Synthesis of conformationally constrained 5-fluoro- and 5-hydroxymethanopyrrolidines. Ring-puckered mimics of gauche - And anti -3-fluoro- and 3-hydroxypyrrolidines

Article abstract of DOI:10.1021/jo200117p

N-Acetylmethanopyrrolidine methyl ester and its four 5-syn/anti-fluoro and hydroxy derivatives have been synthesized from 2-azabicyclo[2.2.0]hex-5-ene, a 1,2-dihydropyridine photoproduct. These conformationally constrained mimics of idealized C^β-gauche and C^β-anti conformers of pyrrolidines were prepared in order to determine the inherent bridge bias and subsequent heteroatom substituent effects upon trans/cis amide preferences. The bridgehead position and also the presence of gauche(syn)/anti-5-fluoro or 5-hydroxy substituents have minimal influence upon the K_T/C values of N-acetylamide conformers in both CDCl₃ (43-54% trans) and D ₂O (53-58% trans). O-Benzoylation enhances the trans amide preferences in CDCl₃ (65% for a syn-OBz, 61% for an anti-OBz) but has minimal effect in D₂O. The synthetic methods developed for N-BOC-methanopyrrolidines should prove useful in the synthesis of more complex derivatives containing α-ester substituents. The K_T/C results obtained in this study establish baseline amide preferences that will enable determination of contributions of α-ester substituents to trans-amide preferences in methanoprolines.

Full text of DOI:10.1021/jo200117p

FEATURED ARTICLE
pubs.acs.org/joc
Synthesis of Conformationally Constrained 5-Fluoro- and
5-Hydroxymethanopyrrolidines. Ring-Puckered Mimics of
Gauche- and Anti-3-Fluoro- and 3-Hydroxypyrrolidines
Grant R. Krow,*,† Ram Edupuganti,† Deepa Gandla,† Fang Yu,† Matthew Sender,† Philip E. Sonnet,†
Michael J. Zdilla,† Charles DeBrosse,† Kevin C. Cannon,§ Charles W. Ross, III,‡ Amit Choudhary,^
Matthew D. Shoulders,# and Ronald T. Raines||
†Department of Chemistry, Temple University, Philadelphia, Pennsylvania 19122, United States
‡Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., West Point, Pennsylvania 19486-004,
United States
§Department of Chemistry, Pennsylvania State University, Abington, Pennsylvania, 19001, United States
Departments of Chemistry and Biochemistry, ^Graduate Program in Biophysics, and #Department of Chemistry, University of
WisconsinꢀMadison, Madison, Wisconsin 53706, United States
S Supporting Information
b
ABSTRACT: N-Acetylmethanopyrrolidine methyl ester and its four
5-syn/anti-fluoro and hydroxy derivatives have been synthesized
from 2-azabicyclo[2.2.0]hex-5-ene, a 1,2-dihydropyridine photopro-
duct. These conformationally constrained mimics of idealized Cβ-
gauche and Cβ-anti conformers of pyrrolidines were prepared in
order to determine the inherent bridge bias and subsequent hetero-
atom substituent effects upon trans/cis amide preferences. The bridgehead position and also the presence of gauche(syn)/anti-5-
fluoro or 5-hydroxy substituents have minimal influence upon the KT/C values of N-acetylamide conformers in both CDCl3
(43ꢀ54% trans) and D2O (53ꢀ58% trans). O-Benzoylation enhances the trans amide preferences in CDCl3 (65% for a syn-OBz,
61% for an anti-OBz) but has minimal effect in D2O. The synthetic methods developed for N-BOC-methanopyrrolidines should
prove useful in the synthesis of more complex derivatives containing R-ester substituents. The KT/C results obtained in this study
establish baseline amide preferences that will enable determination of contributions of R-ester substituents to trans-amide
preferences in methanoprolines.
’ INTRODUCTION
(Cγ-pucker toward the ester) and Cγ-exo (Cγ-pucker away from
the ester). Substituents at Cγ, as in (2S,4S)-4-fluoroproline (flp) 2
and (2S,4S)-4-hydroxyproline (hyp) 3, affect the direction of
ring pucker and also influence amide cis/trans conformational
preferences.3 The two effects appear to be correlated.3a,4,8 In an
effort to control the ring pucker variable and isolate the remaining
effect of a substituent upon amide cisꢀtrans preferences, we
synthesized the 2-azabicyclo[2.1.1]hexanes 4ꢀ6 (Table 1),9 ana-
logues of Pro 1, flp 2, and hyp 6. N-Acetylmethanoproline methyl
ester (MetPro) 4 displays a Pro 1 residue with both idealized Cγ-
exo and Cγ-endo ring puckers. The substituted 4-anti-fluoro-
methanoproline (Metflp) 5 and 4-anti-hydroxymethanoproline
(Methyp) 6, when viewed from the perspective of the substituent-
bearing bridges, are pyrrolidines (bolded bonds) with constrained
Cγ-exo ring puckers. The relative substituent effects on KT/C for
these methanoprolines 4ꢀ6 was essentially invariant in D2O,
although in the less polar aprotic solvents CDCl3 and 1,4-dioxane-
d8 Metflp 5 had a slightly larger trans preference than the others.
The abilityofamides toexist ascisꢀtrans isomershas important
implications for protein structure and function.1 The particular
behavior of amides derived from the secondary amine proline has
engendered much interest in this regard because of the importance
of proline cisꢀtrans isomerization to biological functions2 and
structure of proteins.3 There is an emerging interest in bioengi-
neering applications of proline and substituted prolines.4ꢀ6
N-Acetylproline methyl ester (Pro) 1 not only is present as a
mixture of cisꢀtrans isomers but also exists in a variety of ring
conformations. Two of these in which Cγ experiences a large out-
of-plane displacement are major,7 and werefer to them as Cγ-endo
Received: January 17, 2011
Published: April 18, 2011
r
2011 American Chemical Society
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FEATURED ARTICLE
Table 1. KT/C of Methanoprolines 4ꢀ6
Scheme 2. Synthetic Route to N-Protected 5-syn-
Fluoromethanopyrrolidines
a
KT/C
compd
Y
D2O
CDCl3
dioxane-d8
MetPro 4
Metflp 5
Methyp 6
H
3.5
3.5
3.6b
2.4
2.7
2.4
2.2
2.8
2.1
F
bold for emphasis in Scheme 1. The same is true for methanohy-
droxyprolines (MetHyps) 16 and 17, related to Hyp 9. A possible
synthetic approach to methanoprolines could utilize as key
synthons the methanopyrrolidines 10aꢀ13a or related O-pro-
tected derivatives.
OH
a Values of KT/C were measured at 25 ꢀC using 19F NMR spectra for
fluoro isomers and 13C NMR for MetPro 4 and Methyp 6 (see ref 9).
b Values in ref 9 were measured in D2O/CD3OD ∼ 4:1.
Figure 1. Amide equilibrium for a methanopyrrolidine 7.
Scheme 1. Retrosynthesis of Methanoprolines 14ꢀ17 Re-
lated to Flp 8 and Hyp 9
Herein, we describe 1,2-dihydropyridine-based syntheses of
Metpyr 7 as well as N-acetyl-5-syn- and 5-anti-F(OH)-substituted
methanopyrrolidines 10bꢀ13b. The configurational preferences
determined for these amides reveal that only small inherent trans/cis
amide biases accompany the use of methanoprolines as idealized
Cγ-puckered proline mimics. In a separate paper, we shall show how
N-Boc-methanopyrrolidines 10aꢀ13a, or related O-silylated deri-
vatives, can serve as key synthons for a directed lithiation approach
to the desired methanoproline derivatives 14ꢀ17.10,11
This result was taken to indicate that the γ-substituent effect is
primarily related to ringpuckerand a resultant enhancementof the
interaction between the amide carbonyl oxygen and ester carbonyl
carbon.
Our previous study9 did not identify unresolved issues asso-
ciated with using methanoprolines 4ꢀ6 as mimics of prolines
1ꢀ3. For example, it is not known if the carbonyl group of the
amides in the mimics 4ꢀ6 has a structurallyꢀrelated preference
to be adjacent to the bridgehead H1 or the methylene H3
position. Knowledge of the amide preference of a methanopyr-
rolidine (Metpyr) 7 that is missing the R-ester adjacent to
nitrogen (Figure 1) is necessary in order to determine the effect
of a 3-ester substituent upon amide conformations.
’ RESULTS AND DISCUSSION
Metpyr 7 was prepared in 70% yield from N-Boc-methano-
pyrrolidine10 by removal of the Boc group with trifluoroacetic
acid followed by acetylation with acetyl chloride.
Synthesis of 5-Fluoromethanopyrrolidines. N-Boc-5-syn-
fluoro-Metpyr 10a was synthesized, as shown in Scheme 2, from
pyridine-derived intermediate 18 that was prepared by a second-
chance rearrangement route.12 Conversion of fluoro alcohol 18 to
the thionocarbonate 19 using O-phenyl chlorothionoformate13
followed by reductive deoxygenation afforded the N-benzyloxycar-
bonyl fluoride 20. Reductive removal of the protecting group using
H2/Pd(OH)2 in methanol in the presence of (BOC)2O afforded
the N-BOC-5-syn-fluoro synthon 10a. The reduction of 20 in
methanol followed by addition of acetyl chloride afforded the N-
acetyl-5-syn-fluoroamide 10b.
Additionally, the scope of the methanoproline substituent
effect study was limited to the Metflp 5 and Methyp 6 stereo-
isomers related to flp 2 and hyp 3 by the synthetic approach
available at that time. Thus, we were unable to address the
generality of the finding for other methanoproline stereoisomers
related to (2S,4R)-4-fluoroproline 8 (Flp) and the biologically
relevant (2S,4R)-4-hydroxyproline (Hyp) 9 as to whether KT/C
values are always independent of substituent and depend mainly
on ring pucker. To answer these questions, a different synthetic
approach is needed to prepare methanofluoroprolines (MetFlps)
14 and 15, whose idealized Cγ ring puckers contain either
exo(gauche)- or endo(anti)-Flp 8 conformers, embedded in
In the 5-anti-fluoro series, N-Boc-5-anti-fluoro-methanopyr-
rolidine 11a was synthesized from 1,2-dihydropyridine photo-
product 21 as shown in Scheme 3.14,15 Addition of BrF to 11a
was accompanied by rearrangement to afford the 5-anti-bromo-
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FEATURED ARTICLE
Scheme 3. Synthetic Route to N-Protected 5-anti-
Fluoromethanopyrrolidines
Scheme 5. Synthetic Route to N-Acetyl-5-syn-
hydroxymethanopyrrolidines
Scheme 6. Synthetic Route to N-Protected 5-anti-
Hydroxymethanopyrrolidines
Scheme 4. Synthetic Route to N-BOC-5-syn-O-TBS-metha-
nopyrrolidine 28
6-anti-fluoro azabicycle 22. Characteristic for the rearranged 2-
azabicyclo[2.1.1]hexane structure for 22 was the 1H NMR W-plan
coupling between the bridgehead proton H1 at δ 4.61 with H4 at δ
3.20 (J1,4 = 7.2 Hz). Similarly, the 5-anti-6-anti stereochemistry for
22 was demonstrated by its W-plan coupling of proton H5 at δ
4.18 with H6 at δ 5.07 (J5,6 = 7.5 Hz), as well as their vanishingly
small couplings to the flanking bridgehead protons H1 and H4.12,14
Bromo fluoride 22 was reductively debrominated to give 5-anti-
fluoride 23. Reductive removal and reprotection, as described
above for fluoride 20, afforded either the N-BOC-5-anti-fluoro
synthon 11a16 or the N-acetyl fluoride 11b.
followed by reductive debromination gave the ether 27. Hydro-
genolysis in the presence of (BOC)2O gave N-BOC-5-syn-OTBS
synthon 28.
N-Acetyl-5-syn-O-benzoate 29 and N-acetyl-5-syn-alcohol 12a
were prepared from 25 as shown in Scheme 5. Benzoylation of
alcohol 25 gave a benzoate 29 that was reductively debrominated
to afford benzoate 30. Hydrogenolysis and acetylation afforded
the amide ester 31, which upon methanolysis afforded 5-syn-
alcohol 12b.
For the 5-anti-hydroxy series, N-BOC-5-anti-alcohol 13a was
prepared from bromoacetate 32,17 as shown in Scheme 6.
Reductive debromination gave acetate 33. Methanolysis to 34
and then hydrogenolysis in the presence of (BOC)2O gave
N-BOC alcohol 13a. For investigation of trans/cis amide pre-
ferences, alcohol 13a was converted to the N-acyl benzoate18 36,
and this was converted by methanolysis to the alcohol 13b.
NMR Analysis of KT/C for Substituted Methanopyrroli-
dines. A planar amide carbonyl in methanopyrrolidine 7 might
be eclipsed with H1 in a cis conformation or staggered between
the two H3 methylene protons in a trans orientation (Figure 2).
Further, substituents might alter whatever inherent stereochem-
ical preference might exist for 7. To resolve these issues, and to
establish baseline amide conformational preferences for confor-
mationally constrained methanoprolines with heteroatom sub-
stituents, we determined KT/C for the 5-syn- and 5-anti-fluoro-,
hydroxy-, and benzoyloxymethanopyrrolidines in Figure 2.
Synthesis of 5-Hydroxymethanopyrrolidines. For the
5-syn-hydroxy series, a silylated derivative of alcohol 12a,
N-Boc-5-syn-OTBS-methanopyrrolidine 28, was synthesized
from iodohydrin 24 as shown in Scheme 4.12,14 An inefficient,
but necessary, mercuric bromide-mediated nucleophilic substitu-
tion reaction, during which nitrogen has migrated from C1 to C6,
afforded the bromohydrin 25. The rearranged 2-azabicyclo-
[2.1.1]hexane structure of 25 was confirmed by the characteristic
1H NMR W-plan coupling between bridgehead proton H1 at
δ 4.44 with H4 at δ 2.92 (J1,4 = 6.8 Hz) and a geminal H3 proton
0
at δ 3.41 (d, J3,3 = 11.3 Hz) that is not further coupled to H4. The
singlet at δ 3.57 identifies H5 as syn, since there is no coupling
with H1 or H4. Also, the absence of W-plan coupling between H5
and H6 at δ 4.77 identifies H6 as anti. With the crucial 5-syn-
alcohol in place, protection of the alcohol as the TBS ether 26
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FEATURED ARTICLE
Amide trans/cis ratios shown in Table 2 were obtained by integra-
tion of nonoverlapping 1H or 19F NMR peaks. The percentages
of trans isomers obtained by separate 1H NMR integrations are
reliable (1%. For an individual structure, isomer ratios can
depend on the protons chosen to be integrated and compared
and the percentage of trans isomer can vary from the average by (
1.5%. 19F and 1H ratios (KT/C) differ by no more than 0.1.
There is only a slight solvent dependence for methanopyrro-
lidine amide preferences of 7 and 10bꢀ13b (entries 1ꢀ5
Table 2). In polar protic D2O, the 54% trans amide preference
shown by MetPyr 7 is relatively unchanged ((1%) by either the
syn or anti, fluoro or hydroxy, heteroatom substituents of
10bꢀ13b. In CDCl3 solvent there is a bit more sensitivity to
solvent (43ꢀ54% trans). The 5-syn-F 10b and 5-anti-F isomers
11b (entries 2 and 3) show essentially the same trans preferences
in CDCl3 within a few percent as the parent substrate 9 (entry 1),
indicating that the dipolar CꢀF bond does not have a significant
effect on amide preference for these methanopyrrolidine deriva-
tives. With alcohol substitution, the 5-syn-OH 12b (entry 4) in
CDCl3 has a clear cis amide preference, while the 5-anti-OH 15b
(entry 5) has little amide preference.
amide nitrogen is nearly flat in both the cis and trans amide forms
(see the Supporting Information).
Benzoylation of the alcohol groups results in little change in
preference for trans amides in D2O for both the 5-syn-OBz 31
(entry 6) and 5-anti-OBz 36 (entry 7) isomers. However, upon
benzoylation the trans preference is enhanced in the less polar
aprotic solvent CDCl3. Especially noteworthy is the switch from
a cis amide preference for 5-syn-OH 12b (entry 4) to a clear trans
amide preference for the 5-syn-OBz 31. In this constrained ring
system a change in preferred ring pucker upon O-acylation can be
ruled out as the cause of the enhancement effect.5b,f
’ CONCLUSION
N-Acetylmethanopyrrolidine and its 5-syn/5-anti-F(OH) de-
rivatives have been synthesized from pyridine via a 1,2-dihydro-
pyridine photoproduct. The trans/cis amide preferences (KT/C
)
for the parent 7 were compared with those of the stereoisomeric
pairs of 5-syn(gauche)/anti-fluoro 10b/11b, hydroxy 12b/13b,
and O-Bz isomers 31/36 in both D2O and CDCl3 solvent. The
substituent effect differences (KT/C functionalized isomer ꢀ KT/C
for 7) were extremely small (ΔKT/C = ꢀ0.3 to þ0.1) for all cases
studied, with the single minor exception of the OBz isomers in
CDCl3 (ΔKT/C = 0.5ꢀ0.7). Further, in all of the pairs of
stereoisomers studied the trans/cis amide preference was mini-
mally influenced by the stereochemical orientation of the sub-
stituent (KT/C syn-isomer ꢀ KT/C anti-isomer = ΔKT/C = ꢀ0.2
to þ0.3).
The KT/C results in Table 2 in apolar CDCl3 solvent are in
somewhat qualitative agreement with gas-phase relative energy
calculations that generally favor small trans amide preferences.
Only the 5-syn-OH 12b, in agreement with experiment, is
calculated to have a cis amide preference. An X-ray analysis of
12b shows that that there is no unusual distortion of the ring or
internal hydrogen bonding interaction in the solid phase; the
The small trans amide preferences for methanopyrrolidine 7
in CDCl3 or D2O show that it is the interaction of the R-ester
group and the amide of MetPro 4 that plays a major role in
determining trans/cis ratios. Further, the small trans amide
preferences for the substituted fluoro- and hydroxy-methano-
pyrrolidines is confirmation of previous work with the stereo-
isomers Metflp 5 and Methyp 6 that indicated the remote anti
heteroatom has little additional effect upon trans amide
preferences.9 The findings with rigid methanopyrrolidines are
consistent with the proposal for prolines that substituent influ-
ences upon the pucker energetics of ring conformations, and the
resulting impact upon the amide carbonyl and proline side-chain
Figure 2. Amide conformations for methanopyrrolidines.
Table 2. Ktrans/cis for N-Acetylmethanopyrrolidine Derivatives
Ktrans/cis
dipole moment (μ)
a
entry
substrate
parent 7
X
Y
D2Oa
CDCl3
trans
cis
Ktrans/cis calcdb
1
2
3
4
5
6
7
H
H
1.2 (54:46)
1.1 (53:47)
1.2 (55:45)d
1.2 (54:46)
1.2 (54:46)
1.4 (58:42)
1.3 (56:44)
1.1 (52:48)
0.9 (48:52)c
1.2 (54:46)e
0.8 (43:57)
1.0 (51:49)
1.8 (64:36)
1.6 (61:39)
4.34
5.05
2.40
5.51
3.91
4.30
4.61
4.36
2.90
2.93
1.2
1.2
2.0
0.06
1.2
syn-F 10b
F
H
anti-F 11b
H
F
synꢀOH 12b
antiꢀOH 13b
syn-OBz 31
anti-OBz 36
OH
H
H
OH
H
OBz
H
OBz
a Ratios were obtained from 1H NMR spectra. b MP2/6-31G(d,p)//RHF/6-31G(d) level. c Ktrans/cis 0.9 (46:54) by 19F NMR. d Ktrans/cis = 1.3 (56:44)
by 19F NMR. e Ktrans/cis = 1.3 (57:43) by 19F NMR.
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carbonyl interaction, play the major role in determining trans/cis
amide equilibria.3a,4,8
N-Acetyl-2-azabicyclo[2.1.1]hexane (9): 1H NMR (400 MHz,
CDCl3) (italics denote minor rotamer peaks) δ4.78 (dt, J =6.9, 1.8 Hz, 1H,
H1), 4.25 (dt, J = 6.9, 1.8 Hz, 1H, H1), 3.39 (s, 2H, H3), 3.38 (s, 2H, H3),
2.89 (m, 1H, H4), 2.06 (s, 3H, COCH3), 2.01 (s, 3H, COCH3), 1.98 (m,
2H, H5anti), 1.93 (m, 2H, H5anti), 1.43 (m, 2H, H5syn), 1.33 (m, 2H, H5syni);
13C NMR (400 MHz, CDCl3) δ 168.6 and 168.0, 62.5 and 59.1, 50.1 and
48.3, 41.1 and 40.2, 38.7 and 37.9, 21.6 and 21.5; HRMS m/z found
125.0834, calcd for C7H11NO (M) 125.0836.
N-(Benzyloxycarbonyl)-5-syn-fluoro-6-anti-(phenoxycar-
bonothioyloxy)-2-azabicyclo[2.1.1]hexane (19). To 5-syn-fluoro-
6-anti-hydroxy-2-azabicyclo[2.1.1]hexane12 18 (170 mg, 0.68 mmol) in
CH2Cl2 (15 mL) were added pyridine (219 μL, 2.7 mmol) and a catalytic
amount of DMAP. To the resulting solution was added O-phenyl
chlorothionoformate (111 μL, 1.02 mmol) carefully under argon at rt.13
After 2 h, the reaction mixture was quenched with satd NH4Cl (aq) (5 mL)
and diluted with CH2Cl2 (10 mL). The aqueous layer was extracted with
CH2Cl2 (3 ꢁ 15 mL), and all of the CH2Cl2 layers were combined and
dried using Na2SO4. Removal of the solvent in vacuo followed by silica gel
flash chromatography gave 230 mg (88%) of 19 at Rf = 0.60 (1:1 hexane/
diethyl ether): 1H NMR (400 MHz, CDCl3) δ 7.37ꢀ7.01, 5.12 (dd, J =
56.4, 6.8 Hz, 1H, H5), 5.11 (s, 2H), 4.86 (d, J = 20.8 Hz, 1H, H6), 4.78 (dd,
J = 21.1, 6.8 Hz, 1H, H1), 3.61 (two d, J = 9.0 Hz, 1H, H3), 3.45 (d, J = 9.0
Hz, 1H, H3), 3.27 (br, 1H, H4); 13C NMR (100 MHz) δ 194.1 (CdS),
156.9, 156.3 (CdO), 153.5, 136.69, 130.1, 128.9, 128.6, 128.5, 128.3,
127.3, 122.0, 85.9, 83.5, 78.9, 78.7, 67.7, 64.6, 64.4, 47.3, 47.1, 44.3, 44.3;
HRMS m/z 388.1019, calcd for C20H19FNO4S (M þ H), m/z 388.1014,
calcd for 410.0844 C20H18FNaNO4S (M þ Na) 410.0833.
For the four possible N-acetyl-5-fluoro- and -5-hydroxymetha-
nopyrrolidines, we now have obtained KT/C values that establish
baseline amide preferences in the absence of R-ester function-
ality. With this evidence, it will be possible to determine the
contribution to trans amide preferences by R-ester substituents
when other methanoprolines are synthesized. The N-BOC-
methanopyrrolidines 10b, 11b, 28, and 13b should prove useful
in this endeavor to prepare fluoro- and hydroxymethanoprolines
14ꢀ17, constrained mimics of Flp and Hyp in idealized Cγ-exo
and Cγ-endo conformations through which insights may be
gained concerning amide preferences of prolines.
’ EXPERIMENTAL SECTION
General Methods. Thin-layer chromatography was performed on
precoated plates of silica gel GF 250 μm. Column chromatography was
performed on silica gel, Merck grade 60 (230ꢀ400 mesh). Reagent
chemicals were obtained from commercial suppliers, and reagent grade
1
solvents were used without further purification. The standard for H
NMR was CHCl3 δ 7.26, for 13C NMR CDCl3 δ 77.0, and for 19F NMR
CFCl3 δ 0.00; undecoupled 19F spectra were referenced indirectly
against a D-lock and required minor shift correction. Some NMR
resonances appear as pairs because of carbamate conformations and
italics denote minor rotamer peaks. Assignments of NMR resonances,
N -(Benzyloxycarbonyl)-5-syn-fluoro-2-azabicyclo[2.1.1]-
hexane (20). Compound 19 (129 mg, 0.33 mmol) was dissolved in dry
toluene (8.3 mL) and degassed for 1 h with Ar. Separately, AIBN (8.2
mg, 0.05 mmol) and (TMS)3SiH (100 mg, 0.5 mmol) were dissolved in
dry toluene (13.7 mL) and degassed for 1 h with Ar. The flask was then
lowered into a 90 ꢀC oil bath, and the AIBN/(TMS)3SiH solution was
added slowly via canula. The reaction was monitored by TLC for
disappearance of starting material at Rf = 0.6 (1:1 hexane/ether). After
22 h, a second portion of AIBN/TTMSS dissolved in dry toluene
degassed for 1 h with Ar was added to the flask. After 3 h, TLC showed
no remaining starting material. Solvent was removed in vacuo resulting in
a pale yellow oil. The crude material after preparative TLC at Rf = 0.3
(1:1 hexane/ether) yielded 53 mg (71%) of 20: 1H NMR (400 MHz,
CDCl3) δ 7.16 (m, 5H), 5.02 (s, 2H), 4.36 (br, 1H, H1), 4.27 (d, J =
58.8 Hz, 1H, H5), 3.37, 3.35 (two d, J = 8.0, 7.6 Hz, 1H, H3), 3.19, 3.17 (two
d, J = 7.6, 7.6 Hz, 1H, H3), 2.77 (br, 1H, H4), 1.12 (dd, J = 37.2, 5.9 Hz, 1H,
H6), 1.14 (s, H6); 13C NMR (100 MHz, CDCl3) δ 157.3, 137.2, 129.0,
128.8, 128.6, 128.4, 128.3, 128.2, 85.0, 84.9, 82.7, 82.7, 67.2, 62.6, 62.5, 62.2,
62.1, 45.3, 42.4, 42.2, 42.0, 29.9, 26.7, 26.6, 26.4; HRMS m/z 258.0898,
calcd for C13H14FNO2Na (M þ Na) 258.0901.
1
1
where necessary, were facilitated by NOE, Hꢀ H-COSY, and HET-
COR experiments. The trans/cis amide assignments were based upon
observations of an NOE effect on either the characteristic bridgehead H1
hydrogen or alternatively at the H3 methylene hydrogen signals upon
irradiation of the major or minor acetyl methyl singlets; italics denote
minor rotamer peaks. Amide trans/cis ratios were obtained by integra-
tion of nonoverlapping 1H or 19F NMR peaks. Throughout this paper,
we have chosen to use syn/anti nomenclature to identify the stereo-
chemistry of substituents on the non-nitrogen containing bridges. This is
to avoid the use of exo/endo nomenclature, confusing to those
accustomed to naming related all-carbon-bridged bicyclic structures.
The bridge with the nitrogen heteroatom is always the main bridge of
highest priority. Thus, all substituents anti to nitrogen are endo.
N-Acetyl-2-azabicyclo[2.1.1]hexane (7). To a solution of N-
BOC-2-azabicyclo[2.1.1]hexane10 (42 mg, 0.229 mmol) in CH2Cl2
(5.0 mL) was added TFA (261 mg, 2.29 mmol) at rt under argon. After
6 h, the crude amine obtained upon workup was dissolved in CH2Cl2
(7.5 mL) to which DMAP (84 mg, 0.69 mmol) was added. The solution
was cooled to 0 ꢀC, and AcCl (54 mg, 0.69 mmol) was added to the
reaction mixture. After being stirred for 3 h at room temperature, the
reaction mixture was washed with water (2 ꢁ 5 mL) and then the
combined aqueous layer was backwashed with CH2Cl2 (4 mL). The
organic layer was dried over Na2SO4 and filtered, and the solvent was
removed in vacuo. Preparative TLC (1:9 MeOH/EtOAc) afforded 20
mg (70%) of 39 as a colorless oil at Rf = 0.39 (1:9 MeOH/ethyl acetate):
1H NMR (400 MHz, D2O) (italics denote minor rotamer peaks) δ 4.64
(dt, J = 6.9, 1.8 Hz, 1H, H1), 4.46 (dt, J = 6.9, 1.8 Hz, 1H, H1), 3.54 (s, 2H,
H3), 3.36 (s, 2H, H3), 2.93 (m, 1H, H4), 2.11 (s, 3H, COCH3), 2.07
(s, 3H, COCH3), 2.07 (m, 2H, H5anti), 2.04 (m, 2H, H5anti), 1.44 (m,
2H, H5syn), 1.37 (m, 2H, H5syn); NOE (D2O) the major H1 signal at δ
4.46 on irradiation sees the acetyl signal at δ 2.11 and the minor H1
signal at δ 4.64 sees no acetyl signal. The minor H3 signal at δ 3.54 on
irradiation enhances the acetyl signal at δ 2.07 and the major H3 signal at
δ 3.36 on irradiation enhances no acetyl signal. Ktrans/cis = 52/48
(CDCl3) based upon H1 integrations; the major upfield H1 is trans.
Ktrans/cis = 54/46 (D2O) based upon H1 integrations.
N-(tert-Butoxycarbonyl)-5-syn-fluoro-2-azabicyclo[2.1.1]-
hexane (10a). General Procedure for N-COOBn to N-BOC
Conversion. To a solution of 20 (190 mg, 0.81 mmol) in MeOH
(10 mL) was added Pd(OH)2 (56 mg, 10 mol %) followed by (BOC)2O
(231 mg, 1.1 mmol). The resulting solution was stirred at rt for 2 h under
hydrogen. Filtration of the catalyst followed by silica gel flash chroma-
tography gave 80 mg (50%) of the fluoride 10a at Rf= 0.45 (1:1 hexane/
diethyl ether): 1H NMR (500 MHz, CDCl3) δ 4.46 (br, 1H, H1), 4.41
(d, J = 58.8 Hz, 1H, H5), 3.41 (dd, J = 23.5, 7.5 Hz, 1H, H3n), 3.24 (br,
1H, H3x), 2.88 (br, 1H, H4), 1.46 (s, 9H), 1.29 (m, 2H, 2H6); 13C NMR
(100 MHz, CDCl3) δ 157.2, 85.2, 82.8, 79.9, 62.8, 62.6, 61.7, 61.6, 45.5,
44.9, 42.3, 42.1, 29.0, 28.8, 28.6, 28.4, 26.8, 26.6, 26.4; HRMS m/z
224.1072, calcd for C10H16FNO2 Na (M þ Na) 224.1063.
N-Acetyl-5-syn-fluoro-2-azabicyclo[2.1.1]hexane (10b). Gen-
eral Procedure for Acetylation. Carbamate 20 (56 mg, 0.24 mmol)
and10%Pd/C(13mg, 0.012mmol) wereplacedunder Arandsuspended
in dry THF (5.6 mL). The vessel was repeatedly evacuated and placed
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FEATURED ARTICLE
under H2 six times. H2 was bubbled through the suspension for 15 min
followed by capping with a H2ꢀfilled balloon (2 L). Acetic anyhdride
(0.025 mL, 0.26 mmol) and TEA (0.033mL, 0.024 mmol) freshlydistilled
from CaH2 were added via syringe. After being sitrred for 3 h, the Pd/C
was filtered through a Celite plug, and the solvent was removed in vacuo.
The crude oil purified by silica gel flash chromatography at Rf = 0.14
(1% MeOH in DCM) gave 19.5 mg (59%) of amide 10b: 1H NMR (500
MHz, CDCl3) δ 4.88 (dm, J = 6.9 Hz, 1H, major H1), 4.49 (ddd, J = 58.4,
2.8, 2.3 Hz, 1H, minor H5), 4.46 (ddd, J = 58.3, 2.9, 2.0 Hz, 1H, major H5),
4.33 (dddd, J = 6.4, 1.8, 1.74, 1.74 Hz, 1H, minor H1), 3.54 (d, J = 9.7 Hz,
1H, minor H3), 3.50 (d, J = 8.0 Hz, 1H, major H3), 3.37 (overlapping d, 2H,
H3), 2.98 (m, 1H, H4), 2.07 (two s, 6H, COCH3). 1.45ꢀ1.23 (m, 2H, H6);
13C NMR (100 MHz, CDCl3) δ 170.2, 169.7, 83.8 (d, J = 241.1 Hz), 83.2
(d, J= 240.8 Hz), 63.86 (d, J= 17.4 Hz), 60.67 (d, J= 17.0 Hz), 45.91 (d, J=
3.3 Hz), 44.29 (d, J = 2.8 Hz), 42.42 (d, J = 18.4 Hz), 41.75 (d, J = 18.6 Hz),
27.43 (d, J = 17.6 Hz), 26.26 (d, J = 18.0 Hz), 22.10, 21.70; 1H NMR (500
MHz, D2O) δ 4.72 (1H, minor H1), 4.67 (ddd, J = 58.9, 3.1, 2.0, 1H, H5),
4.65 (major coupling from HSQC J= 59 Hz, 1H, H5), 4.56 (dq, J= 6.3, 1.82
Hz, 1H, major H1), 3.56 (dt, J = 8.7, 1.1 Hz, 1H, minor H3), 3.53 (dd, J =
8.7, 0.7 Hz, 1H, minor H3), 3.41 (d br, J = 9.7 Hz, 1H, major H3), 3.34 (d, J
= 9.7Hz, 1H, majorH3), 3.08ꢀ 3.04(m, 1H, H4), 3.04 ꢀ 3.01 (m, 1H, H4),
2.1 (s, 3H, major COCH3), 2.09 (s, 3H, minor COCH3), 1.47 (dm, J = 9.3
Hz, 1H, H6eq), 1.42 (dm, J = 9.3 Hz, 1H, H6eq), 1.42 (dd, J = 9.3 Hz,
1H, H6ax), 1.34 (dd, J = 9.3 Hz, 1H, H6ax); 19F NMR (376 MHz, CDCl3) δ
ꢀ177.2 and ꢀ177.6 (ratio 1:1.16); 19F NMR (376 MHz, D2O) δ ꢀ176.9
(br, overlapping conformers); 1H NMR NOE (CDCl3) pulse δ 4.33
ppm (minor H1) hits δ 2.09, 4.57, 1.38. Pulse δ 4.88 (major H1) hits δ
4.46 (H5 major), 1.33; NOE (D2O) pulse δ 1.97 hits δ 3.55 and 4.57. and
pulse δ 2.04 hits δ 4.57 only; Ktrans/cis = 48/52 (CDCl3) and 53/47 (D2O)
Pd(OH)2 (15 mg) followed by (BOC)2O (47 mg, 2.15 mmol). After the
mixture was stirred at rt for 2 h under hydrogen there was obtained 25 mg
(71%) of 11a: Rf = 0.39 (1:1 hexane/ether); 1H NMR (400 MHz, CDCl3)
δ 4.80 (dd, J = 62, 7.9 Hz, H5), 4.30 (br, H1), 3.36 (q, J = 9.7 Hz, 2H3),
2.83 (m, 2H, H4 and H6x), 1.70 (ddd, J = 7.9, 7.3, 2.7 Hz, H6n), 1.45 (s,
9H, BOC); 13C NMR (100 MHz, CDCl3) δ 155.4, 98.6 (d, JCF = 210
Hz, C5), 79.9, 62.2, 47.2, 43.4 and 43.2, 36.7, 28.4; HRMS m/z found
224.1052, calcd for C10H16FNO2 [M þ Na] 224.1063.
N-(Acetyl)-5-anti-fluoro-2-azabicyclo[2.1.1]hexane (11b).
According to the general procedure, carbamate 23 (96 mg, 0.41 mmol)
and 10% Pd/C (22 mg, 0.02 mmol) were placed under Ar and
suspended in dry THF (5.6 mL). Hydrogenation, followed by addition
of acetic anyhdride (0.042 mL, 0.45 mmol) and TEA (0.056 mL, 0.41
mmol), and workup afforded 14 mg (24%) of amide 11b: Rf = 0.16
(1% MeOH in DCM); 1H NMR (500 MHz, CDCl3) 4.82 (dd, J = 62.4,
7.2 Hz, 1H, H5 major), 4.78 (dd, J = 62.2, 7.3 Hz, 1H, H5 minor)
4.77(1H, H1, minor) 4.26 (d, J = 6.7 Hz, 1H, H1 major), 3.49 (m, 2H,
H3), 2.91 (m, 2H, H4, H6) 1.78 (td, J = 7.8, 2.4 Hz, 1H, H6x) 1.71 (td, J =
7.8, 2.4 Hz, 1H, H6y); 13C NMR (75 MHz, CDCl3) δ 169.17, 168.72,
98.51 (d, J = 214.2 Hz), 98.43 (d, J = 213.3 Hz), 64.13 (d, J = 21.8 Hz),
60.76 (d, J = 21.9 Hz), 48.62 (d, J = 5.1 Hz), 46.79 (d, J = 4.9 Hz), 43.79
(d, J = 18.4 Hz), 43.15 (d, J = 17.8 Hz), 37.70, 36.70; HRMS m/z 144.0823,
calcd for C7H10FNO (M þ H) 144.0819. 19F NMR (376 MHz, CDCl3)
δ ꢀ206.1 and ꢀ206.8 (ratio =1.3:1.0); 19F NMR (376 MHz, D2O)
1
δ ꢀ205.2 and ꢀ206.8 (ratio =1.0:0.79); H NMR (500 MHz, D2O)
δ 4.89 (dd, J = 62.1, 7.3 Hz, 1H, H5 major), 4.87 (dd, J = 62.2, 7.3 Hz, 1H
H1 minor), 4.62 (ddd, J = 7.4, 1.9, 1.1 Hz, 1H, H1 minor), 4.48 (ddd, J =
0
7.1, 1.9, 1.0 Hz, 1H, H1 major), 3.62 (m, 1H, H3,3 , minor), 3.45 (dd, J =
0
10.0, 3.5 Hz, 1H, H3, major), 3.41 (d, J = 10.2 Hz, 1H, H3 , major), 2.97
based upon H1 integrations or Ktrans/cis = 46/54 (CDCl3) based upon 19
F
(m, 1H, H4), 2.89 (m, 1H, H6anti), 2.08 (s, 3H), 2.03 (s, 3H), 1.80
(ddd, J = 8.5, 7.3, 2.7 Hz, 1H, H6syn, major), 1.74 (ddd, J = 8.5, 7.3, 2.7
Hz, 1H, H6syn, minor); NOE (D2O) pulse δ 2.03 hits δ 3.62 (H3
minor); pulse δ 2.08 (pulls 2.03 into pulse) hits δ 3.62, 4.47 (H1 major).
NOE (CDCl3): pulse δ 2.02 hits δ 3.48; pulse δ 2.06 (pulls 2.02 into
pulse) hits δ 4.25 (major H1), δ 3.48; Ktrans/cis = 54/46 (CDCl3) and
Ktrans/cis = 55/45 (D2O) based upon H1 integrations or Ktrans/cis = 57/
43 (CDCl3) and 56:44 (D2O) based upon 19F integrations.
integrations; HRMS m/z 144.0823, calcd for C7H10FNO (M þ H)
144.0819.
N-(Benzyloxycarbonyl)-5-anti-bromo-6-anti-fluoro-2-aza-
bicyclo[2.1.1]hexane (22). To a solution of alkene14 21 (398 mg,
1.85 mmol) in CH3NO2 (15 mL) was added NBS (461 mg, 2.6 mmol)
at 0 ꢀC followed by Et3N 3HF (753 μL, 4.62 mmol) dropwise over a
3
period of 10 min.15 The reaction mixture was brought to rt and stirred
for 16 h, after which it was diluted with CH2Cl2 (40 mL), washed with
NaHCO3 (15 mL) and brine (15 mL), and dried over Na2SO4 to give
876 mg of a crude oil. Silica gel flash column chromatography gave 150
mg of the unreacted olefin 21 (37%) and 212 mg (38%) of 22 at Rf = 0.45
(1:1 hexane/ether); 1H NMR (400 MHz, CDCl3) δ 7.43 (m, 5H), 5.22
(s, 2H), 5.07 (dd, J = 59.4, 7.5 Hz, H6), 4.61 (d, J = 7.2 Hz, 1H, H1), 4.18
(dd, J = 7.5, 3.0 Hz, H5), 3.68 (dd, J = 12.0, 1.8 Hz, H3), 3.58 (d, J = 12.0
Hz, H3), 3.20 (br, 1H, H4); 13C NMR (100 MHz, CDCl3) δ 155.5,
136.8, 128.8, 128.3, 128.2, 100.2 (J = 224 Hz), 65.1, 64.8, 50.3, 49.6,
48.5; HRMS m/z found 336.0014, calcd for C13H13NO2FNaBr79
(M þ Na) 336.0011.
N-(Benzyloxycarbonyl)-5-anti-bromo-6-syn-hydroxy-2-
azabicyclo[2.1.1]hexane (25). To a stirred solution of iodohydrin
24 (1000 mg, 2.784 mmol) in MeNO2 (100 mL) was added mercuric
bromide (2509 mg, 6.961 mmol, 2.5 equiv).12,14 The solution was
heated at 65 ꢀC for 15 h. The mixture was diluted with brine (50 mL)
and extracted with ether (4 ꢁ 150 mL). The ether extracts were combined,
washed with brine (2 ꢁ 100 mL), dried over MgSO4, evaporated under
reduced pressure, and chromatographed (gradient: 25ꢀ40% ether in
hexanes) to afford 269 mg (31%) of rearranged bromohydrin 25 as a
colorlessoil:Rf= 0.44(2:3 ethyl acetate/hexanes) (unreactedHgBr2 is UV
active and NMR blind, and separation was difficult); 1H NMR (400 MHz,
CDCl3) δ7.39ꢀ7.29(m, 5H), 5.15(br, 2H), 4.77(br, 1H, H6), 4.44 (dd, J=
6.8, 1.7 Hz, 1H, H1), 4.41 (dd, J = 6.8, 1.7 Hz, 1H, H1), 3.57 (s, 1H, H5),
3.58ꢀ3.51 (m, 3H, 2H3 and H5), 3.41 (d, J = 11.3 Hz, 1H, H3), 3.36 (d, J =
N-(Benzyloxycarbonyl)-5-anti-fluoro-2-azabicyclo[2.1.1]-
hexane (23). General Procedure for Reductive Debromina-
tion. To a solution of 22 (222 mg, 0.71 mmol) in benzene (25 mL)
were added n-Bu3SnH (263 μL, 0.98 mmol) and AIBN (21 mg). The
resulting solution was refluxed for 16 h. Solvent was removed in vacuo,
and the crude was chromatographed to give 130 mg (78%) of 23 at Rf =
0.39 (1:1 hexane/ether): 1H NMR (400 MHz, CDCl3) δ 7.34 (m, 5H),
5.15 (s, 2H), 4.80 (dd, J = 62.1, 7.2 Hz, H5), 4.41 (brd, J = 6.0 Hz, 1H, H1),
3.45 (s, 2H, 2H3), 2.86 (brm, 2H, H4 and H6x), 1.74 (ddd, J = 7.8, 7.7, 2.6
Hz, H6n); 13C NMR (100 MHz, CDCl3) δ 157.3, 136.3, 128.8, 128.3,
128.2, 98.4 (d, JCF = 209 Hz), 66.9 and 66.8, 62.0, 47.3, 43.4 and 43.1, 36.7;
HRMS m/z found 258.0907, calcd for C13H14NO2FNa
(M þ Na) 258.0907.
0
11.9 Hz, 1H, H3 ), 3.13 (br, 1H, OH), 2.92 (m, 1H, H4), 2.87 (m, 1H, H4);
13C NMR (100 MHz, CDCl3) δ 156.8, 136.3, 128.5, 128.1, 127.9, 71.4
and 70.2, 67.4 and 67.3, 49.9 and 49.7, 45.5, 43.1, 14.7; HRMS m/z
found 334.0045, calcd for C13H14BrNO3Na (M þ Na) 334.0049.
N-(Benzyloxycarbonyl)-5-anti-bromo-6-syn-(tert-butyldime-
thylsilyloxy)-2-azabicyclo[2.1.1]hexane (26). To a solution of
bromohydrin 25 (257 mg, 0.823 mmol) in dry CH2Cl2 (10 mL) under
argon was added imidazole (280 mg, 4.116 mmol, 5.0 equiv) followed by
TBSCl (149 mg, 0.988 mmol, 1.2 equiv) in small portions. The resulting
solution was stirred at rt for 6 h. The solvent was removed in vacuo and
then chromatographed (10% ethyl acetate in hexanes) on silica gel to
gave 312 mg (89%) of bromo-O-silyl ether 26 as a colorless oil: Rf = 0.44
(1:5 ethyl acetate/hexanes); 1H NMR (400 MHz, CDCl3) δ 7.39ꢀ7.27
N-(tert-Butoxycarbonyl)-5-anti-fluoro-2-azabicyclo[2.1.1]-
hexane (11a)16. According to the general procedure for 10a, to
carbamate 23 (42 mg, 0.18 mmol) in MeOH (10 mL) was added
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FEATURED ARTICLE
(m, 5H), 5.21ꢀ5.00 (m, 2H), 4.67 (br s, 1H, H6), 4.65 (br s, 1H, H6),
4.44 (dd, J = 6.9, 1.4 Hz, 1H, H1), 4.38 (dd, J = 6.9, 1.4 Hz, 1H, H1), 3.58
(s, 1H, H5), 3.57ꢀ3.28 (m, 2H, 2H3), 2.91ꢀ2.79 (m, 1H, H4),
0.91ꢀ0.78 (m, 9H), 0.09ꢀ0.01 (m, 6H); 13C NMR (100 MHz, CDCl3)
δ 156.7 and 156.1, 136.6 and 136.4, 128.4, 128.1, 128.0, 127.9, 127.8,
70.4 and 70.3, 68.0 and 67.6, 67.0 and 66.8, 50.4 and 50.3, 45.7 and 45.6,
43.2 and 43.0, 25.5, 17.8, ꢀ5.1 and -5.2; HRMS m/z found 448.0923,
calcd for C19H28BrNO3SiNa (M þ Na) 448.0914.
were added Bu3SnH (285 μL, 1.072 mmol) and AIBN (9 mg). After 3 h
at 70 ꢀC, workup and flash chromatography (1:5 ethyl acetate/hexanes)
gave 130 mg (72%) of benzoate ester 30 as a light orange oil: Rf = 0.34
(1:3 ethyl acetate/hexanes); 1H NMR (400 MHz, CDCl3) δ 7.96ꢀ7.20
(m, 10H), 5.08 (d, J = 12.4 Hz, 1H), 5.02 (d, J = 12.3 Hz, 1H), 4.8 (m,
1H, H5 and its conformer), 4.67 (brd, J = 6.6 Hz, 1H, H1), 4.61 (brd, J =
6.6 Hz, 1H, H1), 3.59 (d, J = 9.1 Hz, 1H, H3), 3.50 (d, J = 9.1 Hz, 1H, H3),
0
0
3.40 (d, J = 9.1 Hz, 1H, H3 ), 3.37 (d, J = 9.1 Hz, 1H, H3 ), 3.07 (m, 1H,
H4), 1.64 (m, 1H, H6anti and its conformer), 1.47 (m, 1H, H6syn and its
conformer); 13C NMR (100 MHz, CDCl3) δ 165.4 and 165.3, 157.5 and
156.8, 136.8 and 136.6, 133.3, 129.6, 128.5, 128.3, 127.8, 127.7, 69.4,
66.8 and 66.7, 62.6 and 62.0, 45.9 and 45.6, 42.0 and 41.6, 30.1 and 29.8;
HRMS m/z found 338.1386, calcd for C20H20NO4 (M þ H) 338.1387.
N-Acetyl-5-syn-benzoyloxy-2-azabicyclo[2.1.1]hexane
(31). According to the general procedure, to a solution of benzoate ester
30 (102 mg, 0.302 mmol) in MeOH (2 mL) was added Pd(OH)2
(30 mg). After 3 h under hydrogen at RT workup gave a crude amine
that was dissolved in dry CH2Cl2 (10 mL) and cooled to 0 ꢀC. DMAP
(110 mg, 0.907 mmol, 3 equiv) and AcCl (65 μL, 0.907 mmol, 3 equiv)
was added to the reaction mixture maintained for 30 min at 0 ꢀC and
then brought to RT. After 3 h at RT workup and chromatography (1:4
hexanes/ethyl acetate) afforded 45 mg (61%) of 31 as a light orange oil
at Rf = 0.24 (ethyl acetate); 1H NMR (400 MHz, CDCl3) δ 7.93
(m, 2H), 7.54 (m, 1H), 7.40 (m, 2H), 4.98 (dt, J = 6.8, 1.8 Hz, 1H, H1),
4.75 (dd, J = 3.0, 1.9 Hz, 1H, H5), 4.72 (dd, J = 3.0, 1.9 Hz, 1H, H5), 4.50
(dt, J = 6.4, 1.8 Hz, 1H, H1), 3.60 (brd, J = 9.7 Hz, 1H, H3), 3.40 (m, 1H,
N-(Benzyloxycarbonyl)-5-syn-(tert-butyldimethylsilyloxy)-2-
azabicyclo[2.1.1]hexane (27). According to the general reductive
procedure for 23, to a solution of bromo-O-silyl ether 26 (304 mg, 0.713
mmol) in dry toluene (20 mL) were added (TMS)3SiH (440 μL, 1.426
mmol, 2.0 equiv) and AIBN (30 mg). After 2 h at 70 ꢀC, workup and
flash chromatography (1:9 ethyl acetate/hexanes) gave 183 mg (74%) of
O-silyl ether 27 as a colorless oil: Rf = 0.41 (1:6 ethyl acetate/hexanes);
1H NMR (400 MHz, CDCl3) δ 7.41ꢀ7.22 (m, 5H), 5.21ꢀ5.01 (m,
2H,), 4.29 (dt, J = 6.7, 1.5 Hz, 1H, H1), 4.23 (dt, J = 6.7, 1.5 Hz, 1H, H1),
3.69 (m, 1H, H5), 3.47 (d, J = 8.4 Hz, 1H, H3), 3.45 (d, J = 8.4 Hz, 1H, H3),
0
0
3.22 (d, J = 8.4 Hz, 1H, H3 ), 3.19 (d, J = 8.3 Hz, 1H, H3 ), 2.64
(m, 1H, H4), 1.28 (m, 1H, H6anti), 1.26 (m, 1H, H6anti), 1.20 (d, J = 8.1
Hz, 1H, H6syn), 1.17 (d, J = 8.1 Hz, 1H, H6syn), 0.84 (s, 9H,), 0.04 (s, 6H),
0.03 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 157.4 and 156.9, 137.2 and
137.0, 128.3, 127.9, 127.7, 69.6 and 69.5, 66.5 and 66.4, 63.7 and 63.4,
45.3 and 45.2, 42.8 and 42.7, 28.6 and 28.2, 25.6, 17.8, -5.1 and ꢀ5.2;
HRMS m/z found 348.1994, calcd for C19H30NO3Si (M þ H)
348.1989.
0
H3 conformer and 1H, H3 and its conformer), 3.15 (m, 1H, H4), 3.08
N-(tert-Butoxycarbonyl)-5-syn-(tert-butyldimethylsilyloxy)-2-
azabicyclo[2.1.1]hexane (28). To a solution of O-silyl ether 27
(231 mg, 0.665 mmol) in MeOH (10 mL) was added Pd(OH)2 (50 mg)
followed by (BOC)2O (174 mg, 0.798 mmol, 1.2 equiv). After 3 h under
hydrogen at rt, workup and silica gel chromatography gave 184 mg
(88%) of carbamate 28 as a colorless oil: Rf = 0.52 (1:6 ethyl acetate/
hexanes); 1H NMR (400 MHz, CDCl3) δ 4.21 (dt, J = 6.8, 1.6 Hz, 1H,
H1), 4.11 (dt, J = 6.8, 1.6 Hz, 1H, H1), 3.65 (m, 1H, H5), 3.36 (d, J = 8.3
(m, 1H, H4), 2.05 (s, 3H, Ac), 2.00 (s, 3H, Ac), 1.69 (m, 1H, H6anti), 1.63
(m, 1H, H6anti), 1.51 (d, J = 8.6 Hz, 1H, H6syn), 1.39 (d, J = 8.7 Hz, 1H,
H6syn); 13C NMR (100 MHz, CDCl3) δ 169.9 and 169.5, 165.6 and
165.3, 133.4 and 133.3, 129.6 and 129.5, 129.3 and 129.0, 128.5 and
128.4, 69.8 and 69.1, 64.0 and 60.3, 46.1 and 44.7, 42.2 and 41.0, 30.9
and 29.6, 21.6 and 21.4; HRMS m/z found 246.1125, calcd for
1
C14H16NO3 (M þ H) 246.1125; H NMR (400 MHz, D2O) δ 7.93
0
(m, 2H, Bz), 7.68 (m, 1H, Bz), 7.51 (m, 2H, Bz), 4.86 (dt, J = 6.8, 1.7 Hz,
1H, H1), 4.78 (m, 1H, H5 and its conformer, some part of signal is under
D2O peak), 4.71 (dt, J = 6.4, 1.7 Hz, 1H, H1), 3.62 ꢀ 3.36 (m, 2H, 2H3 and
their conformers), 3.17 (m, 1H, H4), 2.05 (s, 3H, Ac), 2.03 (s, 3H, Ac), 1.81
(m, 1H, H6anti), 1.76 (m, 1H, H6anti), 1.58 (d, J = 9.1 Hz, 1H, H6syn), 1.49
(d, J = 9.0 Hz, 1H, H6syn); NOE (500 MHz, CDCl3) the major acetyl
signal at δ 2.00 on irradiation enhances major H1 at δ 4.50. The minor
acetyl signal at δ 2.05 on irradiation enhances minor H3 at δ 3.40; NOE
(500 MHz, D2O) the major acetyl signal at δ 2.03 on irradiation
enhances the major H1 at δ 4.71. The minor acetyl signal at δ 2.05 on
irradiation enhances the minor H3 at δ 3.60. Ktrans/cis = 64/36 (CDCl3);
Ktrans/cis = 58/42 (D2O) based on H6syn peaks.
Hz, 1H, H3), 3.31 (d, J = 8.3 Hz, 1H, H3), 3.13 (d, J = 8.3 Hz, 1H, H3 ),
0
3.09 (d, J = 8.3 Hz, 1H, H3 ), 2.60 (m, 1H, H4), 1.45 (s, 9H, Boc), 1.44
(s, 9H, Boc), 1.23 (m, 1H, H6anti), 1.21 (m, 1H, H6anti), 1.56 (d, J = 8.9
Hz, 1H, H6syn), 1.13 (d, J = 8.9 Hz, 1H, H6syn), 0.86 (s, 9H, TBS), 0.04 (s,
6H, TBS); 13C NMR (100 MHz, CDCl3) δ 156.7 and 156.4, 78.8, 69.6,
63.8 and 62.7, 45.2 and 44.6, 42.8, 28.7, 28.5, 25.7, 17.9, ꢀ5.0; HRMS m/
z found 314.2154, calcd for C16H32NO3Si (M þ H) 314.2146.
N-(Benzyloxycarbonyl)-5-anti-bromo-6-syn-benzoyloxy-
2-azabicyclo[2.1.1]hexane (29). Bromohydrin 25 (51 mg, 0.163
mmol) was dissolved in dry CH2Cl2 (2.5 mL). The solution was cooled
to 0 ꢀC and treated sequentially with triethylamine (115 μL, 0.817
mmol), DMAP (22 mg, 0.180 mmol), and benzoyl chloride (40 μL,
0.327 mmol).18 The reaction mixture was stirred for 30 min at 0 ꢀC,
allowed to come to room temperature, and then stirred for 3 h. The
reaction mixture was quenched with water (2 ꢁ 1 mL) and extracted
with CH2Cl2 (2 ꢁ 0.5 mL). The combined organic layers were dried and
evaporated to dryness. The residue was purified by chromatography on
silica gel (prep TLC: 1:4 ethyl acetate/hexanes) to afford 59 mg (87%)
bromobenzoate ester 29 as a light orange oil at Rf = 0.33 (4:1 hexanes/
ethyl acetate); 1H NMR (400 MHz, CDCl3) δ 8.10 ꢀ 7.17 (m, 10H),
5.70 (br s, 1H, H6 and its rotamer), 5.09 (m, 2H), 4.80 (d, J = 6.6 Hz, 1H,
H1), 4.74 (d, J = 6.6 Hz, 1H, H1), 3.78 (s, 1H, H5), 3.69 ꢀ 3.47 (m, 3H,
2H3 and H5 rotamer), 3.28 (dd, J = 6.6, 2.7 Hz, 1H, H4), 3.23 (dd, J = 6.6,
2.7 Hz, 1H, H4); 13C NMR (100 MHz, CDCl3) δ 165.0, 156.7, 136.0,
133.5, 129.6, 128.9, 128.5, 128.4, 128.1, 127.8, 72.0 and 70.9, 67.3 and
67.1, 66.9 and 66.3, 49.5 and 49.2, 46.0, 43.5 and 43.2; HRMS m/z found
416.0510, calcd for C20H19BrNO4 (M þ H) 416.0492.
N-Acetyl-5-syn-hydroxy-2-azabicyclo[2.1.1]hexane (12b).
General Procedure for Benzoate Removal. Et3N (770 μL, 5.504
mmol) was added to the benzoate 31 (27 mg, 0.110 mmol) in methanol
(1 mL) and stirred at room temperature for 1 day under argon. After the
solvent was removed in vacuo, the crude was chromatographed (prep
TLC: 9:1 ethyl acetate/MeOH) to afford 11 mg (71%) of alcohol 12b as
an off-white solid: Rf = 0.29 (9:1 ethyl acetate/MeOH); mp 52ꢀ54 ꢀC
(ethyl acetate); 1H NMR (400 MHz, CDCl3) δ 4.60 (dt, J = 6.8, 1.7 Hz,
1H, H1), 4.55 (d, J= 4.2 Hz, 1H, H5), 4.27 (bd, J = 6.9 Hz, 1H, H5), 4.16 (dt,
J = 6.6, 1.8 Hz, 1H, H1), 3.84 (m, 1H, OH), 3.50 (brd, J = 7.9 Hz, 1H, H3),
0
3.46 (brd, J = 9.8 Hz, 1H, H3), 3.27 (m, 1H, H3 and its conformer), 2.78
(m, 1H, H4 and its conformer), 2.05 (s, 3H, Ac), 2.04 (s, 3H, Ac), 1.39
(m, 1H, H6anti), 1.34 (m, 1H, H6anti), 1.23 (d, J = 8.6 Hz, 1H, H6syn), 1.14
(d, J = 8.6 Hz, 1H, H6syn); 13C NMR (100 MHz, CDCl3) δ 170.5 and
169.8, 70.1 and 68.9, 65.1 and 62.0, 46.1 and 44.1, 42.1 and 42.0, 29.6 and
28.6, 21.9 and 21.4; HRMS m/z found 164.0682, calcd for C7H11NO2-
Na (M þ Na) 164.0682. 1H NMR (400 MHz, D2O) δ 4.55 (dt, J = 6.7,
1.8 Hz, 1H, H1), 4.37 (dt, J = 6.5, 1.8 Hz, 1H, H1), 3.95 (bdd, J = 3.1, 1.8
N-(Benzyloxycarbonyl)-5-syn-benzoyloxy-2-azabicyclo[2.1.1]-
hexane (30). According to the general procedure, to a solution of
bromobenzoate ester 29 (223 mg, 0.536 mmol) in dry toluene (15 mL)
3632
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The Journal of Organic Chemistry
FEATURED ARTICLE
0
Hz, 1H, H5), 3.93 (dd,
(s, 2H, H3), 3.32 (two d, J = 9.8, 9.7 Hz, 2H, H3), 2.84 (m, 1H, H4
and its conformer), 2.09 (s, 3H, Ac), 2.08 (s, 3H, Ac), 1.51 (m, 1H,
J
=
3.1, 1.8 Hz, 1H, H5), 3.48
1H, H1), 3.53 (br d, J = 9.0 Hz, 1H, H3), 3.45 (br d, J = 9.0 Hz, 1H, H3 ),
2.99 (dd, J = 7.2, 2.8 Hz, 1H, H4), 2.79 (d, J = 8.1 Hz, 1H, H6anti), 1.67
(dd, J = 8.1, 7.3 Hz, 1H, H6syn), 1.49 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 166.3, 155.6, 133.3, 129.8, 129.6 and 128.5, 82.6, 79.8, 62.2,
48.2, 43.0, 37.1, 28.5; HRMS m/z found 326.1367, calcd for
C17H21NO4Na (M þ Na) 326.1363.
H
6anti), 1.45 (m, 1H, H6anti), 1.29 (d, J = 8.8 Hz, 1H, H6syn), 1.21 (d, J =
8.8 Hz, 1H, H6syni); NOE (500 MHz, CDCl3, some C6D6 added to
resolve peaks) the minor H1 signal at δ 4.16 on irradiation enhances the
minor COCH3 at δ 2.04 and vice versa; NOE (500 MHz, D2O) the
major H1 resonance at δ 4.37 on irradiation enhances the major COCH3
at δ 2.08. The minor H3 resonance at δ 3.48 on irradiation enhances the
minor COCH3 at δ 2.09. KT/C = 43/57 (CDCl3) and KT/C = 54/46
(D2O) based on H6syn peaks.
N-(Benzyloxycarbonyl)-5-anti-acetoxy-2-azabicyclo[2.1.1]-
hexane (33). According to the general procedure, AIBN (600 mg) and
(TMS)3SiH (10.45 mL, 33.8 mmol) were added to bromoacetate17 32
(6.00 g, 16.9 mmol) in dry toluene (300 mL). The resulting solution was
stirred vigorously at 70 ꢀC for 3 h under an argon-filled balloon. Workup
and chromatography (10% and then 25% ether in hexanes) afforded
3.52 g (76%) of acetate 33 as a light yellow oil at Rf = 0.44 (1:1 ether/
hexanes): 1H NMR (400 MHz, CDCl3) δ 7.30ꢀ7.18 (m, 5H, Ph), 5.07
(s, 2H, OCH2), 4.48 (d, J = 7.3 Hz, 1H, H5), 4.34 (br dd, J = 7.1, 1.2 Hz,
N-Acetyl-5-anti-benzoyloxy-2-azabicyclo[2.1.1]hexane
(36). To a solution of carbamate 35 (108 mg, 0.356 mmol) in dry
CH2Cl2 (10 mL) was added TFA (275 μL, 3.559 mmol) at rt. The
solution was stirred for 6 h at room temperature under argon, and then
solvent was removed in vacuo to afford the 173 mg of crude amine as an
orange oil. To the crude amine in dry CH2Cl2 (15 mL) was added
DMAP (130 mg, 1.068 mmol) under argon, and the solution was cooled
to 0 ꢀC. AcCl (75 μL, 1.068 mmol) was added to the reaction mixture
that was maintained for 30 min at 0 ꢀC and then brought to rt. After
being stirred for 4 h at rt, the reaction mixture was washed with water
(2 ꢁ 5 mL) and then the combined aqueous layer was backwashed with
CH2Cl2 (4 mL). The organic layer was dried over Na2SO4 and filtered,
and the solvent was removed in vacuo. The crude (122 mg) was
chromatographed (prep tlc, 1:9 hexanes/ethyl acetate) to afford 67
mg (77%) of amide 36 as a light orange oil: Rf = 0.22 (1:9 hexanes/ethyl
acetate); 1H NMR (400 MHz, CDCl3) δ 8.06ꢀ8.01 (m, 2H), 7.61ꢀ7.55
(m, 1H), 7.48ꢀ7.42 (m, 2H), 4.89 (dd, J = 7.4, 1.8 Hz, 1H, H1,), 4.77 (d, J =
7.3 Hz, 1H, H5), 4.76 (d, J = 7.3 Hz, 1H, H5), 4.41 (dd, J =
7.0, 1.8 Hz, 1H, H1), 3.65ꢀ3.51 (m, 2H, 2H3), 3.06 (m, 1H, H4), 2.84
(m, 1H, H6anti), 2.10 (s, 3H), 2.05 (s, 3H), 1.72 (dd, J = 8.3, 7.3 Hz, 1H,
0
1H, H1), 3.43 (d, J = 9.0 Hz, 1H, H3), 3.37 (d, J = 9.0 Hz, 1H, H3 ), 2.78
(dd, J = 7.1, 2.8 Hz, 1H, H4), 2.60 (br d, J = 8.1 Hz, 1H, H6anti), 2.00
(s, 3H, COCH3), 1.52 (dd, J = 8.1, 7.3 Hz, 1H, H6syn); 13C NMR (100
MHz, CDCl3) δ 170.4, 155.5 (br), 136.5, 128.2, 127.8, 127.6, 81.8, 65.6,
61.8 (br), 47.9, 42.4, 36.7, 24.9 and 20.6; HRMS m/z found 298.1060,
calcd for C15H17NO4Na (M þ Na) 298.1055.
H
6syn), 1.65 (dd, J = 8.3, 7.3 Hz, 1H, H6syn);13C NMR (100 MHz, CDCl3) δ
N-(Benzyloxycarbonyl)-5-anti-hydroxy-2-azabicyclo[2.1.1]-
hexane (34). According to the general procedure, Et3N (15 mL, 0.109
mol) was added to acetate 33 (3.00 g, 0.011 mol) in methanol (270 mL)
and the mixture stirred at rt for 12 h. Workup and chromatography (1:1
ethylacetate/hexanes) afforded2.20 g(87%) of alcohol34 asa light yellow
oil at Rf 0.50 (2:1 ethyl acetate/hexanes): 1H NMR (300 MHz, CDCl3) δ
7.38ꢀ7.25 (m, 5H), 5.12 (s, 2H), 4.42 (br, 1H, OH), 4.18 (dd, J =
7.2, 1.2 Hz, 1H, H1), 4.03 (d, J = 7.1 Hz, 1H, H5), 3.37 (s, 2H, H3), 2.89
(br, 1H, H6anti), 2.63 (dd, J = 7.2, 3.1 Hz, 1H, H4), 1.60 (dd, J = 7.8, 7.1 Hz,
1H, H6syn); 13C NMR (100 MHz, CDCl3) δ 155.6, 136.6, 128.4, 127.9,
127.7, 80.9, 66.7, 63.6 and 63.2, 48.2 (br), 43.8, 36.7 (br); HRMS m/z
found 256.0946, calcd for C13H15NO3Na (M þ Na) 256.0950.
168.7 and 168.5, 166.2 and 166.1, 133.4 and 133.3, 129.6 (2C), 128.5 and
128.4, 82.4 and 82.0, 63.8 and 60.4, 49.0 and 47.1, 43.1 and 42.0, 37.6 and
36.7, 21.6 and 20.9; HRMS m/z found 246.1125, calcd for C14H16NO3 (M
þ H) 246.1125.
N-Acetyl-5-anti-hydroxy-2-azabicyclo[2.1.1]hexane
(13b). Et3N (450 μL, 3.180 mmol) was added to the benzoate 36 (52.0
mg, 0.212 mmol) in methanol (5 mL) and stirred at room temperature
for 17 h under argon. After the solvent was removed in vacuo, the crude
was chromatographed (9:1 ethyl acetate/MeOH) to afford 23.6 mg
(79%) of alcohol 13b as a colorless oil: Rf = 0.26 (9:1 ethyl acetate/
MeOH); 1H NMR (400 MHz, CDCl3) δ 4.69 (br, 1H, OH), 4.48 (dd, J =
7.3, 1.7 Hz, 1H, H1), 4.05 (d, J = 7.0 Hz, 1H, H5), 4.04 (dd, J = 7.0, 1.9 Hz,
1H, H1), 3.98 (d, J = 7.0 Hz, 1H, H5), 3.40 (s, 2H, H3), 3.37 (s, 2H, H3),
2.94 (br dd, J = 8.1, 8.1 Hz, 1H, H6anti), 2.71 (dd, J = 7.1, 3.2 Hz, 1H, H4),
2.67 (dd, J = 7.0, 3.3 Hz, 1H, H4), 2.01 (s, 3H, COCH3), 1.98 (s, 3H,
COCH3), 1.62 (dd, J = 8.0, 7.0 Hz, 1H, H6syn), 1.55 (dd, J = 8.0, 7.0 Hz,
1H, H6syn); 13C NMR (100 MHz, CDCl3) δ 168.9 and 168.3, 80.9 and
80.5, 65.5 and 62.3, 49.4 and 47.6, 43.8 and 43.4, 37.3 and 36.3, 21.4 and
20.8); HRMS m/z found 164.0692, calcd for C17H11NO2Na (M þ Na)
164.0687. 1H NMR (400 MHz, D2O) δ 4.46 (dd, J = 7.3, 1.8 Hz, 1H, H1,),
4.29 (dd, J = 7.1, 1.9 Hz, 1H, H1), 4.08 (d, J = 7.1 Hz, 1H, H5), 4.05 (d, J =
7.1 Hz, 1H, H5), 3.61 (s, 2H, 2H3), 3.42 (s, 2H, 2H3), 2.88 (m, 1H, H4),
2.78 (m, 1H, H6anti), 2.09 (s, 3H, COCH3), 2.06 (s, 3H, COCH3), 1.74
(dd, J = 7.5, 7.1 Hz, 1H, H6syn), 1.68 (dd, J = 7.5, 7.1 Hz, 1H, H6syn); NOE
(CDCl3) the major acetyl signal at δ 2.01 on irradiation sees the major H1
at δ 4.04. The minor acetyl signal at δ 1.98 on irradiation sees the minor
H3 at δ 3.40. NOE (D2O): the major acetyl signal at δ 2.09 on irradiation
enhances the major H1 at δ 4.29. The minor acetyl signal at δ 2.06 on
irradiation enhances the minor H3 at δ 3.61. KT/C = 50.5/49.5 (CDCl3)
based on H6syn and 54/46 (D2O) based on H1.
N-(tert-Butoxycarbonyl)-5-anti-hydroxy-2-azabicyclo-
[2.1.1]hexane (13a). According to the general procedure, (Boc)2O
(954 mg, 4.37 mmol) and Pd(OH)2 (150 mg) were added to alcohol 34
(1.00 g, 4.28 mmol) in methanol (40 mL) and stirred at rt for 2 h under a
H2-filled balloon. Workup and chromatography (1:2 ethyl acetate/
hexanes) afforded 733 mg (86%) of alcohol 13a as an off-white solid:
Rf = 0.32 (2:3 ethyl acetate/hexanes); mp 113ꢀ114 ꢀC; 1H NMR (400
MHz, CDCl3) δ 4.07 (br d, J = 7.3 Hz, 1H, H1), 4.03 (br d, J = 6.8 Hz,
1H, H5), 3.66 (br, 1H, OH), 3.29 (s, 2H, H3), 2.86 (br, 1H, H6anti), 2.61
(br d, J = 6.8 Hz, 1H, H4), 1.57 (dd, J = 7.3, 7.3 Hz, 1H, H6syn), 1.43
(s, 9H, Boc); 13C NMR (100 MHz, CDCl3) δ155.7, 81.0, 79.6, 63.8 and
62.9 (br), 48.6 and 48.0 (br), 43.9, 36.8, 28.4; HRMS m/z found
222.1104, calcd for C10H17NO3Na (M þ Na) 222.1104.
N-(tert-Butoxycarbonyl)-5-anti-benzoyloxy-2-azabicyclo-
[2.1.1]hexane (35). Alcohol 34 (85 mg, 0.427 mmol) was dissolved in
dry CH2Cl2 (5 mL) under argon. The reaction mixture was cooled to
0 ꢀC and sequentially treated with triethylamine (300 μL, 2.133 mmol),
DMAP (57 mg, 0.469 mmol), and benzoyl chloride (125 μL, 1.067
mmol). The mixture was stirred for 30 min at 0 ꢀC, allowed to come to
room temperature, and then stirred for 3 h. The solution was washed
with water (3 ꢁ 2 mL), and the combined organic layers were dried and
evaporated to dryness. The residue was purified by chromatography on
silica gel (10% ethyl acetate in hexanes) to afford 119 mg (92%) of
benzoate 35 as a light orange oil: Rf = 0.54 (4:1 hexanes/ethyl acetate);
1H NMR (400 MHz, CDCl3) δ 8.09ꢀ8.03 (m, 2H), 7.62ꢀ7.56
(m, 1H), 7.50ꢀ7.43 (m, 2H), 4.81 (d, J = 7.3 Hz, 1H, H5), 4.45 (br,
N-Acetyl-5-anti-benzoyloxy-2-azabicyclo[2.1.1]hexane
(36): H NMR (400 MHz, D2O) δ 8.14ꢀ8.09 (m, 2H), 7.77ꢀ7.71
1
(m, 1H), 7.62ꢀ7.56 (m, 2H), 4.80 (m, 2H, H5 and H1 rotamer are under
D2O peak), 4.66 (dd, J = 7.0, 1.7 Hz, 1H, H1), 3.80 (d, J = 9.1 Hz, 1H, H3),
0
3.75 (d, J = 9.1 Hz, 1H, H3 ), 3.61 (d, J = 9.9 Hz, 1H, H3), 3.56 (d, J = 9.9
Hz, 1H, H3 ), 3.16 (m, 1H, H4), 2.96 (m, 2H, H6anti both conformers),
2.17 (s, 3H), 2.13(s, 3H), 1.81(dd, J =8.0, 8.0Hz, 1H, H6syn), 1.75 (dd, J =
0
3633
dx.doi.org/10.1021/jo200117p |J. Org. Chem. 2011, 76, 3626–3634

The Journal of Organic Chemistry
FEATURED ARTICLE
8.0, 8.0 Hz, 1H, H6syn); NOE (CDCl3) the major acetyl signal at δ 2.10 on
irradiation sees the major H1 at δ 4.41 and vice versa. The minor H1 signal
at δ 4.89 on irradiation sees no proton. NOE (D2O): the major acetyl
signal at δ 2.17 on irradiation enhances the major H1 at δ 4.66. The minor
acetyl signal at δ 2.13 on irradiation enhances the H3 signal δ 3.80 and the
H3 signal δ 3.75. KT/C = 61/39 (CDCl3) based on H1 and 56/44 (D2O)
based on H3.
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’ ASSOCIATED CONTENT
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S
Supporting Information. Coordinates of optimized geo-
b
metries, selected angles, and energy calculations for 9 and
10bꢀ13b; data from the X-ray diffraction analysis of syn-alcohol
12b, copies of H NMR, 13C NMR, and 19F NMR for new
1
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: grkrow@temple.edu.
’ ACKNOWLEDGMENT
Financial support was provided by the National Science Foun-
dation (CHE 0515635) and (DGE-0841377). M.D.S. was sup-
ported by an American Chemical Society Division of Medicinal
Chemistry graduate fellowship; M.S. was supported by a Der Min
Fan Fellowhip. We thank Alex Shaffer and Zilun Hu for assistance
and Hans Reich and David Dalton for helpful discussions.
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