De novo syntheses of racemic deoxy-C-nucleosides

Full text of DOI:10.1021/jo9818834

J . Org. Chem. 1999, 64, 1415-1419
1415
and couple the aryl group to this ring.3 We used the
sequence to produce 3a (Ar ) Ph), which we employed
in model studies to determine the optimal route for
conversion of 2 to 4 (Scheme 2). Compound 3a exists as
rapidly equilibrating, ∼1:1 mixture of cis and trans
isomers. Thus, reduction of the ketone moiety of 3a
determines the stereochemistry at both C3′ and C4′. Our
attempts at controlling the stereoselectivity of such a
reduction met with limited success.4 Under no conditions
did we observe selectivity for any particular isomer, and
furthermore, no conditions afforded detectable amounts
of the desired diastereomer, 5.
De Novo Syn th eses of Ra cem ic
Deoxy-C-n u cleosid es
Michael A. Calter* and Cheng Zhu
Department of Chemistry, Virginia Polytechnic Institute and
State University, Blacksburg, Virginia 24061-0212
Received September 16, 1998
In tr od u ction
C-Nucleosides have demonstrated potential as anti-
cancer and anti-HIV agents.1 These compounds mimic
the action of regular nucleosides; however, the replace-
ment of a C-N with a C-C linkage in C-nucleosides
provides these compounds with impressive oral bioavail-
ablities and therapeutic lifetimes. Despite the activity
focused on the synthesis and testing of C-nucleosides,
relatively little work has been done on their deoxy
analogues, deoxy-C-nucleosides. Several groups have
synthesized deoxy-C-nucleosides by C-C bond formation
between an existing deoxyribose moiety and an appropri-
ate aryl nucleophile.2 However, these syntheses suffer
from low stereoselectivity and lack of tolerance for
functionality in the aryl nucleophile. To correct these
deficiencies, we have developed a short, diastereoselective
synthesis of deoxy-C-nucleosides from nonribosyl precur-
sors (Scheme 1). This synthesis is also tolerant of a
variety of hydrogen-bond-donating and -accepting func-
tional groups in the aryl substituent.
Sch em e 2
Sch em e 1
The results from the direct reduction of 3a indicated
that we might want to separate the steps in which we
formed the C3′ and C4′ stereocenters. Our strategy to
accomplish this separation involved tert-butyldimethyl-
silyl (TBS) enol ether formation, ester reduction, stereo-
selective enol ether protonation, and stereoselective
ketone reduction (Scheme 3). The silyl enol ether inter-
mediates in this reaction sequence were both prone to
hydrolysis, so we did not attempt to purify them. The
enol ether and ester reduction steps were trivial; how-
ever, achieving decent levels of stereoselectivity in the
protonation of the silyl enol ether required much experi-
mentation. We found Et3N‚HF to be the optimal reagent
for this conversion (vide infra). Directed reduction of the
resulting hydroxy ketone to give 4a proceeded with
essentially complete stereocontrol.2a,5 The NMR spectral
data for racemic 4a produced in this fashion exactly
Resu lts a n d Discu ssion
The current synthesis uses our recently developed
diazoketone aldol/O-H insertion reaction sequence to
both construct the tetrahydrofuran ring of the product
(1) (a) Hacksell, U.; Daves, G. D. The Chemistry and Biochemistry
of C-Nucleosides and C-Arylglycosides. In Progress in Medicinal
Chemistry; Ellis, G. P., West, G. B., Eds.; Elservier Science Publish-
ers: London, 1985; Vol. 22, pp 1-65. (b) Watanabe, K. A. The
Chemistry of C-Nucleosides. In Chemistry of Nucleosides and Nucleo-
tides; Townsend, L. B., Ed.; Plenum Press: New York, 1994; Vol. 3,
pp 421-535.
(2) (a) Chen, J . J .; Walker, J . A., III; Liu, W.; Wise, D. S.; Townsend,
L. B. Tetrahedron Lett. 1995, 36, 8363-8366. (b) Ren, R. X.-F.;
Chaudhuri, N. C.; Paris, P. L.; Rumney, S.; Kool, E. T. J . Am. Chem.
Soc. 1996, 118, 7671-7678.
(3) Calter, M. A.; Sugathapala, P. M.; Zhu, C. Tetrahedron Lett.
1997, 38, 3837-3840.
(4) We determined the stereochemistries of 6 and 7 by reduction to
the corresponding diols followed by single-crystal X-ray diffraction. We
will report the X-ray structures in a separate publication. We deter-
mined the stereochemistry of 5 by reduction to the diol and comparison
to the known compound (ref for 5).
(5) (a) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J . Am. Chem.
Soc. 1988, 110, 3560-3578. (b) Farr, R. N.; Daves, G. D., J r. J .
Carbohydr. Chem. 1990, 9, 653-660.
10.1021/jo9818834 CCC: $18.00 © 1999 American Chemical Society
Published on Web 02/04/1999

1416 J . Org. Chem., Vol. 64, No. 4, 1999
Notes
Sch em e 3
also slowed the insertion reactions of these compounds
relative to that of 2a , but did not lower the yields of 3b-
d .10
Sch em e 4
matched those reported for nonracemic 4a ,6 confirming
our stereochemical assignments.
As expected, the ratio of diastereomers produced in the
protonation was highly dependent on the steric bulk of
the proton source (eq 1, Table 1).7 Trialkylammonium
fluoride salts gave the highest yields and diastereoselec-
tivities. Trialkylammonium chloride salts in the absence
of a fluoride source did not protonate the silyl enol ether,
implying that the fluoride is necessary to activate the
silyl enol ether prior to protonation.8
The conversion of 3b-d to 9b-d using the silylation-
reduction-protonation sequence proceeded in a straight-
forward fashion in moderate overall yields. The dia-
stereoselectivities for the protonations to yield 9c and 9d
were equivalent to those observed in the formation of 9a ;
however, the diastereoselectivity of the protonation to
yield 9b was only 5.5:1. Fortunately, we were able to
separate 9b and 9c from their cis isomers by chroma-
tography. We were not able to separate 9d from its
diastereomer at this stage. Directed reduction of 9b-d
again proceeded in high yields and diastereoselectivities
to afford 4b-d . At this point, we were able to separate
4d from its 1′-4′ trans diastereomer. Compounds 4b and
4c are known,11,12 but we could find no reports on their
biological activity. Therefore, we are having 4b-d tested
by the NCI and NIAID for anticancer and antiviral
activity.
We also explored the synthesis of deoxy-C-nucleosides
with hydrogen-bond-donating ability (Scheme 5). Initial
attempts at carrying out the reaction scheme with
unprotected anilines led to poor conversions and compli-
cated product mixtures, so we opted to use a protected
amino group as our hydrogen-bond-donating moiety. As
the benzoyl-protected amino group did not contain a basic
nitrogen to interfere with the titanium aldol reaction, we
used these conditions to form 2e,f. The insertion reactions
of 2e,f proceeded at the same rate as for 2a , indicating
that the protected amino group was not coordinating to
the Rh(II) catalyst. The conversions of 3e,f to 9e,f were
very diastereoselective, giving selectivities greater than
19:1.13 This selectivity is understandable in the case of
9e, which contains a sterically demanding, ortho-
substituted aryl ring. However, we have no explanation
Ta ble 1. Dia ster eoselectivities for th e P r od u ction of 9a
a n d 10a
condns
9a :10a
Na2CO3, MeOH
TBAF
HF‚pyridine
TBAF, Et3N‚HCl
Et3N‚HF
2.0:1
2.5:1
5.0:1
6.6:1
8.0:1
With a facile synthesis of 4a in hand, we next turned
to synthesizing deoxy-C-nucleosides with aromatic moi-
eties functionalized to donate or accept hydrogen bonds.
We first chose to synthesize substituted pyridines (Scheme
4). The presence of the basic pyridine nitrogen in the
aldehydes necessary to construct 2b-d interfered with
the titanium aldol reactions required to form these
intermediates. Therefore, we developed an alternative
procedure for these aldol reactions, employing instead
Mukaiyama’s conditions.9 The pyridine nitrogens of 2b-d
(6) Millican, T. A.; Mock, G. A.; Chauncey, M. A.; Patel, T. P.; Eaton,
M. A. W.; Gunning, J .; Cutbush, D.; Neidle, S.; Mann, J . Nucleic Acids
Res. 1984, 12, 7435-7453.
(7) We determined the ratio of 9a :10a by integration of the signal
for the C1′-H in the 1H NMR spectra of the unpurified reaction
mixtures. The stereochemical assignment of 9a was confirmed by
conversion to 4a .
(8) For another example of a diastereoselective silyl enol ether
protonation, see: Takano, S.; Kudo, J .; Takahashi, M.; Ogasawara, K.
Tetrahedron Lett. 1986, 37, 2405-2408.
(9) Mukaiyama, T.; Banno, K.; Narasaka, K. J . Am. Chem. Soc.
1974, 96, 6. 7503-7509.
(10) Moyer, M. P.; Feldman, P. L.; Rapoport, H. J . Org. Chem. 1985,
50, 5223-5230.
(11) Yokoyama, M.; Akiba, T.; Togo, H. Synthesis 1995, 6, 638-640.
(12) Eaton, M. A. W.; Millican, T. A.; Mann, J . J . Chem. Soc., Perkin
Trans. 1 1988, 545-548.
(13) We determined the ratio of 9e and 9f to their respective trans
isomers by integration of the signal for the C1′-H in the 1H NMR spectra
of the unpurified reaction mixtures.

Notes
J . Org. Chem., Vol. 64, No. 4, 1999 1417
was purchased from United Chemical Technologies, Inc., and
distilled at reduced pressure prior to use. Rh2(OAc)4 was
purchased from Engelhard Corp. Titanium tetrachloride was
purchased from Aldrich and distilled prior to use. All 2-diazo-
3-oxobutanoate esters were prepared by the general procedure
of Regitz et al.14 Benzene, Et3N, and CH2Cl2 were distilled over
CaH2. Flash chromatography was performed using E. Merck
silica gel 60 (230-400 mesh). N-(2-Formyl)phenylbenzamide and
N-(4-formyl)phenylbenzamide were prepared by reaction of the
corresponding aminobenzaldehyde with benzoyl chloride.
Sch em e 5
Gen er a l P r oced u r e for th e F or m a tion of 2 by Tita n iu m
Ald ol Rea ction . To a solution of 0.856 g (5.48 mmol) 1 in 30
mL of CH2Cl2 at -78 °C was added dropwise 0.65 mL (1.1 g, 5.9
mmol) of TiCl4 followed by 0.83 mL (0.60 g, 5.9 mmol) of Et3N.
The resulting red solution was stirred at -78 °C for 1 h, after
which time it was cannulated to a -78 °C solution of 1.03 g (4.57
mmol) of N-(2-formyl)phenylbenzamide in 20 mL of CH2Cl2. The
reaction mixture was stirred at -78 °C for 2 h and then the
reaction quenched with 40 mL of saturated aqueous NH4Cl and
warmed to room temperature. The organic layer was separated
and then washed with saturated aqueous NaHCO3 (1 × 40 mL).
The aqueous layers were extracted with 20 mL of CH2Cl2. The
combined organic layers were dried over Na2SO4 and concen-
trated in vacuo. The product was purified by flash chromatog-
raphy (20% and 30% EtOAc in hexane) to yield 1.24 g (71%) of
2e as pale yellow needles: mp 120-122 °C; 1H NMR (CDCl3,
360 MHz) δ 10.19 (br s, 1H), 8.37 (d, 1H, J ) 8.1 Hz), 7.94-7.97
(m, 2H), 7.54-7.46 (m, 3H), 7.36 (td, 1H, J ) 7.8, 1.6 Hz), 7.19
(dd, 1H, J ) 7.7, 1.6 Hz), 7.10 (td, 1H, J ) 7.5, 1.2 Hz), 5.35-
5.40 (m, 1H), 4.23 (q, 2H, J ) 7.1 Hz), 4.14 (d, J ) 2.8 Hz), 3.45
(dd, 1H, J ) 18.2, 4.2 Hz), 3.38 (dd, 1H, J ) 18.2, 8.9 Hz), 1.26
(t, 3H, J ) 7.1 Hz); 13C NMR (CDCl3, 90 MHz) δ 192.9, 165.4,
160.9, 137.4, 135.1, 131.8, 130.5, 129.0, 128.9, 127.4, 124.4, 122.9,
why the para-substituted aryl group of 9f affords higher
diastereoselectivity than the unsubstituted phenyl ring
of 9a , for example. In any case, reduction of 9e,f yielded
deoxy-C-nucleosides 4e,f. These compounds have not
been synthesized previously, so we have submitted them
to NIAID for testing for antiviral activity.
Finally, we sought to further increase the efficiency
and practicality of our deoxy-C-nucleoside synthesis.
Instead of forming and later hydrolyzing a covalent metal
enolate such as a silyl enol ether, we reasoned that it
might be possible to form, reduce, and hydrolyze a more
ionic metal enolate, all without intermediate isolation (eq
2). This sequence of reactions would allow a one-pot
71.1, 62.0, 46.2, 14.4; IR (CDCl3) 3341, 2142, 1716, 1660 cm-1
.
Anal. Calcd for C20H19N3O5: C, 62.99; H, 5.02; N, 11.02. Found:
C, 62.86; H, 5.08; N, 10.89.
2a : yield ) 80%; yellow oil; 1H NMR (CDCl3, 360 MHz) δ
7.38-7.22 (m, 5H), 5.20-5.15 (m, 1H), 4.26 (q, 2H, J ) 7.1 Hz),
3.42 (d, 1H, J ) 3.9 Hz), 3.33-3.20 (m, 2H), 1.29 (t, 3H, J ) 7.1
Hz);13C NMR (CDCl3, 90 MHz) δ 192.2, 161.1, 142.7, 128.4,
127.5, 125.7, 70.2, 61.6, 48.5, 14.2; IR (neat) 3505, 2138, 1716,
1649 cm-1. Anal. Calcd for C13H14N2O4: C, 59.52; H, 5.38; N,
10.69. Found: C, 59.52; H, 5.43; N, 10.66.
2f: yield ) 70%; yellow needles; mp 125-127 °C; 1H NMR
(CDCl3, 360 MHz) δ 7.88-7.85 (m, 2H), 7.80 (br s, 1H), 7.63-
7.39 (m, 7H), 5.20 (td, 1H, J ) 6.2, 3.9 Hz), 4.29 (q, 2H, J ) 7.1
Hz), 3.38 (d, 1H, J ) 3.9 Hz), 3.28 (d, 2H, J ) 6.2 Hz), 1.31 (t,
3H, J ) 7.1 Hz); 13C NMR (CDCl3, 90 MHz) δ 192.4, 166.0, 161.3,
139.2, 137.5, 135.1, 132.0, 128.9, 127.3, 126.7, 120.6, 70.1, 61.9,
48.6, 14.5; IR (CDCl3) 3433, 2141, 1713, 1664 cm-1. HRMS(FAB)
calcd for C20H19N3O5Na (MNa+) 404.1212, found 404.1208.
Gen er a l P r oced u r e for th e F or m a tion of 2 by Mu -
k a iya m a Ald ol Rea ction . To a solution of 0.408 g (2.61 mmol)
of 1 and 0.41 mL (0.30 g, 2.9 mmol) of Et3N in 10 mL of CH2Cl2
at 0 °C was added 0.55 mL (0.63 g, 2.8 mmol) of TMSOTf
dropwise. The resulting yellow solution was stirred at 0 °C for
1 h. In a separate flask, 0.55 mL (0.62 g, 4.4 mmol) of BF3‚OEt2
was added dropwise to a solution of 0.207 mL (0.233 g, 2.18
mmol) of 2-pyridinecarboxaldehyde in 10 mL of CH2Cl2 at -78
°C. To this heterogeneous mixture was cannulated the above
silyl enol ether solution over 5 min. The combined reaction
mixture was stirred at -78 °C for 1 h and then the reaction
quenched by the addition of 5 mL of concentrated pH 7 buffer
solution and warmed to room temperature. The mixture was
stirred vigorously at room temperature overnight and then
diluted with 15 mL of water. The organic phase was separated,
and the aqueous phase was extracted with CH2Cl2 (3 × 15 mL).
The combined organic layers were dried over Na2SO4 and
concentrated. The product was purified by flash chromatography
(25% and 33% EtOAc in hexane) to yield 0.320 g (56%) of 2b as
yellow crystals: mp 74-76 °C; 1H NMR (CDCl3, 360 MHz) δ
8.51 (d, 1H, J ) 4.9 Hz), 7.67 (td, 1H, J ) 7.7, 1.7 Hz), 7.43 (d,
1H, J ) 7.9 Hz), 7.18-7.15 (m, 1H), 5.24 (dd, 1H, J ) 8.7, 3.4
conversion of 3 to 4 and would also avoid the use of the
somewhat expensive TBSCl. Preliminary experiments
with 3a ,b,e indicate that such a one-pot transformation
involving a sodium enolate is possible. The diastereo-
selectivities of these reactions are higher than those for
the silyl enol ether route, although the overall yields are
not yet as high.
In summary, we have developed a short, diastereo-
selective, and flexible synthesis of racemic deoxy-C-
nucleosides that incorporate hydrogen-bonding function-
ality in their aryl moieties. These compounds are being
tested for their biological activity. Further efforts will
focus on incorporating more highly functionalized aryl
groups into these compounds and on developing an
asymmetric variant of this reaction sequence.
Exp er im en ta l Section
Gen er a l Meth od s. Unless otherwise mentioned, all reagents
were purchased from Aldrich Chemical Co. and used without
purification. Trimethylsilyltrifluoromethanesulfonate (TMSOTf)
(14) Regitz, M.; Hocker, J .; Liedhegener, A. Organic Syntheses; J ohn
Wiley: New York, 1973; Collect. Vol. V, pp 179-183.

1418 J . Org. Chem., Vol. 64, No. 4, 1999
Notes
Hz), 4.26 (q, 2H, J ) 7.1 Hz), 3.39 (dd, 1H, J ) 16.7, 3.5 Hz),
3.27 (dd, 1H, J ) 16.7, 8.8 Hz), 1.28 (t, 3H, J ) 7.1 Hz); 13C
NMR (CDCl3, 90 MHz) δ 191.7, 161.4, 161.2, 148.7, 137.0, 122.6,
120.5, 70.2, 61.7, 48.3, 14.5; IR (CDCl3) 3492, 2140, 1715, 1650
cm-1. Anal. Calcd for C12H13N3O4: C, 54.75; H, 4.98; N, 15.96.
Found: C, 54.69; H, 5.05; N, 15.87.
To a solution of 0.654 g (1.87 mmol) of the silyl enol ether
ester in 19 mL CH2Cl2 at -78 °C was added 1.0 mL (0.80 g, 5.6
mmol, an additional 1 equiv was used for 3e and 3f) of DIBAL
dropwise. After being maintained at -78 °C for 2 h, the reaction
mixture was warmed to 0 °C for 15 min and then the reaction
quenched by the addition of 0.8 mL of MeOH dropwise. After
this addition, 15 mL of a 20% aqueous solution of potassium
tartrate was added in one portion, and the reaction mixture was
vigorously stirred at room temperature for 3 h. After filtration
through Celite, the organic layer was separated. The Celite and
the aqueous layer were washed with CH2Cl2 (3 × 10 mL). The
combined organic layer was dried over Na2SO4 and concentrated
to yield 0.539 g (94%) of the silyl enol ether alcohol as yellow
oil.
2c: yield ) 73%; yellow oil; 1H NMR (CDCl3, 360 MHz) δ 8.61
(d, 1H, J ) 2.2 Hz), 8.52 (dd, 1H, J ) 4.8, 1.6 Hz), 7.76-7.73
(m, 1H), 7.28 (ddd, 1H, J ) 7.9, 4.8, 0.6 Hz), 5.25 (dd, 1H, J )
8.4, 3.8 Hz), 4.28 (q, 2H, J ) 7.1 Hz), 3.66 (br s, 1H), 3.32 (dd,
1H, J ) 17.5, 3.9 Hz), 3.25 (dd, 1H, J ) 17.5, 8.4 Hz), 1.31 (t,
3H, J ) 7.1 Hz); 13C NMR (CDCl3, 90 MHz) δ 192.0, 161.2, 149.1,
147.8, 138.5, 133.9, 123.7, 68.3, 61.9, 48.5, 14.5; IR (neat) 3194,
2139, 1716, 1652 cm-1. Anal. Calcd for C12H13N3O4: C, 54.75;
H, 4.98; N, 15.96. Found: C, 54.63; H, 5.02; N, 15.81.
2d : yield ) 77%; yellow oil; 1H NMR (CDCl3, 360 MHz) δ 8.53
(dd, 2H, J ) 4.5, 1.6 Hz), 7.31 (ddd, 2H, J ) 4.5, 1.6, 0.6 Hz),
5.18 (dd, 1H, J ) 8.8, 3.4 Hz), 4.27 (q, 2H, J ) 7.1 Hz), 3.98 (br
s, 1H), 3.29 (dd, 1H, J ) 17.3, 3.4 Hz), 3.21 (dd, 1H, J ) 17.3,
8.8 Hz), 1.30 (t, 3H, J ) 7.1 Hz); 13C NMR (CDCl3, 90 MHz) δ
191.9, 161.2, 152.1, 150.0, 120.9, 69.0, 62.0, 48.1, 14.5; IR (neat)
3170, 2141, 1708, 1654 cm-1. Anal. Calcd for C12H13N3O4: C,
54.75; H, 4.98; N, 15.96. Found: C, 54.65; H, 5.00; N, 15.88.
Gen er a l P r oced u r e for th e F or m a tion of 3 by a n In ser -
tion Rea ction . To a suspension of 0.0042 g (0.0095 mmol) of
Rh2(OAc)4 in 20 mL of refluxing benzene was added 0.248 g
(0.945 mmol) of 2a in 5 mL of benzene over 15 min. After an
additional 15 min at reflux, the mixture was cooled to room
temperature and filtered through Celite, which was then rinsed
with CH2Cl2 (3 × 10 mL). Concentration yielded 0.217 g (98%)
of 3a as yellow oil. Data for the major diastereomer: 1H NMR
(CDCl3, 360 MHz) δ 7.53-7.35 (m, 5H), 5.68 (dd, 0.4H, J ) 9.6,
6.5 Hz), 5.28 (dd, 0.6H, J ) 10.7, 6.0 Hz), 4.76 (s, 0.4H), 4.58 (s,
0.6H), 4.33-4.25 (m, 2H), 2.99-2.90 (m, 1H), 2.69-2.58 (m, 1H),
1.33 (t, 3H, J ) 7.1 Hz).
To a solution of 0.533 g (1.73 mmol) of the silyl enol ether
alcohol in 8 mL of THF at 0 °C was added 0.73 mL (0.53 g, 5.2
mmol) of Et3N followed by 0.28 mL (0.28 g, 1.7 mmol) of Et3N‚
3HF. The reaction mixture was stirred at 0 °C for 3 h, at which
time it was diluted with 50 mL of CH2Cl2 and then washed with
10 mL of saturated aqueous NaHCO3 (1 × 10 mL). The organic
layer was separated, and the aqueous layer was extracted with
CH2Cl2 (4 × 10 mL). The combined organic layers were dried
over Na2SO4 and concentrated. The product was purified by
column chromatography (2%, 3%, and 4% MeOH in CH2Cl2) to
afford 0.183 g of 9b as one diastereomer (55%, 51% overall from
2b) as a pale yellow oil: 1H NMR (CDCl3, 360 MHz) δ 8.60 (ddd,
1H, J ) 4.8, 1.7, 0.9 Hz), 7.72 (td, 1H, J ) 7.7, 1.8 Hz), 7.33 (dt,
1H, J ) 7.7, 0.8 Hz), 7.29-7.25 (m, 1H), 5.54 (br s, 1H), 5.41 (t,
1H, J ) 8.4 Hz), 4.15 (t, 1H, J ) 2.4 Hz), 3.97 (dd, 1H, J ) 12.1,
2.6 Hz), 3.90 (dd, 1H, J ) 12.1, 2.1 Hz), 2.96 (ddd, 1H, J ) 18.7,
7.8, 0.7 Hz), 2.73 (dd, 1H, J ) 18.7, 8.5 Hz); 13C NMR (CDCl3,
90 MHz) δ 213.9, 160.3, 150.1, 137.6, 123.9, 122.1, 82.5, 77.4,
63.4, 43.8; IR (neat) 3222, 1759 cm-1. Anal. Calcd for C10H11
-
NO3: C, 62.17; H, 5.74; N, 7.25. Found: C, 62.09; H, 5.79; N,
7.32.
3b: reaction time 1.5 h; yield 100%; yellow oil. Data for the
major diastereomer: 1H NMR (CDCl3, 360 MHz) δ 8.59-8.58
(m, 1H), 7.73 (td, 1H, J ) 7.7, 1.8 Hz), 7.50 (d, 1H, J ) 7.8 Hz),
7.27-7.24 (m, 1H), 5.73(t, 1H, J ) 7.3 Hz), 4.76 (s, 1H), 4.35-
4.17 (m, 2H), 3.01 (dd, 1H, J ) 18.2, 7.3 Hz), 2.96 (dd, 1H, J )
18.2, 7.3 Hz), 1.32 (t, 3H, J ) 7.1 Hz).
3c: reaction time 24 h; yield ) 96%; orange solid. Data for
the major diastereomer: 1H NMR (CDCl3, 360 MHz) δ 8.68 (br
s, 1H), 8.62 (br s, 1H), 7.79 (d, 1H, J ) 7.4 Hz), 7.38-7.36 (m,
1H), 5.73 (dd, 1H, J ) 9.9, 6.5 Hz), 4.78 (s, 1H), 4.34-4.25 (m,
2H), 3.01 (dd, 1H, J ) 18.0, 6.4 Hz), 2.59 (dd, 1H, J ) 18.0, 9.9
Hz), 1.34 (t, 3H, J ) 7.2 Hz).
3d : reaction time 24 h; yield ) 97%; yellow oil. Data for the
major diastereomer: 1H NMR (CDCl3, 360 MHz) δ 8.65 (br s,
1H), 7.47 (d, 0.4H, J ) 5.5 Hz), 7.33 (d, 0.6H, J ) 5.4 Hz), 5.69
(dd, 0.6H, J ) 9.8, 6.7 Hz), 5.31 (dd, 0.4H, J ) 10.4, 6.4 Hz),
4.77 (s, 0.6H), 4.61 (s, 0.4H), 4.33-4.26 (m, 2H), 3.05-2.98 (m,
1H), 2.61-2.49 (m, 1H), 1.34 (t, 3H, J ) 7.1 Hz).
3e: yield ) 100%; white foam. Data for the major diastereo-
mer: 1H NMR (CDCl3, 360 MHz) δ 9.46 (br s, 1H), 8.40 (dd, 1H,
J ) 8.1, 0.8 Hz), 8.00-7.98 (m, 2H), 7.55-7.18 (m, 6H), 5.83
(dd, 1H, J ) 11.3, 5.8 Hz), 4.77 (s, 1H), 4.27 (dq, 1H, J ) 10.7,
7.1 Hz), 4.14 (dq, 1H, J ) 10.7, 7.1 Hz), 3.04 (ddd, 1H, J ) 17.4,
11.3, 0.8 Hz), 2.91 (ddd, 1H, J ) 17.4, 5.8, 0.6 Hz), 1.22 (t, 3H,
J ) 7.1 Hz).
3f: yield ) 100%; orange-yellow solid. Data for the major
diastereomer: 1H NMR (CDCl3, 360 MHz) δ 7.89-7.42 (m, 10H),
5.67 (dd, 0.75H, J ) 9.7, 6.5 Hz), 5.29 (dd, 0.25H, J ) 10.5, 6.3
Hz), 4.76 (s, 0.75H), 4.58 (s, 0.25H), 4.33-4.27 (m, 2H), 2.99-
2.92 (m, 1H), 2.66-2.60 (m, 1H), 1.33 (t, 3H, J ) 7.1 Hz).
Gen er a l P r oced u r e for th e F or m a tion of 9 fr om 3 via
Silyla tion . To 0.447 g (1.90 mmol) of 3b in 6 mL of CH2Cl2 at
ambient temperature was added 0.80 mL (0.58 g, 5.7 mmol) of
Et3N followed by a solution of 0.57 g (3.8 mmol) of TBSCl in 3
mL of CH2Cl2 via cannula. The reaction mixture was stirred at
room temperature overnight and then concentrated. A solution
of 0.3 mL of Et3N in 10 mL of anhydrous Et2O was added to
this viscous yellow oil, and then the resulting salt was removed
by filtration through a fritted glass filter. The filter was then
rinsed with dry ether (3 × 3 mL). Concentration of the combined
filtered solution yielded 0.660 g (99%) of the silyl enol ether ester
as a brown yellow oil.
9a : diastereomers were separated by column chromatography
(2%, 4% EtOAc in CH2Cl2): yield of cis diastereomer ) 48%;
viscous colorless oil; 1H NMR (CDCl3, 360 MHz) δ 7.45-7.35
(m, 5H), 5.23 (dd, 1H, J ) 11.0, 5.8 Hz), 4.05 (t, 1H, J ) 3.4
Hz), 3.97-3.94 (m, 2H), 2.89 (dd, 1H, J ) 18.1, 5.8 Hz), 2.56
(dd, 1H, J ) 18.1, 11.0 Hz), 1.98 (dd, 1H, J ) 7.1, 6.1 Hz); 13C
NMR (CDCl3, 90 MHz) δ 214.1, 139.8, 129.0, 128.8, 126.4, 82.5,
77.9, 61.7, 45.5; IR (neat) 3468, 1756 cm-1. HRMS(FAB) calcd
for C11H13O3 (MH+) 193.0865, found 193.0860.
9c: diastereomers were separated by column chromatography
(2%, 5% MeOH in CH2Cl2) followed by crystallization (EtOAc):
yield of cis diastereomer ) 35%; colorless crystals; mp 100-101
1
°C; H NMR (CDCl3, 360 MHz) δ 8.68 (d, 1H, J ) 1.9 Hz), 8.57
(dd, 1H, J ) 4.8, 1.5 Hz), 7.80-7.78 (m, 1H), 7.32 (ddd, 1H, J )
7.9, 4.8, 0.6 Hz), 5.24 (dd, 1H, J ) 11.0, 5.9 Hz), 4.06 (t, 1H, J
) 3.2 Hz), 3.96 (d, 2H, J ) 3.2 Hz), 3.03 (br s, 1H), 2.91 (dd, 1H,
J ) 17.9, 5.9 Hz), 2.51 (dd, 1H, J ) 17.9, 11.0 Hz); 13C NMR
(CDCl3, 90 MHz) δ 213.2, 149.9, 148.1, 135.9, 134.2, 123.9, 82.7,
75.6, 61.6, 45.3; IR (KBr) 3199, 1762 cm-1. Anal. Calcd for
C10H11NO3: C, 62.17; H, 5.74; N, 7.25. Found: C, 62.19; H, 5.77;
N, 7.19.
9d : an analytical sample was prepared by crystallization
(EtOAc/hexanes): colorless needles; mp 89-92 °C; 1H NMR
(CDCl3, 360 MHz) δ 8.54 (dd, 2H, J ) 4.6, 1.6 Hz), 7.33-7.31
(m, 2H), 5.19 (dd, 1H, J ) 11.0, 6.0 Hz), 4.06 (t, 1H, J ) 3.2
Hz), 3.98 (dd, 1H, J ) 12.2, 3.0 Hz), 3.94 (dd, 1H, J ) 12.2, 3.5
Hz), 3.49 (br s, 1H), 2.90 (dd, 1H, J ) 17.8, 6.0 Hz), 2.43 (dd,
1H, J ) 17.8, 11.0 Hz); 13C NMR (CDCl3, 90 MHz) δ 212.8, 150.1,
149.4, 121.1, 82.8, 76.1, 61.5, 45.0; IR (CDCl3) 3187, 1763 cm-1
.
Anal. Calcd for C10H11NO3: C, 62.17; H, 5.74; N, 7.25. Found:
C, 62.07; H, 5.77; N, 7.20.
9e. The diastereomers were separated by column chromatog-
raphy (30% EtOAc in hexane): yield of cis diastereomer ) 30%;
1
colorless needles; mp 133-134 °C; H NMR (CDCl3, 360 MHz)
δ 9.50 (br s, 1H), 8.22 (d, 1H, J ) 7.5 Hz), 7.88-7.86 (m, 2H),
7.54-7.42 (m, 4H), 7.25 (dd, 1H, J ) 7.7, 1.7 Hz), 7.18 (td, 1H,
J ) 7.5, 1.2 Hz), 5.37 (t, 1H, J ) 8.6 Hz), 4.10 (t, 1H, J ) 3.3
Hz), 3.91 (br s, 2H), 2.83-2.74 (m, 2H), 1.55 (br s, 1H); 13C NMR
(CDCl3, 90 MHz) δ 212.2, 166.4, 137.3, 135.2, 132.1, 129.8, 128.8,
128.2, 127.5, 127.4, 124.9, 124.1, 82.7, 77.7, 61.2, 42.6; IR (CDCl3)
3357, 1762, 1663 cm-1. HRMS(FAB) calcd for C18H18NO4 (MH+)

Notes
J . Org. Chem., Vol. 64, No. 4, 1999 1419
312.1236, found 312.1233. Anal. Calcd for C18H17NO4: C, 69.44;
H, 5.50; N, 4.50. Found: C, 69.34; H, 5.51; N, 4.37.
9f. The diastereomers were separated by column chromatog-
4c:11 yield ) 94%; colorless oil; 1H NMR (CDCl3, 360 MHz) δ
8.61 (d, 1H, J ) 2.2 Hz), 8.51 (dd, 1H, J ) 4.9, 1.6 Hz), 7.69-
7.66 (m, 1H), 7.28 (dd, 1H, J ) 7.9, 4.9 Hz), 5.20 (dd, 1H, J )
10.2, 5.6 Hz), 4.49-4.46 (m, 1H), 4.06-4.03 (m, 1H), 3.82 (dd,
1H, J ) 11.7, 4.2 Hz), 3.72 (dd, 1H, J ) 11.7, 4.8 Hz), 2.60 (br
s, 2H), 2.30 (ddd, 1H, J ) 13.2, 5.6, 2.0 Hz), 2.02 (ddd, 1H, J )
13.2, 10.2, 6.2 Hz); 13C NMR (CDCl3, 90 MHz) δ 149.1, 147.9,
137.5, 134.2, 123.8, 87.8, 78.1, 73.8, 63.5, 44.1.
raphy (CH2Cl2, then 1%, 2%, 4% MeOH in CH2Cl2): yield of cis
1
diastereomer ) 39%; white crystals; mp 184-186 °C; H NMR
(CDCl3, 360 MHz) δ 7.89-7.44 (m, 10H), 5.22 (dd, 1H, J ) 10.9,
5.8 Hz), 4.05 (t, 1H, J ) 3.5 Hz), 3.97-3.95 (m, 2H), 2.88 (dd,
1H, J ) 18.0, 5.8 Hz), 2.54 (dd, 1H, J ) 18.0, 11.0 Hz), 1.99 (dd,
1H, J ) 7.0, 6.2 Hz); 13C NMR (CD3OD, 90 MHz) δ 215.6, 169.1,
140.0, 138.3, 136.4, 133.1, 129.8, 128.8, 128.2, 122.3, 84.5, 78.7,
62.1, 47.0; IR (KBr) 3482, 3292, 1757, 1649 cm-1. Anal. Calcd
for C18H17NO4: C, 69.44; H, 5.50; N, 4.50. Found: C, 69.43; H,
5.58; N, 4.43.
4d . The diastereomers were separated by column chromatog-
raphy (5%, 10% MeOH in CH2Cl2) followed by crystallization
(EtOAc/hexanes): yield ) 39% from 2d ; white crystals; mp 89-
1
92 °C; H NMR (CDCl3, 360 MHz) δ 8.55 (dd, 2H, J ) 4.5, 1.6
Hz), 7.27-7.25 (m, 2H), 5.17 (dd, 1H, J ) 10.2, 5.8 Hz), 4.46-
4.44 (m, 1H), 4.06 (td, 1H, J ) 4.5, 2.9 Hz), 3.84 (dd, 1H, J )
11.6, 4.3 Hz), 3.76 (dd, 1H, J ) 11.6, 4.8 Hz), 2.33 (ddd, 1H, J )
13.2, 5.8, 2.0 Hz), 2.14 (br s, 1H), 1.95 (ddd, 1H, J ) 13.2, 10.2,
6.2 Hz), 1.64 (br s, 1H); 13C NMR (CDCl3, 90 MHz) δ 150.9, 150.1,
120.9, 87.8, 78.7, 73.8, 63.6, 44.0; IR (KBr) 3346, 3144, 1611
cm-1. Anal. Calcd for C10H13NO3: C, 61.53; H, 6.71; N, 7.17.
Found: C, 61.41; H, 6.69; N, 7.22.
Gen er a l P r oced u r e for th e F or m a tion of 9 fr om 3 via
Sod iu m En ola te. To a suspension of 0.064 g of 60% NaH (1.6
mmol, prewashed with 1 mL of hexane) in 3.5 mL of THF at 0
°C was cannulated a solution of 0.315 g (1.34 mmol) of 3b in 3.5
mL of THF. The reaction mixture was stirred at 0 °C for 0.5 h,
over which time it turned to an orange-red, almost transparent
solution (enolization time varied from 0.5 to 2 h for the other
substrates). After the solution was cooled to -78 °C, 0.60 mL
(0.48 g, 3.3 mmol, an additional 1 equiv was used for 3e and 3f)
of DIBAL was added, and the reaction mixture was stirred at
-78 °C for 3 h. After being warmed to 0 °C for 10 min, the
reaction mixture was cooled to -78 °C and then cannulated to
a solution of 2.52 mL (1.98 g, 26.8 mmol) of t-BuOH in 7 mL of
THF at -78 °C over 5 min. This combined reaction mixture was
stirred at 78 °C for 0.5 h and then quenched with 10 mL of
concentrated pH7 buffer solution and diluted with 70 mL of
CH2Cl2. The heterogeneous mixture was warmed to room
temperature and vigorously stirred overnight. The portion of the
organic layer not contaminated with solids was separated, and
the aqueous layer and the rest of the organic layer were filtered
through Celite, which was then rinsed with water (2 × 5 mL)
and CH2Cl2 (2 × 10 mL). The organic phase was separated, and
the aqueous layer was extracted with CH2Cl2 (5 × 10 mL). The
combined organic layers were dried over Na2SO4 and concen-
trated. The product was purified by column chromatography (2%,
3%, and 4% MeOH in CH2Cl2) to afford 0.128 g of 9b (50%).
4e: yield ) 93%; white crystals; mp 132-134 °C; 1H NMR
(CDCl3, 360 MHz) δ 9.75 (br s, 1H), 8.32 (d, 1H, J ) 8.3 Hz),
7.90-7.87 (m, 2H), 7.53-7.35 (m, 4H), 7.17 (dd, 1H, J ) 7.7,
1.5 Hz), 7.10 (td, 1H, J ) 7.5, 1.2 Hz), 5.29 (dd, 1H, J ) 10.9,
5.2 Hz), 4.44-4.42 (m, 1H), 4.11-4.08 (m, 1H), 3.77-3.67 (m,
2H), 2.32 (ddd, 1H, J ) 13.1, 10.9, 6.0 Hz), 2.23 (ddd, 1H, J )
13.1, 5.2, 1.5 Hz), 1.97 (d, 1H, J ) 3.7 Hz), 1.52 (t, 1H, J ) 5.9
Hz); 13C NMR (CDCl3, 90 MHz) δ 166.0, 137.6, 135.3, 132.1,
129.1, 128.94, 128.85, 127.3, 126.9, 124.5, 122.8, 88.1, 79.4, 73.1,
63.2, 40.9; IR (KBr) 3346, 3245, 1648 cm-1. Anal. Calcd for
C
18H19NO4: C, 69.00; H, 6.11; N, 4.47. Found: C, 68.76; H, 6.11;
N, 4.46.
4f: yield ) 84%; white powder; mp 179-181 °C; 1H NMR
(CD3OD, 360 MHz) δ 7.94-7.40 (m, 9H), 5.13 (dd, 1H, J ) 10.5,
5.4 Hz), 4.34-4.33 (m, 1H), 3.95 (td, 1H, J ) 5.1, 2.4 Hz), 3.72-
3.64 (m, 2H), 2.19 (ddd, 1H, J ) 13.1, 5.4, 1.6 Hz), 1.97 (ddd,
1H, J ) 13.1, 10.6, 5.9 Hz); 13C NMR (CD3OD, 90 MHz) δ 169.0,
139.5, 139.4, 136.4, 133.0, 129.8, 128.8, 127.8, 122.3, 89.3, 81.5,
74.6, 64.2, 45.1; IR (KBr) 3289, 1648 cm-1; HRMS(FAB) calcd
for C18H20NO4 (MH+) 314.1392, found 314.1386.
Gen er a l P r oced u r e for t h e F or m a t ion of 4 b y Dia -
ster eoselective Red u ction of 9. To a mixture of 0.83 g (3.9
mmol) of NaBH(OAc)3 in 4 mL of CH3CN at 0 °C was added
0.45 mL (0.47 g, 7.9 mmol) of CH3CO2H, followed by a solution
of 0.152 g (0.787 mmol) of 3b in 3 mL of CH3CN via cannula.
The reaction mixture was stirred at 0 °C for 1 h and then
quenched by the addition of 8 mL of CH3OH. After concentration,
CH3OH (2 × 8 mL) was added, and the mixture was concen-
trated again. The product was purified by chromatography (2%,
5% CH3OH in CH2Cl2) to yield 0.141 g (92%) of 4b as a colorless
oil:15 1H NMR (CDCl3, 360 MHz) δ 8.56-8.54 (m, 1H), 7.66 (td,
1H, J ) 7.7, 1.8 Hz), 7.25-7.20 (m, 2H), 5.28 (dd, 1H, J ) 8.9,
6.9 Hz), 4.65-4.63 (m, 1H), 4.19-4.17 (m, 1H), 3.95 (dd, 1H, J
) 12.3, 2.7 Hz), 3.71 (dd, 1H, J ) 12.3, 2.1 Hz), 3.10-2.50 (br s,
2H), 2.43 (ddd, 1H, J ) 13.3, 9.0, 5.4 Hz), 2.33 (ddd, 1H, J )
13.3, 6.8, 1.9 Hz); 13C NMR (CDCl3, 90 MHz) δ 161.6, 149.7,
137.4, 123.4, 122.3, 89.2, 80.6, 75.2, 64.2, 43.9; IR (neat) 3383,
1597 cm-1. Anal. Calcd for C10H13NO3: C, 61.53; H, 6.71; N, 7.17.
Found: C, 61.32; H, 6.75; N, 7.04.
6: colorless oil; 1H NMR (CDCl3, 360 MHz) δ 7.52-7.25 (m,
5H), 5.01 (t, 1H, J ) 7.5 Hz), 4.71-4.68 (m, 1H), 4.52 (d, 1H, J
) 5.3 Hz), 4.32-4.25 (m, 2H), 2.66 (ddd, 1H, J ) 13.3, 7.4, 6.5
Hz), 2.51 (d, 1H, J ) 6.3 Hz), 2.07 (ddd, 1H, J ) 13.3, 7.6, 4.6
Hz), 1.32 (t, 3H, J ) 7.1 Hz); 13C NMR (CDCl3, 90 MHz) δ 170.1,
141.7, 128.6, 127.9, 126.3, 82.2, 80.5, 73.6, 61.5, 42.8, 14.4; IR
(neat) 3473, 1742 cm-1. Anal. Calcd for C13H16O4: C, 66.09; H,
6.83. Found: C, 66.19; H, 6.79.
7: pale yellow oil; 1H NMR (CDCl3, 360 MHz) δ 7.34-7.25
(m, 5H), 5.43 (dd, 1H, J ) 10.2, 5.5 Hz), 4.81-4.77 (m, 2H), 4.36-
4.22 (m, 2H), 2.73 (br s, 1H), 2.47-2.41 (m, 1H), 2.07-1.99 (m,
1H), 1.32 (t, 3H, J ) 7.1 Hz); 13C NMR (CDCl3, 90 MHz) δ 170.7,
141.5, 128.6, 127.9, 125.9, 82.9, 81.0, 73.9, 61.6, 44.1, 14.5; IR
(neat) 3465, 1742 cm-1. Anal. Calcd for C13H16O4: C, 66.09; H,
6.83. Found: C, 66.06; H, 6.79.
8: colorless oil; 1H NMR (CDCl3, 360 MHz) δ 7.42-7.26 (m,
5H), 5.29 (t, 1H, J ) 7.4 Hz), 4.68-4.63 (m, 1H), 4.58 (d, 1H, J
) 3.8 Hz), 4.31-4.23 (m, 2H), 2.73-2.65 (m, 1H), 2.10 (d, 1H, J
) 5.1 Hz), 2.08-2.01 (m, 1H), 1.32 (t, 3H, J ) 7.1 Hz); 13C NMR
(CDCl3, 68 MHz) δ 171.6, 141.9, 128.4, 127.7, 125.8, 84.5, 80.8,
75.9, 61.3, 42.5, 14.2; IR (neat) 3453, 1736 cm-1. Anal. Calcd for
4a :8 yield ) 94%; colorless needles; mp 82-83 °C; 1H NMR
(CDCl3, 360 MHz) δ 7.35-7.27 (m, 5H), 5.16 (dd, 1H, J ) 10.2,
5.7 Hz), 4.41-4.38 (m, 1H), 4.01-3.98 (m, 1H), 3.79 (dd, 1H, J
) 11.6, 4.3 Hz), 3.72 (dd, 1H, J ) 11.6, 5.0 Hz), 2.34 (br s, 2H),
2.24 (ddd, 1H, J ) 13.3, 5.7, 2.0 Hz), 2.02 (ddd, 1H, J ) 13.2,
10.2, 6.3 Hz).
C
13H16O4: C, 66.09; H, 6.83. Found: C, 66.14; H, 6.85.
Ack n ow led gm en t. We thank the Petroleum Re-
search Fund and the Virginia Tech Chemistry Depart-
ment for financial support of this project.
(15) Although 4b is a known compound, no analytical data were
reported in ref 11 for this compound.
J O9818834