Highly stereoselective kinetic resolution of α-allenic alcohols: An enzymatic approach

Article abstract of DOI:10.1016/j.tetlet.2015.12.098

A highly efficient lipase AK-catalyzed direct kinetic resolution of a variety of α-allenic alcohols was developed. With the complementary to previous studies, the current reaction system is effective on a broad range of substituents (R¹) at C(1), such as alkyl, aryl, alkenyl, and alkynyl groups. The Jones-Burgess empirical model was modified to interpret the reversed selectivity during the acetylation of secondary alcohol. The methyl group at C(2) of allenic alcohols implied a small structural adjustment in the catalytic triad of lipase AK, representing a potential direction for future site-directed mutagenesis.

Full text of DOI:10.1016/j.tetlet.2015.12.098

Tetrahedron Letters 57 (2016) 603–606
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Highly stereoselective kinetic resolution of
enzymatic approach
a-allenic alcohols: an
a,
Wenhua Li a, Zuming Lin a, Long Chen a, Xuechao Tian b, Yan Wang a, Sha-Hua Huang a,b, , Ran Hong
⇑
⇑
a CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry (CAS), Shanghai 200032, China
b School of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai 201418, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly efficient lipase AK-catalyzed direct kinetic resolution of a variety of a-allenic alcohols was devel-
Received 2 December 2015
Revised 23 December 2015
Accepted 24 December 2015
Available online 25 December 2015
oped. With the complementary to previous studies, the current reaction system is effective on a broad
range of substituents (R1) at C(1), such as alkyl, aryl, alkenyl, and alkynyl groups. The Jones–Burgess
empirical model was modified to interpret the reversed selectivity during the acetylation of secondary
alcohol. The methyl group at C(2) of allenic alcohols implied a small structural adjustment in the catalytic
triad of lipase AK, representing a potential direction for future site-directed mutagenesis.
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Kinetic resolution
Enzyme
a-Allenic alcohol
High enantioselectivity
Suzuki–Miyaura coupling
Biotransformation has emerged into the chemical arsenal for
organic synthesis due to the advantages of high stereoselectivity
and relatively simple operations.1 In particular, enzymatic
transesterification and its reverse transformation have found a
wide application in numerous syntheses of natural products and
pharmaceutically interesting compounds.2 With the innovative
site-directed mutagenesis approach in the past two decades,
biotransformation has been expanded into the field of unnatural
reactions which was conventionally considered as a formidable
challenge for natural enzymes.3 While new and unnatural chemical
reactions with enzymes are enrolled into the frontier of biotech-
nology, defining a new substrate scope remains a useful approach
since many enzymes and mutants are commercialized and some of
them have been immobilized for the practical use both in academia
and industry.4
a.
OH
1
R
= Me, Et, HC
C
C
R
R' = bulky alkyl or
aryl groups
R'
directly enzymatic KR
b.
c.
OH
OH
Crabbe
1
1
R
C
R
2
2
directly enzymatic KR
OH
1
OH
1
R
C
R
C
2
2
Me
Scheme 1. Enzymatic approaches to chiral
a
-allenic alcohols.
During our study on the development of a non-aldol approach
to construct chiral polyol units in biologically significant polyke-
enzymatic resolution of propargylic alcohols8 and subsequent
Crabbé homologation or SN20 substitution was developed8f
(Scheme 1b). However, the products bearing a methyl group at C
(2) (Scheme 1c) were not feasible from these protocols. Our
initial approach on asymmetric cycloisomerization achieved a
limited success.9
As a particular interest on lipase AK-catalyzed reaction, Burgess
and co-workers rationalized the enzymatic kinetic resolution of
secondary alcohols.10 Despite the fitness of secondary alcohols in
these empirical models, the state-of-art of various allenic alcohols
remains to be scholarly appreciated. We intended to design a new
tides,5 an optical
a
-allenic alcohol was chosen as the suitable start-
ing material due to its multiple functionalizable sites.6 Enzymatic
kinetic resolution (EKR) of -allenic alcohols by Novozym 435
resulted in several useful chiral building blocks (Scheme 1a).7
a
A
variety of groups can be tolerated at C(2) albeit that substituents
at C(1) were limited to simple alkyls (methyl, ethyl, or ethynyl).
This problem was partially solved when the combination of
⇑
Corresponding authors.
E-mail addresses: shahua@sit.edu.cn (S.-H. Huang), rhong@sioc.ac.cn (R. Hong).
http://dx.doi.org/10.1016/j.tetlet.2015.12.098
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

604
W. Li et al. / Tetrahedron Letters 57 (2016) 603–606
Table 1
bulky functional groups in the hydrophobic pocket to expand the
scope of enzymatic kinetic resolution in organic synthesis.
Enzymatic kinetic resolution of
a
-allenic alcohol 4aa
As a model substrate, 1-alkyl allenic alcohol 4a was subjected to
the desired kinetic resolution. Several commercially available
lipases were examined (Table 1) and lipase AK (Pseudomonas
fluorescens) was identified as a superior candidate to match the
criteria in terms of the reaction rate, isolated yield, and enantiose-
lectivity of products (enantiomeric ratio E > 1000)11 (entry 8).
Although Novozym 435 was very efficient for the kinetic resolution
biocatalyst
(wt%)
BPSO
OH
BPSO
OH
BPSO
OAc
1
+
C
C
C
R.T.
4a
4a
(R)-
5a
(S)-
BPS = t-Bu(Ph)2Si-
Entry Biocatalyst
Time (h) Cc (%) (R)-4a ee%d (S)-5a ee%d
E
of several a
-allenic alcohols as in Ma and Li’s report,7b it was found
1
2
3
4
5
6
7
8
PPL
PLE
PS
162b
162
262
<1
<1
—
—
—
—
—
—
741
4
92
less effective on a bulky alkyl substituent at C(1) in 4a (entry 4,
E = 4). Lipase PS (Pseudomonas cepacia lipase) was found to have
a close activity to lipase AK (entry 3, E = 741) and would be an
alternative catalyst in the future application. Polar solvents
(CH3CN and diethyl ether in entries 9 and 10, respectively) have
shown less efficiency than nonpolar solvents (toluene, hexane,
and octane) in terms of selectivity and reaction time (entries
11–13).12 With the consideration of solubility in hydrocarbon
42.7
48.3
53.8
21.5
13.0
50.2
37.5
38.9
45.5
50.7
50.5
73.9
43.2
99.8
13.5
5.7
99.6
59.1
62.7
82.7
98.2
97.6
99.4
44.2
86.4
49.7
19.7
99.0
98.8
99.1
99.3
98.8
98.6
Novozym 435 162b
CAL-A
CAL-B
CRL
AK
AK (CH3CN)
AK (Et2O)
AK (toluene)
AK (hexane)
AK (octane)
262
162b
162b
197
144
144
144
72
3
2
1630
303
423
741
785
632
9
10
11
12
13
t
solvents, BuOMe was then chosen as the reaction media for the
optimal conditions (entry 8).
72
Encouraged by the optimized enzymatic kinetic resolution
event, we thus explored the substrate scope, particularly those
bearing functional groups at C(1) which could be applied in future
polyketide synthesis.5 The current reaction system offers an excel-
lent stereoselectivity outcome and a broad substrate scope with
alkyl substituents at C(1) as well as alkenyl chains (4a–f, Table 2).
The more encouraging C(2)-methylated allenic alcohols are also
tolerated and a good resolution was obtained (4g–i). The less ster-
ically bulky substrate 4h bearing a flexible side chain displayed a
lower selectivity (E = 27). Since methylated allenic alcohols cannot
be prepared directly from propargylic alcohol through the Crabbé
homologation,13 the generality of enzymatic resolution of
mono-substituted and 1,1-disubstituted allenes (R2 = H or Me)
offers a powerful approach to access such synthetically useful
building blocks.
a
Standard reaction conditions: biocatalyst (amount: 100 Units, 1–20 mg),
alcohol 4a (0.1 mmol), vinyl acetate (8.0 equiv), solvent (1.0 mL), 23 °C, (tBuOMe
for entries 1–8; other solvents indicated in parentheses from entries 9–13).
Enantiomeric ratio (E) was calculated according to the equation in Ref 11.
b
The reaction temperature was 37 °C for 162 h.
C (conversion) = 100 ꢀ (ees/(ees + eep)), ees for the recovered starting material,
c
eep for the resulting acetate.
d
Enantiomeric excess (ee) was determined by chiral HPLC. PPL: porcine
pancreatic lipase; PLE: pig liver esterase; PS: Pseudomonas cepacia lipase; CAL-A:
Candida antarctica lipase A; CAL-B: Candida antarctica lipase B; CRL: Candida rugosa
lipase.
type of substrates to explore EKR, which is compatible with the use
of other asymmetric syntheses without a complete new design of
catalysis. From this approach, an allene group is considered as a
medium group and orientates toward the medium pocket (M)
while a variety of substituents may reside in the hydrophobic
pocket (L). If this assumption does work, we may readily introduce
The current protocol was also applicable for C(1)-aryl substi-
tuted allenic alcohols (Table 3), which was more challenging for
Table 2
Enzymatic kinetic resolution of alkyl and alkenyl substituted
a
-allenic alcohols 4a–la,b14
OH OH
OAc
C
1
Lipase AK
C
C
R1
R1
R1
+
2
R2
rac-4a-l
R2
4a-l
R2
5a-l
BPSO
OH
Ph OH
OH
BPSO
OH
C
C
Ph
C
C
4a: 99.6% ee (49% y)
4b: 99.9% ee (47% y)
4c: 99.5% ee (49% y)
4d: 99.7% ee (44% y)
5a
5b
5c
5d
: 89.1% ee (55% y)
: 99.2% ee (50% y)
: 95.0% ee (53% y)
: 92.2% ee (49% y)
24h, E = 1630
24h, E = 301
183h, E = 146
24h, E = 111
BPSO
OH
Ph OH
OH
C
TrO
OH
C
C
C
Ph
Me
Me
4e
4f
4g
4h
: 99.3% ee (49% y)
5e: 96.8% ee (51% y)
24h, E = 347
: 99.5% ee (49% y)
: 99.7% ee (49% y)
: 98.9% ee (31% y)
5h: 69.3% ee (58% y)
336h, E = 27
5f: 98.9% ee (49% y)
65h, E = 1064
5g: 94.4% ee (50% y)
72h, E = 222
OH
OH
C
Me
OH
OH
C
C
Ph
TrO
C
Me
TMS
Me
4i: 97.8% ee (49% y)
4j: 99.7% ee (46% y)
4k: 99.2% ee (49% y)
4l: 85.6% ee (45% y)
5i
5j
5k
5l
: 73.0% ee (54% y)
: 97.5% ee (50% y)
: 99.5% ee (53% y)
: 99.4% ee (49% y)
30h, E = 358
21.5h, E = 2471
25h, E = 1740
30h, E = 17
a
Reaction conditions: allenic alcohol 4 (0.5 mmol), lipase AK (25 mg), vinyl acetate (8.0 equiv),
tBuOMe (5.0 mL), 30 °C; enantiomeric excess (ee) was determined by chiral HPLC; isolated yield in
parentheses; enantiomeric ratio (E) was calculated according to the equation in Ref. 11.
b
For substrates 4g, 4h, 4i, and 4l, the reaction was performed at 37 °C with lipase AK (250 mg).
TMS = trimethylsilyl; Tr = triphenylmethyl.

W. Li et al. / Tetrahedron Letters 57 (2016) 603–606
605
Table 3
Enzymatic kinetic resolution of aryl substituted
a
-allenic alcohols 4m–wa,b
OH
OH OAc
1
R1
Lipase AK
C
C
C
R1
R1
+
2
R2
R2
4m-w
R2
5m-w
rac-4m-w
OH
OH
OH
OH
C
C
C
C
O2N
Cl
F
4m: 98.3% ee (45% y)
4n: 99.2% ee (47% y)
4o: >99.9% ee (49% y)
4p: >99.9% ee (49% y)
5m
5n
5o
5p
: 90.9% ee (54% y)
: 94.0% ee (53% y)
:
99.5% ee (50% y)
: 97.1% ee (51% y)
19h, E = 99
44h, E = 177
41h, E = 3031
46h, E = 568
OH
OH
C
OH
C
OH
C
C
Me
O2N
Br
Me
MeO
4q: 99.6% ee (46% y)
4r: 95.2% ee (47% y)
4s: 98.9% ee (34% y)
4t: 97.3% ee (48% y)
5q
5r
5s
5t
: 88.5% ee (49% y)
: 93.0% ee (53% y)
: 88.1% ee (52% y)
: 69.9% ee (58% y)
58h, E = 169
59h, E = 59
71h, E = 28
67h, E = 70
OH
C
OH
OH
C
C
O
S
Me
Br
4u
4v
4w
: 99.1% ee (38% y)
: 95.1% ee (7% y)
: 99.2% ee (34% y)
5u: 71.2% ee (61% y)
131h, E = 30
5v: 60.9% ee (60% y)
16.5h, E = 15
5w: 53.8% ee (64% y)
26h, E = 16
a
Reaction conditions: allenic alcohol 4 (0.5 mmol), lipase AK (25 mg), vinyl acetate (8.0 equiv),
tBuOMe (5.0 mL), room temperature (23 °C); enantiomeric excess (ee) was determined by chiral
HPLC; isolated yield in parentheses; enantiomeric ratio (E) was calculated according to the equation
in Ref. 11.
b
For substrates 4t and 4u, the reaction was performed at 37 °C with lipase AK (250 mg).
other enzymatic resolution. Both electron-donating and electron-
deficient groups were tolerated on the arene moiety to deliver
the recycled alcohols 4m–w and the corresponding acetates 5m–
w in excellent selectivities (E > 25). The para-fluorinated substrate
4o gave the best result among all the substrates executed
(E = 3031). Hetereoaryl substituents (4v and 4w) demonstrated to
be not good substances (E = 15–16) probably due to their
interfering with amino acid residues by a possible hydrogen bond-
ing interaction.15 Such phenomenon might be severe when an
intramolecular hydrogen bonding interaction in 4x (Scheme 2) dis-
turbs the active site to differentiate a particular enantiomer (E = 4)
while the resolution of 4f bearing a bulky protecting group at the
primary alcohol resulted in an excellent selectivity (E = 1064).
To further rationalize the structure–activity relationship of
ble interaction of chlorine with the amino residue in the large
hydrophobic pocket (L). On the basis of aforementioned structural
features, we assumed that lipase AK may have a deeper medium
pocket (M) than that suggested in Novozym 435 (Fig. 1). The
hydrophobic pocket (L) of lipase AK can tolerate a bigger size of
functional groups, such as in 4a, 4d, 4f, 4g, and 4k, that were not
realized in previous Letters.7a,16,17
To illustrate the utility of the corresponding chiral allenic alco-
hols, we turned to carry out several transformations to access key
intermediates bearing a b-amino alcohol for potentially interesting
bioactivity (Scheme 3). A gram-scale enzymatic kinetic resolution
of 4a was realized to give sufficient amount (2.6 g) of (ꢁ)-4a in
>99% ee. Following the Friesen procedure,18 (ꢁ)-4a was converted
to vinyl iodide 6 (trans/cis = 9/1) in 89% yield in 2 steps. Although
the removal of the carbonyl group was usually undertaken with
basic conditions, the facile elimination of vinyl iodide to alkyne19
rendered the deprotection challenging. After several experiments,
we were pleased to find that hydrolysis proceeded smoothly under
acid conditions to afford the requisite amino alcohol 7. The follow-
ing Suzuki–Miyaura coupling of vinyl iodide also confirmed the
sensitivity of such structural motif. Gratifyingly, after optimization,
Pd(dppf)Cl2 was effective to promote this reaction with different
borane reagents.20 With the following removal of silyl group, a
potentially useful structural variant of 8 and 9 were isolated in
good yields, respectively.
lipase AK on the resolution of
a-allenic alcohols, more substrates
bearing a longer carbon chain at C(1) were examined (Scheme 2).
A significant loss in selectivity (E = 8 and 6 for 4y and 4z, respec-
tively) was found with the comparison of similar compounds 4d
and 4f (Table 2). This deterioration might reside on the closer size
between two groups around the secondary alcohol. The lower
selectivity of meta-chlorinated 4aa may be attributed to the possi-
Me
OH
O
OH
C
C
4x
4y
5y
: 99.0% ee (10% y)
: 95.5% ee (29% y)
: 40.0% ee (70% y)
17.5h, E = 8
5x: 11% ee (89% y)
89h, E = 4
Novozym 435
Lipase AK
active site
active site
OH
OH
OH
Me
OH
Cl
C
2
2
C
R
C
C
1
1
M
medium
pokect
L
Me
R
L
M
large
pokect
large
4aa
4z
5z
: 98.1% ee (36% y)
5aa: 49.0% ee (63% y)
162h, E = 12
: 95.5% ee (29% y)
: 39% ee (70% y)
17.5h, E = 6
medium
pokect
pokect
Figure 1. Stereoselectivity rational of lipase AK and Novozym 435 (the enatiomer
Scheme 2. Other substrates for EKR.
shown reacts faster with lipase).

606
W. Li et al. / Tetrahedron Letters 57 (2016) 603–606
Enzyme Catalysis in Organic Synthesis; Karlheinz, D., Harald, G., Oliver, M., Eds.,
O
OH OH
3rd ed.; Wiley-VCH: Weinheim, 2012. vols. 1–3; For a very recent review: (d)
Friedrich, S.; Hahn, F. Tetrahedron 2015, 71, 1473.
2. Otte, K. B.; Hauer, B. Curr. Opin. Biotechnol. 2015, 35, 16.
BPSO
O
BPSO
OH
a)
b)
c)
NH
I
C
NH2
3. For a very recent perspective, see: Prier, C. K.; Arnold, F. H. J. Am. Chem. Soc.
2015. http://dx.doi.org/10.1021/jacs.5b09348.
I
6
7
4. (a) Schmid, A.; Dordick, J. S.; Hauer, B.; Kiener, A.; Wubbolts, M.; Witholt, B.
Nature 2001, 409, 258; (b) Bornscheuer, U. T.; Huisman, G. W.; Kazlauskas, R. J.;
Lutz, S.; Moore, J. C.; Robins, K. Nature 2012, 485, 185.
5. Yang, L.; He, G.; Yin, R.; Zhu, L.; Wang, X.; Hong, R. Angew. Chem., Int. Ed. 2014,
53, 11600.
O
O
OH
OH
O
O
d), e)
f)
NH
NH
6. Selected monographs and reviews: (a) Modern Allene Chemistry; Krause, N.,
Hashimi, A. S. K., Eds.; Wiley-VCH: Weinheim, Germany, 2004; (b) Deng, Y.-Q.;
Gu, Z.-H.; Ma, S.-M. Chin. J. Org. Chem. 2006, 26, 1468; (c) Yu, S.; Ma, S. Angew.
Chem., Int. Ed. 2012, 51, 3074.
Ph
8
9
Scheme 3. Synthesis of b-amino alcohols: (a) OCNCOCCl3, CH2Cl2, 96%; (b) I2,
K2CO3, THF, dr 9/1, 93%; (c) HCl (6 N), MeOH, 88%; (d) PhB(OH)2, Pd(dppf)Cl2
(10 mol %), THF/H2O (4/1), NaOH, 91%; (e) TBAF, THF, 81%; (f) AllylB(pin), Pd(dppf)
Cl2 (10 mol %); TBAF, THF, 50% for 2 steps.
7. (a) Burgess, K.; Jennings, L. D. J. Am. Chem. Soc. 1990, 112, 7434; (b) Xu, D.; Li, Z.;
Ma, S. Chem. Eur. J. 2002, 8, 5012; (c) Xu, D.; Li, Z.; Ma, S. Tetrahedron:
Asymmetry 2003, 14, 3657; (d) Xu, D.; Li, Z.; Ma, S. Chin. J. Chem. 2004, 22, 310;
(e) Asikainen, M.; Krause, N. Adv. Synth. Catal. 2009, 351, 2305; (f) Deska, J.;
Bäckvall, J.-E. Org. Biomol. Chem. 2009, 7, 3379; (g) Sapu, Manzuna; Bäckvall, C.;
Deska, J.-E. Angew. Chem., Int. Ed. 2011, 50, 9731; (h) Sapu, Manzuna; Deska, C. J.
Org. Biomol. Chem. 2013, 11, 1376.
8. Enzymatic KR of propargylic alcohols: (a) Glänzer, B. I.; Faber, K.; Griengl, H.
Tetrahedron 1987, 43, 5791; (b) Treihou, M.; Fauve, A.; Pougny, J.-K.; Prome, J.-
C.; Veschambre, H. J. Org. Chem. 1992, 57, 3203; (c) Waldinger, C.; Schneider,
M.; Botta, M.; Corelli, F.; Summa, V. Tetrahedron: Asymmetry 1996, 7, 1485; (d)
Nakamura, K.; Takenaka, K.; Ohno, A. Tetrahedron: Asymmetry 1998, 9, 4429; (e)
Xu, D.; Li, Z.; Ma, S. Tetrahedron Lett. 2003, 44, 6343; (f) Li, J.; Kong, W.; Fu, C.;
Ma, S. J. Org. Chem. 2009, 74, 5104.
In summary, we have developed an efficient lipase AK-cat-
alyzed direct kinetic resolution of a-allenic alcohols bearing a vari-
ety of alkyl, aryl, alkenyl, and alkynyl substituents at C(1), which is
complementary to previous methods to prepare highly enan-
tiomeric pure chiral building blocks.21,22 The substituent pattern
around the secondary alcohol was rationalized by a refined
Jones–Burgess model of lipase AK. Further mechanistic insights
related to the protein structure of lipase AK and the site-directed
mutagenesis to tolerate more challenging substrates in the context
of application in natural product synthesis are currently underway
in our laboratory.
9. Wang, Y.; Zheng, K.; Hong, R. J. Am. Chem. Soc. 2012, 134, 4096.
10. (a) Toone, E. J.; Werth, M. J.; Jones, J. B. J. Am. Chem. Soc. 1990, 112, 4946; (b)
Burgess, K.; Jennings, L. D. J. Am. Chem. Soc. 1991, 113, 6129.
11. Enantiomeric ratio for enzymatic catalysis, E = ln[(1 ꢁ C)(1 ꢁ ees)]/ln[(1 ꢁ C)(1
+ ees)], C for the conversion, ees for the recovered starting material. See: Chen,
C. S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J. J. Am. Chem. Soc. 1982, 104, 7294.
12. (a) Carrea, G.; Ottolina, G.; Riva, S. Trends Biotechnol. 1995, 13, 63; (b) Huang, S.-
H.; Li, W.; Chen, L.; Xu, J.; Hong, R. Bioresour. Bioprocess 2015, 2, 10.
13. Crabbé, P.; André, D.; Fillion, H. Tetrahedron Lett. 1979, 20, 893.
14. The amount of all biocatalysts for screening was 100 Units. For instance, the
activity of immobilized lipase AK is 20,000 Units/g. That means only 5 mg of
lipase AK was used for optimization in Table 1. However, for the C(1)-
methylated allenic alcohols in Table 2, 250 mg of lipase AK (5000 Units) was
used for 0.5 mmol of substrate to complete the reaction in a reasonable time
(3 days for most of substrates). See the Supporting information for details.
15. Compound 4v was unstable on silica gel column even the neutralization was
taken before the chromatography. Based on the enantioselectivity, conversion,
and isolated yield of the ester 5v, E for 4v was close to 4w.
Acknowledgments
Financial supports from the National Natural Science Founda-
tion of China (21402121 to S.H. Huang and 21472223 to R Hong),
the National Basic Research Program of China (2011CB710800 to
R. Hong), and the Shanghai Institute of Technology (XTCX2015-
16 to S.H. Huang). S.H. Huang thanks the partial support by the
Open Funding Project of the State Key Laboratory of Bioreactor
Engineering at ECUST. We thank Professor Huilei Yu (ECUST) and
Professor Jia-Hai Zhou (SIOC) for invaluable discussions.
16. The absolute configuration of the recovered alcohols 4a and 4g were
determined to be (R) by Mosher’s ester. For the determination of absolute
configuration, see the Supporting information for details.
17. Burgess and co-workers also found the reversed stereoselectivity when the
sizes of two groups were inversed during the lipase AK-catalyzed kinetic
resolution, see Ref. 7a.
Supplementary data
18. (a) Friesen, R. W. Tetrahedron Lett. 1990, 30, 4249; (b) Friesen, R. W.;
Kolaczewska, A. E. J. Org. Chem. 1991, 56, 4888.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.12.
098.
19. For instance, sodium hydroxide resulted in elimination of iodine to generate a
terminal alkyne as major product (>30% yield).
20. (a) Hayashi, T.; Konishi, M.; Kobori, Y.; Kumada, M.; Higuchi, T.; Hirotsu, K. J.
Am. Chem. Soc. 1984, 106, 158; (b) Brown, J. M.; Guiry, P. J. Inorg. Chim. Acta
1994, 220, 249.
21. An alternative method to access syn-b-amino alcohols from secondary alcohols
via palladium-catalyzed allylic C–H amination: Fraunhoffer, K. J.; White, M. C. J.
Am. Chem. Soc. 2007, 129, 7274.
22. The recycled lipase AK was subjected to the second run of the resolution of rac-
4b to deliver the desired products without a considerable deterioration of
enantioselectivity (94.6% ee for (S)-4b, 89.3% ee for (R)-5b, E = 65).
References and notes
1. Selected monographs and reviews: (a) Wong, C.-H.; Whitesides, G. M. Enzymes
in Synthetic Organic Chemistry; Pergamon Press, Elsevier: Oxford, 1994; (b)
Kazlauskas, R. J.; Bornscheuer, U. T. Hydrolases in Organic Synthesis: Regio- and
Stereoselective Biotransformations, 2nd ed.; Wiley-VCH: Weinheim, 2005; (c)