Formation of optically pure cyclic amines by intramolecular conjugate displacement

Article abstract of DOI:10.1021/jo3001657

Intramolecular conjugate displacement (ICD) has been applied to the Morita-Baylis-Hillman adducts formed from (5S)-5-(l-menthyloxy)-2(5H)-furanone and aldehydes that carry a protected β- or γ-amino group. DIBAL-H reduction of the resulting ICD products releases optically pure six- or seven-membered cyclic amines having a stereogenic center α to nitrogen.

Full text of DOI:10.1021/jo3001657

Article
pubs.acs.org/joc
Formation of Optically Pure Cyclic Amines by Intramolecular
Conjugate Displacement
Ping Cheng and Derrick L. J. Clive*
Chemistry Department, University of Alberta, Edmonton, Alberta T6G 2G2, Canada
S
* Supporting Information
ABSTRACT: Intramolecular conjugate displacement (ICD) has
been applied to the Morita−Baylis−Hillman adducts formed from
(5S)-5-(l-menthyloxy)-2(5H)-furanone and aldehydes that carry a
protected β- or γ-amino group. DIBAL-H reduction of the resulting
ICD products releases optically pure six- or seven-membered cyclic
amines having a stereogenic center α to nitrogen.
INTRODUCTION
Intramolecular conjugate displacement (ICD), the transition-
metal-free process summarized by Scheme 1, is a useful method
■
Scheme 1. Intramolecular Conjugate Displacement
modified the ICD process in a way that leads to optically pure
cyclic amines having a stereogenic center α to nitrogen. Existing
methods for making cyclic amines with asymmetric centers α to
nitrogen are often based on one or more of the following
strategies:5 ring-closing metathesis of olefinic pendants attached
to an acyclic chiral amine;5a−d catalyzed asymmetric addition of
diethylzinc to acyclic imines, followed by cyclization;5e
Grignard addition to pyridinium salts having a chiral auxiliary
on nitrogen;5f−i asymmetric hydrogenation of cyclic imines;5j
asymmetric allylboration of cyclic imines;5k and Diels−Alder
cycloaddition of imines bearing a chiral auxiliary on nitrogen.5l
The principle of the new route (Scheme 3) is to attach to the
acceptor double bond a removable chiral auxiliary R*, and for
this purpose compounds of type 11 (n = 1, 2) were prepared by
linking a lactone 9, or a synthetic equivalent, with a variety of
N-protected β-amino- or γ-aminoaldehydes (10, n = 1, 2)
(Scheme 3). The resulting alcohols (11) are acetylated, and
then one of the nitrogen protecting groups is removed so that
the ICD (see arrows in structure 13) can take place to afford
the bicyclic lactone 14. We anticipated6 that the nitrogen would
attack from the face opposite to the substituent R*O if steric
factors were the determining influence; finally, reduction should
serve to dismantle the lactone subunit, release the chiral
auxiliary, and afford the optically pure functionalized amine 15.
for constructing bicyclic amines having nitrogen at a ring
fusion1 position; the procedure has been used as a key step
(Scheme 2) in the total synthesis of the marine alkaloid
halichlorine.2 The method is also applicable to the formation of
carbocycles, and an advanced example from this laboratory,3
again not requiring the use of a transition metal,4 is the
conversion of 7 into 8 (eq 1), a substance that resembles the
core structures of CP-225,917 and CP-263,114. We have now
Scheme 2. Intramolecular Conjugate Displacement Step in
the Synthesis of Halichlorine
RESULTS AND DISCUSSION
■
A suitable starting lactone appeared to be the known menthol
derivative 16,7 which is easily prepared in two steps from
furfural by photooxygenation in methanol, followed by reaction
Received: January 21, 2012
Published: March 6, 2012
© 2012 American Chemical Society
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double bond was best done by the Lemieux−Johnson method,
which gave a much higher yield (79%) than ozonolysis (32%),
to afford the required aldehyde 19. We later found that a two-
step procedure (OsO4, NMO, aqueous THF, followed by
NaIO4/silica gel12) allowed further improvement to 81%. The
aldehyde should be used within a couple of days.
Scheme 3. Asymmetric Intramolecular Conjugate
Displacement
with (−)-menthol. Since the enantiomer of 16 is also readily
available,7a both chiralities for 15 should also be accessible. As
described below, lactone 16 was used for coupling with a
number of aldehydes, either directly or after conversion to the
selenide 18, which was obtained by hydrogenation of 168 [H2
(50 psi), Pd/C, EtOAc, Et3N, 100%], followed by deprotona-
tion and selenation with PhSeCl (66%) (eq 2). The selenation
The next higher homologue (20) was prepared in a very
similar way13 (Scheme 5). Again, the final diol cleavage was
Scheme 5. Preparation of Aldehyde 20
best done using NaIO4/silica gel;12 by this method the yield in
the last two steps was 89%, while ozonolysis (O3, MeOH;
Me2S) gave 70%.
The preparation of 21 (Scheme 6) began with the known14
conversion of o-vinylbenzaldehyde (21a) to the benzylamine
21b and N-protection with Boc2O (21b → 21c15). N-
of 17 produced both C(2) epimers with the 2S isomer 18 being
the major component.9 The stereochemical assignment to 18
was made after deprotonation (LDA) and reprotonation
(aqueous NH4Cl) to give the crystalline 2R isomer, whose
structure was determined by X-ray analysis.
Scheme 6. Preparation of Aldehyde 21
Preparation of Amino Aldehydes. The aldehydes 19−
25, which were used for condensation with 16 and 18,9 were
made by the methods summarized in Schemes 4−10. In a
typical approach, the known N-benzyl amine 19a10 (Scheme 4)
was protected as its N-Boc derivative 19b,10 and when this was
treated with i-Pr3SiOSO2CF3 in the presence of 2,6-lutidine, it
was converted into the O-silyl carbamate 19c.11 Cleavage of the
Scheme 4. Preparation of Aldehyde 19
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Methylation (NaH, MeI), treatment with i-Pr3SiOSO2CF3, and
double bond cleavage (Lemieux−Johnson) then gave 21.
Compound 22, a methyl-substituted version of 21, was made
by the route summarized in Scheme 7. The iodo ester 22a,
Reduction of the nitrile group, using NaBH4/CF3CO2H,17 gave
the substituted benzylamine 23b (Scheme 8). This was
protected as its carbamate (Boc2O) and then subjected to a
Stille coupling to install the vinyl group (23b → 23c → 23d).
N-Benzylation,18 conversion to the triisopropylsilyl carbamate
23f, and double bond cleavage (OsO4, NaIO4) led to 23. We
had first carried out the Stille coupling after N-benzylation, but
the route shown in Scheme 8 is better, as some of the
intermediates are easier to purify.
Scheme 7. Preparation of Aldehyde 22
The naphthalene aldehyde 24 was made (Scheme 9) starting
from 1-bromonaphthalene-2-carbaldehyde (24a), which is
Scheme 9. Preparation of Aldehyde 24
which is readily available from 2-methylbenzoic acid,16 was
reduced (DIBAL-H) and subjected to Stille coupling with
tributyl(vinyl)tin to give alcohol 22c. Replacement of the
hydroxyl by bromine and displacement with BnNH2 produced
the N-benzyl amine 22e, which was protected (Boc2O) and
subjected to the same reactions as 21d.
Aldehyde 23, containing a trifluoromethyl substituent, was
prepared (Scheme 8) from the commercial bromonitrile 23a.
Scheme 8. Preparation of Aldehyde 23
readily available19 from commercial 1-bromo-2-methylnaph-
thalene. Following reported procedures, Wittig reaction
converted 24a into the bromo olefin 24b,20 and the aldehyde
24c was then obtained20 by halogen/metal exchange and
quenching with DMF. Simple reduction with NaBH4 gave
alcohol 24d, which was converted into bromide 24e. Reaction
with BnNH2 generated the secondary amine 24f, and the
remainder of the synthesis followed the pattern used for the
other examples (24f → 24g → 24h → 24). An attempt at
reductive amination to convert 24c directly into 24f (BnNH2,
MgSO4, CH2Cl2; NaBH4, MeOH) gave a complex mixture.
The substituted pyridine aldehyde 25 was made (Scheme 10)
starting from 2-bromopyridine, which was formylated by a
literature procedure (Scheme 10)21 and reductively aminated
with BnNH2, again following a reported method.22 With 25c in
hand, we applied the operations used earlier to elaborate the
compound into aldehyde 25 (Scheme 10).
Coupling of the Aldehydes with Chiral Auxiliaries.
Our first attempt to couple aldehyde 19 with the optically pure
lactone 16 involved addition of a mixture of the lactone and
aldehyde to a solution of PhSeLi in THF, as this version of the
Baylis−Hillman condensation had been reported23 to work well
(high yield and high diastereoselectivity) with 16 and a number
of other aldehydes, such as PhCHO, i-PrCHO, t-BuCHO, and
cinnamaldehyde. In the present case, however, the reaction did
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a
Scheme 10. Preparation of Aldehyde 25
Table 1. Condensation of Auxiliaries with Aldehydes
not work and we recovered both starting materials; therefore,
we tried condensation with lactone 18. Deprotonation of 18
with LDA or (Me3Si)2NK and addition of aldehyde 19 gave the
expected hydroxy selenide as an inconsequential mixture of
diastereoisomers, the yield with (Me3Si)2NK (75%) being
higher than that with LDA (ca. 60%) (Table 1, entry 1).
Oxidation with H2O2 generated the unsaturated alcohol 19d, in
accord with the normal regiochemical outcome for oxidation of
β-hydroxy selenides,24 and the alcohol 19d was then acetylated,
using AcCl (19d → 19e) (Table 1, entry 1). As expected, the
C(2) epimer of 18 behaved in the same way, as did mixtures of
the two epimers.9
When we came to examine aldehyde 20, we again tried the
procedure using PhSeLi,23 and in this case, the desired alcohol
20d was formed in good yield (81%); the same method worked
equally well for aldehydes 21−25. The reactions with aldehydes
20−25 were conducted at −42 °C because, under these
conditions, the required double bond was generated in situ
without the need for an additional step (addition of BnBr23) to
eliminate the PhSe group. We assume that for the products
derived from 20−25 (i.e., for compounds 20d, 21f, 22h, 23g,
24i, 25g) the stereochemistry at the hydroxyl-bearing carbon of
the isolated alcohols follows the uniform pattern observed for
this type of Morita−Baylis−Hillman process.23 We tried to
obtain crystals of four of the alcohols (19d, 20d, 24i, 25g), but
were successful only with 19d, and single crystal X-ray analysis
of this compound established the indicated stereochemistry,
which follows the same pattern observed previously,23 even
though the condensation method (via deprotonation of 18)
was different from that (via addition of PhSeNa to 16) used for
the other examples (entries 2−7).
a
R*O = l-menthyloxy.
spectrum by itself did not distinguish between the presence of
rotamers or isomers, we observed signal coalescence in the H
The condensation method leading to the results shown in
entries 2−7 is known23,25 to give essentially (>99% de) a single
1
1
isomer, but the H NMR spectra of our alcohols and their
NMR spectrum run at 60 °C, indicating we were dealing with
1
acetates are complex, and we had to decide if rotamers or
isomers were present. For some alcohols the 13C NMR
spectrum clearly corresponded to a single isomer (19d, 21f,
22h, 23g, 24i). In the case of acetate 20e, where the 13C NMR
rotamers. Likewise, the 13C and H NMR spectra of alcohol
1
25g showed several pairs of signals, but the H NMR signals
coalesced at (or below) 60 °C, establishing that the material
consisted of rotamers.
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a
Intramolecular Conjugate Displacement. When acetate
19e was treated with Bu4NF in THF at room temperature, the
silicon protecting group was removed and the bicyclic amine
19f was isolated as a single stereoisomer (1H and 13C NMR) in
81% yield, after workup with aqueous NH4Cl. The structure of
19f was established by a number of NMR measurements, and
we initially assumed that the stereochemistry would conform to
the expectation summarized in Scheme 3 (see 14, R*O and
adjacent H syn). However, a crystalline sample was eventually
obtained, and surprisingly, single crystal X-ray analysis showed
that the R*O group and nitrogen were syn. The coupling
constant 3J7,7a (see 19f) was 5.5 Hz. Examination of the reaction
mixture before flash chromatography revealed the presence of a
minor isomer (10:1). This compound (3J7,7a = 6 Hz) was
isolated and, presumably, differs from 19f only at C(7a), but we
were unable to obtain it in crystalline form for rigorous
stereochemical determination.
Table 2. Intramolecular Conjugate Displacements
In the case of compound 20e two products were always
formed, and the optimum procedure involved running the
reaction at room temperature for 1 h; under these conditions
the product ratio was 1:31 ratio in favor of 20f (3J8,8a = 2.5 Hz)
in a combined yield of 78%. The total product from several
runs (at different temperatures) was pooled and subjected to
preparative TLC so as to isolate the minor component, which
1
proved to be the C(8a) isomer [COSY, H NMR (3J8,8a = 5.1
Hz) and 13C NMR].
Acetate 21g, derived from an aromatic aldehyde, cyclized
efficiently (92%) at 0 °C, giving the ICD product (21h) as a
single stereoisomer (3J6,7 = 3.2 Hz). The choice of 0 °C was
arbitrarily made to illustrate the mildness of the conditions
required for cyclization.
Acetate 22i gave mainly 22j, but the outcome was more
complicated than for 21g. When the ICD was conducted at
1
−78 °C, the H NMR spectrum of the isolated sample of 22j
(3J6,7 = 3.0 Hz) showed a small signal at δ 7.65. On the
assumption that this represents the olefinic signal of a
stereoisomer of 22j, then the ratio of 22j and its stereoisomer
is 23:1 (combined yield 96%); when the reaction was done at 0
°C, this ratio was 9.6:1. When a small sample of the 23:1
mixture was subjected to preparative TLC (silica, 1:1 hexane/
CH2Cl2), it was possible to isolate 22j free of the minor
component). We assume that the minor component (which we
did not get pure by the preparative TLC) is the C(7) epimer of
22j.
Acetate 23h, in which the benzene ring carries a
trifluoromethyl group, reacted smoothly with Bu4NF in THF
at 0 °C to give the expected heterocycle 23i (3J6,7 = 3.5 Hz) in
91% yield. The reaction product is crystalline, and the structure
and absolute stereochemistry were confirmed by single crystal
X-ray diffraction.
The naphthyl acetate 24j also cyclized in very high yield
(99%) to give 24k (3J15,16 = 2.0 Hz) as a single stereoisomer. Its
structure was confirmed by single crystal X-ray diffraction.
Acetate 25h gave 25i (3J6,7 = 3.5 Hz) as a single isomer.
The stereochemistry for the products of entries 2−4 and 7 in
Table 2 was assigned by analogy to the firmly established
results for 23i and 24k and the fact that all products, with the
exception of 19f, have appropriate 3J values consistent with the
indicated stereochemistry.
a
b
R*O = l-menthyloxy. Ratio of 20f to C(8) epimer = 31:1; combined
c
yield = 78%. Ratio of 22j to C(7) epimer = 23:1; Combined yield =
96%.
respect, and once the stereochemical assignment to 19f had
been established (by X-ray analysis), we were prompted to
make a determined effort to obtain crystals of its precursor 19d.
These efforts were eventually successful, as indicated earlier,
and we had expected that the stereochemistry of the hydroxyl-
bearing carbon of 19d would be opposite to that in the other
examples, especially as 19d had been prepared by a different
route. Had that been the case, our results would suggest a
general preference for attack syn to the leaving group and the
stereochemistry of 19f would then imply that such a
With the exception of example 1 of Table 2, all of the ICD
products result from attack of nitrogen anti to the menthyloxy
substituent and syn to the acetate leaving group. The formation
of the six-membered ring shown in entry 1 is anomalous in this
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stereoelectronic effect was more powerful than steric factors.26
In the event, X-ray analysis showed that the stereochemistry of
19d conforms to the standard pattern, and we have not
established the reason for the stereochemical outcome of the
ICD process 19e → 19f.
Table 3. Removal of Chiral Auxiliary
In addition to the ICD substrates from aldehydes 19-25, we
also prepared (see Supporting Information for flowchart)
amine 26, but the yield in one step of the route (-NO2 →
-NH2, using Zn, NH4Cl27) was poor; and subsequent attempts
at an ICD reaction were unsuccessful, as only an O → N acetyl
transfer appeared to occur.
Reduction of the Lactones. Each of the products
produced by the ICD process was reduced with DIBAL-H in
THF, and, with the exception of the pyridyl example 25i, which
gave a product containing slight impurities, yields were in the
range of 75−90% (Table 3).
CONCLUSION
■
Our experiments show that intramolecular conjugate displace-
ment, using the chiral auxiliaries 16 or 18, leads to nitrogen
heterocycles having a stereogenic center α to nitrogen. Six- and
seven-membered rings can be formed, including those fused to
aromatic rings. Removal of the auxiliary from the ICD products
leads to optically pure amines; these carry functionality that is
ready for further manipulations.
EXPERIMENTAL SECTION
■
General Procedures. Solvents used for chromatography were
distilled before use. Commercial thin layer chromatography plates
(silica gel, Merck 60F-254) were used. Silica gel for flash
chromatography was Merck type 60 (230−400 mesh). Dry solvents
were prepared under an inert atmosphere and transferred by syringe or
cannula. The symbols s, d, t and q used for 13C NMR spectra indicate
zero, one, two, or three attached hydrogens, respectively, the
assignments being made by from APT spectra. Solutions were
evaporated under water pump vacuum, and the residue was then kept
under oil pump vacuum.
(3S,5R)-5-{[(1R,2S,5R)-5-Methyl-2-(propan-2-yl)cyclohexyl]-
oxy}-3-(phenylselanyl)oxolan-2-one (18). BuLi (2.5 M in hexane,
1.45 mL, 3.63 mmol) was added dropwise to a stirred and cooled
(−78 °C) solution of i-Pr2NH (0.52 mL, 3.72 mmol) in THF (30
mL). After 30 min at −78 °C, 178 (860.0 mg, 3.58 mmol) in THF (4
mL) was added dropwise, and stirring was continued for 70 min at
−78 °C. PhSeCl (329.2 mg, 1.72 mmol) in THF (1 mL) was then
added quickly to the reaction mixture by syringe. After 16 min,
saturated aqueous NH4Cl (20 mL) was added, and the mixture was
extracted with Et2O. The combined organic extracts were dried
(MgSO4) and evaporated. Flash chromatography of the residue over
silica gel (2.8 × 14 cm), using 1:20 Et2O/hexanes, gave 18 (451.0 mg,
In some runs, a small amount (ca. 9%) of the C(2) epimer was also
isolated: mp 105−108 °C; [α]20 −97.75 (c 1.04, CHCl3); FTIR
D
(CHCl3, cast) 3073, 2991, 2947, 2917, 2866, 1779, 1745, 1577, 1478,
1
1452, 1439 cm−1; H NMR (CDCl3, 500 MHz) δ 0.80−1.07 (m, 12
H), 1.24−1.29 (m, 1 H), 1.37−1.44 (m, 1 H), 1.66−1.73 (m, 2 H),
2.09−2.14 (m, 1 H), 2.26−2.35 (m, 2 H), 2.89 (ddd, J = 5.5, 9.5, 14.5
Hz 1 H), 3.58 (dt, J = 4.0, 10.5 Hz, 1 H), 3.84 (dd, J = 4.0, 9.5 Hz, 1
H), 5.74 (dd, J = 2.0, 6.0 Hz, 1 H), 7.32−7.38 (m, 3 H), 7.72−7.75
(m, 2 H); 13C NMR (CDCl3, 125 MHz) δ 15.5 (q), 21.1 (q), 22.3 (q),
22.8 (t), 25.1 (d), 31.4 (d), 34.3 (t), 35.2 (d), 37.2 (t), 39.6 (t), 47.7
(d), 99.0 (d), 128.5 (d), 129.1 (s), 129.3 (d), 134.8 (d), 176.0 (s);
exact mass (electrospray) m/z calcd for C20H28NaO3Se (M + Na)
419.1097, found 419.1096.
66%) as a light yellow oil: [α]20 −93.54 (c 1.04, CHCl3); FTIR
D
(CHCl3, cast) 3057, 2954, 2924, 2869, 1774, 1578, 1477, 1455, 1439
1
cm−1; H NMR (CDCl3, 400 MHz) δ 0.75−1.05 (m, 12 H), 1.14−
Tris(propan-2-yl)silyl N-Benzyl-N-(but-3-en-1-yl)carbamate
(19c). 2,6-Lutidine (0.12 mL, 1.03 mmol) and i-Pr3SiOSO2CF3
(0.24 mL, 0.89 mmol) were added successively to a stirred solution
of 19b10 (130.2 mg, 0.50 mmol) in ClCH2CH2Cl (10 mL). After 15
min, the mixture was lowered into a preheated oil bath set at 96 °C,
and stirring was continued for 18 h. The mixture was cooled,
evaporated and diluted with Et2O (10 mL). The solution was washed
with saturated aqueous NH4Cl and brine, dried (MgSO4), and
evaporated. Flash chromatography of the residue over silica gel (2.8 ×
1.23 (m, 1 H), 1.26−1.40 (m, 1 H), 1.59−1.67 (m, 2 H), 1.95−2.07
(m, 2 H), 2.34−2.40 (m, 1 H), 2.46−2.52 (m, 1 H), 3.43−3.50 (m, 1
H), 4.09 (dd, J = 8.0, 8.4 Hz, 1 H), 5.45 (dd, J = 2.8, 5.6 Hz, 1 H),
7.30−7.40 (m, 3 H), 7.60−7.68 (m, 2 H); 13C NMR (CDCl3, 125
MHz) δ 15.6 (q), 20.9 (q), 22.2 (q), 23.0 (t), 25.4 (d), 31.3 (d), 34.2
(t), 35.9 (d), 37.5 (t), 39.8 (t), 47.7 (d), 77.1 (d), 99.2 (d), 126.4 (s),
129.0 (d), 129.4 (d), 136.0 (d), 175.1 (s); exact mass (electrospray)
m/z calcd for C20H28NaO3Se (M + Na) 419.1096, found 419.1093.
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18 cm), using 1:20 t-BuOMe/hexanes, gave 19c (177.1 mg, 98%) as a
of the residue over silica gel (1.2 × 14 cm), using 3:20 EtOAc/
hexanes, gave 19d (60.0 mg, 90%) as a colorless oil that became a solid
after being covered with pentane and slow evaporation of the solvent:
mp 103−105 °C; FTIR (CHCl3, cast) 3416, 3089, 3065, 3031, 2950,
colorless oil: FTIR (CHCl3, cast) 3066, 3031, 2945, 2893, 2868, 1681,
1
1642, 1496 cm−1; H NMR (CDCl3, 500 MHz) δ 1.06−1.14 (m, 18
H), 1.24−1.42 (m, 3 H), 2.25−2.33 (m, 2 H), 3.26 (t, J = 7.5 Hz, 1
H), 3.33 (t, J = 7.5 Hz, 1 H), 4.52 (s, 2 H), 4.99−5.07 (m, 2 H), 5.68−
5.81 (m, 1 H), 7.22−7.34 (m, 5 H); 13C NMR (CDCl3, 125 MHz) δ
12.13 (d), 12.15 (d), 17.87 (q), 17.92 (q), 19.95 (q), 32.3 (t), 32.9 (t),
46.4 (t), 46.6 (t), 50.4 (t), 51.3 (t), 116.6 (s), 116.8 (s), 127.0 (d),
127.18 (d), 127.24 (d), 127.7 (d), 128.5 (d), 135.1 (d), 135.4 (d),
138.17 (s), 138.19 (s), 155.0 (s), 155.4 (s); exact mass (electrospray)
m/z calcd for C21H35NNaO2Si (M + Na) 384.2329, found 384.2332.
Tris(propan-2-yl)silyl N-Benzyl-N-(3-oxopropyl)carbamate
(19). N-Methyl-morpholine-N-oxide (1.39 g, 11.87 mmol), followed
by OsO4 (tiny crystal, catalytic), was added to a stirred solution of 19c
(1.07 g, 2.97 mmol) in THF (15 mL) and water (15 mL). The flask
was stoppered and covered with Al foil, and the mixture was stirred for
3 h. The mixture was diluted with EtOAc and washed with water and
brine. The organic extract was dried (MgSO4) and evaporated. The
residue was dissolved in CH2Cl2 (30 mL), and NaIO4/SiO212 (18%w/
w, 12.71 g, 10.69 mmol) was then added with stirring. After 30 min, no
starting material was left (TLC control, silica gel, 3:20 EtOAc/
hexanes). The mixture was filtered through Celite and evaporated.
Flash chromatography of the residue over silica gel (3.8 × 18 cm),
using 3:20 EtOAc/hexanes, gave 19 (0.85 g, 79%) as a light yellow oil:
FTIR (CHCl3, cast) 3065, 2946, 2893, 2868, 2726, 1725, 1679, 1606,
1
2927, 2868, 1769, 1677, 1652, 1587, 1496 cm−1; H NMR (CDCl3,
400 MHz) δ 0.79−1.13 (m, 30 H), 1.20−1.53 (m, 6 H), 1.64−1.68
(m, 2 H), 2.07−2.14 (m, 2 H), 2.19−2.23 (m, 1 H), 3.01−3.05 (m, 1
H), 3.63 (dt, J = 4.0, 10.4 Hz, 1 H), 3.86−3.93 (m, 1 H), 4.23 and 4.27
(two s, 1 H), 4.42−4.60 (m, 1 H), 4.80 and 4.84 (two s, 1 H), 4.97 and
4.98 (two s, 1 H), 5.99 (s, 1 H), 7.07 (s, 1 H), 7.23−7.36 (m, 5 H);
13C NMR (CDCl3, 100 MHz) δ 12.0 (d), 15.8 (q), 17.8 (q), 20.8 (q),
22.2 (q), 23.2 (t), 25.3 (d), 31.5 (d), 33.8 (t), 34.2 (t), 40.5 (t), 42.2
(t), 47.7 (d), 50.7 (t), 63.5 (d), 79.1 (d), 99.3 (d), 127.1 (d), 127.5
(d), 128.7 (d), 137.1 (s), 140.2 (s), 143.5 (d), 157.0 (s), 170.2 (s);
exact mass (electrospray) m/z calcd for C34H56NO6Si (M + H)
602.3871, found 602.3874. A sample was crystallized from petroleum
ether (35−60 °C) for X-ray analysis.
(1S)-3-[Benzyl({[tris(propan-2-yl)silyl]oxy}carbonyl)amino]-
1-[(5R)-5-{[(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl]-
oxy}-2-oxo-2,5-dihydrofuran-3-yl]propyl Acetate (19e). DMAP
(4.7 mg, 0.039 mmol) was added to a stirred solution of 19d (72.6 mg,
0.12 mmol) in CH2Cl2 (2 mL). The mixture was cooled to −78 °C,
and AcCl (0.026 mL, 0.37 mmol) and pyridine (0.07 mL, 0.87 mmol)
were added sequentially. The dry ice bath was replaced by an ice bath
that was left in place but not recharged, and stirring was continued for
7.5 h. The mixture was quenched with hydrochloric acid (1 M, 2 mL)
and water (4 mL), and the aqueous phase was extracted with CH2Cl2.
The combined organic extracts were washed with brine, dried
(MgSO4), and evaporated. Flash chromatography of the residue over
silica gel (1.2 × 14 cm), using 3:20 EtOAc/hexanes, gave 19e (66.9
mg, 86%) as a colorless oil: FTIR (CHCl3, cast) 3089, 3066, 3031,
2949, 2868, 1771, 1679, 1606, 1587, 1559, 1496 cm−1; 1H NMR
(CDCl3, 400 MHz) δ 0.79−1.12 (m, 29 H), 1.22−1.43 (m, 6 H),
1.64−1.69 (m, 2 H), 1.90−2.28 (m, 7 H), 3.20−3.46 (m, 2 H), 3.59−
3.64 (m, 1 H), 4.41−4.57 (m, 2 H), 5.50−5.52 (m, 1 H), 5.96 (s, 1 H),
6.79 and 6.86 (two s, 1 H), 7.20−7.33 (m, 5 H); 13C NMR (CDCl3,
100 MHz) δ 12.1 (d), 15.8 (q), 17.8 (q), 17.9 (q), 20.7 (q), 20.75 (q),
20.83 (q), 22.2 (q), 23.1 (t), 25.30 (d), 25.34 (d), 30.4 (t), 31.3 (t),
31.5 (d), 34.2 (t), 40.5 (t), 42.5 (t), 43.3(t), 47.7 (d), 50.4 (t), 50.8
(t), 66.4 (d), 66.9 (d), 79.3 (d), 79.5 (d), 98.88 (d), 98.91 (d), 127.1
(d), 127.3 (d), 127.4 (d), 127.9 (d), 128.6 (d), 136.6 (s), 137.7 (s),
137.8 (s), 143.83 (d), 143.85 (d), 144.37 (d), 144.39 (d), 154.9 (s),
155.2 (s), 168.5 (s), 168.8 (s), 169.5 (s), 169.8 (s); exact mass
(electrospray) m/z calcd for C36H58NO7Si (M + H) 644.3977, found
644.3977.
1
1496 cm−1; H NMR (CDCl3, 500 MHz) δ 1.06−1.11 (m, 18 H),
1.26−1.40 (m, 3 H), 2.65 (dt, J = 1.0, 7.0 Hz) and 2.69 (dt, J = 1.5, 7.0
Hz, both signals together 2 H), 3.51−3.57 (m, 2 H), 4.52 and 4.54
(two s, 2 H), 7.23−7.35 (m, 5 H), 9.72−9.75 (m, 1 H); 13C NMR
(CDCl3, 125 MHz) δ 12.1 (d), 17.8 (q), 17.9 (q), 40.7 (t), 41.1 (t),
42.8 (t), 43.4 (t), 50.9 (t), 51.9 (t), 127.1 (d), 127.4 (d), 127.5 (d),
127.9 (d), 128.7 (d), 137.8 (s), 137.9 (s), 155.0 (s), 155.2 (s), 200.2
(d), 200.8 (d); exact mass (electrospray) m/z calcd for C20H34NO3Si
(M + H) 364.2303, found 364.2307.
Tris(propan-2-yl)silyl N-Benzyl-N-{(3S)-3-hydroxy-3-[5-(5R)-
{[(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}-2-oxo-3-
(phenylselanyl)oxolan-3-yl]propyl}carbamate (pre-19d). Sele-
nide 18 (91.7 mg, 0.23 mmol) in THF (0.5 mL) was added dropwise
to a stirred and cooled (−78 °C) solution of (Me3Si)2NK (0.5 M in
PhMe, 0.48 mL, 0.24 mmol) in THF (4 mL). Stirring at −78 °C was
continued for 70 min, and then 19 (88.9 mg, 0.25 mmol) in THF (0.5
mL) was added dropwise. Stirring at −78 °C was continued for 70
min. The mixture was quenched with saturated aqueous NH4Cl (5
mL) and extracted with Et2O. The combined organic extracts were
dried (MgSO4) and evaporated. Flash chromatography of the residue
over silica gel (1.8 × 14 cm), using 3:25 EtOAc/hexanes, gave pre-19d
(136.0 mg, 77%) as an oil: FTIR (CHCl3, cast) 3386, 3061, 3031,
2950, 2927, 2868, 1772, 1677, 1650, 1607, 1579, 1496 cm−1; 1H NMR
(CDCl3, 300 MHz) δ 0.72−1.14 (m, 30 H), 1.19−1.44 (m, 6 H),
1.55−1.69 (m, 2 H), 1.89−1.98 (m, 1 H), 2.04−2.17 (m, 1 H), 2.27−
2.55 (m, 2 H), 2.82−3.03 (m, 1 H), 3.43−3.61 (m, 1 H), 3.66−3.87
(m, 3 H), 4.36−4.62 (m, 2 H), 5.64−5.73 (m, 1 H), 7.18−7.41 (m, 8
H), 7.55−7.77 (m, 2 H); 13C NMR (CDCl3, 100 MHz) δ 12.0 (d),
12.1 (d), 12.2 (d), 15.5 (q), 17.80 (q), 17.82 (q), 18.0 (q), 21.1 (q),
22.2 (q), 22.3 (q), 22.8 (t), 24.9 (d), 29.6 (t), 31.4 (d), 34.3 (t), 34.4
(t), 35.5 (t), 39.6 (t), 42.3 (t), 47.7 (d), 47.8 (d), 50.3 (t), 50.4 (t),
68.0 (d), 77.1 (d), 97.7 (d), 126.5 (s), 127.0 (d), 127.5 (d), 128.6 (d),
128.7 (d), 128.98 (d), 129.03 (d), 129.20 (d), 129.24 (d), 134.8 (d),
137.27 (d), 137.30 (s), 137.9 (d), 156.7 (s), 176.7 (s); exact mass
(electrospray) m/z calcd for C40H62NO6SeSi (M + H) 760.3506,
found 760.3509.
(7R,7aS)-1-Benzyl-7-{[(1R,2S,5R)-5-methyl-2-(propan-2-yl)-
cyclohexyl]oxy}-1H,2H,3H,5H,7H,7aH-furo[3,4-b]pyridin-5-one
(19f). Bu4NF (1.0 M in THF, 0.09 mL, 0.09 mmol) was added to a
stirred solution of 19e (39.0 mg, 0.059 mmol) in THF (4 mL). After
21 min, the mixture was quenched with saturated aqueous NH4Cl (2
mL) and diluted with EtOAc (4 mL). The organic phase was washed
with brine, dried (MgSO4), and evaporated. Flash chromatography of
the residue over silica gel (1.0 × 14 cm), using 3:20 EtOAc/hexanes,
gave 19f (28.7 mg, 81%) as white crystals: mp 123−124 °C; [α]20
D
−154.10 (c 1.07, CHCl3); FTIR (CHCl3, cast) 3062, 3029, 2954,
2922, 2869, 2804, 2759, 1774, 1694, 1636, 1603, 1495, 1454 cm−1; 1H
NMR (CDCl3, 500 MHz) δ 0.81−0.90 (m, 10 H), 0.91−1.06 (m, 2
H), 1.37−1.44 (m, 2 H), 1.62−1.67 (m, 2 H), 2.00−2.07 (m, 2 H),
2.20−2.25 (m, 2 H), 2.44−2.52 (m, 1 H), 2.99 (dd, J = 6.5, 11.0 Hz, 1
H), 3.33 (d, J = 13.0 Hz, 1 H), 3.39−3.42 (m, 1 H), 3.61 (dt, J = 4.0,
11.0 Hz, 1 H), 3.99 (d, J = 13.0 Hz, 1 H), 5.78 (d, J = 5.5 Hz, 1 H),
6.90 (d, J = 3.0 Hz, 1 H), 7.27−7.36 (m, 5 H); 13C NMR (CDCl3, 100
MHz) δ 15.5 (q), 20.8 (q), 22.2 (q), 23.1 (t), 25.1 (d), 26.4 (t), 31.5
(d), 34.3 (t), 39.8 (t), 47.4 (d), 47.7 (t), 59.1 (t), 62.2 (d), 77.1 (d),
99.0 (d), 127.2 (s), 127.6 (d), 128.4 (d), 129.7 (d), 135.8 (d), 136.5
(s), 167.8 (s); exact mass (electrospray) m/z calcd for C24H34NO3 (M
+ H) 384.2533, found 384.2534.
Tris(propan-2-yl)silyl N-Benzyl-N-[(3S)-3-hydroxy-3-[(5R)-5-
{[(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}-2-oxo-
2,5-dihydrofuran-3-yl)propyl]carbamate (19d). H2O2 (30%, 0.08
mL, 0.71 mmol) and AcOH (2 drops) were added to a stirred and
cooled (0 °C) solution of pre-19d (82.4 mg, 0.11 mmol) in THF (2
mL). After 30 min, the ice bath was removed, and stirring was
continued for 15 min. The mixture was neutralized with saturated
aqueous NaHCO3 and extracted with CH2Cl2. The combined organic
extracts were dried (MgSO4) and evaporated. Flash chromatography
In some experiments a small amount of the C(7a) epimer was
isolated (10:1 ratio of major to minor products): [α]20 −116.93 (c
D
1.24, CHCl3); FTIR (CHCl3, cast) 2954, 2922, 2869, 2810, 1773,
3354
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Article
1692, 1495, 1454 cm−1; 1H NMR (CDCl3, 500 MHz) δ 0.81−1.10 (m,
12 H), 1.29−1.35 (m, 1 H), 1.36−1.44 (m, 1 H), 1.64−1.71 (m, 2 H),
2.12−2.19 (m, 2 H), 2.23−2.32 (m, 2 H), 2.35−2.42 (m, 1 H), 2.93
(dd, J = 6.5, 12.0 Hz, 1 H), 3.32 (d, J = 13.5 Hz, 1 H), 3.38−3.42 (m, 1
H), 3.69 (dt, J = 4.0, 11.0 Hz, 1 H), 4.24 (d, J = 14.0 Hz, 1 H), 5.59 (d,
J = 6.0 Hz, 1 H), 6.86 (q, J = 3.5 Hz, 1 H), 7.30−7.40 (m, 5 H); 13C
NMR (CDCl3, 125 MHz) δ 16.0 (q), 20.9 (q), 22.2 (q), 23.2 (t), 25.5
(d), 26.5 (t), 31.4 (d), 34.3 (t), 39.7 (t), 47.8 (t), 47.9 (d), 59.2 (t),
65.4 (d), 78.5 (d), 104.0 (d), 127.3 (d), 128.4 (d), 129.2 (d), 129.4
(s), 135.1 (d), 137.5 (s), 166.1 (s); exact mass (electrospray) m/z
calcd for C24H34NO3 (M + H) 384.2533, found 384.2528.
1.2, 7.2 Hz, both signals together 2 H), 3.24 (t, J = 7.6 Hz) and 3.28 (t,
J = 7.6, both signals together 2 H), 4.51 (s, 2 H), 7.22−7.34 (m, 5 H),
9.71−9.74 (m, 1 H); 13C NMR (CDCl3, 100 MHz) δ 12.1 (d), 17.85
(q), 17.91 (q), 20.1 (t), 20.7 (t), 40.9 (t), 41.1 (t), 46.0 (t), 46.1 (t),
50.2 (t), 51.0 (t), 127.0 (d), 127.3 (d), 127.4 (d), 127.8 (d), 128.6 (d),
137.9 (s), 138.0 (s), 155.2 (s), 155.4 (s), 201.0 (d), 201.6 (d); exact
mass (electrospray) m/z calcd for C21H35NNaO3Si (M + Na)
400.2278, found 400.2281.
Tris(propan-2-yl)silyl N-Benzyl-N-{(4S)-4-hydroxy-4-[(5R)-5-
{[(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}-2-oxo-
2,5-dihydrofuran-3-yl]butyl]carbamate (20d). BuLi (2.5 M in
hexane, 0.115 mL, 0.29 mmol) was added dropwise to a stirred and
cooled (−20 °C) solution of PhSeSePh (88.9 mg, 0.28 mmol) in THF
(1 mL). After 10 min, the mixture was cooled to −42 °C (dry ice/
MeCN), and a mixture of 16 (62.0 mg, 0.26 mmol) and 20 (146.7 mg,
0.39 mmol) in THF (1.5 mL) was added dropwise. Stirring at −42 °C
was continued for 9 h, and the mixture was quenched with saturated
aqueous NH4Cl (3 mL) and extracted with Et2O. The combined
organic extracts were washed with brine, dried (MgSO4), and
evaporated. Flash chromatography of the residue over silica gel (1.6
× 15 cm), using 1:5 EtOAc/hexanes, gave 20d (130.6 mg, 81%) as a
colorless oil: FTIR (CHCl3, cast) 3440, 3089, 3065, 2948, 2868, 1767,
1673, 1559, 1496 cm−1; 1H NMR (CDCl3, 400 MHz) δ 0.79−1.12 (m,
29 H), 1.21−1.85 (m, 11 H), 2.07−2.14 (m, 2 H), 3.23−3.29 (m, 2
H), 3.42−3.49 (m, 1 H), 3.59−3.65 (m, 1 H), 3.96 (br s, 1 H), 4.41−
4.57 (m, 3 H), 5.97 (s, 1 H), 6.83 and 6.93 (two s, 1 H), 7.21−7.34
(m, 5 H); 13C NMR (CDCl3, 100 MHz) δ 12.1 (d), 15.7 (q), 15.8 (q),
17.7 (q), 17.8 (q), 17.9 (q), 20.9 (q), 22.2 (q), 23.1 (t), 23.2 (t), 23.7
(t), 24.1 (t), 25.3 (d), 31.4 (t), 31.5 (d), 32.5 (t), 34.2 (t), 40.4 (t),
46.1 (t), 46.6 (t), 47.7 (d), 50.1 (t), 50.9 (t), 66.4 (d), 67.0 (d), 79.1
(d), 79.3 (d), 99.2 (d), 127.0 (d), 127.26 (d), 127.31 (d), 127.8 (d),
128.5 (d), 128.6 (d), 137.8 (s), 138.1 (s), 139.8 (s), 140.5 (s), 142.9
(d), 143.2 (d), 155.5 (s), 155.8 (s), 170.39 (s), 170.42 (s); exact mass
(electrospray) m/z calcd for C35H57NNaO6Si (M + Na) 638.3847,
found 638.3847.
[(2R)-1-Benzyl-2-(hydroxymethyl)-1,2,5,6-tetrahydropyri-
din-3-yl]methanol (19g). DIBAL-H (1.0 M in PhMe, 1.60 mL, 1.60
mmol) was added dropwise to a stirred and cooled (−78 °C) solution
of 19f (123.2 mg, 0.32 mmol) in THF (3 mL). Stirring at −78 °C was
continued for 1 h, the cold bath was left in place but not recharged,
and stirring was continued for 10 h. MeOH (0.5 mL) and a saturated
aqueous solution of Rochelle’s salt (ca. 5 mL) were then added
sequentially. Stirring was continued for 2 h, and the mixture was
extracted with EtOAc. The combined organic extracts were washed
with brine, dried (MgSO4), and evaporated. Flash chromatography of
the residue over silica gel (1.2 × 14 cm), using 1:20 MeOH/EtOAc,
gave 19g (60.2 mg, 80%) as a light yellow oil: [α]20 −26.86 (c 1.13,
D
CHCl3); FTIR (CHCl3, cast) 3360, 3085, 3062, 3028, 2923, 2873,
1
1592, 1495 cm−1; H NMR (CDCl3, 500 MHz) δ 1.88 (dd, J = 3.0,
18.0 Hz, 1 H), 2.26−2.32 (m, 1 H), 2.63 (ddd, J = 2.5, 5.0, 13.0 Hz, 1
H), 2.85−2.97 (m, 3 H), 3.21−3.23 (m, 1 H), 3.51 (dd, J = 8.5, 11.0
Hz, 1 H), 3.67−3.77 (m, 3 H), 4.00 (AB q, J = 12.5 Hz, ΔνAB = 32.3
Hz, 2 H), 5.95 (s, 1 H), 7.25−7.33 (m, 5 H); 13C NMR (CDCl3, 125
MHz) δ 20.7 (t), 42.0 (t), 57.5 (t), 60.3 (d), 61.3 (t), 65.3 (t), 124.6
(d), 127.3 (d), 128.5 (d), 129.0 (d), 135.7 (s), 138.7 (s); exact mass
(electrospray) m/z calcd for C14H20NO2 (M + H) 234.1489, found
234.1490.
Tris(propan-2-yl)silyl N-Benzyl-N-(pent-4-en-1-yl)carbamate
(20c). 2,6-Lutidine (0.26 mL, 2.24 mmol) and i-Pr3SiOSO2CF3 (0.60
mL, 2.23 mmol) were added successively to a stirred solution of 20b13
(0.60 g, 2.18 mmol) in ClCH2CH2Cl (30 mL). After 15 min, the
mixture was lowered into a preheated oil bath set at 96 °C, and stirring
was continued for 12 h. The mixture was cooled, evaporated, and
diluted with Et2O (40 mL). The solution was washed with saturated
aqueous NH4Cl and brine, dried (MgSO4), and evaporated. Flash
chromatography of the residue over silica gel (2.8 × 18 cm), using
1:20 t-BuOMe/hexanes, gave 20c (0.756 g, 92%) as a colorless oil:
FTIR (CHCl3, cast) 3066, 3031, 2945, 2867, 1680, 1642, 1496 cm−1;
1H NMR (CDCl3, 300 MHz) δ 1.06−1.14 (m, 18 H), 1.22−1.44 (m, 3
(1S)-4-[Benzyl({[tris(propan-2-yl)silyl]oxy}carbonyl)amino]-
1-[(5R)-5-{[(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl]-
oxy}-2-oxo-2,5-dihydrofuran-3-yl]butyl Acetate (20e). DMAP
(3.4 mg, 0.028 mmol) was added to a stirred solution of 20d (87.4 mg,
0.14 mmol) in CH2Cl2 (2.5 mL). The mixture was cooled to −78 °C,
and AcCl (0.03 mL, 0.42 mmol) and pyridine (0.07 mL, 0.85 mmol)
were added sequentially. The mixture was cooled in an ice bath that
was left in place but not recharged, and stirring was continued for 7.5
h. The mixture was quenched with hydrochloric acid (1 M, 1 mL) and
water (5 mL), and the aqueous phase was extracted with CH2Cl2. The
combined organic extracts were washed with brine, dried (MgSO4),
and evaporated. Flash chromatography of the residue over silica gel
(1.2 × 14 cm), using 1:1 EtOAc/hexanes, gave 20e (84.4 mg, 90%) as
a colorless oil: FTIR (CHCl3, cast) 3064, 3030, 2948, 2868, 1772,
H), 1.58−1.70 (m, 2 H), 2.02 (quintet, J = 7.5 Hz, 2 H), 3.17−3.29
(m, 2 H), 4.51 (s, 2 H), 4.93−5.03 (m, 2 H), 5.69−5.86 (m, 1 H),
7.22−7.35 (m, 5 H); 13C NMR (CDCl3, 125 MHz) δ 12.15 (d), 12.17
(d), 17.9 (q), 18.0 (q), 26.9 (t), 27.5 (t), 31.0 (t), 31.1 (t), 46.6 (t),
46.7 (t), 50.4 (t), 51.1 (t), 114.9 (s), 115.0 (s), 127.0 (d), 127.16 (d),
127.21 (d), 127.7 (d), 128.49 (d), 128.50 (d), 137.7 (d), 138.0 (d),
138.2 (s), 138.3 (s), 155.0 (s), 155.5 (s); exact mass (electrospray) m/
z calcd for C22H37NNaO2Si (M + Na) 398.2486, found 398.2488.
Tris(propan-2-yl)silyl N-Benzyl-N-(4-oxobutyl)carbamate
(20). N-Methylmorpholine-N-oxide (590 mg, 5.04 mmol), followed
by OsO4 (1.0 M in PhMe, 0.1 mL, 0.1 mmol), was added to a stirred
solution of 20c (612.3 mg, 1.63 mmol) in THF (6 mL) and water (6
mL). The mixture was stirred for 45 min, during which time the
solution turned dark brown. The mixture was diluted with EtOAc,
washed with water and brine, dried (MgSO4), and evaporated. The
1
1749, 1678, 1606, 1559, 1496 cm−1; H NMR (CDCl3, 500 MHz) δ
0.78−1.12 (m, 30 H), 1.23−1.44 (m, 5 H), 1.53−1.88 (m, 6 H), 2.06
and 2.07 (two s, 3 H), 2.09−2.12 (m, 2 H), 3.21 (t, J = 7.5 Hz) and
3.27 (t, J = 7.5 Hz, both signals together 2 H), 3.60−3.66 (m, 1 H),
4.44−4.52 (m, 2 H), 5.51−5.56 (m, 1 H), 5.96 (s, 1 H), 6.81 and 6.84
(two s, 1 H), 7.21−7.34 (m, 5 H); 13C NMR (CDCl3, 125 MHz) δ
12.1 (d), 15.8 (q), 15.9 (q), 17.87 (q), 17.94 (q), 20.7 (q), 20.82 (q),
20.84 (q), 20.9 (q), 22.2 (q), 23.16 (t), 23.18 (t), 23.4 (t), 24.0 (t),
25.4 (d), 30.2 (t), 30.4 (t), 31.5 (d), 34.2 (t), 40.5 (t), 46.1 (t), 46.5
(t), 47.7 (d), 50.2 (t), 51.0 (t), 68.19 (d), 68.24 (d), 79.3 (d), 79.5
(d), 98.85 (d), 98.90 (d), 127.0 (d), 127.2 (d), 127.3 (d), 127.8 (d),
128.53 (d), 128.54 (d), 137.0 (s), 138.0 (s), 138.1 (s), 143.9 (d),
144.1 (d), 155.0 (s), 155.4 (s), 168.76 (s), 168.82 (s), 169.6 (s), 169.8
(s); exact mass (electrospray) m/z calcd for C37H59NNaO7Si (M +
Na) 680.3953, found 680.3955.
(8R,8aR)-1-Benzyl-8-{[(1R,2S,5R)-5-methyl-2-(propan-2-yl)-
cyclohexyl]oxy}-1H,2H,3H,4H,6H,8H,8aH-furo[3,4-b]azepin-6-
one (20f). Bu3NF (1.0 M in THF, 0.059 mL, 0.059 mmol) was added
to a stirred solution of 20e (39.0 mg, 0.059 mmol) in THF (0.8 mL).
After 2 min, the reaction mixture was quenched with saturated
aqueous NH4Cl (1 mL) and diluted with EtOAc (4 mL). The organic
12
residue was dissolved in CH2Cl2 (18 mL), and NaIO4/SiO2 (20.4%
w/w, 6.616 g, 5.587 mmol) was then added with stirring. Stirring was
continued for 20 min by which time all of the diol had reacted (TLC
control, silica, 1:10 EtOAc/hexane). The mixture was filtered through
Celite, using CH2Cl2 as a rinse, and the filtrate was evaporated. Flash
chromatography of the residue over silica gel (2.8 × 15 cm), using
1:10 EtOAc/hexanes, gave 20 (550 mg, 89%) as an oil: FTIR (CHCl3,
cast) 3065, 2945, 2893, 2868, 2720, 1727, 1678, 1606, 1496 cm−1; 1H
NMR (CDCl3, 400 MHz) δ 1.06−1.12 (m, 18 H), 1.26−1.42 (m, 3
H), 1.80−1.90 (m, 2 H), 2.39 (dt, J = 1.2, 7.2 Hz) and 2.44 (dt, J =
3355
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phase was washed with brine, dried (MgSO4), and evaporated. Flash
chromatography of the residue over silica gel (1.0 × 14 cm), using
3:25 EtOAc/hexanes, gave 20f (18.3 mg, 78%) as a light yellow oil:
FTIR (CHCl3, cast) 3086, 3061, 3028, 2952, 2926, 2869, 1764, 1678,
1603, 1495, 1454 cm−1; 1H NMR (CDCl3, 500 MHz) isomer mixture
δ 0.78−1.05 (m, 12 H), 1.21−1.26 (m, 1 H), 1.31−1.39 (m, 1 H),
1.49−1.53 (m, 1 H), 1.61−1.67 (m, 2 H), 1.80−1.87 (m, 1 H), 2.06−
2.14 (m, 2 H), 2.36−2.48 (m, 1 H), 2.52−2.58 (m, 1 H), 2.81−2.86
(m, 1 H), 3.08−3.12 (m, 1 H), 3.41−3.47 (m, 1 H), 3.55−3.67 (m, 1
H), 3.73−3.93 (m, 1 H), 4.09 (d, J = 2.5 Hz, 1 H), 5.54−5.69 (m, 1
H), 7.13−7.39 (m, 6 H); 13C NMR (CDCl3, 125 MHz) δ 12.3 (q),
15.7 (q), 15.8 (q), 17.7 (q), 20.8 (t), 20.9 (q), 22.3 (q), 23.1 (t), 23.4
(t), 24.7 (t), 25.4 (d), 25.5 (d), 26.8 (t), 28.5 (t), 29.1 (t), 31.4 (d),
34.3 (t), 36.7 (t), 39.1 (t), 39.6 (t), 47.7 (d), 47.8 (d), 52.6 (t), 53.9
(t), 54.5 (t), 57.8 (t), 66.9 (d), 68.4 (d), 76.3 (d), 77.2 (d), 97.3 (d),
101.6 (d), 127.19 (d), 127.23 (d), 128.2 (d), 128.5 (d), 128.7 (s),
129.1 (d), 130.7 (s), 138.8 (s), 142.1 (d), 144.1 (d), 168.6 (s); exact
mass (electrospray) m/z calcd for C25H36NO3 (M + H) 398.2690,
found 398.2687.
solution of 21c15 (153.3 mg, 0.66 mmol) in THF (6 mL). After 15
min, the mixture was cooled to 0 °C, and MeI (0.16 mL, 2.57 mmol)
was added. The ice bath was left in place but not recharged, and
stirring was continued for 18 h. Water (4 mL) was added to destroy
the excess of NaH, and the mixture was extracted with Et2O. The
combined organic extracts were washed with water and brine, dried
(MgSO4), and evaporated. Flash chromatography of the residue over
silica gel (1.8 × 14 cm), using 1:20 EtOAc/hexanes, gave 21d (140.6
mg, 87%) as a colorless oil: FTIR (CHCl3, cast) 3064, 2976, 2931,
1
1696, 1628, 1603, 1572, 1481, 1453 cm−1; H NMR (CDCl3, 500
MHz) δ 1.49 (s, 9 H), 2.71 and 2.78 (two br s, 3 H), 4.54 (s, 2 H),
5.30 (d, J = 11.0 Hz, 1 H), 5.63 (d, J = 17.5 Hz, 1 H), 6.98 (br s, 1 H),
7.15−7.16 (m, 1 H), 7.23−7.29 (m, 2 H), 7.49−7.51 (m, 1 H); 13C
NMR (CDCl3, 125 MHz) δ 28.4 (q), 33.4 (q), 49.6 (t), 50.1 (t), 79.6
(s), 116.0 (s), 126.1 (d), 127.5 (d), 127.8 (d), 128.6 (d), 134.2 (d),
134.8 (s), 137.2 (s), 155.8 (s); exact mass (electrospray) m/z calcd for
C15H21NNaO2 (M + Na) 270.1465, found 270.1465.
Tris(propan-2-yl)silyl N-[(2-Ethenylphenyl)methyl]-N-meth-
ylcarbamate (21e). 2,6-Lutidine (0.10 mL, 0.86 mmol) and i-
Pr3SiOSO2CF3 (0.20 mL, 0.72 mmol) were added successively to a
stirred solution of 21d (123.6 mg, 0.50 mmol) in CH2Cl2 (5 mL), and
stirring was continued for 9.5 h. The mixture was washed with
saturated aqueous NH4Cl and brine, dried (MgSO4), and evaporated.
Flash chromatography of the residue over silica gel (1.8 × 14 cm),
using 1:20 Et2O/hexanes, gave 21e (167.8 mg, 96%) as a colorless oil:
FTIR (CHCl3, cast) 3064, 2945, 2892, 2868, 1682, 1559, 1465, 1421
Data for the major isomer: [α]20 −94.57 (c 1.22, CHCl3); FTIR
D
(CHCl3, cast) 3086, 3063, 3028, 2952, 2927, 2869, 1764, 1678, 1603,
1
1495, 1454 cm−1; H NMR (CDCl3, 500 MHz) δ 0.77−1.07 (m, 12
H), 1.25−1.30 (m, 1 H), 1.33−1.42 (m, 1 H), 1.51−1.58 (m, 1 H),
1.63−1.70 (m, 2 H), 1.83−1.90 (m, 1 H), 2.08−2.20 (m, 2 H), 2.44−
2.51 (m, 1 H), 2.55−2.61 (m, 1 H), 2.83−2.89 (m, 1 H), 3.13 (ddd, J
= 2.5, 5.5, 14.5 Hz, 1 H), 3.61 (dt, J = 4.0, 10.5 Hz, 1 H), 3.63 (AB q, J
= 14.3 Hz, ΔνAB = 143.0 Hz, 2 H), 4.12 (q, J = 2.5 Hz, 1 H), 5.57 (d, J
= 2.5 Hz, 1 H), 7.27−7.30 (m, 2 H), 7.34−7.38 (m, 4 H); 13C NMR
(CDCl3, 125 MHz) δ 15.7 (q), 20.85 (t), 20.94 (q), 22.3 (q), 23.1 (t),
25.4 (d), 29.1 (t), 31.4 (d), 34.3 (t), 39.6 (t), 47.8 (d), 52.6 (t), 54.5
(t), 68.4 (d), 77.2 (d), 101.6 (d), 127.2 (d), 128.47 (d), 128.48 (d),
130.7 (s), 138.8 (s), 144.1 (d), 168.6 (s); exact mass (electrospray) m/
z calcd for C25H36NO3 (M + H) 398.2690, found 398.2691.
1
cm−1; H NMR (CDCl3, 400 MHz) δ 1.04−1.13 (m, 18 H), 1.28−
1.40 (m, 3 H), 2.79 and 2.85 (two s, 3 H), 4.61 (s, 2 H), 5.30 (t, J =
10.4 Hz, 1 H), 5.64 (d, J = 17.2 Hz, 1 H), 6.94 (dd, J = 10.8, 17.2 Hz)
and 7.01 (dd, J = 10.8, 17.2 Hz, both signals together 1 H), 7.16−7.20
(m, 1 H), 7.23−7.28 (m, 2 H), 7.49−7.53 (m, 1 H); 13C NMR
(CDCl3, 125 MHz) δ 12.1 (d), 17.86 (q), 17.90 (q), 33.7 (q), 34.0
(q), 50.0 (t), 50.9 (t), 116.1 (s), 116.5 (s), 126.0 (d), 126.2 (d), 127.3
(d), 127.5 (d), 127.68 (d), 127.72 (d), 127.9 (d), 128.8 (d), 133.7 (d),
134.1 (d), 134.4 (s), 134.5 (s), 136.7 (s), 137.3 (s), 155.0 (s), 155.1
(s); exact mass (electrospray) m/z calcd for C20H33NNaO2Si (M +
Na) 370.2173, found 370.2172.
Data for the minor isomer: [α]20 −157.58 (c 0.99, CHCl3); FTIR
D
(CHCl3, cast) 3061, 3026, 2952, 2923, 2868, 2801, 2732, 1770, 1684,
1630, 1494, 1452 cm−1; 1H NMR (CDCl3, 500 MHz) δ 0.77−1.09 (m,
12 H), 1.33−1.46 (m, 2 H), 1.64−1.81 (m, 4 H), 2.08−2.13 (m, 2 H),
2.27−2.35 (m, 1 H), 2.42 (ddd, J = 2.5, 8.8, 13.8 Hz, 1 H), 2.49−2.55
(m, 1 H), 3.14 (ddd, J = 2.5, 7.6, 13.6 Hz, 1 H), 3.67 (dt, J = 4.0, 10.8
Hz, 1 H), 3.70 (AB q, J = 13.3 Hz, ΔνAB = 246.4 Hz, 2 H), 3.90−3.93
(m, 1 H), 5.72 (d, J = 5.0 Hz, 1 H), 7.16−7.19 (m, 1 H), 7.28−7.31
(m, 1 H), 7.34−7.37 (m, 2 H), 7.41−7.43 (m, 2 H); 13C NMR
(CDCl3, 125 MHz) δ 15.8 (q), 20.8 (q), 23.4 (t), 25.5 (d), 26.8 (t),
28.5 (t), 31.4 (d), 34.3 (t), 39.1 (t), 47.7 (d), 53.9 (t), 57.8 (t), 66.9
(d), 76.7 (d), 97.3 (d), 127.2 (d), 128.2 (d), 128.7 (s), 129.1 (d),
138.8 (s), 142.1 (d), 169.4 (s); exact mass (electrospray) m/z calcd for
C25H36NO3 (M + H) 398.2690, found 398.2692.
Tris(propan-2-yl)silyl N-[(2-Formylphenyl)methyl]-N-methyl-
carbamate (21). OsO4 (1.0 M in PhMe, 0.05 mL, 0.05 mmol) was
added to a stirred solution of 21e (157.5 mg, 0.45 mmol) in THF (4
mL) and water (1.5 mL). The mixture was stirred for 7 min, during
which time the solution turned dark brown. NaIO4 (301.1 mg, 1.41
mmol) was then added slowly, and stirring was continued for 1.5 h.
The mixture was filtered through Celite, using EtOAc as a rinse. The
filtrate was washed with water and brine, dried (MgSO4), and
evaporated. Flash chromatography of the residue over silica gel (1.8 ×
14 cm), using 1:10 EtOAc/hexanes, gave 21 (129.3 mg, 82%) as a light
yellow oil: FTIR (CHCl3, cast) 3071, 2945, 2892, 2867, 2729, 1683,
1601, 1576, 1464 cm−1; 1H NMR (CDCl3, 500 MHz) δ 0.95−1.11 (m,
18 H), 1.19−1.35 (m, 3 H), 2.94 and 2.99 (two s, 3 H), 4.96 (s, 2 H),
7.35 (d, J = 7.5 Hz, 1 H), 7.46 (q, J = 8.0 Hz, 1 H), 7.58 (q, J = 7.5 Hz,
1 H), 7.84 (d, J = 7.5 Hz, 1 H) 10.14 and 10.20 (two s, 1 H); 13C
NMR (CDCl3, 125 MHz) δ 12.0 (d), 12.1 (d), 17.7 (q), 17.9 (q), 35.0
(q), 35.3 (q), 49.8 (t), 51.4 (t), 126.4 (d), 127.3 (d), 127.5 (d), 127.8
(d), 133.3 (s), 133.5 (d), 133.9 (d), 134.0 (d), 135.1 (d), 140.1 (s),
140.5 (s), 155.29 (s), 155.33 (s), 193.0 (d), 193.4 (d); exact mass
(electrospray) m/z calcd for C19H31NNaO3Si (M + Na) 372.1965,
found 372.1962.
Tris(propan-2-yl)silyl N-({2-[(S)-Hydroxy[(5R)-5-{[(1R,2S,5R)-
5-methyl-2-(propan-2-yl)cyclohexyl]oxy}-2-oxo-2,5-dihydro-
furan-3-yl)methyl]phenyl}methyl)-N-methylcarbamate (21f).
BuLi (2.5 M in hexane, 0.22 mL, 0.55 mmol) was added dropwise
to a stirred and cooled (−20 °C) solution of PhSeSePh (174.0 mg,
0.55 mmol) in THF (1.58 mL). After 10 min, a portion of the freshly
prepared PhSeLi solution (0.6 mL) was added dropwise by syringe to
a stirred and cooled (−42 °C) solution of 16 (42.6 mg, 0.18 mmol)
and 21 (87.5 mg, 0.25 mmol) in THF (2 mL). Stirring at −42 °C (dry
ice/MeCN) was continued for 9 h, and the mixture was quenched
with saturated aqueous NH4Cl (3 mL) and extracted with Et2O. The
combined organic extracts were washed with brine, dried (MgSO4),
[(2R)-1-Benzyl-3-(hydroxymethyl)-2,5,6,7-tetrahydro-1H-
azepin-2-yl]methanol (20g). DIBAL-H (1.0 M in PhMe, 0.66 mL,
0.66 mmol) was added dropwise to a stirred and cooled (−78 °C)
solution of 20f (52.5 mg, 0.13 mmol) in THF (1.5 mL). Stirring at
−78 °C was continued for 2 h, the cold bath was left in place but not
recharged, and stirring was continued for 12 h. MeOH (0.3 mL) and a
saturated aqueous solution of Rochelle’s salt (ca. 5 mL) were then
added sequentially. Stirring was continued for 3 h, and the mixture was
extracted with EtOAc. The combined organic extracts were washed
with brine, dried (MgSO4), and evaporated. Flash chromatography of
the residue over silica gel (1.2 × 14 cm), using 3:100 MeOH/EtOAc,
gave 20g (29.6 mg, 90%) as an oil: [α]20 −2.10 (c 1.00, CHCl3);
D
FTIR (CHCl3, cast) 3363, 3086, 3061, 3028, 2926, 2848, 1559, 1522,
1
1452 cm−1; H NMR (CDCl3, 300 MHz) δ 1.40−1.47 (m, 1 H),
1.74−1.86 (m, 2 H), 2.18−2.38 (m, 3 H), 2.97−3.03 (m, 1 H), 3.12−
3.22 (m, 1 H), 3.46−3.57 (m, 2 H), 3.73−3.87 (m, 3 H), 3.93 (s, 2 H),
5.99 (t, J = 5.7 Hz, 1 H), 7.21−7.35 (m, 5 H); 13C NMR (CDCl3, 100
MHz) δ 21.4 (t), 28.1 (t), 49.9 (t), 55.9 (t), 59.2 (t), 64.3 (d), 68.1
(t), 127.4 (d), 128.7 (d), 129.0 (d), 130.6 (d), 139.5 (s), 140.9 (s);
exact mass (electrospray) m/z calcd for C15H22NO2 (M + H)
248.1645, found 248.1648.
tert-Butyl N-[(2-Ethenylphenyl)methyl]-N-methylcarbamate
(21d). NaH (60% in oil, 60.0 mg, 1.50 mmol) was added to a stirred
3356
dx.doi.org/10.1021/jo3001657 | J. Org. Chem. 2012, 77, 3348−3364

The Journal of Organic Chemistry
Article
and evaporated. Flash chromatography of the residue over silica gel
(1.2 × 15 cm), using 1:5 EtOAc/hexanes, gave 21f (91.2 mg, 87%) as
a colorless oil: FTIR (CHCl3, cast) 3410, 3068, 2949, 2869, 2726,
was extracted with EtOAc. The combined organic extracts were
washed with brine, dried (MgSO4), and evaporated. Flash chromatog-
raphy of the residue over silica gel (1.2 × 14 cm), using 1:20 MeOH/
EtOAc, gave 21i (58.0 mg, 90%) as a white solid: [α]20D 59.87 (c 1.18,
CHCl3); FTIR (CHCl3, cast) 3349, 3059, 3018, 2928, 2878, 1665,
1
1771, 1660, 1606, 1465 cm−1; H NMR (CDCl3, 500 MHz) δ 0.76−
1.75 (m, 38 H), 2.09 (s, 2 H), 2.87−3.23 (m, 3 H), 3.62 (dt, J = 4.0,
10.5 Hz, 1 H), 4.24−4.81 (m, 2 H), 5.78−6.01 (m, 2 H), 6.65−6.97
(m, 1 H), 7.25−7.42 (m, 4 H); 13C NMR (CDCl3, 125 MHz) δ 12.0
(d), 15.9 (q), 17.8 (q), 20.8 (q), 22.2 (q), 23.3 (t), 25.4 (d), 31.5 (d),
35.6 (q), 40.3 (t), 47.7 (d), 49.5 (t), 65.8 (d), 79.2 (d), 99.3 (d), 127.7
(d), 127.8 (d), 128.4 (d), 128.6 (d), 135.4 (s), 137.9 (s), 139.4 (s),
144.6 (d), 155.6 (s), 170.0 (s); exact mass (electrospray) m/z calcd for
C33H53NNaO6Si (M + Na) 610.3534, found 610.3527.
1
1600, 1577, 1559, 1541, 1491 cm−1; H NMR (CDCl3, 500 MHz) δ
2.29 (s, 3 H), 3.16 (s, 2 H), 3.43 (t, J = 10.0 Hz, 1 H), 3.51 (dd, J =
5.0, 9.5 Hz, 1 H), 3.78 (dd, J = 5.0, 10.0 Hz, 1 H), 3.89 (AB q, J = 15.0
Hz, ΔνAB = 229.78 Hz, 2 H), 4.19 (AB q, J = 13.0 Hz, ΔνAB = 28.58
Hz, 2 H), 6.63 (s, 1 H), 7.16−7.26 (m, 4 H); 13C NMR (CDCl3, 100
MHz) δ 21.4 (t), 41.5 (q), 54.1 (t), 62.2 (t), 67.3 (d), 67.4 (t), 127.27
(d), 127.30 (d), 128.8 (d), 129.2 (d), 131.0 (d), 135.3 (s), 137.9 (s),
140.8 (s); exact mass (electrospray) m/z calcd for C13H18NO2 (M +
H) 220.1332, found 220.1332.
(S)-(2-{[Methyl({[tris(propan-2-yl)silyl]oxy}carbonyl)amino]-
methyl}phenyl)-[(5R)-5-{[(1R,2S,5R)-5-methyl-2-(propan-2-yl)-
cyclohexyl]oxy}-2-oxo-2,5-dihydrofuran-3-yl)methyl Acetate
(21g). DMAP (3.4 mg, 0.028 mmol) was added to a stirred solution
of 21f (199.5 mg, 0.34 mmol) in CH2Cl2 (9 mL). The mixture was
cooled to 0 °C, and AcCl (0.09 mL, 1.24 mmol) and pyridine (0.19
mL, 2.35 mmol) were added sequentially. The ice bath was left in
place but not recharged, and stirring was continued for 5.5 h. The
mixture was quenched with hydrochloric acid (1 M, 3 mL) and water
(6 mL), and the aqueous phase was extracted with CH2Cl2. The
combined organic extracts were washed with brine, dried (MgSO4),
and evaporated. Flash chromatography of the residue over silica gel
(1.8 × 14 cm), using 3:20 EtOAc/hexanes, gave 21g (199.3 mg, 93%)
as a colorless oil: FTIR (CHCl3, cast) 3069, 2949, 2928, 2895, 2868,
2725, 1775, 1749, 1680, 1606, 1583, 1553, 1465 cm−1; 1H NMR
(CDCl3, 400 MHz) δ 0.74−1.43 (m, 35 H), 1.63−1.68 (m, 2 H),
2.01−2.10 (m, 5 H), 2.90 and 2.92 (two s, 3 H), 3.59−3.65 (m, 1 H),
4.71 and 4.79 (two s, 2 H), 6.01 (d, J = 6.0 Hz, 1 H), 6.73 and 6.78
(two s, 1 H), 6.89 (s, 1 H), 7.20−7.39 (m, 4 H); 13C NMR (CDCl3,
100 MHz) δ 12.0 (d), 12.1 (d), 15.8 (q), 17.8 (q), 17.9 (q), 20.8 (q),
22.2 (q), 23.18 (t), 23.20 (t), 25.30 (d), 25.34 (d), 31.4 (d), 34.2 (t),
34.57 (q), 34.61 (q), 40.4 (t), 47.7 (d), 48.7 (t), 49.9 (t), 65.9 (d),
66.7 (d), 79.3 (d), 79.4 (d), 98.8 (d), 98.9 (d), 126.1 (d), 127.4 (d),
127.5 (d), 127.6 (d), 127.9 (d), 128.1 (d), 129.2 (d), 133.7 (s), 134.2
(s), 135.8 (s), 135.9 (s), 136.6 (s), 136.9 (s), 144.9 (d), 145.5 (d),
155.4 (s), 155.6 (s), 168.30 (s), 168.35 (s), 169.1 (s), 169.2 (s); exact
mass (electrospray) m/z calcd for C35H55NNaO7Si (M + Na)
652.3640, found 652.3632.
(2-Iodo-6-methylphenyl)methanol (22b). DIBAL-H (1.0 M in
PhMe, 4.0 mL, 4.0 mmol) was added dropwise to a stirred and cooled
(−78 °C) solution of 22a16 (440.9 mg, 1.60 mmol) in PhMe (5 mL).
Stirring at −78 °C was continued for 2.25 h, the cooling bath was
removed, and stirring was continued for 15 min. The mixture was
quenched with saturated aqueous NH4Cl and extracted with Et2O.
The combined organic extracts were dried (MgSO4) and evaporated to
give 22b as a white solid (96%): FTIR (CHCl3, cast) 3280, 3053,
3009, 2967, 2934, 2732, 2618, 1588, 1555, 1480, 1445 cm−1; 1H NMR
(CDCl3, 500 MHz) δ 1.77−1.80 (m, 1 H), 2.50 (s, 3 H), 4.84 (d, J =
6.5 Hz, 2 H), 6.88 (t, J = 7.5 Hz, 1 H), 7.17 (d, J = 7.5 Hz, 1 H), 7.70
(d, J = 8.0 Hz, 1 H); 13C NMR (CDCl3, 125 MHz) δ 20.5 (q), 67.1
(t), 101.7 (s), 129.9 (d), 131.0 (d), 137.6 (d), 139.2 (s), 140.5 (s);
HRMS (EI) m/z calcd for C8H9IO 247.9698, found 247.9700.
(2-Ethenyl-6-methylphenyl)methanol (22c). Ph3P (135.0 mg,
0.51 mmol) was added to a stirred solution of Pd(OAc)2 (27.6 mg,
0.12 mmol) in PhMe (2.5 mL). The mixture turned yellow after
several minutes. Alcohol 22b (297.6 mg, 1.20 mmol) and then a
solution of tributyl(vinyl)tin (456.6 mg, 1.44 mmol) in PhMe (1.0
mL) were added, the latter by syringe. The solution was purged with a
stream of Ar for 10 min and then heated to 110−120 °C for 15 h,
during which time the solution turned black. The mixture was cooled
and filtered through Celite, using MeOH as a rinse. Evaporation of the
filtrate and flash chromatography of the red residue over silica gel (2.8
× 14 cm), using 1:5 Et2O/hexanes, gave 22c (165.9 mg, 93%): FTIR
(CHCl3, cast) 3256, 3085, 3070, 3027, 2958, 2933, 2720, 2591, 1626,
1591, 1581, 1497, 1470 cm−1; 1H NMR (CDCl3, 500 MHz) δ 1.49 (t,
J = 5.5 Hz, 1 H), 2.47 (s, 3 H), 4.80 (d, J = 5.5 Hz, 2 H), 5.39 (dd, J =
1.5, 11.0 Hz, 1 H), 5.69 (dd, J = 1.5, 17.0 Hz, 1 H), 7.15−7.25 (m, 3
H), 7.39 (d, J = 8.0 Hz, 1 H); 13C NMR (CDCl3, 125 MHz) δ 19.5
(q), 58.9 (t), 117.1 (t), 124.4 (d), 128.3 (d), 130.1 (d), 134.8 (d),
135.4 (s), 137.4 (s), 138.2 (s); HRMS (EI) m/z calcd for C10H12O
148.0888, found 148.0886.
(6R,7R)-8-Methyl-6-{[(1R,2S,5R)-5-methyl-2-(propan-2-yl)-
cyclohexyl]oxy}-5-oxa-8-azatricyclo[8.4.0.03,7]tetradeca-1-
(14),2,10,12-tetraen-4-one (21h). Bu3NF (1.0 M in THF, 0.317
mL, 0.317 mmol) was added to a stirred and cooled (0 °C) solution of
21g (199.3 mg, 0.317 mmol) in THF (4 mL). After 15 min, the
mixture was quenched with saturated aqueous NH4Cl (4 mL) and
diluted with EtOAc (4 mL). The organic phase was washed with brine,
dried (MgSO4), and evaporated. Flash chromatography of the residue
over silica gel (1.4 × 14 cm), using 1:5 EtOAc/hexanes, gave 21h
2-(Bromomethyl)-1-ethenyl-3-methylbenzene (22d). Ph3P
(394.6 mg, 1.49) was added to a stirred and cooled (0 °C) mixture
of 22c (183.7 mg, 1.24 mmol) and CBr4 (479.6 mg, 1.49 mmol) in
CH2Cl2 (6 mL). Stirring at 0 °C was continued for 50 min, at which
point no starting material remained (TLC, silica, 1:20 EtOAc/hexane).
Evaporation of the mixture and flash chromatography of the residue
over silica gel (2.8 × 14 cm), using hexanes, gave 22d (236.0 mg, 90%)
as a white solid: FTIR (CHCl3, cast) 3085, 3067, 3028, 3008, 2978,
(108.1 mg, 92%) as a light yellow oil: [α]20 119.87 (c 1.12, CHCl3);
D
FTIR (CHCl3, cast) 3064, 3017, 2953, 2924, 2870, 2852, 2794, 1763,
1
1657, 1600, 1568, 1454 cm−1; H NMR (CDCl3, 400 MHz) δ 0.77−
1.06 (m, 12 H), 1.17−1.26 (m, 1 H), 1.35−1.44 (m, 1 H), 1.61−1.69
(m, 2 H), 2.06−2.18 (m, 2 H), 2.44 (s, 3 H), 3.21 (t, J = 3.2 Hz, 1 H),
3.61 (dt, J = 4, 10.4 Hz, 1 H), 3.80 (AB q, J = 15.2 Hz, ΔνAB = 116.8
Hz, 2 H), 5.57 (d, J = 3.2 Hz, 1 H), 7.28−7.43 (m, 4 H), 7.73 (d, J =
2.8 Hz, 1 H); 13C NMR (CDCl3, 100 MHz) δ 15.7 (q), 20.9 (q), 22.3
(q), 23.1 (t), 25.3 (d), 31.4 (d), 34.3 (t), 39.7 (t), 40.8 (q), 47.7 (d),
59.1 (t), 68.6 (d), 77.7 (d), 103.5 (d), 127.8 (d), 129.4 (d), 129.6 (s),
130.7 (d), 131.3 (d), 135.6 (s), 139.2 (s), 139.4 (d), 168.5 (s); exact
mass (electrospray) m/z calcd for C23H32NO3 (M + H) 370.2377,
found 370.2379.
1
2950, 2912, 2868, 1628, 1581, 1472, 1462 cm−1; H NMR (CDCl3,
500 MHz) δ 2.47 (s, 3 H), 4.65 (s, 2 H), 5.48 (dd, J = 1.0, 11.0 Hz, 1
H), 5.75 (dd, J = 1.0, 17.0 Hz, 1 H), 7.12−7.18 (m, 2 H), 7.24 (t, J =
7.5 Hz, 1 H), 7.37 (d, J = 7.5 Hz, 1 H); 13C NMR (CDCl3, 125 MHz)
δ 19.2 (q), 28.8 (t), 117.6 (t), 124.7 (d), 128.8 (d), 130.2 (d), 132.8
(s), 134.2 (d), 137.5 (s), 138.2 (s); HRMS (EI) m/z calcd for
C10H11Br 212.0024, found 212.0021.
Benzyl[(2-ethenyl-6-methylphenyl)methyl]amine (22e).
BnNH2 (0.2 mL, 1.79 mmol) was added to a stirred solution of 22d
(127.9 mg, 0.61 mmol) in THF (3 mL), and stirring was continued for
12 h. The mixture was diluted with EtOAc and washed twice with
aqueous NaOH (1 N) and then with brine. The combined organic
extracts were dried (MgSO4) and evaporated. Flash chromatography
of the residue over silica gel (1.4 × 14 cm), using 3:20 EtOAc/
hexanes, gave 22e (130.0 mg, 90%) as a yellow oil: FTIR (CHCl3,
[(3R)-3-(Hydroxymethyl)-2-methyl-2,3-dihydro-1H-2-benza-
zepin-4-yl]methanol (21i). DIBAL-H (1.0 M in PhMe, 1.46 mL,
1.46 mmol) was added dropwise to a stirred and cooled (−78 °C)
solution of 21h (108.1 mg, 0.29 mmol) in THF (3 mL). Stirring at
−78 °C was continued for 1 h, the cold bath was left in place but not
recharged, and stirring was continued for 6.5 h. MeOH (0.5 mL) and a
saturated aqueous solution of Rochelle’s salt (ca. 6 mL) were then
added sequentially. Stirring was continued for 12 h, and the mixture
3357
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cast) 3323, 3084, 3063, 3027, 2976, 2950, 2915, 2859, 1626, 1604,
1582, 1495, 1453 cm−1; 1H NMR (CDCl3, 500 MHz) δ 1.35 (s, 1 H),
2.37 (s, 3 H), 3.83 (s, 2 H), 3.90 (s, 2 H), 5.31 (dd, J = 1.5, 11.0 Hz, 1
H), 5.66 (dd, J = 1.5, 17.0 Hz, 1 H), 7.06 (dd, J = 11.0, 17.0 Hz, 1 H),
7.12 (d, J = 7.5 Hz, 1 H), 7.17 (t, J = 7.5 Hz, 1 H), 7.27−7.31 (m, 1
H), 7.35−7.41 (m, 5 H); 13C NMR (CDCl3, 125 MHz) δ 19.5 (q),
46.7 (t), 54.1 (t), 116.2 (t), 124.0 (d), 127.0 (d), 127.3 (d), 128.2 (d),
128.3 (d), 130.0 (d), 135.2 (d), 135.7 (s), 137.2 (s), 137.9 (s), 140.5
(s); exact mass (electrospray) m/z calcd for C17H20N (M + H)
238.1590, found 238.1591.
tert-Butyl N-Benzyl-N-[(2-ethenyl-6-methylphenyl)methyl]-
carbamate (22f). DMAP (126.7 mg, 1.03 mmol) and Boc2O
(226.3 mg, 1.03 mmol) were added successively to a stirred solution of
22e (137.5 mg, 0.50 mmol) in MeCN (6 mL), and stirring was
continued for 37 h. Evaporation of the solvent and flash
chromatography of the residue over silica gel (1.8 × 14 cm), using
1:20 Et2O/hexanes, gave 22f (158.9 mg, 92%) as a colorless oil: FTIR
(CHCl3, cast) 3087, 3065, 3030, 3006, 2976, 2930, 1693, 1626, 1605,
1581, 1540, 1496 cm−1; 1H NMR (CDCl3, 500 MHz) δ 1.53 (s, 9 H),
2.13 (s, 3 H), 4.15 (s, 2 H), 4.72 (s, 2 H), 5.20 (dd, J = 1.5, 11.0 Hz, 1
H), 5.55 (d, J = 17.5 Hz, 1 H), 6.87 (br s, 1 H), 7.06−7.09 (m, 3 H),
7.19−7.36 (m, 5 H); 13C NMR (CDCl3, 125 MHz) δ 19.8 (q), 28.5
(q), 42.8 (t), 47.4 (t), 80.0 (s), 116.0 (t), 124.6 (d), 126.8 (d), 127.0
(d), 127.8 (d), 128.4 (d), 130.1 (d), 132.3 (s), 135.5 (d), 138.2 (s),
139.2 (s), 155.8 (s); exact mass (electrospray) m/z calcd for
C22H27NNaO2 (M + Na) 360.1934, found 360.1937.
(s); exact mass (electrospray) m/z calcd for C26H38NO3Si (M + H)
440.2615, found 440.2615.
Tris(propan-2-yl)silyl N-Benzyl-N-({2-[(S)-hydroxy[(5R)-5-
{[(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}-2-oxo-
2,5-dihydrofuran-3-yl]methyl]-6-methylphenyl}-methyl)-
carbamate (22h). BuLi (2.5 M in hexane, 0.28 mL, 0.70 mmol) was
added dropwise to a stirred and cooled (−20 °C) solution of
PhSeSePh (220.6 mg, 0.70 mmol) in THF (1.72 mL). After 10 min, a
portion of the freshly prepared PhSeLi solution (1.0 mL) was added
dropwise by syringe to a stirred and cooled (−42 °C) solution of 16
(75.0 mg, 0.32 mmol) and 22h (190.1 mg, 0.43 mmol) in THF (4
mL). Stirring was continued for 10 h at −42 °C (dry ice/MeCN), and
the mixture was quenched with saturated aqueous NH4Cl (3 mL) and
extracted with Et2O. The combined organic extracts were washed with
brine, dried (MgSO4), and evaporated. Flash chromatography of the
residue over silica gel (1.8 × 15 cm), using 3:20 EtOAc/hexanes, gave
22h (167.4 mg, 78%) as a colorless oil: FTIR (CHCl3, cast) 3431,
3066, 3032, 2951, 2927, 2868, 1773, 1674, 1607, 1552, 1496, 1462
1
cm−1; H NMR (CDCl3, 500 MHz) δ 0.79−1.46 (m, 35 H), 1.64−
1.72 (m, 2 H), 2.06−2.14 (m, 2 H), 2.25−2.27 (m, 3 H), 3.43−3.63
(m, 2 H), 4.37−4.90 (m, 4 H), 5.43−5.66 (m, 1 H), 5.97 (s, 1 H),
6.62−6.90 (m, 1 H), 7.10−7.51 (m, 8 H); 13C NMR (CDCl3, 125
MHz) δ 12.1 (d), 15.8 (q), 15.9 (q), 17.9 (q), 20.1 (q), 20.2 (q), 20.8
(q), 20.9 (q), 22.2 (q), 23.1 (t), 23.3 (t), 25.2 (d), 25.4 (d), 31.5 (d),
34.2 (t), 40.3 (t), 40.5 (t), 43.7 (t), 44.0 (t), 47.7 (d), 47.8 (d), 65.4
(d), 65.6 (d), 78.9 (d), 79.3 (d), 99.1 (d), 99.2 (d), 125.1 (d), 125.2
(d), 126.5 (d), 126.6 (d), 127.2 (d), 128.2 (d), 128.7 (d), 130.9 (d),
131.0 (d), 137.9 (s), 138.6 (s), 138.7 (s), 139.6 (s), 139.8 (s), 140.0
(s), 144.3 (d), 155.5 (s), 169.8 (s); exact mass (electrospray) m/z
calcd for C40H60NO6Si (M + H) 678.4184, found 678.4185.
[Tris(propan-2-yl)silyl N-Benzyl-N-[(2-ethenyl-6-
methylphenyl)methyl]carbamate (22g). 2,6-Lutidine (0.10 mL,
0.86 mmol) and i-Pr3SiOSO2CF3 (0.21 mL, 0.76 mmol) were added
successively to a stirred solution of 22f (147.1 mg, 0.44 mmol) in
ClCH2CH2Cl (5 mL). The mixture was lowered into a preheated oil
bath set at 96 °C, and stirring was continued for 4 h. The mixture was
cooled, evaporated, and diluted with Et2O (10 mL). The solution was
washed with saturated aqueous NH4Cl and brine, dried (MgSO4), and
evaporated. Flash chromatography of the residue over silica gel (2.8 ×
18 cm), using 1:25 Et2O/hexanes, gave 22g (186.6 mg, 98%) as a
colorless oil: FTIR (CHCl3, cast) 3087, 3065, 3030, 2945, 2893, 2867,
(S)-(2-{[Benzyl({[tris(propan-2-yl)silyl]oxy}carbonyl)amino]-
methyl}-3-methylphenyl)[(5R)-5-{[(1R,2S,5R)-5-methyl-2-(prop-
an-2-yl)cyclohexyl]oxy}-2-oxo-2,5-dihydrofuran-3-yl]methyl
Acetate (22i). DMAP (2.2 mg, 0.018 mmol) was added to a stirred
solution of 22h (62.2 mg, 0.092 mmol) in CH2Cl2 (1.5 mL). The
mixture was then cooled to 0 °C, and AcCl (0.03 mL, 0.41 mmol) and
pyridine (0.05 mL, 0.62 mmol) were added sequentially. The ice bath
was left in place but not recharged, and stirring was continued for 40
min. The mixture was quenched with hydrochloric acid (1 M, 2 mL)
and water (3 mL), and the aqueous phase was extracted with CH2Cl2.
The combined organic extracts were washed with brine, dried
(MgSO4), and evaporated. Flash chromatography of the residue over
silica gel (1.2 × 14 cm), using 1:10 EtOAc/hexanes, gave 22i (64.0
mg, 96%) as a colorless oil: FTIR (CHCl3, cast) 3066, 3032, 2950,
2868, 1778, 1753, 1676, 1606, 1555, 1496, 1459 cm−1; 1H NMR
(CDCl3, 500 MHz) δ 0.80−1.46 (m, 35 H), 1.64−1.72 (m, 2 H),
2.02−2.18 (m, 8 H), 3.54−3.72 (m, 1 H), 4.14−4.44 (m, 2 H), 4.77−
4.94 (m, 2 H), 5.77 and 5.94 (two s, 1 H), 6.70−6.85 (m, 2 H), 7.03−
7.29 (m, 8 H); 13C NMR (CDCl3, 125 MHz) δ 12.1 (d), 15.9 (q),
17.8 (q), 18.0 (q), 20.0 (q), 20.7 (q), 20.80 (q), 20.85 (q), 22.2 (q),
23.3 (t), 25.5 (d), 31.5 (d), 34.2 (t), 40.5 (t), 43.5 (t), 47.7 (d), 48.2
(t), 67.5 (d), 79.3 (d), 98.6 (d), 125.7 (d), 125.9 (d), 126.1 (d), 126.7
(d), 127.1 (d), 128.1 (d), 128.4 (d), 131.4 (d), 131.6 (d), 132.8 (s),
133.1 (s), 136.0 (s), 136.3 (s), 136.7 (s), 136.9 (s), 137.1 (s), 137.9
(s), 138.2 (s), 139.5 (s), 139.6 (s), 145.8 (d), 155.4 (s), 168.0 (s),
169.0 (s), 169.1 (s); exact mass (electrospray) m/z calcd for
C42H61NNaO7Si (M + Na) 742.4110, found 742.4106.
1
1677, 1606, 1581, 1550, 1496 cm−1; H NMR (CDCl3, 500 MHz) δ
1.07−1.20 (m, 18 H), 1.31−1.48 (m, 3 H), 2.05 and 2.08 (two s, 3 H),
4.19 (s, 2 H), 4.74 and 4.78 (two s, 2 H), 5.15 (d, J = 11.0 Hz, 1 H),
5.50−5.57 (m, 1 H), 6.78 (dd, J = 11.0, 17.0 Hz) and 6.85 (dd, J =
11.0, 17.5 Hz, both signals together 1 H), 7.01−7.06 (m, 3 H), 7.17−
7.35 (m, 5 H); 13C NMR (CDCl3, 125 MHz) δ 12.17 (d), 12.23 (d),
17.9 (q), 18.0 (q), 19.7 (q), 19.8 (q), 43.2 (t), 44.1 (t), 47.1 (t), 47.9
(t), 116.1 (t), 116.4 (t), 124.3 (d), 124.7 (d), 126.5 (d), 126.9 (d),
127.4 (d), 127.8 (d), 127.9 (d), 128.3 (d), 128.4 (d), 130.1 (d), 130.2
(d), 131.4 (s), 132.0 (s), 135.0 (d), 135.2 (d), 137.9 (s), 138.0 (s),
138.1 (s), 138.4 (s), 139.1 (s), 139.2 (s), 155.1 (s), 155.3 (s); exact
mass (electrospray) m/z calcd for C27H40NO2Si (M + H) 438.2823,
found 438.2820.
Tris(propan-2-yl)silyl N-Benzyl-N-[(2-formyl-6-
methylphenyl)methyl]carbamate (22). OsO4 (1.0 M in PhMe,
0.05 mL, 0.05 mmol) was added to a stirred solution of 22g (184.4
mg, 0.42 mmol) in THF (3 mL) and water (1 mL). The mixture was
stirred for 8 min, during which time the solution turned dark brown.
NaIO4 (280.0 mg, 1.31 mmol) was then added slowly, and stirring was
continued for 50 min. The mixture was then filtered through Celite,
using EtOAc as a rinse. The filtrate was washed with water and brine,
dried (MgSO4), and evaporated. Flash chromatography of the residue
over silica gel (1.8 × 14 cm), using 1:20 EtOAc/hexanes, gave 22
(155.3 mg, 84%) as a light yellow oil: FTIR (CHCl3, cast) 3066, 3031,
2946, 2892, 2867, 2728, 1676, 1591, 1552, 1496, 1465 cm−1; 1H NMR
(CDCl3, 500 MHz) δ 1.09−1.20 (m, 18 H), 1.30−1.50 (m, 3 H), 2.24
(s, 3 H), 4.26 (s, 2 H), 5.10 (s, 2 H), 6.97−7.03 (m, 2 H), 7.24−7.29
(m, 3 H), 7.34−7.39 (m, 2 H), 7.71 (d, J = 7.0 Hz, 1 H), 9.94 and
10.07 (two s, 1 H); 13C NMR (CDCl3, 125 MHz) δ 12.1 (d), 17.9 (q),
18.0 (q), 19.3 (q), 41.4 (t), 42.2 (t), 47.8 (t), 48.5 (t), 126.6 (d), 127.2
(d), 127.4 (d), 127.9 (d), 128.1 (d), 128.6 (d), 135.98 (d), 136.02 (s),
136.8 (s), 137.5 (s), 139.7 (s), 155.1 (s), 155.3 (s), 191.5 (s), 192.2
(6R,7R)-8-Benzyl-11-methyl-6-{[(1S,2S,5R)-5-methyl-2-(prop-
an-2-yl)cyclohexyl]oxy}-5-oxa-8-azatricyclo[8.4.0.03,7]-
tetradeca-1(14),2,10,12-tetraen-4-one (22j). Bu3NF (1.0 M in
THF, 0.0385 mL, 0.0385 mmol) was added to a stirred and cooled
(−78 °C) solution of 22i (27.7 mg, 0.0385 mmol) in THF (0.8 mL).
After 15 min, the mixture was quenched with saturated aqueous
NH4Cl (3 mL) and diluted with EtOAc (4 mL). The organic phase
was washed with brine, dried (MgSO4), and evaporated. Flash
chromatography of the residue over silica gel (1.0 × 14 cm), using
1:20 EtOAc/hexanes, gave 22j (17.0 mg, 96%) as a foam: [α]20D 97.44
(c 1.07, CHCl3); FTIR (CHCl3, cast) 3063, 3028, 2954, 2924, 2869,
1
1763, 1661, 1586, 1495, 1454 cm−1; H NMR (CDCl3, 500 MHz) δ
0.76−1.06 (m, 12 H), 1.14−1.20 (m, 1 H), 1.34−1.40 (m, 1 H), 1.59−
1.67 (m, 2 H), 2.02−2.12 (m, 2 H), 2.21 (s, 3 H), 3.40 (t, J = 3.0 Hz, 1
3358
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H), 3.61 (dt, J = 4.0, 10.5 Hz, 1 H), 3.76 (AB q, J = 15.0 Hz, ΔνAB
=
0.92 mmol) in DMF (2 mL) was added dropwise to a stirred
suspension of NaH (60% in oil, 47.0 mg, 1.18 mmol) in DMF (7 mL).
Stirring was continued for 30 min, and then BnBr (0.24 mL, 1.38
mmol) was added. Stirring was continued for 19.5 h, and the mixture
was quenched with hydrochloric acid (1 N) and extracted with Et2O.
The combined organic extracts were washed with saturated aqueous
NaHCO3 and brine, dried (MgSO4), and evaporated. Flash
chromatography of the residue over silica gel (2.8 × 14 cm), using
1:50 EtOAc/hexanes, gave 23e (268.7 mg, 75%) as a colorless oil:
FTIR (CHCl3, cast) 3089, 3066, 3032, 2978, 2931, 1696, 1620, 1573,
104.9 Hz, 2 H), 3.82 (AB q, J = 15.0 Hz, ΔνAB = 41.4 Hz, 2 H), 5.65
(d, J = 3.0 Hz, 1 H), 7.15−7.48 (m, 8 H), 7.82 (d, J = 2.5 Hz, 1 H);
13C NMR (CDCl3, 125 MHz) δ 15.7 (q), 20.1 (q), 20.9 (q), 22.2 (q),
23.1 (t), 25.3 (d), 31.3 (d), 34.3 (t), 39.6 (t), 47.7 (d), 49.1 (t), 56.6
(t), 67.6 (d), 77.3 (d), 103.9 (d), 127.3 (d), 127.4 (d), 128.2 (d),
128.5 (d), 128.9 (d), 129.3 (s), 131.5 (d), 137.0 (s), 138.1 (s), 138.2
(s), 139.0 (s), 140.4 (d), 168.7 (s); exact mass (electrospray) m/z
calcd for C30H38NO3 (M + H) 460.2846, found 460.2846.
[(3-R)-2-Benzyl-3-(hydroxymethyl)-9-methyl-2,3-dihydro-
1H-2-benzazepin-4-yl]methanol (22k). DIBAL-H (1.0 M in
PhMe, 0.38 mL, 0.38 mmol) was added dropwise to a stirred and
cooled (−78 °C) solution of 22j (35.2 mg, 0.077 mmol) in THF (1
mL). Stirring at −78 °C was continued for 2 h, the cold bath was left
in place but not recharged, and stirring was continued for 5 h. MeOH
(0.3 mL) and a saturated aqueous solution of Rochelle’s salt (ca. 3
mL) were then added sequentially. Stirring was continued for 1.2 h,
and the mixture was extracted with EtOAc. The combined organic
extracts were washed with brine, dried (MgSO4), and evaporated.
Flash chromatography of the residue over silica gel (1.2 × 14 cm),
using 1:1 EtOAc/hexanes, gave 22k (17.7 mg, 75%) as a light yellow
1
1496 cm−1; H NMR (CDCl3, 500 MHz) δ 1.50 (s, 9 H), 4.31−4.55
(m, 4 H), 5.39 (dd, J = 1.0, 11.0 Hz, 1 H), 5.68 (dd, J = 1.0, 17.5 Hz, 1
H), 6.90 (br s, 1 H), 7.17 (br s, 2 H), 7.25−7.38 (m, 4 H), 7.50 (d, J =
8.5 Hz, 1 H), 7.56 (d, J = 8.0 Hz, 1 H); 13C NMR (CDCl3, 125 MHz)
δ 28.3 (q), 46.8 (t), 49.4 (t), 80.5 (s), 118.4 (t), 120.9 (s), 123.1 (s),
124.3 (d), 125.2 (s), 126.6 (d), 127.4 (d), 128.6 (d), 129.7 (CCF3,
2JCF = 33.1 Hz), 133.1 (d), 135.5 (s), 137.6 (s), 140.7 (s), 155.7 (s);
exact mass (electrospray) m/z calcd for C22H24F3NNaO2 (M + Na)
414.1651, found 414.1654.
Tris(propan-2-yl)silyl N-Benzyl-N-{[2-ethenyl-5-
(trifluoromethyl)phenyl]methyl}carbamate (23f). 2,6-Lutidine
(0.14 mL, 1.20 mmol) and i-Pr3SiOSO2CF3 (0.30 mL, 1.11 mmol)
were added successively to a stirred solution of 23e (236.9 mg, 0.61
mmol) in ClCH2CH2Cl (6 mL). The mixture was lowered into a
preheated oil bath set at 96 °C, and stirring was continued for 4 h. The
mixture was cooled, evaporated and diluted with Et2O (10 mL). The
solution was washed with saturated aqueous NH4Cl and brine, dried
(MgSO4), and evaporated. Flash chromatography of the residue over
silica gel (2.8 × 18 cm), using 1:50 EtOAc/hexanes, gave 23f (282.0
mg, 95%) as a colorless oil: FTIR (CHCl3, cast) 3089, 3065, 3032,
2947, 2893, 2868, 1681, 1620, 1574, 1549, 1496 cm−1; 1H NMR
(CDCl3, 500 MHz) δ 1.09−1.16 (m, 18 H), 1.34−1.44 (m, 3 H),
4.44−4.64 (m, 4 H), 5.42 (d, J = 11.0 Hz, 1 H), 5.70−5.76 (m, 1 H),
6.84 (dd, J = 11.0, 17.5 Hz) and 6.97 (dd, J = 11.0, 17.0 Hz, both
signals together 1 H), 7.21 (d, J = 7.5 Hz, 1 H), 7.27−7.38 (m, 4 H),
7.43 (d, J = 12.0 Hz, 1 H), 7.54 (d, J = 7.5 Hz, 1 H), 7.58−7.63 (m, 1
H); 13C NMR (CDCl3, 125 MHz) (because of the presence of
rotamers, the signal splitting by fluorine is ignored) δ 12.08 (d), 12.15
(d), 17.8 (q), 17.9 (q), 47.0 (t), 47.7 (t), 50.0 (t), 118.6 (t), 118.9 (t),
120.9 (s), 123.0 (s), 123.89 (d), 123.92 (d), 124.2 (d), 124.3 (d),
124.4 (d), 124.5 (d), 125.21 (d), 125.24 (d), 126.6 (d), 126.7 (d),
127.3 (d), 127.5 (d), 127.55 (d), 127.64 (d), 127.8 (d), 128.0 (d),
128.4 (d), 128.7 (d), 129.3 (s), 129.5 (s), 129.6 (s), 129.8 (s), 129.9
(s), 130.07 (s), 130.12 (s), 130.3 (s), 132.6 (d), 133.0 (d), 135.2 (s),
135.4 (s), 137.2 (s), 137.4 (s), 140.1 (s), 140.7 (s), 155.2 (s), 155.4
(s); exact mass (electrospray) m/z calcd for C27H36F3NNaO2Si (M +
Na) 514.2360, found 514.2359.
solid: [α]20 21.97 (c 0.83, CHCl3); FTIR (CHCl3, cast) 3384, 3062,
D
3028, 2922, 2858, 1733, 1671, 1585, 1495, 1454 cm−1; 1H NMR
(CDCl3, 500 MHz) δ 1.93 (s, 3 H), 3.43 (t, J = 9.5 Hz, 1 H), 3.61 (s, 2
H), 3.72 (dd, J = 5.5, 9.5 Hz, 1 H), 3.77 (dd, J = 5.5, 10 Hz, 1 H), 3.87
(s, 2 H), 4.25 (AB q, J = 13.0 Hz, ΔνAB = 30.3 Hz, 2 H), 6.71 (s, 1 H),
7.03 (dd, J = 1.5, 7.0 Hz, 1 H), 7.13−7.22 (m, 4 H), 7.26−7.35 (m, 3
H); 13C NMR (CDCl3, 125 MHz) δ 19.7 (q), 46.2 (t), 58.1 (t), 62.6
(t), 66.1 (d), 67.6 (t), 126.8 (d), 127.4 (d), 128.5 (d), 129.0 (d), 129.3
(d), 129.67 (d), 129.70 (d), 135.9 (s), 136.0 (s), 136.8 (s), 138.5 (s),
140.6 (s); exact mass (electrospray) m/z calcd for C20H24NO2 (M +
H) 310.1802, found 310.1803.
tert-Butyl N-{[2-Bromo-5-(trifluoromethyl)phenyl]methyl}-
carbamate (23c). Boc2O (157.7 mg, 0.72 mmol) in CH2Cl2 (2
mL) was added to a stirred solution of 23b17 (181.9 mg, 0.72 mmol)
in CH2Cl2 (5 mL). Stirring was continued for 14 h, and the solvent
was evaporated. Flash chromatography of the residue over silica gel
(2.8 × 14 cm), using 1:20 EtOAc/hexanes, gave 23c (242.1 mg, 95%)
as a white solid: FTIR (CHCl3, cast) 3296, 3062, 2986, 2936, 2817,
1
1678, 1646, 1603, 1582, 1518, 1475 cm−1; H NMR (CDCl3, 500
MHz) δ 1.48 (s, 9 H), 4.43 (d, J = 6.0 Hz, 2 H), 5.16 (s, 1 H), 7.40 (d,
J = 7.5 Hz, 1 H), 7.62 (s, 1 H), 7.67 (d, J = 8.5 Hz, 1 H); 13C NMR
1
(CDCl3, 125 MHz) δ 28.3 (q), 44.6 (t), 80.1 (s), 123.8 (CF3, JCF
=
3
272 Hz), 125.4 (CCCF3, JCF = 3.6 Hz), 125.7 (d), 127.0 (s), 130.1
2
(CCF3, JCF = 33.1 Hz), 133.3 (d), 139.2 (s), 155.8 (s); exact mass
(electrospray) m/z calcd for C13H15BrF3NNaO2 (M + Na) 376.0130,
found 376.0127.
Tris(propan-2-yl)silyl N-Benzyl-N-{[2-formyl-5-
(trifluoromethyl)phenyl]methyl}carbamate (23). OsO4 (1.0 M
in PhMe, 0.05 mL, 0.05 mmol) was added to a stirred solution of 23f
(273.1 mg, 0.56 mmol) in THF (4.5 mL) and water (1.5 mL). The
mixture was stirred for 8 min, during which time the solution turned
dark brown. NaIO4 (369.0 mg, 1.72 mmol) was then added slowly and
stirring was continued for 1 h. The mixture was filtered through Celite,
using EtOAc as a rinse. The filtrate was washed with water and brine,
dried (MgSO4), and evaporated. Flash chromatography of the residue
over silica gel (2.8 × 14 cm), using 1:20 EtOAc/hexanes, gave 23
(257.1 mg, 94%) as a light yellow oil: FTIR (CHCl3, cast) 3089, 3066,
3032, 2947, 2893, 2869, 2740, 1703, 1681, 1583, 1553, 1496 cm−1; 1H
NMR (CDCl3, 500 MHz) δ 0.99−1.14 (m, 18 H), 1.25−1.42 (m, 3
H), 4.57 and 4.62 (two s, 2 H), 4.97 and 5.01 (two s, 2 H), 7.22−7.35
(m, 5 H), 7.63 (s, 1 H), 7.71 (t, J = 8.0 Hz, 1 H), 7.95 (d, J = 8.0 Hz, 1
H), 10.17 and 10.22 (two s, 1 H); 13C NMR (CDCl3, 125 MHz)
(because of the presence of rotamers, the signal splitting by fluorine is
ignored) δ 12.0 (d), 12.1 (d), 17.7 (q), 17.8 (q), 47.47 (t), 47.54 (t),
51.4 (t), 51.6 (t), 120.0 (s), 120.1 (s), 122.2 (s), 122.3 (s), 123.97 (d),
123.99 (d), 124.18 (d), 124.21 (d), 124.3 (d), 124.4 (d), 124.5 (s),
124.79 (d), 124.81 (d), 126.6 (s), 126.7 (s), 127.3 (d), 127.6 (d),
127.7 (d), 128.0 (d), 128.4 (d), 128.7 (d), 128.8 (d), 133.4 (d), 134.6
(d), 134.8 (s), 134.9 (s), 135.0 (s), 135.2 (s), 135.3 (s), 135.4 (s),
tert-Butyl N-{[2-Ethenyl-5-(trifluoromethyl)phenyl]methyl}-
carbamate (23d). Ph3P (110.0 mg, 0.42 mmol) was added to a
stirred solution of Pd(OAc)2 (22.0 mg, 0.096 mmol) in PhMe (5 mL).
The color of the mixture turned yellow after several minutes. Bromide
23c (340.8 mg, 0.96 mmol) and tributyl(vinyl)tin (351.0 mg, 1.11
mmol) were then added sequentially. The solution was purged with a
stream of Ar for 5 min and then heated (Ar atmosphere) to 110−120
°C for 19 h, during which time the mixture turned black. The mixture
was cooled and filtered through Celite, using MeOH as a rinse.
Evaporation of the filtrate and flash chromatography of the residue
over silica gel (2.8 × 14 cm), using 1:20 EtOAc/hexanes, gave 23d
(275.8 mg, 95%) as a light yellow solid: FTIR (CHCl3, cast) 3342,
1
2980, 2934, 1696, 1619, 1514, 1456 cm−1; H NMR (CDCl3, 500
MHz) δ 1.48 (s, 9 H), 4.44 (d, J = 4.0 Hz, 2 H), 4.87 (s, 1 H), 5.48 (d,
J = 11.0 Hz, 1 H), 5.48 (d, J = 17.0 Hz, 1 H), 6.99 (dd, J = 11.0, 17.0
Hz, 1 H), 7.52−7.54 (m, 2 H), 7.60 (d, J = 7.5 Hz, 1 H); 13C NMR
(CDCl3, 125 MHz) δ 28.3 (q), 42.2 (t), 79.9 (s), 118.8 (t), 120.8 (s),
123.0 (s), 124.49 (d), 124.52 (d), 125.1 (d), 125.16 (d), 125.19 (s),
126.6 (d), 127.3 (s), 129.8 (CCF3, 2JCF = 32 Hz), 132.8 (d), 136.4 (s),
140.2 (s), 155.6 (s); exact mass (electrospray) m/z calcd for
C15H18F3NNaO2 (M + Na) 324.1182, found 324.1183.
tert-Butyl N-Benzyl-N-{[2-ethenyl-5-(trifluoromethyl)-
phenyl]methyl}carbamate (23e). A solution of 23d (275.8 mg,
3359
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135.5 (s), 136.1 (s), 137.0 (s), 137.2 (s), 141.2 (s), 141.9 (s), 155.3
(s), 155.4 (s), 191.8 (d), 192.0 (d); exact mass (electrospray) m/z
calcd for C26H34F3NNaO3Si (M + Na) 516.2152, found 516.2151.
Tris(propan-2-yl)silyl N-Benzyl-N-({2-[(S)-hydroxy[(5R)-5-
{[(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}-2-oxo-
2,5-dihydrofuran-3-yl]methyl]-5-(trifluoromethyl)phenyl}-
methyl)carbamate (23g). BuLi (2.5 M in hexane, 0.24 mL, 0.60
mmol) was added dropwise to a stirred and cooled (−20 °C) solution
of PhSeSePh (189.1 mg, 0.60 mmol) in THF (0.96 mL). After 10 min,
a portion of the freshly prepared PhSeLi solution (0.8 mL) was added
dropwise by syringe to a stirred and cooled (−42 °C) solution of 16
(92.0 mg, 0.39 mmol) and 23 (257.1 mg, 0.52 mmol) in THF (4.5
mL). Stirring was continued for 8 h at −42 °C (dry ice/MeCN), and
the mixture was quenched with saturated aqueous NH4Cl (4 mL) and
extracted with Et2O. The combined organic extracts were washed with
brine, dried (MgSO4), and evaporated. Flash chromatography of the
residue over silica gel (2.8 × 15 cm), using 1:5 EtOAc/hexanes, gave
23g (240.4 mg, 85%) as a colorless oil: FTIR (CHCl3, cast) 3421,
3089, 3066, 3033, 2951, 2929, 2869, 1770, 1680, 1655, 1587, 1556,
was washed with brine, dried (MgSO4), and evaporated. Flash
chromatography of the residue over silica gel (1.0 × 14 cm), using
1:20 EtOAc/hexanes, gave 23i (35.6 mg, 91%) as a white solid: mp
136−140 °C; [α]20 159.11 (c 1.47, CHCl3); FTIR (CHCl3, cast)
D
3087, 3064, 3029, 2955, 2925, 2870, 1764, 1666, 1617, 1496, 1455
1
cm−1; H NMR (CDCl3, 500 MHz) δ 0.79−1.06 (m, 12 H), 1.16−
1.22 (m, 1 H), 1.34−1.43 (m, 1 H), 1.61−1.69 (m, 2 H), 2.07−2.13
(m, 2 H), 3.52 (t, J = 3.5 Hz, 1 H), 3.61 (dt, J = 4.5, 11.0 Hz,1 H), 3.72
(AB q, J = 15 Hz, ΔνAB = 67.3 Hz, 2 H), 3.74 (AB q, J = 13.8 Hz, ΔνAB
= 27.5 Hz, 2 H), 5.69 (d, J = 3.5 Hz, 1 H), 7.32−7.42 (m, 6 H), 7.56
(d, J = 8.0 Hz, 1 H), 7.65 (dd, J = 1.5, 8.0 Hz, 1 H), 7.76 (d, J = 3.0
Hz, 1 H); 13C NMR (CDCl3, 125 MHz) δ 15.8 (q), 20.9 (q), 22.2 (q),
23.1 (t), 25.3 (d), 31.4 (d), 34.3 (t), 39.9 (t), 47.7 (d), 53.3 (t), 57.1
(t), 68.2 (d), 78.1 (d), 104.1 (d), 120.4 (s), 122.6 (s), 124.8 (JCF = 4.1
Hz), 126.9 (s), 127.4 (JCF = 3.6 Hz), 127.67 (d), 127.73 (d), 128.5
2
(d), 128.6 (d), 128.7 (d), 128.8 (d), 130.7 (CCF3, JCF = 32.7 Hz),
131.4 (d), 132.8 (s), 137.3 (d), 138.1 (s), 139.4 (s), 140.2 (s), 167.9
(s); exact mass (electrospray) m/z calcd for C30H35F3NO3 (M + H)
514.2564, found 514.2567.
1
1496 cm−1; H NMR (CDCl3, 500 MHz) δ 0.79−1.09 (m, 29 H),
[(3R)-2-Benzyl-3-(hydroxymethyl)-8-(trifluoromethyl)-2,3-di-
hydro-1H-2-benzaze-pin-4-yl]methanol (23j). DIBAL-H (1.0 M
in PhMe, 0.11 mL, 0.11 mmol) was added dropwise to a stirred and
cooled (−78 °C) solution of 23i (11.3 mg, 0.022 mmol) in THF (0.6
mL). Stirring at −78 °C was continued for 1 h, the cold bath was left
in place but not recharged, and stirring was continued for 7 h. MeOH
(0.1 mL) and a saturated aqueous solution of Rochelle’s salt (ca. 3
mL) were then added sequentially. Stirring was continued overnight,
and the mixture was extracted with EtOAc. The combined organic
extracts were washed with brine, dried (MgSO4), and evaporated.
Flash chromatography of the residue over silica gel (0.6 × 8 cm), using
2:1 EtOAc/hexanes, gave 23j (6.0 mg, 75%) as a light yellow solid:
1.22−1.47 (m, 5 H), 1.65−1.73 (m, 2 H), 2.11 (br s, 2 H), 3.32 (br s,
1 H), 3.60−3.68 (m, 1 H), 4.32−4.78 (m, 5 H), 5.67−6.02 (m, 2 H),
6.54 and 6.98 (two s, 1 H), 7.27−7.53 (m, 8 H); 13C NMR (CDCl3,
125 MHz) (because of the presence of rotamers, the signal splitting by
fluorine is ignored) δ 12.0 (d), 16.0 (q), 17.8 (q), 20.8 (q), 22.2 (q),
23.3 (t), 25.5 (d), 31.5 (d), 34.2 (t), 40.4 (t), 47.0 (t), 47.7 (d), 52.2
(t), 65.4 (d), 79.5 (d), 99.5 (d), 120.6 (s), 122.8 (s), 124.5 (d), 124.90
(d), 124.94 (s), 125.0 (d), 127.1 (s), 127.5 (d), 127.8 (d), 128.1 (d),
128.9 (d), 130.6 (s), 130.8 (s), 131.1 (s), 136.6 (s), 137.1 (s), 138.6
(s), 141.6 (s), 144.5 (d), 145.0 (d), 155.6 (s), 169.9 (s); exact mass
(electrospray) m/z calcd for C40H56F3NNaO6Si (M + Na) 754.3721,
found 754.3717.
[α]20 65.42 (c 1.35, CHCl3); FTIR (CHCl3, cast) 3375, 3087, 3064,
D
3030, 2922, 2855, 1650, 1616, 1495, 1455 cm−1; H NMR (CDCl3,
(S)-(2-{[Benzyl({[tris(propan-2-yl)silyl]oxy}carbonyl)amino]-
methyl}-4-(trifluoromethyl)phenyl)[(5R)-5-{[(1R,2S,5R)-5-meth-
yl-2-(propan-2-yl)cyclohexyl]oxy}-2-oxo-2,5-dihydrofuran-3-
yl]methyl Acetate (23h). DMAP (3.5 mg, 0.031 mmol) was added
to a stirred solution of 23g (240.0 mg, 0.33 mmol) in CH2Cl2 (4 mL).
The mixture was then cooled to 0 °C, and AcCl (0.11 mL, 1.52 mmol)
and pyridine (0.19 mL, 2.35 mmol) were added sequentially. The ice
bath was left in place but not recharged, and stirring was continued for
50 min. The mixture was quenched with hydrochloric acid (1 M, 3
mL) and water (3 mL), and the aqueous phase was extracted with
CH2Cl2. The combined organic extracts were washed with brine, dried
(MgSO4), and evaporated. Flash chromatography of the residue over
silica gel (2.8 × 14 cm), using 1:10 EtOAc/hexanes, gave 23h (243.7
mg, 96%) as a colorless oil: FTIR (CHCl3, cast) 3033, 2951, 2869,
1
500 MHz) δ 3.50−3.58 (m, 3 H), 3.72−3.77 (m, 2 H), 3.87 (dd, J =
5.5, 11.0 Hz, 1 H), 4.20 (d, J = 15.5 Hz, 1 H), 4.24 (AB q, J = 13.5 Hz,
ΔνAB = 20.6 Hz, 2 H), 6.76 (s, 1 H), 7.15−7.22 (m, 3 H), 7.28−7.35
(m, 3 H), 7.42 (d, J = 8.0 Hz, 1 H), 7.55 (d, J = 8.0 Hz, 1 H); 13C
NMR (CDCl3, 125 MHz) δ 56.1 (t), 57.2 (t), 62.4 (t), 65.9 (d), 67.0
(t), 120.8 (s), 122.9 (s), 124.2 (JCF = 3.9 Hz), 125.1 (s), 126.4 (JCF
=
3.6 Hz), 127.4 (d), 127.7 (d), 128.5 (d), 128.6 (d), 128.7 (s), 129.0
(s), 129.1 (d), 131.6 (d), 137.8 (s), 138.6 (s), 138.7 (s), 144.2 (s);
exact mass (electrospray) m/z calcd for C20H21F3NO2 (M + H)
364.1519, found 364.1514.
(2-Ethenylnaphthalen-1-yl)methanol (24d). NaBH4 (138.5 mg,
3.65 mmol) was added to a solution of 24c20 (132.7 mg, 0.73 mmol)
in THF (2 mL) and EtOH (2 mL) at room temperature. The mixture
was stirred for 30 min and quenched with cold water. The pH was
adjusted to 5−6, and the solution was stirred for 15 min. The mixture
was extracted with Et2O, and the combined organic extracts were dried
(MgSO4) and evaporated. Flash chromatography of the residue over
silica gel (1.4 × 14 cm), using 3:10 EtOAc/hexanes, gave 24d (127.7
mg, 95%) as a white solid: FTIR (CHCl3, cast) 3396, 3082, 3057,
1
1775, 1680, 1623, 1496, 1466 cm−1; H NMR (CDCl3, 500 MHz) δ
0.74−1.13 (m, 30 H), 1.20−1.42 (m, 5 H), 1.62−1.70 (m, 2 H), 2.00−
2.09 (m, 5 H), 3.57−3.64 (m, 1 H), 4.46−4.58 (m, 2 H), 4.69−4.84
(m, 2 H), 5.97 (d, J = 10.0 Hz, 1 H), 6.60 and 6.69 (two s, 1 H), 6.85
and 6.91 (two s, 1 H), 7.22−7.35 (m, 5 H), 7.44−7.53 (m, 3 H); 13C
NMR (CDCl3, 125 MHz) (because of the presence of rotamers, the
signal splitting by fluorine is ignored) δ 12.0 (d), 12.1 (d), 15.8 (q),
17.7 (q), 17.8 (q), 20.57 (q), 20.62 (q), 20.8 (q), 22.2 (q), 23.2 (t),
24.7 (t), 25.4 (d), 31.5 (d), 34.2 (t), 36.6 (t), 40.4 (t), 46.6 (t), 47.5
(t), 47.7 (d), 50.8 (t), 51.0 (t), 65.2 (d), 66.1 (d), 79.5 (d), 79.6 (d),
98.9 (d), 99.0 (d), 122.65 (s), 122.70 (s), 123.1 (d), 124.2 (d), 124.3
(d), 124.8 (s), 124.9 (s), 127.0 (s), 127.48 (d), 127.54 (d), 128.2 (d),
128.4 (d), 128.6 (d), 128.7 (d), 130.82 (s), 130.85 (s), 131.08 (s),
131.11 (s), 131.3 (s), 131.4 (s), 131.60 (s), 131.63 (s), 135.7 (s),
136.1 (s), 137.0 (s), 137.2 (s), 137.3 (s), 137.38 (s), 137.43 (s), 137.6
(s), 138.1 (s), 145.2 (d), 145.9 (d), 155.5 (s), 155.6 (s), 168.0 (s),
168.8 (s), 169.0 (s); exact mass (electrospray) m/z calcd for
C42H58F3NNaO7Si (M + Na) 796.3827, found 796.3825.
(6R,7R)-8-Benzyl-6-{[(1R,2S,5R)-5-methyl-2-(propan-2-yl)-
cyclohexyl]oxy}-12-(trifluoromethyl)-5-oxa-8-azatricyclo-
[8.4.0.03,7]tetradeca-1(14),2,10,12-tetraen-4-one (23i). Bu3NF
(1.0 M in THF, 0.076 mL, 0.076 mmol) was added to a stirred and
cooled (0 °C) solution of 23h (58.9 mg, 0.076 mmol) in THF (1 mL).
After 10 min, the mixture was quenched with saturated aqueous
NH4Cl (3 mL) and diluted with EtOAc (4 mL). The organic phase
1
2993, 2948, 2911, 1620, 1596, 1513, 1497 cm−1; H NMR (CDCl3,
500 MHz) δ 1.71 (s, 1 H), 5.19 (s, 2 H), 5.50 (dd, J = 1.0, 11.0 Hz, 1
H), 5.81 (dd, J = 1.0, 17.5 Hz, 1 H), 7.33 (dd, J = 11.0, 17.5 Hz, 1 H),
7.46−7.50 (m, 1 H), 7.54−7.75 (m, 1 H), 7.65 (d, J = 8.5 Hz, 1 H),
7.79 (d, J = 9.0 Hz, 1 H), 7.83 (d, J = 9.0 Hz, 1 H), 8.23 (d, J = 8.5 Hz,
1 H); 13C NMR (CDCl3, 125 MHz) δ 58.1 (t), 118.1 (t), 124.4 (d),
124.5 (d), 126.1 (d), 127.2 (d), 128.8 (d), 129.2 (d), 132.5 (s), 132.6
(s), 133.7 (s), 134.7 (d), 135.1 (s); HRMS (EI) m/z calcd for
C13H12O 184.0888, found 184.0885.
1-(Bromomethyl)-2-ethenylnaphthalene (24e). Ph3P (156.2
mg, 0.59 mmol) and CBr4 (195.7 mg, 0.59 mmol) were added
successively to a stirred and cooled (0 °C) solution of 24d (90.4 mg,
0.49 mmol) in CH2Cl2 (2.5 mL). After 1 h at 0 °C, the solvent was
evaporated. Flash chromatography of the residue over silica gel (1.4 ×
14 cm), using 1:50 EtOAc/hexanes, gave 24e (104.5 mg, 86%) as a
white solid: FTIR (CHCl3, cast) 3085, 3057, 3020, 1618, 1595, 1564,
1
1512, 1470 cm−1; H NMR (CDCl3, 500 MHz) δ 5.07 (s, 2 H), 5.60
(dd, J = 1.0, 11.0 Hz, 1 H), 5.89 (dd, J = 1.0, 17.5 Hz, 1 H), 7.27 (dd, J
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= 11.0, 17.5 Hz, 1 H), 7.49−7.52 (m, 1 H), 7.60−7.63 (m, 2 H), 7.81
(d, J = 8.5 Hz, 1 H), 7.84 (d, J = 8.5 Hz, 1 H), 8.15 (d, J = 8.5 Hz, 1
H); 13C NMR (CDCl3, 125 MHz) δ 27.3 (t), 118.4 (t), 123.6 (d),
124.2 (d), 126.0 (d), 127.0 (d), 128.6 (d), 129.4 (s), 129.5 (d), 131.4
(s), 133.4 (s), 134.0 (d), 135.0 (s); HRMS (EI) m/z calcd for
C13H11Br 246.0044, found 246.0046.
and the filtrate was washed with water and brine, dried (MgSO4), and
evaporated. Flash chromatography of the residue over silica gel (1.8 ×
14 cm), using 1:20 EtOAc/hexanes, gave 24 (193.7 mg, 86%) as a light
yellow oil: FTIR (CHCl3, cast) 3287, 3064, 2945, 2892, 2867, 1675,
1
1623, 1599, 1549, 1496 cm−1; H NMR (CDCl3, 500 MHz) δ 1.10−
1.29 (m, 18 H), 1.37−1.57 (m, 3 H), 4.21−4.24 (m, 2 H), 5.55 (s, 2
H), 6.94−7.01 (m, 2 H), 7.23−7.29 (m, 3 H), 7.58 (t, J = 7.5 Hz, 1
H), 7.65−7.67 (m, 1 H), 7.90−7.95 (m, 3 H), 8.34−8.43 (m, 1 H),
9.98 and 10.11 (two s, 1 H); 13C NMR (CDCl3, 125 MHz) δ 12.2 (d),
12.3 (d), 17.7 (q), 17.9 (q), 18.1 (q), 39.7 (t), 40.7 (t), 47.7 (t), 48.6
(t), 123.4 (d), 123.57 (d), 123.64 (d), 125.3 (d), 126.0 (d), 126.6 (d),
127.2 (d), 127.4 (d), 127.5 (d), 128.7 (d), 128.8 (d), 128.9 (d), 129.3
(d), 129.39 (d), 129.42 (d), 132.4 (s), 133.3 (s), 133.5 (s), 136.1 (s),
136.6 (s), 137.0 (s), 137.1 (s), 137.2 (s), 155.1 (s), 155.3 (s), 190.4
(d), 190.9 (d); exact mass (electrospray) m/z calcd for C29H38NO3Si
(M + H) 476.2615, found 476.2612.
Benzyl[(2-ethenylnaphthalen-1-yl)methyl]amine (24f). A sol-
ution of 24e (147.3 mg, 0.60 mmol) and BnNH2 (0.2 mL, 1.79 mmol)
in THF (1.5 mL) was stirred at room temperature for 22 h and then
diluted with EtOAc. The mixture was washed twice with aqueous
NaOH (1 M) and brine, dried (MgSO4), and evaporated. Flash
chromatography of the residue over silica gel (1.8 × 14 cm), using 1:5
EtOAc/hexanes, gave 24f (149.1 mg, 92%) as a yellow oil: FTIR
(CHCl3, cast) 3324, 3084, 3061, 3026, 2917, 2850, 1665, 1622, 1597,
1564, 1511, 1495 cm−1; 1H NMR (CDCl3, 500 MHz) δ 1.57 (s, 1 H),
3.98 (s, 2 H), 4.26 (s, 2 H), 5.43 (dd, J = 1.0, 11.0 Hz, 1 H), 5.80 (dd,
J = 1.0, 17.5 Hz, 1 H), 7.22 (dd, J = 11.0, 17.0 Hz, 1 H), 7.29−7.32 (m,
1 H), 7.36−7.52 (m, 6 H), 7.66 (d, J = 8.5 Hz, 1 H), 7.75 (d, J = 9.0
Hz, 1 H), 7.81 (d, J = 8.0 Hz, 1 H), 8.06 (d, J = 8.5 Hz, 1 H); 13C
NMR (CDCl3, 125 MHz) δ 45.3 (t), 54.2 (t), 116.9 (t), 123.9 (d),
124.3 (d), 125.6 (d), 126.6 (d), 127.1 (d), 128.0 (d), 128.35 (d),
128.43 (d), 128.5 (d), 132.6 (s), 132.7 (s), 133.5 (s), 134.4 (s), 134.8
(d), 140.4 (s); exact mass (electrospray) m/z calcd for C20H20N (M +
H) 274.1590, found 274.1591.
tert-Butyl N-Benzyl-N-[(2-ethenylnaphthalen-1-yl)methyl]-
carbamate (24g). DMAP (155.0 mg, 1.26 mmol) and Boc2O
(222.0 mg, 1.01 mmol) were added successively to a stirred solution of
24f (137.5 mg, 0.50 mmol) in MeCN (5 mL). Stirring was continued
for 24 h, and the solvent was evaporated. Flash chromatography of the
residue over silica gel (1.8 × 14 cm), using 1:20 Et2O/hexanes, gave
24g (155.6 mg, 83%) as a colorless oil: FTIR (CHCl3, cast) 3087,
3062, 3031, 3007, 2975, 2931, 1689, 1622, 1605, 1511, 1496 cm−1; 1H
NMR (CDCl3, 500 MHz) δ 1.40−1.80 (m, 9 H), 4.15 (s, 2 H), 5.19
(s, 2 H), 5.31 (d, J = 11.0 Hz, 1 H), 5.71 (d, J = 17.0 Hz, 1 H), 7.04 (d,
J = 7.0 Hz, 3 H), 7.20−7.30 (m, 3 H), 7.48−7.54 (m, 2 H), 7.64 (d, J =
8.5 Hz, 1 H), 7.80 (d, J = 9.0 Hz, 1 H), 7.82−7.86 (m, 1 H), 8.20 (br s,
1 H); 13C NMR (CDCl3, 125 MHz) δ 28.5 (q), 41.5 (t), 47.6 (t), 80.2
(s), 117.3 (t), 124.0 (d), 124.8 (d), 125.8 (d), 126.7 (d), 126.8 (d),
126.9 (d), 127.0 (d), 128.3 (d), 128.5 (d), 128.7 (d), 132.9 (s), 133.4
(s), 134.8 (d), 136.2 (s), 138.5 (s), 155.9 (s); exact mass
(electrospray) m/z calcd for C25H27NNaO2 (M + Na) 396.1934,
found 396.1937.
Tris(propan-2-yl)silyl N-Benzyl-N-({2-[(S)-hydroxy[(5R)-5-
{[(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}-2-oxo-
2,5-dihydrofuran-3-yl]methyl]naphthalen-1-yl}methyl)-
carbamate (24i). BuLi (2.5 M in hexane, 0.37 mL, 0.87 mmol) was
added dropwise to a stirred and cooled (−20 °C) solution of
PhSeSePh (274.0 mg, 0.87 mmol) in THF (2.03 mL). After 10 min, a
portion of the freshly prepared PhSeLi solution (0.8 mL) was added
dropwise by syringe to a stirred and cooled (−42 °C) solution of 16
(64.8 mg, 0.27 mmol) and 24 (168.1 mg, 0.35 mmol) in THF (3 mL).
Stirring was continued for 9 h at −42 °C (dry ice/MeCN), and the
mixture was quenched with saturated aqueous NH4Cl (3 mL) and
extracted with Et2O. The combined organic extracts were washed with
brine, dried (MgSO4), and evaporated. Flash chromatography of the
residue over silica gel (1.8 × 15 cm), using 3:20 EtOAc/hexanes, gave
24i (145.0 mg, 75%) as a colorless oil: FTIR (CHCl3, cast) 3434,
3061, 3033, 2950, 2928, 2868, 2726, 1770, 1671, 1605, 1553, 1513,
1
1496, 1461 cm−1; H NMR (CDCl3, 500 MHz) δ 0.77−1.68 (m, 37
H), 2.02−2.16 (m, 2 H), 3.21 (s, 1 H), 3.58−3.67 (m, 1 H), 4.09 (d, J
= 16.5 Hz, 1 H), 4.61−4.78 (m, 1 H), 4.90−5.10 (m, 1 H), 5.39−5.48
(m, 1 H), 5.71 (s, 1 H), 5.94 (s, 1 H), 6.68 (s, 1 H), 6.99−7.17 (m, 2
H), 7.28−7.34 (m, 3 H), 7.50−7.54 (m, 3 H), 7.84−7.86 (m, 2 H),
8.21 (d, J = 8.0 Hz, 1 H); 13C NMR (CDCl3, 125 MHz) δ 12.2 (d),
15.8 (q), 17.9 (q), 20.8 (q), 22.2 (q), 23.3 (t), 25.3 (d), 31.5 (d), 34.2
(t), 40.4 (t), 42.1 (t), 47.6 (d), 48.9 (t), 65.6 (d), 79.4 (d), 99.3 (d),
124.1 (d), 125.1 (d), 126.3 (d), 126.4 (d), 126.9 (d), 127.3 (d), 128.5
(d), 128.7 (d), 129.4 (d), 129.8 (s), 132.5 (s), 133.5 (s), 137.3 (s),
137.7 (s), 139.5 (s), 144.4 (d), 155.5 (s), 169.9 (s); exact mass
(electrospray) m/z calcd for C43H59NNaO6Si (M + Na) 736.4004,
found 736.4002.
Tris(propan-2-yl)silyl N-Benzyl-N-[(2-ethenylnaphthalen-1-
yl)methyl]carbamate (24h). 2,6-Lutidine (0.036 mL, 0.31 mmol)
and i-Pr3SiOSO2CF3 (0.075 mL, 0.27 mmol) were added successively
to a stirred solution of 24g (57.1 mg, 0.15 mmol) in ClCH2CH2Cl (2
mL) and stirring was continued for 24 h. The mixture was washed with
saturated aqueous NH4Cl and brine, dried (MgSO4), and evaporated.
Flash chromatography of the residue over silica gel (1.2 × 14 cm),
using 1:25 Et2O/hexanes, gave 24h (71.0 mg, 98%) as a colorless oil:
FTIR (CHCl3, cast) 3087, 3063, 3033, 2945, 2892, 2867, 1674, 1623,
(S)-(1-{[Benzyl({[tris(propan-2-yl)silyl]oxy}carbonyl)amino]-
methyl}naphthalen-2-yl)[(5R)-5-{[(1R,2S,5R)-5-methyl-2-(prop-
an-2-yl)cyclohexyl]oxy}-2-oxo-2,5-dihydrofuran-3-yl]methyl
Acetate (24j). DMAP (2.8 mg, 0.023 mmol) was added to a stirred
solution of 24i (129.8 mg, 0.18 mmol) in CH2Cl2 (2.5 mL). The
mixture was then cooled to 0 °C, and AcCl (0.06 mL, 0.83 mmol) and
pyridine (0.11 mL, 1.36 mmol) were added sequentially. The ice bath
was left in place but not recharged, and stirring was continued for 1 h.
The mixture was quenched with hydrochloric acid (1 M, 3 mL) and
water (4 mL), and the aqueous phase was extracted with CH2Cl2. The
combined organic extracts were washed with brine, dried (MgSO4),
and evaporated. Flash chromatography of the residue over silica gel
(1.4 × 14 cm), using 3:25 EtOAc/hexanes, gave 24j (133.0 mg, 97%)
as a colorless oil: FTIR (CHCl3, cast) 3063, 3033, 2949, 2868, 2726,
1775, 1751, 1672, 1605, 1558, 1513, 1496, 1459 cm−1; 1H NMR
(CDCl3, 500 MHz) δ 0.76−1.56 (m, 35 H), 1.66−1.70 (m, 2 H),
2.03−2.13 (m, 5 H), 3.64 (dt, J = 4.0, 10.5 Hz, 1 H), 4.27−4.41 (m, 2
H), 5.31−5.49 (m, 2 H), 5.96 (s, 1 H), 6.76−6.92 (m, 2 H), 7.04 (d, J
= 7.0 Hz, 2 H), 7.10−7.22 (m, 3 H), 7.46−7.54 (m, 3 H), 7.83 (d, J =
9.0 Hz, 2 H), 8.21 and 8.30 (two d, J = 8.5 Hz, 1 H); 13C NMR
(CDCl3, 125 MHz) δ 12.2 (d), 12.3 (d), 15.9 (q), 17.8 (q), 18.1 (q),
20.7 (q), 20.9 (q), 22.2 (q), 23.3 (t), 25.4 (d), 31.5 (d), 34.2 (t), 40.5
(t), 42.8 (t), 47.7 (d), 48.4 (t), 67.4 (d), 79.4 (d), 98.7 (d), 124.2 (d),
125.6 (d), 125.9 (d), 126.6 (d), 126.7 (d), 127.0 (d), 128.3 (d), 128.4
(d), 129.3 (d), 131.6 (s), 132.8 (s), 133.6 (s), 133.7 (s), 136.8 (s),
1
1606, 1560, 1511, 1496 cm−1; H NMR (CDCl3, 500 MHz) δ 1.11−
1.30 (m, 18 H), 1.36−1.56 (m, 3 H), 4.22 (s, 2 H), 5.23−5.29 (m, 3
H), 5.66−5.72 (m, 1 H), 6.86−7.07 (m, 3 H), 7.21−7.29 (m, 3 H),
7.42−7.51 (m, 2 H), 7.62−7.65 (m, 1 H), 7.79−7.85 (m, 2 H), 8.11−
8.23 (m, 1 H); 13C NMR (CDCl3, 125 MHz) δ 12.2 (d), 12.3 (d),
17.9 (q), 18.1 (q), 42.0 (t), 43.0 (t), 47.4 (t), 48.2 (t), 117.4 (t), 123.9
(d), 124.1 (d), 124.3 (d), 125.0 (d), 125.8 (d), 125.9 (d), 126.5 (d),
126.6 (d), 126.8 (d), 127.3 (d), 128.2 (d), 128.3 (d), 128.4 (d), 128.5
(d), 128.7 (d), 128.8 (d), 129.3 (s), 132.8 (s), 132.9 (s), 133.3 (s),
134.5 (d), 134.6 (d), 136.2 (s), 137.9 (s), 138.0 (s), 155.2 (s), 155.4
(s); exact mass (electrospray) m/z calcd for C30H40NO2Si (M + H)
474.2823, found 474.2821.
Tris(propan-2-yl)silyl N-Benzyl-N-[(2-formylnaphthalen-1-
yl)methyl]carbamate (24). OsO4 (1.0 M in PhMe, 0.05 mL, 0.05
mmol) was added to a stirred solution of 24g (224.5 mg, 0.48 mmol)
in THF (4 mL) and water (1.3 mL). The mixture was stirred for 7
min, during which time the solution turned dark brown. NaIO4 (315.0
mg, 1.47 mmol) was then added slowly, and stirring was continued for
1.5 h. The mixture was filtered through Celite, using EtOAc as a rinse,
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137.8 (s), 145.9 (d), 155.6 (s), 168.0 (s), 169.1 (s); exact mass
(electrospray) m/z calcd for C45H61NNaO7Si (M + Na) 778.4110,
found 778.4103.
stirred solution of Pd(OAc)2 (15.7 mg, 0.071 mmol) in PhMe (4 mL).
The color of the mixture turned yellow after several minutes. Bromide
25d (258.9 mg, 0.69 mmol) and tributyl(vinyl)tin (261.3 mg, 0.82
mmol) were then added sequentially. The solution was purged with a
stream of Ar for 10 min and then heated (Ar atmosphere) to 110−120
°C for 18 h, during which time the solution turned black. The mixture
was cooled and filtered through Celite, using MeOH as a rinse.
Evaporation of the filtrate and flash chromatography of the red residue
over silica gel (2.8 × 14 cm), using 1:5 EtOAc/hexanes, gave 25e
(203.9 mg, 91%) as a light yellow oil: FTIR (CHCl3, cast) 3088, 3063,
3027, 2976, 2928, 2873, 1695, 1605, 1584, 1561, 1496 cm−1; 1H NMR
(CDCl3, 500 MHz) δ 1.48 (s, 9 H), 4.29−4.53 (m, 4 H), 5.47 (dd, J =
2.0, 10.5 Hz, 1 H), 6.35 (dd, J = 2.0, 17.0 Hz, 1 H), 6.93 (br s, 1 H),
7.12−7.22 (m, 3 H), 7.24−7.33 (m, 3 H), 7.42 (d, J = 7.5 Hz, 1 H),
8.50 (dd, J = 1.5, 4.5 Hz, 1 H); 13C NMR (CDCl3, 125 MHz) δ 28.4
(q), 45.8 (t), 49.3 (t), 80.5 (s), 120.2 (t), 122.4 (d), 127.4 (d), 128.6
(d), 130.0 (s), 132.3 (d), 137.5 (s), 148.4 (d), 155.7 (s); exact mass
(electrospray) m/z calcd for C20H25N2O2 (M + H) 325.1911, found
325.1911.
(15R,16R)-17-Benzyl-15-{[(1R,2S,5R)-5-methyl-2-(propan-2-
yl)cyclohexyl]oxy}-14-oxa-17-azatetracyclo[8.8.0.02,7.012,16]-
octadeca-1,3,5,7,9,11-hexaen-13-one (24k). Bu3NF (1.0 M in
THF, 0.16 mL, 0.16 mmol) was added to a stirred and cooled (0 °C)
solution of 24j (120.0 mg, 0.16 mmol) in THF (2 mL). After 10 min,
the mixture was quenched with saturated aqueous NH4Cl (3 mL) and
diluted with EtOAc (4 mL). The organic phase was washed with brine,
dried (MgSO4), and evaporated. Flash chromatography of the residue
over silica gel (1.2 × 14 cm), using 3:50 EtOAc/hexanes, gave 24k
(78.3 mg, 99%) as a light yellow solid: mp 183−184 °C; [α]20D 54.89
(c 0.98, CHCl3); FTIR (CHCl3, cast) 3057, 3026, 2954, 2924, 2869,
1763, 1658, 1618, 1596, 1559, 1511, 1495, 1454 cm−1; 1H NMR
(CDCl3, 500 MHz) δ 0.74−1.17 (m, 13 H), 1.32−1.43 (m, 1 H),
1.61−1.67 (m, 2 H), 2.05−2.15 (m, 2 H), 3.20 (t, J = 2.0 Hz, 1 H),
3.64 (dt, J = 4.0, 10.5 Hz, 1 H), 3.84 (AB q, J = 15.0 Hz, ΔνAB = 19.4
Hz, 2 H), 4.08 (AB q, J = 15.0 Hz, ΔνAB = 276.1 Hz, 2 H), 5.73 (d, J =
2.0 Hz, 1 H), 7.41 (t, J = 7.0 Hz, 1 H), 7.48−7.59 (m, 7 H), 7.81 (d, J
= 8.5 Hz, 1 H), 7.90 (t, J = 7.0 Hz, 2 H), 8.02 (d, J = 2.5 Hz, 1 H); 13C
NMR (CDCl3, 125 MHz) δ 15.7 (q), 20.9 (q), 22.2 (q), 23.1 (t), 25.3
(d), 31.4 (d), 34.3 (t), 39.6 (t), 46.9 (t), 47.7 (d), 57.7 (t), 67.3 (d),
77.2 (d), 124.4 (d), 126.5 (d), 126.9 (d), 127.0 (d), 127.6 (d), 128.2
(d), 128.5 (d), 128.66 (d), 128.71 (d), 130.9 (s), 133.4 (s), 133.5 (s),
135.3 (s), 137.8 (s), 138.9 (s), 140.8 (d), 168.7 (s); exact mass
(electrospray) m/z calcd for C33H38NO3 (M + H) 496.2846, found
496.2843.
[(3R)-2-Benzyl-3-(hydroxymethyl)-1H,2H,3H-naphtho[1,2-c]-
azepin-4-yl]methanol (24l). DIBAL-H (1.0 M in PhMe, 0.79 mL,
0.79 mmol) was added dropwise to a stirred and cooled (−78 °C)
solution of 24k (78.3 mg, 0.16 mmol) in THF (2 mL). Stirring at −78
°C was continued for 1 h, the cold bath was left in place but not
recharged, and stirring was continued overnight. MeOH (0.3 mL) and
a saturated aqueous solution of Rochelle’s salt (ca. 5 mL) were then
added sequentially. Stirring was continued for 2.5 h, and the mixture
was extracted with EtOAc. The combined organic extracts were
washed with brine, dried (MgSO4), and evaporated. Flash chromatog-
raphy of the residue over silica gel (1.2 × 14 cm), using 1:20 MeOH/
Et2O, gave 24l (45.0 mg, 82%) as a white solid: [α]20D −26.39 (c 0.91,
CHCl3); FTIR (CHCl3, cast) 3367, 3079, 3063, 3024, 2983, 2964,
2946, 2918, 2894, 2874, 2843, 1598, 1511, 1493, 1453 cm−1; 1H NMR
(CDCl3, 500 MHz) δ 2.05 (br s, 2 H), 3.36 (t, J = 9.5 Hz, 1 H), 3.65−
3.75 (m, 4 H), 4.26−4.39 (m, 4 H), 6.89 (s, 1 H), 7.20−7.22 (m, 2 H),
7.29−7.31 (m, 3 H), 7.37−7.39 (m, 2 H), 7.44−7.47 (m, 1 H), 7.71
(d, J = 8.5 Hz, 1 H), 7.77 (d, J = 8.5 Hz, 1 H), 7.83 (dd, J = 1.3, 8.5
Hz, 1 H); 13C NMR (CDCl3, 125 MHz) δ 46.3 (t), 59.1 (t), 62.9 (t),
65.8 (d), 67.6 (t), 123.4 (d), 125.7 (d), 126.4 (d), 127.4 (d), 127.5
(d), 128.3 (d), 128.49 (d), 128.53 (d), 129.1 (d), 129.7 (d), 132.1 (s),
132.7 (s), 133.5 (s), 133.7 (s), 138.7 (s), 142.5 (s); exact mass
(electrospray) m/z calcd for C23H24NO2 (M + H) 346.1802, found
346.1801.
Tris(propan-2-yl)silyl N-Benzyl-N-[(2-ethenylpyridin-3-yl)-
methyl]carbamate (25f). 2,6-Lutidine (0.15 mL, 1.29 mmol) and
i-Pr3SiOSO2CF3 (0.31 mL, 1.13 mmol) were added successively to a
stirred solution of 25e (193.9 mg, 0.60 mmol) in ClCH2CH2Cl (6.5
mL). After 15 min, the mixture was lowered into a preheated oil bath
set at 96 °C, and stirring was continued for 4 h. The mixture was
cooled, evaporated, and diluted with Et2O (10 mL). The solution was
washed with saturated aqueous NH4Cl and brine, dried (MgSO4), and
evaporated. Flash chromatography of the residue over silica gel (2.8 ×
18 cm), using 1:5 t-BuOMe/hexanes, gave 25f (232.8 mg, 92%) as a
colorless oil: FTIR (CHCl3, cast) 3063, 3028, 2945, 2892, 2867, 2726,
1
1680, 1606, 1584, 1561, 1496 cm−1; H NMR (CDCl3, 500 MHz) δ
1.05 (d, J = 7.5 Hz) and 1.09 (d, J = 7.5 Hz, both signals together 18
H), 1.29−1.39 (m, 3 H), 4.36−4.59 (m, 4 H), 5.47 (dd, J = 2.0, 11.0
Hz, 1 H), 6.33−6.40 (m, 1 H), 6.85 (dd, J = 10.5, 17.0 Hz) and 6.99
(dd, J = 11.0, 17.0 Hz, both signals together 1 H), 7.11−7.17 (m, 2 H),
7.21−7.34 (m, 4 H), 7.41−7.45 (m, 1 H), 8.49−8.52 (m, 1 H); 13C
NMR (CDCl3, 125 MHz) δ 12.05 (d), 12.11 (d), 17.8 (q), 17.9 (q),
46.1 (t), 46.7 (t), 49.6 (t), 49.7 (t), 120.4 (t), 120.5 (t), 122.4 (d),
122.5 (d), 127.1 (d), 127.4 (d), 127.5 (d), 128.0 (d), 128.7 (d), 129.6
(s), 129.7 (s), 131.8 (d), 132.4 (d), 135.0 (d), 136.9 (d), 137.1 (s),
137.3 (s), 148.2 (d), 148.5 (d), 153.0 (s), 153.8 (s), 155.2 (s), 155.3
(s); exact mass (electrospray) m/z calcd for C25H37N2O2Si (M + H)
425.2619, found 425.2621.
Tris(propan-2-yl)silyl N-Benzyl-N-[(2-formylpyridin-3-yl)-
methyl]carbamate (25). OsO4 (1.0 M in PhMe, 0.1 mL, 0.1
mmol) was added to a stirred solution of 25f (216.0 mg, 0.51 mmol)
in THF (4.5 mL) and water (1.5 mL). The mixture was stirred for 7
min, during which time the solution turned dark brown. NaIO4 (338.0
mg, 1.58 mmol) was then added slowly, and stirring was continued for
2 h. The mixture was filtered through Celite, using EtOAc as a rinse.
The filtrate was washed with water and brine, dried (MgSO4), and
evaporated. Flash chromatography of the residue over silica gel (1.8 ×
14 cm), using 3:20 EtOAc/hexanes, gave 25 (156.3 mg, 79%) as a light
yellow oil: FTIR (CHCl3, cast) 3063, 3028, 2945, 2892, 2867, 2726,
tert-Butyl N-Benzyl-N-[(2-bromopyridin-3-yl)methyl]-
carbamate (25d). DMAP (54.6 mg, 0.44 mmol) and then a solution
of Boc2O (97.6 mg, 0.44 mmol) in MeCN (0.5 mL) were added
successively to a stirred solution of 25c22 (61.4 mg, 0.22 mmol) in
MeCN (2.5 mL), and stirring was continued for 30 h. Evaporation of
the solvent and flash chromatography of the residue over silica gel (1.2
× 14 cm), using 1:5 EtOAc/hexanes, gave 25d (70.4 mg, 84%) as a
colorless oil: FTIR (CHCl3, cast) 3031, 2976, 2930, 1697, 1605, 1578,
1561, 1496 cm−1; 1H NMR (CDCl3, 500 MHz) δ 1.43 and 1.51 (two
br s, 9 H), 4.41−4.53 (m, 4 H), 7.22−7.35 (m, 6 H), 7.43 and 7.54
(two s, 1 H), 8.26 (dd, J = 1.5, 4.5 Hz, 1 H); 13C NMR (CDCl3, 125
MHz) δ 28.4 (q), 49.1 (t), 49.4 (t), 50.5 (t), 50.9 (t), 80.7 (s), 123.0
(d), 127.6 (d), 128.1 (d), 128.7 (d), 134.6 (s), 134.7 (s), 135.9 (d),
136.9 (d), 137.4 (s), 137.5 (s), 142.4 (s), 142.8 (s), 148.5 (d), 155.8
(s); exact mass (electrospray) m/z calcd for C18H22BrN2O2 (M + H)
377.0859, found 377.0860.
1
1680, 1606, 1584, 1561, 1496 cm−1; H NMR (CDCl3, 500 MHz) δ
0.98 (d, J = 7.5 Hz) and 1.11 (d, J = 7.5 Hz, both signals together 18
H), 1.21−1.40 (m, 3 H), 4.52 and 4.59 (two s, 2 H), 4.95 and 5.02
(two s, 2 H), 7.20−7.34 (m, 5 H), 7.44−7.48 (m, 1 H), 7.73 (d, J = 7.5
Hz) and 7.78 (d, J = 7.5 Hz, both signals together 1 H), 8.70 (t, J = 6.0
Hz, 1 H), 10.11 and 10.14 (two s, 1 H); 13C NMR (CDCl3, 125 MHz)
δ 12.0 (d), 12.1 (d), 17.7 (q), 17.9 (q), 46.6 (t), 47.5 (t), 51.5 (t), 52.0
(t), 126.91 (d), 126.95 (d), 127.3 (d), 127.5 (d), 127.7 (d), 128.0 (d),
128.6 (d), 128.7 (d), 134.7 (d), 135.6 (d), 136.2 (s), 136.7 (s), 137.19
(s), 137.23 (s), 148.2 (d), 148.3 (d), 149.1 (s), 149.4 (s), 155.5 (s),
155.6 (s), 195.5 (d), 195.6 (d); exact mass (electrospray) m/z calcd
for C24H35N2O3Si (M + H) 427.2411, found 427.2410.
Tris(propan-2-yl)silyl N-Benzyl-N-({2-[(R)-hydroxy[(5R)-5-
{[(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}-2-oxo-
2,5-dihydrofuran-3-yl]methyl]pyridin-3-yl}methyl)carbamate
(25g). BuLi (2.5 M in hexane, 0.21 mL, 0.525 mmol) was added
tert-Butyl N-Benzyl-N-[(2-ethenylpyridin-3-yl)methyl]-
carbamate (25e). Ph3P (79.0 mg, 0.30 mmol) was added to a
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dropwise to a stirred and cooled (−20 °C) solution of PhSeSePh
(167.2 mg, 0.525 mmol) in THF (0.99 mL). After 10 min, a portion of
the freshly prepared PhSeLi solution (0.4 mL) was added dropwise by
syringe to a stirred and cooled (−42 °C) solution of 16 (40.5 mg, 0.17
mmol) and 25 (108.8 mg, 0.255 mmol) in THF (1.7 mL). Stirring was
continued for 9 h at −42 °C (dry ice/MeCN). The mixture was
quenched with saturated aqueous NH4Cl (3 mL) and extracted with
Et2O. The combined organic extracts were washed with brine, dried
(MgSO4), and evaporated. Flash chromatography of the residue over
silica gel (1.4 × 15 cm), using 3:10 EtOAc/hexanes, gave 25g (70.0
mg, 62%) as a colorless oil: FTIR (CHCl3, cast) 3412, 3089, 3064,
3031, 2949, 2928, 2868, 1770, 1680, 1606, 1579, 1496, 1465 cm−1; 1H
NMR (CDCl3, 500 MHz) δ 0.75−1.44 (m, 34 H), 1.67 (t, J = 12.5 Hz,
2 H), 2.02−2.12 (m, 2 H), 3.60 (dt, J = 4.0, 10.5 Hz, 1 H), 4.38−4.65
(m, 4 H), 4.72−4.92 (m, 1 H), 5.49−5.66 (m, 1 H), 5.94 (s, 1 H), 6.80
and 6.89 (two s, 1 H), 7.21−7.37 (m, 6 H), 7.54−7.59 (m, 1 H), 8.49
(d, J = 4.5 Hz, 1 H); 13C NMR (CDCl3, 125 MHz) δ 12.0 (d), 12.1
(d), 15.78 (q), 15.83 (q), 17.9 (q), 20.9 (q), 22.2 (q), 23.1 (t), 23.2
(t), 25.3 (d), 31.5 (d), 34.2 (t), 40.6 (t), 45.6 (t), 46.2 (t), 47.7 (d),
50.7 (t), 51.1 (t), 64.3 (d), 64.9 (d), 79.0 (d), 79.4 (d), 99.19 (d),
99.24 (d), 123.4 (d), 127.2 (d), 127.3 (d), 127.7 (d), 128.1 (d), 128.2
(d), 128.75 (d), 128.78 (d), 130.8 (s), 130.9 (s), 135.1 (d), 136.5 (d),
137.0 (s), 137.2 (s), 139.0 (s), 139.2 (s), 145.1 (d), 145.3 (d), 147.2
(d), 147.4 (d), 154.7 (s), 155.3 (s), 155.5 (s), 155.6 (s), 169.5 (s);
exact mass (electrospray) m/z calcd for C38H57N2O6Si (M + H)
665.3980, found 665.3977.
2.13 (m, 2 H), 3.53 (t, J = 3.5 Hz, 1 H), 3.57−3.77 (m, 5 H), 5.68 (d, J
= 3.5 Hz, 1 H), 7.21 (dd, J = 5.0, 8.0 Hz, 1 H), 7.29−7.44 (m, 6 H),
7.85 (d, J = 3.0 Hz, 1 H), 8.67 (dd, J = 1.5, 4.5 Hz, 1 H); 13C NMR
(CDCl3, 125 MHz) δ 15.7 (q), 20.9 (q), 22.2 (q), 23.1 (t), 25.3 (d),
31.3 (d), 34.3 (t), 39.8 (t), 47.7 (d), 52.3 (t), 56.9 (t), 68.2 (d), 77.9
(d), 103.7 (d), 122.8 (d), 127.7 (d), 128.7 (d), 128.8 (d), 133.3 (s),
135.7 (s), 138.1 (d), 138.2 (s), 139.2 (d), 149.2 (d), 155.0 (s), 167.7
(s); exact mass (electrospray) m/z calcd for C28H35N2O3 (M + H)
447.2642, found 447.2641.
[(7R)-6-Benzyl-7-(hydroxymethyl)-5H,6H,7H-pyrido[3,2-c]-
azepin-8-yl]methanol (25j). DIBAL-H (1.0 M in PhMe, 0.14 mL,
0.14 mmol) was added dropwise to a stirred and cooled (−78 °C)
solution of 25i (12.1 mg, 0.027 mmol) in THF (0.6 mL). Stirring at
−78 °C was continued for 3 h, the cold bath was left in place but not
recharged, and stirring was continued for 4 h. MeOH (0.1 mL) and a
saturated aqueous solution of Rochelle’s salt (ca. 3 mL) were then
added sequentially. Stirring was continued for 1 h, and the mixture was
extracted with EtOAc. The combined organic extracts were washed
with brine, dried (MgSO4), and evaporated. Flash chromatography of
the residue over silica gel (0.6 × 8 cm), using 1:25 MeOH/EtOAc,
gave 25j (2.7 mg, 34%) as an yellow solid: [α]20 69.92 (c 1.15,
D
CHCl3); FTIR (CHCl3, cast) 3346, 3062 3028, 2922, 2855, 1650,
1582, 1494, 1444 cm−1; 1H NMR (CDCl3, 500 MHz) δ 2.18 (s, 1 H),
3.35 (s, 1 H), 3.46−3.60 (m, 3 H), 3.66 (d, J = 16.0 Hz, 1 H), 3.82
(dd, J = 5.0, 9.5 Hz, 1 H), 3.89−3.94 (m, 1 H), 4.18 (d, J = 15.5 Hz, 1
H), 4.24 (AB q, J = 13.5 Hz, ΔνAB = 19.1 Hz, 2 H), 7.02 (s, 1 H), 7.12
(dd, J = 5.0, 7.5 Hz, 1 H), 7.18 (d, J = 7.5 Hz, 2 H), 7.28−7.35 (m, 4
H), 8.57 (d, J = 5.0 Hz, 1 H); 13C NMR (CDCl3, 125 MHz) δ 49.6
(t), 57.1 (t), 62.5 (t), 66.0 (d), 67.3 (t), 121.6 (d), 127.6 (d), 128.5
(d), 129.0 (d), 130.5 (d), 133.8 (s), 137.3 (d), 137.9 (s), 145.2 (s),
148.3 (d), 154.1 (s); exact mass (electrospray) m/z calcd for
C18H21N2O2 (M + H) 297.1598, found 297.1597.
(R)-(3-{[Benzyl({[tris(propan-2-yl)silyl]oxy}carbonyl)amino]-
methyl}pyridin-2-yl)[(5R)-5-{[(1R,2S,5R)-5-methyl-2-(propan-2-
yl)cyclohexyl]oxy}-2-oxo-2,5-dihydrofuran-3-yl]methyl Ace-
tate (25h). DMAP (4.0 mg, 0.032 mmol) was added to a stirred
solution of 25g (65.8 mg, 0.099 mmol) in CH2Cl2 (1.5 mL). The
mixture was then cooled to 0 °C, and AcCl (0.032 mL, 0.44 mmol)
and pyridine (0.06 mL, 0.74 mmol) were added sequentially. The ice
bath was left in place but not recharged, and stirring was continued for
40 min. The mixture was quenched with hydrochloric acid (1 M, 1
mL) and water (3 mL), and the aqueous phase was extracted with
CH2Cl2. The combined organic extracts were washed with brine, dried
(MgSO4), and evaporated. Flash chromatography of the residue over
silica gel (1.2 × 14 cm), using 3:10 EtOAc/hexanes, gave 25h (57.0
mg, 81%) as a colorless oil: FTIR (CHCl3, cast) 3064, 3032, 2949,
ASSOCIATED CONTENT
* Supporting Information
■
S
Flowchart for the preparation of amine 26; X-ray data (cif) for
compounds epi-18, 19d, 19f, 23i, and 24k; and copies of NMR
spectra. This material is available free of charge via the Internet
at http://pubs.acs.org.
1
2868, 1771, 1749, 1681, 1576, 1496, 1466 cm−1; H NMR (CDCl3,
AUTHOR INFORMATION
Corresponding Author
*E-mail: derrick.clive@ualberta.ca.
500 MHz) δ 0.73−1.40 (m, 33 H), 1.57−1.68 (m, 2 H), 2.04−2.10
(m, 5 H), 2.16−2.17 (m, 2 H), 3.61 (dt, J = 4.5, 10.5 Hz, 1 H), 4.45−
4.55 (m, 2 H), 4.72−4.86 (m, 2 H), 6.02 (d, J = 5.0 Hz, 1 H), 6.54 and
6.65 (two s, 1 H), 7.00 (d, J = 14.5 Hz, 1 H), 7.21−7.34 (m, 6 H), 7.52
(d, J = 8.0 Hz) and 7.56 (d, J = 8.0 Hz, both signals together 1 H),
8.49 (d, J = 5.0 Hz, 1 H); 13C NMR (CDCl3, 125 MHz) δ 12.0 (d),
12.1 (d), 15.9 (q), 17.8 (q), 17.9 (q), 20.6 (q), 20.7 (q), 20.9 (q), 22.2
(q), 23.2 (t), 25.26 (d), 25.29 (d), 31.5 (d), 34.2 (t), 40.60 (t), 40.64
(t), 45.8 (t), 46.6 (t), 47.7 (d), 50.7 (t), 50.8 (t), 66.0 (d), 66.8 (d),
78.9 (d), 79.1 (d), 99.45 (d), 99.51 (d), 123.7 (d), 123.8 (d), 127.46
(d), 127.54 (d), 127.6 (d), 128.4 (d), 128.66 (d), 128.70 (d), 132.4
(s), 134.3 (d), 135.3 (s), 135.5 (s), 135.8 (d), 137.3 (s), 137.4 (s),
146.2 (d), 146.3 (d), 148.2 (d), 148.3 (d), 152.1 (s), 152.7 (s), 155.57
(s), 155.63 (s), 168.87 (s), 168.88 (s), 169.46 (s), 169.53 (s); exact
mass (electrospray) m/z calcd for C40H58N2NaO7Si (M + Na)
729.3905, found 729.3897.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Natural Sciences and Engineering Research
Council of Canada for financial support and Dr. R. McDonald
for X-ray measurements.
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