Stereoselective syntheses of β-L-FD4C and β-L-FddC

Article abstract of DOI:10.1021/jo970177k

Stereocontrolled syntheses of two potent antiviral agents, β-L-FD4C and β-L-FddC, were accomplished both in 10-step sequences, with an overall yield of 27% and 25%, respectively. It is worthwhile to mention that the introduction of a phenylseleno moiety to the C-2α position of the lactone 4 can now be performed in a stereocontrolled fashion, providing the key intermediate 5α in 75% yield.

Full text of DOI:10.1021/jo970177k

J . Org. Chem. 1997, 62, 3449-3452
3449
Ster eoselective Syn th eses of â-L-F D4C a n d â-L-F d d C
Shu-Hui Chen,* Xiuyan Li,* J un Li, Chuansheng Niu, Ellen Carmichael, and
Terrence W. Doyle
Vion Pharmaceuticals, Inc., 4 Science Park, New Haven, Connecticut 06511
Received J anuary 30, 1997X
Stereocontrolled syntheses of two potent antiviral agents, â-L-FD4C and â-L-FddC, were ac-
complished both in 10-step sequences, with an overall yield of 27% and 25%, respectively. It is
worthwhile to mention that the introduction of a phenylseleno moiety to the C-2R position of the
lactone 4 can now be performed in a stereocontrolled fashion, providing the key intermediate 5R in
75% yield.
In tr od u ction
Since the approval of 3′-deoxy-3′-azidothymidine (AZT)1
as a first-line therapeutic agent for the treatment of
human immunodeficiency virus (HIV), considerable effort
has been devoted to design and synthesis of nucleoside
analogs that would inhibit the replication of this and
related viruses. Out of this effort came the discovery of
F igu r e 1. Structures of representative L-nucleosides.
a series of novel nucleoside analogs possessing potent
antiviral activity, including 2′,3′-dideoxycytidine (D-ddC),2
be promising new leads. When evaluated in vitro against
HIV, both of these agents were found to be more potent
than 3TC (1). Thus, the design of a convergent synthesis
for these highly potent antiviral agents is an important
endeavor. In this paper, we wish to report a highly
stereoselective and high-yielding synthesis for both 2 and
3.
2′,3′-dideoxyinosine (D-ddI),3 and 2′,3′-dideoxy-2′,3′-dide-
hydrothymidine (D-D4T).4
More recently, a number of L-configuration nucleo-
side analogs, the enantiomers of the natural D-
nucleosides, have emerged as potent antiviral agents
against HIV and HBV.5 The interest in L-nucleosides
was spurred in recent years by the fact that L-nucleosides
would be recognized by virus-encoded or bacterial en-
zymes but not by normal mammalian enzymes.6a For
example, Spadari et al. reported that L-thymidine is not
recognized by human thymidine kinase but functions as
a specific substrate for the herpes simplex virus type 1
(HSV-1) viral enzyme and reduces HSV-1 multiplication
in HeLa cells.6b Thus, L-nucleosides are generally en-
dowed with minimal host toxicity while maintaining good
antiviral/antibacterial activity.
Discu ssion
The first synthesis and the antiviral activity assess-
ment of â-L-FD4C (2) was reported recently by Lin and
Cheng at Yale.8 Prompted by the impressive anti-HIV
and anti-HBV activity displayed by this novel L-nucleo-
side, we launched a synthetic program with the aim of
designing a high-yielding and practical synthesis of â-L-
FD4C (2).
To date, â-L-SddC (3TC, 1) is the first and only
L-nucleoside derivative that has been approved by the
FDA for use in combination therapy against HIV and
HBV.7 In light of this encouraging finding, a large
number of 2′,3′-dideoxy (dd)- and 2′,3′-didehydro-2′,3′-
dideoxy (D4)-L-nucleoside analogs have been synthesized
and evaluated as potential antiviral agents. 2′,3′-Dideoxy-
2′,3′-didehydro-â-L-fluorocytidine (â-L-FD4C, 2)8 and 2′,3′-
dideoxy-â-L-fluorocytidine (â-L-FddC, 3)9 were found to
As depicted in Scheme 1, the logic of our approach is
based on the recent findings from Chu,11 Liotta,12 and
others.13 These authors have shown that a bulky sub-
stituent (e.g. R ) SePh, SAr) bonded to the C-2R position
of lactol 7 can exert a remarkable directing effect in the
N-glycosylation reaction at C-1, ensuring the formation
(8) Lin, T.-S.; Luo, M.-Z; Liu, M.-C.; Zhu, Y.-L.; Gullen, E.; Dutsch-
man, G. E.; Cheng, Y.-C. J . Med. Chem. 1996, 39, 1757.
(9) (a) Lin, T.-S.; Luo, M.-Z.; Liu, M.-C.; Pai, S. B.; Dutschman, G.
E.; Cheng, Y.-C. J . Med. Chem. 1994, 37, 798. (b) Schinazi, R. F.;
Gosselin, A.; Faraj, B. E.; Korba, D.; Liotta, D.; Chu, C. K.; Mathe, C.;
Imbach, J .-L.; Sommadossi, J .-D. Antimicrob. Agents Chemother. 1994,
38, 2172. (c) Van Draanen, N. A.; Tisdale, M.; Parry, N. R.; J ansen,
R.; Dornsife, R. E.; Tuttle, J . V.; Averett, D. R.; Koszalka, G. W.
Antimicrob. Agents Chemother. 1994, 38, 868.
(10) Imazawa, M.; Eckstein, F. J . Org. Chem. 1978, 43, 3044.
(11) (a) For the preparation of lactone 4, see: Taniguchi, M.; Koga,
K.; Yamada, S. Tetrahedron 1974, 30, 3547. (b) Chu, C. K.; Babu, R.;
Beach, J . W.; Ahn, S. K.; Huang, H.; J eong, L. S.; Lee, S. J . J . Org.
Chem. 1990, 55, 1418. (c) Beach, J . W.; Kim, H. O.; J eong, L. S.;
Nampalli, S.; Islam, Q.; Ahn, S. K.; Babu, J . R.; Chu, C. K. J . Org.
Chem. 1992, 57, 3887. (d) For references related to the neighboring
group participation of phenylselenyl group in glycosylation reaction,
see: Niedballa, U.; Vorbruggen, H. J . Org. Chem. 1974, 39, 3654. Also
see, Vorbruggen, H.; Krolikiewicz, K. Angew. Chem., Int. Ed. Engl.
1975, 14, 421. (e) c.f. Bolon, P. J .; Wang, P.; Chu, C. K.; Gosselin, G.;
Boudou, V.; Pierra, C.; Mathe, C.; Imbach, J .-L.; Faraj, A.; Alaoui, M.
A.; Sommadossi, J .-P.; Pai, S. Balakrishna, Zhu, Y.-L.; Lin, J .-S.;
Cheng, Y.-C.; Schinazi, R. F. Bioorg. Med. Chem. Lett. 1996, 6, 1657.
(12) Wilson, L. J .; Liotta, D. Tetrahedron Lett. 1990, 31, 1815.
X Abstract published in Advance ACS Abstracts, May 1, 1997.
(1) De Clercq, E. Adv. Drug Res. 1988, 17, 1.
(2) Mitsuya, H.; Broder, S. Proc. Natl. Acad. Sci. U.S.A. 1986, 83,
1911.
(3) Yarchoan, R.; Mitsuya, H.; Thomas, R. V.; Pluda, J . M.; Hartman,
N. R.; Perno, C.-F.; Marczyk, K. S.; Allain, J .-P.; J ohns, D. G. Broder,
S. Science (Washington, D.C.) 1989, 245, 412.
(4) Mansuri, M. M.; Starett, J . E.; Ghazzouli, I.; Hitchcock, M. J .
M.; Sterzycki, R. Z.; Brankovan, V.; Lin, T.-S.; August, E. M.; Prusoff,
W. H.; Sommadossi, J .-P.; Martin, J . C. J . Med. Chem. 1989, 32, 461.
(5) c.f. Nair, V.; J ahnke, T. S. Antimicrob. Agents Chemother. 1995,
39, 1017-1029.
(6) (a) Holy, A.; Sorm, F. Collect. Czech. Chem. Commun. 1971, 36,
3282. (b) Spadari, S.; Maga, G.; Focher, F.; Ciarrocchi, R.; Manaservigi,
F.; Arcamone, M.; Capobianco, A.; Carcuro, F.; Colonna, S.; Iotti, S.;
Garbesi, A. J . Med. Chem. 1992, 35, 4214.
(7) c.f. (a) Chang, C.-N.; Doong, S.-L.; Zhou, J . H.; Beach, J . W.;
J eong, L. S.; Chu, C. K.; Tasi, C.-H.; Cheng, Y.-C. J . Biol. Chem. 1992,
267, 13938-13942. (b) Doong, S.-L.; Tasi, C.-H.; Schinazi, R. F.; Liotta,
D. C.; Cheng, Y.-C. Proc. Natl. Acad. Sci. U.S.A. 1991, M, 8495-8499.
S0022-3263(97)00177-1 CCC: $14.00 © 1997 American Chemical Society

3450 J . Org. Chem., Vol. 62, No. 11, 1997
Sch em e 1. P r op osed Syn th etic P la n
Chen et al.
Sch em e 2
of the desired cis-nucleosides (e.g. 9). On the basis of
observations made by the above investigators, we envi-
sioned that high stereoselectivity in the N-glycosylation
step (7 to 9) may be achieved via a similar Lewis acid-
catalyzed coupling between lactol 7 and the bis-TMS-
fluorocytosine (8). Successful incorporation of 5-fluoro-
cytosine directly can shorten the synthesis of 2 and 3 by
two steps (in comparison with ref 8), thereby contributing
to the overall efficiency of the synthesis. Furthermore,
since oxidative removal of the arylsulfenyl group in
compound 9 (R ) SAr) requires elevated temperature,
we decided to use the phenylseleno moiety at C-2 as the
handle for stereoselectivity. Thus, at the end of the
sequence, oxidative removal of the phenylseleno group
in 9 should provide the â-L-FD4C (2). On the other hand,
reductive removal of the 2R-phenylseleno moiety from 9
should produce the â-L-FddC (3).
As shown in Scheme 2, we began our synthetic effort
with C-2 phenylselenation of the lactone 4,11a a known
intermediate prepared in four steps from readily avail-
able D-glutamic acid. In agreement with the report from
Chu,11b,c C-2 phenylselenation of the lactone 4 with
phenylseleno bromide provided a mixture of products (5R
and 5â) with a ratio of 2.5:1 favoring the desired
2R-phenylseleno lactone 5R. As expected, chromato-
graphic separation of 5R from its diastereomer 5â proved
to be a rather difficult undertaking. Although compound
5â can be converted partially to the desired diastereomer
5R by refluxing a THF solution of 5â with DBU, the
tedious labor required and the overall cost associated
with this process precluded its utility as a choice for scale-
up. In view of this problem, we felt that the use of bulkier
phenylseleno reagents could in principle lead to higher
level of facial selectivity in the C-2 phenylselenation
reaction. Indeed, reaction of the trimethylsilylenol ether
(generated in situ from 4) with (phenylseleno)caprolac-
tam yielded a slightly higher ratio of 5R/5â (3:1).14
Following the same logic, we then decided to use another
bulky N-(phenylseleno)phthalimide15 as our phenylsel-
enation reagent. To our satisfaction, attempted C-2
phenylselenation at -78 °C gave an excellent level of
selectivity (5R/5â > 40:1), affording the desired diaste-
reomer 5R in 70-75% yield. Thus, a stereospecific
method for the C-2R phenylselenation of lactone 4 has
been firmly established.
Having solved the problem encountered in the stereo-
selective synthesis of the C-2R phenylseleno lactone 5R,
our next goal was to explore the reaction conditions that
will allow the stereospecific N-glycosylation at C-1. As
shown in Scheme 3, C-2R phenylseleno lactone 5R was
first reduced with DIBAL-H in toluene at -78 °C to afford
the lactol 10 in 87-98% yield. Acetylation of lactol 10
yielded the corresponding C-1 acetyl-lactol 11 in nearly
quantitative yield. Coupling of the bis-TMS-5-fluorocy-
tosine 8 (prepared in situ from 5-fluorocytosine) with 11
in the presence of trimethylsilyl trifluoromethane-
sulfonate (TMSOTf) provided, to our satisfaction, the
desired 1,4-cis-nucleoside 12 in greater than 95% yield.11b-d
As also shown in Scheme 3, the syntheses of both â-L-
FD4C (2) and â-L-FddC (3) were completed in two steps
from 12. Treatment of 12 with hydrogen peroxide in the
presence of pyridine afforded up to 95% yield of the D4
nucleoside 13, thereby the final â-L-FD4C 2, upon tri-
ethylamine trihydrofluoride-mediated desilylation.16 On
(13) Young, R. J .; Shaw-Ponter, S.; Thomson, J . B.; Miller, J . A.;
Cumming, J . G.; Pugh, A. W.; Rider, P. Bioorg. Med. Chem. 1995, 5,
2599.
(14) Wilson, L. J .; Liotta, D. J . Org. Chem. 1992, 57, 1948.
(15) Crystalline N-(phenylseleno)phthalimide can be purchased from
Beta Chemicals, Inc. Fax: (203)786-5437.

Stereoselectivity Syntheses of â-L-FD4C and â-L-FddC
J . Org. Chem., Vol. 62, No. 11, 1997 3451
Sch em e 3
10.80 g (60%) of the 2′R-phenylselenide 5R along with 4.40 g
(24%) of its isomer 5â.
the other hand, reductive removal of the phenylseleno
moiety in 12 was accomplished using tributyltin hydride
as the reductant11b,c and afforded the 2′,3′-dideoxy nu-
cleoside 14 in almost quantitative yield. After final
desilylation, the desired â-L-FddC 3 was isolated in 78%
yield.
Both â-L-FD4C (2) and â-L-FddC (3) synthesized in our
laboratory as well as 3TC (1) were evaluated for their
anti-HBV activity using a slightly modified literature
procedure.17 The EC50 (extracellular) values of these
L-nucleosides were found to be 7.5 nM for 2, 74 nM for 3
and 45 nM for 1. Thus, â-L-FD4C is six-fold more potent
than 3-TC in this assay, whereas, â-L-FddC is 1.6-fold
less potent than 3-TC in the same assay. Given the
variability of this assay, the result obtained in our
laboratory is in good agreement with that reported by
Lin and Cheng.8
In summary, we have reported herein a convergent
synthetic route that allows large scale synthesis of potent
antiviral agents â-L-FD4C (2) and â-L-FddC (3) in a
stereocontrolled fashion. These two L-nucleosides were
constructed in 10 steps from commercial available D-
glutamic acid. It is important to note that simply
switching the staring material to L-glutamic acid, the
same reaction sequence described herein also allows the
synthesis of the enantiomers of 2 and 3.
A THF solution (35 mL) of 5â (4.40 g, 8.64 mmol) was
treated with DBU (3.10 mL, 20.74 mmol) at rt for 24 h. The
solvent was then partially removed in vacuo. The reaction
mixture was diluted with EtOAc (150 mL) and washed with
saturated NaHCO3 solution and brine. The organic layer was
dried, evaporated, and purified to provide 2.3 g (52%) of 5R
along with 1.3 g (30%) of recovered 5â.
Ster eoselective Con ver sion of 4 to 5R Usin g N-(P h en -
ylselen o)p h th a lim id e. Lithium bis(trimethysilyl) amide in
THF (1 M, 32.2 mL, 32.20 mmol) was added to 6 mL of THF
under N2 and cooled to -78 ˚C. Compound 12 (10.36 g, 29.30
mmol) dissolved in 20 mL of THF was added slowly to the
above solution over 45 min at -78 ˚C. After 1h, TMSCl (5.0
mL, 64.46 mmol) was added dropwise over 5 min. This
mixture was then stirred at -78 °C for 1 h, warmed to rt, and
stirred for 2 h. The reaction mixture was then cooled to -78
°C, and N-(phenylseleno)phthalimide (11.0 g, 36.40 mmol) was
added through a powder additional funnel over 1 h. Stirring
at -78 °C was continued for 3 h, followed by warming to rt
for 30 min. The reaction mixture was poured into 150 mL of
NaHCO3 solution and 300 mL of ether, and the organic layer
was then extracted twice with NaHCO3 and once with NaCl
solution. The aqueous layers were back-extracted with 100
mL of ether, and the organic layers were combined, and dried
over MgSO4, and the solvent was removed in vacuo. Purifica-
tion of the crude by column chromatography afforded 11.20 g
of 5R (yield 75%). Minor cis-isomer 5â (200 mg) (1%) was also
obtained.
1H NMR of 5R (CDCl3, 300 MHz): δ 7.75-7.32 (m, 15H),
4.40 (m, 1H), 4.16 (dd, J ) 5.4, 9.2 Hz, 1H), 3.90 (dd, J ) 2.9,
11.5 Hz, 1H), 3.66 (dd, J ) 3.1, 11.5 Hz, 1H), 2.75 (m, 1H),
2.33 (m, 1H), 1.10 (s, 9H); 13C NMR of 5R (CDCl3, 75 MHz): δ
176.1, 135.8, 135.7, 135.6, 132.9, 132.5, 130.1, 129.5, 129.1,
Exp er im en ta l Section
C-2′ P h en ylselen o La cton es (5r a n d 5â). A THF solution
(106 mL) of the lactone 4 (12.50 g, 35.27 mmol) ([R]23
)
D
-25.42° (c ) 1.06, CHCl3)) was treated at -78 °C with
LiHMDS (35.30 mL, 1 M in THF) for 15 min, and neat TMSCl
(4.48 mL, 35.27 mmol) was then added over 2 min. The
resulting reaction mixture was stirred at -78 °C for 1 h. A
THF solution (40 mL) of PhSeBr (8.34 g, 35.27 mmol) was
added slowly over 20 min. The reaction mixture was stirred
at -78 °C for 30 min and then at rt for 2 h. The reaction was
then quenched with saturated NH4Cl solution. The reaction
solvent was partially removed in vacuo. The resulting mixture
was extracted with EtOAc (3 × 100 mL). The combined
organic layer was washed with brine and dried over Na2SO4.
Upon evaporation, the resulting residue was purified by silica
gel column chromatography (10-20% EtOAc/hexanes) to afford
128.0, 127.2, 78.8, 65.0, 37.3, 32.5, 27.0, 19.3. [R]23 of 5R )
D
-15.94° (c ) 1.44, CHCl3).
1H NMR of 5â (CDCl3, 300 MHz): δ 7.70-7.26 (m, 15H),
4.54 (m, 1H), 4.07 (t, J ) 9.5 Hz, 1H), 3.76-3.63 (m, 2H), 2.68
(m, 1H), 2.27 (m, 1H), 1.10 (s, 9H); 13C NMR of 5â (CDCl3, 75
MHz): δ 175.8, 135.7, 135.5, 133.0, 132.9, 130.0, 129.4, 128.9,
127.9, 127.5, 78.8, 64.8, 37.1, 31.8, 26.9, 19.4.
La ctol 10. A toluene solution (10 mL) of the 2′R-phenylse-
lenide lactone 5R (1.63 g, 3.20 mmol) was treated at -78 °C
with DIBAL-H (2.35 mL, 1.5 M in toluene, 3.53 mmol). After
1 h, an additional amount of DIBAL-H (0.32 mL, 1.5 M in
toluene, 0.48 mmol) was added. After 30 min, the reaction
was quenched at -78 °C with a saturated solution of sodium
potassium tartrate (40 mL). The reaction mixture was warmed
to rt and extracted with EtOAc (2 × 50 mL). The combined
organic layer was further washed with saturated sodium
potassium tartrate solution until a clear solution was obtained.
The organic layer thus obtained was dried and evaporated in
(16) Pirrung, M. C.; Shuey, S. W.; Lever, D. C.; Fallon, L. Bioorg.
Med. Chem. Lett. 1994, 4, 1345.
(17) Korba, B. E.; Milman, G. A cell culture assay for compounds
which inhibit hepatitis B virus replication. Antiviral Res. 1991, 15,
217-228.

3452 J . Org. Chem., Vol. 62, No. 11, 1997
Chen et al.
vacuo. The residue was chromatographed on silica gel (10-
20% EtOAc/hexanes) to provide 1.60 g (98%) of 10.
3.1, 11.6 Hz, 1H), 3.77 (dd, J ) 3.4, 11.7 Hz, 1H), 1.05 (s, 9H);
13C NMR (CDCl3, 75 MHz): δ 158.6, 158.4, 154.4, 138.4, 135.7,
135.2, 133.1, 132.9, 132.7, 130.1, 130.0, 127.9, 127.7, 125.4,
125.0, 91.2, 87.2, 65.3, 27.0, 19.3. HRMS (FAB) calcd for
1H NMR (CDCl3, 300 MHz): δ 7.80-7.26 (m, 15H), 5.64-
5.44 (m, 1H), 4.45 (m, 1H), 4.10-3.52 (m, 4H), 2.79-2.00 (m,
2H), 1.13-1.06 (m, 9H).
C25H29FN3O3Si (MH+): 466.1962, found: 466.1963. [R]23 of
D
La ctol Aceta te 11. To a dichloromethane solution (18 mL)
of the lactol 10 (4.50 g, 8.80 mmol) were added triethylamine
(1.59 mL, 11.44 mmol) and acetic anhydride (1.08 mL, 11.44
mmol) at 0 °C. A catalytic amount of DMAP was also added.
The reaction was stirred at 0 °C for 1 h and then at rt for 12
h. The reaction was quenched with saturated NaHCO3
solution (20 mL), and the resulting reaction mixture was
extracted with CH2Cl2 (2 × 100 mL). The combined organic
layer was washed with brine, dried, and concentrated in vacuo.
The residue was purified through a short silica gel column
(15% ethyl acetate/hexanes) to provide 4.75 g (98%) of 11 as a
thick oil.
13 ) -24.51° (c ) 3.90, CHCl3).
â-l-F D4C (2). To a 0 °C cooled THF solution (14 mL) of
silyl ether 13 (321 mg, 0.690 mmol) was added triethylamine
trihydrofluoride (0.449 mL, 2.72 mmol). After stirring at rt
for 5 h, a second dose of reagent was added at 0 °C. The
reaction mixture was stirred at rt for 15 h. The solvent was
then removed in vacuo. The residue was chromatographed
(5-10-20% EtOH/CH2Cl2) to afford 146 mg (94%) of 2.
1H NMR (DMSO-d6, 300 MHz): δ 8.01 (d, J ) 7.2 Hz, 1H),
7.77 (bs, 1H), 7.52 (bs, 1H), 6.81 (d, J ) 1.1 Hz, 1H), 6.30 (dd,
J ) 1.2, 5.9 Hz, 1H), 5.86 (dd, J ) 1.3, 5.9 Hz, 1H), 5.07 (bs,
1H), 4.76 (s, 1H), 3.31-3.60 (m, 2H). The 1H NMR of â-L-
FD4C (2) obtained in our lab matches the spectrum reported
by Lin et al. (ref 8). HRMS (FAB) calcd for C9H11FN3O3
1H NMR (300 MHz, CDCl3): δ 7.74-7.20 (m, 15H), 6.44-
6.22 (m, 1H), 4.44-3.52 (m, 4H), 2.58-2.08 (m, 2H), 1.86 and
1.55 (s, 1H), 1.02 and 0.92 (s, 9H). LRFAB mass calcd for
C29H35O4SiSe (MH+): 554, found: 554.
(MH+): 228.0784, found: 228.0784. [R]23 of 2 ) -29.00° (c
D
) 0.7-1.0, MeOH).
Com p ou n d 12. A mixture of 5-F-cytosine (1.11 g, 8.58
mmol) and ammonium sulfate (40 mg) in (TMS)2NH (10 mL)
was heated to reflux for 2 h. A clear solution resulted. The
reaction mixture was cooled to rt, and the solvent was removed
in vacuo. The resulting white solids (bis-TMS-5-FC, 8) were
dried under high vacuum for 30 min.
Com p ou n d 14. To a degassed benzene solution (5 mL) of
12 (323 mg, 0.519 mmol) and a catalytic amount of AIBN was
added tributyltin hydride (0.279 mL, 1.038 mmol). The
reaction mixture was heated to reflux for 1.5 h. The reaction
mixture was cooled to rt, and the solvent was removed in
vacuo. The residue was purified by silica gel chromatography
To 8 thus prepared was added a dichloroethane solution (30
mL) of 11 (4.75 g, 8.58 mmol). To the above solution was then
added at 0 °C a dichloroethane solution (10 mL) of TMSOTf
(1.99 mL, 10.30 mmol). The reaction mixture was stirred at
0 °C for 30 min and then at rt for 90 min. The reaction was
then quenched with saturated NH4Cl solution (30 mL) and
extracted with dichloromethane (250 mL). The organic layer
was washed with brine, dried, and concentrated in vacuo. The
resulting residue was chromatographed on silica gel (60-80%
EtOAc/hexanes and then 10% EtOH/CH2Cl2) to afford 5.40 g
(100%) of the desired product 12 as white foam.
Cl2) to afford 240 mg (100%) of 14.
(5-10% EtOH/CH2
1H NMR (CDCl3, 300 MHz): δ 8.17 (d, J ) 4.2 Hz, 1H), 7.71-
7.28 (m, 10H), 6.40 (bs, 1H), 5.98 (d, J ) 6.0 Hz, 1H), 4.16-
4.09 (m, 2H), 3.75-3.70 (m, 1H), 2.60-1.78 (m, 4H). CI mass
calcd for C25H31FN3O3Si (MH+): 468, found: 468. [R]23D of 14
) -50.00° (c ) 2.10, CHCl3).
â-L-F d d C (3). To a THF solution (10 mL) of 14 (240 mg,
0.52 mmol) was added triethylamine trihydrofluoride (0.339
mL, 2.08 mmol) at 0 °C. The reaction mixture was stirred at
rt for 3 h. At this point, an additional 6 equiv of the same
desilylating agent was added, and the reaction mixture was
stirred overnight at rt. The solvent was then removed in
vacuo, and the resulting residue was chromatographed (10-
20% EtOH/CH2Cl2) to provide 95 mg (78%) of the desired â-L-
FddC (3) as white foam.
1H NMR (300 MHz, CDCl3): δ 8.00 (d, J ) 5.5 Hz, 1H),
7.66-7.25 (m, 15H), 6.13 (dd, J ) 1.4, 4.9 Hz, 1H), 4.32 (m,
1H), 4.11 (d, J ) 11.2 Hz, 1H), 3.85 (dd, J ) 6.5, 11.6 Hz, 1H),
3.69 (dd, J ) 2.3, 11.8 Hz, 1H), 2.47 (m, 1H), 2.06 (m, 1H),
1.11 (s, 9H); 13C NMR (CDCl3, 75 MHz): δ 156.2, 156.0, 151.9,
137.8, 135.8, 135.7, 135.5, 134.6, 132.6, 132.3, 130.2, 130.0,
129.4, 128.6, 128.1, 127.9, 126.9, 126.1, 125.7, 91.3, 80.5, 65.1,
44.9, 32.3, 27.1, 19.3. HRMS (FAB) calcd for C31H35FN3O3-
1H NMR (DMSO-d6, 300 MHz): δ 8.26 (d, J ) 7.4 Hz, 1H),
7.65 (bs, 1H), 7.43 (bs, 1H), 5.83 (m, 1H), 5.15 (bs, 1H), 4.01
(m, 1H), 3.72 (d, J ) 11.7 Hz, 1H), 3.52 (d, J ) 11.9 Hz, 1H),
2.27-2.20 (m, 1H), 1.91-1.75 (m, 3H). The 1H NMR of â-L-
FddC (3) obtained in our lab matches the spectrum reported
by Lin et al. (ref 9a). HRMS (FAB) calcd for C9H13FN3O3
SiSe (MH+): 624.1597, found: 624.1601. [R]23 of 12 )
D
-63.68° (c ) 0.92, CHCl3).
(MH+): 230.0941, found: 230.0943. [R]23 of 3 ) -84.70° (c
) 1.74, MeOH).
Com p ou n d 13. To a THF solution of phenylselenide 12
(437 mg, 0.702 mmol) was added at 0 °C 30% wt hydrogen
peroxide aqueous solution (0.22 mL, 7.02 mmol). The reaction
was stirred at 0 °C for 1 h and then pyridine (0.57 mL, 7.02
mmol) was added at 0 °C. The reaction was stirred at rt for
3 h. The reaction mixture was diluted with EtOAc (50 mL)
and Et2O (10 mL) and then washed with saturated NaHCO3
solution and brine. The organic layer was dried over Na2SO4
and then evaporated in vacuo to afford a residue, which was
purified by silica gel chromatography (5-10% EtOH/CH2Cl2)
to provide 280 mg (86%) of 13.
D
Ack n ow led gm en t. The authors thank Professor Y.-
C. Cheng for helpful discussions.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
compounds 2, 3, 4, 5R, 5â, 10, 11, 12, and 13 (9 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
can be ordered from ACS; see any current masthead page for
ordering information.
1H NMR (CDCl3, 300 MHz): δ 8.95 (bs, 1H), 7.74-7.34 (m,
10H), 6.98 (d, J ) 1.5 Hz, 1H), 6.10 (d, J ) 5.9 Hz, 1H), 5.92
(d, J ) 5.7 Hz, 1H), 5.83 (bs, 1H), 4.85 (s, 1H), 3.95 (dd, J )
J O970177K