Unexpected cleavage of 2-azido-2-(hydroxymethyl)oxetanes: Conformation determines reaction pathway?

Article abstract of DOI:10.1021/jo101328c

An unanticipated cleavage of 2-azido-2-(hydroxymethyl)oxetanes is reported. In attempts to oxidize the title oxetanyl alcohols to the corresponding carboxylic acids with RuO₄, cleaved nitriles were formed as the sole isolable products, while a

Full text of DOI:10.1021/jo101328c

pubs.acs.org/joc
Unexpected Cleavage of 2-Azido-2-(hydroxymethyl)oxetanes:
Conformation Determines Reaction Pathway?
ꢀ
Elisa Farber, Jackson Herget, Jose A. Gascon, and Amy R. Howell*
ꢀ
Department of Chemistry, University of Connecticut, Storrs, Connecticut 06269-3060, United States
*Corresponding author. amy.howell@uconn.edu Phone: 860-486-3460. Fax: 860-486-2981.
Received July 6, 2010
An unanticipated cleavage of 2-azido-2-(hydroxymethyl)oxetanes is reported. In attempts to oxidize
the title oxetanyl alcohols to the corresponding carboxylic acids with RuO4, cleaved nitriles were
formed as the sole isolable products, while a closely related tetrahydrofuran gave solely the expected
carboxylic acid. Quantum chemical calculations suggest that the divergent outcomes are governed by
conformational differences in the azidoalcohols.
Introduction
et al., demonstrated that Pd(II) could promote a ring expan-
sion involving an oxidative cleavage of cyclic 2-azidoalcohols
to azaheterocycles.5
We have been interested in the synthesis of oxetane con-
taining natural product derivatives. As part of this focus we
targeted oxetane analogs of hydantocidin, a natural product
which has shown potent herbicidal activity1 (Figure 1). In an
attempt to oxidize a model system to the corresponding
carboxylic acid, 2-azido-2-(hydroxymethyl)oxetane 1a was
Ruthenium tetroxide is well-known for oxidizing primary
alcohols to carboxylic acids, as well as for cleaving double bonds
to carbonyl products.6 A limited number of other C-C cleavage
reactions mediated by RuO4 have been described. In 1994,
Ranganathan and co-workers reported the C-C cleavage of a
β-hydroxyamide from a protein backbone using RuO4.7 Also,
cleavage of β-hydroxyethers under similar oxidative conditions
was noted by Ferraz and co-workers.8 However, C-C scission
of β-hydroxyazides with RuO4 has not been previously reported.
Due to the unexpected result when 1a was treated with RuO4, we
decided to investigate the reactivity of other 2-azido-2-(hydroxy-
methyl)oxetanes under these conditions.
treated with RuO4, generated in situ from RuCl3 3H2O and
3
NaIO4; only nitrile 2a was isolated. This was a surprising
outcome since Sano and co-workers previously reported that
azidoalcohol 3 was oxidized to carboxylic acid 4 in good
yield.2 No mention was made of nitrile formation (Figure 1).
To our knowledge, there are only three examples of
β-hydroxyazide oxidative cleavage described in the literature
(Figure 2). In 2004, Suarez and co-workers reported a radical
fragmentation with the use of a hypervalent iodine reagent.3
Then, in 2006, Ye and co-workers noted that oxidative
cleavage tonitriles resulted whenβ-azidoalcohols weretreated
with PCC.4 This outcome was attributed to the lability of
β-azidoaldehydes under the conditions. The third, by Chiba
Results and Discussion
2-Azido-2-(hydroxymethyl)oxetanes 1 were synthesized from
the corresponding β-lactones in four steps (Table 1). β-Lactones
6a-6c and 6e were prepared following the Mukaiyama aldol-
lactonization protocol developed by Yang and Romo.9 Com-
pound 6d was synthesized under Mitsunobu conditions as
(1) (a) Cseke, C.; Gerwick, B. C.; Crouse, G. D.; Murdoch, M. G.; Green,
S. B.; Heim, D. R. Pest. Biochem. Physiol. 1996, 55, 210. (b) Siehl, D. L.;
Subramanian, M. V.; Walter, E. W.; Lee, S.-F.; Anderson, R. J.; Toschi,
A. G. Plant Physiol. 1996, 110, 753.
(2) Sano, H.; Mio, S.; Kitagawa, J.; Shindou, M.; Honma, T.; Sugai, S.
Tetrahedron 1995, 51, 12563.
(3) Hernandez, R.; Leon, E. I.; Moreno., P.; Concepcion, R. F.; Suarez,
E. J. Org. Chem. 2004, 69, 8437.
(4) Fan, Q.; Ni, N.; Li, Q.; Zhang, L.; Ye, X. Org. Lett. 2006, 8, 1007.
(5) Chiba, S.; Xu, Y.-Z.; Wang, Y.-F. J. Am. Chem. Soc. 2009, 131, 12886.
(6) (a) Plietker, B. Synthesis 2005, 2453. (b) Arends, I. W. C. E.; Kodama,
T.; Sheldon, R. A. Top. Organomet. Chem. 2004, 11, 277.
(7) Ranganathan, D.; Vaish, N. K.; Shah, K. J. Am. Chem. Soc. 1994, 116,
6545.
(8) Ferraz, H. M. C.; Longo, L. S. Org. Lett. 2003, 5, 1337.
(9) Yang, H. W.; Romo, D. J. Org. Chem. 1997, 62, 4.
DOI: 10.1021/jo101328c
r
Published on Web 10/18/2010
J. Org. Chem. 2010, 75, 7565–7572 7565
2010 American Chemical Society

Farber et al.
JOCArticle
FIGURE 1. Outcome of reaction of oxetane 1a and psico-furanose 3 with RuO4.
TABLE 1. Synthesis of 2-Azido-2-(hydroxymethyl)oxetanes
entry
reactant
yield (%) of 7
yield (%) of 1a
1
2
3
4
5
(a) R = CH2OTBDPS; R1 = CH3
(b) R = (CH2)6CH3; R1 = CH3
(c) R = (CH2)2Ph; R1 = CH3
(d) R = H; R1 = Ph
55
67
67
30
7411
7611
33b
34
5614
32
(e) R = c-Hexyl; R1 = H
aPercent yield over 3 steps. bThis compound is somewhat volatile.
deduced from NOESY experiments.15 Compound 1d was
known.14
Initially, the conditions to oxidize oxetane 1a were based on
Kumaraswamy and co-workers’ report for the oxidation of a
2-hydroxymethyloxetane.16 First, RuO4 was generated from
RuCl3 3H2O (0.06 equiv) and NaIO4 (4 equiv) in a biphasic
3
solvent system (CCl4/CH3CN/H2O). Then, the supernatant was
added to a solution of 2-azido-2-(hydroxymethyl)oxetane 1a in
CH3CN, followed by additional NaIO4 (2 equiv). The resulting
mixture was stirred for 3 h at rt. NMR spectra (1H and 13C) of
the crude product showed only nitrile 2a and no carboxylic acid.
However, the mass balance was low, and the yield of isolated
nitrile was only 16%. To ascertain if other products were form-
ing and being degraded, the reaction was repeated and mon-
itored by NMR. After 15 min, starting material was still present;
however, after 30 min, no starting material remained. The NMR
spectra (1H and 13C) of the crude product (after workup)
showed the nitrile as the major component. In addition, there
were minor peaks which could not be assigned to any specific,
isolable byproduct. The NMR spectra (1H and 13C) of the crude
product after 3 h of reaction was cleaner than the corresponding
30 min reaction. To better understand this result, two reactions,
one for 1 h and one for 2 h, were run. Again, the NMR spectra
after workup were not as clean as the 3 h reaction, and in both
reactions the nitrile was the only isolated product. This suggested
that byproducts formed were further degraded at longer reac-
tion times and became either water-soluble or volatile. Then, to
clarify if the nitrile was stable under these conditions, nitrile 2b
was subjected to the same conditions. After stirring the reaction
FIGURE 2. β-Hydroxyazide oxidative cleavages described in the
literature.
previously described.10 β-Lactones 6 were then subjected to
methylenation with the Petasis reagent.11 Subsequent epox-
idation with acetone-free dimethyldioxirane,12 produced
1,5-dioxaspiro[3.2]hexanes 8 in quantitative yields.13 Diox-
aspirohexanes 8 were then treated with azidotrimethylsilane,14
followed by deprotection of the primary alcohol with tetra-n-
butylammonium fluoride or potassium carbonate. The latter
deprotection method was utilized only for t-butyldiphenylsilyl-
containing oxetane 1a. The diastereomers of 1 were separable.
The relative stereochemistries of the diastereomers of 1a-c were
(10) Hmamouchi, M.; Prud’homme, R. E. J. Polym. Sci. Part A: Polym.
Chemistry 1991, 29, 1281.
(11) Dollinger, L. M.; Ndakala, A. J.; Hashemzadeh, M.; Wang, G.;
Wang, Y.; Martinez, I.; Arcari, J. T.; Galluzzo, D. J.; Howell, A. R.;
Rheingold, A. L.; Figuero, J. S. J. Org. Chem. 1999, 64, 7074.
(12) Ferrer, M.; Gibert, M.; Sanchez-Baeza, F.; Messeguer, A. Tetrahe-
dron Lett. 1996, 37, 3585.
(15) See Supporting Information.
(16) Kumaraswamy, G.; Padmaja, M.; Markondaiah, B.; Jena, N.;
Sridhar, B.; Kiran, M. U. J. Org. Chem. 2006, 71, 337.
(13) Ndakala, A. J.; Howell, A. R. J. Org. Chem. 1998, 63, 6098.
(14) Howell, A. R.; Ndakala, A. J. Org. Lett. 1999, 1, 825.
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TABLE 2. Synthesis of Nitriles
entry
reactant
diastereomer
antia
yield (%) of 2
(%) of recovered 1
1
2
3
4
5
6
7
(a) R = CH2OTBDPS; R1 = CH3
(b) R = (CH2)6CH3; R1 = CH3
(b) R = (CH2)6CH3; R1 = CH3
(b) R = (CH2)6CH3; R1 = CH3
(c) R = (CH2)2Ph; R1 = CH3
(d) R = H; R1 = Ph
20
26
23
13
15
22
16
33
47
26
25
24
0c
syn/antia
syna
antia
antia
antib
(e) R = c-Hexyl; R1 = H
0c
d
c
aSyn/anti defined by relative stereochemistry of N3 and R. bSyn/anti defined by relative stereochemistry of N3 and R1. See text for discussion.
dReaction done on minor diastereomer; relative stereochemistry not determined.
mixture at rt for 2 h, only nitrile (>90%) was recovered. Thus,
any loss of material balance could not be associated with
degradation of the nitrile under the reaction conditions.
would result. Further oxidative cleavage could lead to water-
soluble and/or volatile byproducts.
To ascertain if the cleavage was being effected by RuO4 or
simply by NaIO4, β-hydroxyazide 1b was treated with 4 equiv of
NaIO4 in CCl4/CH3CN/H2O, with no addition of RuO4. After
25 min nitrile 2b was isolated in 36% yield; no starting material
was recovered. The fact that NaIO4 effects nitrile formation is
interesting and will be discussed later. However, these condi-
tions were different from the conditions utilized in Table 2,
where only the supernatant was transferred. To mimic these
conditions the supernatant of a mixture of 4 equiv of NaIO4 in
CCl4/CH3CN/H2O was added to a solution of β-hydroxyazide
1b in acetonitrile. After 25 min, only 6% of nitrile 2b was
isolated. This implies that RuO4 was the main promoter for the
reactions shown in Table 2.
The unexpected nitrile formation resulting from 2-azido-
2-(hydroxymethyl)oxetane cleavage with RuO4 led to three
key questions for us: (1) Is this pathway unique to oxetane
systems? (2) Which oxidation state--the primary alcohol, the
aldehyde or the carboxylic acid--of the R-hydroxymethyl
group is the immediate precursor of oxidative cleavage? (3)
What is the role of the metal in the reaction?
To address the first question, other β-azidoalcohol sys-
tems were treated with RuO4. First, psico-furanose 919 was
subjected to our optimized RuO4 conditions. After 30 min
carboxylic acid 10 was observed, and substantial starting
material remained (based on 1H and 13C NMR). When more
RuO4 (0.5 equiv) was added, following the conditions uti-
lized by Sano and co-workers,2 only amide 11, derived from
carboxylic acid 10, was ultimately isolated. The oxidation
with the increased equivalents of RuO4 took ∼1.5 h. Next,
azidophytosphingosine 1220 was treated with 0.06 equiv of
RuO4, and only carboxylic acid 13 was isolated after 3 h
(Scheme 1). These results suggested that there is something
unique about the β-azidoalcoholoxetanes 1.
A second issue considered was the oxidation state of the
cleaved carbon. Ignoring for now the role of the metal,
plausible cleavage pathways can be drawn from each of the
possible oxidation states (Figure 3). Each reaction was care-
fully monitored (13C NMR) for aldehyde and/or carboxylic
acid formation; at no point was either observed. Never-
theless, oxidation to either of these states, followed by rapid
Next, in an attempt to minimize side reactions, no NaIO4
was added after the RuO4 supernatant was transferred to the
azidoalcohol solution. After 25 min at rt, the NMR spectra
(1H and 13C) of the crude product showed mostly starting
material and nitrile, and it was considerably cleaner than the
previous reactions. On the basis of this result, these condi-
tions were utilized to study the behavior of other 2-azido-
2-(hydroxymethyl)oxetanes 1.
The reactivities of oxetanes 1a-1e were examined. Besides
recovered starting material, nitriles were the only isolable
compounds (Table 2). This was true for both diastereomers,
although the two isomers did not react with equal efficiency
(entries 3 and 4). A slower rate of reaction for the isomers
where the 2-azido and 3-methyl groups were on the same face
of the oxetane was demonstrated by reaction of a mixture of
the diastereomers of 1b (entry 2). The anti-diastereomer
(with the methyl group on the same side of the ring as the
azide) was consumed more slowly, as evidenced by a change
in ratio of the diastereomers in the reactants, compared to
the recovered starting materials. A more rapid consumption
of the syn-diastereomer was also observed when a reaction
was done with a mixture of 1c. This outcome will be discussed
further in the quantum calculations section. In all cases, even
with shorter reaction times and recovery of some of the
starting material, the material balance was not accounted
for. Since nitrile 2b was shown to be stable under the reaction
conditions, we postulated that the azidooxetanes were not
themselves stable and that their byproducts may have been
subjected to further oxidative degradation. For β-azidoalco-
hols 1d and 1e the expected nitriles were the major products
isolated. However, no starting material was recovered, and
based on the NMR spectra prior to purification, many
additional products were observed. For substrate 1d this
outcome was attributed to aromatic ring degradation, as
previously reported by Sharpless and co-workers.17 In addi-
tion, considering 1e, tertiary carbons can be oxidized by
RuO4.18 If this occurs at the cyclohexyl tertiary carbon,
along with the cleavage giving the nitrile, a vicinal diol
(17) Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J. Org.
Chem. 1981, 46, 3936.
(18) (a) Bakke, J. M.; Bethell, D. Acta Chem. Scand. 1992, 46, 644.
(b) Tenaglia, A.; Terranova, E.; Waegell, B. J. Org. Chem. 1992, 57, 5523.
(19) Mio, S.; Kumagawa, Y.; Sugai, S. Tetrahedron 1991, 47, 2133.
(20) Dere, R. T.; Zhu, X. Org. Lett. 2008, 10, 4641.
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SCHEME 1. Oxidation of psico-Furanose 9 and Azidophytosphingosine 12 with RuO4
FIGURE 4. Oxidative cleavage mechanism proposed by Ye and
co-workers.
SCHEME 2. Oxidation of Protected Azidophytosphingosine
FIGURE 3. Possible states involved in the oxidative cleavage.
cleavage, could not be ruled out. Consequently, one goal was
to access an aldehyde and acid by alternative pathways to
investigate their behavior under the reaction conditions.
All attempts to synthesize R-azidoaldehydes from azido-
hydroxyoxetanes were unsuccessful. 2-Azido-2-(hydroxy-
methyl)oxetanes 1a and 1b were treated with a variety of
oxidants, including IBX, Dess-Martin periodinane, Swern con-
ditions, TEMPO/NMO and PCC/NaOAc. In all cases, the
starting material was consumed, but no isolable product
resulted. Similarly, when 1c was treated with PDC in DMF
no carboxylic acid was observed. Thus, the ability to more
directly probe the nature of the intermediate that undergoes
the cleavage has to this point been precluded because
of the sensitivity of the 2-azido-2-(hydroxymethyl)oxetanes.
Nevertheless, there are a number of observations that suggest
that it is the hydroxymethyloxetanes that are cleaved.
Our conviction that the azidoalcohol is cleaved is based both
on a comparison of our results to those reported for the PCC
mediated cleavage of β-azidoalcohols and on the fact that both
RuO4 and IO4- effect the cleavage. The mechanism of oxidative
cleavage proposed by Ye and co-workers4 invoked an intramo-
lecular reaction between the distal nitrogen of the azide and the
carbonyl of the presumed aldehyde intermediate, followed by
proton transfer, oxidation, and loss of CO and N2 (Figure 4).
Considering that R-azidoaldehydes are readily isolated, stable
species,21 it is logical to assume that, if the proposed mechanism
is correct, the equilibrium for the intramolecular addition favors
the aldehyde with ultimate irreversible conversion to the nitrile
driving the reaction to completion over time. We examined one
of the Ye examples, azidophytosphingosine 12, in more detail
(Scheme 2). Compound 12, as well as its corresponding
R-azidoaldehyde 14 (prepared in 99% yield by oxidation of
12 with IBX), required more than two days in the presence of
PCC for complete conversion to nitrile 15. The conversion of 12
to 15 using PCC was slower than that of 14 to 15. Both reactions
were checked intermittently by NMR. Over the course of
reaction of alcohol 12, starting material, aldehyde and the nitrile
could be seen for almost the entire time of monitoring. As
expected, the reaction of aldehyde 14 showed starting material
and nitrile. In neither case was any carboxylic acid observed.
These results are consistent with the mechanism proposed by
Ye. However, for 2-azido-2-(hydroxymethyl)oxetane cleavage
there are several key differences. The reaction is much more
rapid, with complete consumption of the starting material
occurring in less than an hour. Also, with the oxetanes there is
no hydrogen on the carbon attached to the azide, precluding the
type of rearrangement shown in going from A to B (Figure 4).
Thus, the cleavage observed with the 2-azido-2-(hydroxy-
methyl)oxetanes could not proceed by the same pathway as
the PCC mediated oxidative cleavage.
(21) (a) Liu, K. K. C.; Kajimoto, T.; Chen, L.; Zhong, Z.; Ichikawa, Y.;
Wong, C.-H. J. Org. Chem. 1991, 56, 6280. (b) Sugiyama, M.; Hong, Z.;
Liang, P.; Dean, S. M.; Whalen, L. J.; Greenberg, W. A.; Wong, C.-H. J. Am.
Chem. Soc. 2007, 129, 14811. (c) Kandula, S. R. V.; Kumar, P. Tetrahedron
Asymmetry 2005, 16, 326.
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FIGURE 7. Computed minimum energy configurations of model
complexes of oxetane (16a) and tetrahydrofuran (17a) obtained at
DFT level.
FIGURE 5. Proposed mechanism of 2-azido-2-(hydroxymethyl)-
oxetane oxidative cleavage.
energy conformers will be essentially unpopulated at room
temperature (kBT ≈ 0.5 kcal/mol). The structural differences
between 16a and 17a therefore suggest that the most stable open
conformations of the azidooxetanyl alcohols may allow them to
accommodate the RuO4 (or IO4-) in a manner that leads to
cleavage. In contrast, the closed conformation of the tetrahy-
drofuran precludes this, and standard oxidation of the alcohol
to the carboxylic acid occurs. Conformational influences on
oxidation reaction pathways are known for proteins,5 but reports
for simple organic molecules are hard to find. Nevertheless, the
complexity of many oxidation pathways and the difficulty of
reliably oxidizing alcohols with R-oxidation suggest that con-
formation may play a greater role than has been recognized.
We further explored whether these structural differences
persist in the aldehyde and acid oxidation states. Figure 8 shows
the computed minimum energy structures for the aldehydes
(denoted as 16b and 17b) and the acids (denoted as 16c and 17c).
The lowest energy structure for both the oxetanyl alde-
hyde 16b and acid 16c is an open conformation. Compound
16b also presents a stable closed conformation with energies
0.8 kcal/mol higher than the open one. In the acid state (16c),
however, the open conformation is isoenergetic with the
closed one. For the aldehyde (17b) oxidation state in the
tetrahydrofuran model, the open conformation is unstable.
In the acid state, it becomes stable but 4.6 kcal/mol higher in
energy than the closed conformation. Thus, we conclude that
this fundamental structural difference between the model
oxetane and tetrahydrofuran (open versus closed) persists up
to the aldehyde oxidation state.
FIGURE 6. Model oxetanes and tetrahydrofurans for quantum
chemical analysis.
On the basis of observations thus far, we think that the
RuO4 (or NaIO4) plays an integral role and that the cleavage
is most likely occurring from the alcohol oxidation state. We
propose that the azido nitrogen directly bound to C-2 and the
oxygen from the primary alcohol react with RuO4 forming a
five-membered intermediate (Figure 5). Subsequent loss of
N2 occurs with the regeneration of the double bond between
oxygen and ruthenium and the loss of formaldehyde. Finally,
nitrile formation and oxetane ring-opening result from the
regeneration of RuO4. It is important to note that we have
observed no aldehyde or carboxylic acid in any of our
reactions. Further support for the alcohol being the species
cleaved comes from the outcome with NaIO4 (vide supra).
Nitrile formation was observed from the reaction of NaIO4
and oxetane 1b. Periodate is not used to oxidize primary
alcohols without an appropriate catalytic oxidant, while it is
widely used for oxidative cleavages. However, even if the
alcohol is the precursor and RuO4 or NaIO4 is integral to the
cleavage process, a question remains: why do the 2-azido-
2-(hydroxymethyl)oxetanes, but not the corresponding tet-
rahydrofurans, undergo cleavage to nitriles?
Quantum Chemical Analysis. To answer the question pre-
sented above, a series of density functional theory (DFT)
calculations (see Experimental section for details on the level
of theory) for model oxetanes 16 and tetrahydrofurans 17
(Figure 6) was undertaken.
DFT calculations reveal an important structural difference
between 16a and 17a. Oxetane 16a exhibits what we refer to as
an “open” conformation, characterized by a dihedral angle
between atoms C1-C2-N1-N2 of φ=171°. On the other hand,
the minimum energy structure of 17a has a “closed” conforma-
tion with φ = 70° (Figure 7). The possibility for 16a to present a
stable closed conformation was explored, as was the potential
for 17a to present an open conformation. In the case of 16a,
a closed conformation is stable, but it is 0.7 kcal/mol higher
in energy. For 17a, the open conformation is also stable, but
5.0 kcal/mol in energy above the closed one. Thus, these higher
Analysis of the molecular electrostatic potential (MEP)
surface reveals a potential explanation for why the oxetane
prefers the open conformation, while the tetrahydrofuran
favors the closed. Figure 9 shows a crucial difference in
the electrostatic interaction between the azide and the rest
of the molecule in 16a open and 17a open. More precisely,
the unfavorable electrostatic repulsion between the distal
azide nitrogen and one of the oxygens in the formal group is
not present in the lowest energy conformation of 17a.
To test whether the formal group is entirely responsible for
this conformational difference a tetrahydrofuran 18 in which
this group was removed from 17a was evaluated. This change
gave rise to an open conformation 1.5 kcal/mol higher than the
closed one, thus reducing the energy difference by 3.5 kcal/mol.
Although this is consistent with the electrostatic argument
above, it is apparent that the formal is not entirely responsible
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FIGURE 8. DFT computed minimum energy configurations of model oxetane and tetrahydrofuran in their aldehyde (16b and 17b,
respectively) and acid (16c and 17c, respectively) oxidation states.
In conclusion, an unexpected cleavage of 2-azido-
2-(hydroxymethyl)oxetanes appears to be a result of a con-
formational preference that allows RuO4 or IO4- to interact
with both the alcohol and azido moieties, leading to cleav-
age. The lowest energy conformation for a closely related
tetrahydrofuran blocks similar access of the oxidant, and this
is consistent with the observed conversion of the alcohol to
the corresponding carboxylic acid.
Experimental Section
Typical Procedure for the Synthesis of Methyleneoxetanes
FIGURE 9. Molecular electrostatic potential obtained from the
(7). trans-4-(tert-Butyldiphenylsilanyloxymethyl)-3-methyl-2-methy-
DFT electron density. Negative and positive potentials are repre-
leneoxetane (7a). Dimethyltitanocene (2.54 mmol, 5.00 mL, 0.50 M
sented by red and blue, respectively. The double arrows mark the
in toluene)11 and trans-4-(tert-butyldiphenylsilanyloxymethyl)-3-
crucial interaction that makes the open conformation in 17a less
methyloxetan-2-one (6a) (0.36 g, 1.05 mmol) were stirred at 80 °C
stable relative to the same conformation in 16a.
under N2 in the dark. After 2 h, TLC (petroleum ether/EtOAc, 98:2)
showed the presence of starting material; so more dimethyltitano-
cene (1.0 mL, 0.50 mmol) was added. After 40 min, TLC indicated
for the differential preference of the closed versus the open
conformation.
reaction completion. The solution was then cooled to rt, and
Another question that might be addressed by a quantum
mechanical analysis is the observed difference in reactivity
petroleum ether (10 mL) was added, at which point a yellow
precipitate formed. The resulting mixture was stirred for 18 h at rt.
between the syn and anti stereoisomers of azidooxetanes
1a-c (see Table 2 for how syn and anti are defined). The
The solid residue was filtered through a pad of Celite, rinsing with
petroleum ether. The solvent was removed under reduced pressure
anti-isomer (which has the 2-azido and 3-methyl groups on
the same face) gave a lower yield of nitrile (see entries 3 and 4,
Table 2) and reacted at a slower rate (see discussion of
Table 2) than the syn. The corresponding energies of the
open and closed conformations for the anti isomer of 16a, as
well as the transition state between the two, were computed.
For the anti-isomer theopen and closed conformations have the
same energy, and they are separated by a 0.5 kcal/mol barrier.
Considering that only cleavage was observed, the result suggests
that, for the anti-isomer case, RuO4 promoted cleavage com-
petes with the interconversion between the open and closed
forms. Furthermore, the oxidation to the carboxylic acid
of azidotetrahydrofuran 9 is somewhat slower than the
cleavage/degradation of the azidooxetanes 1. By transitivity,
this last observation suggests that the back and forth equilibra-
tion between the open and closed forms in the oxetane anti-
isomers will also compete with the oxidation to the carboxylic
acid. That is: although we have argued that oxidation to the
carboxylic acid occurs from the closed form, it is possible that
the fact that no carboxylic acid was observed for the anti
isomers of 1a-c could be due to rapid cleavage depleting the
open azidoalcohols and conversion between the forms being
faster than oxidation to the carboxylic acid.
to 5 mL (total volume), and the residue was purified by flash
chromatography on silica gel, packing the column with petroleum
ether/triethylamine (96:4) and eluting with petroleum ether/EtOAc/
triethylamine (97.5:2.0:0.5) to afford methyleneoxetane 7a as white
crystals (196 mg, 55%): mp 52-54 °C; IR (neat): 3072, 2930, 1691
cm-1; 1H NMR (300 MHz, CDCl3) δ 7.66 (m, 4H), 7.39 (m, 6H),
4.42 (ddd, J = 4.3, 4.3, 4.3 Hz, 1H), 4.08 (m, 1H), 3.82 (m, 2H), 3.73
(m, 1H), 3.30 (m, 1H), 1.26 (d, J = 7.1 Hz, 3H), 1.05 (s, 9H); 13
C
NMR (75 MHz, CDCl3) δ 168.7, 135.9, 135.7, 129.9, 127.9, 127.9,
86.6, 78.0, 65.2, 38.2, 27.0, 19.5, 16.6; HRMS (ESI) calcd for
C22H28NaO2Si (Mþ þ Na) m/z 375.1751, found 375.1739.
Typical Procedure for the Synthesis of 1,5-Dioxaspiro-
[3.2]hexanes (8). (2S*,3R*,4S*/R*)-2-(tert-Butyldiphenylsilany-
loxymethyl)-3-methyl-1,5-dioxaspiro[3.2]hexanes (8a). A flask was
charged with trans-4-(tert-butyldiphenylsilanyloxymethyl)-3-meth-
yl-2-methyleneoxetane (7a) (0.72 g, 2.0 mmol) in dry CH2Cl2 (6mL),
and the resulting solution was cooled to -78 °C (dry ice/acetone
bath) under N2. A solution of dimethyldioxirane13 (9.50 mL, 4.08
mmol, 0.43 M in CH2Cl2) was added dropwise. The reaction
solution was stirred for 1 h at -78 °C under N2. The solvent was
removed under reduced pressure, and the resulting clear oil 8a (3:1
mixture of diastereomers) was used in the next reaction without
purification: IR (neat): 3071, 3050, 3014, 2998, 2931, 2857, 1589,
;
1472, 1462, 1428 cm-1 1H NMR (300 MHz, CDCl3) minor
diastereomer: δ 7.75 (m, 4H), 7.43 (m, 6H), 4.24 (ddd, J = 4.3,
7570 J. Org. Chem. Vol. 75, No. 22, 2010

Farber et al.
JOCArticle
4.3, 4.3 Hz, 1H), 3.93 (m, 2H), 3.26 (qd, J= 6.8, 6.4 Hz, 1H), 2.89 (d,
J = 3.2 Hz, 1H), 2.79 (d, J = 3.2 Hz, 1H), 1.27 (d, J = 7.2 Hz, 3H),
1.14 (s, 9H); major diastereomer: δ 7.75 (m, 4H), 7.43 (m, 6H), 4.39
(ddd, J = 3.7, 3.7, 3.7 Hz, 1H), 3.93 (m, 2H), 3.45 (qd, J = 7.0, 6.4
Hz, 1H), 3.00 (d, J = 3.1 Hz, 1H), 2.70 (d, J = 3.2 Hz, 1H), 1.27 (d,
J = 7.2 Hz, 3H), 1.13 (s, 9H); 13C NMR (75 MHz, CDCl3) minor
diastereomer: δ 135.8, 135.7, 133.5, 133.3, 129.9, 129.9, 127.9, 127.9,
92.1, 80.6, 65.4, 49.1, 38.3, 26.9, 19.4, 14.1; major diastereomer: δ
135.8, 135.7, 133.5, 133.3, 129.9, 129.9, 127.8, 127.9, 91.5, 83.2, 65.1,
51.1, 36.5, 26.9, 19.4, 12.7; HRMS (ESI) calcd for C22H28O3SiNa
(Mþ þ Na) m/z 391.1705, found 391.1743.
13C NMR (100 MHz, CDCl3) δ 135.7, 135.7, 132.8, 132.7, 130.3,
128.2, 120.8, 72.5, 65.4, 29.6, 27.0, 19.5, 14.8; HRMS (ESI)
calcd for C21H27NNaO2Si (Mþ þ Na) m/z 376.1703, found
376.1728.
1-β-Azido-1-r-carbamoyl-1-dehydro-1-deoxy-5-O-benzoyl-
2,3-O-isopropylidene-D-ribofuranose (11). 2-Azido-2-deoxy-6-O-
benzyl-2,3-O-isopropylidene-β-D-psicofuranose (9)19 (99 mg,
0.30 mmol) and sodium periodate (0.33 g, 1.5 mmol) in CH3CN
(1.6 mL), CCl4 (1.6 mL) and H2O (2.4 mL) were stirred vigorously
in the presence of RuCl3 3H2O (32 mg, 0.15 mmol) at rt for 90 min.
3
Then, the mixture was diluted with CH2Cl2 (10 mL) and H2O
(5 mL), and the layers were separated. The aqueous layer was
extracted with CH2Cl2 (3 ꢀ 5 mL), the combined organic layers
were dried (MgSO4), and the solvents were removed in vacuo to
give a mixture of carboxylic acids (diastereomers). The mixture
was then dissolved in dry THF (3 mL) and treated with triethyla-
mine (0.09 mL, 0.62 mmol) and ethyl chloroformate (0.08 mL,
0.86 mmol) at 0 °C. After 5 min, NH3 (gas) was bubbled through
the solution for 10 min. Then, H2O (5 mL) was added, and the two
layers were separated. The aqueous layer was washed with MTBE
(5 ꢀ 10 mL), and the combined organic layers were dried (MgSO4)
and concentrated. The crude product was purified by flash chro-
matography on silica gel (petroleum ether/EtOAc, 50:50) to afford
Typical Procedure for the Synthesis of 2-Azido-2-(hydroxy-
methyl)oxetanes (1). (2R*/S*,3R*,4R*)-2-Azido-4-heptyl-2-(hy-
droxymethyl)-3-methyloxetanes (1b). (2S*,3S*,4S*/R*)-2-Heptyl-
3-methyl-1,5-dioxaspiro[3.2]hexanes (8b) (1.83mmol) weredissolved
in Et2O (3 mL) at rt under N2. Trimethylsilyl azide (0.36 mL,
2.74 mmol) was added dropwise, and the resulting solution was
stirred overnight at rt. Then, the solvent was removed in vacuo to
afford a yellow oil which was dissolved in THF (9.2 mL), and the
resulting solution was cooled to 0 °C (ice bath). Tetra-n-butylam-
monium fluoride (2.74 mmol, 2.74 mL, 1 M in THF) was added
dropwise, and the solution was stirred for 2 h at 0 °C. Then, the
solvent was removed under reduced pressure, and CH2Cl2 (10 mL)
was added. The resulting solution was washed with H2O (10 mL)
andbrine(10mL),dried(MgSO4) and the solvent removed in vacuo.
Purification by flash chromatography on silica gel (petroleum
ether/EtOAc, 90:10) provided β-azidoalcohols 1b as a clear oil
(diastereomeric ratio 4:1) (132 mg, 30% over 3 steps). The two
diastereomers were separated by careful chromatography: Charac-
terization of (2S*,3R*,4R*)-2-azido-4-heptyl-2-(hydroxymethyl)-3-
methyloxetane (minor diastereomer): IR (neat) 3447, 2930, 2114,
1458, 1379, 1251 cm-1; 1H NMR (300 MHz, CDCl3) δ 4.06 (ddd,
J = 6.7, 6.7, 6.7 Hz, 1H), 3.62 (m, 2H), 2.73 (dq, J = 7.0, 7.0 Hz,
1H), 2.17 (m, 1H), 1.79-1.63 (m, 2H), 1.25-1.21 (m, 13H), 0.86 (t,
J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 97.1, 82.2, 64.0,
44.4, 36.8, 31.9, 29.5, 29.3, 24.4, 22.8, 14.2, 12.1; HRMS (ESI) calcd
for C12H23N3NaO2 (Mþ þ Na) m/z 264.1682, found 264.1671.
Characterization of (2R*,3R*,4R*)-2-azido-4-heptyl-2-(hydroxy-
methyl)-3-methyloxetane (major diastereomer): IR (neat) 3432,
2924, 2857, 2115, 1456.9, 1260 cm-1; 1H NMR (300 MHz, CDCl3)
δ 4.35 (ddd, J = 6.8, 6.8, 6.8 Hz, 1H), 3.52 (dd, J = 12.4, 4.8 Hz,
1H), 3.40 (dd, J = 12.4, 8.5 Hz, 1H), 2.82 (dq, J = 7.1, 7.1 Hz, 1H),
2.25 (dd, J = 8.4, 5.2 Hz, 1H), 1.72-1.62 (m, 2H), 1.25 (m, 10H),
1.14 (d, J = 7.1 Hz, 3H), 0.85 (t, J = 6.9 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 99.0, 85.8, 66.1, 41.1, 36.3, 31.9, 29.6, 29.4, 24.6,
22.8, 14.2, 13.0; HRMS (ESI) calcd for C12H23N3NaO2 (Mþ þ Na)
m/z 264.1682, found 264.1696.
amide 11 (50 mg, 50%) as a white solid: [R]23 -47 (c 0.10,
D
CH2Cl2); mp 170-171 °C; IR (mineral oil) 3446, 3162, 2850, 2118,
1721, 1657, 1459 cm-1;1HNMR(500MHz, CDCl3) δ8.07(d, J=
7.2 Hz, 2H), 7.57 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.8 Hz, 2H), 6.61
(bs, 1H), 5.81 (bs, 1H), 4.86 (dd, J = 5.7, 1.2 Hz, 1H), 4.76 (d, J =
5.7 Hz, 1H), 4.72 (ddd, J = 6.5, 6.5, 1.0 Hz, 1H), 4.53 (dd, J =
11.8, 6.5 Hz, 1H), 4.47 (dd, J = 11.8, 6.7 Hz, 1H), 1.49 (s, 3H), 1.32
(s, 3H); 13C NMR (125 MHz, CDCl3) δ 167.2, 166.3, 133.7, 130.0,
129.6, 128.8, 114.2, 100.9, 86.3, 86.0, 82.1, 64.1, 26.6, 24.9; HRMS
(ESI) calcd for C16H19N4O6 (Mþ þ H) m/z 363.1299, found
363.1296.
(2R,3S,4R)-2-Azido-3,4-O-isopropylidene-1-octadecanoic acid
(13). Sodium periodate (0.11 g, 0.52 mmol) was added to a flask
charged with CCl4/CH3CN/H2O (1:1:1, 0.8 mL), and the resulting
mixture was stirred at 0 °C(icebath). RuCl3 3H2O(1.60mg, 0.0078
3
mmol) was added, and the biphasic orange mixture was vigorously
stirred for 1 h. Then, the supernatant was added to (2S,3S,4R)-2-
azido-3,4-O-isopropylidene-1-octadecanol (12) (50 mg, 0.13 mmol)
in CH3CN (0.3 mL) at rt, followed by the addition of more sodium
periodate (56 mg, 0.26 mmol). The resulting mixture was vigorously
stirred for 3 h at rt and then diluted with CH2Cl2 (5 mL). The two
layers were separated, and the aqueous layer was extracted with
CH2Cl2 (3 ꢀ 5 mL). The combined organic layers were dried
(MgSO4) and concentrated. Purification by flash chromatography
on silica gel (petroleum ether/EtOAc, 80:20) yielded carboxylic acid
13 as a white solid (30 mg, 60%): [R]23D -8.0 (c 0.12, CH2Cl2); mp
69-71 °C; IR (neat) 3162, 2919, 2850, 2103, 1702; 1H NMR (400
MHz, CDCl3) δ 4.23 (m, 2H), 3.84 (d, J = 8.4 Hz, 1H), 1.62 (m,
3H), 1.45 (s, 3H), 1.34 (s, 3H), 1.24 (m, 24 H), 0.86 (t, J = 7.0 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 173.6, 109.3, 77.9, 76.3, 61.1,
32.2, 29.9, 29.9, 29.9, 29.8, 29.7, 29.6, 28.9, 28.0, 27.0, 25.7, 22.9, 14.3;
HRMS (ESI) calcd for C21H39N3NaO4 (Mþ þ Na) m/z 420.2833,
found 420.2815.
Typical Procedure for the Synthesis of Nitriles (2). (2S*,3S*)-
4-(tert-Butyldiphenylsilanyloxy)-3-hydroxy-2-methylbutanenitrile
(2a). A flask was charged with CCl4:CH3CN:H2O (1:1:1, 0.9 mL)
and NaIO4 (133 mg, 0.62 mmol). The resulting mixture was cooled
to 0 °C (ice bath), and RuCl3 3H2O (2.0 mg, 0.009 mmol) was
3
added at once. The mixture was stirred for 1 h at 0 °C. Then, the
supernatant was added to (2R*,3R*,4S*)-2-azido-4-(tert-butyldi-
phenylsilanyloxymethyl)-2-(hydroxymethyl)-3-methyloxetane (1a)
(64 mg, 0.16 mmol) in CH3CN (0.30 mL), and the mixture was
stirred at rt for 25 min. It was then diluted with CH2Cl2 (5 mL) and
H2O (3 mL), and the layers were separated. The aqueous layer was
extracted with CH2Cl2 (3 ꢀ 5 mL), the combined organic extracts
were dried (MgSO4), and the solvents removed under reduced
pressure. Purification by flash chromatography on silica gel
(petroleum ether/EtOAc, 85:15) provided recovered starting material,
(2R*,3R*,4S*)-2-azido-4-(tert-butyldiphenylsilanyloxymethyl)-
2-(hydroxymethyl)-3-methyloxetane (1a) (20 mg, 33%), and nitrile
2a as a clear oil (10 mg, 20%): IR (neat) 3462 (br), 3072, 2930, 2857,
2117, 1472, 1428 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.63 (m,
4H), 7.41 (m, 6H), 3.70 (m, 3H), 2.84 (dq, J = 7.2, 4.2 Hz, 1H),
2.49 (d, J = 4.6 Hz, 1H), 1.30 (d, J = 7.1 Hz, 3H), 1.06 (s, 9H);
(2R,3S,4R)-2-Azido-3,4-O-isopropylidene-1-octadecanal (14).
2-Iodoxybenzoic acid (0.95 g, 3.4 mmol) was added to
(2S,3S,4R)-2-azido-3,4-O-isopropylidene-1-octadecanol (12)
(0.43 g, 1.1 mmol) in EtOAc (17 mL) at rt. The reaction mixture
was refluxed at 90 °C for 3.5 h. Then, it was cooled to rt and
filtered through a pad of Celite, rinsing with EtOAc. The filtrate
was concentrated in vacuo to afford aldehyde 14 (0.43 g, 99%)
as a pale yellow oil which solidified overnight: [R]23 -8.3 (c
D
0.10, CH2Cl2); mp 52-54 °C; IR (neat) 2987, 2925, 2114, 1735,
1468, 1372 cm-1; 1H NMR (400 MHz, CDCl3) δ 9.71 (s, 1H),
4.19 (m, 2H), 3.90 (d, J = 7.6 Hz, 1H), 1.58 (m, 3H), 1.44 (s, 3H),
1.32 (s, 3H), 1.24 (m, 23H), 0.85 (t, J = 6.9 Hz, 3H); 13C NMR
J. Org. Chem. Vol. 75, No. 22, 2010 7571

Farber et al.
JOCArticle
(100 MHz, CDCl3) δ 197.1, 109.4, 77.9, 76.8, 66.4, 32.1, 29.9,
29.9, 29.8, 29.8, 29.7, 29.6, 29.4, 27.8, 26.9, 25.4, 22.9, 14.3, 1.21;
HRMS (ESI) calcd for C21H39N3O3 (Mþ) m/z 381.2986, found
381.2956.
Computational Method and Theory Level. Full geometry
optimization at the DFT level were carried out using the hybrid
functional B3LYP with basis set 6-31 g(d,p) using the program
Gaussian 09.22 All energies reported were obtained in vacuum.
On benchmark calculations of 16a and 17a, in which we
computed the relative energy between the open and closed
conformation, we found that inclusion of zero point energy
effects and thermal corrections only changes the energy differ-
ences by a tenth of a kcal/mol. Since all of our conclusions would
be unaltered by such correction, we reported energies without
the inclusion of zero point energy and thermal effects. Transi-
tion state calculations were carried out with the program Jaguar
using the quadratic synchronous transit (QST) method. Anal-
ysis of the Molecular Electrostatic Potential was performed with
the quantum chemical software Jaguar,23 at the same theory
level specified above. Image rendering in Figures 7, 8, and 9 was
performed with the program Maestro.24
Acknowledgment. Dr. Martha Morton is acknowledged
for assistance with NMR experiments. Professors Nicholas
Leadbeater and Mark Peczuh are acknowledged for helpful
discussion. This manuscript is based upon work partially
supported by the National Science Foundation (NSF) under
Grant No. CHE-0111522. J.A.G. acknowledges financial
support from the Camille and Henry Dreyfus foundation
and an NSF Career award (CHE-0847340).
(22) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson,
G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.;
Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.;
Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.;
Nakai, H.; Vreven, T.; Montgomery, Jr., J. A.; Peralta, J. E.; Ogliaro, F.;
Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.;
Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.;
Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, N. J.; Klene, M.;
Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.;
Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.;
Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth,
G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas,
Supporting Information Available: General experimental
1
methods and procedures, spectroscopy data and H and 13C
NMR spectra for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
€
O.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian 09,
Revision A.1; Gaussian, Inc.: Wallingford, CT, 2009.
(23) Jaguar version 7.5; Schrodinger LLC: New York, NY, 2008.
(24) Maestro, version 9.0; Schrodinger LLC: New York, NY, 2010.
7572 J. Org. Chem. Vol. 75, No. 22, 2010