Optically active cyclobutanone chemistry: synthesis of (-)-cyclobut-a and (±)-3′-epi-cyclobut-a

Article abstract of DOI:10.1021/jo9817063

The carbocyclic nucleoside analogues (-)-cyclobut-A and (±)-3′-epi-cyclobut-A were synthesized utilizing photolysis of the (benzyloxymethyl)(methoxy) chromium carbene complex 4 with optically active ene-carbamate 5 to produce the corresponding optically active α,α-disubstituted cyclobutanone 6. Stereoselective removal of the a-ethoxy group with inversion gave cyclobutanone 7, which was converted by existing methodology to the title compounds.

Full text of DOI:10.1021/jo9817063

8012
J . Org. Chem. 1998, 63, 8012-8018
Op tica lly Active Cyclobu ta n on e Ch em istr y: Syn th esis of
(-)-Cyclobu t-A a n d (()-3′-Epi-Cyclobu t-A
Brian Brown and Louis S. Hegedus*
Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523
Received August 21, 1998
The carbocyclic nucleoside analogues (-)-cyclobut-A and (()-3′-epi-cyclobut-A were synthesized
utilizing photolysis of the (benzyloxymethyl)(methoxy) chromium carbene complex 4 with optically
active ene-carbamate 5 to produce the corresponding optically active R,R-disubstituted cyclobutanone
6. Stereoselective removal of the R-ethoxy group with inversion gave cyclobutanone 7, which was
converted by existing methodology to the title compounds.
In tr od u ction
etanocin, was first synthesized in 1989 by Honjo,11 and
its remarkable antiviral activity12 has prompted numer-
ous subsequent syntheses of both the parent and related
compounds.13 The observation of differing activities
between opposite enantiomers14 highlights the need for
asymmetric syntheses, and several nonracemic ap-
proaches have succeeded in providing material of high
optical purity. In some early studies, chiral resolutions
were performed to deliver nonracemic intermediates.15
J ung et al. utilized an enzymatic desymmetrization16 of
a meso-cyclobutene as the enantioselecive step in their
formation of nonracemic cyclobut-A. In another notable
approach, Ichikawa employed a chiral titanium complex
as the catalyst in an asymmetric [2 + 2] cyclization to
provide a functionalized cyclobutane intermediate in
>98% ee, which was readily converted to the final
product.17
Recent methodology developed in these laboratories
provides efficient access to optically active cyclobu-
tanones.1 These cyclobutanones underwent Baeyer-
Villiger oxidation/ring expansion regio- and stereoselec-
tively to form optically active butyrolactones2 which were
converted to butenolides and used in the synthesis of (+)-
tetrahydrocerulenin,3 (+)-cerulenin,4 optically active
spiroketals,5 and a template for nucleoside analogues.6
Cyclobutanones are also subject to carbocyclic ring
expansions7 by reaction with a variety of reagents includ-
ing diazomethane, sulfur-stabilized carbanions, and sa-
marium iodide/diiodomethane8 as well as two-step pro-
cedures involving methylenation/epoxidation. Carbocyclic
ring expansion of the optically active cyclobutanone used
as a template for nucleoside analogues6 should provide
cyclopentanones convertible to carbocyclic nucleoside
analogues, provided the ring expansion proceeds with the
desired regiochemistry. Carbocyclic nucleoside analogues
are of substantial current interest as antiviral com-
pounds, since many display potent biological activity, and
possess substantially greater metabolic stability than
their carbohydrate-derived analogues.9
The recent discovery of oxetanocin A (1), a natural
product containing an unusual four-membered oxetane
ring substituting the ribose of adenosine and possessing
potent anti-HIV properties, has further expanded the
scope in the search for therapeutic nucleoside deriva-
tives.10 Cyclobut-A (2), the carbocyclic analogue of ox-
A series of studies examining the reactivity of an
appropriately substituted optically active cyclobutanone
in the context of the synthesis of (-)-cyclobut-A are
described below.
(11) Honjo, M.; Maruyama, T.; Sato, Y.; Horii, T. Chem. Pharm. Bull.
1989, 37, 1413.
(12) Norbeck, D. W.; Kern, E.; Hayashi, S.; Rosenbrook, W.; Sham,
H.; Herrin, T.; Plattner, J . J .; Erickson, J .; Clement, J .; Swanson, R.;
Shipkowitz, N.; Hardy, D.; Marsh, K.; Arnett, G.; Shannon, W.; Broder,
S.; Mitsuya, H. J . Med. Chem. 1990, 33, 1281.
(13) (a) Somekawa, K.; Hara, R.; Kinnami, K.; Muraoka, F.; Suishu,
T.; Shimo, T. Chem. Lett. 1995, 407. (b) Gharbaoui, T.; Legraverend,
M.; Ludwig, O.; Bisagni, E.; Aubertin, A.-M.; Chertanova, L. Tetrahe-
dron 1995, 51, 1641, and references therein. (c) Bisacchi, G. S.; Singh,
J .; Godfrey, J . D., J r.; Kissick, T. P.; Mitt, T.; Malley, M. F.; Di Marco,
J . D.; Gougoutas, J . Z.; Mueller, R. H.; Zahler, R. J . Org. Chem. 1995,
60, 2902. Also see ref 9 (c) for a review of several approaches.
(14) Terry, B. J .; Cianci, C. W.; Hagen, M. E. Mol. Pharm. 1991,
40, 591.
(15) (a) Cotterill, I. C.; Roberts, S. M. J . Chem. Soc., Perkin Trans.
1 1992, 2585. (b) Bissachi, G. S.; Braitman, A.; Cianci, C. W.; Clark,
J . M.; Field, A. K.; Hagen, M. E.; Hockstein, D. R.; Malley, M. F.; Mitt,
T.; Slusarchyk, W. A.; Sundeen, J . E.; Terry, B. J .; Tuomari, A. V.;
Weaver, E. R.; Young, M. G.; Zahler, R. J . Med. Chem. 1991, 34, 1415.
(16) J ung, M. E.; Sledeski, A. W. J . Chem. Soc., Chem. Commun.
1993, 589.
(1) (a) So¨derberg, B. C.; Hegedus, L. S.; Sierra, M. A. J . Am. Chem.
Soc. 1990, 112, 4364. (b) Hegedus, L. S.; Bates, R. W.; So¨derberg, B.
C. J . Am. Chem. Soc. 1991, 113, 923. (c) Riches, A. G.; Wernersbach,
L. A.; Hegedus, L. S. J . Org. Chem. 1998, 63, 4691.
(2) Reed, A. D.; Hegedus, L. S. J . Org. Chem. 1995, 60, 3787.
(3) Miller, M.; Hegedus, L. S. J . Org. Chem. 1993, 58, 6779.
(4) Kedar, T. E.; Miller, M. W.; Hegedus, L. S. J . Org. Chem. 1996,
61, 6121.
(5) Bueno, A. B.; Hegedus, L. S. J . Org. Chem. 1998, 63, 684.
(6) Reed, A. D.; Hegedus, L. S. Organometallics 1997, 16, 2313.
(7) For a review on cyclobutanone chemistry, including ring expan-
sion see: Bellus, D.; Ernst, B. Angew. Chem., Int. Ed. Engl. 1988, 27,
797.
(8) Fukuzawa, S-i.; Tsuchimoto, T. Tetrahedron Lett. 1995, 36,
5937.
(9) For review see: (a) Agrofoglio, L.; Suhas, E.; Farese, A.; Condom,
R.; Challand, S. R.; Earl, R. A.; Guedj, R. Tetrahedron 1994, 50, 10611.
(b) Borthwick, A. D.; Biggadike, K. Tetrahedron 1992, 48, 571. (c)
Huryn, D. M.; Okabe, M. Chem. Rev. 1992, 92, 1745.
(10) Hoshino, H.; Shimizu, N.; Shimada, M.; Takita, T.; Takeuchi,
T. J . Antibiot. 1987, 40, 1077.
(17) Ichikawa, Y.-i.; Narita, A.; Shiozawa, A.; Hayashi, Y.; Narasaka,
K. J . Chem. Soc., Chem. Commun. 1989, 1919.
10.1021/jo9817063 CCC: $15.00 © 1998 American Chemical Society
Published on Web 10/14/1998

Optically Active Cyclobutanone Chemistry
J . Org. Chem., Vol. 63, No. 22, 1998 8013
direct the hydroboration24 to the opposite face of 8
utilizing the adjacent hydroxymethyl group also failed
(Table 1, eq 2).
Ta ble 1.
substrate
conditions
yield, %
ratio a /b
8
BH3‚THF
82
63
84
79
85
75
4/1
1/1
15/1
7/1
5/1
1/1
9-BBN
c-Hex2BH
catecholborane/RhI
BH3‚THF (3 equiv)
9-BBN
10
Resu lts a n d Discu ssion
The requisite optically active cyclobutanone precursor
to carbocyclic nucleoside analogues was synthesized,
using a previously developed procedure,6 by the photoly-
sis of chromium carbene complex 4 with optically active
ene-carbamate 5 (eq 1). Attempted ring expansion to the
8
cyclopentanone using SmI2/CH2I2 in THF resulted in-
stead in R-deoxygenation of the cyclobutanone. Optimi-
zation of this deoxygenation provided 7 in excellent yield
with high selectivity (eq 1). This reductive cleavage of
R-heteroatom-substituted carbonyl compounds is a well-
known process for SmI2, and is thought to proceed via
the enolate or enol.18 In the case of cyclobutanone 6,
protonation of the reduction intermediate gave the more
stable trans-disubstituted cyclobutanone 7. Since this
cyclobutanone has many of the structural features found
in cyclobut-A (2), its reaction chemistry was examined
in the context of the synthesis of 2.
In contrast to hydroboration, epoxidation of 8 with
mCPBA occurred predominantly from the bottom face
giving a 4:1 mixture of isomers. Epoxide ring opening,
even under Lewis-acidic conditions, produced the tertiary
alcohol rather than the desired primary alcohol.
Both Swern and Dess-Martin oxidation of alcohols 9a ,
9b followed by epimerization with NaOMe gave the more
stable trans-aldehyde in good yield and as a >17:1
mixture of â to R-epimers (eq 4). Attempts to produce
this aldehyde directly from methylenecyclobutane 8 using
Wacker oxidation chemistry28 met with limited success
(eq 5). Although some aldehyde was formed, the major
products arose from ring expansion of the product from
Wacker hydroxylation at the more substituted olefin
terminus (eq 4).29 This ring expansion is under current
study.
The most efficient route to 9b was a sequence of
hydroboration/oxidation (Swern)/epimerization (NaOMe)/
reduction (NaBH4), carried out sequentially with minimal
purification of the intermediates. In this way, (-)-9b was
obtained in 67% overall yield from (-)-8. With optically
active precursors to cyclobut-A and 3′-epi-cyclobut-A in
hand, elaboration of the nucleoside base was addressed.
Direct introduction of a hydroxymethyl group surrogate
using basic methylenation reagents Ph3PdCHOMe,19
[TMSCHOMe]Li,20 or [t-BuNdCHN(Me)CHTMS]Li21 re-
sulted in consumption of the starting material and
production of free oxazolidinone, but failed to provide any
of the desired compounds. It is likely that base-induced
â-elimination of the oxazolidinone occurred, and the
resulting cyclobutenone decomposed, as has previously
been observed for related compounds.1c As a consequence,
a two-step hydroxymethylation of 7 was next examined.
Methylenation of 7 was successful with both the
Petasis reagent, Cp2TiMe2,22 and the Takai reagent, Zn/
CH2I2/TiCl4,23 although the latter was preferred for its
higher yields. Hydroboration/oxidation of methylenecy-
clobutane 8 under a variety of conditions always led
to the undesired cis-dialkyl product 9a as the major
product, with only minor (50% maximum) amounts of the
desired trans compound 9b (Table 1, eq 2). Attempts to
(24) For examples of directed hydroborations, see: (a) Evans, D. A.;
Fu, G. C.; Hoveyda, A. H. J . Am. Chem. Soc. 1992, 114, 6671. (b)
Garrett, C. E.; Fu, G. C. J . Org. Chem. 1998, 63, 1370, and references
therein.
(25) Ishihara, K.; Mori, A.; Yamamoto, H. Tetrahedron 1990, 46,
(18) Molander, G. A. Org. React. 1994, 46, 211.
(19) Majetich, G.; Defauw, J . Tetrahedron 1988, 44, 3833.
(20) Magnus, P.; Roy, G. J . Chem. Soc., Chem. Commun. 1979, 822.
(21) Meyers, A. I.; J adgmann, G. E., J r. J . Am. Chem. Soc. 1982,
104, 877.
4595.
(26) Vankar, Y. D.; Arya, P. S.; Rao, C. T. Synth. Commun. 1983,
13, 869.
(27) Hutchins, R. O.; Taffer, I. M.; Burgoyne, W. J . Org. Chem. 1981,
46, 5214.
(22) Petasis, N. A.; Bzowej, E. I. J . Am. Chem. Soc. 1990, 112, 6392.
(23) Hibino, J .-i.; Okazoe, T.; Takai, K.; Nozaki, H. Tetrahedron Lett.
1985, 26, 5579.
(28) For a review see: Tsuji, J . Synthesis 1984, 369.
(29) Boontanonda, P.; Grigg, R. J . Chem. Soc., Chem. Commun.
1977, 583.

8014 J . Org. Chem., Vol. 63, No. 22, 1998
Brown and Hegedus
performed by M-H-W Laboratories, Phoenix, AZ. All reac-
tions were performed under an atmosphere of Ar unless
otherwise noted.
Cyclobu ta n on e 6. A solution of carbene complex 4 (4.19
g, 11.2 mmol) and (4R,5S)-oxazolidinone 5 (5.77 g, 21.7 mmol)
in CH2Cl2 (110 mL, degassed) in a Pyrex pressure tube was
placed under CO (∼80 psi), cooled to -35 °C, and irradiated
with a 400 W Hg-vapor lamp for 6 days. Concentration of the
crude reaction mixture followed by removal of Cr(CO)6 by
sublimation gave 9.2 g of a light green solid. Purification by
flash chromatography (80% Hex/CH2Cl2 to 25% EtOAc/Hex
gradient elution) provided 3.28 g of recovered oxazolidinone 5
(12.4 mmol, 57%) as a white solid and slightly impure
cyclobutanone 6 (2.57 g, 5.45 mmol, 49% of ∼95% pure
material) as a yellow gum, which was used without further
purification: 1H NMR δ 7.38-7.50 (m, 5 H), 6.97-7.10 (m, 6
H), 6.74-6.80 (m, 2 H), 6.54 (bs, 2 H), 5.59 (d, J ) 7.5 Hz, 1
H), 5.03 (d, J ) 7.5 z, 1 H), 4.81 (t, J ) 10.2 Hz, 1 H), 4.70 (d,
J ) 11.1 Hz, 1 H), 4.55 (d, J ) 11.1 Hz, 1 H), 4.06 (d, J ) 9.0
Hz, 1 H), 3.87 (d, J ) 9.0 Hz, 1 H), 3.75 (m, 2 H), 2.71 (dd, J
) 9.6, 18.0 Hz, 1 H), 2.45 (dd, J ) 10.6, 18.0 Hz, 1 H), 1.23 (t,
J ) 7.0 Hz, 3 H); 13C NMR δ 206.4, 158.5, 137.2, 135.5, 133.6,
128.7, 128.3, 128.1, 128.0, 127.9, 127.7, 126.7, 125.9, 97.7, 80.3,
Hydrogenolytic cleavage of the oxazolidinone [Pd(OH)2/
H2] to generate the free amine is normally straightfor-
ward. However, with these substrates it proved more
efficient to silylate the free hydroxyl group prior to
hydrogenolysis. Treatment of the resulting free amine
with 5-amino-4,6-dichloropyrimidine introduced the core
of the adenine, giving 16 in good yield. Elaboration of
16 to cyclobut-A by conventional methodology,30 followed
by removal of the protecting groups with BCl3 gave
cyclobut-A in 64% yield for the three steps (eq 6). This
material had physical properties identical to those
reported15b,17 for authentic material, and was found to
be optically pure (>98% ee) by chiral HPLC analysis
(Chiralcel OD) of its bis-TBS derivative.
74.4, 69.0, 64.8, 61.6, 48.0, 46.1, 15.6; IR (film) 1791, 1752 cm-1
;
[R]24 42.4 (c 1.0, CHCl3).
D
Racemic cyclobutanone 6 was formed similarly, but using
carbene complex 4 (3.64 g, 9.71 mmol) and oxazolidinone 5
(5.302 g, 20.0 mmol) in CH2Cl2 (35 mL, degassed) to provide
recovered oxazolidinone 5 (2.95 g, 11.1 mmol, 56%) and
cyclobutanone 6 (3.36 g, 7.13 mmol, 73%) as a white solid: mp
170-172 °C. Anal. Calcd for C29H29NO5: C, 73.87; H, 6.20;
N, 2.97. Found: C, 73.66; H, 6.12; N, 2.97.
Cyclobu ta n on e 7. A freshly prepared solution of SmI2
(0.17 M in THF, 32 mL, 5.3 mmol) was added slowly (5 min)
to a 0 °C suspension of 6 (1.00 g, 2.12 mmol) and MeOH (3.5
mL) in THF (7.0 mL, degassed). The mixture was stirred for
5 min and allowed to warm to room temperature, over which
time the blue color disappeared. More SmI2 (1.0 mL, 0.17
mmol) was added until the blue remained for a few seconds,
at which point the reaction mixture was quenched with H2O
(2 mL) and concentrated. The crude mixture was diluted with
1 N HCl (15 mL) and H2O (30 mL) and extracted with EtOAc
(2 × 40 mL) and CH2Cl2 (15 mL). The organic phase was
washed with saturated aqueous NaHCO3 (15 mL), washed
with brine (15 mL), dried (Na2SO4), and concentrated to give
1.06 g of crude material. Flash chromatography (25% EtOAc/
Hex) provided 0.82 g of 7 as a clear gum (1.92 mmol, 90%):
1H NMR δ 7.22-7.33 (m, 4H), 7.07-7.18 (m, 7H), 6.98-7.04
(m, 2H), 6.89-6.95 (m, 2H), 5.91 (d, J ) 8.0 Hz, 1H), 5.08 (d,
J ) 8.0 Hz, 1H), 4.34 (d, J ) 12.0 Hz, 1H), 4.28 (d, J ) 12.0
Hz, 1H), 4.18 (dt, J ) 6.9, 8.4 Hz, 1H), 4.09 (m, 1H), 3.68 (dd,
J ) 3.2, 10.0 Hz, 1H), 3.47 (ddd, J ) 3.2, 7.2, 17.6 Hz, 1H),
3.30 (dd, J ) 3.7, 10.0 Hz, 1H), 3.04 (ddd, J ) 2.1, 8.4, 17.6
Hz, 1H); 13C NMR δ 204.8, 157.5, 137.8, 134.6, 134.1, 128.7,
128.5, 128.4, 128.3, 128.0, 127.9, 127.8, 127.7, 127.6, 127.4,
125.8, 79.7, 73.2, 66.5, 65.8, 64.7, 49.7, 42.9; IR (film) 1789,
1746 cm-1; mp 98-100 °C.
( )-3′-epi-Cyclobut-A was synthesized from (()-9a by
the same sequence of steps, albeit in lower overall yield
((9a f epi-19; 34%: epi-19 f epi-2; 49%) because efforts
to optimize the process were minimal. The characteriza-
tion of this material was in agreement with previously
reported data.31
In summary, the above studies reveal a number of
unusual reactions of four-membered ring compounds, as
well as some unexpected stereoselectivities, and resulted
in the synthesis of (-)-cyclobut-A and (()-3′-epi-cyclobut-
A.
Nonracemic 7 was prepared as above by adding SmI2 (120
mL, 0.15 M in THF, 18 mmol) to (+)-6 (3.14 g, 6.66 mmol) in
MeOH (11 mL) and THF (25 mL) to provide 90% pure (+)-7
as a white solid (2.00 g, ∼4.68 mmol, ∼70%), which could be
taken on without further purification. Recrystallization (EtOAc/
Hex) affords analytically pure material as a white solid (1.10
Exp er im en ta l Section
g, 2.56 mmol, 39%): mp 111-112 °C. Anal. Calcd for C27H25
-
Gen er a l Meth od s. THF was distilled from sodium-
benzophenone ketyl, CH2Cl2, DMF, and Et3N were distilled
from CaH2, and n-BuOH was distilled from Na. 1H NMR (300
MHz) and 13C NMR (75 MHz) were recorded in CDCl3 except
where noted, and chemical shifts are given in ppm relative to
NO4: C, 75.86; H, 5.89; N, 3.28. Found: C, 76.06; H, 5.79; N,
3.32. [R]24 3.1 (c 0.70, CHCl3).
D
Meth ylen ecyclobu ta n e 8. Following the general proce-
dure of Takai,23 neat CH2I2 (0.75 mL, 9.3 mmol) was added
dropwise to a suspension of activated Zn (1.10 g, 16.9 mmol)
in THF (17.5 mL). The mixture was stirred for 30 min and
cooled to 0 °C, and TiCl4 (1.0 M in CH2Cl2, 2.10 mL, 2.10 mmol)
was added dropwise. After the addition, the cooling bath was
removed, and the resulting slurry was stirred for 30 min. A
solution of cyclobutanone 7 (0.801 g) in THF (4 mL) was added
dropwise and allowed to react for 30 min. The reaction
1
Me4Si (0 ppm, H), CDCl3 (77.0 ppm, 13C). Column chroma-
tography was performed with ICN 32-63 nm, 60 Å silica gel
using flash column techniques. Elemental analyses were
(30) Harnden, M. R.; J arvest, R. L.; Parratt, M. J . J . Chem. Soc.,
Perkin Trans. 1 1992, 2259.
(31) Mevellec, L.; Huet, F. Tetrahedron 1997, 53, 5797.

Optically Active Cyclobutanone Chemistry
J . Org. Chem., Vol. 63, No. 22, 1998 8015
mixture was quenched with 1 N HCl (20 mL) and water (10
mL) and extracted with Et2O (2 × 40 mL). The combined
organic layers were washed with brine (20 mL), dried (Na2-
SO4), and concentrated to give a green foam. Purification by
flash chromatography (20% EtOAc/Hex) provided methyl-
enecyclobutane 8 as an off-white solid (0.663 g, 1.56 mmol,
83%): 1H NMR δ 7.23-7.40 (m, 5H), 7.00-7.15 (m, 5H), 6.92-
6.99 (m, 3H), 6.84-6.91 (m, 2H), 5.79 (d, J ) 8.0 Hz, 1H), 5.07
(d, J ) 8.0 Hz, 1H), 4.89 (q, J ) 2.4 Hz, 1H), 4.79 (dd, J ) 1.7,
2.4 Hz, 1H), 4.47 (s, 2H), 4.06 (q, J ) 8.2 Hz, 1H), 3.50-3.66
(m, 3H), 2.53-2.74 (m, 2H); 13C NMR δ 157.6, 143.0, 138.4,
135.6, 134.3, 128.3, 128.2, 127.8, 127.7, 127.5, 126.0, 105.9,
79.9, 73.2, 70.5, 64.5, 49.7, 48.7, 35.8; IR (film) 1751 cm-1; mp
90-91 °C.
9.1 Hz, 1H), 3.69 (dd, J ) 4.4, 9.0 Hz, 1H), 3.52 (dd, J ) 3.3,
10.5 Hz, 1H), 3.31 (t, J ) 9.1 Hz, 2H), 2.99 (bs, 1H), 2.64 (dq,
J ) 4.4, 8.5 Hz, 1H), 1.88 (m, 2H), 1.56 (m, 1H); 13C NMR δ
157.5, 137.5, 135.5, 134.1, 128.3, 128.2, 127.7, 127.3, 125.9,
79.8, 73.3, 71.6, 65.9, 64.1, 47.9, 46.8, 36.2, 27.1; IR (film) 3445,
1748 cm-1; mp 118-119 °C; Anal.calcd for C28H29NO4: C,
75.82; H, 6.59; N, 3.16. Found: C, 75.64; H, 6.43; N, 3.08.
[R]24 -8.8 (c 0.60, CHCl3).
D
Alternatively, 9b was obtained more selectively via an
oxidation-epimerization-reduction sequence using a mixture
of 9a /b. Hydroboration of 8 (0.626 g, 1.47 mmol) with BH3‚
THF (3.0 mL) as described above provided 0.63 g of a 4:1
mixture (1H NMR) of crude 9a :b as a white solid, which was
used without purification. Swern oxidation was performed by
adding (COCl)2 (0.250 mL, 2.90 mmol) to a -78 °C solution of
DMSO (0.300 mL, 4.23 mmol) in CH2Cl2 (7.0 mL), followed by
stirring for 10 min. A solution of crude 9a /b in CH2Cl2 (2.5
mL) was then added dropwise and allowed to react for 20 min.
To the reaction mixture was added Et3N (0.79 mL, 5.7 mmol).
The resultant solution was stirred for 2 min at -78 °C, allowed
to warm over 20 min, quenched with saturated aqueous
NaHCO3 (20 mL), and extracted with CH2Cl2 (2 × 20 mL).
The combined organic extracts were washed with brine (10
mL), dried (Na2SO4), concentrated, and purified by flash
chromatography (30 to 50% EtOAc/Hex gradient elution) to
provide 0.488 g of a 4:1 mixture (1H NMR) of diastereomeric
aldehydes as a yellow foam. Major: 1H NMR δ 9.76 (d, J )
2.2 Hz, 1H), 6.84-7.35 (m, 15H), 5.84 (d, J ) 8.0 Hz, 1H), 4.98
(d, J ) 8.0 Hz, 1H), 4.26 (d, J ) 11.6 Hz, 1H), 4.14 (d, J )
11.6 Hz, 1H), 4.03 (q, J ) 8.8 Hz, 1H), 3.59 (m, 1H), 3.42 (dd,
J ) 3.6, 10.2 Hz, 1H), 3.19 (dd, J ) 5.8, 10.2 Hz, 1H), 3.11 (m,
1H), 2.42 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 202.2, 157.2,
137.7, 135.2, 134.2, 128.3, 128.2, 127.7, 127.5, 127.4, 125.8,
79.5, 73.0, 67.7, 65.4, 48.9, 44.6, 42.1, 23.8. Minor: 1H NMR
δ 9.62 (d, J ) 2.2 Hz, 1H), 7.23-7.36 (m, 5H), 7.03-7.10 (m,
6H), 6.93-6.99 (m, 2H), 6.84-6.89 (m, 2H), 5.80 (d, J ) 8.1
Hz, 1H), 5.04 (d, J ) 8.1 Hz, 1H), 4.44 (d, J ) 11.8 Hz, 1H),
4.39 (d, J ) 11.8 Hz, 1H), 4.08 (q, J ) 8.6 Hz, 1H), 3.55 (dd,
J ) 4.3, 9.8 Hz, 1H), 3.43 (dd, J ) 5.5, 9.8 Hz, 1H), 3.17 (m,
1H), 2.75 (m, 1H), 2.17 (dt, J ) 9.8, 11.2 Hz, 1H), 2.02 (dt, J
) 8.1, 11.2 Hz, 1H); 13C NMR δ 201.0, 157.4, 138.1, 135.4,
134.1, 128.3, 128.2, 128.1, 127.7, 127.5, 127.4, 125.9, 79.8, 73.0,
Nonracemic 8 was prepared as above using CH2I2 (1.00 mL),
Zn (1.45 g, 22.3 mmol), TiCl4 (1.0 M in CH2Cl2, 2.70 mL, 2.70
mmol), and cyclobutanone 7 (1.05 g, 2.45 mmol) to give (-)-8
(0.720 g, 1.69 mmol, 69%) as a white solid: mp 60-61 °C. Anal.
Calcd for C28H27NO3: C, 79.03; H, 6.40; N, 3.29. Found: C,
79.16; H, 6.55; N, 3.32. [R]24 -3.0 (c 0.71, CHCl3).
D
22
Alternatively, a solution of Cp2TiMe2 (0.40 M in THF, 4.7
mL, 1.9 mmol) was added to 7 (0.200 g, 0.47 mmol), and the
resultant solution was heated in a sealed tube to 75 °C for 4
h. The crude mixture was adsorbed onto florisil and purified
by flash chromatography (10% to 15% EtOAc/Hex gradient
elution) to provide 8 as a yellow film (0.135 g, 0.32 mmol, 68%).
Hyd r obor a t ion of 8. (a) With BH3‚THF: A solution of
BH3‚THF (1.0 M in THF, 0.11 mL, 0.11 mmol) was added
dropwise to a 0 °C solution of 8 (31 mg, 0.072 mmol) in THF
(0.40 mL), and the resultant solution was stirred at 0 °C for 1
h. 1 N NaOH (0.15 mL) and 30% H2O2 (0.05 mL) were added
and allowed to react for 1.5 h. The mixture was diluted with
saturated aqueous sodium potassium tartrate (5 mL) and H2O
(2 mL) and extracted with CH2Cl2 (2 × 7 mL). The combined
organic layer was washed with brine (5 mL), dried (Na2SO4),
and concentrated to give 33.5 mg of a white foam. Purification
by flash chromatography (60% EtOAc/Hex) afforded 26 mg of
a 4:1 mixture (1H NMR) of 9a :b as a white foam (0.059 mmol,
82%).
(b) With [Rh(COD)Cl]2‚4PPh3/catecholborane: A solution of
[Rh(COD)Cl]2 (2.9 mg, 0.0059 mmol) and PPh3 (6.2 mg, 0.024
mmol) in THF (0.50 mL) was stirred for 20 min, with care
being taken to exclude oxygen. A solution of 8 (50.2 mg, 0.118
mmol) in THF (0.40 mL) was added, and the resultant solution
was cooled to 0 °C. Catecholborane (0.037 mL, 0.30 mmol)
was added, the cooling bath was removed, and the reaction
mixture was stirred for 3 h. Workup as above (0.35 mL 1 N
NaOH, 0.11 mL 30% H2O2) provided a 7.3:1 ratio (1H NMR)
of 9a :b (41.4 mg, 0.0933 mmol, 79%).
69.9, 64.3, 47.3, 43.4, 41.7, 25.0; IR (film) 1747, 1721 cm-1
.
The mixture of aldehydes was dissolved in a 0.1 M solution
of NaOMe in MeOH (10 mL) and stirred for 13 h. The reaction
mixture was diluted with saturated aqueous NaHCO3 (30 mL)
and extracted with CH2Cl2 (3 × 25 mL). The combined organic
layers were dried (Na2SO4) and concentrated to afford 0.49 g
of a white foam, which was dissolved in EtOH (7.0 mL) and
treated with NaBH4 (41.7 mg, 1.10 mmol). After stirring for
2.5 h, the reaction mixture was diluted with saturated aqueous
NaHCO3 (15 mL) and extracted with CH2Cl2 (3 × 15 mL). The
combined organic layers were dried (Na2SO4) and concentrated
to give 0.474 g of white solid. Purification by trituration with
Et2O provided a >17:1 mixture (1H NMR) of 9b:a as a white
solid (0.424 g, 0.956 mmol, 67% from 8).
(c) With 9-BBN: A solution of 9-BBN (0.5 M in THF, 0.10
mL, 0.050 mmol) was added to a solution of 8 (19.7 mg, 0.0463
mmol) in THF (0.20 mL) and was allowed to react for 15 h.
Workup as above (0.15 mL 1 N NaOH, 0.06 mL 30% H2O2)
gave a 1:1 mixture of 9a :b (1H NMR) (13.0 mg, 0.0293 mmol,
63%).
(d) With cHex2BH: BH3‚DMS (0.105 mL, 1.11 mmol) was
added to a 0 °C solution of cyclohexene (0.23 mL, 2.3 mmol)
in CH2Cl2 (1.5 mL), and stirred for 3 h. A solution of 8 (0.355
g, 0.835 mmol) in CH2Cl2 (1.5 mL) was added, and the
resultant solution was stirred for 18 h, allowing it to warm
slowly. Workup as above (4.5 mL of 1 N NaOH, 0.51 mL of
30% H2O2) afforded a ∼15:1 mixture (1H NMR) of 9a :b (0.311
g, 0.702 mmol, 84%). 9a : 1H NMR δ 7.21-7.38 (m, 5H), 7.04-
7.11 (m, 6H), 6.94-7.00 (m, 2H), 6.83-6.89 (m, 2H), 5.81 (d,
J ) 8.0 Hz, 1H), 5.00 (d, J ) 8.0 Hz, 1H), 4.39 (s, 2H), 4.06 (q,
J ) 9.0 Hz, 1H), 3.49-3.70 (m, 4H), 3.19-3.31 (m, 2H), 2.44
(m, 1H), 2.21 (dt, J ) 9.8, 11.6 Hz, 1H), 1.75 (ddd, J ) 2.9,
9.0, 11.6 Hz, 1H); 13C NMR δ 157.4, 137.2, 135.6, 134.3, 128.4,
128.2, 128.1, 127.8, 127.7, 127.4, 125.9, 79.7, 73.4, 68.6, 64.7,
62.1, 49.3, 41.6, 33.3, 26.4; IR (film) 3452, 1748 cm-1; mp 145-
147 °C. Anal. Calcd for C28H29NO4: C, 75.82; H, 6.59; N, 3.16.
Found: C, 75.99; H, 6.36; N, 3.19. 9b: 1H NMR δ 7.24-7.38
(m, 5H), 7.00-7.11 (m, 6H), 6.91-7.00 (m, 2H), 6.80-6.88 (m,
2H), 5.80 (d, J ) 8.0 Hz, 1H), 5.01 (d, J ) 8.0 Hz, 1H), 4.51 (d,
J ) 11.8 Hz, 1H), 4.46 (d, J ) 11.8, Hz, 1H), 3.83 (dt, J ) 7.9,
Meth ylen ecyclobu ta n e 10. A solution of BCl3 (1.0 M in
CH2Cl2, 2.8 mL, 2.8 mmol) was added dropwise to a -78 °C
solution of 8 (0.150 g, 0.353 mmol) in CH2Cl2 (2.5 mL), and
the mixture was stirred for 3 h. The reaction was quenched
with MeOH (5 mL) and allowed to warm. The crude mixture
was concentrated, diluted with saturated aqueous NaHCO3
(10 mL), and extracted with CH2Cl2 (3 × 8 mL). The combined
organic layer was washed with brine (5 mL), dried (Na2SO4),
and concentrated to give 0.135 g of a gummy brown solid.
Purification by flash chromatography (50% EtOAc/Hex) pro-
vided 10 as a light yellow solid (92.3 mg, 0.275 mmol, 78%):
1H NMR δ 7.05-7.15 (m, 6H), 6.96-7.03 (m, 2H), 6.81-6.89
(m, 2H), 5.91 (d, J ) 7.9 Hz, 1H), 5.14 (d, J ) 7.9 Hz, 1H),
4.80-4.88 (m, 2H), 3.94 (dd, J ) 2.6, 9.3 Hz, 1H), 3.73-3.87
(m, 2H), 3.67 (ddd, J ) 2.6, 8.6, 11.3 Hz, 1H), 3.41-3.52 (m,
1H), 2.63-2.76 (m, 1H), 2.42 (dddd, J ) 2.0, 4.1, 8.1, 15.0 Hz,
1H); 13C NMR δ 158.7, 141.6, 134.5, 133.7, 128.4, 127.9, 127.8,
127.1, 125.9, 106.7, 80.2, 64.9, 63.1, 54.2, 50.3, 34.9; IR (film)

8016 J . Org. Chem., Vol. 63, No. 22, 1998
Brown and Hegedus
3424, 1736 cm-1; mp 110-112 °C; HRMS m/z (M + H) calcd
336.1600, obsd 336.1600.
(m, 1H), 2.80 (d, J ) 4.9 Hz, 1H), 2.60 (d, J ) 4.9 Hz, 1H),
2.49 (dd, J ) 9.0, 12.5 Hz, 1H), 2.22 (ddd, J ) 0.9, 8.2, 12.5
Hz, 1H); 13C NMR δ 157.6, 138.1, 135.2, 134.1, 128.4, 128.3,
127.9, 127.7, 127.6, 127.4, 126.0, 80.0, 73.2, 67.6, 64.5, 56.8,
49.6, 48.0, 43.5, 33.8; IR (film) 1752 cm-1; mp 117-118 °C.
12b: 1H NMR δ 7.23-7.36 (m, 5H), 7.05-7.11 (m, 6H), 6.95-
7.00 (m, 2H), 6.86-6.92 (m, 2H), 5.84 (d, J ) 8.1 Hz, 1H), 5.06
(d, J ) 8.1 Hz, 1H), 4.39 (s, 2H), 4.11 (dt, J ) 7.8, 9.1 Hz, 1H),
3.56 (q, J ) 6.1 Hz, 1H), 3.40 (dd, J ) 1.0, 6.1 Hz, 2H), 2.74
(ddd, J ) 1.0, 7.8, 13.4 Hz, 1H), 2.67 (d, J ) 4.8 Hz, 1H), 2.64
(d, J ) 4.8 Hz, 1H), 2.31 (ddd, J ) 1.2, 9.1, 13.4 Hz, 1H); 13C
NMR δ 157.4, 138.2, 135.0, 134.2, 128.3, 128.2, 127.8, 127.6,
127.5, 127.3, 125.8, 79.7, 73.0, 67.5, 65.3, 59.0, 49.6, 47.8, 46.0,
34.0; IR (film) 1751 cm-1; mp 99-101 °C. Anal. Calcd for
C28H27NO4: C, 76.17; H, 6.16; N, 3.17. Found: C, 76.00; H,
6.13; N, 3.14.
Hyd r obor a tion of 10. (a) With BH3‚THF: A solution of
BH3‚THF (1.0 M in THF, 0.059 mL, 0.059 mmol) was added
dropwise to a -78 °C solution of 10 (19 mg, 0.057 mmol) in
THF (0.50 mL), and the resultant solution was stirred for 12
h, allowing it to warm slowly. The reaction mixture was
heated to 55 °C for 1 h and allowed to cool. NaOH (1 N) (0.24
mL) and 30% H2O2 (0.04 mL) were added and allowed to react
for 45 min. The mixture was diluted with saturated aqueous
sodium potassium tartrate (2 mL) and saturated aqueous
NaHCO3 (4 mL) and extracted with CH2Cl2 (3 × 7 mL). The
combined organic layer was washed with brine (5 mL), dried
(Na2SO4), and concentrated to give 20 mg of a 7:1 mixture of
11a :b (1H NMR) as a clear film. Purification by flash chro-
matography (35 to 50% EtOAc/Hex to 15% MeOH/CH2Cl2
gradient elution) afforded 15 mg of 11a as a clear film (0.043
mmol, 75%).
(b) With 9-BBN: A solution of 9-BBN in THF (0.5 M, 0.30
mL, 0.15 mmol) was added to a solution of 10 (20.3 mg, 0.0606
mmol) in THF (0.30 mL) and allowed to react for 14 h. Workup
as above (0.45 mL 1 N NaOH, 0.08 mL 30% H2O2) gave a 33.7
mg of a 1:1 mixture of 11a :b as judged by crude 1H NMR.
Deben zyla tion of 9a . A solution of BCl3 (1.0 M in CH2-
Cl2, 1.3 mL, 1.3 mmol) was added dropwise to a -78 °C
solution of 9a (60.8 mg, 0.137 mmol) in CH2Cl2 (0.5 mL). The
reaction mixture was allowed to warm over 30 min following
the addition and then quenched with MeOH (2 mL) and
concentrated. MeOH (2 mL) was added and concentrated
twice more, and the residue was then dissolved in a solution
of NH3 in MeOH (2 mL, satd at 0 °C) and concentrated again.
The resulting film was purified by flash chromatography (2%
MeOH/CH2Cl2) to afford an 11:1 mixture (1H NMR) of 11a :b
as a white solid (33.3 mg, 0.0942 mmol, 69%). 11a : 1H NMR
δ 7.05-7.13 (m, 6H), 6.94-7.00 (m, 2H), 6.82-6.88 (m, 2H),
5.86 (d, J ) 7.9 Hz, 1H), 5.10 (d, J ) 7.9 Hz, 1H), 4.12 (q, J )
9.2 Hz, 1H), 3.60-3.80 (m, 4H), 3.00 (m, 1H), 2.45 (m, 1H),
2.03 (dt, J ) 9.7, 11.6 Hz, 1H), 1.60 (ddd, J ) 2.0, 9.2, 11.6
Hz, 1H); 13C NMR δ 158.1, 135.4, 134.0, 128.3, 127.9, 127.8,
127.2, 126.0, 80.2, 64.2, 62.2, 60.9, 49.3, 44.6, 33.0, 26.3; IR
(film) 3382, 1732 cm-1; mp 154-155 °C; HRMS m/z (M + H)
calcd 354.1705, obsd 354.1706.
Deben zyla tion of 9b. A solution of BCl3 (1 M in CH2Cl2,
1.0 mL, 1.0 mmol) was added dropwise to a -78 °C solution
of 9b (49.4 mg, 0.111 mmol) in CH2Cl2 (0.5 mL). The reaction
mixture was allowed to warm over 30 min following the
addition and then quenched with MeOH (2 mL) and concen-
trated. MeOH (2 mL) was added and concentrated twice more,
and the residue was then dissolved in a solution of NH3 in
MeOH (2 mL, satd at 0 °C) and concentrated again. The
resulting film was purified by flash chromatography (3%
MeOH/CH2Cl2) to afford 11b as a white solid (24.0 mg, 0.063
mmol, 61%): 1H NMR δ 7.05-7.15 (m, 6H), 6.95-7.02 (m, 2H),
6.82-6.89 (m, 2H), 5.87 (d, J ) 7.0 Hz, 1H), 5.10 (d, J ) 7.0
Hz, 1H), 3.69-3.80 (m, 2H), 3.63 (dd, J ) 3.0, 10.5 Hz, 1H),
3.55 (dd, J ) 6.9, 10.5 Hz, 1H), 3.43 (dd, J ) 6.7, 10.0 Hz,
1H), 2.54-2.92 (m, 3H), 1.84 (quin, J ) 6.8 Hz, 2H), 1.66 (m,
1H); 13C NMR δ 158.2, 135.1, 134.0, 128.4, 128.0, 127.9, 127.3,
126.0, 80.2, 65.0, 64.5, 49.2, 48.7, 35.1, 26.6; IR (film) 3379,
1732 cm-1; mp 160-161 °C; HRMS m/z (M + H) calcd
354.1705, obsd 354.1715.
Ep oxid es 12a /b. A suspension of 8 (60.3 mg, 0.142 mmol),
NaHCO3 (68.3 mg, 0.813 mmol), and mCPBA (50%, 120 mg,
0.35 mmol) in CH2Cl2 (1 mL) at 0 °C was stirred for 10 h,
allowing it to warm to room temperature. The mixture was
diluted with saturated aqueous NaHCO3 (7 mL) and extracted
with CH2Cl2 (3 × 8 mL). The combined organic extracts were
washed with brine (5 mL), dried (Na2SO4), and concentrated
to give 91 mg of a clear gum. Purification by flash chroma-
tography (20% EtOAc/Hex) and crystallization (Et2O/Hex)
afforded 12a (10.0 mg, 0.0226 mmol, 16%) and 12b (37.7 mg,
0.854 mmol, 60%) as white solids. 12a : 1H NMR δ 7.26-7.38
(m, 5H), 7.05-7.12 (m, 6H), 6.95-7.00 (m, 2H), 6.86-6.92 (m,
2H), 5.84 (d, J ) 8.0 Hz, 1H), 5.07 (d, J ) 8.0 Hz, 1H), 4.42 (s,
2H), 4.08 (q, J ) 8.2 Hz, 1H), 3.48 (d, J ) 4.7 Hz, 2H), 3.38
Cyclobu ta n ol 13. To a solution of 12b (38 mg, 0.085 mmol)
and NaCNBH3 (10 mg, 0.16 mmol) in THF (0.80 mL) contain-
ing bromocresol green indicator was added BF3‚OEt2 (0.01 mL)
until the solution became yellow. The solution was stirred for
2 h, when more BF3‚OEt2 (0.01 mL) was added. After stirring
an additional 3 h, the reaction mixture was quenched with
saturated aqueous NaHCO3 (7 mL) and extracted with CH2-
Cl2 (3 × 7 mL). The combined organic layers were washed
with brine (5 mL), dried (Na2SO4), and concentrated to give
56 mg of a pale gum. Flash chromatography (25 to 50%
EtOAc/Hex gradient elution) provided 13 as a clear film (19
mg, 0.043 mmol, 51%): 1H NMR δ 7.20-7.36 (m, 5H), 7.05-
7.11 (m, 6H), 6.97-7.01 (m, 2H), 6.85-6.89 (m, 2H), 5.82 (d,
J ) 8.1 Hz, 1H), 4.96 (d, J ) 8.1 Hz, 1H), 4.42 (d, J ) 11.7 Hz,
1H), 4.34 (d, J ) 11.7 Hz, 1H), 4.01 (q, J ) 8.6 Hz, 1H), 3.66
(dd, J ) 4.1, 9.8 Hz, 1H), 3.57 (dd, J ) 6.7, 9.8 Hz, 1H), 2.96
(m, 2H), 2.18 (dd, J ) 8.6, 12.1 Hz, 1H), 2.05 (dd, J ) 8.6,
12.1 Hz, 1H), 1.35 (s, 3H); 13C NMR δ 157.4, 137.8, 135.2,
134.4, 128.4, 128.3, 127.9, 127.8, 127.7, 127.6, 126.0, 79.6, 73.3,
71.3, 68.5, 65.5, 49.0, 46.7, 39.2, 29.3; IR (film) 3444, 1749 cm-1
;
mp 117-118 °C. Anal. Calcd for C28H29NO4: C, 75.82; H,
6.59; N, 3.16. Found: C, 76.00; H, 6.56; N, 3.14.
Cyclobu ta n ol 14. A solution of TiCl4 (1.0 M in CH2Cl2,
0.110 mL, 0.110 mmol) was added dropwise to a -78 °C
solution of 12b (40.1 mg, 0.091 mmol) and Et3SiH (0.023 mL,
0.14 mmol) in CH2Cl2 (0.80 mL). After stirring for 1 h, the
reaction mixture was quenched with 1 N HCl (7 mL) and
extracted with CH2Cl2 (3 × 7 mL). The combined organic
extracts were washed with brine (5 mL), dried (Na2SO4), and
concentrated to give 45 mg of a clear film. Purification by flash
chromatography (25% EtOAc/Hex) afforded 14 as a clear film
(41.2 mg, 0.086 mmol, 95%): 1H NMR δ 7.17-7.36 (m, 5H),
7.04-7.14 (m, 6H), 6.95-7.01 (m, 2H), 6.84-6.92 (m, 2H), 5.83
(d, J ) 7.9 Hz, 1H), 4.98 (d, J ) 7.9 Hz, 1H), 4.38 (d, J ) 11.7
Hz, 1H), 4.30 (d, J ) 11.7 Hz, 1H), 4.04 (q, J ) 8.6 Hz, 1H),
3.44-3.68 (m, 5H), 3.16 (m, 1H), 2.41 (dd, J ) 8.6, 12.4 Hz,
1H), 2.06 (dd, J ) 9.0, 12.4 Hz, 1H); 13C NMR δ 157.4, 137.5,
135.2, 134.3, 129.7, 128.5, 128.5, 128.4, 127.9, 127.8, 127.7,
127.6, 125.9, 79.6, 73.4, 72.6, 68.4, 65.8, 52.7, 46.4, 46.1, 36.5;
IR (film) 3418, 1746 cm-1; mp 129-131 °C. Anal. Calcd for
C
28H28ClNO4: C, 70.36; H, 5.90; N, 2.93. Found: C, 70.27; H,
6.02; N, 2.92.
P d Cl2-Ca ta lyzed Rin g Exp a n sion of 8. A suspension of
racemic 8 (17.3 mg, 0.0407 mmol), PdCl2 (1.4 mg, 0.0079
mmol), CuCl (4.4 mg, 0.044 mmol), and 70% aqueous HClO4
(0.008 mL, 0.1 mmol) in 7:1 MeCN:water (0.41 mL) was stirred
under O2 (1 atm) at room temperature for 19 h and then heated
to 60 °C for 22 h. The mixture was diluted with aq NH4Cl/
NH4OH (pH 10, 7 mL) and extracted with CH2Cl2 (3 × 5 mL).
The combined organic layer was washed with brine (5 mL),
dried (Na2SO4), and concentrated to give 16.2 mg of a clear
film. Purification by flash chromatography provided impure
R-(benzyloxymethyl)-â-(diphenyloxazolidinonyl)cyclopenta-
none (3.8 mg, 0.0086 mmol, ∼21%) and impure â-(benzyloxym-
ethyl)-â-(diphenyloxazolidinonyl)cyclopentanone (3.5 mg, 0.0079
mmol, ∼19%), each contaminated with ∼4% of the desired
cyclobutyl aldehyde.
R-(Benzyloxymethyl)-â-(diphenyloxazolidinonyl)cyclopenta-
none: 1H NMR δ 6.84-7.34 (m, 15H), 5.59 (d, J ) 8.2 Hz, 1H),

Optically Active Cyclobutanone Chemistry
J . Org. Chem., Vol. 63, No. 22, 1998 8017
5.03 (d, J ) 8.2 Hz, 1H), 4.32-4.45 (m, 3H), 4.36 (d, J ) 11.3
Hz, 1H), 4.36 (d, J ) 11.3 Hz, 1H), 3.74 (d, J ) 4.5 Hz, 2H),
2.92 (m, 1H), 2.27-2.39 (m, 1H), 2.01-2.16 (m, 2H), 1.54-
1.69 (m, 1H); 13C NMR δ 213.2, 158.1, 137.8, 135.7, 134.3,
128.6, 128.5, 128.3, 128.2, 128.0, 127.8, 127.6, 127.5, 126.0,
80.0, 73.7, 67.8, 63.7, 56.0, 51.4, 37.5, 25.4.
â-(Benzyloxymethyl)-â-(diphenyloxazolidinonyl)cyclopenta-
none: 1H NMR δ 6.83-7.37 (m, 15H), 5.59 (d, J ) 8.1 Hz, 1H),
5.00 (d, J ) 8.1 Hz, 1H), 4.51 (d, J ) 11.3 Hz, 1H), 4.45 (d, J
) 11.3 Hz, 1H), 4.33-4.44 (m, 1H), 3.61 (d, J ) 4.9 Hz, 2H),
2.87 (m, 1H), 2.53 (dd, J ) 8.7, 18.9 Hz, 1H), 2.38 (dd, J )
7.5, 18.9 Hz, 1H), 1.93-2.16 (m, 2H).
min following the addition, at which point MeOH (1 mL) was
added and the solution was concentrated. This addition/
evaporation process was repeated twice more, and followed by
the addition of a solution of NH3 in MeOH (2 mL, satd at 0
°C) and concentration to provide a brown solid. Purification
by flash chromatography (15% MeOH/CH2Cl2) provided a clear
film which was triturated (5% MeOH/CH2Cl2) to remove any
inorganic impurities. Concentration of the triturating solvent
gave 16.1 mg of a tan solid, which was triturated with Et2O
to afford 2 as a tan film (15.3 mg, 0.0614 mmol, 64%): 1H NMR
(DMSO) δ 8.23 (s, 1H), 8.12 (s, 1H), 7.19 (bs, 2H), 4.76 (t, J )
5.1 Hz, 1H), 4.56-4.67 (m, 2H), 3.48-3.55 (m, 4H), 2.77 (m,
1H), 2.43 (dt, J ) 8.0, 10.2 Hz, 1H), 2.22 (q, J ) 9.8 Hz, 1H),
2.08 (m, 1H); 13C NMR (DMSO) δ 156.0, 152.2, 149.4, 139.6,
119.1, 63.6, 61.6, 47.7, 47.4, 33.2, 29.2; IR (film) 3329, 3196,
1648, 1601, 1572 cm-1; mp 155-156 °C (lit. 149-151 °C).15b
Anal. Calcd for C11H15N5O2: C, 53.00; H, 6.07; N, 28.10.
Silyl Eth er 15. To a solution of alcohol 9b (0.411 g, 0.926
mmol) and imidazole (94.6 mg, 1.39 mmol) in DMF (5 mL) was
added TBDMSCl (0.174 g, 1.16 mmol). After stirring for 45
min, the reaction mixture was diluted with Et2O (40 mL),
washed with H2O (2 × 20 mL), and washed with brine (20
mL). The organic layer was dried (Na2SO4) and concentrated
to provide 0.515 g of a white solid. Purification by flash
chromatography (15% EtOAc/Hex) afforded silyl ether 15 as
a white solid (0.465 g, 0.834 mmol, 90%): 1H NMR δ 7.26-
7.37 (m, 5H), 7.00-7.09 (m, 6H), 6.91-6.97 (m, 2H), 6.82-
6.87 (m, 2H), 5.74 (d, J ) 8.0 Hz, 1H), 5.04 (d, J ) 8.0 Hz,
1H), 4.49 (d, J ) 12.0 Hz, 1H), 4.45 (d, J ) 12.0 Hz, 1H), 4.05
(q, J ) 9.3 Hz, 1H), 3.54 (d, J ) 5.1 Hz, 2H), 3.49 (dd, J ) 4.8,
10.3 Hz, 1H), 3.41 (dd, J ) 4.9, 10.3 Hz, 1H), 2.69 (m, 1H),
1.80-1.98 (m, 2H), 1.57 (m, 1H), 0.84 (s, 9H), -0.04 (s, 3H),
-0.05 (s, 3H); 13C NMR δ 157.6, 138.6, 136.0, 134.4, 128.2,
128.0, 127.7, 127.6, 127.4, 127.3, 126.0, 80.0, 73.0, 71.4, 64.8,
Found: C, 52.87; H, 6.09; N, 28.28. [R]24 -39.7 (c 1.0,
D
pyridine) [lit. -45.7 (c 1.0, pyridine)17].
3′-epi-15. To a solution of alcohol 9a (0.126 g, 0.283 mmol)
and imidazole (29.8 mg, 0.438 mmol) in DMF (1 mL) was added
TBDMSCl (53.6 mg, 0.356 mmol). The solution was stirred
for 2.5 h, diluted with Et2O (15 mL), and washed with water
(2 × 8 mL) and brine (5 mL). The organic layer was dried
(Na2SO4) and concentrated to give a 0.16 g of white solid.
Purification by flash chromatography (15% EtOAc/Hex) af-
forded a ∼9:1 ratio of epimers (1H NMR) of 3′-epi-15 as a white
solid (0.140 g, 0.251 mmol, 89%): 1H NMR δ 7.24-7.36 (m,
5H), 7.01-7.07 (m, 6H), 6.90-6.96 (m, 2H), 6.84-6.89 (m, 2H),
5.71 (d, J ) 8.0 Hz, 1H), 5.07 (d, J ) 8.0 Hz, 1H), 4.49 (d, J )
11.7 Hz, 1H), 4.42 (d, J ) 11.7 Hz, 1H), 4.23 (q, J ) 9.1 Hz,
1H), 3.53-3.68 (m, 4H), 3.11 (m, 1H), 2.24 (m, 1H), 1.92 (m,
1H), 1.78 (m, 1H), 0.81 (s, 9H), -0.04 (s, 6H); 13C NMR δ 157.8,
138.5, 136.0, 134.5, 128.3, 128.1, 128.0, 127.7, 127.6, 127.5,
127.4, 126.0, 79.9, 73.2, 69.9, 64.0, 62.5, 51.0, 41.8, 32.7, 27.3,
25.8, 18.0, -5.6, -5.7; IR (film) 1752 (CO) cm-1; mp 104-105
°C. Anal. Calcd for C34H43NO4Si: C, 73.21; H, 7.77; N, 2.51.
Found: C, 73.34; H, 7.59; N, 2.56.
63.8, 48.3, 43.4, 33.6, 27.2, 25.9, 18.2, -5.5; IR (film) 1752 cm-1
;
mp 98-99 °C. Anal. Calcd for C34H43NO4: C, 73.21; H, 7.77;
N, 2.51. Found: C, 73.45; H, 7.79; N, 2.49. [R]24 2.7 (c 1.0,
D
CHCl3).
P yr im id in e 16. A mixture of silyl ether 15 (0.460 g, 0.825
mmol), Et3N (1.15 mL, 8.25 mmol), and 20% Pd(OH)2/C (0.405
g) in EtOH (8.2 mL) was stirred under H2 (35 psi) for 25 h,
filtered through Celite, and concentrated to give 0.40 g of clear
oil. Purification by flash chromatography (30% EtOAc/Hex to
10% MeOH/CH2Cl2, 1% Et3N gradient elution) provided 0.198
g of impure free amine as a clear oil, which was used without
further purification: 1H NMR δ 7.23-7.37 (m, 5H), 4.50 (s,
2H), 3.43-3.61 (m, 4H), 3.07 (q, J ) 7.8 Hz, 1H), 2.25 (dt, J )
7.8 10.8 Hz, 1H), 1.92-2.03 (m, 1H), 1.79-1.92 (m, 1H), 1.70
(bs, 2H), 1.35 (dt, J ) 9.1, 10.4 Hz, 1H), 0.89 (s, 9H), 0.03 (s,
6H); 13C NMR δ 138.7, 128.2, 127.4, 72.9, 72.1, 65.8, 49.7, 48.3,
33.0, 32.7, 25.9, 18.3, -5.4.
3′-epi-16. A suspension of 3′-epi-15 (0.216 g, 0.388 mmol),
Et3N (0.16 mL, 1.1 mmol), and 20% Pd(OH)2/C (0.156 mg) was
stirred under H2 (35 psi) for 21 h. The mixture was filtered
through Celite and evaporated to give 0.19 g of a clear oil.
Purification by flash chromatography (30% EtOAc/Hex to 5%
MeOH/CH2Cl2, 1% Et3N gradient elution) provided 94.2 mg
of the free amine as a clear oil, which was used without further
purification: 1H NMR δ 7.24-7.37 (m, 5H), 4.49 (s, 2H), 3.53-
3.69 (m, 4H), 3.31 (m, 1H), 2.52 (bs, 2H), 2.32-2.41 (m, 2H),
2.07 (m, 1H), 1.72 (dt, J ) 8.6, 11.0 Hz, 1H), 0.87 (s, 9H), 0.01
(s, 6H); 13C NMR δ 138.6, 128.3, 127.6, 127.5, 73.1, 70.2, 63.2,
50.4, 48.1, 32.2, 32.0, 25.9, 18.1, -5.5.
A solution of the crude oil, Et3N (0.16 mL, 1.1 mmol), and
5-amino-4,6-dichloropyrimidine (92.5 mg, 0.564 mmol) in
n-BuOH (2.5 mL) was heated in a sealed vial to 120 °C for 44
h. Concentration and flash chromatographic purification (20%
EtOAc/Hex) of the reaction mixture yielded the desired product
3′-epi-16 as a white foam which was crystallized (Et2O/Hex)
to give a white solid (74.4 mg, 0.161 mmol, 41%): 1H NMR δ
8.02 (s, 1H), 7.22-7.32 (m, 5H), 5.12 (d, J ) 6.6 Hz, 1H), 4.45-
4.55 (m, 3H), 3.71-3.82 (m, 3H), 3.61-3.71 (m, 1H) 3.40 (bs,
2H), 2.64 (m, 1H), 2.46 (quin, J ) 8.1 Hz, 1H), 2.29 (t, J ) 2.2,
9.1 Hz, 1H), 1.88 (dt, J ) 9.1, 11.3 Hz, 1H), 0.90 (s, 9H), 0.05
(s, 3H), 0.04 (s, 3H); 13C NMR δ 154.4, 149.7, 143.0, 138.3,
128.3, 127.6, 121.5, 73.3, 70.1, 63.0, 48.9, 45.6, 33.0, 30.9, 25.9,
18.2, -5.4, -5.5; IR (film) 3352, 3246, 1576 cm-1; mp 112-
113 °C; HRMS m/z (M + H) calcd 463.2296, obsd 463.2280.
5′-O-Ben zyl-3′-epi-2. Concentrated aq HCl (0.04 mL) was
added to a solution of 3′-epi-16 (44.3 mg, 0.0956 mmol) in EtOH
(0.5 mL) and concentrated. The residue was dissolved in DMF
(0.30 mL), and HC(OEt)3 (0.11 mL) was added. The solution
was heated to 80 °C in a sealed vial for 3.5 h, transferred to a
pressure tube, and concentrated. The resultant residue was
dissolved in a solution of NH3 in MeOH (0.75 mL, satd at 0
°C) and heated to 60 °C for 20 h. Evaporation of the reaction
mixture gave 42 mg of a brown film, which was purified by
flash chromatography (3% to 6% MeOH/CH2Cl2 gradient
A solution of the crude oil, Et3N (0.33 mL, 2.4 mmol), and
5-amino-4,6-dichloropyrimidine (0.194 g, 1.18 mmol) in n-
BuOH (4.0 mL) was heated in a sealed vial to 110 °C for 23 h.
Concentration and flash chromatographic purification (20%
EtOAc/Hex) of the reaction mixture yielded the desired product
16 as a yellow gum (0.226 g, 0.487 mmol, 59%): 1H NMR δ
8.04 (s, 1H), 7.22-7.38 (m, 5H), 4.96 (d, J ) 6.9 Hz, 1H), 4.53
(d, J ) 12.1 Hz, 1H), 4.49 (d, J ) 12.1 Hz, 1H), 4.30 (quin, J
) 9.0 Hz, 1H), 3.53-3.66 (m, 4H), 3.32 (bs, 2H), 2.46 (dt, J )
7.9 10.7 Hz, 1H), 2.33 (ddt, J ) 5.9, 6.2, 8.3 Hz, 1H), 2.09 (m,
1H), 1.62 (q, J ) 9.9 Hz, 1H), 0.90 (s, 9H), 0.05 (s, 6H); 13C
NMR δ 154.5, 149.7, 138.5, 128.3, 127.5, 127.4, 121.5, 73.1,
71.9, 65.1, 46.7, 46.4, 34.0, 30.5, 26.0, 18.3, -5.3; IR (film) 3352,
3246, 1643, 1576 cm-1
. Anal. Calcd for C23H35N4O2Si: C,
59.65; H, 7.62; N, 12.10. Found: C, 60.00; H, 7.63; N, 12.24.
[R]24 -46.0 (c 1.0, CHCl3).
D
Cyclobu t-A 2. Following the general procedure of Par-
ratt,30 concentrated aq HCl (0.04 mL) was added to a solution
of pyrimidine 16 (44.4 mg, 0.0959 mmol) in EtOH (1 mL),
which was then concentrated to a gummy foam. Following
the addition of HC(OEt)3 (0.11 mL, 0.66 mmol) and DMF (0.25
mL), the resultant solution was heated to 70 °C for 3 h,
transferred to a pressure tube, concentrated, and redissolved
in a solution of NH3 in MeOH (1.5 mL, satd at 0 °C). After
heating to 70 °C in the sealed tube for 24 h, the mixture was
concentrated, dried by coevaporation with PhMe, and diluted
with CHCl3 (0.90 mL). The brown mixture was cooled to -78
°C, and a solution of BCl3 in CH2Cl2 (1.0 M, 1.35 mL, 1.35
mmol) was added. The mixture was allowed to warm over 30

8018 J . Org. Chem., Vol. 63, No. 22, 1998
Brown and Hegedus
elution) to yield 5′-O-benzyl-3′-epi-2 as a white solid (17.9 mg,
0.0527 mmol, 55%): 1H NMR δ 8.34 (s, 1H), 7.86 (s, 1H), 7.27-
7.38 (m, 5H), 5.88 (bs, 2H), 5.01 (m, 1H), 4.56 (s, 2H), 3.80-
3.90 (m, 2H), 3.69-3.80 (m, 2H), 3.44 (m, 2H), 2.78 (m, 2H),
2.43 (t, J ) 8.1 Hz, 1H); 13C NMR δ 155.5, 152.7, 150.2, 139.2,
137.1, 128.5, 128.1, 127.9, 120.1, 73.6, 68.0, 62.0, 49.7, 44.0,
33.8, 28.8; IR (film) 3322, 3169, 1652, 1599, 1574 cm-1; mp
145-147 °C.
3′-epi-Cyclobu t-A. A solution of BCl3 (1.0 M in CH2Cl2,
0.84 mL, 0.84 mmol) was added to a -78 °C suspension of 5′-
O-benzyl-3′-epi-2 (28.6 mg, 0.0843 mmol) in CHCl3 (0.85 mL).
After the addition, the cooling bath was removed and the
mixture was stirred for 30 min. The reaction was quenched
with MeOH (0.5 mL) and evaporated. This process was
repeated twice and followed by the addition of a solution of
NH3 in MeOH (0.5 mL, satd at 0 °C) and concentration to
afford a brown solid. Flash chromatography (15% MeOH/CH2-
Cl2) followed by trituration (5% MeOH/CH2Cl2) and evapora-
tion to remove insoluble material provided 18.6 mg of ∼90%
pure 3′-epi-2 as a white foam (0.0746 mmol, 89%). Recrystal-
lization (EtOH/EtOAc) provided analytically pure material (8.2
mg, 0.033 mmol, 39%): 1H NMR (DMSO) δ 8.29 (s, 1H), 8.12
(s, 1H), 7.19 (bs, 2H), 4.82 (q, J ) 8.6 Hz, 1H), 4.76 (t, J ) 4.9
Hz, 1H), 4.60 (t, J ) 4.9 Hz, 1H), 3.52-3.75 (m, 4H), 3.19 (m,
1H), 2.62 (q, J ) 9.5 Hz, 1H), 2.50 (m, 1H), 2.26 (t, J ) 9.8
Hz, 1H); 13C NMR (DMSO) δ 156.0, 152.1, 149.4, 139.8, 119.2,
60.6, 59.8, 50.0, 45.8, 32.5, 28.7; IR (film) 3330, 3180, 1652,
1601, 1571 cm-1; mp 187-188 °C (lit. 190-191);31 HRMS m/z
(M + H) calcd 250.1304, obsd 250.1305.
Ack n ow led gm en t. Support for this research under
Grant No. GM26178 from the National Institutes of
General Medical Sciences (Public Health Service) is
gratefully acknowledged. Mass spectra were obtained
on instruments supported by the National Institutes of
Health shared instrumentation grant GM49631.
J O9817063