Enzymatic racemic resolution of a fluorinated substrate and syntheses of E and Z alkenes as precursors for some biologically active fluorohexoses

Article abstract of DOI:10.1515/znb-1997-0320

A fluorinated substrate 6 was prepared and then the enantiomers (6a and 7a) were separated by an enzyme in presence of an acetylating agent. The optical purity of 6a and 7a were determined by derivatising them into their MTPA-esters and then by taking their ¹⁹F NMR spectra. It was observed that, PL 266 (enzyme), benzene (solvent), 24 h (time), 40 °C (temp.) and vinyl acetate (acetylating agent) were the ideal conditions for racemic resolution. The optical purity was further improved by changing the solvent (hexane), amount of enzyme (PL 266; 3000 units), reaction time (12 h) and amount of acetylating agent (vinyl acetate; two molar). The optically pure species was used for the preparation of E and Z alkenes.

Full text of DOI:10.1515/znb-1997-0320

Enzymatic Racemic Resolution of a Fluorinated Substrate and Syntheses of
E and Z Alkenes as Precursors for Some Biologically Active Fluorohexoses
M u h am m ad S haiq A li* a, T om oya K ita z u m e b, V iq a r U d d in A h m a d 3
a H. E. J. Research Institute of Chemistry, University of Karachi, Karachi-75270, Pakistan
b D epartm ent of Bioengineering, Faculty of Biosciences & Biotechnology, Tokyo Institute
of Technolgy, 4259 Nagatsuta-cho, M idori-ku, Yokohama 227, Japan
Z. Naturforsch. 52b, 413-418 (1997); received D ecem ber 9, 1996
Fluorinated Substrate, Enzymatic Racemic Resolution, Alkenes
A fluorinated substrate 6 was prepared and then the enantiom ers (6a and 7a) were sepa-
rated by an enzyme in presence of an acetylating agent. The optical purity of 6a and 7a were
determ ined by derivatising them into their M TPA-esters and then by taking their 19F NMR
spectra. It was observed that, PL 266 (enzyme), benzene (solvent), 24 h (time), 40 °C (temp.)
and vinyl acetate (acetylating agent) were the ideal conditions for racemic resolution. The
optical purity was further improved by changing the solvent (hexane), amount of enzyme
(PL 266; 3000 units), reaction time (12 h) and am ount of acetylating agent (vinyl acetate;
two molar). The optically pure species was used for the preparation of E and Z alkenes.
Introduction
Results and Discussion
P reparation o f flu orin ated substrate
F lu o rin a te d com p o u n d s h av e b e e n of g re a t in -
te re st to sy n th etic an d m ed icin al chem ists fo r
a
T he m o n o -e th e r 1 w as p re p a re d by tre a tin g p ro -
p a n e-d io l w ith so dium h y d rid e in D M F an d th e n
w ith benzyl bro m id e. T he hydroxyl p ro to n w as a b -
c o n sid erab le tim e du e to th e u n iq u e physical an d
biological p ro p e rtie s im p a rte d by flu o rin e [1 -2 ].
A n u m b e r o f review s have b e e n p u b lish ed o n this
to p ic [3]. In c o rp o ra tio n of flu o rin e a to m (s) in to
th e organic m olecules m ay b rin g a b o u t drastic
changes in th e n a tu re of th e p a re n t m aterials. T he
flu o rin ated c o m p o u n d s have b e e n b ro ad ly ap p lied
in th e d e v e lo p m en t of n o v el p h arm a c e u tic a lly
active co m p o u n d s [4 -6 ] an d o p tical devices [7 -9 ].
M o n o flu o ro acetic acid is w ell k n o w n to show very
high toxicity, w hich is co n sid ered to be d u e to th e
in h ib ito ry block effect of m e ta b o lic p ath w a y of
T C A cycle [10].
strac te d by N aH an d su b stitu te d by
a benzyl
group. A s th e re actio n m ix tu re w as left o v ern ig h t,
in a d d itio n to m o n o -e th e r 1, d i-e th e r 2 w as also
fo rm ed as a b y -p ro d u ct b u t, 1 w as th e m ajo r p ro -
d u ct as w e used e q u im o lar a m o u n t o f N aH . T he
d e sired p ro d u c t 1 w as co n firm ed by th e p resen ce
o f a m u ltip let at Ö 1 .2 - 1 A p pm having five p ro to n s
in te g ra tio n in th e 'H N M R sp ectru m . T he strongly
U V active an d less-p o lar b y -p ro d u ct 2 w as d is-
c a rd e d w ith o u t tak in g sp ectro sco p ic d ata. T he 3-
benzyloxy p ro p a n o l 1 w as oxidized in to th e c o rre -
sp o n d in g ald eh y d e 3 by Sw ern o x id atio n . It w as
co n firm ed by th e d isap p earan ce o f h y droxyl a b -
so rp tio n an d ap p ea ra n c e o f ald eh y d ic carb o n y l a b -
so rp tio n b a n d at 1735 c m -1 in th e IR sp ectru m .
T h e ald eh y d e 3 w as tre a te d w ith u n stab le flu o ri-
n a te d in te rm e d ia te 5 w hich w as fo rm ed by tre atin g
O v er th e last th irty five y ea rs th e b io ch em ical
d eriv atisatio n o f organic c o m p o u n d s by enzym es,
b acte ria an d fungi has assu m ed c o n sid erab le im -
p o rta n c e as
a m e th o d w hich o fte n co m p lim en ts
chem ical tra n sfo rm a tio n [1 1 -1 3 ]. T he fu n ctio n al
g ro u p s can b e in tro d u ce d in to th e m olecu le in a
regio- an d stereo sp ecific m a n n e r u n d e r th e c o n d i-
tio n s th a t are q u ite m ild [14], T h ese m e th o d s a re
also ap p licable to resolve th e racem ic m ixtures.
2 -b ro m o -3 ,3 ,3 -triflu o ro -p ro p en e
4 w ith L D A to
fo rm flu o rin ate d su b strate 6. T he c o m p o u n d 6 w as
co n firm ed by re a p p e a ra n c e o f hydroxyl fu n ctio n
in th e IR sp ectru m at 3400 cm -1 . It w as also c o n -
firm ed by its flu o rin e N M R w hich ex h ib ited sin -
glet at d 29.46 (ch aracteristic fo r F 3C = m o iety ) in
th e 19F N M R sp ectru m . T he p re p a ra tio n o f su b -
stra te is illu strated in th e S chem e 1.
* Reprint requests to Dr. M. S. Ali.
N
0932-0776/97/0300-0413 $06.00 © 1997 Verlag der Zeitschrift für Naturforschung. All rights reserved.
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414
M. S. Ali et al. ■Enzymatic Racemic Resolution of a Fluorinated Substrate
NaH
tu re 6. T h e co n v ersio n ra te o r the a m o u n t o f este r
0
Ph
OH
O
RO'
HO'
PhCH2Br
ac c u m u la te d 7a d u rin g th e re actio n w as m o n ito re d
by 19F N M R . A fte r 24 h o u rs th e tw o c o m p o n en ts
1: R = H
2: R = PhCH2
6
a an d 7a w ere se p a ra te d by colum n c h ro m a to g ra -
0
Swern
oxidation
phy (S ch em e 2). T h e ir o p tical ro tatio n s w ere m e a -
H
O
Ph
HO'
F,C
Ph
su red to be -2 9 .3 7 ° at 14 °C fo r
6
a an d +46.21° at
3
th e sam e te m p e ra tu re fo r 7a.
LDA
LDA
F-jC —=
F-iC —— Li
> =
Determination of Optical Purity
Br
P reparation o f M T P A -ester
A t first,
6
a w as h y d ro g e n a te d using p allad iu m /
ch arco al w hich re su lte d th re e p ro d u cts
10
8
, 9 and
F,C
Scheme 1
T he p re p a re d su b strate 6 w as te a te d w ith lipase
PS (P seu dom on as cepacia, A m an o S eiyaku Co.
L td .), lipase M Y ( C andida rugosa, M eito Sangyo
C o., L td .) an d PL 266 (lipase Q L , A lcaligenes sp.,
M eito S angyo C o., L td.) in various solvents at 30°
o r 40 °C in th e p resen ce o f vinyl a c eta te o r chlo-
rovinyl a ce ta te as an acetylating agent for differen t
tim e p e rio d s (T able I). It w as observ ed th a t P L 266
in b en z en e at 40 °C in th e presence o f vinyl a ce -
ta te is able to resolve th e p re p a re d racem ic m ix-
O
Ph
+
F,C
O
Ph
+ P3C
T h e c o m p o u n d 8 w as co n firm e d by its 19F N M R
w hich d isp lay ed d o u b le t at <3 20.98 (d o u b le b o n d
reg io n , F 3C - C H = ) . T h e d esire d co m p o u n d 9 w as
also co n firm e d by its 19F N M R w hich ex h ib ited
Lipase PL 266
O '^ 'P h
Vinyl acetate
O
O
Ph
Ph
F,C
FoC
FaC
Benzene
40°C
Racemic
substrate
Scheme 2
Table I.
No
Amount of E sterh
Enzyme
Solvent
Temp. (°C)
A cO -A genta
Time (hr)
1
2
3
4
5
6
7
8
9
lipase PS
lipase PS
lipase PS
lipase PS
lipase MY
lipase MY
lipase MY
lipase MY
lipase MY
PL 266
hexane
hexane
THF
CH 2C12
hexane
hexane
Et'.O
68
17
24
24
70
17
22
24
24
26
24
24
30
30
30
30
30
30
30
30
30
40
40
40
C.V.A.
V.A.
V.A.
05
02
00
05
00
00
00
03
00
00
04
40
V.A.
C.V.A.
V.A.
V.A.
V.A.
V.A.
V.A.
V.A.
V.A.
THF
CH 2C12
hexane
acetone
benzene
10
11
1 2
PL 266
PL 266
a C.V.A.: chlorovinyl acetate, V.A.: vinyl acetate; b in percent.
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415
M. S. Ali et al. • Enzymatic Racemic Resolution of a Fluorinated Substrate
Table II.
signal at
ö 11.68 as a trip le t (F 3C - C H 2- ) . T he
co m p o u n d 10 w as id en tified by its flu o rin e an d
p ro to n N M R w hich sh o w ed trip le t a t d 11.59 in
19F N M R and th e ab sen ce o f a ro m atic p ro to n s in
th e 'H N M R sp ectra, respectively. T he co m p o u n d
9 w as used fo r th e p re p a ra tio n o f M T P A -ester 11
by n o rm al p ro c ed u re (S chem e 3). Its p u rity w as
ch eck ed by gas c h ro m a to g ra p h y an d finally, by 19F
N M R w hich show ed 80% ee.
vinyl acetate
PL 266 (unit)
time (hr)
No. solvent
1
2
3
4
benzene
benzene
9000
9000
benzene 18000
3000
48
27
48
12
equim olar
equim olar
equim olar
two molar
hexane
w as fo u n d th a t a fter lo n g er p e rio d th e som e
am o u n t o f alcohol w as p ro d u ce d w hich w as c o n -
firm ed th e reversibility o f the re ac tio n (S ch em e 5).
F,C
OAc
Ac20
Scheme 3
-------
»
py
F.C
F,C
C onfirm ation o f optical pu rity
T he optical p u rity o f e ste r 7a w as also ch eck ed .
In th e first step, it w as h y d ro g en a te d in to 12 an d
th en hydrolyzed by K 2C 0 3 to affo rd alcohol 13
having o p p o site stereo ch e m istry at C -3 w ith re fe r-
ence to 6a. Finally, c o m p o u n d 13 w as also c o n -
v erted in to th e c o rre sp o n d in g M T P A -ester w hich
w as also fo u n d to be 80% ee (S chem e 4).
Scheme 5
FoC
D u rin g th e im p ro v em en t o f o p tical p u rity th e
so lv en t o f th e reactio n w as also ch an g ed . It w as
fo u n d th a t w hen b en zen e w as re p laced by h ex an e,
th e re actio n tim e d ecreased to 12 hours, c o n c e n -
tra tio n o f enzym e red u ced to (3000 u n its) an d vi-
nyl ac e ta te w ith d o u b le m o lar a m o u n t, th e n it is
possible to se p a ra te th e u n re a c ted su b stra te w ith
96.3% ee a fte r 60% conversion.
OAc
OAc
0
Ph
P reparation o f E and. Z alkenes
T he optically p u re co m p o u n d 6a w as used fo r
th e p re p a ra tio n o f E an d Z alk en es (S chem e 6).
O
Ph
Opposite stereochemistry
OH
Scheme 4
O
Ph
FqC'
F,C.
14
Im provem en t o f optical p u rity
F,C
OH
A fte r o b tain in g th e alcohol 6a an d a c e ta te 7a in
80% ee, it w as decid ed to im p ro v e th e o p tical p u -
rity e ith e r by changing th e tim e o f re a ctio n o r th e
am o u n t o f enzym e used at 40 °C (T able II).
O
Ph
Scheme 6
15
T he E olefin 14 w as p re p a re d by tre a tin g c o m -
p o u n d 6a w ith R ed -A l. It w as co n firm e d by th e
presen ce o f signal as d d q at d 5.95 (1 H , 7 = 2.01,
15.62, 6.57 H z, C F 3C H ) an d at (3 6.37 (1 H , d dq ,
7 = 4.01, 15.60, 2.01 H z, C F 3C H = C H ) in th e 'H
N M R sp ectru m . T he Z olefin 15 w as p re p a re d by
tre a tin g th e sam e co m p o u n d 6a w ith L in d lar cata-
It w as o b serv ed th a t w h en th e re a c tio n w as left
for lo n g er p erio d th e c o n v ersio n w as very low. It
w as th o u g h t th a t m ay be this reactio n is rev ersib le
after a long tim e o r m ay be d u e to th e a tm o sp h e ric
m oisture. D u e to th ese re aso n th e su b stra te (ra c e -
m ic) 6 w as ac e ety la te d chem ically in to 7 an d
tre a te d w ith th e sam e enzym e for th re e days. It
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416
M. S. Ali et al. • Enzymatic Racemic Resolution of a Fluorinated Substrate
ate as a m o b ile phase. T he first (less p o lar) p ro d u ct
2 e lu te d fro m co lu m n w as d isca rd ed w ith o u t ta -
king sp ectro sco p ic d ata. T he seco n d p ro d u c t (p o -
lar) o b ta in e d fro m co lu m n w as 1. T he rem ain in g
D M F w as re m o v ed by sh o rt p a th d istillatio n . T he
w hole re a ctio n w as re p e a te d tw o tim es in o rd e r to
o b tain 1 in bulk.
Yield: 65% ; Mass (F D ): M + 166 m/z; ‘H NMR:
6 1.95 (2 H , m , H -2 ), 3.63 (2 H , t, J = 7.0 H z, H -
3), 3.80 (2 H , dd , J = 7.0, 5.1 H z, H -l), 4.45 (2 H ,
s, C H 2P h ), 1 .2 - 1 A (5 H , m , P h).
lyst u n d e r h y dro gen. It w as also confirm ed by its
N M R w hich d isplayed signals at d 5.58 (1 H ,
ddq, /
= 1.23, 11.94. 8.76 H z, C F 3C H ) and at Ö
6.03 (1 H , dd, J = 8.81, 11.94 H z, C F 3C H = C H ) in
th e sp ectru m .
T hese E an d Z optically p u re olefins can be used
as p re cu rso rs fo r th e syntheses o f biologically
active flu o ro -h ex o ses having reverse stere o c h e m -
istry at a chiral center. T hese sequences can also
b e ap p lied fo r th e syntheses of various n a tu ra l
products, especially in th e area of c arb o h y d rates
co n tain in g flu o rin e atom /atom s.
l-B en zyloxy-6,6,6-triflu oro-4-h exyn -3-ol (6 )
Experimental
D M S O (20 m l) a n d d ic h lo ro m e th a n e (200 m l)
w ere ta k e n at - 7 8 °C u n d e r n itro g en atm o sp h e re
an d o xaly l-ch lo rid e (18.2 m l) w as ad d ed . A fte r 10
A ll com m ercially available reag en ts w ere used
w ith o u t fu rth e r p ru ificatio n . A ll reactio n s in v o l-
ving air-sensitive m aterials w ere p erfo rm ed u n d e r
n itro g en atm o sp h ere . T H F and C H 2C12 w ere d is-
tilled from so d iu m /b e n z o p h e n o n e an d calcium h y -
dride, respectively, u n d e r n itro g en im m ed iately
p rio r to use.
'H an d 13C N M R sp e c tra w ere re co rd e d on V ar-
ian G iem ini-200 (200 M H z) o r V arian V X R -500
(500 M H z) in CD C13. C hem ical shifts w ere re -
co rd e d in p a rts p e r m illion((3) dow nfield from in -
te rn a l te tram e th y lsilan e (T M S ). 19F N M R sp ectra
w ere scan n ed by H itach i R -1200F (56.451 M H z)
in C D C I3 an d th e chem ical shifts w ere re p o rte d in
p p m dow nfield from e x tern al triflu o ro -acetic acid
(T F A ). In fra re d (IR ) sp ectra w ere o b ta in e d on
JA S C O A -102 o r JA S C O FT /IR -5000 sp e c tro m e -
ters. O p tical ro ta tio n s w ere m easu red on JA S C O
D IP -140 digital p o la rim e te r in chloroform . Silica
gel colum n ch ro m ato g rap h y w as p erfo rm ed (E .
M erck, 7 0 -2 3 0 m esh) by using m ixtures of h e x a-
ne :e th y la c e ta te (v/v) as a m obile phase. G as liquid
c h ro m a to g ra p h y (G L C ) w as c o n d u cte d on Shi-
m adzu G C -8A .
m in u tes stirrin g , th e p re p a re d b en z h y l-eth e r
1
(15.5 g) d ilu te d w ith C H 2C12 (150 m l) w as ad d ed
d ropw ise. A fte r 0.5 h E t3N (68.3 m l) w as in tro -
d u ced in to th e re a c tio n m ix tu re an d th e reactio n
w as left fo r fu rth e r stirrin g a b o u t 0.5 h. T h en th e
m ix tu re w as e x tra c te d w ith C H 2C12. A fte r drying
o v er N a 2S 0 4 it w as p u rified by co lu m n c h ro m a-
to g ra p h y using h e x a n e :eth y la c e ta te (4:1) w hich
y ield ed 13.2 g o f c o rresp o n d in g ald eh y d e 3.
T h e L D A w as p re p a re d by m ixing tre a tin g diiso-
p ro p y l am in e (26 m l), T H F (150 m l) an d B uL i
(68.6 m l) u n d e r n itro g en a tm o sp h e re at -7 8 °C.
To th is so lu tio n , a p re co o le d so lu tio n o f 2 -b ro m o -
3 ,3 ,3 -triflu o ro p ro p e n e (8.32 m l) in T H F (40 m l)
w as a d d e d d ropw ise. A fte r 5 m in u tes, p re p a re d a l-
d eh y d e 3 (13 g) d ilu te d w ith T H F (78 m l) w as in -
tro d u c e d in to th e re actio n m ixture. T he w hole
m ix tu re w as left fo r 0.5 h stirrin g an d th e n
q u en c h e d by N H 4C1. T he o rg an ic m a teria l w as ex -
tra c te d w ith d ieth y l e th er, d rie d o v er N a 2S 0 4, an d
c h ro m a to g ra p h e d o n a silica gel co lu m n affo rd ed
c o m p o u n d 6 .
Elution: H e x a n e :e th y la c e ta te (4:1); Yield: 85% ;
IR (n e a t): v 3400, 3100, 3075, 3025, 2950, 2925,
2275 c m “ 1; Mass (F D ): M + 258 m /z; HRMS: fo und
258.0852 m /z (C alcd 258.0868 m /z fo r C n H n F 3 0 2;
*H NMR: (3 1.98 (1 H , d d d d , J = 3.46, 5.57, 6.45,
14.76 H z, H -2 ), 2.17 (1 H , d d t, J = 8.91, 14.77, 4.15
H z, H -2 ), 3.44 (1 H , d, J = 6.84 H z, O H ), 3.70 (1 H ,
d d d , J = 4.15, 5.50, 9.64 H z, H -l) , 3.86 (1 H , dt, J =
3.54, 9.28 H z, H -l) , 4.54 (2 H , s, C H 2P h ), 4.71
(1 H , d tq , J = 3.81, 6.73, 2.97 H z, H -3 ), 1 .2 -1 A
(5 H , m , P h); 13C NMR: Ö 35.39, 60.91 (q, J = 1.17
H z), 67.13, 72.03 (q, J = 52.99 H z), 73.55, 87.50 (q,
J = 6.30 H z), 114.02 (q, J = 257.46 H z), 127.73,
127.98, 128.53, 137.30: 19F NMR: (3 29.46 (d, J =
2.77 H z).
3 -(B en zylo x yj-p ro p a n o l (1)
To
a stirrin g slurry of N aH (9.5 g) in D M F
(160 m l), th e p ro p a n e diol (11.5 m l) w as ad d ed
dropw ise at 0 °C u n d e r th e n itro g en an d th e w hole
w as stirre d fo r 0.5 h. T h en b enzylborm ide (19 m l)
w as ad d ed grad u ally an d the reactio n m ixture w as
left o v ern ig h t. T he reactio n w as q u en ch ed by
N H 4CI an d th e p ro d u c t w as ex trac ted w ith a m ix-
tu re of hexane: diethyl e th e r (1:1). T he organic
layer w as d ried o v er N a 2S 0 4 and c o n c e n tra ted in
vacuo. T he cru d e m ass w as p urified by silica gel
colum n c h ro m a to g ra p h y using h exane :eth y lacet-
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M. S. Ali et al. • Enzymatic Racemic Resolution of a Fluorinated Substrate
417
E n zym atic esterification
m e th a n o l w as rem o v ed by vacuo an d w a te r w as
ad d ed . T he p ro d u c t w as ex trac te d w ith e th y la c e-
ta te an d p u rified by silica gel colum n c h ro m a -
tography.
T he racem ic alcohol 6 (1 1 .0 g ) w as dissolved in
h ex an e (85 m l). T hen, vinyl a cetate (7.27 m l) and
P L 226 (M eito S angyo C o., L td., 4.26 g) w ere
a d d ed into it. T he w hole m ix tu re w as stirre d at
40 °C fo r 12 hrs. A fte r filtratio n an d c o n ce n tratio n ,
it w as ch ro m ato g ra p h e d on silica gel colum n using
h e x a n e : ethyl acetate 'w hich yielded optically
active alcohol 6a an d e ste r 7a. TTie physical p ro p -
erties o f racem ic alcohol 6 an d optically active al-
cohol 6a w ere th e sam e w hich w ere d escrib ed p re -
viously, ex cept th e optical ro tatio n .
Elution: H e x a n e :e th y lacetate
(8:1); Yield:
86% ; [a]i>9 -1 7 .9 8 ° (c 1.19, CHC13). M ass (F D ):
M + 262 m /z (C 13H 17F 30 2); lH N M R : (5 1.88 (4 H ,
m , H -2 an d H -4), 2.25 (2 , m , H -5), 3.68 (1 H , dd d ,
J = 4.15, 5.50, 9.64 H z, H -l), 3.78 (1 H , d t, J = 3.54,
9.28 H z, H -l), 3.89 (1 H , d tq , J = 3.81, 6.73, 2.97
H z, H -3 ), 4.52 (2 H , s, C H 2P h), 7.33 (5 H , m , P h).
C atalytic hydrogenation o f 1-B en zylo x y-6,6,6-
trifluoro-4-hexyn-3-ol (6a)
Yield: 41% ; [ a ] g -3 4 ° (c 1.26, CHC13); o ptical
purity: 96.3% ee
T he optically p u re alcolhol 6a (515 m g), w as d is-
solved in e th an o l (30 m l) an d tre a te d w ith 10%
P d - C (0.04 g u n d e r hyd ro g en . T he rea c tio n w as
left o v ern ig h t. A fte r filtratio n , th e cru d e m aterial
w as c h ro m a to g ra p h e d on silica gel colum n. A fte r
p u rifica tio n tw o p ro d u cts could be id en tified . T he
sp ectro sco p ic d a ta o f c o m p o u n d 8 having d o u b le
b o n d is id en tified as Z olefin 15. T he d a ta o f d e -
sired sa tu ra te d c o m p o u n d 9 is id en tical to co m -
p o u n d 13; [a ] o +12.80° (c 1.27, CHC13).
6 -B en zylo x y-l ,1,l-triflu oro-4-acetoxy-2-h exyne
(7a)
Elution: H e x a n e :e th y l a c etate (6:1); Yield:
59% ; [ a ß 2 +40° (c 2.09, CH C13); M ass((F D ): M +
300 m /z (C 15H 15F 30 3); IR (n eat):
v 3090, 3065,
3035, 2935, 2865, 2800, 2275, 1735 cm “ 1; 'H NMR:
(5 2.06 (3 H , s, A e), 2 .0 -2 .3 (2 H , m , H -5), 3.53
(1 H , d t, J = 9.83, 5.70 H z, H -6), 3.59 (1 H , dt, J =
9.86, 5.89 H z, H -6), 4.46 (1 H , d, J = 11.94 H z,
C H 2P h), 4.52 (1 H , d, J = 11.94 H z, C H 2P h ), 5.63
(1 H , tq , J = 7.02, 2.88 H z, H -4); 13C NMR: <5 20.63,
34.08, 60.04 (q, J = 1.32 H z), 64.85, 72.29 (q, J =
52.87 H z), 73.16, 84.40 (q, J = 6.31 H z), 113.81 (q,
P reparation and purification o f M T P A -ester
T h e optically p u re sa tu ra te d alcohols 9 an d 13
h avin g o p p o site stereo ch em istry at C-3, w ere c o n -
v e rte d in to th e ir co rresp o n d in g M T P A -esters
separately . In each case, 0.5 m .m ol alcohol w as d is-
solved in an h y d ro u s C H 2C12 an d M TPA -C1 (0.13
m l), 4 -d im eth y lam in o p y rid in e (catalytic a m o u n t)
an d trie th y l am ine (0.08 m l) w ere ad d ed in to it at
ro o m te m p e ra tu re u n d e r n itro g en o v ern ig h t.
T h en , th e m ix tu re w as q u en ch ed w ith 1 N HC1 an d
e x tra c te d w ith C H 2C12. T he cru d e m aterials w ere
p assed th ro u g h silica gel colum n an d th e optical
p u rity w as ch eck ed by G L C an d flu o rin e N M R .
J
= 257.86 H z), 127.73, 127.80, 128.46, 137.82,
169.39; 19F NMR: 6 28.38 (d, J = 2.77 H z).
6 -B e n zy lo x y -l,1,1 -trifluoro-4-acetoxyhexane (12)
To a suspension o f 10% P d - C (0.03 g) in an h y -
d ro u s eth an o l (15 m l) u n d e r hyd ro g en , w as a d d ed
co m p o u n d 7a (387 m g), an d th e w hole m ix tu re
w as stirred overnight. A fte r rem oval o f th e c a ta -
lyst ( P d - C ) by filtratio n , th e so lution w as co n c e n -
tra te d . T he crude p ro d u c t th u s o b ta in e d , w as p u ri-
fied by silica gel colum n chrom atography.
Elution: H e x a n e :e th y la c e ta te
(9:1); Yield:
(E )-l-B en zyloxy-6,6,6-triflu oro-4-h exen -3-ol (14)
98.2% ; [<x]d +8.69° (c 1.105, CHC13); IR (n e a t): v
3020, 1735, 1216 c m - 1; MS (F D ): M + 304 m /z
To a stirrin g so lu tio n o f R e d -A l (0.53 m l) in to l-
u en e (5 m l) at - 7 8 °C w as ad d ed optically p u re
alco h o l 6a (0.387 g). A fte r stirrin g fo r 3 hrs., th e
m ix tu re w as q u en c h ed w ith 1 N HC1 an d th e p ro -
d u ct w as ex tra cte d w ith eth y lacetate. T he cru d e
o lefin w as p u rified by silica gel colum n c h ro m a -
tography.
Elution: H e x a n e :e th y l a c eta te (4:1); Yield:
90.4% ; [ a ] o +5.06° (c 1.304, CHC13). M ass
(H R M S ): F o u n d M + 260.2561 m /z (C alcd for
(C 15H 19F 30 3);
NMR: (5 1.90 (2 H , q, J = 6.27
H z, H -5), 2.00 (3 H , s, A c), 2 .1 1 -2 .2 2 (4 H , m , H -
3 an d H -2), 3.49 (1 H , d t, J = 9.52, 6.47 H z, H -6),
3.51 (1 H , dt, J = 9.52, 5.86 H z, H -6), 4.47 (2 H , s,
C H 2P h ), 5.09 (1 H , dq, J = 3.42, 6.43 H z, H -4), 7.12
(5 H , m , Ph).
1-B enzyloxy-6,6,6-trifluorohexen-3-ol (13)
C o m p o u n d 12 (387 m g) w as dissolved in m e th a -
nol (15 m l) and K 2C 0 3 (288 m g) w as a d d e d in to it
at ro o m te m p eratu re. A fte r 2 hrs. of stirring, th e
C 13H 15F 30 2 m /z 260.1024); IR (n eat):
3075, 3050, 2950, 2875, 1650 c m - 1; l H N M R : Ö
1 .7 -2 .1 (2 H , m , H -2), 3.41 (1 H ,'d , J = 3.81 H z,
v 3450,
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418
M. S. Ali et al. ■Enzymatic Racemic Resolution of a Fluorinated Substrate
O H ), 3.65 (1 H , dt, J = 9.34, 4.27 H z, H -l), 3.73
(1 H . dt, J = 9.38, 4.04 H z, H -l), 4 .4 -4 .6 (1 H , m ,
H -3), 4.52 (2 H . s, C H 2Ph), 5.95 (1 H , dd q, J = 2.01,
15.62, 6.57 H z, H -5), 6.37 (1 H , ddq, J = 4.01,15.60,
2.01 H z, H -4), 1 .2 -1 A (5 H , m , Ph); U C N M R : (3
35.38 (q, J = 1.32 H z), 68.33, 69.78, 75.53, 117.90
(q, J = 33.65 H z), 123.37 (q, J = 268.84 H z), 127.77,
128.01, 128.58, 137.44, 141.78 (q. J = 6.30 H z); 19F
N M R : ö 15.01 (d, J = 5.53 H z).
(H R M S ): F o u n d M + 260.2561 m /z (C alcd 260.1024
fo r C n H i5F 30 7 m /z); IR (n eat): 3425, 3075,
v
3050, 2950', 2875, 1650, 675 c m - 1; >H N M R : <5 1 .6 -
2.1 (2 H , m , H -2 ), 3.31 (1 H , d, J = 3.25 H z, O H ),
3.66 (1 H . d d d , J = 4.06, 4.90, 8.91 H z, H -l), 3.73
(1 H , d d d , J = 2.56, 4.88, 9.38 H z, H -l), 4.48 (1 H ,
d, J = 11.9 H z, C H 2P h), 4.55 (1 H , d, / = 11.72 H z,
C H 2P h ), 4 .7 -5 .0 (1 H , m , H -3), 5.58 (1 H , ddq, J =
I.23, 11.94, 8.76 H z, H -5), 6.03 (1 H , dd, J = 8.81,
II.9 4 H z, H -4 ), 7 .2 -7 .5 (5 H , m , P h); 13C N M R : (3
36.18, 67.53 (q, J = 1.42 H z), 68.29, 73.41, 117.72
(q, J = 34.47 H z), 122.87 (q, J = 272.00 H z), 127.75,
127.90, 128.53, 137.62, 144.48 (q, J = 5.19 H z); ,9F
N M R : (3 20.92 (d, J = 8.24 H z).
(Z )-l-B en zyloxy-6,6,6-triflu oro-4-h exen -3-ol (15)
A so lu tio n of opticall active alcohol 6a (2 g) in
h ex an e (40 m l) an d L in d lar catalyst (0.31 g) w as
a d d e d into it u n d e r hydrogen. A fte r 2 hrs., catalyst
w as rem o v ed by filtratio n and th e solution w as
c o n c e n tra te d u n d e r red u ced pressure, w hich w as
th e n p u rified by colum n ch ro m ato g rap h y to afford
olefin 15.
A ckn ow ledgem en ts
E lu tio n : H e x a n e :e th y l a c etate (9:1); Y ield:
63% ; [ a ß 4 +5.89° (c 1.083, CHC13): M ass
T h e financial su p p o rt from U N E S C O and G ovt,
o f Jap an is g ratefu lly acknow ledged.
[8] M. Koden, M. Shiomi, K. Nakagawa, F. Fukuda, K.
Awane, T. Yamazaki, T. Kitazume, Jpn. J. Appl.
Phys. 30, L I300 (1991).
[1] R. E. Banks, E. Horwood, “Organic Fluorine Chem-
ical and their Industrial Applications”, Ed: Halsted
New York (1979).
[9] D. M. Walba, H. A. Razavi, N. A. Clark, D. S.
Parmar. J. Am. Chem. Soc. 110, 8688 (1988).
[10] C. walsh, J. Wiley, Adv. Enzyme Related Areas Mol.
Biol. 55, 203 (1993).
[2] M. Hudlicky, “Chemistry of Organic Fluorine Com-
pounds”, John Wiley and Sons, New York (1976).
[3] T. Yamazaki, T. Kitazume, H eteroatom Chem. 7.
132 (1992).
[11] For a review, see “Enzymes in Organic Chemistry”,
Ciba Foundation Symposium III, Eds: R. Porter, S.
Clark. Pitman. London (1985).
[4] J. T. Welch, S. Eswarakrishnan, “Fluorine in Bioor-
ganic Chemistry”, John Wiley and Sons, New York
(1991).
[12] For a review see, G. M. Whitesides, C. H. Wong, A n-
gew. Chem., Int. Ed. Engl. 24, 61 (1985).
[13] For a review see. J. B. Jones, Tetrahedron 42, 3351
(1986).
[5] J. T. Welch, Tetrahedron 43, 3123 (1987).
[6] R. Filler, Y. Kobayashi "Biomedicinal Aspects of
Fluorine Chemistry”, Kodansha and Elsevier Bio-
medical, Tokyo (1982).
[14] J. Conforth, Interdisciplinary Sei. Rev. 9, 107 (1984).
[7] M. Johno. K. Itoh, J. Lee. Ouchi. Y. Takezoe, A.
Fukuda, T. Kitazume. Jpn. J. Appl. Phys. 29, L107
(1990).
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