Conversion of allylic alcohols into allylic nitromethyl compounds via a palladium-catalyzed solvolysis: An enantioselective synthesis of an advanced carbocyclic nucleoside precursor

Article abstract of DOI:10.1021/jo951510s

A two-step reaction sequence to homoallylic nitro compounds from allylic alcohols is presented. Ethoxy carbonylation of the alcohols with ethyl chloroformate provides the corresponding allylic ethyl carbonates in high yields. Exposure of these substrates to catalytic palladium(0) in CH₃NO₂ initiates a reaction sequence, ionization-decarboxylation-nitromethylation, that culminates with the formation of nitroalkenes. The regio- and stereochemical outcomes of the nitromethyl allylation reaction can be explained by the behavior of the transient π-allylpalladium complexes. This methodology serves as a centerpiece for the synthesis of an important carbocyclic nucleoside intermediate.

Full text of DOI:10.1021/jo951510s

3616
J . Org. Chem. 1996, 61, 3616-3622
Con ver sion of Allylic Alcoh ols in to Allylic Nitr om eth yl
Com p ou n d s via a P a lla d iu m -Ca ta lyzed Solvolysis: An
En a n tioselective Syn th esis of a n Ad va n ced Ca r bocyclic
Nu cleosid e P r ecu r sor 1
Donald R. Deardorff,*,† Kenneth A. Savin, Craig J . J ustman, Zarir E. Karanjawala,
J ames E. Sheppeck II, David C. Hager, and Nebil Aydin
Department of Chemistry, Occidental College, Los Angeles, California 90041
Received August 10, 1995 (Revised Manuscript Received March 7, 1996X)
A two-step reaction sequence to homoallylic nitro compounds from allylic alcohols is presented.
Ethoxy carbonylation of the alcohols with ethyl chloroformate provides the corresponding allylic
ethyl carbonates in high yields. Exposure of these substrates to catalytic palladium(0) in CH3NO2
initiates a reaction sequence, ionization-decarboxylation-nitromethylation, that culminates with
the formation of nitroalkenes. The regio- and stereochemical outcomes of the nitromethyl allylation
reaction can be explained by the behavior of the transient π-allylpalladium complexes. This
methodology serves as a centerpiece for the synthesis of an important carbocyclic nucleoside
intermediate.
In tr od u ction
Ganet,8c,10 and Hesse11 next explored the use of nitroal-
kanes and their derivatives with allylic carbonates. This
modification obviated the need for external base and
allowed these allylation reactions to proceed under
neutral conditions. Interestingly, despite the fact that
the nitro group is well-equipped to stabilize an adjacent
carbanion, there are relatively few examples9,10 of “un-
activated” nitroalkanes participating in metal-catalyzed
reactions under the exceptionally mild conditions af-
forded by carbonates.
Our interest in nitroalkane allylation reactions was in
response to the challenge of appending the nitromethyl
functionality to a cyclopentenyl skeleton in a stereo- and
regiocontrolled fashion. The nitromethyl moiety was
visualized as a masked hydroxymethyl group that could
later be elaborated12,13 into the pseudo-sugar fragment
that distinguishes carbocyclic nucleosides from conven-
tional nucleosides. Success in this venue prompted us
to investigate the nitromethylation of other π-allylpal-
ladium complexes prepared from allylic carbonates in the
presence of nitromethane. This paper therefore reports
the scope, mechanism, and application of this methodol-
ogy to the practice of organic synthesis.
Allylation reactions involving cationic π-allylpalladium
complexes provide an effective synthetic methodology for
the formation of carbon-carbon and carbon-heteroatom
bonds.2 The combination of high stereospecificity, broad
nucleophilic compatibility, and widespread availability
of π-allylic precursors account for the reaction's consider-
able popularity. Still, as measured by the dearth in
literature reports, stabilized anions derived from nitroal-
kanes are underappreciated as nucleophilic components
in these reactions. This is rather surprising since the
nitro group has played an illustrious role in traditional
organic synthesis.3
The first examples of couplings between nitronate
anions and π-allylpalladium complexes derived from
allylic esters4 were published in 1981 by Wade5 and
Aleksandrowicz.6 In both instances, researchers used
strong base to generate the desired anion prior to the
palladium-catalyzed step. A sprinkling of closely related
papers by these,7 and other researchers,8 followed. Tsuji,9
† Camille and Henry Dreyfus Scholar, 1993-94.
X Abstract published in Advance ACS Abstracts, May 1, 1996.
(1) Presented in part by K. A. S. at the Undergraduate Research
Conference, April 22, 1989, UCLA and by K. A. S. and D. R. D. at the
J oint 45th Northwest/Rocky Mountain Regional Meeting, J une 13-
15, 1990, Salt Lake City, UT; Abstracts 190 and 220, respectively.
(2) For a recent review see: Godleski, S. A. In Comprehensive
Organic Syntheses; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford,
U.K., 1991; Vol. 4, pp 585-661.
Resu lts a n d Discu ssion
P a lla d iu m -Ca ta lyzed Nitr om eth yla tion . We have
found that palladium(0) catalyzes the addition of unac-
tivated nitroalkanes to vinyl epoxides (eq 1).12a,14 The
(3) Denmark, S. E.; Marcin, L. R. J . Org. Chem. 1993, 58, 3850 and
references cited therein.
(4) Tsuji has reported the nucleophilic attack of nitroethane on the
intermediate telomer complex derived from palladium and butadiene:
Tsuji, J .; Yamakawa, T.; Mandai, T. Tetrahedron Lett. 1978, 565.
(5) Wade, P. A.; Hinney, H. R.; Amin, N. V.; Vail, P. D.; Morrow, S.
D.; Hardinger, S. A.; Saft, M. S. J . Org. Chem. 1981, 46, 765.
(6) Aleksandrowicz, P.; Piotrowska, H.; Sas, W. Pol. J . Chem. 1981,
55(6), 1469.
(7) (a) Aleksandrowicz, P.; Piotrowska, H.; Sas, W. Tetrahedron
1982, 38, 1321. (b) Aleksandrowicz, P.; Piotrowska, H.; Sas, W.
Monatsh. Chem. 1982, 113, 1221. (c) Wade, P. A.; Morrow, S. D.;
Hardinger, S. A. J . Org. Chem. 1982, 47, 365.
(8) (a) Lalonde, J . J .; Bergbreiter, D. E.; Wong, C.-H. J . Org. Chem.
1988, 53, 2323. (b) Ferroud, D.; Genet, J . P.; Muzart, J . Tetrahedron
Lett. 1984, 25, 4379. (c) Genet, J . P.; Ferroud, D. Tetrahedron Lett.
1984, 25, 3579.
(9) (a) Tsuji, J .; Yamada, T.; Minami, I.; Yuhara, M.; Nisar, M.;
Shimizu, I. J . Org. Chem. 1987, 52, 2988. (b) Tsuji, J .; Shimizu, I.;
Minami, I.; Ohashi, Y.; Sugiura, T.; Takahashi, K. J . Org. Chem. 1985,
50, 1523.
resulting 5-nitro-2-alken-1-ols are especially versatile
intermediates since the nitro group can be readily
(10) Ganet, J . P.; Grisoni, S. Tetrahedron Lett. 1986, 27, 4165.
(11) Ognyanov, V. I.; Hesse, M. Synthesis 1985, 645.
(12) (a) Deardorff, D. R.; Schulman, M. J .; Sheppeck, J . E., II.
Tetrahedron Lett. 1989, 30, 6625. (b) Lackey, J . W.; Mook, R. A., J r.;
Partridge J . J . (Glaxo, Inc.) U.S. US 5,057,630, 1991; Chem. Abstr.
1992, 116, 40967r.
(13) For similar approaches to carbocyclic nucleosides using “acti-
vated” nitromethyl derivatives see: (a) Peel, M. R.; Sternbach, D. D.;
J ohnson, M. R. J . Org. Chem. 1991, 56, 4990. (b) Trost, B. M.; Huo,
G.; Benneche, T. J . Am. Chem. Soc. 1988, 110, 621.
(14) Deardorff, D. R.; Kaufman, J . Palladium(0)-Catalyzed Prepara-
tion of Homoallylic Nitroalkenyl Compounds from Vinyl Epoxides,
Manuscript in preparation.
S0022-3263(95)01510-6 CCC: $12.00 © 1996 American Chemical Society

Allylic Nitromethyl Compounds from Allylic Alcohols
J . Org. Chem., Vol. 61, No. 11, 1996 3617
Ta ble 1. Tw o-Step Con ver sion of Allylic Alcoh ols in to Hom oa llylic Nitr o Com p ou n d s via a P d (0)-Ca ta lyzed
F r a gm en ta tion of th e Cor r esp on d in g Eth yl Ca r bon a tes
transformed into a wide variety of functionalities. As an
extension of this chemistry, we have discovered that
palladium also catalyzes the addition of nitromethane to
allylic carbonates (eq 2). This reaction opens an ad-
pounds are more acidic than nitromethane.16 However,
since nitromethylation occurs by solvolysis, competition
from less-abundant nucleophiles is suppressed.
Allylic alcohol entries 1-5 were selected in part for
their commercial availability whereas entries 6 and 7
were prepared as starting points for our ongoing syn-
thetic studies on carbocyclic analogs of purine and
pyrimidine nucleosides.17 Our method of nitromethyla-
tion is quite versatile since it is compatible with a number
of allylic skeletal types. The reaction is effective with
both primary and secondary allylic carbonates as well
as with cyclic and acyclic substrates. Tertiary allylic
carbonates were not examined in this study. Overall
yields for the two steps are good with generally high
regio- and stereoselectivities.
Previous studies18 have argued that allylic carbonates
are more reactive than their acetoxy counterparts. This
assertion was confirmed with the chemoselective nitro-
methylation of allylic acetoxy carbonate 7 (entry 7). This
differential reactivity provides a useful handle for devel-
oping selective synthetic processes via the sequential
generation of π-allylpalladium complexes. Such a strat-
egy is actualized in the preparation of a nucleoside
precursor (vide infra).
ditional avenue to synthetically valuable intermediates.
For example, upon exposure to palladium, nitromethane
adds to the corresponding ethyl carbonate of cis-4-
(benzyloxy)-2-buten-1-ol (1) at room temperature (entry
1, Table 1). The reaction is complete within 35 min and
affords a 62% yield of the homoallylic nitro product 8.
The trans stereochemistry was confirmed using 1H NMR
spectroscopy (CHdCH, J > 15 Hz). Especially notewor-
thy is that no bisallylated compound was detected.
Bisallylated product often accompanies reactions involv-
ing additions of diprotic soft nucleophiles to π-allylpal-
ladium complexes.15 One might expect that monoally-
lated nitroalkenes (e.g., 8) are especially vulnerable to
secondary allylation because R-substituted nitro com-
(16) Reutov, O. A.; Beletskaya, I. P.; Butin, K. P. CH-Acids;
Pergamon Press: Oxford, p 59, 1978.
(15) For example see: Doi, T.; Yanagisawa, A.; Miyazawa, M.;
Yamamoto, K. Tetrahedron: Asymmetry 1995, 6, 389.
(17) Results from this study will be reported at a later date.
(18) Tsuji, J . Synthesis 1990, 739.

3618 J . Org. Chem., Vol. 61, No. 11, 1996
Deardorff et al.
Sch em e 1
Sch em e 2
direct nucleophiles toward the more distant and less
sterically encumbered terminus of the η3-allyl system. In
the case of carbonates 2 and 3, which lack a directing
heteroatom, preservation of olefin-aromatic conjugation
dictates the regiochemical outcome (entries 2 and 3).
Entries 4 and 5 show only modest regioselectivity as
expected. Of interest is that regioisomeric carbonates 4
and 5 produce surprisingly similar ratios (3.0:1 and 3.4:
1, respectively) of nitromethyl adducts 11 and 12. This
evidence suggests that the two reactions travel through
a common π-allyl intermediate en route to nitromethy-
lated product.
Mech a n istic Con sid er a tion s. Nitromethylation is
believed to proceed via a palladium-induced ionization-
fragmentation sequence19 that concomitantly generates
equal concentrations of the transient metal complex and
alkoxide base (Scheme 1). Decarboxylation (as evidenced
by the evolution of CO2) ensures irreversibility of this
transformation. Rather than attacking the soft, electro-
philic π-allyl center directly, unfettered ethoxide ab-
stracts a proton from the solvent nitromethane (pKa )
10.2),20 generating the stabilized nitronate that serves
as a nucleophile. This cascade of events yields a signifi-
cantly softer nucleophilic species that readily attacks a
terminus of the η3-allyl system.
The nitromethylation reaction is completely stereospe-
cific as evidenced by entries 6 and 7 (vide infra). This is
consistent with previous mechanistic findings that pos-
tulate that palladium approaches the allylic leaving
group from the back side prior to ionization.24 Eventual
attack by the nitronate on the π-allyl face opposite the
metal would account for the double inversion or observed
retention of configuration relative to the original stereo-
genic center.
π-Allyl intermediates derived from (Z)-olefins yield
complexes in the anti configuration21 whereas (E)-olefins
lead to more stable syn isomers. Accordingly, nucleo-
philic additions to these transition-metal allyls afford Z
products in the former case and E products in the latter.22
Yet, in entries 1-5, E products are produced overwhelm-
ingly, if not exclusively, regardless of the stereochemistry
of the starting carbonate. This suggests that the π-σ-π
interconversion23 between the syn and anti complexes
occurs at a faster rate than the nitronate attack.
Regiochemical outcomes are influenced by the steric
differential between the two termini of unsymmetrical
π-allylpalladium complexes. Moreover, when steric and
electronic effects act in concert, absolute regiocontrol is
possible. This point is readily manifested in entries 1,
6, and 7 where the allylic polar heteroatoms strongly
During purification of nitromethyl adduct 8, we noted
the presence of a small amount of the corresponding
nitroethyl counterpart (5%). This anomalous result
prompted us to assay our distilled nitromethane. GC
analysis confirmed the solvent was contaminated with
4.5% of the homologue nitroethane. We were surprised
by the disproportionately high percentage of nitroethyl
adduct compared to nitromethyl. Nucleophilicity based
solely on steric arguments intuitively favors formation
of 8. Consequently, an experiment was designed to
measure qualitatively the relative nucleophilicity of
nitromethane and nitroethane under our standard condi-
tions. In this reaction, nitromethylation was carried out
in a 1:1 nitromethane and nitroethane solvent mixture
instead of neat nitromethane. Solvolysis led to complete
conversion of carbonate 1 into the corresponding nitro-
ethyl adduct. Such dramatic discrimination between
nucleophiles appears driven by the difference in solvent
pKa: 10.2 for nitromethane and 8.5 for nitroethane.20
(19) Tsuji, J . Tetrahedron 1986, 42, 4361.
(20) Reference 16, p 62.
(21) For accepted nomenclature for planar allyl ligands see: Con-
siglio, G.; Waymouth, R. M. Chem. Rev. 1989, 89, 257.
Syn th esis of a Ca r bocyclic Nu cleosid e P r ecu r sor .
Preparation of carbocyclic nucleoside precursor 23 hinged
on the new nitromethylation methodology. Outlined in
Scheme 2 is our retrosynthetic approach to that molecule.
We envisioned that the nitromethyl moiety on 19 would
serve as a chemical progenitor to the hydroxymethyl
function that adorns conventional nucleosides. Germane
to this study is the stereo- and regiospecific nitromethy-
lation of the optically pure starting material (+)-16.25,26
(22) Sjogren, M.; Hansson, S.; Norrby, P.-O.; Akermark, B.; Cucci-
olito, M. E.; Vitagliano, A. Organometallics 1992, 11, 3954.
(23) Corradini, P.; Maglio, G.; Musco, A.; Paiaro, G. Chem. Commun.
1966, 618.
(24) Trost, B. M.; Verhoeven, T. R. J . Am. Chem. Soc. 1980, 102,
4730.
(25) Deardorff, D. R.; Myles, D. C.; MacFerrin, K. D. Tetrahedron
Lett. 1985, 5615.

Allylic Nitromethyl Compounds from Allylic Alcohols
J . Org. Chem., Vol. 61, No. 11, 1996 3619
Sch em e 3
18, was obtained in one step from the palladium-
catalyzed reaction between nitromethane and cyclo-
pentadiene monoepoxide.12a NMR analysis on dia-18 at
200 MHz provided enough dispersion to resolve clearly
differences between the two diastereomers in both the
vinylic and methylene spectral regions of the five-
membered ring. To our delight, a comparative analysis
with the MTPA ester 18 derived from the enzymatic-
nitromethylation pathway illustrated in Scheme 3 re-
vealed an enantiomeric excess >99%.
Already properly configured for a second Pd(PPh3)4-
catalyzed substitution reaction and secure in its optical
purity, allylic acetate 14 was reacted with catalyst and
NaN3 in a THF:H2O (1:1) solution at 52 °C. These
conditions28 provided an excellent means to introduce the
surrogate amino function. The desired cis-1,4-product 19
was obtained in 68% yield along with the isomeric cis-
1,2-product (13.5%) 20 (not shown) and a trace of the
trans-1,4-azide. Longer reaction times, higher temper-
atures, and larger concentrations of catalyst all favored
formation of the thermodynamic trans-1,4 product. Ac-
cordingly, it is imperative that the reaction be quenched
immediately following the consumption of starting mate-
rial. Allylic azide 20 probably arises via the Winstein
rearrangement29 although 1,2-attack by azide ion on the
intermediate π-allyl cannot be ruled out as a contributing
mechanism. NMR measurements indicate that the equi-
librium ratio of 19 and 20 is 5:1. The tendency for allylic
azides to equilibrate has also been a problem in other
carbocyclic nucleoside syntheses.30
Sch em e 4
The cis-dihydroxylation-protection sequence with OsO4/
NMO and p-TSA in 2,2-dimethoxypropane afforded the
expected acetonide 21 in 57% yield, and a 10% yield of
the undesired all-cis epimer 22 (not shown). Attempts
to improve upon this reaction proved frustrating. For
example, while the use of cold KMnO4 greatly enhanced
stereoselectivity,31 yields were decreased to an unaccept-
ably low level. Cleavage of the C-N bond in the nitro
group by the oxidant is the apparent culprit for the
diminished yields.
The undertaking began with the ethoxycarbonylation
of (+)-16 with ethyl chloroformate in cold pyridine to
furnish 7 (R ) OCO2Et; Scheme 3) in near quantitative
yield. The nitromethylation step proved particularly
challenging due to the unexpected subtle difference in
reactivities between the allylic acetate and carbonate
functionalities. Fortunately, conditions (0.05 M 7 in 4:1
CH2Cl2/CH3NO2, 5 mol % Pd, rt) that led predominantly
to the desired cis-nitromethyl adduct 14 (R ) CH2NO2;
63% yield), accompanied by a 16% yield of meso-diacetate
15, were identified. Formation of this side product, which
presumably results from competitive attack by acetate
ion on the π-allylpalladium intermediate that leads to
14, is strong evidence that the unwanted acetoxy ioniza-
tion has occurred. We have found that if the above
conditions are not enforced, this fragmentation-nitro-
methylation reaction can lead to other extraneous prod-
ucts such as the trans-nitromethyl acetate or the cis and
trans-dinitromethyl adducts.
In the first of a two-step sequence, the nitromethyl
function was converted into the corresponding aldehyde
under basic Nef conditions32 (KMnO4, KOH, MeOH). The
instability of this carbonyl intermediate dictated that the
subsequent reduction step be carried out immediately.
Exposure to excess NaBH4 resulted in the successful
preparation of optically active 23 [R]19 -35.2° (c 0.515,
D
CHCl3) in a 44% two-step yield. The same carbocycle has
been previously prepared from D-erythrose in 22 steps
by Tadano et al.33 Structure proof and enantiopurity
determinations for azido alcohol (-)-23 were realized
through an exact match with the authentic spectra
(NMR, IR, UV-vis) and optical rotation data ([R]19D -35.2°
(c 1.05, CHCl3)) generously provided by Professor Tadano.
Tadano and co-workers have used this advanced nucleo-
side precursor in the formal synthesis of the notable
The nature of these products prompted us to question
if the absolute configuration of 14 had been compromised
under the above permutating conditions. To verify that
1
the enantiomeric integrity of 14 through H NMR analy-
sis, the Mosher-derived ester27 derivative 18 was pre-
pared in two steps (Scheme 4). Transformation of
nitromethyl acetate 14 with concentrated NH4OH into
the corresponding alcohol 17 followed by esterification
with Mosher’s acid chloride, (R)-(+)-R-methoxy-R-(tri-
fluoromethyl)phenylacetyl chloride (MTPA) provided 18
in 72% yield. Racemic nitromethyl alcohol rac-17, pre-
cursor to the MTPA diastereomeric control mixture dia-
carbocyclic nucleoside (-)-aristeromycin (A, NR1R2
adenine).
)
(28) Murahashi, S.-I.; Taniguchi, Y.; Imada, Y.; Tanigawa, Y. J . Org.
Chem. 1989, 54, 3292.
(29) Gagneux, A.; Winstein, S.; Young, W. G. J . Am. Chem. Soc. 1960,
82, 5956.
(26) (a) Deardorff, D. R.; Windham, C. Q.; Craney, C. L. Org. Synth.
1996, 73, 25. (b) Deardorff, D. R.; Mathews, A. J .; McMeekin, D. S.;
Craney, C. L. Tetrahedron Lett. 1986, 27, 1255.
(27) Mosher, H. S.; Dale, J . A.; Dull, D. L. J . Org. Chem. 1969, 34,
2543.
(30) Maag, H.; Rydzewski, R. M. J . Org. Chem. 1992, 57, 5823.
(31) Honel, M.; Mosher, H. S. J . Org. Chem. 1985, 50, 4386.
(32) Steliou, K.; Poupart, M.-A. J . Org. Chem. 1985, 50, 4971.
(33) Tadano, K.; Hoshino, M.; Ogawa, S.; Suami, T. J . Org. Chem.
1988, 53, 1427.

3620 J . Org. Chem., Vol. 61, No. 11, 1996
Deardorff et al.
3H); 13C NMR (CDCl3) δ 154.8, 135.9, 134.3, 128.3, 127.9,
Con clu sion s
126.4, 122.4, 67.8, 63.7, 14.0; IR (CDCl3) 2984, 1748, 1448 cm-1
;
HRMS (EI) calcd for C12H14O3 (M+) 206.0943, found 206.0954.
Eth yl (Z)-2-p en ten yl ca r bon a te (4): colorless oil; 88%
yield; Rf 0.59 (3:1 hexanes-CH2Cl2); bp (bulb-to-bulb) 60 °C
We have shown that nitromethylation of allylic carbon-
ates via a palladium-induced fragmentation reaction is
a viable adjunct to existing synthetic methodologies. The
reaction proceeds with predictable regio- and stereospeci-
ficity in good to very good yield. A mechanism, catalytic
in palladium, has been proposed to account for the
observed products. Finally, the utility of this new
methodology was demonstrated with a linear, formal
synthesis of aristeromycin.
1
at 0.40 Torr; 89.2% cis by GC; H NMR (CDCl3) δ 5.75-5.47
(m, 2H), 5.67 (dd, J ) 7.1, 0.8 Hz, 2H), 4.19 (q, J ) 7.2 Hz),
2.13 (dq (app br quintet), J ) 8.0 Hz), 1.30 (t, J ) 7.2 Hz, 3H),
0.99 (t, J ) 7 Hz, 3H); 13C NMR (CDCl3) δ 155.0, 137.1, 122.3,
63.5, 63.1, 20.7, 14.0, 13.7; IR (neat) 2969, 1745, 1464, 1374
cm-1
.
Eth yl 1-p en ten -3-yl ca r bon a te (5): colorless oil; 47%
yield; Rf 0.37 (4:1 hexanes-CH2Cl2); bp (bulb-to-bulb) 27 °C
1
at 0.40 Torr; H NMR (CDCl3) δ 5.79 (overlapping ddd, J )
Exp er im en ta l Section
17.3, 11.7, 6.9 Hz, 1H), 5.23 (m, 2H), 4.99 (ddd (app br q), J )
6.9 Hz, 1H), 4.18 (q, J ) 7.3 Hz, 2H), 1.78-1.70 (m, 2H), 1.30
(t, J ) 7.3 Hz, 3H), 0.92 (dd (app t), J ) 7.3 Hz); 13C NMR
(CDCl3) δ 154.6, 135.9, 117.1, 79.8, 63.5, 27.2, 14.1, 9.1; IR
(neat) 2976, 1744, 1263, 992 cm-1; HRMS (CI) calcd for
C8H15O3 (MH+) 159.1021, found 159.1012.
Gen er a l. All reactions were carried out in flame-dried
glassware under positive pressure of dry N2. Pyridine, ni-
tromethane, and CH2Cl2 were distilled under N2 from CaH2.
THF was distilled under N2 from a midnight blue solution of
sodium benzophenone ketyl. Ethyl chloroformate, osmium
tetraoxide, N-methylmorpholine N-oxide (NMO), triphenylphos-
phine (PPh3), and palladium catalysts, tris(dibenzylideneac-
etone)dipalladium(0) (DBA3Pd2) and tetrakis(triphenylphos-
phine)palladium(0) (PdL4), were commercially available from
Aldrich and used without further purification. Starting mate-
rial alcohols were purchased from Lancaster unless otherwise
indicated. (-)-MTPA-Cl was prepared from (+)-R-methoxy-
R-(trifluoromethyl)phenylacetic acid.27 Solutions were con-
centrated by rotary evaporation using water aspirator (ca. 30
Torr). Separations were performed by radial chromatography,
and TLC analyses were conducted on Baker Si 250 precoated
glass plates (0.25 mm). Plates were developed using either
ethanolic p-anisaldehyde reagent or phosphomolybdic acid.
Optical rotations were obtained in a 1-cm3 water-jacketed
microcell. Isomeric ratios were determined by gas chromato-
graph using a HP-101 column (25 m). Chromatographed
products were distilled bulb-to-bulb and submitted to UC
Riverside Mass Spectrometry Facility for HRMS and Desert
Analytics for elemental analyses.
Illu str a tive Exa m p le for th e Eth oxyca r bon yla tion of
Allylic Alcoh ols. cis-4-(Ben zyloxy)-2-bu ten yl Eth yl Ca r -
bon a te (1). A flask purged with N2 was charged with pyridine
(0.4 M, 7.0 mL). Next, 0.47 mL of cis-4-(benzyloxy)-2-buten-
1-ol (97% cis, 2.81 mmol, 500 mg) was syringed into the flask.
The solution was cooled to 0 °C with an ice-water bath, and
cold ethyl chloroformate (4.21 mmol, 0.34 mL) was syringed
in dropwise over 5 min. Upon completion of addition, the ice-
water bath was removed and the reaction was monitored by
TLC analysis (6:1 hexanes-EtOAc, Rf 0.63). The reaction was
quenched by diluting with ether, followed by extraction of the
organic layer with 8 mL portions of saturated NH4Cl (3 ×), 1
N HCl (3 ×), and saturated NaHCO3 (3 ×). The organic layer
was then dried over MgSO4 and concentrated under reduced
pressure. Radial chromatography (4 mm plate, 12:1 hexanes-
EtOAc) was effected on 760 mg of crude product. Removal of
solvent in vacuo afforded 659 mg (93% yield) 1 as a colorless
(+)-(1S,4R)-4-(6-Ch lor o-9H -p u r in -9-yl)-2-cyclop en t e-
n yl Eth yl Ca r bon a te (6). The alcohol was reacted with ethyl
chloroformate in 1:1 CH2Cl2-pyridine with 4 Å sieves, and
upon completion the reaction was diluted with EtOAc followed
by extraction of the organic layer with saturated NH4Cl (3 ×),
1 N HCl (3 ×), and saturated NaHCO3 (3 ×). The organic layer
was dried over MgSO4 and concentrated under reduced pres-
sure. Residual pyridine was removed in vacuo. The crude
material was passed through a plug of SiO2 and chromato-
graphed via radial chromatography (4 mm plate, solvent
gradient, starting 1:1, then 3:1 EtOAc-hexane) yielding 6 as
a colorless solid in 80% yield: mp 94.8-95.9 °C; Rf 0.52 (3:1
EtOAc-hexanes); [R]25 -9.20° (c 0.915, CHCl3); 1H NMR
D
(CDCl3) δ 8.76 (s, 1H), 8.20 (s, 1H), 6.44 (dt, J ) 5.4, 3.9 Hz,
1H), 6.22 (dd, J ) 5.4, 2.1 Hz, 1H), 5.77 (m, 1H), 5.68 (br dt,
J ) 7.2, 2.6 Hz, 1H), 4.20 (q, J ) 7.2 Hz, 2H), 3.16 (overlapping
dt, J ) 15.2, 8.0 Hz, 1H), 2.04 (dt, J ) 15.2, 3.4 Hz, 1H), 1.31
(t, J ) 7.2 Hz, 3H); IR (CDCl3) 1734.1, 1591.4, 1550.5, 1402.3
cm-1; HRMS (FAB) calcd for C13H14O3N4Cl (MH+) 309.0754,
found 309.0771. Anal. Calcd: C, 50.58; H, 4.24; N, 18.15.
Found: C, 50.46; H, 4.16; N, 17.87.
(+)-(1S,4R)-4-Acetoxy-2-cyclop en ten yl Eth yl Ca r bon -
a te (7). To a N2-flushed flask containing 115.0 mg (0.810
mmol) of 2 ([R]26 +67.6° (c 1.46, CHCl3)) was added 2 mL of
D
pyridine (0.04 M). The clear, colorless solution was stirred in
an ice-water bath for 10 min prior to the dropwise addition
of cold ethyl chloroformate (0.465 mL, 4.86 mmol) over a 15
min period. The reaction was judged complete by TLC
analysis (3:1 hexanes-EtOAc, Rf 0.50) in about 1 hour. (Since
the starting material lies under the UV-active pyridine streak,
the glass TLC slide was heated on a hotplate to remove the
pyridine prior to staining.) The reaction was quenched by the
addition of aqueous saturated NH4Cl solution and then layered
with ether. The organic phase was washed three times each
with saturated NH4Cl, ice-cooled 1 N HCl, and saturated
NaHCO3 solution. The organic phase was then dried over
MgSO4, vacuum filtered, and concentrated by rotary evapora-
tion. The residue was dissolved twice in 20 mL of heptane
and azeotroped under aspirator vacuum to remove the final
traces of pyridine. Following exposure to high vacuum, 168
mg (96.6%) of clear oil was obtained. A slight enrichment in
purity may be realized by chromatographing the product 7 over
SiO2 using 4:1 hexanes-EtOAc: [R]25D -9.71° (c 1.605, CHCl3);
1H NMR (CDCl3) δ 6.10 (br s, 2H), 5.50 (ddd, J ) 7.5, 3.7, 1.0
Hz, 1H), 5.44 (ddd, J ) 7.5, 3.7, 1.0 Hz, 1H), 4.17 (q, J ) 7.1
Hz, 2H), 2.87 (dt (app quintet), J ) 7.5, 15.0 Hz, 1H), 2.02 (s,
3H), 1.80 (dt, J ) 3.8, 15.0 Hz, 1H), 1.28 (t, J ) 7.1 Hz, 3H);
1
oil: 98.4% cis by GC; H NMR (CDCl3) δ 7.32 (m, 5H), 5.92-
5.68 (m, 2H), 4.69 (d, J ) 6.2 Hz, 2H), 4.52 (s, 2H), 4.20 (q, J
) 6.9 Hz, 2H), 1.31 (t, J ) 6.9 Hz, 3H); 13C NMR (CDCl3) δ
155.0, 138.0, 131.3, 128.4, 127.8, 127.7, 126.2, 72.5, 65.7, 64.0,
63.4, 14.3; IR (neat) 1745, 1710, 1450, 1375 cm-1; HRMS (CI)
calcd for C14H19O4 (MH+) 251.1283, found 251.1285.
Eth yl p-n itr ocin n a m yl ca r bon a te (2): yellow solid; 77-
99% yield; mp 34.2-35.0 °C; bp (bulb-to-bulb) 142 °C at 0.38
1
Torr; H NMR (CDCl3) δ 8.19 (br d, J ) 8.9 Hz, 2H), 7.52 (br
d, J ) 8.9 Hz, 2H), 6.76 (br d, J ) 15.9 Hz), 6.45 (dt, J ) 15.9,
5.8 Hz, 1H), 4.83 (dd, J ) 5.8, 1.3 Hz, 2H), 4.24 (q, J ) 7.2 Hz,
2H), 1.34 (t, J ) 7.2 Hz, 3H); 13C NMR (CDCl3) δ 154.8, 147.4,
142.5, 131.5, 127.7, 127.1, 123.9, 123.9, 67.1, 64.2, 14.1; IR
(neat) 2985, 2941, 1745, 1597, 1516 cm-1; HRMS calcd for
C12H13O5N (M+) 251.0794; found 251.0797.
IR (neat) 2990, br 1740, 795 cm-1
(MNH4+) 232.1185, found 232.1205.
; HRMS (CI) calcd for C10H18-
NO5
Illu str a tive Exa m p le of th e P d -Ca ta lyzed F r a gm en ta -
tion -Nitr om eth yla tion Rea ction . cis-4-(Ben zyloxy)-1-
n itr o-3-p en ten e (8). A flask was purged with N2 and charged
with nitromethane (6.0 mL, 0.2 M). Carbonate 1 (1.20 mmol,
300 mg) was dissolved in a portion of nitromethane and was
subsequently syringed into the flask followed by PPh3 (10
mol%, 31 mg) and DBA3Pd2 (2.5 mol%, 27 mg). After 35 min,
(E)-Cin n a m yl eth yl ca r bon a te (3): clear oil; 85% yield;
Rf 0.45 (1:1 hexanes-EtOAc); bp (bulb-to-bulb) 96-100 °C at
0.18 Torr; 1H NMR (CDCl3) δ 7.34-7.17 (m, 5H), 6.61 (br d, J
) 15.9 Hz, 1H), 6.23 (dt, J ) 15.9, 6.3 Hz, 1H), 4.71 (dd, J )
6.3, 1.2 Hz, 2H), 4.15 (q, J ) 7.1 Hz, 2H), 1.24 (t, J ) 7.1 Hz,

Allylic Nitromethyl Compounds from Allylic Alcohols
J . Org. Chem., Vol. 61, No. 11, 1996 3621
the reaction was judged complete by TLC analysis. The
reaction was concentrated under reduced pressure, followed
by elution with ether (30 mL) through a glass frit layered with
MgSO4 and SiO2. (This step ensures removal of the palladium
catalyst.) After concentration of the solution under reduced
pressure, purification was effected via radial chromatography
(2 mm plate, 12:1 hexanes-EtOAc). Concentration of the
solution in vacuo yielded 165 mg (62% yield) of 8 as a clear
(m, 1H), 4.63 (d, J ) 6.4 Hz, 2H), 3.66 (m, 1H), 3.09 (dt, J )
14.2, 8.5 Hz, 1H), 1.94 (dt, J ) 14.2, 6.4 Hz, 1H); 13C NMR
(DMSO-d6) δ 151.5, 151.2, 148.9, 145.8, 135.7, 131.2, 130.8,
78.2, 60.2, 42.9, 34.5 cm-1; IR (CDCl3) 3092, 3064, 1588, 1562,
1556, 1494; HRMS (FAB) calcd for C11H11O2N5Cl (MH+)
280.0602, found 280.0601. Anal. Calcd: C, 47.24; H, 3.60;
N, 25.04. Found: C, 47.27; H, 3.56; N, 24.95.
(+)-(1R ,4S )-1-Ace t oxy-4-(n it r om e t h yl)-2-cyclop e n -
ten e (14). Carbonate 7 (22.4 mg, 0.105 mmol) was weighed
into a flame-dried flask under a N2 atmosphere and then
dissolved in a mixture of nitromethane (0.35 mL) and CH2Cl2
(1.75 mL). PPh3 (5.0 mg, 0.021 mmol, 20 mol%) was added to
the colorless solution followed by the catalyst, DBA3Pd2 (4.8
mg, 0.0052 mmol, 5 mol %). Initially the solution turned dark
brown, but gradually became lighter until a bright yellow color
was achieved, usually after 5 min. The reaction progress was
monitored by TLC (4:1 hexanes-EtOAc, Rf 0.30) and judged
complete in typically 15-60 min. The reaction mixture was
diluted with ether and washed through a premoistened (ether)
plug of layered MgSO4 and silica gel (40-140 mesh) with
anhydrous ether. The solvent was removed under reduced
pressure. The crude material was chromatographed over SiO2
(7 g) with 10:1 hexanes-EtOAc as the eluent. Concentration
under high vacuum produced a 15.3 mg mixture of 14 and 15
in a 4:1 ratio (63% and 16%, respectively) as measured by
NMR. Scale-up to gram quantities of reactants afforded more
modest yields (45-55%) of 14. Further chromatography under
1
oil: 10:1 trans-cis by GC; H NMR (CDCl3) δ 7.33 (m, 5H),
5.72 (m, 2H), 4.50 (s, 2H), 4.43 (t, J ) 6.9 Hz, 2H), 3.98 (dd, J
) 4.4, 1.1 Hz, 2H,), 2.75 (dt (app br q), J ) 6.9, 5.5 Hz, 2H);
13C (CDCl3) δ 138.2, 131.1, 128.5, 128.4, 127.8, 127.8, 127.7;
IR (neat) 1555, 1500, 1455, 1430 cm-1; HRMS (CI) calcd for
C12H16O3N (MH+) 222.1130, found 222.1138.
4-Nitr o-1-(p-n itr op h en yl)bu ten e (9): yellow solid; 74%
yield; mp 77.0-78.5 °C; Rf 0.60 (2:1 hexanes-EtOAc); bp (bulb-
1
to-bulb) 160 °C at 0.40 Torr; H NMR (CDCl3) δ 8.19 (br d, J
) 8.9 Hz, 2H), 7.46 (br d, J ) 8.9 Hz, 2H), 6.60 (br d, J ) 15.9
Hz, 1H), 6.32 (dt, J ) 15.9, 6.9 Hz, 1H), 4.56 (t, J ) 6.7 Hz,
2H), 2.97 (ddt (app br q), J ) 6.7, 1.3 Hz, 2H); 13C NMR (CDCl3)
δ 147.4, 142.8, 132.2, 128.2, 126.9, 124.0, 74.5, 30.6; IR (neat)
2356, 1556, 1519, 1345 cm-1; HRMS calcd for C10H10O4N2 (M+)
222.0641, found 222.0650.
4-Nitr o-1-p h en ylbu ten e (10): colorless oil; 71% yield; Rf
1
0.55 (5:1 hexanes-EtOAc); H NMR (CDCl3) δ 7.4-7.15 (m,
5H), 6.51 (br d, J ) 15.8 Hz, 1H), 6.09 (dt, J ) 15.8, 7.0 Hz,
1H), 4.48 (t, J ) 7.0 Hz, 2H), 2.89 (ddt (app br q), J ) 7.0, 1.2,
7.0 Hz, 2H); 13C NMR (CDCl3) δ 136.5, 134.1, 128.6, 127.8,
126.3, 122.9, 75.0, 30.7; IR (CHCl3) 2860, 1558, 1500, 1450
similar conditions led to pure 14: [R]27 +83.4° (c 1.535, CH2-
D
Cl2); 1H NMR (CDCl3) δ 5.98 (br s, 2H), 5.63 (ddd, J ) 7.6,
3.4, 0.9 Hz, 1H), 4.43 (dd, J ) 12.4, 6.7 Hz, 1H), 4.31 (dd, J )
12.4, 7.9 Hz, 1H), 3.40 (m, 1H), 2.57 (dt (app quintet), J )
15.2, 7.8 Hz, 1H), 2.02 (s, 3H), 1.62 (dt, J ) 15.2, 3.6 Hz, 1H);
13C NMR (CDCl3) δ 169.9, 134.7, 132.3, 78.7, 75.7, 42.0, 33.5,
20.5; IR (neat) 2950, 1727, 1551, 1377, 1243 cm-1; HRMS (CI)
calcd for C8H12NO4 (MH+) 186.0766, found 186.0774.
cm-1
.
(E)-1-Nitr o-3-h exen e (11) a n d 3-Eth yl-4-n itr o-1-bu ten e
(12). Carbonate 4 (300 mg, 1.90 mmol) was added to a flask
charged with 9.0 mL of nitromethane (0.2 M). The flask was
fitted with a cold finger condenser and purged with N2. The
solution was heated to a 65 °C oil bath temperature followed
by addition of PPh3 (10 mol %, 50 mg) and DBA3Pd2 (2.5 mol
%, 43 mg). Ionization-decarboxylation of the carbonate was
confirmed by immediate bubbling of CO2 gas. The reaction
was monitored and judged compete by TLC analysis (ca. 1.5
h). (High volatility of the desired product precluded the use
of rotary evaporation with heat for the removal of ni-
tromethane.) Accordingly, the entire reaction mixture was
chromatographed over 40 g of SiO2 with 6:1 hexanes-CH2Cl2
as the eluent. All product spots were collected for GC analysis
and were subsequently separated via radial chromatography
(2 mm plate, 10:1 hexanes-CH2Cl2). Concentration in vacuo
yielded 175 mg of a colorless oil containing inseparable
regioisomers 11 and 12, 3.0:1, respectively, from 4 in 71% yield
(3.4:1 from 5 in 70% yield): Rf 0.35 (4:1 hexanes-CH2Cl2); bp
(bulb-to-bulb) 30 °C at 0.28 Torr; 1H NMR (CDCl3) δ 5.63 (dtt,
J ) 15.4, 6.2, 1.1 Hz, 1H, 11), 5.33 (dtt, J ) 15.4, 6.6, 1.5 Hz,
1H, 11), 5.16 (dd, J ) 9.9, 1.5 Hz, 1H, 12), 5.14 (d, J ) 17.3
Hz, 1H, 11), 4.39 (t, J ) 6.94 Hz, 2H, 11), 4.39 (dd, J ) 11.7,
4.4 Hz, 1H, 12), 4.29 (dd, J ) 11.7, 8.77 Hz, 1H, 12), 2.9-2.7
(m, 2H, 12), 2.67 (dq, J ) 6.9, 1.1 Hz, 2H, 11), 2.01 (br quintet,
J ) 7.3 Hz, 2H, 11), 1.56-1.20 (m, 2H, 12), 0.96 (t, J ) 7.3
Hz, 3H, 11), 0.95 (dd, J ) 7.7, 7.3 Hz, 3H, 12); IR (neat) 2924,
1601, 1492, 1452 cm-1; HRMS (CI) calcd for C6H12O2N (MH+)
130.0868, found 130.0864.
(+)-(3R, 5S)-3-(6-Ch lor o-9H-pu r in -9-yl)-5-(n itr om eth yl)-
1-cyclop en ten e (13). A flask containing 650 mg (2.11 mmol)
of carbonate 6 was charged with 10.5 mL of nitromethane (0.2
M) followed by addition of DBA3Pd2. The mixture was heated
with an oil bath at 50 °C for 30 min after which 0.062 mL (3
mol %) of triisopropyl phosphite was added via syringe.
Shortly thereafter, evolution of a gas was observed. The
reaction was judged complete by TLC (3:1 EtOAc-hexanes,
Rf 0.46) after 20 min. The solution was concentrated under
reduced pressure and passed through a glass frit layered with
MgSO4 (4 g) and SiO2 (7 g) with 170 mL of EtOAc. The solvent
was concentrated and the residue purified via radial chroma-
tography (4 mm plate, 1:1 EtOAc-hexanes) and afforded 350
mg of a crystalline colorless solid (13) with mp 130.4-131.8
°C (recrystallized from MeOH) in 60% yield: [R]25D +29.97° (c
0.94, CHCl3); 1H NMR (CDCl3) δ 8.75 (s, 1H), 8.12 (s, 1H), 6.24
(dt, J ) 5.4, 2.1 Hz, 1H), 6.05 (dt, J ) 5.4, 2.1 Hz, 1H), 5.82
cis-4-Cyclop en ten e-1,3-d iol d ia ceta te (15): 1H NMR
(CDCl3) δ 6.06 (s, 2H), 5.51 (m, 2H), 2.85 (overlapping dt, J )
7.5, 15 Hz, 1H), 2.02 (s, 6H), 1.71 (dt, J ) 3.8, 15 Hz, 1H).
(+)-(1R,4S)-4-(Nitr om eth yl)-2-cyclop en ten -1-ol (17). A
solution of 14 (50 mg, 0.27 mmol) in 2 mL of concd NH4OH
was stirred at rt under N2 for 3 h. The reaction mixture was
concentrated under reduced pressure and purified by column
chromatography using 12 g of SiO2 and a 1:1 hexanes-EtOAc
solvent system. Removal of solvent in vacuo provided 36.3 mg
(94% yield) as a colorless oil: [R]25 +19.91 (c 0.905, MeOH);
D
1H NMR (CDCl3) δ 5.98 (dt, J ) 5.6, 2.0 Hz, 1H), 5.86 (ddd, J
) 5.6, 2.0, 1.0 Hz, 1H), 4.87 (m, 1H), 4.46 (dd, J ) 12.3, 6.6
Hz, 1H), 4.37 (dd, J ) 12.3, 7.4 Hz, 1H), 3.33 (m, 1H), 2.56
(ddd (app quintet), J ) 14.2, 7.9, 7.6 Hz, 1H), 1.70 (br s, 1H),
1.52 (ddd (app dt), J ) 14.2, 4.4, 4.2 Hz, 1H); 13C NMR (CDCl3)
δ 136.3, 132.3, 79.5, 75.6, 42.4, 36.7; IR (neat) 3361, 2916, 1556,
1381, 1084 cm-1; HRMS calcd for C6H8O2N (M+ - OH)
126.0555, found 126.0548.
P r ep a r a tion of th e (R)-(+)-MTP A Ester of (+)-(1R,4S)-
4-(Nitr om eth yl)-2-cyclop en ten -1-ol (18). A solution of 17
(18.1 mg, 0.127 mmol), (R)-(+)-R-methoxy-R-(trifluoromethyl)-
phenylacetyl chloride (96 mg, 0.38 mmol), and pyridine (0.70
mL, 0.18 M in 17) stirred at rt under N2 for 12 h. The reaction
was quenched with 5 mL of H2O, layered with ether, and
transferred to a separatory funnel. The aqueous phase was
extracted (8 ×) with ether. The combined extracts were dried
over MgSO4, filtered, and concentrated. The final traces of
pyridine were removed by azeotroping with heptane. The
residual viscous oil was purified by radial chromatography (1
mm plate, 4:1 hexanes-EtOAc). The spot at TLC Rf 0.31 was
collected and concentrated in vacuo to give 33.9 mg (77% yield)
of 18 as a colorless oil: [R]23 +102.5° (c 1.055, MeOH); 1H
D
NMR (CDCl3) δ 7.55-7.35 (m, 5H, 6.05 (br s, 2H), 5.85 (m,
1H), 4.25 (dd, J ) 12.7, 6.8 Hz, 1H), 4.12 (dd, J ) 12.7, 8.0
Hz, 1H), 3.51 (s, 3H), 3.40 (m (app dq), 1H), 2.57 (dt (app
quintet), J ) 15.0, 7.6 Hz, 1H), 1.68 (dt, J ) 15.0, 2.9 Hz, 1H);
IR (neat) 2952, 1745, 1553, 1379, 1270, 1172 cm-1; HRMS (CI)
calcd for C16H20O5N2F3 (MNH4+) 377.1324, found 377.1324.
P r ep a r a tion of th e (R)-(+)-MTP A Ester of cis-(()-4-
(Nitr om eth yl)-2-cyclop en ten -1-ol (d ia -18). See the prepa-
ration of 18 above. The NMR spectrum consists of a 1:1

3622 J . Org. Chem., Vol. 61, No. 11, 1996
Deardorff et al.
diastereomeric mixture of spectrum 18 (above) overlapping
with the following diastereomer: 1H NMR (CDCl3) δ 7.55-
7.35 (m, 5H), 6.09 (br s, 2H), 5.84 (m, 1H), 4.30 (dd, J ) 12.6,
6.5 Hz, 1H), 4.15 (dd, J ) 12.6, 8.2 Hz, 1H), 3.49 (s, 3H), 3.41
(m, 1H), 2.58 (dt (app quintet), J ) 15.0, 7.6 Hz, 1H), 1.78 (dt,
J ) 15.0, 3.0 Hz, 1H).
as a colorless oil: 1H NMR (CDCl3) δ 4.65 (dd, J ) 14.0, 7.8
Hz, 1H), 4.63 (m, 2H), 4.41 (dd, J ) 6.7, 14.0 Hz, 1H), 3.30
(m, 1H), 3.28 (m, 1H), 1.98 (ddd (app br quintet), J ) 11.6,
5.9, 5.9 Hz, 1H), 1.79 (ddd (app q), J ) 11.9, 11.8, 11.8 Hz,
1H), 1.47 (s, 3H), 1.29 (s, 3H); IR (neat) 2983, 2938, 2105, 1450,
1376 cm-1
.
(+)-(3R,5S)-3-Azido-5-(n itr om eth yl)-1-cyclopen ten e (19).
To a stirred solution of allylic acetate 14 (108 mg, 0.583 mmol)
in THF (1.16 mL, 0.25 M) was added in one portion to a
solution of NaN3 (80.0 mg, 1.23 mmol) in water (1.23 mL). The
reaction vessel was immersed into an oil bath held at 52 °C.
After 5 min, Pd(PPh3)4 (13.5 mg, 0.0117 mmol) was added. The
reaction was followed by TLC analysis and judged complete
in 20 min. The mixture was passed through a 40-140 silica
gel plug with ether. The solvent was concentrated to ap-
proximately 75 mL, dried over MgSO4, and vacuum filtered.
Purification via radial chromatography (1 mm plate, 6:1
hexanes-EtOAc) afforded, after concentration in vacuo, 54.0
mg (67.7% yield) of the cis-1,4 product 19 and 10.8 mg (13.5%
yield) of the cis-1,2 product 20.
(-)-(1R,2R,3S,4R)-4-Azid o-1-(h yd r oxym eth yl)-2,3-(iso-
p r op ylid en ed ioxy)cyclop en ta n e (23). To a stirring, ice-
water cooled solution of compound 21 (142.9 mg, 59 mmol) in
MeOH (4.2 mL) was added dropwise over 5 min a freshly
prepared solution of KOH (87%, 42.1 mg, 0.65 mmol) in MeOH
(6.5 mL). After an additional 15 min, a freshly prepared
solution of KMnO4 (74.7 mg, 0.470 mmol) and MgSO4 (51.9
mg, 0.430 mmol) in 10.5 mL of H2O was added dropwise over
15 min. The reaction stirred at 0 °C for 45 min and was then
quenched by passing it through a Celite plug with ether. Brine
was added and the aqueous layer extracted with 1:1 ether-
EtOAc (5 ×). The combined organic layers were dried over
MgSO4, filtered, and concentrated in vacuo to give 108 mg of
crude aldehyde. The unstable aldehyde was immediately
dissolved in 2-propanol (5.1 mL), cooled in an ice-water bath,
and combined with NaBH4 (107 mg, 0.78 mmol). The reaction
ran at rt and was judged complete in about 1 h using TLC
analysis. The mixture was cooled in an ice-water bath,
layered with ether, and quenched with the addition of H2O.
When the gas evolution had ceased, a saturated NaCl solution
was added and the aqueous phase was extracted with EtOAc
(7 ×). The combined organic layers were dried over MgSO4,
filtered, and concentrated under vacuum. Column chroma-
tography performed over SiO2 with 3:1 hexanes-EtOAc to
provided 8 mg of recovered 21 and 54 mg (45.5% yield) of pure
Major isomer 19: [R]25 +178.6° (c 1.4, CHCl3); Rf 0.31 (6:1
D
hexanes-EtOAc); 1H NMR (CDCl3) δ 5.95 (br s, 2H), 4.47 (m,
1H), 4.44 (dd, J ) 12.6, 6.6 Hz, 1H), 4.31 (dd, J ) 12.6, 8.1
Hz, 1H), 3.34 (m, 1H), 2.58 (dt, J ) 14.4, 8.2 Hz, 1H), 1.62 (dt,
J ) 14.4, 4.4 Hz, 1H); 13C NMR (CDCl3): δ 134.6, 132.4, 79.1,
66.2, 42.9, 34.2; IR (neat) 2923, 2096, 1552, 1380, 1368, 1248
cm-1: HRMS (CI) calcd for C6H9O2N4 (MH+) 169.0726, found
169.0736.
1
Minor isomer 20: Rf 0.36 (6:1 hexanes-EtOAc); H NMR
(CDCl3) δ 6.16 (m, 1H), 5.92 (m, 1H), 4.67 (dd, J ) 14.0, 8.3
Hz, 1H), 4.43 (dd, J ) 14.0, 7.0 Hz, 1H), 4.50 (m, 1H), 3.07 (m
(app sextet), 1H), 2.54 (m, 1H), 2.26 (ddq, J ) 17.0, 8.0, 2.5
23: [R]19 -35.2° (c 0.515, CHCl3); Rf 0.26 (3:1 hexanes-
Hz, 1H); IR (neat) 2940, 2101, 1553, 1380, 1250 cm-1
.
D
EtOAc); 1H NMR (CDCl3) δ 4.55 (dd, J ) 6.2, 1.6 Hz, 1H), 4.43
(dd, J ) 6.2, 1.9 Hz, 1H), 3.95 (ddd, J ) 6.7, 4.4, 6.7 Hz, 1H),
3.63 (d, J ) 6.4 Hz, 2H), 2.39-2.20 (m, 2H), 1.63 (br s, 1H),
1.60 (m, 1H), 1.44 (s, 3H), 1.27 (s, 3H); 13C NMR (CDCl3) δ
111.6, 85.2, 82.6, 67.0, 63.8, 47.2, 32.0, 26.7, 24.3; IR (neat)
3436, 2988, 2936, 2105, 1455, 1440, 1381, 1376, 1263, 1211,
1161, 1065, 1039, 865 cm-1; HRMS (CI) calcd for C9H16O3N3
(MH+) 214.1192, found 214.1183.
(-)-(1R,2R,3S,4R)-4-Azid o-1-(n itr om eth yl)-2,3-(isop r o-
p ylid en ed ioxy)cyclop en ta n e (21). To a N2-flushed flask
containing a solution of 19 (167.6 mg, 0.9970 mmol) in 3.3 mL
of an 8:1 acetone-water solution was added NMO (350.4 mg,
2.991 mmol). The reaction vessel, equipped with a glass-coated
magnetic stirbar, was placed in a salt-ice bath in which the
temperature was held between -5 and -15 °C prior to the
addition of a small crystal of OsO4. TLC analysis indicated
that the reaction was complete in 2 h (Rf 0.32, 1:1 hexanes-
EtOAc). The mixture was then eluted through a SiO2 plug
with 400 mL of ether and concentrated under reduced pres-
sure. The crude diols were chromatographed over SiO2 (9 g,
40-140) with 200 mL of 1:1 hexanes-EtOAc. All of the eluent
was collected and concentrated under vacuum to afford 202
mg of a yellow oil. The diols were then transferred to a flame-
dried flask and dissolved in 4.95 mL of freshly distilled acetone
and 20 drops of 2,2-dimethoxypropane. Two crystals of p-TSA
were added to the solution, and the reaction was stirred for 1
h before it was quenched by passing it through a MgSO4/SiO2
plug with ether. The solvent was removed under vacuum, and
the crude mixture of acetonides 21 and 22 was purified by
radial chromatography (2 mm plate, 6:1 hexanes-EtOAc). The
spot at TLC Rf 0.29 was collected and concentrated in vacuo
Ack n ow led gm en t. The authors are indebted to the
National Science Foundation (CHE-8908212) and the
donors of the Petroleum Research Fund, administered
by the American Chemical Society, for support of this
research. D.R.D. gratefully acknowledges the Camille
and Henry Scholar/Fellow Program for Undergraduate
Institutions. K.A.S. and C.J .J . wish to thank the Ford
Foundation for their summer undergraduate research
stipends. Finally, D.C.H. and N.A. (community college
student participant) express their appreciation to the
NSF REU Program (Research Experiences for Under-
graduates; CHE-9100606) for summer financial support.
We thank Professor Tadano for the authenticating
spectra.
to give 56.6% yield of 21 as a colorless oil.
1
Major isomer 21: [R]26.5 -28.1° (c 1.31, CHCl3); H NMR
D
(CDCl3) δ 4.65-4.35 (m, 2H), 4.55 (dd, J ) 13.1, 7.8 Hz, 1H),
4.39 (dd, J ) 13.1, 7.2 Hz, 1H), 4.05 (m, 1H), 2.88 (m (app dq),
2.39 (ddd, J ) 14.2, 7.8, 5.6 Hz, 1H), 1.60 (br d, J ) 14.2 Hz,
1H), 1.44 (s, 3H), 1.27 (s, 3H): 13C NMR (CDCl3) δ 111.7, 84.7,
82.7, 66.6, 43.7, 32.3, 29.5, 26.4, 24.1; IR (neat) 2989, 2938,
2113, 1552, 1378, 1212 cm-1; HRMS (CI) calcd for C9H15O4N4
(MH+) 243.1093, found 243.1080.
Su p p or tin g In for m a tion Ava ila ble: Copies of the 1H
NMR spectra for compounds 1-15, 17-22, and dia-18 (20
pages). This material is contained in libraries on microfiche,
immediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
Minor isomer 22: The spot at TLC Rf 0.16 was collected
and concentrated in vacuo to give 24.1 mg (10% yield) of 22
J O951510S