Synthesis of 1-amino-3-[(dihydroxyboryl)methyl]-cyclobutanecarboxylic acid as a potential therapy agent

Article abstract of DOI:10.1021/jo048824c

A novel boronated aminocyclobutanecarboxylic acid (1) was synthesized for potential use in boron neutron capture therapy. Starting from the readily available 3-(bromomethyl)cyclobutanone ketal (4), several synthetic routes to 1 were evaluated. After sever

Full text of DOI:10.1021/jo048824c

Synthesis of 1-Amino-3-[(dihydroxyboryl)methyl]-
cyclobutanecarboxylic Acid as a Potential Therapy Agent
George W. Kabalka* and Min-Liang Yao
Departments of Chemistry and Radiology, The University of Tennessee, Knoxville, Tennessee 37996-1600
kabalka@utk.edu
Received July 12, 2004
A novel boronated aminocyclobutanecarboxylic acid (1) was synthesized for potential use in boron
neutron capture therapy. Starting from the readily available 3-(bromomethyl)cyclobutanone ketal
(4), several synthetic routes to 1 were evaluated. After several unsuccessful attempts with traditional
synthetic methods, a novel synthetic strategy to generate the new boronated cyclic amino acid was
developed. The tolerance of the hydantoin group to the selenoxide elimination reaction conditions
in the preparation of alkenyl compound 7 proved to be the key step in the new strategy.
Introduction
rins,7 and peptides.8 In recent years, encouraging results
have been obtained by using 4-dihydroxyborylphenyl-
alanine (BPA) as the tumor-specific boronated agent.9
It is believed that the amino acids are preferentially
taken up by growing tumor cells. Positron emission
tomography (PET) investigations10 with carbon-11 la-
beled 1-aminocyclobutanecarboxylic acid (ACBC) dem-
onstrated that this amino acid localizes in tumors more
avidly than BPA. Recently Goodman reported that flu-
orine-18 labeled 1-amino-3-(fluoromethyl)cyclobutanecar-
boxylic acid also localizes in tumors.11 For these reasons,
we have focused our efforts on the synthesis of boronated
In recent years, there has been renewed interest in
boron neutron capture therapy1 (BNCT), a binary ap-
proach for cancer treatment. The potential use of boron
compounds for the treatment of cancer is based upon the
unique nuclear properties of the 10B nucleus. After
absorption of a neutron, the high-energy 11B nucleus that
is produced undergoes fission and releases an R-particle
and a high-energy lithium-7 ion. These heavy charged
particles have a range of approximately one cell diameter
and thus they are lethal to the cells in which they are
generated. To minimize the damage to normal tissues,
the selective targeting of tumor cells by boron compounds
is the key for the clinical success of BNCT. To date, a
variety of molecules have been used to deliver boron to
tumor cells. These include carbohydrates,2 polyamines,3
amino acids,4 nucleosides,5 antisense agents,6 porphy-
(5) (a) Tjarks, W. J. Organomet. Chem. 2001, 614-615, 37. (b)
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* Address correspondence to this author. Fax: 865-974-2997.
Phone: 865-974-3260.
(1) For recent reviews, see: (a) Valliant, J. F.; Guenther, K. J.; King,
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10.1021/jo048824c CCC: $27.50 © 2004 American Chemical Society
Published on Web 10/27/2004
8280
J. Org. Chem. 2004, 69, 8280-8286

1-Amino-3-[(dihydroxyboryl)methyl]cyclobutanecarboxylic Acid
SCHEME 1
ACBC derivatives.12-14 Herein we wish to report the
synthesis of 1-amino-3-[(dihydroxyboryl)methyl]cyclobu-
tanecarboxylic acid 1.
produce terminal alkene 7. Interestingly both routes use
3-(bromomethyl)cyclobutanone ketal, 4, as the starting
material.
3-(Bromomethyl)cyclobutanone ketal, 4, could be ob-
tained in 51% overall yield by using the sequence outlined
in Scheme 2. The synthesis of 11 and 12 was described
earlier.18 As noted in the earlier report, the use of 1,2-
hexanediol in place of ethanediol stabilizes the ketal
during the subsequent debenzylation reaction. The use
of the unsymmetrical diol does result in the formation of
a new chiral center and leads to the formation of a
mixture (1:1) of diastereomers (readily observable in the
13C NMR spectra). Starting from 4, the two synthetic
routes (Scheme 1) were evaluated and the results are
presented below.
Results and Discussion
The retrosynthetic analyses for 1 are outlined in
Scheme 1. There are two reasonable synthetic routes to
1: initial introduction of the boronic acid function to the
target molecule (defined as route A) and initial introduc-
tion of the amino acid, or its precursor hydantoin (defined
as route B). The key step in route A is the preparation of
ketal 3. With ketal 3 in hand, the amino acid portion can
be constructed with use of Bu¨cherer-Strecker methodol-
ogy. To prepare ketal 3, three literature methods are
available (the reaction of a Grignard reagent derived from
4 with a borate ester,15 hydroboration of alkene 5,16 or
Miyaura borylation of alkenyl bromide 6).17 The key
step in route B is the elimination reaction required to
Evaluation of Route A. The preparation of the
prerequisite boronic acid with use of Grignard methodol-
ogy was investigated.15 The reaction of ketal 4 with 1.2
SCHEME 2a
(11) Martarello, L.; McConathy, J.; Camp, V. M.; Malveaux, E. J.;
Simpson, N. E.; Simpson, C. P.; Olson, J. J.; Bowers, G. D.; Goodman,
M. M. J. Med. Chem. 2002, 45, 2250.
(12) (a) Das, B. C.; Das, S.; Li, G.; Bao, W.; Kabalka, G. W. Synlett
2001, 1419. (b) Das, B. C.; Kabalka, G. W.; Srivastava, R. R.; Bao, W.;
Das, S.; Li, G. J. Organomet. Chem. 2000, 614-615, 255. (c) Srivastava,
R. R.; Singhaus, R.; Kabalka, G. W. J. Org. Chem. 1997, 62, 4476.
(13) Srivastava, R. R.; Singhaus, R.; Kabalka, G. W. J. Org. Chem.
1999, 64, 8495.
(14) (a) Kabalka, G. W.; Yao, M.-L. Appl. Organomet. Chem. 2003,
17, 398. (b) Kabalka, G. W.; Yao, M.-L. Synthesis 2003, 2890.
(15) (a) Brown, H. C.; Cole, T. E. Organometallics 1983, 2, 1316. (b)
Washburn, R. M.; Levens, E.; Albright, C. F.; Billig, F. A. Org. Synth.
1959, 39, 3.
(16) (a) Ishiyama, T.; Yamamoto, M.; Miyaura, N. Chem. Commun.
1996, 2073. (b) Wang, K.-K.; Liu, C.; Gu, Y.-G.; Burnett, F. N. J. Org.
Chem. 1991, 56, 1914.
(17) (a) Giroux, A. Tetrahedron Lett. 2003, 44, 233. (b) Furstner,
A.; Seidel, G. Org. Lett. 2002, 4, 541. (c) Takahashi, K.; Takagi, J.;
Ishiyama, T.; Miyaura, N. Chem. Lett. 2000, 127. (d) Ishyiyama, T.;
Ahiko, T.-A.; Miyaura, N. Tetrahedron Lett. 1997, 38, 3447. (e)
Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60, 7508.
a Reagents and conditions: (a) Cl3CCOCl, POCl3, Zn-Cu, Et2O;
(b) Zn, HOAc; (c) hexane-1,2-diol, PTSA, benzene, reflux; (d) Pd/
C, CH3OH, H2 (1 atm), rt; (e) CBr4, PPh3, DCM, rt.
J. Org. Chem, Vol. 69, No. 24, 2004 8281

Kabalka and Yao
equiv of magnesium powder in THF proceeded smoothly
to generate the corresponding Grignard reagent.19 Sur-
prisingly the reaction of this Grignard reagent with the
borate esters was unsuccessful.
Dehydrobromination of 4 with NaOH in PEG-600 gen-
erated 3-methylenecyclobutanone ketal, 5, in 67% yield20
(eq 1). Hydroboration of 5 to generate 3 with either
catecholborane or diisopinocampheylborane (Ipc2BH)
proved problematic due to reduction of the ketal group.
produce the anticipated hydantoin 19. A mixture was
obtained with hydantoin 20 being the main product
(Scheme 5).23
SCHEME 5a
We then evaluated the Miyaura borylation reaction,17
a palladium-catalyzed coupling of an alkenyl halide with
bis(pinacolato)diboron. Alkenyl bromide 6 was prepared
a Reagents and conditions: (a) HCl (2 M), EtOH/H2O, reflux;
(b) (NH4)2CO3, KCN, EtOH/H2O (1:1), 60 °C.
21
from alkene 5 in two steps (Scheme 3). Under typical
Miyaura conditions (5 mol % of PdCl2(PPh3)2‚2PPh3 and
1.5 equiv of PhOK in toluene at 50 °C),17c the reaction of
6 with 1.1 equiv of bis(pinacolato)diboron afforded only
a trace of the anticipated alkenylboronic ester 14. How-
ever, dicyclobutylideneethane 15 was obtained in 84%
isolated yield.
Generation of alkene 7 by selenoxide elimination ap-
peared to be a reasonable approach (Scheme 6). Treat-
ment of 3-(bromomethyl)cyclobutanone ketal, 4, with
benzeneselenolate anion (generated from either benzene-
selenol24 or diphenyl diselenide25) provided selenide 21
in high yield. Removal of the ketal group with dilute HCl
in refluxing ethanol produced 3-(phenylselanylmethyl)-
cyclobutanone, 22. It should be pointed out that the prep-
aration of ketone 22 from allylbenzylselane via a [2+2]
cycloaddition reaction with dichloroketene was reported
to be unsuccessful.26 The reaction of ketone 22 with am-
monium carbonate and potassium cyanide in an Ace pres-
sure tube afforded hydantoin 23 in a 3:1 ratio of stereo-
isomers with the cis-isomer being the major product.27
Oxidation of 23 with NaIO4 in aqueous methanol pro-
duced 24 in quantitative yield.28 In the presence of sodi-
um bicarbonate, selenoxide elimination occurred in re-
fluxing methanol29 to produce 7 in moderate yield (45%).
SCHEME 3a
a Reagents and conditions: (a) Br2, DCM, 0 °C to rt; (b) KOH,
EtOH, reflux; (c) di(pinacolato)diboron, PhOK, Pd(PPh3)2Cl2, PPh3.
(18) Kabalka, G. W.; Yao, M.-L. Tetrahedron Lett. 2003, 44, 1879.
(19) To verify formation of the Grignard reagent derived from 4,
we quenched a reaction with D2O (separate experiment). 1H NMR
analysis revealed the presence of the monodeuterated product: ap-
pearance of a new multiplet at 1.11 ppm (-CH2D) and disapperance
of the multiplet at 3.49 ppm (-CH2Br).
Evaluation of Route B. We then turned our attention
to route B, in which the hydantoin group is introduced
first. This synthetic strategy proved quite efficient in the
synthesis of ACBC derivatives bearing long alkylboronic
acid side chains (Scheme 4).14
(20) Kimura, Y.; Regen, S. L. J. Org. Chem. 1982, 47, 2493.
(21) Du, Z.-M.; Haglund, M. J.; Pratt, L. A.; Erickson, K. L. J. Org.
Chem. 1998, 63, 8880.
SCHEME 4
(22) (a) Jennings, L. D.; Rayner, D. R.; Jordan, D. B.; Okonya, J.
F.; Basarab, G. S.; Amorose, D. K.; Anaclerio, B. M.; Lee, J. K.;
Schwartz, R. S.; Whitemore, K. A. Bioorg. Med. Chem. 2000, 8, 897.
(b) Hoz, S.; Livneh, M. J. Am. Chem. Soc. 1987, 109, 7483.
(23) The unanticipated ring expansion reaction presumably proceeds
via a bicyclic intermediate under basic conditions.
As part of our study, we attempted to remove the ketal
group in 5 using dilute HCl. The reaction generated
undesired ketone 17, resulting from addition of HCl to
the highly strained methylenecyclobutanone 16 (eq 2).22
(24) Miyashita, M.; Yoshikoshi, A. Synthesis 1980, 664.
(25) Liotta, D.; Sunay, U.; Santiesteban, H.; Markiewicz, W. J. Org.
Chem. 1981, 46, 2605.
(26) Johnston, B. D.; Czyzewska, E.; Oehlschlager, A. C. J. Org.
Chem. 1987, 52, 3693.
(27) Rammeloo, T.; Stevens, C. Chem. Commun. 2002, 250.
(28) (a) Zhu, Y.; van der Donk, W. A. Org. Lett. 2001, 3, 1189. (b)
Evans, P. A.; Holmes, A. B.; Russell, K. Tetrahedron: Asymmetry 1990,
1, 593.
(29) Selenoxide elimination reactions are generally carried out in
1,2-dichloroethane. In our case, this proved problematic due to the NH
group in hydantoin 24. In the presence of base, a SN2 reaction between
1,2-dichloroethane and 24 took place.
Thus, generation of the alkene moiety, after construc-
tion of the hydantoin group, was the only remaining route
for the preparation of 1. Removal of the ketal group from
3-(bromomethyl)cyclobutanone ketal, 3, regenerated ke-
tone 18, but the Bu¨cherer-Strecker reaction did not
8282 J. Org. Chem., Vol. 69, No. 24, 2004

1-Amino-3-[(dihydroxyboryl)methyl]cyclobutanecarboxylic Acid
SCHEME 6a
a Reagents and conditions: (a) PhSeNa (or PhSNa), CH3OH, rt; (b) HCl (2 M), EtOH/H2O, reflux; (c) KCN, (NH4)2CO3, EtOH/H2O
(1:1), 60 °C; (d) NaIO4, CH3OH, rt; (e) NaHCO3, CH3OH, 70 °C; (f) (Ipc)2BH, THF, 0 °C to rt; (g) CH3CHO, THF, 0 °C to rt; (h) HCl (2 M)
rt; (i) HCl (12 M) HCl, 150 °C.
an addition funnel and reflux condenser, was charged with
allyl benzyl ether (30 mmol, 4.4 g), freshly prepared zinc-
copper couple (100 mmol, 6.5 g), and anhydrous diethyl ether
(50 mL). A solution of trichloroacetyl chloride (60 mmol, 6.7
mL) and phosphorus oxychloride (60 mmol, 5.6 mL) in diethyl
ether (100 mL) was placed in the addition funnel and the
solution added dropwise over a period of 30 min. After the
addition was complete, the mixture was refluxed at 55 °C (oil
bath) for 2 days under an argon atmosphere, cooled to room
temperature, and filtered through a pad of Celite. Additional
diethyl ether was used to wash the Celite. The solvent from
the combined filtrates was removed in vacuo and the resi-
due dissolved in petroleum ether (3 × 100 mL). The clear
yellow solution was decanted into a separatory funnel, washed
with water (2 × 50 mL) and brine (50 mL), dried over
anhydrous magnesium sulfate, and concentrated with a rotary
evaporator to obtain 9 as a light yellow liquid. Compound 9
was unstable on silica gel and was therefore used directly for
the next step.
Considering both the toxicity and the expense of
selenium compounds, a similar synthetic route, using
sulfur in place of selenium, was examined. However, the
synthetic route was hampered by the resistance of
sulfoxide 28 to elimination.
The hydroboration of 7 was realized by treatment of 7
with 3.0 equiv of diisopinocampheylborane (Ipc2BH) in
THF at room temperature.30 The hydrolysis of 29 in the
presence of concentrated HCl gave 1 in good yield.
Conclusion
We report the synthesis of a novel 1-aminocyclobutane-
carboxylic acid containing an alkylboronic acid. Several
synthetic routes to 1 starting from 3-(bromomethyl)-
cyclobutanone ketal, 4, were evaluated. A novel synthetic
strategy to boronated cyclic amino acid was developed
after failures encountered with traditional synthetic
methods. The generation of the alkenyl group via a
selenoxide elimination in the presence of a hydantoin
group proved to be the key step in the novel strategy.
The new agent is currently being evaluated as a BNCT
agent.
3-(Benzyloxymethyl)cyclobutanone (10). Crude 9 was
dissolved in glacial acetic acid (20 mL) and zinc dust (10 g,
excess) was added in portions. The mixture was stirred at room
temperature for 30 min and then heated at 120 °C (oil bath)
for 12 h. Thin-layer chromatography indicated the disappear-
ance of the starting material. The mixture was cooled to room
temperature, neutralized with saturated sodium bicarbonate
at 0 °C, and passed through a pad of Celite. Ethyl acetate was
used to wash the Celite. The combined filtrate was then
extracted with ethyl acetate (3 × 50 mL). The combined
organic layer was washed with water (2 × 20 mL) and brine
(20 mL), dried over anhydrous magnesium sulfate, and
concentrated under reduced pressure to obtain a thick light
yellow liquid. The crude product was purified by column
chromatography (EtOAc:hexanes ) 1:15). 3-Benzyloxymeth-
ylcyclobutanone, 10, was obtained as a colorless liquid (3.2 g,
Experimental Section
General Methods. All reagents were used as received.
Diethyl ether and tetrahydrofuran were distilled from sodium
benzophenone ketyl. Column chromatography was performed
with silica gel (60 Å, 230-400 mesh). Analytical thin-layer
chromatography was performed with 250-µm silica and was
visualized by phosphomolybdic acid.
1H NMR and 13C NMR spectra were recorded at 250.13 and
62.89 MHz, respectively. In cases where more than one isomer
formed, we have reported the 13C NMR of the major isomer.
Chemical shifts for 1H NMR and 13C NMR spectra were
referenced to TMS and measured with respect to the residual
protons in the deuterated solvents. HR-FAB-MS (M + 1) were
obtained in a glycerol matrix.
1
56%, yield based on allyl benzyl ether). H NMR (250 MHz,
CDCl3) δ 7.22-7.42 (m, 5H), 4.55 (s, 2H), 3.58 (d, J ) 6.68
Hz, 2H), 3.05-3.17 (m, 2H), 2.78-2.94 (m, 2H), 2.62-2.71 (m,
1H). 13C NMR δ 207.2, 138.0, 128.3, 127.6, 127.5, 73.1, 72.8,
50.0, 23.6.
3-(Benzyloxymethyl)cyclobutanone Ketal (11). A 250-
mL, round-bottomed flask equipped with a Dean-Stark ap-
paratus and a reflux condenser was charged with 10 (7.6 g,
40 mmol), hexane-1,2-diol (6.2 g, 44 mmol), and p-toluene-
sulfonic acid (500 mg) in benzene (150 mL). The mixture was
refluxed at 120 °C (oil bath) for 14 h and the progress of the
3-Benzyloxymethyl-2,2-dichlorocyclobutanone (9). A
250-mL, three-necked, round-bottomed flask, equipped with
(30) Petter, A.; Smith, K.; Brown, H. C. Borane Reagents; Academic
Press: New York, 1988; p 427.
J. Org. Chem, Vol. 69, No. 24, 2004 8283

Kabalka and Yao
reaction was monitored by TLC. After 14 h the flask was cooled
to room temperature and saturated aqueous NaHCO3 (20 mL)
was added. The mixture was transferred to a separatory
funnel, washed with H2O (15 mL) and brine (15 mL), dried
(MgSO4), and concentrated under reduced pressure to give a
colorless oil. The product was purified by column chromatog-
raphy (EtOAc:hexanes ) 1:20) to yield 11.2 g (97%) of 11 as a
colorless liquid. 1H NMR (250 MHz, CDCl3) δ 7.25-7.41 (m, 5
H), 4.50 (s, 2 H), 3.90-4.02 (m, 2 H), 3.48 (d, J ) 6.26 Hz, 2
H), 3.42 (dd, J ) 12.3, 6.7 Hz, 1 H), 2.18-2.46 (m, 3 H), 2.05-
2.17 (m, 2 H), 1.17-1.65 (m, 6 H), 0.90 (t, J ) 6.49 Hz, 3 H).
13C NMR δ 138.4, 128.2, 127.5, 106.8, 106.7, 75.8, 75.5, 74.2,
72.8, 68.9, 68.6, 39.1, 38.7, 33.3, 33.0, 27.8, 24.7, 24.5, 22.6,
14.0. Anal. Calcd for C18H26O3: C, 74.45, H, 9.02. Found: C,
74.23; H, 9.08.
3-(Hydroxymethyl)cyclobutynone Ketal (12). To a 100-
mL, round-bottomed flask fitted with a septum cap were added
compound 11 (11.2 g, 38.6 mmol), 10% Pd/C (1.12 g), and
MeOH (60 mL). The air in the flask was removed under
vacuum and H2 was introduced by using a H2-filled balloon.
After being stirred for 24 h at room temperature, the mixture
was filtered and the residual Pd/C was washed with MeOH.
Concentration of the filtrate and washings under reduced
pressure yielded the colorless product 12 (7.6 g, 99%). 1H NMR
(250 MHz, CDCl3) δ 3.93-4.05 (m, 2 H), 3.63 (d, J ) 6.18 Hz,
2 H), 3.45 (dd, J ) 12.4, 6.7 Hz, 1 H), 3.68 (s, 1 H), 2.23-2.47
(m, 3 H), 2.00-2.17 (m, 2 H), 1.16-1.64 (m, 6 H), 0.91 (t, J )
6.48 Hz, 3 H). 13C NMR δ 106.7, 106.5, 75.9, 75.7, 69.0, 68.8,
66.7, 66.6, 38.6, 38.5, 38.3, 33.3, 33.1, 27.8, 26.8, 26.6, 22.6,
13.9. HRMS m/z calcd for C11H20O3 + 1 201.1491, found
201.1490. Anal. Calcd for C11H20O3: C, 65.97; H, 10.07.
Found: C, 65.44; H, 10.09.
mmol) and dry CH2C12 (30 mL). The solution was cooled to 0
°C, and bromine (2.5 g, 15.6 mmol) in dry CH2C12 (10 mL)
was added dropwise. After the addition was complete, the
mixture was stirred for an additional 4 h while warming slowly
to room temperature. The mixture was transferred to a
separatory funnel and washed sequentially with aqueous
saturated NaHSO3 (10 mL), H2O (10 mL) and then brine (10
mL). After the solution was dried over anhydrous MgSO4, the
solvent was removed under reduced pressure. The residue was
purified by column chromatography (EtOAc:hexanes ) 1:30)
1
to yield 3.3 g (71%) of 13 as a colorless liquid. H NMR (250
MHz, CDCl3) δ 3.92-4.05 (m, 4H), 3.44-3.53 (m, 1H), 2.69-
3.13 (m, 4H), 1.27-1.62 (m, 6H), 0.91 (t, J ) 6.75 Hz, 3H). 13
C
NMR δ 104.0, 76.4, 76.2, 69.4, 69.0, 52.9, 52.5, 51.4, 51.2, 43.9,
39.1, 33.0, 32.7, 27.7, 22.6, 13.9. Anal. Calcd for C11H18O2Br2:
C, 38.62; H, 5.30. Found: C, 38.51; H, 5.23.
3-(Bromomethylene)cyclobutanone Ketal (6). Com-
pound 13 (3.1 g, 9.0 mmol) was dissolved in aqueous ethanol
(95% ethanol in water, 10 mL), the solution treated with KOH
(1.12 g, 20 mmol), and the mixture refluxed for 1 h. The
mixture was diluted with EtOAc (50 mL), washed with brine
(10 mL), and dried over anhydrous MgSO4 and the solvent was
removed by distillation (Caution: compound 6 is volatile). The
residue was purified by chromatography (EtOAc:hexanes )
1:30) to give 1.5 g (64%) of 6 as a colorless liquid. 1H NMR
(250 MHz, CDCl3) δ 5.98 (m, 1H), 3.99-4.06 (m, 2H), 3.47-
3.51 (m, 1H), 2.97-3.00 (m, 2H), 2.89-2.93 (m, 2H), 1.16-
1.63 (m, 6H), 0.91 (t, J ) 6.38 Hz, 3H). 13C NMR δ 135.5, 104.5,
98.9, 76.5, 69.4, 46.3, 46.0, 45.0, 44.7, 33.0, 27.8, 22.6, 14.0.
HRMS calcd for M + 1 261.0446, found 261.0430.
Diene 15. Compound 6 (260 mg, 1.0 mmol), bis(pinacolato)-
diboron (280 mg, 1.1 mmol), Pd(PPh3)2Cl2 (35 mg, 0.05 mmol),
PPh3 (26 mg, 0.10 mmol), and PhOK (200 mg, 1.5 mmol) were
placed in a flask under argon atmosphere. Toluene (5 mL) was
added, the mixture was stirred at 50 °C, and the reaction was
monitored by TLC. On completion, the mixture was diluted
with ether (25 mL) and filtered through a short pad of silica
gel, and the solvent was evaporated. Purification of the residue
by column chromatography (EtOAc:hexanes ) 1:20) yielded
3-(Bromomethyl)cyclobutanone Ketal (4). To a 250-mL,
round-bottomed flask fitted with a septum cap were added
compound 12 (6.0 g, 30.0 mmol), CBr4 (12.5 g, 37.5 mmol), and
CH2C12 (50 mL). The solution was cooled with an ice-water
bath. Then Ph3P (11.8 g, 45.0 mmol) in CH2C12 (70 mL) was
added dropwise via syringe. After addition was complete, the
bath was removed and the mixture stirred for an additional 6
h. The solvent was removed under reduced pressure and the
residue extracted into ether (5 × 40 mL). The ether layer was
concentrated in vacuo and the residue purified by column
chromatography (EtOAc:hexanes ) 1:30) to yield 7.4 g (94%)
1
152 mg (84%) of diene 15. H NMR (250 MHz, CDCl3) δ 5.84
(s, 2H), 3.97-4.06 (m, 4H), 3.46-3.52 (m, 2H), 3.05 (m, 4H),
2.96 (m, 4H), 1.16-1.60 (m, 12H), 0.91 (t, J ) 6.36 Hz, 6H).
13C NMR δ 130.0, 120.0, 106.2, 76.2, 69.2, 45.2, 44.9, 43.7, 43.4,
33.1, 27.8, 22.6, 13.9. HRMS calcd for C22H34O4 362.2457, found
362.2449.
1
of 4 as a colorless liquid. H NMR (250 MHz, CDCl3) δ 3.93-
4.06 (m, 2H), 3.49 (d, J ) 7.02 Hz, 2H), 3.42-3.48 (m, 1H),
2.42-2.54 (m, 3H), 2.03-2.15 (m, 2H), 1.16-1.58 (m, 6H), 0.91
(t, J ) 6.78 Hz, 3H). 13C NMR δ 105.4, 105.2, 76.0, 75.8, 69.1,
68.8, 41.2, 41.1, 40.9, 38.4, 33.2, 33.0, 27.8, 27.7, 27.6, 22.6,
13.9. Anal. Calcd for C11H19O2Br: C, 50.20; H, 7.28. Found:
C, 50.23; H, 7.30.
3-(Bromomethyl)cyclobutanone (18). A 100-mL, round-
bottomed flask was charged with compound 4 (526 mg, 2.0
mmol) dissolved in a mixture of ethanol (10 mL) and aqueous
hydrochloric acid (3 mL, 2 M). The mixture was refluxed
overnight at which time TLC indicated complete disappearance
of the starting ketal. After cooling to room temperature, the
mixture was extracted with ether (3 × 20 mL), the combined
organic phases dried over anhydrous MgSO4, and the solvent
removed by distillation (Caution: compound 18 is volatile).
The residue was purified with silica gel column chromatog-
raphy (Et2O:pentane ) 1:20) to give 283 mg (87%) of product
3-(Methylene)cyclobutanone Ketal (5). A 100-mL, round-
bottomed flask equipped with a reflux condenser was charged
with 4 (6.6 g, 25 mmol), PEG-600 (1.5 g), 50% NaOH aqueous
solution (15 mL), and benzene (20 mL). The mixture was
refluxed at 90 °C (oil bath) and the progress of the reaction
was monitored by TLC. After 16 h, the flask was cooled to room
temperature and water (20 mL) added. The mixture was
transferred to a separatory funnel, the product extracted with
ether (3 × 20 mL), and the combined ether layer washed with
H2O (2 × 15 mL) and then brine (15 mL). After the solution
was dried over anhydrous MgSO4, the solvent was removed
by distillation (Caution: compound 5 is volatile). The product
was purified by column chromatography (Et2O: hexanes )
1:20) to afford 5 as a colorless liquid (3.1 g, 67%). 1H NMR
(250 MHz, CDCl3) δ 4.94-4.98 (m, 2H), 3.98-4.06 (m, 2H),
3.47-3.52 (m, 1H), 3.03-3.04 (m, 2H), 2.95-2.97 (m, 2H),
1.12-1.61 (m, 6H), 0.91 (t, J ) 6.33 Hz, 3H). 13C NMR δ 138.5,
107.9, 105.7, 76.2, 69.2, 45.7, 45.5, 33.1, 27.2, 22.6, 14.0. Anal.
Calcd for C11H18O2: C, 72.49; H, 9.95. Found: C, 72.60; H,
9.78.
1
18. H NMR (250 MHz, CDCl3) δ 3.62 (d, J ) 5.90 Hz, 2H),
3.14-3.27 (m, 2H), 2.68-2.98 (m, 3H). 13C NMR δ 204.8, 51.9,
37.2, 26.2. Anal. Calcd for C5H7OBr: C, 36.84; H, 4.33.
Found: C, 36.63; H, 4.33.
3-(Phenylselanylmethyl)cyclobutanone ketal (21).
Method A:24 Diphenyl diselenide (4.7 g, 15 mmol) was
suspended in methanol (50 mL), and solid sodium borohydride
was added in small amounts until the yellow color disappeared
(about 650 mg of NaBH4 was added). Compound 4 (5.3 g, 20
mmol) was added dropwise to the mixture at room tempera-
ture. After the addition was complete, the mixture was stirred
for an additional 1.5 h. The volatile components were removed
under reduced pressure, and the residue was taken up in
methylene chloride (60 mL) and then washed with 10%
aqueous K2CO3 solution (2 × 20 mL). The organic layer was
dried over anhydrous MgSO4 and concentrated under reduced
3-Bromo-3-(bromomethyl)cyclobutanone Ketal (13). To
a 100-mL, round-bottomed flask were added 5 (2.5 g, 13.7
8284 J. Org. Chem., Vol. 69, No. 24, 2004

1-Amino-3-[(dihydroxyboryl)methyl]cyclobutanecarboxylic Acid
pressure. The residue was purified by silica gel chromatogra-
phy (EtOAc-hexanes, 1:30) to give 21 as a colorless oil (6.1 g,
90%). 1H NMR (250 MHz, CDCl3) δ 7.46-7.50 (m, 2H), 7.21-
7.26 (m, 3H), 3.93-4.00 (m, 2H), 3.40-3.46 (m, 1H), 3.04 (d,
J ) 5.91 Hz, 2H), 2.33-2.53 (m, 3H), 1.94-2.06 (m, 2H), 1.23-
1.65 (m, 6H), 0.90 (t, J ) 6.67 Hz, 3H). 13C NMR δ 132.7, 129.7,
129.0, 126.9, 105.7, 69.0, 68.7, 42.3, 42.0, 34.4, 33.3, 27.8, 25.4,
22.6, 14.1. HRMS calcd for C17H24O2Se 340.0942, found
340.0950. Method B:25 Benzeneselenol (1.0 g, 6.4 mmol) was
treated with NaH (168 mg, 7.0 mmol) in THF (15 mL) under
nitrogen at room temperature. After 30 min, compound 4 (1.7
g, 6.4 mmol) in THF (10 mL) was added dropwise to the
mixture, and the mixture was stirred for another hour. The
workup procedure was identical with that described in method
A (yield 88%).
slowly to room temperature and stirred for another 16 h. The
mixture was then poured into water (50 mL), the products
extracted with ether (3 × 20 mL), and the combined ether
extracts washed with brine (2 × 10 mL), dried over anhydrous
MgSO4, and concentrated. The residue was purified by column
chromatography (EtOAc:hexanes ) 1:25) to give 3.7 g (85%)
of 25 as a colorless oil. 1H NMR (250 MHz, CDCl3) δ 7.16-
7.34 (m, 5H), 3.92-4.00 (m, 2H), 3.42-3.46 (m, 1H), 3.04 (d,
J ) 6.40 Hz, 2H), 2.39-2.49 (m, 2H), 2.23-2.38 (m, 1H), 1.97-
2.15 (m, 2H), 1.23-1.66 (m, 6H), 0.90 (t, J ) 6.64 Hz, 3H). 13
C
NMR δ 136.2, 130.5, 129.5, 128.8, 126.0, 106.3, 106.1, 76.1,
69.0, 41.6, 40.0, 33.5, 33.3, 27.8, 24.7, 22.6, 13.9. Anal. Calcd
for C17H24O2S: C, 69.82; H, 8.27. Found: C, 69.83; H, 8.28.
3-(Phenylsulfanylmethyl)cyclobutanone (26). The syn-
thesis was carried out as described for compound 18. A solution
of 25 (3.7 g, 12.7 mmol) and aqueous hydrochloric acid (6 mL,
2 M) in ethanol (20 mL) was refluxed for 20 h. The product
was purified by silica gel chromatography (EtOAc: hexanes
) 1:30) to obtain 26 as a colorless liquid (2.3 g, 94% yield). 1H
NMR (250 MHz, CDCl3) δ 7.21-7.40 (m, 5H), 3.10-3.23 (m,
4H), 2.76-2.88 (m, 2H), 2.53-2.64 (m, 1H). 13C NMR δ 206.3,
135.3, 130.0, 129.0, 126.5, 52.2, 39.9, 23.5. Anal. Calcd for
C11H12OS: C, 68.71; H, 6.29. Found: C, 68.74; H, 6.29.
Hydantoin 27 of 3-(Phenylsulfanylmethyl)cyclobu-
tanone (26). The synthesis was carried out as described for
23. Compound 26 (960 mg, 5.0 mmol), aqueous ethanol (50%,
12 mL), potassium cyanide (650 mg, 10 mmol), and ammonium
carbonate (2.4 g, 25 mmol) were sealed in a 25-mL Ace
pressure tube and heated at 60 °C (oil bath) for 8 h. The
product was purified by column chromatography (EtOAc:
hexanes ) 2:1) to afford 920 mg of 27 as a white solid (yield:
70%). 1H NMR (250 MHz, DMSO-d6) δ 9.99 (s, 1H), 7.15-7.67
(m, 6H), 2.99 (d, J ) 7.52 Hz, 2H), 2.56-2.74 (m, 3H), 1.94-
2.16 (m, 2H). 13C NMR δ 180.5, 158.2, 137.4, 130.5, 130.1,
127.2, 59.3, 37.9, 37.4, 27.5. Anal. Calcd for C13H14N2O2S: C,
59.52; H, 5.38. Found: C, 59.05; H, 5.39.
3-(Phenylselanylmethyl)cyclobutanone (22). The syn-
thesis was carried out as described for compound 18. A solution
of 21 (6.1 g, 17.9 mmol) and aqueous hydrochloric acid (8 mL,
2 M) in ethanol (30 mL) was refluxed for 19 h. The product
was purified by silica gel chromatography (EtOAc:hexanes )
1
1:30) to obtain 22 as a colorless liquid (3.8 g, 88% yield). H
NMR (250 MHz, CDCl3) δ 7.43-7.47 (m, 2H), 7.18-7.21 (m,
3H), 3.03-3.12 (m, 4H), 2.67-2.76 (m, 2H), 2.50-2.65 (m, 1H).
13C NMR δ 206.4, 133.3, 129.1, 127.3, 52.8, 33.8, 24.3. HRMS
calcd for C10H12OSe 240.0054, found 240.0060.
Hydantoin 23 of 3-(Phenylselanylmethyl)cyclobu-
tanone (22). A 50-mL Ace pressure tube was charged with
ketone 22 (3.6 g, 15 mmol), aqueous ethanol (50%, 20 mL),
potassium cyanide (2.0 g, 30 mmol), and ammonium carbonate
(7.2 g, 75 mmol). The reaction vessel was sealed and heated
at 60 °C (oil bath) for 8 h. A faint yellow precipitate formed.
The mixture was cooled to room temperature and the vessel
carefully opened in a fume hood. The mixture was concentrated
under reduced pressure and the solid obtained was purified
by column chromatography (EtOAc:hexanes ) 2:1) to afford
1
3.1 g of 23 as a white solid (yield: 67%). H NMR (250 MHz,
CD3OD) δ 7.60-7.65 (m, 2H), 7.37-7.45 (m, 3H), 3.14 (d, J )
6.62 Hz, 2H), 2.63-2.76 (m, 3H), 2.12-2.19 (m, 2H). 13C NMR
δ 180.4, 158.2, 133.7, 131.0, 130.3, 128.1, 58.7, 38.7, 34.7, 28.3.
HRMS calcd for C13H14N2O2Se 310.0221, found 310.0217.
Sulfoxide (28). The synthesis was carried out as described
for 24. The crude sulfoxide was sufficiently pure for NMR
analysis. 1H NMR (250 MHz, CDCl3) δ 9.42 (s, 1H), 7.49-7.68
(m, 6H), 3.04-3.15 (m, 2H), 2.53-2.78 (m, 2H), 2.03-2.29 (m,
3H). 13C NMR δ 177.8, 156.7, 142.8, 131.5, 129.4, 124.2, 60.6,
59.5, 38.6, 21.9.
Selenoxide (24). Hydantoin 23 (2.8 g, 9.0 mmol) was
dissolved in methanol (30 mL) and cooled in an ice bath prior
to the dropwise addition of a solution of sodium metaperiodate
(1.9 g, 9.0 mmol) in a minimum amount of water (about 4.5
mL). When addition was complete, the ice bath was removed
and the reaction was stirred at room temperature. TLC
analysis showed complete disappearance of the starting mate-
rial after 24 h. The mixture was filtered and the precipitate
washed several times with methanol. The combined filtrate
and washings were concentrated in vacuo to quantitatively
yield a pale yellow solid. The crude selenoxide was essentially
pure and was utilized directly for the next step. 1H NMR (250
MHz, CD3OD + DMSO-d6) δ 7.69-7.78 (m, 2H), 7.43-7.55 (m,
3H), 3.14-3.16 (m, 2H), 2.43-2.72 (m, 3H), 1.97-2.19 (m, 2H).
13C NMR δ 177.2, 155.2, 138.8, 130.1, 128.4, 124.8, 57.4, 37.8,
36.4, 20.5.
Boronohydantoin (29). Diisopinocampheylborane, (Ipc)2BH,
was prepared according to the literature procedure.30 A 100-
mL, round-bottomed flask was fitted with a septum and a
magnetic stirring bar and connected to a nitrogen bubbler. The
flask was flushed with nitrogen and held at a positive static
pressure of nitrogen. Borane-THF (50 mmol, 50 mL, 1.0 M)
was added to the flask, which was cooled to 0 °C, then R-pinene
(18.4 mL, 115 mmol) was added slowly and the mixture stirred
at 0 °C for 1 h. The reaction was maintained at 0 °C for 3
days to give the required crystalline product. Compound 7 (380
mg, 2.5 mmol) was placed in a 150-mL round-bottomed flask
and dissolved in THF (10 mL) at 0 °C. (Ipc)2BH (7.5 mmol) in
THF (10 mL) was added dropwise via a syringe. The mixture
was allowed to warm to room temperature and stirred for 16
h. Freshly distilled acetaldehyde (12 mmol) was added and
the mixture was stirred for an additional 12 h. Excess
acetaldehyde was removed under vacuum and the mixture was
hydrolyzed with aqueous hydrochloric acid (5 mL, 2 M). The
mixture was extracted with EtOAc (3 × 30 mL) and the
combined organic phase dried over anhydrous MgSO4. The
solvent was removed under reduced pressure and the residue
purified by column chromatography (methanol) to afford 29
3-(Methylene)cyclobutanone Hydantoin (7). To a 100-
mL round-bottomed flask were added 25 (3.9 g, 9.0 mmol),
NaHCO3 (756 mg, 9.0 mmol), and CH3OH (20 mL). The
mixture was stirred at 70 °C (oil bath) for 14 h. After the
reaction was complete, the solvent was removed under reduced
pressure. The residue was purified by column chromatography
(EtOAc:hexanes ) 2.5:1) to yield 620 mg (45%) of 7 as a
1
colorless solid. H NMR (250 MHz, DMSO-d6) δ 8.37 (s, 1H),
6.65 (s, 1H), 4.88 (s, 2H), 2.88-3.11 (m, 4H). 13C NMR δ 177.5,
158.1, 137.9, 107.4, 57.2, 41.8. HRMS calcd for C7H8N2O2
152.0586, found 152.0580. Anal. Calcd for C7H8N2O2: C, 55.26;
H, 5.30; N, 18.41. Found: C, 54.83; H, 5.38; N, 18.02.
as a white solid (302 mg, yield: 61%). H NMR (DMSO-d6) δ
1
8.49 (s, 1H), 7.44 (s, 1H), 1.74-2.48 (m, 5H), 0.72-0.88 (m,
2H). 13C NMR δ 177.5, 156.3, 59.5, 34.2, 25.7. HR-FAB-MS
(M + H + gly - 2H2O; obtained in a glycerol matrix) calcd for
C10H16BN2O5 255.1154, found 255.1148.
3-(Phenylsulfanylmethyl)cyclobutanone Ketal (25).
Compound 4 (4.0 g, 15 mmol) in 50 mL of THF was added
dropwise to 1 M NaSPh in MeOH (24 mL, 24 mmol) at 0 °C.
After completion of the addition, the mixture was warmed
1-Amino-3-[(dihydroxyboryl)methyl]cyclobutane-
carboxylic Acid (1). Boronohydantoin 29 (297 mg, 1.5 mmol)
was placed in a 25-mL Ace pressure tube along with hy-
J. Org. Chem, Vol. 69, No. 24, 2004 8285

Kabalka and Yao
drochloric acid (4 mL, 12 M). The tube was sealed and heated
to 150 °C (oil bath) for 40 h. It was then cooled to room
temperature and carefully opened (Hood!), charcoal was added,
and the resulting mixture was filtered through a pad of Celite.
The Celite pad was washed with water. Removal of the water
under reduced pressure gave a white solid (210 mg, yield:
81%). 1H NMR (D2O) δ 1.84-2.62 (m, 5H), 0.73-0.89 (m, 2H).
13C NMR δ 179.5, 59.4, 41.2, 35.4, 16.7. HR-FAB-MS (M + H
+ gly - 2H2O; obtained in a glycerol matrix) calcd for C9H17-
BNO5 230.1201, found 230.1202
Acknowledgment. The authors wish to thank the
U.S. Department of Energy and the Robert H. Cole
Foundation for support of this research.
JO048824C
8286 J. Org. Chem., Vol. 69, No. 24, 2004