Enantioselective total syntheses of (-)-FR901483 and (+)-8- epi -FR901483

Article abstract of DOI:10.1021/jo302362b

The enantioselective total syntheses of the potent immunosuppressant FR901483 (1) and its 8-epimer (47) have been accomplished. Our approach features the use of building block 6 as the chiron, the application of the one-pot amide reductive bis-alkylation method to construct the chiral aza-quaternary center (dr = 9:1), regio- and diastereoselective intramolecular aldol reaction to build the bridged ring, and RCM to form the 3-pyrrolin-2-one ring.

Full text of DOI:10.1021/jo302362b

Article
pubs.acs.org/joc
Enantioselective Total Syntheses of (−)-FR901483 and (+)-8-epi-
FR901483
Hao-Hua Huo,† Xiao-Er Xia,† Hong-Kui Zhang,*,† and Pei-Qiang Huang*,†,‡
†Department of Chemistry, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, Fujian 361005, P. R. China
‡The State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, P. R. China
S
* Supporting Information
ABSTRACT: The enantioselective total syntheses of the
potent immunosuppressant FR901483 (1) and its 8-epimer
(47) have been accomplished. Our approach features the use
of building block 6 as the chiron, the application of the one-
pot amide reductive bis-alkylation method to construct the
chiral aza-quaternary center (dr = 9:1), regio- and diaster-
eoselective intramolecular aldol reaction to build the bridged
ring, and RCM to form the 3-pyrrolin-2-one ring.
ring-containing alkaloids,9 we have embarked on the
enantioselective total synthesis of FR901483. The preliminary
INTRODUCTION
Immunosuppressants are molecules capable of exerting
selective effects on the immune response, which have become
indispensable tools in the prevention of rejection in organ
■
results involving a formal enantioselective total synthesis of
FR901483 have been reported recently.10 We describe herein
the full details of this work, including the final completion of
the total synthesis of (−)-FR901483 (1) as well as the synthesis
of (+)-8-epi-FR901483 (47).
transplantation and in the treatment of immune-related
diseases.1 Search of immunosuppressants from natural products
have been proven fruitful, which resulted in the discovery of
cyclosporine A, FK506, and rapamycin as effective immuno-
suppressive agents currently in clinical use. In addition, FK506
and rapamycin have served as tools in the investigation of the
molecular mechanisms of signal transduction. However, there is
a continuing demand for the development of more potent and
less-toxic immunosuppressive agents. FR901483 (1, Figure 1)
RESULTS AND DISCUSSION
As depicted in Scheme 1, our retrosynthetic analysis of
FR901483 (1) is based on the use of two key synthetic
■
Scheme 1. Retrosynthetic Analysis of FR901483 (1)
Figure 1. Potent immunosuppressant FR901483 (1).
is a potent immunosuppressant isolated from the fermentation
broth of the Cladobotryum sp. No. 11231 in 1996.2 The potent
activity and unique yet challenging structural features of this
molecule have rendered it an attractive target for synthetic
organic chemists. Among numerous synthetic studies3−6
toward FR901483 (1), only six enantioselective total
syntheses3a−g and a formal total syntheses3h have been
reported. As a continuation of our endeavor to develop step-
economical7 and 3-benzyloxyglutarimide8-based synthetic
methodologies for the asymmetric synthesis of piperidine
methodologies developed in our laboratory as the cornerstones,
namely, the use of the chiral building block 69 as the chiron and
the one-pot amides reductive bis-alkylation method7a for the
synthesis of polysubstituted piperidine 4 from piperidin-2-one
Received: October 24, 2012
Published: December 5, 2012
© 2012 American Chemical Society
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5. On the basis of our strategy for the construction of the
tricyclic core, FR901483 (1) was envisioned to be available
from compound 2 via lactam α-amination followed by selective
phosphate esterification. The amination was envisioned to
occur diastereoselectively from the more accessible convex face
of the tricyclic core to establish the correct stereochemistry.
Although the stereochemistry at C-8 was uncertain, either C-8
epimer could be convertible to the required phosphate ester
with conversion3a or inversion3b of configuration. In addition,
Sorensen and co-workers have demonstrated that the two
hydroxyl groups are easily distinguishable.3b Compound 2, in
turn, could be obtainable from compound 3 via allylic oxidation
and cis-diastereoselective reduction by the Fukuyama procedur-
e.4b Retro-aldol reaction3a−d,4b,c and retro-RCM11 disconnec-
tions of compound 3 suggested polysubstituted piperidine 4 as
a precursor. In the light of our method for the one-pot
reductive bis-alkylation of lactams/amides7a and that for the
two-step reductive trans-diastereoselective alkylation of
imides,8,9 (R)-3-benzyloxyglutarimide 6 was deduced to be
the starting material.
equiv of Grignard reagents G1a (or more reactive G1b).
Nevertheless, no desired product was observed. The sluggish
reaction may thus be attributed to the steric hindrance of
lactam 5. The assumption was further confirmed by the
reductive bis-alkylation of 5 with an even more reactive lithium
reagent L1 (6 equiv), in which the desired product 7 was
produced in 35% yield.
In view of the unfavorable steric effect of p-methoxybenzyl
group on the reductive bis-alkylation, this group had to be
introduced at the late stage of our synthetic route. In the
modified approach, piperidin-2-one 9 was first prepared from
imide 6 by partial and regioselective reduction with NaBH4
(−30 °C, 15 min) and the subsequent reductive dehydrox-
ylation (Et3SiH, BF3·OEt2, CH2Cl2, −78 °C−rt, 12 h) of the
resultant hemiaminal intermediate (Scheme 3). The observed
Scheme 3. Stereoselective Synthesis of the Key Intermediate
11
The synthesis commenced with the regio- and diastereose-
lective reductive alkylation of (R)-3-benzyloxyglutarimide 6
(Scheme 2). Treatment of imide 6 with p-methoxybenzyl
Scheme 2. Attempted Synthesis of 4 via Bisalkylation of 5
high regioselectivity in the reduction of 6 with NaBH4 to give
the corresponding hemiaminal intermediate is in agreement
with the well documented malimide derivatives14 and is
attributable to the higher reactivity of the C-2 carbonyl as a
result of the attractive inductive effect of the α-O-benzyl
group,14 although a chelation-promoted regioselective reduc-
tion could not be excluded.15 The subsequent bis-alkylation of
lactam 9 proceeded as planned to produce the desired amine 8
in 75% yield with a remarkable 9:1 diastereoselectivity
(determined by 1H NMR of the crude sample). The
stereochemistry of the major diastereomer was deduced to be
trans based on mechanistic consideration that the vinyl group
would approach the N-acyliminium ion intermediate from the
α-side opposing the benzyloxy group, which was confirmed at a
later stage. It is worth mentioning that among various synthetic
approaches developed for the synthesis of FR901483 (1), this is
the first example utilizing the one-pot amide reductive bis-
alkylation method to construct the quaternary chiral center.
For O-debenzylation of compound 8, the standard hydro-
genolytic conditions were obviously unsuitable due to the
presence of two olefinic groups. Lithium naphthalenide (LN)16
was chosen as the proper reagent for the selective O-
debenzylation of piperidine 8 (diastereomeric mixture), which
gave, after chromatographic separation, the piperidin-3-ol 10 as
a pure diastereomer in 85% yield.
magnesium chloride in CH2Cl2 at −78 °C for 3 h, followed by a
reductive dehydroxylation (Et3SiH, BF3·OEt2, CH2Cl2, −78
°C−rt, 12 h) of the resulting hemiaminal,9 afforded lactam 5 in
72% yield as the sole observable diastereomer (determined by
1H NMR). Next, we attempted to construct the quaternary
carbon center by using the amide reductive bis-alkylation
method developed in our laboratory.7a Lactam 5 was thus
successively treated with triflic anhydride (Tf2O, 1.1 equiv),
DTBMP (1.0 equiv), Grignard reagent G1a, and vinyl
magnesium bromide (G2) in CH2Cl2 at −78 °C. Unfortu-
nately, no desired product 4 was observed. When more reactive
Buchi Grignard reagent12 (G1b) or 3,3-dimethoxypropyl
̈
magnesium bromide13 (G1c) was used instead of G1a, no
desired product was produced. To ascertain if the failure of this
reaction was caused by the less nucleophilic vinyl magnesium
bromide, the reductive bis-alkylation was undertaken with 6
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Before the key intramolecular aldol ring closure reaction was
taken, the piperidin-3-ol 10 needed to be oxidized to the ketone
11. The oxidation with the Dess−Martin periodinane failed to
give the desired ketone, and the Ley oxidation gave only 35% of
11, whereas the Swern oxidation was successful, which yielded
ketone 11 in 90% yield in the presence of an extreme excess of
triethylamine [6 equiv (COCl)2, 12 equiv DMSO, CH2Cl2,
−78 °C, 1 h; then 25 equiv NEt3].
Scheme 5. Attempted Regioselective Intramolecular
Mukaiyama Aldol Reaction
Although the utilization of an intramolecular aldol reaction
has been reported in the syntheses of FR901483,3a−d,4b,c this
key step turned out to be a challenge in our case. After the
acetal 11 was deprotected with a 4 N HCl solution (Scheme 4)
Scheme 4. Attempted Regioselective Deacetalization−
Intramolecular Aldol Reaction
and neutralized with a saturated aqueous solution of NaHCO3,
the crude 12 was subjected to the aldol reaction under either
basic (tBuOK/tBuOH, or MeONa/MeOH) or acidic (CSA,
toluene, 90 °C) conditions. Unfortunately, only the regioisomer
14 was obtained in moderate yields (45−62%). The stereo-
chemistries of the newly formed stereogenic centers of
compound 14 were assigned as shown in Figure 2 by
regioselectively the desired silyl enol ethers 18 and 21.
However, both of them failed to yield the desired Mukaiyama
aldol product 19 (or 20) under various Lewis acid mediated
conditions (cf. Scheme 5). Treatment of compound 18 with a
mixture of TFA/H2O led to the formation of keto-aldehyde 12.
The failure of the regioselective aldol reaction (Scheme 4)
might be attributed to the influence of the basic amino group.
To our surprise, when compound 11 was treated with a 4 N
HCl solution and the resulting deacetalization product, in the
form of its hydrochloride salt, was reacted with CSA (1.0
equiv), adduct 14 and concomitantly acetalized regioisomer 22
were obtained as a 1:1 ratio in a combined yield of 60%.
Encourage by this result, compound 11 was treated with a 4 N
HCl aqueous solution (6.0 equiv) in THF at rt for 1 h. After
further reaction at 50 °C for 30 min, ethylene glycol (EG, 4.0
equiv) was added, and the resulting mixture was concentrated.
The resultant residue, in the form of its hydrochloride salt, was
reacted with CSA (0.3 equiv) in toluene at 90 °C for 10 min,
which produced predominantly compound 22 as the sole
observable diastereomer in 53% yield, along with 5% of the
regioisomer 14 (Scheme 6). It was remarkable that the
regioselectivity of the intramolecular aldol reaction was inversed
just by changing the reaction conditions (cf. Scheme 4). The
relative stereochemistry of 22 was established on the basis of
the observed strong NOE correlations between the carbinolic
proton at δ 3.83 and the four β-face methylenic protons at δ
1.41, 1.65, 2.12, and 2.24.
Figure 2. Observed key NOE correlations of compound 14.
NOESY experiments, in which the NOE correlations between
the carbinolic proton at δ 4.00 and the two β-face oriented
methylenic protons at δ 1.87 and δ 2.10, as well as the carbonyl
α-H appearing at δ 3.44, were observed, while no correlations
were observed between the carbinolic proton (δ 4.00) and the
two α-face oriented methylenic protons at δ 1.59 and δ 1.69.
The one-pot deacetalization−aldol reaction (4 N HCl, THF,
reflux, 1 h) was also attempted, but the undesired regioisomer
14 (yield 65%) was once again produced.
To tackle the problem of regioselectivity, the use of
preformed silyl enol ether appeared attractive.4a To facilitate
the deacetalization reaction, piperidin-3-one 17 was synthesized
from 8 (Scheme 5) following the procedures described in
Scheme 3. Silylation (TIPSOTf, NEt3, CH2Cl2, 0 °C or
TMSOTf, NEt3, CH2Cl2, 0 °C) of ketone 17 produced
The regioselections of the intramolecular aldol reactions can
be understood from the conformational analysis shown in
Scheme 7. Under the HCl-only conditions (in THF at rt, cf.
Scheme 4), among the four possible regio-conformers of the
amino-enol hydrochloride salt 12a−12d, only 12b and 12d can
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Scheme 6
Scheme 8
Scheme 7
plan, selective deacetalization of 24 and α-alkylation of the
resulting ketone 25 followed by reacetalization would give
compound 3. However, we were unable to perform the
selective deacetalization of 24. The synthetic plan had to be
modified.
Diene 23 was to be selectively deacetalized before the ring-
closing olefin metathesis. However, treatment of 23 with PPTS
in wet acetone or CH3CN at reflux failed to give ketone 26,
while p-TsOH-catalyzed reaction (TsOH, acetone/H2O, rt) led
chemoselectively to desilylation, giving back hydroxy-acetal 22
in 76% yield (Scheme 9). We therefore selected benzyl group
Scheme 9. Synthesis of Piperidin-3-one 28
lead to the aldol products. The latter conformers are particular
favored due to an overlap of orbitals of the quasi parallelly
disposed carbonyl and enol. The aldol product 14a-HCl is
disfavored by the severe interaction between the N-allyl group
and the cyclohexyl protion compared to the synclinal
interaction between the vinyl and the allyl groups in 14-HCl.
Consequently, aldol product 14 was obtained as the sole
observable regio- and diastereomer.
For the reaction of the hydrochloride salt of compound 11 in
the presence of both CSA and ethylene glycol in toluene at 90
°C (cf. Scheme 6), as discussed above, among the four possible
regio-conformers of the amino-enol hydrochloride salt 12e−
12h, only 12f and 12h can lead to the aldol products, and regio-
and diastereomer 22-HX is favored due to the stabilization
effect of the hydrogen bonding between the axial acetal oxygen
and N−H, and between the equatorial acetal oxygen and OH,
in addition to a lack of an unfavorable synclinal interaction
compared with that of 14b (Scheme 7).
as a robust hydroxyl protecting group, which turned out to be
successful. The deacetalization of O-benzylated acetal 27,
generated from O-benzylation of 22 (BnBr, NaH, n-Bu4NI,
DMF, rt, 18 h, yield 90%), went smoothly with 6 N HCl in
refluxing acetone, producing the α-aminoketone 28 in 70%
yield.
The regioselective p-methoxybenzylation of ketone 28
(KHMDS, THF, p-MeOC6H4Br, DMF) proceeded smoothly
to give compound 29 as the sole isolable diastereomer in 80%
yield (Scheme 10). The subsequent SmI2-mediated diaster-
eoselective reductions4b,19 of ketone 29, however, failed to give
the desired piperidinol 30. Enamine 31 was formed instead.
The unsuccessful transformation of α-aminoketone 29 to the
desired β-amino alcohol 30 was attributed to the unfavorable
effect of the amino group. In light of the successful
transformation of a tricyclic keto lactam to the corresponding
β-hydroxylactam by Fukuyama,4b tricyclic lactam 34 was then
envisaged as a key intermediate in our synthesis (Scheme 11).
The hydroxyl group in 22 was then protected as TBS ether
23 (90%) by reaction with TBSOTf/NEt3 in CH2Cl2 at 0 °C
(Scheme 8). The ring-closing olefin metathesis (RCM)11,6f of
23 was undertaken using Grubbs second generation catalyst17
18
in the presence of Ti(OiPr)4 to give the cyclization product
24 in 75%. The construction of the azatricyclic core of
FR901483 was thus accomplished. According to our synthetic
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Scheme 10. Attempted Diastereoselective Reduction of α-
Aminoketone 29
Scheme 12. Diastereoselective Synthesis of the Tricyclic
Core 38
Scheme 11. Synthesis of Tricyclic Core 34
diastereomer in 75% yield. Selective hydrogenation of 36 on
10% Pd/C (30 wt %) under 1 atm of H2 in EtOAc produced
lactam 37 in 90% yield. The SmI2-mediated reduction4b,19 of
ketone 37 (SmI2 5 equiv, HMPA 25 equiv, MeOH 10 equiv,
THF, −78 °C, 12 h) gave the desired cis-diastereomer 38 as the
only observable diastereomer in 85% yield. The spectral data of
38 matched those reported for the racemic one.6d The relative
stereochemistry of our synthetic product 38 was thus
confirmed as shown in Scheme 12.
We next turned our attention to the stereoselective α-
amination of lactam 38. Hydroxyl group in 38 was first
protected (TBSOTf, NEt3, CH2Cl2, 93%) as TBS ether 39
(Scheme 13). Successive treatment of 39 with LDA (3.0 equiv)
For this purpose, compound 27 was subjected to Pd-catalyzed
N-deallylation20 [Pd(Ph3P)4 (0.01 equiv), NDMBA (3 equiv),
CH2Cl2, rt, 1 h], and the resulting amine 32 was acryloylated
with acryloyl chloride and NEt3 in CH2Cl2 at 0 °C to give
acrylamide 33 in 81% yield over two steps.
Scheme 13. Synthesis of Compound 40
The RCM reaction of diene 33 was investigated. Formation
of α,β-unsaturated lactams by the RCM reaction of acrylamides
using either Grubbs first or second generation catalyst have
been well documented.21 The reaction generally proceeded well
in CH2Cl2.6f,21 However, all attempts to perform the RCM
reaction of 33 using the Grubbs first or second generation
catalyst in CH2Cl2 were unsuccessful. Considering the steric
hindrance of the substrate, it was envisioned that higher
reaction temperature would favor the reaction. Indeed, when a
toluene solution of acrylamide 33 was heated together with the
Grubbs second generation catalyst (25 mol %) at 85 °C for 12
h, the desired cyclized product 34 was obtained in 30% yield,
along with 60% of the recovered starting material. Remarkably,
when the reaction (Grubbs II 25 mol %, toluene, 85 °C) was
run in the presence of 30 mol % of Ti(OiPr)4,22 the desired
tricyclic core 34 was obtained in 92% yield.
and TrisN3 (3 equiv) at −78 °C for 5 min, followed by
quenching with HOAc, gave desired azide 40 as a separable
diastereomeric mixture in a 3:1 ratio with a combined yield of
90%. The major diastereomer 40 was formed via the
electrophilic addition from the less hindered β-face, the
stereochemistry of which was determined by NOESY experi-
ments.
To convert the azido group to the N-methylamino group,
azido compound 40 was first hydrogenated (10% Pd/C 30 wt
%, H2 1 atm) in the presence of Boc2O (1.2 equiv) to give the
Acetal 34 was selectively deacetalized by treatment with 4 N
HCl in refluxing acetone to give the keto-amide 35 in 85% yield
(Scheme 12). Ketone 35 was deprotonated with KHMDS (1
equiv) in THF at −50 °C to give the enolate, which was added
to p-methoxybenzyl bromide (3.0 equiv) in DMF at 0 °C to
produce compound 36 as the only observable regio- and
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Scheme 14. Synthesis of FR901483 (1)
Scheme 15. Synthesis of 8-epi-FR901483 (47)
1
protected compound 41 in 90% yield (Scheme 14). Treatment
of compound 41 with a large excess of LiAlH4 (30 equiv) in
THF at 60 °C for 16 h afforded the amino-diol 42 in 92% yield.
in 92% yield. The physical and H and 13C NMR spectral data
of our synthetic compound 1 were in good agreement with
those reported by Snider.3a
1
The H and 13C NMR spectral data of compound 42 are in
In view of the importance of stereoisomers and/or analogues
in drug R & D, the synthesis of 8-epi-FR901483 (47) was
envisioned. Thus, amino-diol 42 was treated with CbzCl
[Na2CO3, CH2Cl2/H2O (3:1 v/v), rt, 2 h] to give the
chemoselectively N-protected product 45 in 95% yield
(Scheme 15). The next task resided in the regioselective
monophosphatation of the equatorial hydroxyl group at C-8.
Since Sorensen has nicely demonstrated, during the synthesis of
FR901483 (1), that the more accessible equatorial hydroxyl
group at C-8 could undergo regioselective Mitsunobu reaction
in the presence of the more hindered axial hydroxyl group at C-
6,3b a direct regioselective monophosphatation of the diol 45
was envisaged. To our delight, treatment of 45 with
(BnO)2PN(i-Pr)2 (1.8 equiv)/tetrazole (10 equiv) at 0 °C
for 2 h, followed by oxidation of the presumed dibenzyl
phosphite ester with t-BuOOH (3 equiv),3a produced
phosphate 46 selectively in 65% yield. Hydrogenolysis (10%
agreement with those reported by Ciufolini.3d It is worth noting
that N-Boc reduction to the N-Me group, lactam reduction to
pyrrolidine, and O-desilylation occurred sequentially in this
scenario.
To complete the total synthesis of (−)-FR901483 (1), an
inversion of the configuration at C-8 was necessary. In light of
previous work by Sorensen3b and Ciufolini,3d compound 42
was converted to 43 by treatment with (BnO)2P(O)OH (6.0
equiv), tris(4-chlorophenyl)phosphine (3.0 equiv), DIAD (3.0
equiv), and Et3N (10.0 equiv) at rt for 1 h. Without
purification, the presumed crude product of 43 was dissolved
in a mixed solvent system of CH2Cl2/H2O (3:1 v/v) and
treated with CbzCl (4.0 equiv) and Na2CO3 (10.0 equiv),
giving compound 44 in 34% over two steps. Final hydro-
genolysis (10% Pd/C 100 wt %, MeOH, H2, 1 atm, rt, 6 h) of
the monohydrochloride salt of 44 produced (−)-FR901483 (1)
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added dropwise. The reaction mixture was allowed to warm to rt and
stirred for 3 h. The reaction was quenched with a saturated aqueous
solution of NH4Cl and extracted with CH2Cl2 (5 × 4 mL). The
combined organic layers were dried over anhydrous Na2SO4, filtered,
and concentrated under reduced pressure. The residue was purified by
flash chromatography on silica gel (eluent, EtOAc/hexane = 1:20) to
give compound 7 (170 mg, yield 35%) as a colorless oil. [α]20D −22.9
(c 1.0, CHCl3); IR (film) νmax 3062, 3037, 2952, 2856, 1611, 1511,
1462, 1248, 1093 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.08 (s, 6H),
0.09 (s, 6H), 0.93 (s, 9H), 0.94 (s, 9H), 1.39−1.74 (m, 10H), 1.79−
1.90 (m, 1H), 1.91−2.01 (m, 1H), 2.56 (dd, J = 13.8, 8.5 Hz, 1H),
3.05 (dd, J = 13.8, 2.2 Hz, 1H), 3.26−3.34 (m, 2H), 3.39 (dd, J = 15.7,
7.4 Hz, 1H), 3.45−3.53 (m, 1H), 3.56−3.68 (m, 4H), 3.82 (s, 3H),
4.24 (d, J = 12.1 Hz, 1H), 4.29 (d, J = 12.1 Hz, 1H), 5.10 (d, J = 10.1
Hz, 1H), 5.30 (d, J = 17.1 Hz, 1H), 5.78−5.93 (m, 1H), 6.81 (d, J =
8.6 Hz, 2H), 7.09 (d, J = 8.6 Hz, 2H), 7.16−7.29 (m, 5H); 13C NMR
(100 MHz, CDCl3) δ −5.2 (4C), 18.29, 18.32, 22.6, 25.96 (3C), 25.97
(3C), 26.8, 27.9, 29.7, 32.4, 32.8, 33.7, 48.0, 55.2, 57.5, 59.4, 63.8, 63.9,
69.5, 73.6, 113.6 (2C), 115.1, 127.0, 127.4 (2C), 128.1 (2C), 130.1
(2C), 133.2, 139.2, 139.6, 157.6; HRMS (ESI, m/z) calcd for
C41H70NO4Si2 [M + H]+ 696.4838, found 696.4840.
Pd/C, 50 wt %, H2, 1 atm, MeOH, rt, 3 h) of the hydrochloride
salt of 46 gave 8-epi-FR901483 (47) in 95% yield.
CONCLUSIONS
■
In summary, we have accomplished a novel enantioselective
total synthesis of FR901483 (1) and 8-epi-FR901483 (47)
starting from (R)-3-benzyloxyglutarimide 6 in 21 steps with
overall yield of 1.3% and 2.4%, respectively. This novel route is
based on two synthetic methodologies developed from our
laboratory, namely, the use of chiron 6 as the starting material,
and the one-pot amide reductive bis-alkylation method for the
highly diastereoselective construction of quaternary α-carbon
center in piperidine 8 from piperidin-2-one 9.
EXPERIMENTAL SECTION
General Methods. Melting points were uncorrected. Infrared
spectra were measured using film KBr pellet techniques. H NMR
■
1
spectra were recorded in CDCl3 with tetramethylsilane as an internal
standard. Chemical shifts are expressed in δ (ppm) units downfield
from TMS. Silica gel (300−400 mesh) was used for flash column
chromatography, eluting (unless otherwise stated) with ethyl acetate/
hexane. Ether and THF were distilled over sodium benzophenone
ketyl under N2. Dichloromethane was distilled over calcium hydride
under N2. High-resolution mass spectra were obtained using
electrospray ionization using an ICR analyzer (ESI-MS).
(1R,5S,8S)-9-Allyl-8-hydroxy-5-vinyl-9-azabicyclo[3.3.1]-
nonan-2-one (14). A solution of piperidin-3-one 11 (230 mg, 0.87
mmol) in THF (8.7 mL) and 4 N HCl (3.2 mL) was refluxed for 1 h.
The cooled reaction mixture was neutralized with a saturated aqueous
solution of NaHCO3, and extracted with EtOAc (5 × 8 mL). The
combined organic layers were dried over anhydrous Na2SO4, filtered,
and concentrated under reduced pressure. The residue was purified by
flash chromatography on silica gel (eluent, EtOAc/hexane = 3:2) to
give compound 14 (125 mg, yield 65%) as a white solid. mp 40−42 °C
(5R,6S)-1-Allyl-5-(benzyloxy)-6-(4-methoxybenzyl)piperidin-
2-one (5). To a solution of the known (R)-3-benzyloxyglutarimide 69a
(7.20 g, 27.8 mmol) in CH2Cl2 (278 mL) at −78 °C was added
dropwise a solution of freshly prepared p-MeOC6H4MgCl in THF (1.0
M, 83.4 mL, 83.4 mmol). The mixture was stirred at −78 °C for 3 h.
The reaction was quenched with a saturated aqueous solution of
NH4Cl. After extraction with ethyl acetate (5 × 100 mL), the
combined organic layers were dried over anhydrous Na2SO4, filtered,
and concentrated under reduced pressure. The residue was purified by
flash chromatography on silica gel (eluent, ethyl acetate/hexane = 1:2)
to give the hemiaminal as a diastereomeric mixture (10.3 g, yield 97%),
which was used in the next step without further separation. To a
cooled (−78 °C) solution of the above diastereomeric mixture of
hemiaminal (10.3 g, 27.0 mmol) in CH2Cl2 (270 mL) were added
dropwise Et3SiH (42.7 mL, 270 mmol) and BF3·OEt2 (10.0 mL, 81.0
mmol) successively. The mixture was stirred at −78 °C for 1 h, then
allowed to warm up slowly, and stirred at room temperature overnight.
The reaction was quenched with a saturated aqueous solution of
NaHCO3 and extracted with CH2Cl2 (5 × 100 mL). The combined
organic layers were dried over anhydrous Na2SO4, filtered, and
concentrated under reduced pressure. The residue was purified by
flash chromatography on silica gel (eluent, EtOAc/hexane = 1:1) to
give compound 5 (7.30 g, yield 72% over two steps) as a colorless oil.
(EtOAc/hexane); [α]20 −31.5 (c 0.5, CHCl3); IR (film) νmax 3259,
D
1
3081, 2934, 1710, 1641 cm−1; H NMR (400 MHz, CDCl3) δ 1.52−
1.65 (m, 1H), 1.70 (ddd, J = 13.8, 5.2, 2.0 Hz, 1H), 1.87 (ddt, J = 13.8,
5.4, 1.7 Hz, 1H), 1.99−2.15 (m, 2H), 2.27−2.41 (m, 1H), 2.47−2.57
(m, 1H), 2.63 (br s, 1H, OH, D2O exchangeable), 2.67 (dddd, J =
18.4, 9.6, 3.5, 1.0 Hz, 1H), 2.90 (dd, J = 14.4, 7.2 Hz, 1H), 3.32−3.52
(m, 2H), 4.02 (dt, J = 11.0, 5.2 Hz, 1H), 5.00−5.21 (m, 4H), 5.69
(dddd, J = 17.5, 10.1, 7.2, 4.8 Hz, 1H), 5.86 (dd, J = 17.5, 11.0 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 28.3, 29.3, 36.0, 37.6, 52.2, 55.6,
67.3, 67.9, 113.7, 117.4, 135.4, 146.0, 215.5; HRMS (ESI, m/z) calcd
for C13H19NO2Na [M + H]+ 244.1308, found 244.1310.
(2R,5R)-1-Allyl-5-(benzyloxy)-2-(3,3-dimethoxypropyl)-2-vi-
nylpiperidine (15). To a solution of lactam 9 (1.20 g, 4.90 mmol)
and 2,6-di-tert-butyl-4-methylpyridine (1.00 g, 4.90 mmol) in
anhydrous CH2Cl2 (49 mL) at −78 °C was added Tf2O (0.91 mL,
5.39 mmol) dropwise. After 3 h of stirring at −78 °C, a solution of 3,3-
dimethoxypropyl magnesium bromide13 (G1c) (0.5 M in THF, 9.8
mL, 4.90 mmol) was added over 1 h, and then vinylMgBr (0.7 M in
THF, 21.0 mL, 14.7 mmol) was added dropwise. After being stirred at
rt for 3 h, the reaction was quenched with a saturated aqueous solution
of NH4Cl and extracted with CH2Cl2 (4 × 30 mL). The combined
organic layers were dried over anhydrous Na2SO4, filtered, and
concentrated under reduced pressure. The residue was purified by
flash chromatography on silica gel (eluent, EtOAc/hexane = 1:4) to
[α]20 −56.1 (c 1.0, CHCl3); IR (film) νmax 3075, 3017, 2951, 1675,
D
1520, 1462, 1248 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.93−2.08 (m,
2H), 2.36 (ddd, J = 17.8, 6.6, 2.4 Hz, 1H), 2.49 (dd, J = 14.1, 10.0 Hz,
1H), 2.63 (ddd, J = 17.8, 11.4, 7.5 Hz, 1H), 3.02 (dd, J = 14.1, 4.6 Hz,
1H), 3.42 (dd, J = 15.6, 7.0 Hz, 1H), 3.55 (dt, J = 4.4, 2.3 Hz, 1H),
3.71 (ddt, J = 10.0, 4.4, 1.7 Hz, 1H), 3.80 (s, 3H), 4.32 (d, J = 12.0 Hz,
1H), 4.37 (d, J = 12.0 Hz, 1H), 4.71 (ddt, J = 15.6, 4.4, 1.7 Hz, 1H),
5.17 (dd, J = 10.2, 1.4 Hz, 1H), 5.25 (dd, J = 17.2, 1.4 Hz, 1H), 5.79
(dddd, J = 17.2, 10.2, 7.0, 4.4 Hz, 1H), 6.83 (d, J = 8.6 Hz, 2H), 6.99
(d, J = 8.6 Hz, 2H), 7.08−7.17 (m, 2H), 7.20−7.29 (m, 3H); 13C
NMR (100 MHz, CDCl3) δ 21.2, 26.9, 37.9, 47.5, 55.2, 61.0, 69.8,
71.1, 114.1 (2C), 117.1, 127.3 (2C), 127.4, 128.2 (2C), 129.2, 129.7
(2C), 133.3, 137.9, 158.4, 169.5; HRMS (ESI, m/z) calcd for
C23H28NO3 [M + H]+ 366.2064, found 366.2068.
give compound 15 (1.23 g, yield 70%) as a diastereomeric mixture (dr
1
= 6:1, determined by H NMR) as a colorless oil. [α]20 −8.2 (c 1.0,
D
CHCl3); IR (film) νmax 3076, 2938, 2871, 1640, 1098 cm−1; 1H NMR
(400 MHz, CDCl3) data of the major diastereomer read from the
mixture spectrum of diastereomers δ 1.32−1.43 (m, 2H), 1.52−1.65
(m, 4H), 1.72−1.85 (m, 2H), 1.85−1.95 (m, 1H), 2.49 (dd, J = 12.1,
8.5 Hz, 1H), 2.84 (dd, J = 14.2, 6.9 Hz, 1H), 2.90 (ddd, J = 12.1, 4.1,
1.1 Hz, 1H), 3.22 (ddt, J = 14.2, 5.3, 1.5 Hz, 1H), 3.31 (s, 3H), 3.32 (s,
3H), 3.44−3.55 (m, 1H), 4.33 (t, J = 5.4 Hz, 1H), 4.54 (s, 2H), 5.05
(dd, J = 10.1, 1.7 Hz, 1H), 5.10−5.14 (m, 1H), 5.14−5.19 (m, 2H),
5.72 (dd, J = 17.6, 11.1 Hz, 1H), 5.69−5.80 (m, 1H), 7.26−7.38 (m,
5H); 13C NMR (100 MHz, CDCl3) δ 24.4, 26.4, 27.5, 31.0, 32.4, 49.6,
52.9, 53.0, 59.7, 70.1, 73.8, 104.4, 114.7, 116.1, 127.4, 127.5 (2C),
128.3 (2C), 137.3, 138.9, 142.7; HRMS (ESI, m/z) calcd for
C22H34NO3 [M + H]+ 360.2533, found 360.2536.
(5R,6S)-1-Allyl-5-(benzyloxy)-2,2-bis[3-(tert-butyldimethyl-
silyloxy)propyl]-6-(4-methoxybenzyl)piperidine (7). To a sol-
ution of lactam 5 (254 mg, 0.70 mmol) and DTBMP (157 mg, 0.77
mmol) in anhydrous CH2Cl2 (7.0 mL) at −78 °C was added Tf2O
(0.13 mL, 0.77 mmol) dropwise. After 3 h of stirring at −78 °C, a
solution of 3-TBSOPrLi (0.45 M in Et2O, 9.3 mL, 4.2 mmol) was
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Article
(3R,6R)-1-Allyl-6-(3,3-dimethoxypropyl)-6-vinylpiperidin-3-
ol (16). To a solution of piperidine 15 (268 mg, 0.746 mmol) in THF
(7.5 mL) at −40 °C was added a solution of lithium naphthalenide
(1.0 M in THF, 2.98 mL, 2.98 mmol) dropwise. After being stirred at
−40 °C for 1 h, the reaction was quenched with a saturated aqueous
solution of NH4Cl and extracted with EtOAc (4 × 5 mL). The
combined organic layers were dried over anhydrous Na2SO4, filtered,
and concentrated under reduced pressure. The residue was purified by
flash chromatography on silica gel (eluent, MeOH/CH2Cl2 = 1:30) to
give compound 16 (146 mg, yield 73%) as a colorless oil. [α]20D +15.7
(c 1.0, CHCl3); IR (film) νmax 3440, 3079, 2934, 1640, 1452, 1126,
1063 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.41−1.56 (m, 2H), 1.58−
1.77 (m, 5H), 1.84 (ddd, J = 13.4, 11.8, 4.7 Hz, 1H), 2.57 (dd, J =
12.1, 2.0 Hz, 1H), 2.69 (ddd, J = 12.1, 4.7, 1.4 Hz, 1H), 2.80 (dd, J =
14.0, 7.5 Hz, 2H), 3.31 (s, 3H), 3.32 (s, 3H), 3.34−3.39 (m, 1H), 3.75
(br s, 1H, OH, D2O exchangeable), 4.33 (t, J = 5.4 Hz, 1H), 5.05−5.18
(m, 3H), 5.25 (dd, J = 11.2, 1.2 Hz, 1H), 5.72 (dddd, J = 17.7, 10.1,
7.5, 4.7 Hz, 1H), 5.86 (dd, J = 17.7, 11.2 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 26.4, 27.5, 28.2, 31.0, 51.5, 52.4, 52.76, 52.81, 59.9,
65.3, 104.9, 115.7, 116.7, 136.9, 138.2; HRMS (ESI, m/z) calcd for
C15H28NO3 [M + H]+ 270.2064, found 270.2068.
mL, 23.2 mmol) was added, and the resulting mixture was
concentrated under reduced pressure. The residue was used in the
next reaction without further purification.
To a solution of the foregoing residue (5.8 mmol estimated on a
100% yield) in toluene (58 mL) at rt was added CSA (0.40 g, 1.7
mmol), and the mixture was heated to 90 °C for 10 min. The reaction
was quenched with a saturated aqueous solution of NaHCO3 and
extracted with EtOAc (4 × 20 mL). The combined organic layers were
dried over anhydrous Na2SO4, filtered, and concentrated under
reduced pressure. The residue was purified by flash chromatography
on silica gel (eluent, EtOAc/hexane = 1:1) to give compound 22 (0.81
g, yield 53%), and compound 14 (64 mg, yield 5%). Compound 22:
colorless oil; [α]20 −12.5 (c 1.0, CHCl3); IR (film) νmax 3514, 3080,
D
2918, 1639, 1075 cm−1; 1H NMR (500 MHz, CDCl3) δ 1.41 (dd, J =
13.1, 2.9 Hz, 1H), 1.65 (dt, J = 13.9, 6.3 Hz, 1H), 1.70−1.83 (m, 1H),
2.17−2.02 (m, 3H), 2.24 (d, J = 2.9 Hz, 1H), 2.76 (dd, J = 13.5, 8.6
Hz, 1H), 2.86 (d, J = 13.0 Hz, 1H), 3.01 (d, J = 13.0 Hz, 1H), 3.52 (dt,
J = 13.5, 2.1 Hz, 1H), 3.86 (br s, 1H, OH, D2O exchangeable), 3.77−
3.85 (m, 1H), 3.93−3.99 (m, 2H), 3.99−4.06 (m, 2H), 5.00−5.12 (m,
3H), 5.17 (d, J = 17.1 Hz, 1H), 5.70−5.85 (m, 2H); 13C NMR (125
MHz, CDCl3) δ 27.7, 31.4, 38.8, 41.5, 55.0, 55.2, 57.4, 63.9, 64.9, 71.4,
109.3, 113.7, 116.7, 136.7, 146.4; HRMS (ESI, m/z) calcd for
C15H24NO3 [M + H]+ 266.1751, found 266.1760.
(S)-1-Allyl-6-(3,3-dimethoxypropyl)-6-vinylpiperidin-3-one
(17). To a solution of oxalyl chloride (2.0 M in CH2Cl2, 1.6 mL, 3.16
mmol) in CH2Cl2 (22 mL) at −78 °C was added DMSO (0.45 mL,
6.32 mmol) slowly. After the mixture was stirred for 30 min, a solution
of 16 (118 mg, 0.439 mmol) in CH2Cl2 (2.0 mL) was added slowly.
After 3 h of stirring at −78 °C, Et3N (1.8 mL, 13.2 mmol) was added
slowly. The mixture was stirred at −78 °C for 1 h and then at 0 °C for
1 h. The reaction was quenched with water and extracted with CH2Cl2
(4 × 15 mL). The combined organic layers were dried over anhydrous
Na2SO4, filtered, and concentrated under reduced pressure. The
residue was purified by flash chromatography on silica gel (eluent,
EtOAc/hexane = 1:4) to give compound 17 (105 mg, yield 90%) as a
(1S,5S,6R)-2-Allyl-6-(tert-butyldimethylsilyloxy)-1-vinyl-2-
azaspiro{bicyclo[3.3.1]nonane-4,2′-[1,3]dioxolane} (23). To a
solution of compound 22 (35 mg, 0.132 mmol) in CH2Cl2 (2.6 mL) at
0 °C were added successively Et3N (73 μL, 0.528 mmol) and TBSOTf
(61 μL, 0.061 mmol). After being stirred at rt for 3 h, the reaction was
quenched with a saturated aqueous solution of NaHCO3 and extracted
with CH2Cl2 (4 × 2 mL). The combined organic layers were dried
over anhydrous Na2SO4, filtered, and concentrated under reduced
pressure. The residue was purified by flash chromatography on silica
gel (eluent, EtOAc/hexane = 1:10) to give compound 23 (45 mg,
colorless oil. [α]20 +5.2 (c 1.0, CHCl3); IR (film) νmax 3079, 2954,
yield 90%) as a colorless oil. [α]20 +16.0 (c 1.0, CHCl3); IR (film)
D
D
2829, 1725, 1126 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.62−1.75 (m,
4H), 1.91−2.02 (m, 2H), 2.33−2.42 (m, 1H), 2.42−2.54 (m, 1H),
3.06 (dd, J = 14.1, 6.1 Hz, 1H), 3.15 (d, J = 17.1 Hz, 1H), 3.13−3.21
(m, 1H), 3.25 (d, J = 17.1 Hz, 1H), 3.32 (s, 3H), 3.33 (s, 3H), 4.30−
4.38 (m, 1H), 5.10 (dq, J = 10.1, 1.6 Hz, 1H), 5.16 (dq, J = 17.1, 1.6
Hz, 1H), 5.23 (dd, J = 17.7, 1.1 Hz, 1H), 5.28 (dd, J = 11.0, 1.1 Hz,
1H), 5.62−5.77 (m, 1H), 5.88 (dd, J = 17.7, 11.0 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 26.7, 30.2, 30.6, 35.8, 51.7, 52.87, 52.93, 56.4,
59.0, 104.8, 115.4, 117.1, 135.8, 140.1, 210.0; HRMS (ESI, m/z) calcd
for C15H26NO3 [M + H]+ 268.1907, found 268.1908.
1
νmax 3073, 2925, 2866, 1637, 1604, 1086 cm−1; H NMR (400 MHz,
CDCl3) δ 0.07 (s, 6H), 0.92 (s, 9H), 1.38 (dd, J = 14.2, 4.1 Hz, 1H),
1.64 (dt, J = 13.5, 7.0 Hz, 1H), 1.83−1.97 (m, 2H), 2.02−2.16 (m,
3H), 2.76 (dd, J = 13.5, 8.7 Hz, 1H), 2.90 (d, J = 12.8 Hz, 1H), 2.97
(d, J = 12.8 Hz, 1H), 3.50 (ddt, J = 13.5, 4.3, 2.2 Hz, 1H), 3.82−4.07
(m, 5H), 4.99−5.08 (m, 3H), 5.15 (d, J = 17.1 Hz, 1H), 5.74−5.88
(m, 2H); 13C NMR (100 MHz, CDCl3) δ −4.8, −4.7, 18.3, 25.9 (3C),
27.6, 30.9, 39.2, 42.7, 55.0, 55.3, 57.3, 63.6, 64.7, 72.5, 108.4, 113.3,
116.7, 136.9, 146.9; HRMS (ESI, m/z) calcd for C21H38NO3Si [M +
H]+ 380.2615, found 380.2616.
(S)-1-Allyl-2-(3,3-dimethoxypropyl)-5-(triisopropylsilyloxy)-
2-vinyl-1,2,3,6-tetrahydropyridine (18). To a solution of com-
pound 17 (240 mg, 0.899 mmol) in CH2Cl2 (9.0 mL) at 0 °C were
added successively Et3N (0.44 mL, 3.15 mmol) and TIPSOTf (0.74
mL, 2.70 mmol). After being stirred at 0 °C for 30 min, the reaction
was quenched with a saturated aqueous solution of NaHCO3 and
extracted with CH2Cl2 (4 × 6 mL). The combined organic layers were
dried over anhydrous Na2SO4, filtered, and concentrated under
reduced pressure. The residue was purified by flash chromatography
on silica gel (eluent, EtOAc/hexane = 1:10) to give compound 18
(285 mg, yield 75%) as a colorless oil. [α]20D +18.7 (c 1.0, CHCl3); IR
(7S,8R,10aS)-8-[(tert-Butyldimethylsilyl)oxy]-3,5,7,8,9,10-
hexahydrospiro[7,10a-methanopyrrolo[1,2-a]azocine-6,2′-
[1,3]dioxolane] (24). To a solution of compound 23 (25 mg, 0.066
mmol) in anhydrous CH2Cl2 (5 mL) at rt was added Ti(OiPr)4 (5.7
μL, 0.020 mmol). After being stirred at rt for 30 min, a solution of the
Grubbs II catalyst (17 mg, 0.020 mmol) in anhydrous CH2Cl2 (2 mL)
was added. The mixture was refluxed for 2 h, until TLC analysis
showed complete consumption of the starting material. The reaction
was quenched with a saturated aqueous solution of NaHCO3 and
extracted with CH2Cl2 (3 × 4 mL). The combined organic layers were
dried over anhydrous Na2SO4, filtered, and concentrated under
reduced pressure. The residue was purified by flash chromatography
on silica gel (eluent, EtOAc/hexane = 1:1) to give compound 24 (16
mg, yield 70%) as a colorless oil. [α]20D −3.5 (c 0.5, CHCl3); IR (film)
1
(film) νmax 3074, 2943, 2866, 1671, 1462 cm−1; H NMR (400 MHz,
CDCl3) δ 1.06 (d, J = 5.2 Hz, 18H), 1.09−1.17 (m, 3H), 1.50−1.72
(m, 4H), 2.05 (dt, J = 16.7, 2.0 Hz, 1H), 2.17 (dt, J = 16.7, 1.9 Hz,
1H), 2.82−2.99 (m, 2H), 3.14 (d, J = 17.2 Hz, 1H), 3.25 (d, J = 5.0
Hz, 1H), 3.28 (s, 3H), 3.29 (s, 3H), 4.31 (t, J = 5.3 Hz, 1H), 4.80 (t, J
= 3.9 Hz, 1H), 5.00−5.11 (m, 2H), 5.12−5.21 (m, 2H), 5.73−5.88 (m,
2H); 13C NMR (100 MHz, CDCl3) δ 12.6 (2C), 18.0, (6C), 26.8,
29.1, 31.7, 49.2, 52.0, 52.5, 52.7, 58.7, 98.5, 104.9, 114.6, 116.2, 137.3,
141.7, 147.6; HRMS (ESI, m/z) calcd for C24H46NO3Si [M + H]+
424.3241, found 424.3250.
(1S,5R,6R)-2-Allyl-1-vinyl-2-azaspiro[bicyclo[3.3.1]nonane-
4,2′-[1,3]dioxolan]-6-ol (22). To a solution of piperidin-3-one 11
(1.53 g, 5.8 mmol) in THF (58.0 mL) was added an aqueous solution
of 4 N HCl (8.7 mL, 34.8 mmol), and the mixture was stirred for 1 h
at rt. After further reaction at 50 °C for 30 min, ethylene glycol (1.50
1
νmax 2927, 2854, 1593, 1107 cm−1; H NMR (400 MHz, CDCl3) δ
0.06 (s, 6H), 0.90 (s, 9H), 1.42 (dd, J = 13.3, 2.9 Hz, 1H), 1.60 (dt, J =
13.3, 5.8 Hz, 1H), 1.65−1.72 (m, 1H), 1.72−1.80 (m, 1H), 2.03 (dt, J
= 13.2, 3.3 Hz, 1H), 2.10 (dd, J = 6.8, 3.3 Hz, 1H), 2.16−2.29 (m,
1H), 2.93 (d, J = 13.6 Hz, 1H), 3.20 (d, J = 13.6 Hz, 1H), 3.66 (dt, J =
14.2, 2.0 Hz, 1H), 3.81−4.00 (m, 6H), 5.55 (dt, J = 6.1, 2.0 Hz, 1H),
5.71 (dt, J = 6.1, 2.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ −4.7
(2C), 18.3, 25.9 (3C), 29.7, 33.1, 36.5, 44.8, 56.3, 60.6, 63.3, 63.8,
64.8, 72.9, 109.2, 126.2, 136.4; HRMS (ESI, m/z) calcd for
C19H34NO3Si [M + H]+ 352.2302, found 352.2302.
(1S,5S,6R)-2-Allyl-6-(benzyloxy)-1-vinyl-2-azabicyclo[3.3.1]-
nonan-4-one (28). The mixture of acetal 27 (180 mg, 0.51 mmol)
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and HCl (6 N, 1.3 mL) in acetone (10 mL) was refluxed for 24 h. The
reaction mixture was cooled and neutralized with a saturated aqueous
solution of NaHCO3. The resulting mixture was extracted with ether
(5 × 3 mL). The combined organic layers were dried over anhydrous
Na2SO4, filtered, and concentrated under reduced pressure. The
residue was purified by flash chromatography on silica gel (eluent,
EtOAc/hexane = 1:4) to give compound 28 (110 mg, yield 75%) as a
pale yellow oil. [α]20D +30.5 (c 1.0, CHCl3); IR (film) νmax 3086, 2931,
methanopyrrolo[1,2-a]azocin-8-yl Dibenzyl Phosphate (44).
To a solution of compound 42 (50 mg, 0.068 mmol) in THF (2.0
mL) at rt were added successively dibenzyl phosphate (30 mg, 0.40
mmol, in 0.5 mL THF), tris(4-chlorophenyl)phosphine (73 mg, 0.20
mmol, in 0.5 mL THF), DIAD (40 μL, 0.20 mmol), and Et3N (94 μL,
0.68 mmol). After being stirred at rt for 1 h, the reaction mixture was
concentrated, and the residue was taken up with EtOAc. The
combined organic layers were concentrated under reduced pressure,
and the residue was dissolved in CH2Cl2/ H2O (3:1 v/v) (8 mL). To
the resulting solution were added Na2CO3 (72 mg, 0.68 mmol) and
CbzCl (48 μL, 0.34 mmol). After being stirred at rt for 1 h, the
reaction was quenched with a saturated aqueous solution of NH4Cl,
and the resulting mixture was extracted with CH2Cl2 (4 × 40 mL).
The combined organic layers were dried over anhydrous Na2SO4,
filtered, and concentrated under reduced pressure. The residue was
purified by flash chromatography on silica gel (eluent, MeOH/CH2Cl2
= 1:10) to give compound 44 (36 mg, yield 34% over two steps) as a
1
2859, 1712, 1658, 1091 cm−1; H NMR (400 MHz, CDCl3) δ 1.53−
1.75 (m, 3H), 2.03 (dt, J = 13.8, 3.6 Hz, 1H), 2.06−2.20 (m, 2H), 2.85
(dd, J = 13.8, 8.0 Hz, 1H), 3.08−3.15 (m, 1H), 3.24 (d, J = 19.7 Hz,
1H), 3.52 (ddt, J = 13.8, 4.5, 1.9 Hz, 1H), 3.67 (dt, J = 11.3, 5.4 Hz,
1H), 3.80 (d, J = 19.7 Hz, 1H), 4.48 (d, J = 11.8 Hz, 1H), 4.81 (d, J =
11.8 Hz, 1H), 5.06−5.20 (m, 4H), 5.66−5.79 (m, 2H), 7.24−7.37 (m,
5H); 13C NMR (100 MHz, CDCl3) δ 27.8, 29.0, 37.5, 47.6, 54.6, 55.3,
61.8, 69.9, 76.3, 114.1, 116.8, 127.6, 127.8 (2C), 128.4 (2C), 136.0,
138.2, 145.6, 207.4; HRMS (ESI, m/z) calcd for C20H25NO2Na [M +
Na]+ 334.1778, found 334.1784.
colorless oil. [α]20 +7.8 (c 1.0, CHCl3); IR (film) νmax 3420, 2958,
D
(1S,3S,5S,6R)-2-Allyl-6-(benzyloxy)-3-(4-methoxybenzyl)-1-
vinyl-2-azabicyclo[3.3.1]nonan-4-one (29). To a solution of
ketone 28 (43 mg, 0.14 mmol) in THF (1.4 mL) at −78 °C were
added TMEDA (100 μL, 0.69 mmol) and KHMDS (0.7 M in toluene,
200 μL, 0.14 mmol). After being stirred at −78 °C for 30 min, a
solution of p-methoxybenzylbromide (61 μL, 0.42 mmol) in THF (1.4
mL) was added over 40 min. The mixture was allowed to warm to 0
°C. The reaction was quenched with a saturated aqueous solution of
NH4Cl, and the mixture was extracted with EtOAc (1 × 4 mL). The
combined organic layers were dried over anhydrous Na2SO4, filtered,
and concentrated under reduced pressure. The residue was purified by
flash chromatography on silica gel (eluent, EtOAc/hexane = 1:10) to
give compound 29 (48 mg, yield 80%) as a colorless oil. [α]20D +73.2
(c 1.0, CHCl3); IR (film) νmax 3061, 3037, 2935, 2864, 1709, 1659,
2924, 1694, 1512 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.42 (dd, J =
13.4, 6.4 Hz, 1H), 1.48 (br d, J = 13.4 Hz, 1H), 1.55−1.67 (m, 1H),
1.73 (d, J = 5.6 Hz, 1H), 1.76−1.96 (m, 5H), 1.98−2.09 (m, 1H), 2.15
(br s, 1H), 2.74 (dd, J = 9.8, 5.6 Hz, 1H), 2.78 (s, 3H), 2.80 (br s, 1H),
3.16 (br s, 1H), 3.23−3.36 (m, 1H), 3.44 (br s, 1H), 3.78 (s, 3H), 4.34
(br s, 1H), 4.78 (br s, 1H), 4.93−5.06 (m, 4H), 5.11 (s, 2H), 6.82 (d, J
= 8.5 Hz, 2H), 7.15 (d, J = 8.5 Hz, 2H), 7.21−7.48 (m, 15H); 13C
NMR (100 MHz, CDCl3) δ 28.7, 29.0, 29.8, 35.6, 43.0, 43.5, 50.2,
51.9, 55.2, 58.3, 58.4, 67.0, 67.1, 69.17, 69.22, 75.0, 113.8 (2C), 127.82,
127.87 (2C), 127.90 (3C), 128.43 (2C), 128.47 (3C), 128.52 (4C),
130.0 (2C), 130.8, 135.9 (2C), 136.9, 156.3, 158.1; HRMS (ESI, m/z)
calcd for C42H50N2O8P [M + H]+ 741.3299, found 741.3299.
(−)-FR901483 (1). To a solution of compound 44 (18 mg, 0.024
mmol) in MeOH (2.0 mL) was added 1 N HCl (29 μL, 0.029 mmol).
The solvent was removed under reduced pressure, and the residue was
dissolved in MeOH (2.0 mL). 10% Pd/C (18 mg) was added, and the
mixture was stirred at rt for 6 h under 1 atm of H2. The resulting
mixture was filtered through Celite and washed with MeOH. The
combined filtrates were concentrated under reduced pressure and then
rinsed with CH3CN to give (−)-FR901483 (1) (11 mg, yield 92%) as
a white solid. Mp 215−220 °C (MeOH/Et2O) (lit.2 mp 210−213
°C); [α]20 −10.2 (c 0.5, MeOH) {lit.2 [α]20 −11.0 (c 0.74,
1
1610, 1511, 1247, 1092 cm−1; H NMR (400 MHz, CDCl3) δ 0.91
(dt, J = 13.9, 3.7 Hz, 1H), 1.13 (dd, J = 13.9, 2.4 Hz, 1H), 1.30−1.43
(m, 1H), 1.52 (dt, J = 13.8, 3.8 Hz, 1H), 1.90−1.98 (m, 1H), 2.04
(ddd, J = 13.8, 6.8, 3.5 Hz, 1H), 2.68−2.74 (m, 1H), 2.83 (dd, J = 13.4,
5.3 Hz, 1H), 3.13 (dd, J = 13.4, 3.5 Hz, 1H), 3.25 (dd, J = 14.6, 7.3 Hz,
1H), 3.42−3.50 (m, 2H), 3.78 (s, 3H), 3.83 (t, J = 4.3 Hz, 1H), 4.43
(d, J = 11.5 Hz, 1H), 4.86 (d, J = 11.5 Hz, 1H), 4.99−5.19 (m, 4H),
5.65 (dd, J = 18.0, 10.5 Hz, 1H), 5.88 (ddt, J = 17.0, 9.9, 7.1 Hz, 1H),
6.79 (d, J = 8.7 Hz, 2H), 7.07 (d, J = 8.7 Hz, 2H), 7.23−7.39 (m, 5H);
13C NMR (100 MHz, CDCl3) δ 27.6, 30.3, 34.0, 39.6, 45.8, 52.9, 55.2,
55.7, 69.5, 69.8, 77.7, 113.0, 113.3 (2C), 117.5, 127.5, 127.8 (2C),
128.4 (2C), 130.7, 131.5 (2C), 137.7, 138.3, 146.4, 158.2, 210.9;
HRMS (ESI, m/z) calcd for C28H33NO3Na [M + Na]+ 454.2353,
found 454.2351.
D
D
MeOH)}; IR (film) νmax 3396, 2960, 1626, 1248, 1010 cm−1; 1H NMR
(600 MHz, CD3OD) δ 1.87 (br d, J = 11.6 Hz, 1H), 2.04−2.25 (m,
6H), 2.44 (br s, 1H), 2.53 (dd, J = 13.7, 8.6 Hz, 1H), 2.67 (s, 3H),
3.03 (br d, J = 9.4 Hz, 1H), 3.25 (dd, J = 11.8, 9.4 Hz, 1H), 3.57 (br s,
1H), 3.78 (s, 3H), 3.71−3.84 (m, 2H), 4.08−4.14 (m, 1H), 4.20 (br d,
J = 8.0 Hz, 1H), 4.39 (dd, J = 13.1, 9.4 Hz, 1H), 6.87 (d, J = 8.5 Hz,
2H), 7.31 (d, J = 8.5 Hz, 2H); 13C NMR (150 MHz, CD3OD) δ 22.6,
28.2, 28.7, 32.3, 34.2, 42.2, 43.1, 51.8, 55.1, 55.8, 61.4, 64.5, 67.6, 70.6,
115.2, 129.1, 131.7, 160.3; HRMS (ESI, m/z) calcd for C20H32N2O6P
[M + H]+ 427.1992, found 427.1995.
(1S,5R,6R)-2-Allyl-6-(benzyloxy)-3-(4-methoxybenzyl)-1-
vinyl-2-azabicyclo[3.3.1]non-3-ene (31). To a mixture of ketone
29 (20 mg, 0.046 mmol) and water (10 μL, 0.56 mmol) in THF (2.0
mL) was added a solution of SmI2 (0.1 M in THF, 1.86 mL, 0.19
mmol). After being stirred at rt for 5 min, the reaction was quenched
with a saturated aqueous solution of NH4Cl and extracted with EtOAc
(3 × 2 mL). The combined organic layers were dried over anhydrous
Na2SO4, filtered, and concentrated under reduced pressure. The
residue was purified by flash chromatography on silica gel (eluent,
MeOH/CH2Cl2 = 1:20) to give compound 31 (18 mg, yield 94%) as a
Benzyl [(2S,5S,6S,7S,8S,10aS)-6,8-Dihydroxy-5-(4-methoxy-
benzyl)octahydro-1H-7,10a-methanopyrrolo[1,2-a]azocin-2-
yl](methyl)carbamate (45). To a solution of compound 42 (196
mg, 0.568 mmol) in CH2Cl2/ H2O (3: 1) (56 mL) at rt were added
successively Na2CO3 (602 mg, 5.68 mmol) and CbzCl (0.40 mL, 2.84
mmol). After being stirred at rt for 1 h, the reaction was quenched
with a saturated aqueous solution of NH4Cl and extracted with
CH2Cl2 (4 × 40 mL). The combined organic layers were dried over
anhydrous Na2SO4, filtered, and concentrated under reduced pressure.
The residue was purified by flash chromatography on silica gel (eluent,
MeOH/CH2Cl2 = 1:20) to give compound 45 (259 mg, yield 95%) as
colorless oil. [α]20 +96.0 (c 1.0, CHCl3); IR (film) νmax 3058, 3032,
D
2931, 2855, 1693, 1659, 1642, 1607, 1511, 1177 cm−1; 1H NMR (400
MHz, CDCl3) δ 1.38−1.52 (m, 2H), 1.59 (dt, J = 13.0, 5.2 Hz, 1H),
1.83−2.01 (m, 3H), 3.32 (d, J = 5.3 Hz, 1H), 3.40−3.54 (m, 4H), 3.77
(s, 3H), 4.32 (t, J = 7.3 Hz, 1H), 4.53 (d, J = 12.3 Hz, 1H), 4.64 (d, J =
12.3 Hz, 1H), 5.02 (dd, J = 10.2, 1.6 Hz, 1H), 5.10 (dd, J = 14.3, 2.6
Hz, 2H), 5.17 (dd, J = 17.1, 1.8 Hz, 1H), 5.78−5.89 (m, 2H), 6.78 (d,
J = 8.6 Hz, 2H), 7.14 (d, J = 8.6 Hz, 2H), 7.21−7.34 (m, 5H); 13C
NMR (100 MHz, CDCl3) δ 26.2, 28.8, 33.8, 40.4, 42.8, 46.8, 55.2,
65.2, 70.3, 79.0, 91.4, 113.4 (2C), 114.8 (2C), 127.3 (2C), 127.4 (2C),
128.2, 129.1 (2C), 136.3, 136.5, 138.9, 142.9, 147.9, 157.4; HRMS
(ESI, m/z) calcd for C28H34NO2 [M + H]+ 416.2584, found 416.2589.
(2S,5S,6S,7R,8S,10aS)-2-[(Benzyloxycarbonyl)methylamino]-
octahydro-6-hydroxy-5-[(4-methoxyphenyl)methyl]-1H-7,10a-
a white foam. [α]20 −3.6 (c 0.6, CHCl3); IR (film) νmax 3435, 2934,
D
1703, 1512, 1246 cm−1; 1H NMR (500 MHz, CD3CN) δ 0.98 (d, J =
11.9 Hz, 1H), 1.45 (br s, 1H), 1.57−1.69 (m, 1H), 1.71−1.91 (m,
4H), 2.09−2.22 (m, 2H), 2.67 (s, 3H), 2.76−3.20 (m, 5H), 3.58 (br s,
2H), 3.64 (br s, 1H), 3.72 (s, 3H), 3.83−3.92 (m, 1H), 4.50−4.76 (m,
1H), 5.05 (s, 2H), 6.82 (d, J = 8.6 Hz, 2H), 7.24 (d, J = 8.6 Hz, 2H),
7.34 (s, 5H); 13C NMR (125 MHz, CD3CN) δ 28.6, 29.7, 31.6, 34.7,
36.4, 43.4, 45.0, 51.7, 53.0, 55.8, 60.4, 66.2, 67.5, 70.4, 114.5 (2C),
128.6 (2C), 128.8, 129.5 (2C), 131.2 (2C), 132.7 138.5, 157.0, 159.0;
463
dx.doi.org/10.1021/jo302362b | J. Org. Chem. 2013, 78, 455−465

The Journal of Organic Chemistry
Article
HRMS (ESI, m/z) calcd for C28H37N2O5 [M + H]+ 481.2697, found
481.2696.
grateful to Dr. A.-E Wang for valuable discussion and Dr. Jian-
Liang Ye for analysis of the NOESY spectra.
Benzyl [(2S,5S,6S,7S,8S,10aS)-8-[[Bis(benzyloxy)phos-
phoryl]oxy]-6-hydroxy-5-(4-methoxybenzyl)octahydro-1H-
7,10a-methanopyrrolo[1,2-a]azocin-2-yl](methyl)carbamate
(46). To a solution of diol 45 (62 mg, 0.129 mmol) and 1-H-tetrazole
(90 mg, 1.29 mmol) in CH2Cl2 (10 mL) at 0 °C was added
dibenzyl(N,N-diisopropyl)phosphoramidite (86 μL, 0.26 mmol, in 5
mL of CH2Cl2) over 60 min. The reaction mixture was cooled to −78
°C before addition of TBHP (5.5 M in decane, 70 μL, 0.39 mmol).
The reaction was allowed to warm to −10 °C slowly, quenched with a
saturated aqueous solution of Na2SO3 and extracted with CH2Cl2 (15
× 4 mL). The combined organic layers were dried over anhydrous
Na2SO4, filtered, and concentrated under reduced pressure. The
residue was purified by flash chromatography on silica gel (eluent,
MeOH/CH2Cl2 = 1:20) to give compound 46 (62 mg, yield 65%) as a
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colorless oil. [α]20 +1.6 (c 1.0, CHCl3); IR (film) νmax 3420, 2956,
D
2919, 2850, 1699, 1512, 1013 cm−1; 1H NMR (400 MHz, CD3OD) δ
1.03 (d, J = 13.1 Hz, 1H), 1.26−1.36 (m, 2H), 1.50 (dd, J = 12.6, 6.9
Hz, 1H), 1.58−1.74 (m, 1H), 1.76−2.12 (m, 4H), 2.26 (br d, J = 12.2
Hz, 1H), 2.39 (br s, 1H), 2.73 (s, 3H), 2.82 (dd, J = 13.2, 5.9 Hz, 1H),
2.86−3.03 (m, 2H), 3.56 (br s, 1H), 3.60 (s, 3H), 3.65 (br s, 1H),
4.56−4.66 (m, 1H), 4.67−4.77 (m, 1H), 4.84−4.91 (m, 4H), 5.08 (s,
2H), 6.78 (d, J = 8.6 Hz, 2H), 7.23 (d, J = 8.6 Hz, 2H), 7.33 (s, 10H),
7.34 (s, 5H); 13C NMR (100 MHz, CD3OD) δ 28.0, 29.6, 30.2 30.7,
34.6, 36.5, 43.1, 43.4, 51.7, 53.4, 55.5, 60.9, 65.6, 68.3, 70.7, 79.2,
114.7, 128.8, 129.1, 129.2, 129.5, 129.66, 129.71, 131.2, 132.6, 137.1,
138.2, 158.0, 159.4; HRMS (ESI, m/z) calcd for C42H50N2O8P [M +
H]+ 741.3299, found 741.3295.
́
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C (30 mg) was added, and the mixture was stirred at rt for 6 h under 1
atm of H2. The resulting mixture was filtered through Celite and
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reduced pressure and then rinsed with CH3CN to give 8-epi-
FR901483 (47) (16 mg, yield 95%) as a white solid. Mp 215−218
́ ́
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1402. (c) Bonjoch, J.; Diaba, F.; Puigbo, G.; Sole, D.; Segarra, V.;
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2960, 1620, 1248, 1010 cm−1; H NMR (500 MHz, CD3OD) δ 1.56
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(br d, J = 12.6 Hz, 1H), 1.93 (br s, 1H), 2.07−2.41 (m, 3H), 2.44−
2.70 (m, 4H), 2.79 (s, 2H), 2.90 (s, 1H), 3.01 (br s, 1H), 3.08−3.17
(m, 1H), 3.35 (s, 3H), 3.78 (s, 3H), 3.87−4.07 (m, 3H), 4.17−4.36
(m, 1H), 4.51 (dd, J = 13.0, 9.5 Hz, 1H), 4.62 (br s, 1H), 6.88 (d, J =
8.5 Hz, 2H), 7.33 (d, J = 8.5 Hz, 2H); 13C NMR (125 MHz, CD3OD)
δ 26.8, 28.3, 31.0, 32.4, 34.2, 41.0, 41.2, 52.0, 55.1, 55.7, 61.8, 63.3,
68.0, 74.6, 115.3, 128.5, 131.6, 160.4; HRMS (ESI, m/z) calcd for
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ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra of all new compounds; NOESY
spectra of compounds 14, 40, and 40a. This material is
available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*E-mail: pqhuang@xmu.edu.cn; hkzhang@xmu.edu.cn.
Notes
■
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
The authors are grateful to the NSF of China (20832005,
21072160), the National Basic Research Program (973
Program) of China (Grant No. 2010CB833200), and the
Fundamental Research Funds for the Central Universities of
China (Grant No. 201112G001) for financial support. We are
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