMgCl (2.0 equiv). ii) KOH.
15 mol% of 1-phenylpropyne in 80% and 70% yields
(Scheme 4). Furthermore, secondary and tertiary Grignard
reagents can also be used under similar reaction conditions
providing (R)-12 and (R)-13 in 70% and 68% yields, respec-
tively. Acetylation of (S)-1c with Ac2O followed by treat-
ment with 3 mol% Li2CuCl4, N-methylpyrrolidone (NMP,
4 equiv) and n-pentylmagnesium bromide (2 equiv), and
subsequent hydrolysis with KOH, provided (R)-11 of ꢁ99%
ee in 76% yield over three steps. In essentially the same
way, (S)-11 of ꢁ99% ee was also obtained in 80% yield
over two steps from (R)-2c. The preparation of (R)-14 of
ꢁ99% ee was carried out by TBS protection of (S)-1c, [Pd-
Scheme 2. Synthesis of chiral tertiary alkyl-containing 1-alcohols from
(S)-1a and (R)-2a. DPEphos=bis[(2-diphenylphosphino)phenyl]ether,
TBS=tert-butyldimethylsilyl.
AHCTUNGTRE(GNNUN DPEphos)Cl2]-catalyzed Negishi coupling, and TBAF desi-
lylation in 82% yield over three steps. Reduction of (R)-2c
with LiAlH4 (1.5 equiv) gave (R)-5 in 86% yield. The prepa-
ration of (R)-6, (S)-10, and (S)-13 was performed by similar
Cu-catalyzed cross-coupling and subsequent hydrolysis from
(R)-2c in 69%, 64%, and 70% yields, respectively. It should
be noted that the enantiomeric purity of alcohols 3, 4, and 5
70% yield by copper-catalyzed cross-coupling of (R)-2a
with ethylmagnesium chloride (2 equiv) in the presence of
5 mol% CuCl2 and 15 mol% 1-phenylpropyne[15] followed
by hydrolysis of the acetate with KOH. As we expected, all
three of these chiral alkanols were obtained with high enan-
tiomeric purity of ꢁ99% ee.
1
can be readily determined by H NMR spectroscopic analy-
Similarly, (S)-1b of ꢁ99% ee, prepared as described earli-
er, was converted into (S)-3, (R)-6, (R)-7, (R)-8, and (R)-9
of ꢁ99% ee by either reduction with LiAlH4 or Cu-cata-
lyzed cross-coupling in 64–80% yields (Scheme 3). (R)-2-
Methyl-1-butanol (3) of ꢁ99% ee was also obtained by re-
duction of (R)-2b with LiAlH4 (1.5 equiv) in 82% yield.
(S)-7 of ꢁ99% ee was prepared from (R)-2b in 62% yield
by Cu-catalyzed cross-coupling and subsequent hydrolysis.
The preparation of (S)-6 and (R)-10 were performed by
cross-coupling reactions of (S)-1c with methylmagnesium
chloride (3.3 equiv) and n-propylmagnesium chloride
(3.3 equiv) in the presence of 5 mol% of CuCl2 and
sis of their corresponding Mosher esters.[16] However, in
those cases where the two alkyl branches at the chiral
carbon atom are very similar to each other, as in the cases
of 6, 7, 9, 10, 11, and 13, the chemical shifts of the diastereo-
meric Mosher esters were not sufficiently separated to allow
quantitative determination of the enantiomeric purity by
1H NMR spectroscopy. The enantiomeric purities of these
compounds were therefore determined by chiral GC (see
the Supporting Information).
In this study, we have developed a highly enantioselective
and widely applicable route to various chiral 2-alkyl-1-alka-
nols, especially those of feeble chirality,[17] by ZACA and
&
&
4
Chem. Asian J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

www.chemasianj.org
Ei-ichi Negishi et al.
To demonstrate synthetic utility of the new protocol re-
ported herein, both (R)- and (S)-arundic acids were pre-
pared. (R)- and (S)-11 of ꢁ99% ee, prepared by ZACA,
lipase-catalyzed purification, and Cu-catalyzed cross-cou-
pling tandem reactions (Scheme 4), were transformed into
the corresponding (R)- and (S)-arundic acids in 98% yield
by oxidation with NaClO2 in the presence of catalytic
amounts of NaClO and 2,2,6,6-tetramethylpiperidin-1-yloxyl
(TEMPO).[21i] Thus, a highly enantioselective and efficient
synthesis of (R)- and (S)-arundic acids was achieved in 25%
and 28% over five steps, respectively, from allyl alcohol
(Scheme 5).
Scheme 5. Synthesis of (R)- and (S)-arundic acids.
Scheme 4. Synthesis of chiral tertiary alkyl-containing 1-alcohols from
ꢂ
(S)-1c and (R)-2c. [a] CuCl2 (5 mol%), PhC CMe (15 mol%), RMgCl
(3.3 equiv). [b] 1) Ac2O; 2) Li2CuCl4 (3 mol%), NMP (4 equiv),
Conclusions
nPentMgBr (2 equiv); 3) KOH/MeOH. [c] 1) Ac2O; 2) CuCl2 (5 mol%),
In summary, the present study has provided a widely appli-
cable and highly enantioselective route to various chiral 2-
alkyl-1-alkanols, especially those of feeble chirality, by a se-
quence of ZACA, lipase-catalyzed acetylation, and Pd- or
Cu-catalyzed cross-coupling. Either enantiomer of the de-
sired alcohols can be readily obtained in very high optical
purity (ꢁ99% ee) from the (R)- or (S)-enantiomer of 1 by
using Pd- or Cu-catalyzed cross-coupling to introduce vari-
ous primary, secondary, and tertiary carbon groups with re-
tention of all carbon skeletal features of (S)-1 or (R)-2. Oxi-
dation of chiral 2-alkyl-1-alkanols provides the correspond-
ing acids with high enantiomeric purity. The synthetic utility
of the present method has been demonstrated in highly
enantioselective syntheses of (R)-2-methyl-1-butanol (3) and
(R)- and (S)-arundic acids. Further studies along these lines
are currently ongoing.
ꢂ
PhC CMe (15 mol%), RMgCl (3 equiv); 3) KOH/MeOH. [d] 1) TBSCl;
2) i) tBuLi; ii) ZnBr2; iii) CH2=CHBr, [Pd
N
[e] LiAlH4 (1.5 equiv). [f] i) Li2CuCl4 (5 mol%), RMgCl (3 equiv);
ii) KOH/MeOH. [g] i) Li2CuCl4 (3 mol%), NMP (4 equiv), nPentMgBr
ꢂ
(2 equiv); ii) KOH/MeOH. [h] i) CuCl2 (5 mol%), PhC CMe (15 mol%),
RMgCl (3 equiv)ii) KOH/MeOH.
Pd- or Cu-catalyzed cross-coupling. Either enantiomer of
such alcohols can be obtained in high enantioselectivity
from the (R)- or (S)-enantiomer of 1. With recent advances
in Pd-, Ni-, and Cu-catalyzed cross-coupling of alkyl halides
with a wide variety of alkyl (primary, secondary, and terti-
ary), cyclic alkyl, vinyl, and aryl Grignard reagents; organo-
zinc species; or organoboron compounds;[18,19] we are in-
clined to believe that this study will provide a widely appli-
cable, convenient, and efficient procedure for the synthesis
of a very broad range of enantiomerically pure (ꢁ99% ee)
chiral tertiary alkyl-containing alcohols. It should also be
noted that chiral 2-alkyl-1-alkanols can be readily trans-
formed into their corresponding optically active aldehydes,
carboxylic acids, and other classes of compounds.
(R)-Arundic acid is currently undergoing Phase II devel-
opment for the treatment of acute ischemic stroke, as well
as clinical development in other neurodegenerative diseases,
such as Alzheimerꢁs disease and Parkinsonꢁs disease.[20]
Thus, arundic acid has been a highly coveted synthetic
target in recent years, and a number of syntheses of this
compound have been reported.[21] However, these methods
have limitations and drawbacks, including the use of highly
expensive chiral auxiliaries, modest enantiomeric purities,
and low yields.
Experimental Section
All reactions were run in a dry Ar atmosphere. Reactions were moni-
tored by thin layer chromatography (TLC) carried out on 0.25 mm
Merck silica gel plates (60F-254) or by GC analysis of reaction aliquots.
Chiral GC analysis was performed on an HP 7890 A gas chromatograph
using a CP-Chirasil-Dex CB capillary column (25 mꢂ0.25 mm, 0.39 mm
film). Flash chromatographic separations were carried out on 230–
400 mesh silica gel. 1H and 13C NMR spectra were recorded on Varian-
Inova-300 or Bruker-ARX-400 instruments. Optical rotations were mea-
sured on an Autopol III automatic polarimeter. ZnBr2 was flame-dried in
vacuo. THF was dried by distillation under Ar from sodium/benzophe-
none. CH2Cl2 was dried by distillation under Ar from CaH2. (+)- and
[(ꢀ)-(NMI)2ZrCl2][14a] were prepared as reported in the literature. Other
commercially available solvents and reagents were of reagent grade and
used without further purification, unless otherwise indicated.
5
&
&
Chem. Asian J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
These are not the final page numbers! ÞÞ

www.chemasianj.org
Ei-ichi Negishi et al.
Representative Procedure for ZACA Reaction and Lipase-Catalyzed
Acetylation. Synthesis of (S)-2-(Iodomethyl)pentan-1-ol (1c)
with LiAlH4. CP-Chirasil-Dex CB capillary column (25 mꢂ0.25 mm,
0.39 mm film). Test conditions: carrier gas 8 psi H2, oven program (608C
for 8 min, then 28Cminꢀ1 to 908C for 20 min, then 208Cminꢀ1 to 1908C
for 2 min), detector FID 2008C. Retention times (min): tR 47.1 (major); tS
47.2 (minor).
To a solution of allyl alcohol (0.68 mL, 10 mmol) in CH2Cl2 (5 mL) was
added dropwise nPr3Al (2.9 mL, 15 mmol) at ꢀ788C under argon, and
the resultant solution was stirred at 238C for 1 h. To a solution of iBu3Al
(2.5 mL, 10 mmol) in CH2Cl2 (10 mL) was added dropwise H2O
(0.18 mL, 10 mmol) at ꢀ788C under argon, and the mixture was slowly
warmed to 238C and stirred for 1 h to give a clear solution of IBAO in
CH2Cl2. To another solution of [(+)-(NMI)2ZrCl2] (334 mg, 0.5 mmol) in
CH2Cl2 (5 mL) at 08C were added consecutively nPr3Al (2.9 mL,
15 mmol), the IBAO solution prepared above, and the pretreated solu-
tion of allyl alcohol. The resultant solution was warmed to 238C and
stirred overnight. The solvents were evaporated in vacuo. The residue
was dissolved in Et2O (50 mL), and I2 (15.3 g, 60 mmol) was introduced
in three portions at 08C. The resultant mixture was stirred for 2 h at
238C, heated at reflux for additional 8 h, quenched with ice water, ex-
tracted with ether, washed with aqueous Na2S2O3, dried over anhydrous
MgSO4, filtered, concentrated, and purified by column chromatography
(silica gel, 20% ethyl acetate in hexanes) to afford (S)-2-(iodomethyl)-
pentan-1-ol (1c, 1.4 g, 59% yield, 82% ee).
Acknowledgements
We thank the National Institutes of Health (GM 36792) and Purdue Uni-
versity for support of this research. We also thank Sigma–Aldrich, Albe-
marle, Boulder Scientific, and Teijin for their support.
[1] I. Ojima et al. in Catalytic Asymmetric Synthesis (Ed.: I. Ojima),
Wiley, 2010, pp. 1–998.
[2] For examples of catalytic asymmetric hydrogenation of alkenes, see:
a) R. Noyori in Asymmetric Catalysis in Organic Synthesis (Ed.: R.
Noyori), Wiley, New York, 1994, pp. 16–94; b) R. Noyori, Angew.
Chem. 2002, 114, 2108–2123; Angew. Chem. Int. Ed. 2002, 41, 2008–
2022; c) A. Lightfoot, P. Schnider, A. Pfaltz, Angew. Chem. 1998,
110, 3047–3050; Angew. Chem. Int. Ed. 1998, 37, 2897–2899; d) S.
Bell, B. Wꢃstenberg, S. Kaiser, F. Menges, T. Netscher, Science 2006,
311, 642–644.
To a solution of (S)-1c (228 mg, 1.0 mmol, 82% ee) was added THF/H2O
(6 mL/6 mL), Amano AK lipase (40 mg), and vinyl acetate (0.9 mL,
10 mmol), and the mixture was stirred for 12 h at 238C. The resultant
mixture was diluted with ether, filtered, concentrated, and purified by
column chromatography (silica gel, 20% ethyl acetate in hexanes) to
afford (S)-1c (132 mg, 58%). The optical purity was determined by
Mosher ester analysis, ꢁ99% ee. ½aꢃ2D3 =ꢀ3.98 (c=1.4, CHCl3). 1H NMR
(300 MHz, CDCl3): d=0.93 (t, J=6.6 Hz, 3H), 1.2–1.4 (m, 6H), 3.30 (dd,
J=9.6, 5.1 Hz, 1H), 3.43 (dd, J=10.2, 4.2 Hz, 1H), 3.4–3.5 (m, 1H), 3.6–
3.7 ppm (m, 1H); 13C NMR (75 MHz, CDCl3): d=12.7, 14.0, 19.6, 32.9,
40.8, 64.9 ppm. HRMS (EI) calcd for C6H13IO [M]+: 228.0011; found:
228.0015.
[3] a) T. Katsuki, K. B. Sharpless, J. Am. Chem. Soc. 1980, 102, 5974–
5976; b) K. B. Sharpless, Angew. Chem. 2002, 114, 2126–2135;
Angew. Chem. Int. Ed. 2002, 41, 2024–2032.
[4] For examples of catalytic asymmetric carboalumination of alkenes,
see: a) D. Kondakov, E. Negishi, J. Am. Chem. Soc. 1995, 117,
10771–10772; b) D. Kondakov, E. Negishi, J. Am. Chem. Soc. 1996,
118, 1577–1578; c) S. Huo, J. Shi, E. Negishi, Angew. Chem. 2002,
114, 2245–2247; Angew. Chem. Int. Ed. 2002, 41, 2141–2143; d) E.
Negishi, Z. Tan, B. Liang, T. Novak, Proc. Natl. Acad. Sci. USA
2004, 101, 5782–5787; e) T. Novak, Z. Tan, B. Liang, E. Negishi, J.
Am. Chem. Soc. 2005, 127, 2838–2839; f) B. Liang, T. Novak, Z.
Tan, E. Negishi, J. Am. Chem. Soc. 2006, 128, 2770–2771; g) E. Ne-
gishi, Arkivoc. 2011, viii, 34–53; h) E. Negishi, Angew. Chem. 2011,
123, 6870–6897; Angew. Chem. Int. Ed. 2011, 50, 6738–6764.
[5] a) S. Huo, E. Negishi, Org. Lett. 2001, 3, 3253–3256; b) Z. Huang,
Z. Tan, T. Novak, G. Zhu, E. Negishi, Adv. Synth. Catal. 2007, 349,
539–545; c) M. Magnin-Lachaux, Z. Tan, B. Liang, E. Negishi, Org.
Lett. 2004, 6, 1425–1427; d) G. Zhu, B. Liang, E. Negishi, Org. Lett.
2008, 10, 1099–1101; e) Z. Tan, E. Negishi, Angew. Chem. 2004, 116,
2971–2974; Angew. Chem. Int. Ed. 2004, 43, 2911–2914; f) E. Pitsi-
nos, N. Athinaios, Z. Xu, G. Wang, E. Negishi, Chem. Commun.
2010, 46, 2200–2202; g) G. Zhu, E. Negishi, Org. Lett. 2007, 9,
2771–2774.
Representative Procedure for Cu-Catalyzed Cross-Coupling. Synthesis of
(S)-2-Ethylpentan-1-ol (6)
To a solution of (S)-1c (92 mg, 0.4 mmol, ꢁ99% ee), CuCl2 (2.8 mg,
0.02 mmol), and 1-phenylpropyne (7.9 mL, 0.06 mmol) in THF (2 mL)
was slowly added methylmagnesium chloride (3m in THF, 0.44 mL,
1.32 mmol) at 08C, and the resultant solution was stirred for 2 h at 08C.
The reaction was then quenched with aqueous NH4Cl, extracted with
Et2O, dried over anhydrous MgSO4, concentrated, and purified by
column chromatography (silica gel, 20% ethyl acetate in hexanes) to
give (S)-2-ethylpentan-1-ol (S)-6 (37 mg, 80%). The optical purity was
determined by chiral GC analysis, ꢁ99% ee. ½aꢃ2D3 = +3.28 (c=1.2,
CH2Cl2). 1H NMR (300 MHz, CDCl3): d=0.85–0.95 (m, 6H), 1.15 (m,
1H), 1.22–1.45 (m, 7H), 3.55 ppm (dd, J=5.4, 5.4 Hz, 2H); 13C NMR
(75 MHz, CDCl3): d=11.1, 14.5, 20.0, 23.3, 32.7, 41.7, 65.2 ppm. The opti-
cal purity of 99.3% ee was determined by chiral GC analysis, CP-Chira-
sil-Dex CB capillary column (25 mꢂ0.25 mm, 0.39 mm film). Test condi-
tions: carrier gas 8 psi H2, oven program (608C for 8 min, then 28Cminꢀ1
to 908C for 20 min, then 208Cminꢀ1 to 1908C for 2 min), detector FID
2008C. Retention times (min): tR 25.18 (minor); tS 25.25 (major).
[6] a) E. Negishi, Bull. Chem. Soc. Jpn. 2007, 80, 233–257; b) B. Liang,
E. Negishi, Org. Lett. 2008, 10, 193–195; c) G. Zhu, E. Negishi,
Chem. Eur. J. 2008, 14, 311–318.
[7] C.-S. Chen, Y. Fujimoto, G. Girdaukas, C. J. Sih, J. Am. Chem. Soc.
1982, 104, 7294–7299.
Synthesis of (R)-2-Propyloctanoic Acid. (R)-Arundic Acid
To a solution of (R)-11 (86 mg, 0.5 mmol) and TEMPO (2,2,6,6-tetra-
methyl-1-piperidinyloxy free radical, 5.5 mg, 0.035 mmol) in CH3CN
(2.5 mL) and 0.67m sodium phosphate buffer (pH 6.7, 1.9 mL) were
added consecutively a solution of NaClO2 (90 mg, 1.0 mmol) in H2O
(0.5 mL) and a solution of dilute NaOCl, prepared by diluting 5.25%
NaOCl (13 mL) with H2O (0.25 mL). The mixture was stirred at 358C for
7 h and was cooled to 08C. 1m HCl (3.0 mL) was added. The mixture was
extracted with EtOAc and dried over anhydrous MgSO4. After removing
the volatiles in vacuo, the title product (89 mg, 98%) was recovered as
[8] (S)-2-Methyl-1-butanol of ꢁ98% ee is commercially available from
TCI ($66.30/25 mL or $285/mol).
[9] For examples of synthesis of (R)-2-methyl-1-butanol from methyl
(S)-3-hydroxy-2-methylpropionate, see: a) K. Mori, H. Takikawa,
Liebigs Ann. Chem. 1991, 497–500; b) E. M. Santangelo, P. H. G.
Zarbin, Q. B. Cass, J. T. B. Ferreira, A. G. Correa, Synth. Commun.
2001, 31, 3685–3698; c) A. Tai, E. Syouno, K. Tanaka, M. Fujita, T.
Sugimura, Y. Higashiura, M. Kakizaki, H. Hara, T. Naito, Bull.
Chem. Soc. Jpn. 2002, 75, 111–121; d) M. G. Organ, Y. V. Bilokin, S.
Bratovanov, J. Org. Chem. 2002, 67, 5176–5183; e) T. Tachihara, S.
Ishizaki, Y. Kurobayashi, H. Tamura, Y. Ikemoto, A. Onuma, K.
Yoshikawa, T. Yanai, T. Kitahara, Helv. Chim. Acta 2003, 86, 274–
279; f) E. M. Santangelo, A. G. Correa, P. H. G. Zarbin, Tetrahedron
Lett. 2006, 47, 5135–5137; g) I. Danila, F. Riob, F. Piron, J. Puigmar-
a colorless oil. ½aꢃ2D3 =ꢀ6.48 (c=2.2, EtOH). H NMR (300 MHz, CDCl3):
1
d=0.8–0.9 (m, 6H), 1.2–1.5 (m, 12H), 1.5–1.6 (m, 2H), 2.3–2.4 ppm (m,
1H); 13C NMR (75 MHz, CDCl3): d=13.9, 14.0, 20.5, 22.6, 27.3, 29.2,
31.7, 32.2, 34.3, 45.4, 183.5 ppm. The optical purity of 99.5% ee was deter-
mined by chiral GC analysis of the corresponding alcohol by reduction
&
&
6
Chem. Asian J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

www.chemasianj.org
Ei-ichi Negishi et al.
tꢄ-Luis, J. D. Wallis, M. Linares, H. ꢅgren, D. Beljonne, D. B. Ama-
bilino, N. Avarvari, J. Am. Chem. Soc. 2011, 133, 8344–8353.
[10] Methyl (S)-(+)-3-hydroxy-2-methylpropionate of 99% ee is com-
mercially available from Aldrich ($485/25 g or $2292/mol).
[11] a) H. C. Brown, T. Imai, M. C. Desai, B. Singaram, J. Am. Chem.
Soc. 1985, 107, 4980–4983; b) H. C. Brown, R. G. Naik, R. K.
Bakshi, C. Pyun, B. Singaram, J. Org. Chem. 1985, 50, 5586–5592.
[12] G. D. McAllister, R. J. K. Taylor, Tetrahedron Lett. 2004, 45, 2551–
2554.
[13] J. K. Kochi, M. Tamura, J. Am. Chem. Soc. 1971, 93, 1485–1487.
[14] a) G. Erker, M. Aulbach, M. Knickmeier, D. Wingbermꢃhle, C.
Krꢃger, M. Nolte, S. Werner, J. Am. Chem. Soc. 1993, 115, 4590–
4601; b) Available from Aldrich Chemical Co., Milwaukee, WI.
[15] J. Terao, H. Todo, S. A. Begum, H. Kuniyasu, N. Kambe, Angew.
Chem. 2007, 119, 2132–2135; Angew. Chem. Int. Ed. 2007, 46, 2086–
2089.
[16] J. A. Dale, H. S. Mosher, J. Am. Chem. Soc. 1973, 95, 512–519.
[17] a) K. Mislow, P. Bickart, Isr. J. Chem. 1976/77, 15, 1–6; b) K. Mislow
in Fuzzy Logic in Chemistry (Ed.: D. H. Rouvray), Academic Press,
1997, pp. 65–90; c) K. Mislow, Collect. Czech Chem. Commun. 2003,
68, 849–864.
[18] For reviews of metal-catalyzed cross-coupling reactions of alkyl hal-
ides, see: a) T.-Y. Luh, M. Leung, K.-T. Wong, Chem. Rev. 2000, 100,
3187–3204; b) A. C. Frisch, M. Beller, Angew. Chem. 2005, 117,
680–695; Angew. Chem. Int. Ed. 2005, 44, 674–688; c) A. Rudolph,
M. Lautens, Angew. Chem. 2009, 121, 2694–2708; Angew. Chem.
Int. Ed. 2009, 48, 2656–2670; d) R. Jana, T. P. Pathak, M. S. Sigman,
Chem. Rev. 2011, 111, 1417–1492; e) N. Kambe, T. Iwasaki, J. Terao,
Chem. Soc. Rev. 2011, 40, 4937–4947.
[19] For selected examples of metal-catalyzed cross-coupling reactions of
alkyl halides, see: a) J. Terao, H. Watanabe, A. Ikumi, H. Kuniyasu,
N. Kambe, J. Am. Chem. Soc. 2002, 124, 4222–4223; b) N. Hadei,
E. A. B. Kantchev, C. J. OꢁBrien, M. G. Organ, J. Org. Chem. 2005,
70, 8503–8507; c) X. L. Hu, Chem. Sci. 2011, 2, 1867–1886; d) C.-T.
Yang, Z.-Q. Zhang, Y.-C. Liu, L. Liu, Angew. Chem. 2011, 123,
3990–3993; Angew. Chem. Int. Ed. 2011, 50, 3904–3907.
[20] a) N. Tateishi, T. Mori, Y. Kagamiishi, S. Satoh, N. Katsube, E. Mori-
kawa, T. Morimoto, T. Matsui, T. Asano, J. Cereb. Blood Flow
Metab. 2002, 22, 723–734; b) L. A. Sorbera, J. Castaner, Drugs
Future 2004, 29, 441–448.
[21] For examples of the synthesis of (R)- or (S)-arundic acid, see: a) T.
Hasegawa, H. Yamamoto, Bull. Chem. Soc. Jpn. 2000, 73, 423–428;
b) T. Hasegawa, H. Yamamoto, Synthesis 2003, 8, 1181–1186; c) T.
Hasegawa, Y. Kawanaka, E. Kasamatsu, Y. Iguchi, Y. Yonekawa, M.
Okamoto, C. Ohta, S. Hashimoto, S. Ohuchida, Org. Process Res.
Dev. 2003, 7, 168–171; d) B. Pelotier, T. Holmes, O. Piva, Tetrahe-
dron: Asymmetry 2005, 16, 1513–1520; e) J. M. Garcia, J. M. Odrio-
zola, A. Lecumberri, J. Razkin, A. Gonzalez, Tetrahedron 2008, 64,
10664–10669; f) R. A. Fernandes, A. Dhall, A. B. Ingle, Tetrahedron
Lett. 2009, 50, 5903–5905; g) T. Hasegawa, Y. Kawanaka, E. Kasa-
matsu, C. Ohta, K. Nakabayashi, M. Okamoto, M. Hamano, K. Ta-
kahashi, S. Ohuchida, Y. Hamada, Org. Process Res. Dev. 2005, 9,
774–781; h) D. Goswami, A. Chattopadhyay, Lett. Org. Chem. 2006,
3, 922–925; i) A. Gualandi, E. Emer, M. G. Capdevila, P. G. Cozzi,
Angew. Chem. 2011, 123, 7988–7992; Angew. Chem. Int. Ed. 2011,
50, 7842–7846.
Received: March 10, 2013
Published online: && &&, 0000
7
&
&
Chem. Asian J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
These are not the final page numbers! ÞÞ

FULL PAPER
Asymmetric Synthesis
Shiqing Xu, Ching-Tien Lee,
Guangwei Wang,
Ei-ichi Negishi*
&&&& — &&&&
Widely Applicable Synthesis of Enan-
tiomerically Pure Tertiary Alkyl-
Containing 1-Alkanols by Zirconium-
Catalyzed Asymmetric Carboalumina-
tion of Alkenes and Palladium- or
Copper-Catalyzed Cross-Coupling
Look, mom, one hand! 2-Alkyl-1-alka-
nols of feeble chirality have been syn-
thesized by a sequence of zirconium-
catalyzed asymmetric carboalumina-
tion of alkenes (ZACA), lipase-cata-
lyzed acetylation, and Pd- or Cu-cata-
lyzed cross-coupling in high enantio-
meric purity of ꢁ99% ee. The syn-
thetic utility of this method has been
demonstrated in highly enantioselec-
tive and efficient syntheses of (R)-2-
methyl-1-butanol, (R)- and (S)-arundic
acids.
&
&
8
Chem. Asian J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!