Stereoselective synthesis of highly-functionalized cyclohexene derivatives having a diethoxyphosphoryldifluoromethyl functionality from cyclohex-2-enyl-1-phosphates

Article abstract of DOI:10.1055/s-2003-40862

Reaction of diethoxyphsphoryldifluoromethylzinc bromide (BrZnCF ₂PO₃Et₂) with highly functionalized cyclohex-2-enyl-1-phosphates in the presence of CuBr in THF was examined. The reaction provides a facile method for introducing a difluoromethylenephosphonate unit to the allylic position within a cyclic array in a stereo- and regioselective manner.

Full text of DOI:10.1055/s-2003-40862

LETTER
1407
Stereoselective Synthesis of Highly-Functionalized Cyclohexene Derivatives
Having a Diethoxyphosphoryldifluoromethyl Functionality from Cyclohex-2-
enyl-1-phosphates
Stereoselective
s
S
ynthesis
u
of Highly-F
t
o
alized Cyclo
m
hexene
D
erivativesu Yokomatsu,* Junya Kato, Chiseko Sakuma, Shiroshi Shibuya
School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
E-mail: yokomatu@ps.toyaku.ac.jp
Received 30 May 2003
CF2PO3H2
OH
CF2PO3Et2
OR
Abstract: Reaction of diethoxyphsphoryldifluoromethylzinc bro-
mide (BrZnCF2PO3Et2) with highly functionalized cyclohex-2-
enyl-1-phosphates in the presence of CuBr in THF was examined.
The reaction provides a facile method for introducing a difluoro-
methylenephosphonate unit to the allylic position within a cyclic
array in a stereo- and regioselective manner.
HO
HO
OH
OH
OR
OR
Et2O3PO
OR
OR
Key words: diastereoselectivity, regioselectivity, phosphonates,
fluorine
MCF2PO3Et2
OR
Scheme 1 MCF2PO3Et2, 1: M = BrZn, 2: M = Br2Zn·Cu
Naturally occurring phosphate derivatives play pivotal
roles in various cellular processes including signal trans-
duction.1 Non-hydrolyzable phosphate mimetics have
been studied for the design of potential enzyme inhibitors
and probes for elucidation of biochemical processes. Ex-
tensive studies have been devoted to synthesis and biolog-
ical evaluation of (a,a-difluoromethylene)phosphonic
acid (DFMPA) derivatives, a non-hydrolyzable mimetic
of phosphates.2,3 While many useful methods for synthe-
sis of DFMPA-based mimetics of phosphorylated amino
acids, sugars and nucleic acids have been reported,3
stereoselective synthesis of DFMPA-derived cyclic com-
pounds that may act as hydrolytically stable analogues
of naturally-occurring inositol phosphates remains a
challenging issue.4
tained by lipase PS (Amano)-catalyzed desymmetrization
of the corresponding diacetate according to the method of
Sih.8 Treatment of 3 with diethyl chlorophosphate in pyri-
dine gave 4a. Hydrolysis (K2CO3, MeOH) of 4a and sub-
sequent pivaloylation (PivCl, pyridine) or silylation
(TBDPSCl, imidazole, DMF) of the resulting alcohol 4b
yielded 4c and 4d, respectively. Compounds 4a–d were
treated with 2 at room temperature for 16 hours to give the
results summarized in Table 1.
AcO
OH
RO
OPO3Et2
3
4a–d
Et2O3PF2C
We examined organometalic-mediated allyl-coupling of
a,a-difluoromethylphosphonate to cyclohex-2-enyl-1-
phosphates to give the DFMPA-derived cyclohexene de-
rivatives, potentially useful intermediates for the synthe-
sis of the DFMPA-based mimetics of inositol phosphates5
(Scheme 1). In this paper, we describe the allyl-coupling
reaction of the copper species 2,6,7 generated from zinc re-
agent 1 and copper(I) bromide in THF, with cyclohex-2-
enyl-1-phosphates gave highly-oxygenated cyclohexene
derivatives having a DFMPA-ester in a high degree of
diastereo- and regioselectivity.
2
+
RO
RO
CF2PO3Et2
THF
5a–d
6a–d
a: R=Ac; b: R=H; c: R=Piv; d: R=TBDPS
Scheme 2
When the acetyl-protected derivative 4a was treated with
2, installation of the DFMPA-ester occurred at the a- and
g-carbon to give 5a and 6a in a ratio of 63:27 in 62% yield.
First, we examined the reaction of 4-oxygeneated cyclo- Diastereomeric excess (de) of 5a was determined to be
hex-2-enyl-1-phosphates 4a–d with the copper species 2 72% (entry 1). In the reaction of non-protected derivative
to investigate the regio- and diastereoselectivity 4b, a mixture of 5b and 6b was formed in a ratio of 43:57
(Scheme 2). The phosphates 4a–d were synthesized in an and formation of g-alkylated product 6b was slightly pre-
optically active form from (+)-(1R,4S)-4-hydroxycyclo- ferred. De of 5b was found to be 61% (entry 2). The reac-
hex-2-en-1-yl acetate 3, [a]D25 +77.0 (c 1.0, CHCl3), ob- tion with pivaloyl-protected derivative 4c afforded a
mixture of 5c and 6c in virtually the same ratio as for the
acetate 4a, but de of both adducts increased to 85% (entry
3). Though the yield of adducts was quite poor, the reac-
tion of TBDPS-protected derivative 4d resulted in prefer-
Synlett 2003, No. 10, Print: 05 08 2003.
Art Id.1437-2096,E;2003,0,10,1407,1410,ftx,en;U10003ST.pdf.
© Georg Thieme Verlag Stuttgart · New York

1408
T. Yokomatsu et al.
LETTER
Table 1 Reaction of Cyclohex-2-enyl-1-phosphates 4a–d with 2 in
OAc
OAc
OR
OX
THFa
O
O
O
O
O
O
c
a
Entry Phosphate (R)
Yield
(%)b
5:6c
De (%) De (%)
of 5
of 6
NDd
NDd
>85e
99
OAc
OPO3Et2
R=H
R=PO3Et2
7
8
9
X=H
X=Bz
10
11
1
2
3
4
4a (Ac)
62
82
91
54
63:27
43:57
65:35
25:75
72
b
d
OX
4b (H)
61
OX
Et2O3PF2C
+
O
O
O
O
e
4c (Piv)
85
4d (TBDPS)
94
CF2PO3Et2
13a–c
a: X=Ac; b: X=Bz; c: X=H
a All reactions were carried out at r.t. for 16 h.
b Combined yield of 5 and 6.
12a–c
c The ratio was determined by 31P NMR analysis.
d Not determined.
Scheme 3 (a) Lipase PS, phosphate buffer (pH = 7.0), r.t., 12 h
(90%); (b) ClPO3Et2, pyridine, cat. DMAP (95%); (c) K2CO3, MeOH
(85%); (d) BzCl, pyridine, cat. DMAP (98%); (e) 2, THF–HMPA, r.t.,
16 h.
e The de could not be precisely determined.
able formation of g-alkylated product 6d to a-alkylated
product 5d. Furthermore, de of 5d and 6d was found to be
94% and 99%, respectively (entry 4). On consideration of
these results, the reaction pathway could not be accounted
for by an SN2/SN2¢ substitution mechanism.9 The reaction
would involve a process in which leaving of the phosphate
group occurs prior to the carbon-carbon bond formation.10
11, through hydrolysis of the acetate and benzoylation of
the resulting alcohol, respectively.
When the acetyl-protected derivative 9 was treated with 2
in THF at room temperature for 16 hours, virtually no re-
action occurred and a significant amount of the starting 9
was recovered unchanged. Treatment of 9 with 2 in the
presence of HMPA (4.0 equiv) as a co-solvent gave a mix-
ture of a- and g-alkylated products 12a and 13a in 10%
yield, along with large amounts of unidentified products.
The reaction of benzoyl-protected derivative 11 with 2 in
THF gave a mixture of 12b and 13b in 17% yield, along
with the recovered 11. However, when the reaction was
carried out in the presence of HMPA (4.0 equiv), the yield
(70%) significantly increased to give a 17:83 mixture of
12b and 13b.17 In this reaction, diastereomeric isomers of
12b and 13b were not detected. The reaction between the
non-protected derivative 10 and 2 in THF containing
HMPA gave a mixture (45:55) of 12c and 13c in 65%
yield and their diastereoisomers were not detected. The
solvent and the protecting group at the 4-hydroxy were
found to play critical role to get the products with high re-
gioselectivity and good yield.
The regioisomers 5d and 6d were not readily separated by
column chromatography on silica gel.11 However, treat-
ment of a mixture of 5d and 6d with 1.0 equivalent of tet-
rabutylammonium fluoride in THF at room temperature
for 12 hours gave 5b by selective desilylation and 6d re-
mained unchanged. Thus, diasteromerically pure 5b and
6d were readily isolated in 24% and 71% yield,12 by chro-
matography on silica gel, respectively. The 2D-NMR
(500 MHz, CDCl3) analyses of the p-bromobenzoate de-
rived from 5b, including HMBC, HMQC, COSY and
NOESY, cleanly demonstrated the relative stereochemis-
try to be trans.13 The stereochemistry of 6d was also as-
certained to be trans by two-dimensional heteronuclear
NOE (HOESY) experiments between 31P and 1H.14 In the
HOESY spectrum, a diagnostic HOESY-correlation be-
tween the phosphorus atom and the proton adjacent to the
TBDPSO-functionality was observed.
We next examined the steric influence of the substituent
at the 4-position. We expected the b-oriented substituent
would suppress approach of the copper species 2 to the g-
position and the a-alkylated products would be formed
preferably. We prepared the allylic phosphates 16–18 in
an optically active form from (–)-15, [a]D25 –204.4 (c 1.0,
CHCl3), obtained by lipase PS-catalyzed resolution of ( )-
1418 according to the procedure of Chung19 (Scheme 4).
To access highly-oxygenated cyclohexene derivatives
having a DFMPA-ester, we next examined reaction with
cyclohex-2-enyl-1-phosphates 9–11 fused to the 1,3-diox-
olane ring. In these ring systems, stereoselective installa-
tion of a DFMPA-ester could be expected, since the attack
of the copper reagent from the a-face is sterically hindered
by the 1,3-dioxolone ring and the oxygenated substituent
at the 4-position, forcing attack of the reagent from the
convex face. Compounds 9–11 were prepared from meso-
diacetate 7 as shown in Scheme 3. Desymmetrization of 7,
derived from the corresponding known diol,15 in a phos-
phate buffer (pH = 7.0) in the presence of lipase PS at
Treatment of the acetyl-protected derivative 16 with 2 in
the presence of HMPA (4.0 equiv) in THF at room tem-
perature for 16 hours gave a separable mixture of 19a and
20a in a ratio of 89:11 in 67% yield and their diastereo-
meric isomers were not detected. The major adduct was
proved to be, unexpectedly, a g-alkylated product, whose
structure was confirmed by careful analysis of the 2D
NMR spectrum (HMQC, HMBC, COSY and NOESY).
The reaction of benzoyl-protected derivative 18 also gave
19b as an isolable product in 42% yield. In contrast to the
25
room temperature for 12 hours gave 8,16 [a]D –57.5 (c
1.08, CHCl3), in 90% yield. Enantiomeric excess of 8 was
determined to be >98% on analyzing the MTPA-esters.
Treatment of 8 with diethyl chlorophosphate in pyridine
gave 9, which was transformed to the phosphates 10 and
Synlett 2003, No. 10, 1407–1410 © Thieme Stuttgart · New York

LETTER
Stereoselective Synthesis of Highly-Functionalized Cyclohexene Derivatives
1409
M. C.; Holt, D. A. Bioorg. Med. Chem. Lett. 1999, 9, 3109.
(f) Yokomatsu, T.; Hayakawa, Y.; Kihara, T.; Koyanagi, S.;
Soeda, S.; Shimeno, H.; Shibuya, S. Bioorg. Med. Chem.
2000, 8, 2571. (g) Otaka, A.; Mitsuyama, E.; Kinoshita, T.;
Tamamura, H.; Fujii, N. J. Org. Chem. 2000, 65, 4888.
(h) Berkowitz, D. B.; Bose, M.; Pfannenstiel, T. J.; Doukov,
T. J. Org. Chem. 2000, 65, 4498. (i) Lopin, C.; Gautier, A.;
Gouhier, G.; Piettre, S. R. J. Am. Chem. Soc. 2002, 124,
14668.
OAc
O
OAc
OH
OX
O
O
O
O
a
b
O
OAc
OPO3Et2
16 X=Ac
17
18
(+/–)-14
(–)-15
c
X=H
X=Bz
d
OX
OX
(4) (a) Blades, K.; Lapotre, D.; Percy, J. M. Tetrahedron Lett.
1997, 38, 5895. (b) Blades, K.; Lequeux, T. P.; Percy, J. M.
Chem. Commun. 1996, 1457. (c)Yokomatsu, T.; Katayama,
S.; Shibuya, S. Chem. Commun. 2001, 1878. (d) Butt, A.
H.; Kariuki, B. M.; Percy, J. M.; Spencer, N. S. Chem.
Commun. 2002, 682.
(5) (a) Campbell, A. S.; Thatcher, G. R. J. Tetrahedron Lett.
1991, 32, 2207. (b) Potter, B. V. L.; Lampe, D. Angew.
Chem., Int. Ed. Engl. 1995, 34, 1933. (c) Hinterding, K.;
Alondo-Díaz, D.; Waldmann, H. Angew. Chem. Int. Ed.
1998, 37, 688. (d) Miller, D. J.; Beaton, M. W.; Wilkie, J.;
Gani, D. Chembiochem 2000, 1, 262.
Et2O3PF2C
e
O
O
O
+
16–18
O
CF2PO3Et2
19a–c
a: X=Ac; b: X=Bz; c: X=H
20a–c
Scheme 4 (a) Lipase PS, phosphate buffer (pH = 7.0), r.t., 3 h;
(b) ClPO3Et2, pyridine, cat. DMAP (86%); (c) K2CO3, MeOH (85%);
(d) BzCl, pyridine, cat. DMAP (98%); (e) 2, THF–HMPA, r.t., 16 h.
reactions with 16 and 18, the reaction of non-protected de-
rivative 17 with 2 gave a-alkylated product 20c20 in 48%
yield, along with a trace amount of a g-alkylated product
19c. It is interesting that the regiochemical outcome of the
allyl-coupling reaction can be controlled by either using
acyl-protected or non-protected derivatives as a substrate,
but we cannot explain clearly these phenomena at the
moment.
(6) (a) Yokomatsu, T.; Suemune, K.; Murano, T.; Shibuya, S. J.
Org. Chem. 1996, 61, 7207. (b) Sprague, L. G.; Burton, D.
J.; Guneratne, R. D.; Bennett, W. E. J. Fluorine Chem. 1990,
49, 75. (c) Zhang, X.; Burton, D. J. Tetrahedron Lett. 2000,
41, 7791.
(7) (a) Yokomatsu, T.; Ichimura, A.; Kato, J.; Shibuya, S.
Synlett 2001, 287. (b) Burton, D. J.; Sparague, L. G. J. Org.
Chem. 1989, 54, 613.
(8) Harris, K. J.; Gu, Q.-M.; Sih, Y.-E.; Cirdaukas, G.; Sih, C.
Tetrahedron Lett. 1991, 32, 3941.
(9) Burton discussed mechanisms for reaction between 2 and
allychlorides and proposed that the reaction may proceed
through an SN2/SN2¢ substitution mechanism.7b
(10) trans-Isomer i of 4c reacted with 2 under the same
conditions to give a 62:38 mixture of a-alkylated product ii
and g-alkylated product iii in 71% yield (Scheme 5). The
a-alkylated product showed virtually no de. However, the
g-alkylated product showed modest de preferable to 1,2-
trans-stereochemistry showing that the reaction proceeded
from the less-hindered syn-face of the phosphate to avoid the
bulky pivaloyl group. These results also support that the
reactions would involve a process for leaving the phosphate
group prior to the carbon–carbon bond formation.
In summary, we have demonstrated a new and simple pro-
cedure for stereoselective synthesis of highly oxygenated
cyclohexene derivatives having diethoxyphosphoryldiflu-
oromethyl functionality, which would be valuable inter-
mediates for stereoselective synthesis of analogous
compounds of inositol phosphates.
Acknowledgment
This work was supported in part by a grant from The Promotion and
Mutual Aid Corporation for Private School of Japan and the Mini-
stry of Education, Culture, Sports, Science and Technology of
Japan.
2
THF
PivO
OPO3Et2
References
i
(1) Hunter, T. Cell 2000, 100, 113.
Et2O3PF2C
(2) (a) Blackburn, G. M. Chem. Ind. (London) 1981, 134.
(b) Blackburn, G. M.; Kent, D. E.; Kolmann, F. J. Chem.
Soc., Perkin Trans. 1 1984, 1149. (c) O’Hagan, D.; Rzepa,
H. S. Chem. Commun. 1997, 645. (d) Thatcher, G. R.;
Campbell, A. S. J. Org. Chem. 1993, 58, 2272. (e) Taylor,
S. D.; Kotoris, C. C.; Hum, G. Tetrahedron 1999, 55,
12431. (f) Burton, D. J.; Yang, Z.-Y. Tetrahedron 1992, 48,
189.
PivO
PivO
+
CF2PO3Et2
ii 3.3% de
Scheme 5
iii 50% de
(11) Compounds 5c and 6c were not readily separated on column
chromatography on silica gel. However, these products were
also separated by using the difference in their chemical
reactivity; selective deprotection of the Piv functional group
of 5d occurred to give 6b upon treatment with
ethylmagnesium bromide in diethyl ether at –15 °C.
(12) All new compounds gave satisfactory spectroscopic and
analytical data. Compound 5b obtained as a colorless oil,
[a]D25 +55.2 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3):
d = 5.94 (1 H, d, J = 10.6 Hz), 5.87 (1 H, dd, J = 10.6, 1.2
Hz), 4.31–4.22 (4 H, m), 3.01–2.85 (1 H, m), 2.21–2.12
(3) (a) Herpin, T. F.; Motherwell, W. B.; Roberts, B. P.; Roland,
S.; Weibel, J.-M. Tetrahedron 1997, 53, 15085.
(b) Yokomatsu, T.; Murano, T.; Suemune, K.; Shibuya, S.
Tetrahedron 1997, 53, 815. (c) Yokomatsu, T.; Abe, H.;
Sato, M.; Suemune, K.; Kihara, T.; Soeda, S.; Shimeno, H.;
Shibuya, S. Bioorg. Med. Chem. 1998, 6, 2495.
(d) Yokomatsu, T.; Murano, T.; Umesue, I.; Soeda, S.;
Shimeno, H.; Shibuya, S. Bioorg. Med. Chem. Lett. 1999, 9,
529. (e) Shakespeare, W. C.; Bohacek, R. S.; Narula, S. S.;
Azimioara, D.; Yuan, R. W.; Dalgarno, D. C.; Madden, L.
Synlett 2003, No. 10, 1407–1410 © Thieme Stuttgart · New York

1410
T. Yokomatsu et al.
LETTER
(1 H, m), 2.10–2.01 (1 H, m), 1.80–1.69 (3 H, m), 1.52–1.40
(1 H, m), 1.39 (3 H, t, J = 7.0 Hz), 1.38 (3 H, t, J = 7.0 Hz).
13C NMR (100 MHz, CDCl3): d = 123.13 (t, JCF = 4.3 Hz),
120.79 (dt, JCF = 262.2 Hz, JCP = 211.0 Hz), 115.36, 77.20,
66.04, 64.56 (d, JCP = 6.9 Hz), 64.38 (d, JCP = 6.9 Hz), 40.93
128.96, 124.00–116.00 (m), 122.17, 109.61, 72.57, 71.53,
69.53, 64.63 (dt, JCF = 22.1 Hz, JCP = 6.8 Hz), 39.90 (dt,
J = 15.3, 19.8 Hz), 27.60, 25.90, 21.00, 16.30. 31P NMR
(162 MHz, CDCl3): d = 6.25 (t, JPF = 105.5 Hz). 19F NMR
(376 MHz, CDCl3): d = –48.79 (1 F, ddd, JFF = 280.5 Hz,
JFP = 105.5 Hz, JFH = 12.0 Hz), –50.22 (1 F, ddd, JFF = 280.5
Hz, JFP = 105.5 Hz, JFH = 23.7 Hz). IR (film): 1750, 1372,
1271, 1233 cm–1. MS (ESI): m/z = 421 [M + Na]+. Anal.
Calcd for C16H25F2O7P: C, 48.24; H, 6.33. Found: C, 48.51;
H, 6.41. Compound 20c obtained as an oil, [a]D25 +3.85 (c
1.0, CHCl3). 1H NMR (400 MHz, CDCl3): d = 6.05 (1 H, d
with small splits, J = 10.0 Hz), 5.81 (1 H, ddd, J = 10.0, 3.1,
2.1 Hz), 4.63 (1 H, dd, J = 6.5, 4.3 Hz), 4.35–4.24 (4 H, m),
4.19–4.16 (1 H, m), 4.15–4.07 (2 H, m), 3.08–2.92 (1 H, m),
1.46 (3 H, m), 1.40–1.31 (9 H, m). 13C NMR (100 MHz,
CDCl3): d = 132.1, 121.0, 108.9, 78.7, 70.0, 68.0, 47.3 (t,
(dt, JCF = 19.9 Hz, JCP = 15.4 Hz), 31.04, 20.15, 16.27. 31
P
F
NMR (162 MHz, CDCl3): d = 7.09 (t, JPF = 107.9 Hz). 19
NMR (376 MHz, CDCl3): d = –51.07 (1 F, ddd, JFF = 300.8
MHz, JFP = 107.9 Hz, JFH = 16.2 Hz), –53.04 (1 F, ddd,
J
FF = 300.8 MHz, JFP = 107.9 Hz, JFH = 13.9 Hz). IR (film):
3433, 1632, 1263 cm–1. MS (ESI): m/z = 307 [M + Na]+.
HRMS (ESI) calcd for C11H19O4F2NaP: 307.0887. Found:
25
307.0876. Compound 6d obtained as a colorless oil, [a]D
–23.4 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): d = 7.72–
7.66 (4 H, m), 7.40–7.36 (6 H, m), 6.06 (1 H, dd, J = 10.3,
1.9 Hz), 5.72 (1 H, d, J = 8.8 Hz), 4.55 (1 H, s), 4.56–4.07 (4
H, m), 2.99–2.85 (1 H, m), 2.38–2.25 (1 H, m), 1.68–1.60
J
CF = 11.8 Hz), 27.6, 25.4, 16.3, 16.1. 31P NMR (162 MHz,
(m), 1.30–1.26 (6 H, m), 1.10 (3 H, s), 1.07 (3 H, s). 13
C
CDCl3): d = 6.74 (dd, JPF = 108.8, 102.9 Hz). 19F NMR (376
MHz, CDCl3): d = –47.25 (1 F, ddd, JFF = 303.4 Hz,
NMR (100 MHz, CDCl3): d = 135.8, 135.3, 132.0, 129.6,
123.0–116.0 (m), 118.0, 65.1, 64.3, 47.1 (dt, JCF = 19.1 Hz,
JCP = 19.1 Hz), 27.3, 26.9, 26.5, 20.3, 19.1, 19.0, 16.2 (d,
JFP = 102.9 Hz, JFH = 16.2 Hz), –49.91 (1 F, ddd, JFF = 304.4
Hz, JFP = 108.8 Hz, JFH = 16.2 Hz). IR (film): 3419, 1645,
1445, 1263 cm–1. MS (ESI): m/z = 379 [M + Na]+. HRMS
(ESI) calcd for C14H23O6F2NaP: 379.1098. Found:
379.1081.
J
CP = 5.4 Hz). 31P NMR (162 MHz, CDCl3): d = 7.00 (t,
JPF = 110.4 Hz). 19F NMR (376 MHz, CDCl3): d = –47.13 (1
F, ddd, JFF = 298.9 Hz, JFP = 110.4 Hz, JFH = 11.3 Hz),
–51.87 (1 F, ddd, JFF = 298.9 Hz, JFP = 110.4 Hz, JFH = 24.8
Hz). IR (film): 1657, 1271 cm–1. MS (EI): m/z = 523 [M+ +
1]. Anal. Calcd for C27H37F2O4PSi: C, 62.05; H, 7.14.
Found: C, 61.58; H, 6.99. Compound 13b obtained as an oil,
[a]D25 –51.4 (c 1.0, CHCl3). 1H NMR (500 MHz, CDCl3):
d = 8.12 (2 H, d. J = 7.3 Hz), 7.57 (1 H, dd, J = 7.3, 7.3 Hz),
7.44 (2 H, dd, J = 7.3, 7.3 Hz), 5.95 (1 H, d with small splits,
J = 10.6 Hz), 5.92 (1 H, d, J = 10.6 Hz), 5.70 (1 H, dd,
J = 8.8, 2.3 Hz), 4.72–4.71 (1 H, m), 4.64–4.62 (1 H, m),
4.28–4.15 (4 H, m), 3.64–3.55 (1 H, m), 1.37 (3 H, s), 1.33
(3 H, s), 1.29 (6 H, t, J = 7.1 Hz). 13C NMR (125 MHz,
CDCl3): d = 165.73, 133.13, 130.06, 129.15, 128.30,
124.00–116.00 (m), 121.59, 110.04, 73.52, 72.58, 67.72 (d,
J = 3.7 Hz), 64.81 (t, J = 5.6 Hz), 42.03 (dt, J = 15.3, 20.2
Hz), 27.51, 26.52, 16.24 (d, J = 5.7 Hz), 16.25 (d, J = 4.9
Hz). 31P NMR (162 MHz, CDCl3): d = 6.12 (t, JPF = 106.7
Hz). 19F NMR (376 MHz, CDCl3): d = –47.73 (2 F, dd,
JFP = 106.7 Hz, JFH = 15.8 Hz). IR (film): 1723, 1602, 1451,
1271 cm–1. MS (ESI): m/z = 483 [M + Na]+. HRMS (ESI)
calcd for C21H27O7F2NaP: 483.1360. Found: 483.1316.
Compound 19a obtained as an oil, [a]D25 –72.6 (c 1.0,
CHCl3). 1H NMR (500 MHz, CDCl3): d = 6.03 (2 H, broad
s), 5.46 (1 H, dd, J = 5.8, 4.3 Hz), 4.63 (1 H, dd, J = 6.0, 2.4
Hz), 4.45 (1 H, t, J = 6.1 Hz), 4.32–4.23 (5 H, m), 3.48–3.39
(1 H, m), 2.07 (3 H, s), 1.40 (3 H, s), 1.37 (3 H, t, J = 6.9 Hz),
1.37 (3 H, s). 13C NMR (125 MHz, CDCl3): d = 170.35,
(13) Compound 5b was chemically correlated to 5a and 5c to
determine their trans-stereochemistry in the usual manner
(Ac2O, pyridine, PivCl, pyridine).
(14) Chin, Y.; Levy, G. C. J. Am. Chem. Soc. 1984, 106, 6533.
(15) Jørgensen, M.; Iversen, E. H.; Paulsen, A. L.; Madsen, R. J.
Org. Chem. 2001, 66, 4630.
(16) The absolute stereochemistry of 8 was determined after its
transformation to (+)-14 by the Mitsunobu inversion of the
hydroxyl group with acetic acid (DEAD, Ph3P, THF). The
sign of the specific rotation was identical to that of the
authentic specimen prepared by resolution of ( )-14
according to the method of Chung, see: Kwon, Y.-U.;
Chung, S.-K. Org. Lett. 2001, 3, 3013.
(17) Although 12b and 13b were not readily separated by column
chromatography on silica gel, 13b was isolated in pure state
after osmium oxidation (cat. OsO4, NMO, quinuclidine,
CH2Cl2). In the osmium oxidation, 12b was rapidly
dihydoxylated but 13b remained unreacted to be isolated by
column chromatography. The details will be described
elsewhere.
(18) (a) Liu, Z.; Classon, B.; Samuelsson, B. J. Org. Chem. 1990,
55, 4273. (b) Pakulski, Z.; Zamojski, A. Carbohydr. Res.
1990, 205, 410. (c) Garegg, P. J. Synthesis 1979, 469.
(19) See the reference in note 16.
(20) Stereo- and regiochemistry of 20c was confirmed by 2D-
NMR including HMBC, HMQC, COSY and NOESY.
Synlett 2003, No. 10, 1407–1410 © Thieme Stuttgart · New York