Carbocyclic nucleoside analogs. 1. Concise enantioselective synthesis of functionalized cyclopentanes and formal total synthesis of aristeromycin

Article abstract of DOI:10.1021/jo970153d

An enantioselective synthesis of functionalized cyclopentanes has been used to access carbocyclic nucleoside analogs. This pathway allows access to carbocyclic C- or carbocyclic N-nucleosides from a common intermediate, ester 16. Additionally, (1R,2R,3S,4R)-4-amino-2,3-dihydroxy-1-cyclopentanemethanol (18), an intermediate in the total synthesis of aristeromycin, has been prepared as a single enantiomer in eight isolated steps from cyclopentadiene. Progress toward the synthesis of novel carbocyclic C-nucleosides is also discussed.

Full text of DOI:10.1021/jo970153d

3976
J . Org. Chem. 1997, 62, 3976-3980
Ca r bocyclic Nu cleosid e An a logs. 1. Con cise En a n tioselective
Syn th esis of F u n ction a lized Cyclop en ta n es a n d F or m a l Tota l
Syn th esis of Ar ister om ycin
Stephen J . Boyer and J ames W. Leahy*
Department of Chemistry, University of California, Berkeley, California 94720-1460
Received J anuary 27, 1997X
An enantioselective synthesis of functionalized cyclopentanes has been used to access carbocyclic
nucleoside analogs. This pathway allows access to carbocyclic C- or carbocyclic N-nucleosides from
a common intermediate, ester 16. Additionally, (1R,2R,3S,4R)-4-amino-2,3-dihydroxy-1-cyclopen-
tanemethanol (18), an intermediate in the total synthesis of aristeromycin, has been prepared as
a single enantiomer in eight isolated steps from cyclopentadiene. Progress toward the synthesis
of novel carbocyclic C-nucleosides is also discussed.
In tr od u ction
is a prominent member of this family7 and has demon-
strated a high degree of cytotoxicity in cell cultures.8
Neplanocin A (3) is an olefinic analog of 2 isolated from
Actinoplanacea ampullariella that possesses pronounced
in vivo antileukemic activity and low toxicity.9 Carbovir
(4)10 and 1592U89 (5)11 are synthetic cyclopentenoid
nucleosides, both of which are actively being studied in
the clinic against HIV. Based on their notable biological
activities, it is not surprising that these targets have
drawn substantial synthetic interest.6
Nucleoside analogs form the basis of several medici-
nally important therapies,1 including antiviral2 and
anticancer3 treatments. For example, compounds such
as acyclovir4 and AZT5 are currently in widespread
clinical use as antiherpetic and anti-AIDS medications.
Given the considerable amount of research currently
underway toward the development of novel nucleosides,
synthetic methods that allow access to multiple classes
of compounds are decidedly valuable. In this paper, we
will discuss a formal total synthesis of the carbocyclic
N-nucleoside aristeromycin (2) and progress made toward
the synthesis of carbocyclic C-nucleoside 1.
Another alteration to the nucleoside structure that has
resulted in profound biological effects is modification of
the heterocyclic base. 9-Deazaadenosine (6), isolated
from the cyanobacterium Anabaena affinis strain VS-1,
is an example of a C-nucleoside, where the site of the
glycosidic linkage is carbon rather than nitrogen.12 These
compounds, which are very stable to both chemical and
enzymatic cleavage, also possess remarkable bioactivity.
Formycin (7)13 and pyrazofurin (8)14 are two naturally
occurring C-nucleosides that exhibit antitumor proper-
ties, and 8 also has notable antiviral properties.
One important class of modified nucleosides is the
carbocyclic nucleosides6 in which the furanose ring has
been replaced by a cyclopentane. The natural product
aristeromycin (2), obtained from Streptomyces citricolor,
X Abstract published in Advance ACS Abstracts, May 1, 1997.
(1) Perigaud, C.; Gosselin, G.; Imbach, J . L. Nucleosides Nucleotides
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(b) Robins, R. K.; Kini, G. D. Ibid; p 299.
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(7) (a) Isolation: Kusaka, T.; Yamamoto, H.; Shibata, M.; Muroi,
M.; Hicki, T.; Mizuno, K. J . Antibiot. 1968, 21, 255. (b) First racemic
synthesis: Shealy, Y. F.; Clayton, J . D. J . Am. Chem. Soc. 1966, 88,
3885.
(8) Shealy, Y. F.; Clayton, J . D. J . Pharm. Sci. 1973, 62, 858.
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26, 369. (b) Good, S. S.; Daluge, S. M.; Ching, S. V.; Ayers, K. M.;
Mahoney, W. B.; Faletto, M. B.; Domin, B. A.; Owens, B. S.; Dornsife,
R. E.; McDowell, J . A.; LaFon, S. W.; Symonds, W. T. Antiviral Res.
1995, 26, A229. (c) Recent synthesis: Crimmins, M. T., King, B. W. J .
Org. Chem. 1996, 61, 4192.
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T.; Hori, S.; Takayama, T.; Takeuchi, T.; Umezawa, H. J . Antibiot.
1968, 21, 5.
S0022-3263(97)00153-9 CCC: $14.00 © 1997 American Chemical Society

Carbocyclic Nucleoside Analogs
J . Org. Chem., Vol. 62, No. 12, 1997 3977
and demonstrates the utility of the catalyst in reactions
with functionalized dienes.
With either antipode of 10 now readily available in
large quantities, we turned our attention to the func-
tionalization of the norbornene skeleton. The Diels-
Alder product 10 was dihydroxylated with osmium
tetroxide/NMO22 from the least hindered face of the
bicyclic system to afford diol 11, which was recrystallized
to a constant optical rotation (Scheme 1). Elimination
of the bromide with DBU then proceeded smoothly to give
12. We found that the order of the dihydroxylation and
the elimination steps was crucial. While dehydrobromi-
nation of 10 was easily accomplished, dihydroxylation of
the subsequent norbornadiene occurred exclusively on the
conjugated olefin.23
Although protection of 12 as an acetonide has previ-
ously been reported,24 the acid sensitivity of the isopro-
pylidene made it an unsuitable protecting group for our
purposes.25 Intermediates available directly from ac-
etonide protected 1226 could not be successfully converted
to the tri-O-benzyl ether 16.27 Therefore, we sought to
introduce the necessary functionality at an earlier point
in the synthesis. The formation of the bisbenzyl ether
of diol 12 proved to be challenging. Under standard basic
protection conditions, the substrate decomposed, most
likely via a retrograde aldol pathway driven by relief of
ring strain (eq 2).28 Although protection with benzyl
Resu lts a n d Discu ssion
We have embarked on a project aimed at the develop-
ment of a versatile pathway that would allow access to a
diverse array of carbocyclic analogs, including unnatural
carbocyclic C-nucleosides such as 1.15 Since the biological
activity of a nucleoside analog typically resides in one
enantiomer,16 an enantioselective synthesis is critical.
Recent reports have described several L-nucleosides that
possess activity comparable to that of D-nucleosides;17
thus, we are interested in accessing either enantiomer
of an analog. Also, since we are interested in a pathway
that allows maximum flexibility, the approach should
branch from a common intermediate to provide either
carbocyclic C- or carbocyclic N-nucleosides.
Based on these criteria, we envisioned that a practical
starting point would be an asymmetric Diels-Alder
reaction. We selected Hawkins’ catalyst, the chiral
dibromoborane shown in eq 1. The dichloro analog of this
trichloroacetimidate provided 13, purification proved
difficult. Silver oxide-promoted ether formation in the
presence of 3 Å molecular sieves cleanly afforded the
desired product in good yield.
compound has been previously reported as an efficient
enantioselective Diels-Alder catalyst.18 Subsequent to
the initial communication, Hawkins has demonstrated
that the dibromoborane is a more selective catalyst.19 In
our hands, the (Z)-bromopropenoate 920 underwent cy-
clization with cyclopentadiene in the presence of Hawk-
ins’ catalyst (10 mol %) to provide the bicyclic adduct 10
in excellent yield and with high enantioselectivity.21 This
reaction could be conveniently performed on a large scale
With a suitably protected intermediate in hand, we
turned to functionalization of the olefin. Ozonolytic
cleavage of 13 followed by reductive workup and perio-
date oxidation generated labile aldehyde 14. During
chromatographic purification, the benzyl ether at the
2-position of 14 underwent elimination to form the
corresponding R,â-unsaturated aldehyde. Thus, the al-
dehyde was immediately oxidized to ester 15 with
bromine in methanol.29 In practice, the direct transfor-
mation of R,â-unsaturated ester 13 into 15 was performed
without any intermediate purification in 66% overall
(14) (a) De Clerq, E.; Torrence, P. F. Nucleosides Nucleotides 1978,
5, 187. (b) Gutowski, G. E.; Sweeney, M. J .; Delong, D. C.; Hamill, R.
L.; Gerzon, K.; Dyke, R. W. Ann. N.Y. Acad. Sci. 1975, 255, 544.
(15) Carbocyclic C-nucleosides such as 1 have not been well explored.
For some examples, see: (a) Dishington, A. P.; Humber, D. C.; Stoodley,
R. J . J . Chem. Soc. Perkin Trans. 1 1993, 57. (b) Kakeno, C.; Katagiri,
N.; Nomura, M.; Sato, H. Israel J . Chem. 1991, 31, 247. (c) Sato, M.;
Takayama, K.; Kakeno, C. Chem. Pharm. Bull. 1989, 37, 2615. (d)
Saksena, A.; Ganguly, A. Tetrahedron Lett. 1981, 22, 5227. (e) J ust,
G.; Kim, S. Tetrahedron Lett. 1976 1063.
(22) Van Rheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett.
1976, 1973.
(23) Boyer, S. J .; Leahy, J . W. unpublished results.
(24) J ust, G.; Reader, G.; Chalard-Faure, B. Can. J . Chem. 1976,
54, 849.
(25) Although the conditions described in this paper are not
incompatible with a 2′,3′-O-isopropylidene, construction of the pyrazolo-
[4,3-d]pyrimidine in 1 takes place using harsh reagents, necessitating
the protecting group scheme chosen here. Boyer, S. J .; Leahy, J . W.
Unpublished results.
(26) Arita, M.; Adachi, K.; Ito, Y.; Sawai, H.; Ohno, M. J . Am. Chem.
Soc. 1983, 105, 4049.
(27) Acetonide deprotection of Ohno’s lactone (ref 26), and benzyl
reprotection under basic conditions resulted in elimination similar to
that seen during purification of aldehyde 14 (vide infra). Benzyl
reprotection under neutral conditions could not be performed due to
insolubility of the substrate in the reaction solvent. Boyer, S, J .; Leahy,
J . W. unpublished results.
(28) An example of this behavior seen for a similar system under
the same conditions has been discussed by Heathcock, C. H.; Ratcliffe,
R. J . Am. Chem. Soc. 1971, 93, 1746.
(16) A specific example can be found in ref 6f.
(17) Lin, T. S.; Luo, M. Z.; Liu, M. C.; Zhu, Y. L.; Gullen, E.;
Dutschman, G. E.; Cheng, Y. C. J . Med. Chem. 1996, 39, 1758 and
references therein.
(18) (a) Hawkins, J . M.; Loren, S. J . Am. Chem. Soc. 1991, 113, 7794.
(b) Hawkins, J . M.; Loren, S.; Nambu, M. J . Am. Chem. Soc. 1994,
116, 1657.
(19) (a) Hawkins, J . M.; Solow, M. A.; Meyer, A. Manuscript in
preparation. (b) Solow, M. A. Ph. D. Thesis, University of California,
1994; see Diss. Abstr. Int., B 1995, 56, 2638.
(20) Synthesized according to the literature procedure: Ma, S.; Lu,
L. Org. Synth. 1993, 72, 112.
(21) Enantiomeric excess determined by chiral gas chromatography
performed with a J & W Cyclodex-B â-cyclodextrin column. Enantio-
merically enriched material was compared with coinjection of racemic
adduct.
(29) Williams, D. F.; Klingler, F. D.; Allen, E. E.; Lichtenthaler, F.
W. Tetrahedron Lett. 1988, 29, 5087.

3978 J . Org. Chem., Vol. 62, No. 12, 1997
Boyer and Leahy
Sch em e 1
Sch em e 2
yield. Protection of the primary alcohol of 15 occurred
under the neutral silver oxide conditions previously
described in order to avoid â-elimination similar to that
experienced during purification of aldehyde 14.
ment of 16 under Weinreb conditions31 provided amide
19, which was subjected to borane reduction and acetyl-
ation to give 20. Work toward the use of 20 in the
preparation of carbocyclic C-nucleosides is underway, and
will be reported in due course.
The viability of this synthetic route as an approach to
carbocyclic nucleosides was demonstrated by the prepa-
ration of amine 18 (Scheme 2). Ester 16 was converted
into the corresponding acyl azide via standard protocol,
and Curtius rearrangement in the presence of benzyl
alcohol yielded fully protected cyclopentane 17. Complete
deprotection with sodium in ammonia provided the
known amino triol 18. The optical rotation of the
product, [R]23D ) -10.5 (c 0.62, H2O), compares favorably
Con clu sion s
We have accomplished a concise, enantioselective
synthesis of the versatile ester 16 that can be used for
the preparation of both carbocyclic C- and carbocyclic
N-nucleosides. The known aminotriol 18, which has
previously been converted into aristeromycin, has been
prepared from cyclopentadiene in eight isolated steps
(overall 12% yield). The synthetic pathway provides
novel, robust intermediates which cannot be obtained
using previous approaches. For example, selective depro-
tection of carbamate 17 would afford the corresponding
tri-O-benzyl amine, which could withstand a wide variety
of reaction conditions in the preparation of novel nucleo-
side analogs. Additionally, a pathway toward an array
of carbocyclic C-nucleosides from ester 16 has also been
discussed.
with the previously reported value of [R]23 ) -10.3 (c
D
1.52, H2O).26 Since 18 has previously been converted into
aristeromycin (2),7b,26 synthesis of the amino triol con-
stitutes a formal total synthesis of the natural product.
To establish the feasibility of using 16 as a versatile
intermediate for the generation of carbocyclic C- or
carbocyclic N- nucleosides, we explored additional func-
tionalization of the ester. Although it has been demon-
strated that esters such as 16 can be transformed into a
variety of C-nucleoside bases such as those contained in
tiazofurin15a and showdomycin,15d carbocyclic pyrazolo-
[4,3-d]pyrimidines such as 1 have never previously been
synthesized. Since 1,3-dipolar cycloadditions have proven
useful in generating this type of heterocycle,30 we chose
to investigate the possibility of converting 16 into an
appropriate diazoalkane precursor, acetamide 20. Treat-
Exp er im en ta l Section
Gen er a l. All solvents were reagent grade quality and
distilled immediately prior to use: acetonitrile and methylene
chloride from calcium hydride, ether from sodium and ben-
zophenone. All reagents were obtained from commercial
suppliers and were used as received. Further purification was
conducted according to known procedures.32 Cyclopentadiene
(30) (a) Sprinzl, M.; Farkas, J .; Sorm, F. Tetrahedron Lett. 1969,
289. (b) Bobek, M.; Farkas, J .; Sorm, F. Tetrahedron Lett. 1970, 4611.
(c) Acton, E. M.; Ryan, K. J .; Goodman, L. J . Chem. Soc. Chem.
Commun. 1970, 313. (d) Acton, E. M.; Ryan, K. J .; Henry, D. W.;
Goodman, L. J . Chem. Soc. Chem. Commun. 1971, 986. (e) Farkas, J .;
Sorm, F. Collect. Czech. Chem. Commun. 1972, 37, 2798. (f) Sauer, D.
R.; Schneller, S. W. J . Org. Chem. 1990, 55, 5535.
(31) Basha, A.; Lipton, M.; Weinreb, S. M.Tetrahedron Lett. 1977,
4171.
(32) Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory
Chemicals, 3rd ed.; Pergamon: Oxford, 1988.

Carbocyclic Nucleoside Analogs
J . Org. Chem., Vol. 62, No. 12, 1997 3979
was obtained from thermally cracked dicyclopentadiene and
was stored neat at -78 °C. Ozone was generated on a
Wellsbach T-816 ozone generator. Merck Kieselgel 60 F-254
silica gel plates were used for thin layer chromatography.
Flash column chromatography was carried out with EM
Science 60 (230-300 mesh) silica gel according to the method
of Still.33 Unless otherwise noted, 1H NMR spectra were
recorded at 400 MHz, 13C{H} NMR spectra were obtained at
100 MHz, and spectra were taken of compounds dissolved in
CDCl3. Elemental analyses were performed by MHW Labo-
ratories, Phoenix, AZ.
added as a solution in 52 mL of benzene, followed by benzyl
bromide (22.6 g, 132 mmol). The flask was covered with
aluminum foil, and the mixture was cooled to 0 °C. To the
rapidly stirring suspension was added silver oxide (31.0 g, 132
mmol) portionwise. The mixture was allowed to warm to rt
over 23 h, at which point the suspension was filtered through
a pad of Celite. The black solid was thoroughly washed with
hexanes/EtOAc (90:10 v/v), and the filtrate was concentrated
to a yellow oil. Flash column chromatography (hexanes/EtOAc
90:10) furnished the protected diol 13 (7.95 g, 80%) as a
colorless oil: [R]23 ) +84.2 (c 1.0 in CHCl3); IR (neat) 3028,
D
2982, 1710 cm-1; 1H NMR δ 1.26 (t, 3H, J ) 7.2), 1.78 (d, 1H,
J ) 9.2), 2.27 (d, 1H, J ) 9.1), 2.98 (s, 1H), 3.26 (s, 1H), 3.53
(d, 1H, J ) 1.29), 3.57 (d, 1H, J ) 1.36), 4.15 (q, 2H, J ) 7.1),
4.58 (d, 1H, J ) 12.0), 4.66 (d, 1H, J ) 12.0), 4.67 (d, 1H, J )
12.1), 4.70 (d, 1H, J ) 12.1), 6.84 (d, 1H, J ) 3.1), 7.25-7.39
(m, 10H); 13C NMR δ 14.2, 43.7, 45.4, 47.8, 60.2, 72.1, 72.4,
76.0, 76.1, 127.4, 127.7, 127.9, 128.2, 138.4, 141.9, 146.8, 164.0.
Anal. Calcd for C24H26O4: C, 76.16; H, 6.92. Found: C, 76.36;
H, 7.11.
(1R,2R,3S,4S)-2-Br om o-3-car beth oxybicyclo[2.2.1]h ept-
5-en e (10). To a stirred solution of the dienophile 9 (47.1 g,
263.2 mmol) and Hawkins’ catalyst (10.0 g, 26.3 mmol) in 280
mL of methylene chloride cooled to -55 °C was slowly added
cyclopentadiene (104 g, 1.28 mol). The mixture was stirred
for 41.5 h, and the reaction was stopped with the addition of
150 mL of saturated aqueous NaHCO3. After slowly being
warmed to rt, the two layers were separated, and the organic
layer was washed with saturated aqueous NaHCO3. The
organic layer was dried (MgSO4), filtered, and concentrated
to provide a yellow oil. Distillation under reduced pressure
yielded the adduct 10 (60.6 g, 94%, 95.4% e.e.) as a colorless
Meth yl (1R,2R,3S,4R)-4-(Hyd r oxym eth yl)-2,3-bis(ben -
zyloxy)cyclop en ta n eca r boxyla te (15). To a solution of the
unsaturated ester 13 (7.95 g, 21.0 mmol) in 215 mL of CH2-
Cl2/CH3OH (38:1 v/v) at -78 °C was bubbled ozone until a blue
color persisted. Nitrogen was bubbled through the solution
to remove excess ozone, lithium borohydride (3.20 g, 147 mmol)
and 21 mL of THF were added, and the reaction was warmed
to 0 °C. The mixture was subsequently allowed to warm to rt
over 20 h. After cooling the solution to 0 °C, 50 mL of CH3-
OH was added dropwise, the mixture was concentrated to a
white paste that was used immediately for the following
transformation.
oil: bp 83-85 °C/0.35 Torr; [R]23 ) -53.3 (c 1.33, CHCl3); IR
D
(neat) 2990, 1745 cm-1; H NMR δ 1.22 (t, 3H, J ) 7.2), 1.34
1
(d, 1H, J ) 9.1), 1.59 (d, 1H, J ) 9.1), 3.05 (s, 1H), 3.14 (d,
1H, J ) 3.0), 3.17 (m, 1H), 4.08 (q, 2H, J ) 7.1), 4.59 (dd, 1H,
J ) 9.2, 3.6), 6.06 (dd, 1H, J ) 5.5, 3.0), 6.49 (dd, 1H, J ) 5.6,
3.0); 13C NMR δ 14.1, 44.6, 47.2, 49.6, 49.6, 51.0, 60.4, 133.8,
136.6, 170.9. Anal. Calcd for C10H13BrO2: C, 49.00; H, 5.35.
Found: C, 49.36; H, 5.61.
(1R ,2R ,3S ,4S ,5S ,6R )-2-Br om o-3-c a r b e t h oxy-5,6-d i-
h yd r oxybicyclo[2.2.1]h ep ta n e (11). To a solution of the
ester 10 (60.6 g, 247.1 mmol) in 500 mL of acetone/water (4:1
v/v) warmed to 40 °C was added N-methylmorpholine N-oxide
(31.8 g, 271.8 mmol), followed by a 4 wt % solution of osmium
tetroxide in water (7.08 mL, 282.8 mg, 1.11 mmol). The
solution was stirred for 13 h, at which point solid NaHSO3 (5
g) was added. After stirring for an additional 2 h, the mixture
was cooled to rt and partitioned between saturated aqueous
NH4Cl and CH2Cl2. The layers were separated, and the
aqueous layer was extracted with CH2Cl2. The combined
extracts were dried (Na2SO4), filtered, and concentrated to
provide an oily solid. Recrystallization of the product to a
constant optical rotation from diethyl ether provided the diol
11 (50.9 g, 74%) as colorless white plates: mp 86.3-86.9 °C;
The white solid obtained from the ozonolysis was dissolved
in 420 mL of THF/water (3:1 v/v), the solution pH was adjusted
carefully to 5 with 12 N HCl, sodium periodate (13.5 g, 63.0
mmol) was added, and the mixture stirred at rt for 2 h.
Removal of the volatiles by rotary evaporation yielded a white
slurry that was extracted with CH2Cl2. The combined organics
were dried overnight (Na2SO4), filtered, and concentrated to
provide the unstable aldehyde 14 as a light yellow oil, which
was carried on without further purification.
To a suspension of NaHCO3 (35.3 g, 420 mmol) in 42 mL of
CH3OH/water (9:1 v/v) containing the aldehyde 14 obtained
above was added a 2 M solution of bromine in CH3OH/water
(9:1 v/v) (52.5 mL, 16.8 g, 105 mmol) dropwise over 30 min.
The mixture was stirred at rt for 1 h, at which point excess
bromine was quenched by addition of Na2S2O4 (10 g). The
solution was diluted with 200 mL water and was extracted
with CH2Cl2. The combined organics were dried (Na2SO4),
filtered, and concentrated to a yellow oil. Flash column
chromatography (hexanes/EtOAc 60:40) yielded the methyl
[R]23 ) -30.0 (c 1.20, CHCl3); IR (NaBr pellet) 3330, 2990,
D
1745 cm-1; H NMR δ 1.28 (t, 3H, J ) 6.8), 2.09 (d, 1H, J )
1
11.1), 2.39 (s, 1H), 2.54 (d, 1H, J ) 3.9), 3.08 (d, 1H, J ) 3.9),
3.10 (d, 1H, J ) 3.9), 3.23 (s, 1H), 4.15 (q, 2H, J ) 7.2), 4.51-
4.47 (m, 2H), 4.89 (d, 1H, J ) 5.6); 13C NMR δ 14.2, 32.8, 46.2,
47.7, 48.3, 50.5, 60.8, 68.1, 71.3, 170.4.
ester 15 (5.13 g, 66%) as a colorless oil: [R]23 ) +17.7 (c 1.0,
D
(1S,4R,5S,6R)-3-Car beth oxy-5,6-dih ydr oxybicyclo[2.2.1]-
h ep t-2-en e (12). To a solution of the diol 11 (7.58 g, 27.2
mmol) in 135 mL of ether was added 1,8-diazabicyclo[5.4.0]-
undec-7-ene (DBU) (10.4 g, 67.9 mmol). The mixture was
stirred at rt for 24 h, diluted with ether, and washed with 2 N
HCl. The combined aqueous layers were extracted with CH2-
Cl2, and the combined organic layers were dried (Na2SO4),
filtered, and concentrated to a yellow oil. Flash column
chromatography (hexanes/EtOAc 50:50) provided the unsatur-
ated ester 12 (5.19 g, 97%) as a colorless oil: bp 97 °C/12
1
CHCl3); IR (neat) 3455, 2948, 1731 cm-1; H NMR δ 1.48 (dt,
1H, J ) 13.3, 4.5), 2.14 (dt, 1H, J ) 13.4, 4.3), 2.37-2.47 (m,
2H), 3.04-3.10 (m,1H), 3.54-3.62 (m, 2H), 3.67 (s, 3H), 3.69
(dd, 1H, J ) 8.0, 4.9), 4.07 (t, 1H, J ) 4.9), 4.45 (d, 1H, J )
11.8), 4.53 (d, 1H J ) 12.0), 4.56 (d, 1H, J ) 11.8), 4.59 (d,
1H, J ) 12.0), 7.23-7.35 (m, 10H); 13C NMR δ 26.5, 43.5, 46.7,
51.9, 64.4, 71.3, 71.5, 80.3, 81.3, 127.6, 127.7, 127.8, 128.2,
128.3, 128.7, 137.8, 138.0, 175.0. Anal. Calcd for C21H26O5:
C, 70.37; H, 7.31. Found: C, 70.55; H, 7.25.
Met h yl (1R,2R,3S,4R)-4-[(Ben zyloxy)m et h yl]-2,3-b is-
(b en zyloxy)cyclop en t a n eca r boxyla t e (16). Alcohol 15
(7.28 g, 19.7 mmol) was treated with benzyl bromide (11.8 g,
68.8 mmol) and silver oxide (15.9 g, 68.8 mmol) in the same
manner as diol 11. Flash column chromatography (hexanes/
EtOAc 90:10) furnished the trisbenzyl ether 16 (7.30 g, 81%)
as a colorless oil: [R]23D ) -15.3 (c 1.04, CHCl3); IR (neat) 3029,
1732 cm-1; 1H NMR δ 1.50-1.58 (m, 1H), 2.17-2.24 (m, 1H),
2.44-2.52 (m, 1H), 3.10 (dt, 1H, J ) 9.2, 2.5), 3.40 (dd, 2H, J
) 6.1, 2.7), 3.66 (s, 3H), 3.73 (t, 1H, J ) 5.2), 4.04 (dd, 1H, J
) 6.7, 5.0), 4.48 (s, 2H), 4.50 (d, 1H, J ) 12.1), 4.51 (d, 1H, J
) 12.5), 4.55 (d, 1H, J ) 12.2), 4.56 (d, 1H, J ) 12.1), 7.24-
7.34 (m, 15H); 13C NMR δ 27.5, 42.3, 46.8, 51.8, 71.3, 71.6,
72.9, 79.7, 81.1, 127.4, 127.5, 127.8, 128.0, 128.2, 128.3, 128.4,
mmHg; [R]23 ) +91.2 (c 1.0, CHCl3); IR (neat) 3380, 2990,
D
1
1710 cm-1; H NMR δ 1.29 (t, 3H, J ) 7.1), 1.76 (d, 1H, J )
9.6), 1.99 (d, 1H, J ) 9.0), 2.89 (d, 1H, J ) 1.2), 3.07 (s, 1H),
3.73-3.76 (m, 1H), 3.79 (bs, 2H), 3.88 (d, 1H, J ) 4.5), 4.18
(q, 2H, J ) 7.2), 6.90 (d, 1H, J ) 3.2); 13C NMR δ 14.2, 42.2,
48.0, 49.9, 60.6, 68.2, 68.4, 141.4, 146.9, 164.4. Anal. Calcd
for C10H14O4: C, 60.59; H, 7.12. Found: C, 60.32; H, 6.91.
(1S,4R,5S,6R)-3-Ca r b et h oxy-5,6-(b en zyloxy)b icyclo-
[2.2.1]h ep t-2-en e (13). To a flask fitted with a mechanical
stirrer and argon inlet was introduced 2.4 g of crushed,
activated 3 Å sieves. The diol 12 (5.19 g, 26.4 mmol) was
(33) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923.

3980 J . Org. Chem., Vol. 62, No. 12, 1997
Boyer and Leahy
128.8, 138.1, 138.3, 138.4, 175.1. Anal. Calcd for C29H32O5:
C, 75.63; H, 7.00. Found: C, 75.67; H, 6.95.
mmol). After the ester solution was warmed to 50 °C and
stirred for 19 h, the mixture was cooled to 0 °C and 2 N HCl
(20 mL) was added. The aqueous and organic layers were
separated, and the aqueous layer was extracted with CH2Cl2.
The combined organics were dried (Na2SO4), filtered, and
concentrated to an off-white solid. Flash column chromatog-
raphy (hexanes/EtOAc 40:60) afforded the amide 19 (2.79 g,
(1R,2S,3R,4R)-4-[(Ben zyloxy)m et h yl]-1-[(b en zyloxy-
ca r bon yl)a m in o]-2,3-bis(ben zyloxy)cyclop en ta n e (17). To
a solution of the methyl ester 16 (500 mg, 1.09 mmol) in 5.5
mL of 95% EtOH was added anhydrous hydrazine (285 mg,
8.9 mmol). The solution was heated at reflux for 46 h. After
cooling to rt, the mixture was concentrated to a cloudy oil. The
unstable hydrazide was dissolved in 6.8 mL of CH2Cl2 and
cooled to -78 °C, and a 6 M solution of dinitrogen tetroxide in
CCl4 (0.75 mL, 411 mg, 4.47 mmol) was added. The mixture
was stirred for 2 h and poured onto ice. The aqueous layer
was extracted with CH2Cl2, and the combined organics were
washed with saturated aqueous NaHCO3 (30 mL), dried
(MgSO4), filtered, and concentrated to afford the acyl azide as
an orange oil, which was submitted to the subsequent reaction
conditions immediately.
81%) as a white solid: mp 104-105.7 °C; [R]23 ) -80.2 (c
D
1.70, CHCl3); IR (CH2Cl2) 3508, 3394, 2986, 1686 cm-1
;
1H
NMR δ 1.53-1.88 (m, 1H), 2.05-2.13 (m, 1H), 2.42-2.46 (m,
1H), 3.00 (q, 1H, J ) 9.3), 3.27 (t, 1H, J ) 9.2), 3.41 (dd, 1H,
J ) 9.4, 5.2), 3.80-3.86 (m, 2H), 4.36 (d, 1H, J ) 11.5), 4.44-
4.51 (m, 4H), 4.59 (d, 1H, J ) 12.0), 5.65 (bs, 1H), 6.20 (bs,
1H), 7.23-7.35 (m, 15H); 13C NMR δ 25.8, 41.6, 47.2, 70.5,
71.8, 73.1, 78.7, 81.9, 127.6, 127.7, 127.8, 128.2, 128.3, 137.6,
138.1, 138.2, 175.9. Anal. Calcd for C28H31NO4: C, 75.48; H,
7.01; N, 3.14. Found: C, 75.30; H, 6.86; N 3.02.
A solution of the acyl azide in 4.4 mL of benzene was heated
to reflux for 1 h, and benzyl alcohol was added (260 mg, 2.4
mmol). The mixture was heated at reflux for 36 h, and then
was concentrated to an orange oil which was purified by flash
column chromatography (hexanes/EtOAc 75:25) to afford the
carboxybenzoyl-protected amine 17 (400 mg, 67%) as a glassy
(1S,2R,3R,5S)-5-(N-Acetyl am in om eth yl)-3-[(ben zyloxy)-
m eth yl]-1,2-bis(ben zyloxy)cyclop en ta n e (20). To a 1.0 M
solution of borane-THF (11.2 mL, 11.2 mmol) at 0 °C was
added the amide 19 (1.0 g, 2.24 mmol) as a solution in THF
(3.5 mL, 2 × 0.75 mL wash). The mixture was slowly warmed
to reflux and heating continued for 19 h. After cooling the
solution to 0 °C, 3 N HCl (8 mL) was slowly added, and the
mixture was stirred for 2 h. The solution was saturated with
solid KOH (1.5 g), and the aqueous and organic layers were
separated. The aqueous layer was extracted with ether. The
combined organics were dried (Na2SO4), filtered, and concen-
trated to provide the amine as a colorless oil, which was used
without further purification.
syrup: [R]23 ) +78.1 (c 0.85, CHCl3); IR (neat) 3334, 3029,
D
2887, 1720 cm-1
;
1H NMR δ 1.31 (bd, 1H, J ) 12.4), 2.42-
2.47 (bm, 2H), 3.44-3.51 (bm, 2H), 3.84 (bs, 1H), 3.85-3.86
(m, 1H), 4.1 (s, 1H), 4.27 (d, 1H, J ) 11.8), 4.38-4.46 (bm,
3H), 4.63 (bd, 1H, J ) 12.1), 4.70 (bd, 1H, J ) 12.1), 4.99-
5.07 (bm, 2H), 5.36 (bd, 1H, J ) 7.0), 7.17-7.40 (m, 20H); 13
C
NMR δ 30.1, 41.4, 53.3, 66.2, 70.3, 71.1, 71.4, 73.2, 79.3, 81.0,
127.4, 127.6, 127.7, 127.9, 128.0, 128.1, 128.2, 128.3, 128.8,
136.6, 137.7, 138.2, 138.3, 155.3. Anal. Calcd for C35H37O5N:
C, 76.20; H, 6.76; N, 2.54. Found: C, 76.02; H, 6.50; N, 2.50.
(1R ,2R ,3S ,4R )-4-Am in o -2,3-d ih y d r o x y -1-c y c lo p e n -
ta n em eth a n ol (18). To a solution of sodium (160 mg, 7.39
mmol) in 9 mL NH3 at -78 °C was added the fully protected
amino triol 17 (76.4 mg, 0.138 mmol) as a solution in 2.6 mL
THF/CH3OH (20:1). The mixture was stirred at -78 °C for 2
h, at which point the reaction was quenched by the careful
addition of NH4Cl (250 mg). All of the volatiles were allowed
to evaporate from the mixture. The resulting white solid was
dissolved in water, the pH of the solution was adjusted to 7
with 2 N HCl, and the mixture was applied to a cation
exchange column (Bio-Rad AG50W-X8). The column was
washed thoroughly with water, and then was eluted with 0.5
N NH4OH to provide the amine 18 (12.4 mg, 61%) as a
colorless oil: [R]23 ) -10.5 (c 0.62, H2O) [lit.26 [R]23 ) -10.3
To a solution of the crude amine in 13.4 mL of ether was
added triethylamine (0.51 mL, 5.4 mmol), followed by acetic
anhydride (1.25 mL, 8.96 mmol). The mixture was stirred at
rt overnight and then washed with saturated aqueous NaH-
CO3. The combined aqueous washes were extracted with CH2-
Cl2, and the combined organics were dried (Na2SO4), filtered,
and concentrated to a yellow oil. Flash column chromatogra-
phy (hexanes/EtOAc 30:70) yielded the amide 20 (1.03 g, 97%)
as a white solid: mp 56.5-59.5 °C; [R]23 ) -46.5 (c 0.95,
D
CHCl3); IR (CH2Cl2) 3302, 3029, 2860, 1653 cm-1; H NMR δ
1
0.89-0.97 (m, 1H), 1.78 (s, 3H), 1.96-2.04 (m, 1H), 2.36-2.44
(m, 2H), 2.91-2.97 (m, 1H), 3.23 (t, 1H, J ) 7.4), 3.38 (dd,
1H, J ) 9.2, 4.9), 3.44 (dd, 1H, J ) 9.6, 4.9), 3.54-3.60 (m,
1H), 3.83 (dd, 1H, J ) 4.8, 2.1), 4.25 (d, 1H, J ) 11.5), 4.44-
4.56 (m, 4H), 4.64 (d, 1H, J ) 12.1), 6.18 (s, 1H), 7.24-7.37
(m, 15H); 13C NMR δ 23.0, 27.2, 40.4, 41.9, 43.3, 70.4, 71.6,
72.1, 73.1, 78.5, 84.4, 127.6, 127.9, 128.3, 128.4, 137.9, 138.2,
169.9. Anal. Calcd for C30H35NO4: C, 76.08; H, 7.45; N, 2.96.
Found: C, 75.98; H, 7.23; N 2.92.
D
D
1
(c 1.52, H2O)]; H NMR (300 MHz, CD3OD): δ 0.94 (dt, 1H J
) 12.7, 8.5), 1.87-2.08 (m, 2H), 3.02 (dt, 1H, J ) 7.2, 5.6),
3.21 (quint, 1H, J ) 1.6), 3.37 (dd, 1H, J ) 7.5, 7.0), 3.44 (dd,
1H, J ) 5.9, 1.9), 3.72 (dd, 1H, J ) 5.3, 4.1); 13C NMR (75
MHz, CD3OD): δ 33.1, 46.9, 57.0, 65.0, 74.5, 80.8.
Ack n ow led gm en t. Financial support of this re-
search by a gift from Burroughs-Wellcome and a pre-
doctoral fellowship from Bayer, Inc. (S.J .B.) is gratefully
acknowledged. J .W.L. is a 1995 Cottrell Scholar and
thanks the Research Corp. for this award. We wish to
thank Dr. Todd Blumenkopf, Dr. J oel Hawkins, and Dr.
Michael Solow for helpful discussions.
(1R,2R,3S,4R)-4-[(Ben zyloxy)m eth yl]-2,3-bis(ben zyloxy)-
cyclop en ta n eca r boxa m id e (19). To a suspension of am-
monium chloride (1.59 g, 29.8 mmol) in 30 mL of benzene at
0 °C was added a 2.0 M solution of trimethylaluminum in
toluene (14.9 mL, 29.8 mmol) dropwise. The mixture was
warmed to rt and stirred for 2 h, at which point it was
transferred to a flask containing the neat ester 16 (3.43 g, 7.74
J O970153D