Asymmetric synthesis of gem-difluoromethylenated dihydroxypyrrolizidines and indolizidines

Article abstract of DOI:10.1021/jo301327s

An asymmetric synthesis of gem-difluoromethylenated dihydroxypyrrolizidines and indolizidines is described. The fluoride-catalyzed nucleophilic addition of PhSCF₂SiMe₃ (1) to chiral imides was achieved in satisfactory yields to provide mixtures of syn- and anti-isomers 6-9 with moderate to good diastereoselectivities. Reductive cleavage of the phenylsulfanyl group followed by intramolecular radical cyclization of the syn-isomers 6-9 occurred under refluxing conditions to afford the corresponding gem-difluoromethylenated 1-azabicyclic compounds 10-13 in moderate yields as a separable mixture of cis- and trans-isomers. The cis-isomers of compounds 10 and 12 and trans-13 were readily transformed to gem-difluoromethylenated dihydroxypyrrolizidines 20 and 27 and indolizidine 28, respectively, by reductive cleavage of the hydroxyl group and organometallic addition followed by hydrogenolysis.

Full text of DOI:10.1021/jo301327s

Article
pubs.acs.org/joc
Asymmetric Synthesis of gem-Difluoromethylenated
Dihydroxypyrrolizidines and Indolizidines
Watcharaporn Thaharn,† Teerawut Bootwicha,† Darunee Soorukram,† Chutima Kuhakarn,†
Samran Prabpai,†,‡ Palangpon Kongsaeree,†,‡ Patoomratana Tuchinda,† Vichai Reutrakul,†
and Manat Pohmakotr*,†
†Center of Excellence for Innovation in Chemistry (PERCH-CIC) and Department of Chemistry, Faculty of Science,
Mahidol University, Rama VI Road, Bangkok 10400, Thailand
‡Center for Excellence in Protein Structure and Function, Faculty of Science, Mahidol University, Rama VI Road,
Bangkok 10400, Thailand
S
* Supporting Information
ABSTRACT: An asymmetric synthesis of gem-difluoromethylenated
dihydroxypyrrolizidines and indolizidines is described. The
fluoride-catalyzed nucleophilic addition of PhSCF2SiMe3 (1) to
chiral imides was achieved in satisfactory yields to provide mixtures
of syn- and anti-isomers 6−9 with moderate to good diastereo-
selectivities. Reductive cleavage of the phenylsulfanyl group
followed by intramolecular radical cyclization of the syn-isomers
6−9 occurred under refluxing conditions to afford the correspond-
ing gem-difluoromethylenated 1-azabicyclic compounds 10−13 in
moderate yields as a separable mixture of cis- and trans-isomers.
The cis-isomers of compounds 10 and 12 and trans-13 were readily
transformed to gem-difluoromethylenated dihydroxypyrrolizidines
20 and 27 and indolizidine 28, respectively, by reductive cleavage
of the hydroxyl group and organometallic addition followed by
hydrogenolysis.
Scheme 1. Preparation of gem-Difluoromethylenated
1-Azabicyclic Derivatives
INTRODUCTION
■
Organic molecules containing gem-difluoromethylene moiety
have been shown to have unique physical, chemical and biological
properties. The presence of the gem-difluoromethylene can
enhance pharmacological activities of drug molecules including
their stability, lipophilicity and bioavailability.1 In this respect,
there is a growing trend for development of efficient methodology
for the preparation of gem-difluoromethylenated compounds,
particularly analogues of natural products for use in pharmaceu-
tical industry.2 In the course of our continuous research on
employing PhSCF2SiMe3 (1) as a gem-difluoromethylene
building block,3 we have recently demonstrated a general method
for the preparation of gem-difluoromethylenated 1-azabicyclic
derivatives (Scheme 1).4 The synthesis involved fluoride-catalyzed
nucleophlilic difluoro(phenylsulfanyl)methylation reaction of
PhSCF2SiMe3 (1) to N-alkenyl succinimide derivatives followed
by sequential intramolecular radical cyclization. The resulting
adducts were employed as useful precursors for the preparation of
gem-difluoromethylenated pyrrolizidines and indolizidines by
reductive cleavage of the hydroxyl group and subsequent organo-
metallic addition to the carbonyl group followed by reduction.
In view of the important biological properties of polyhydroxylated
pyrrolizidine and indolizidine alkaloids, e.g., lentiginosine,
swainsonine and catanospermine as potent glycosidase inhibitors,5
numerous reports described the syntheses of these classes of
natural products and their analogues.6 In the present paper, we
report an asymmetric synthesis of gem-difluoromethylenated
dihydroxypyrrolizidines and indolizidines starting from readily
available chiral N-alkenyl-3,4-dihydroxylated succinimides.
Received: June 29, 2012
Published: September 4, 2012
© 2012 American Chemical Society
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RESULTS AND DISCUSSION
■
At first, suitable chiral imides 2−5 were synthesized starting
from L-tartaric acid (see the Experimental Section).7 With the
chiral imides in hand, we then commenced our study by
examining the stereoselective fluoride-catalyzed nucleophilic
addition of PhSCF2SiMe3 (1) to chiral imides 2−5 (Scheme 2).
Scheme 2. Adducts 6−9 Obtained via Fluoride-Catalyzed
Reaction of PhSCF2SiMe3 (1) with Chiral Imides 2−5
Figure 1. Proposed transition state for the addition of PhSCF2SiMe3
(1) to chiral imides.
Scheme 3. Reductive Cyclization of the Syn Isomers of
Adducts 6−9 to Bicyclic Derivatives 10−13
Treatment of 1 with imide 2 in the presence of 10 mol % of
tetrabutylammonium fluoride (TBAF) in THF at −78 to 0 °C
for 3 h gave adduct 6 as a mixture of syn- and anti-isomers in 58
and 7% yields, respectively. Gratifyingly, better yield and higher
stereoselectivity of adduct 6 were obtained (syn-6 = 72% yield,
anti-6 = 8% yield) when tetrabutylammonium triphenyldi-
fluorosilicate (TBAT) was employed as a fluoride source
(10 mol % TBAT, DMF, 0 °C, 2 h) (Table 1, entries 1 and 2).
Under similar reaction conditions, the reaction of imide 3 with
1 also gave rise to a formation of a mixture of syn-7 (76% yield)
and anti-7 (4% yield) (Table 1, entry 3). Poor results (lower
yield and stereoselectivity) were observed when the benzyl
protected imides 4 were employed as a substrate (Table 1,
entry 4). However, slightly higher yield was obtained when the
reaction was performed in THF at low temperature (−78 °C)
albeit with low stereoselectivity (Table 1, entry 5). Imide 5 gave
comparable results to those of imide 4 (Table 1, entry 6). The
diastereomeric mixtures of the obtained adducts 6−9 can be
separated by column chromatography.
A proposed transition state for fluoride-catalyzed nucleophilic
addition of PhSCF2SiMe3 (1) to chiral imides is illustrated in
Figure 1. The nucleophile (“PhSCF2−”) preferentially attacked
the carbonyl group of the imide in the direction that steric
repulsion to the −OP group is minimized, affording the syn-
isomer as the major isomer. The stereoselectivity of the reduc-
tion was realized, and the stereochemical outcomes can be
rationalized as those previously reported by Speckamp and
Takabe.8
of each isomer can readily be achieved by preparative thin-layer
chromatography on silica gel. The relative stereochemistries of
cis-10, trans-11 and cis-13 were established by X-ray crystallo-
graphy (see the Supporting Information). On the basis of the
X-ray structures of cis-10, trans-11 and cis-13, the stereo-
chemistries of syn-6, syn-7 and syn-9 could be confirmed as
depicted in Scheme 3.
The stereochemical outcome of compounds 10, 11, 12 and
13 can be rationalized as shown in Scheme 4. The radical
cyclization was proposed to proceed via 5-exo or 6-exo cycliza-
tion mode.12 Half-chair transition state A for the radical
intermediate derived from syn-6 or syn-8 is energetically more
favorable due to minimized steric interaction between the
vinylic group and the −CHOP group, giving rise to cis-10 or cis-
12 as the major isomer. Similarly, the radical cyclization of syn-7
or syn-9 proceeded via the favorable chair like transition state C,
of which the vinylic group is at quasi-equatorial position,
leading to trans-11 or trans-13 as the major product.
Having established an efficient strategy to chiral gem-
difluoromethylenated 1-azabicyclic compounds 10−13, we
further demonstrated their conversion to chiral substituted
gem-difluoromethylenated dihydroxypyrrolizidines and indolizi-
dines. Indeed, reductive cleavage of the hydroxyl group of cis-10
was examined. When cis-10 was allowed to react with Et3SiH/
BF3·OEt2 in CH2Cl213 at −78 °C to room temperature for 24 h,
compound 15 of which the hydroxyl group is opposite to that
When the syn-adducts 6−9 were treated with Bu3SnH/AIBN
in refluxing toluene, the corresponding gem-difluoromethyl
radicals9 were formed and subsequently underwent intramo-
lecular cyclization to the alkenyl moiety, affording gem-
difluoromethylenated 1-azabicyclic compounds 10−13 as
mixtures of cis- and trans-isomers (Scheme 3).10,11 Separation
a
Table 1. Results Obtained for the Formation of Adducts 6−9
b
imides
adducts (% yield)
entry
n
P
F−
temp (°C)
time (h)
syn-
anti-
c
1
2
3
4
5
6
2
2
3
4
4
5
1
1
2
1
1
2
TBS
TBS
TBS
Bn
TBAF
−78 to 0
3
6 (58)
6 (72)
7 (76)
8 (28)
8 (48)
9 (40)
6 (7)
d
d
TBAT
TBAT
TBAT
TBAT
TBAT
0
2
6 (8)
0
2.5
2
7 (4)
de
,
0
8 (23)
8 (31)
9 (31)
c
c
Bn
−78
−78
8
Bn
10
a
b
c
d
e
In all cases, 10 mol % of fluoride source were used. Isolated yields. THF was used as the solvent. DMF was used as the solvent. β-Elimination
product derived from adduct 8 was isolated in 18% yield.
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at room temperature within 48 h or refluxing CH2Cl2 within
24 h, affording 18 as a single product in 73 and 62% yield,
respectively. The relative stereochemistries of compounds 14,
16 and 18 were established by the NOE experiments (see the
Supporting Information).
Scheme 4. Proposed Transition States of the Radical
Cyclization for the Formation of Bicyclic Derivatives 10−13
The formation of compounds 14, 15, 18 and 19 could be
rationalized as shown in Scheme 6. The initially formed iminium
intermediate E was trapped by a hydride from Et3SiH or by
HOBF3, which upon hydrolysis, leading to compounds 14 or 18
and 15 or 19, respectively. As mentioned earlier, the reductive
cleavage of cis-10 and cis-12 conducted either at prolonged
reaction time or at refluxing temperature provided exclusively
the reduction products (14 and 16−18). This implies that the
step of intermediate F formation is reversible. Thus, intermediate
F was able to undergo elimination, converting back to the inter-
mediate E, which could then be trapped by the hydride.
The structure and relative stereochemistry of trans-19 was
established by comparing its spectral data with those of trans-19
obtained from the radical cyclization of anti-8 (Scheme 7),
Scheme 7. Radical Mediated Cyclization of anti-8
of the starting compound cis-10 was obtained in 71% yield.
However, when the reaction was carried out at higher
temperature (refluxing CH2Cl2) for 24 h, a mixture of products
were obtained including expected reduction product 14,
accompanied with desilylated compounds 16 and 17 in 20,
12, and 13% yields, respectively (Scheme 5). Similar results
were obtained when cis-12 was employed as the substrate.
Treatment of cis-12 with Et3SiH/BF3·OEt2 in CH2Cl2 at room
temperature for 24 h afforded the expected reduction product
18 accompanied by compound 19 in 18 and 34% yields,
respectively. To our delight, it was discovered that the reaction
of cis-12 with Et3SiH/BF3·OEt2 proceeded to completion either
which provided cis-19 as the major isomer. The relative stereo-
chemistry of cis-19 was finally confirmed by X-ray crystallog-
raphy (see the Supporting Information).
Having compounds 14 and 16 in hand, we then carried out
the hydrolytic deprotection of the t-butyldimethylsilyl group by
using DOWEX 50 WX8 (H⊕-form) in methanol14 and obtained
Scheme 5. Reductive Cleavage of the Hydroxyl Group of cis-10 and cis-12
Scheme 6. Proposed Transition States for the Formation of Compounds 14, 15, 18 and 19
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Scheme 8. Preparation of gem-Difluoromethylenated Dihydroxypyrrolizidine 20
the corresponding dihydroxy derivative 17 in good yields.
Compound 18, on the other hand, was subjected to hydro-
genolysis (H2, PdCl2, MeOH) to provide compound 17 in
quantitative yield. Reduction of 17 with LiAlH4 in refluxing
THF gave gem-difluoromethylenated dihydroxypyrrolizidine 20
in 72% yield. The results are summarized in Scheme 8.
The resulting stereochemical outcomes of the reaction can be
explained by the addition of the organometallic reagents to the
carbonyl carbon of the amide moiety. Subsequent acidification
afforded iminium ions G, which were reduced by the attack of
the hydride from the stereoelectronically pseudoaxial face,
leading to the favorable cis-ring junction adducts 21.15
The synthetic utilities of our method were also extended
to the preparation of 1-alkyl-gem-difluoromethylenated
dihydroxypyrrolizidines. Treatment of 18 with ethylmagnesium
chloride in THF at 0 °C for 30 min followed by sequential
acidification with 4 M HCl and reduction using NaBH3CN
provided 1-alkyl-gem-difluoromethylenated dihydroxypyrrolizi-
dine 21a in 56% yield as a single isomer. n-Butylmagnesium
chloride also worked well, providing product 21b in 58% yield.
However, the reaction using a mixture of n-BuLi/CeCl3 in THF
gave 21b and compound 22b in 15 and 43% yields, respectively.
A sterically hindered iPrMgCl afforded the expected adduct 21c
in 51% yield accompanied with compound 22c in 12% yield.
The results are summarized in Scheme 9 and Table 2. The
relative stereochemistry of 21 was established on the basis
of the NOE experiments (see the Supporting Information).
The competitive formation of compounds 22 was observed
when more bulky organometallic reagents, e.g., iPrMgCl and BuLi/
CeCl3, were employed as nucleophiles. The mechanistic pathways
(A and B) for their formation was depicted in Scheme 10. First,
a more rapid α-deprotonation of 18 occurs to give an enolate
anion 18A, which leads to the elimination of the β-benzyloxy
group, affording 18B. It is worth mentioning base promoted
elimination of β-Boc, β-OAc and β-OBn substituted γ-lactams has
been previously reported.16 Subsequent γ-deprotonation of 18B
followed by elimination of a fluorine atom through dienolate 18C
leads to 18D, which undergoes conjugate addition−elimination via
an intermediate 18E to furnish compounds 22. An alternative
mechanism for the formation of compounds 22 includes base-
induced HF elimination followed by SN2′ displacement of the
β-benzyloxy group, affording 18G. Subsequent α-deprotonation of
18G gave 18E, which can undego elimination of a second fluorine
atom, leading to compounds 22.17
Scheme 9. Preparation of 1-Alkyl gem-Difluoromethylenated
Dihydroxypyrrolizidines 21
The synthesis of 1-alkyl-substituted gem-difluoromethylen-
ated dihydroxyindolizidines also proceeded smoothly, starting
from trans-13. Reduction of trans-13 with Et3SiH and BF3·OEt2
in CH2Cl2 at room temperature for 24 h gave a mixture of cis-
23 and trans-23 in 40 and 22% yields, respectively (Scheme 11).
The relative stereochemistry of trans-23 was confirmed by the
NOE experiments (see the Supporting Information). Subse-
quent reductive alkylation of cis-23 by reacting with EtMgCl
in THF followed by acidification with 4 M HCl in dioxane/
MeOH and reduction with NaBH3CN afforded a mixture of 24a
and 25a in 50 and 22% yields, respectively. The results are
summarized in Scheme 12 and Table 3. Under the similar
reaction conditions, the reaction of cis-23 with n-BuMgCl gave
a mixture of 24b (43%), 25b (16%) together with 26b (14%).
When iPrMgCl in THF was employed under the same
conditions, compound 26c was obtained in 48% yield along
with the starting compound cis-23 in 24% yield: no trace of the
expected products 24c and 25c was detected. The formation of
26b,c can be explained as for compounds 22 from 18 as shown
in Scheme 10. The relative stereochemistries of compounds 24
were established by the NOE experiments (see the Supporting
Information).
Table 2. Results Obtained for the Preparation of 1-Alkyl
gem-Difluoromethylenated Dihydroxypyrrolizidines 21
a
products (% yield)
entry
RM
R
21
22
1
2
3
4
EtMgCl
Et
21a (56)
21b (58)
21b (15)
21c (51)
22a (−)
n-BuMgCl
n-BuLi/CeCl3
iPrMgCl
n-Bu
n-Bu
iPr
22b (trace)
22b (43)
22c (12)
a
Isolated yields.
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Scheme 10. Proposed mechanistic Pathways (A and B) for the Formation of Compounds 22
Scheme 11. Reductive Cleavage of the Hydroxyl Group of trans-13
Scheme 12. Preparation of 1-Alkyl gem-Difluoromethylenated Dihydroxyindolizidines
temperature. The results are summarized in Scheme 13. The
relative stereochemistry of compound 28b was confirmed by
X-ray crystallography (see the Supporting Information).
Table 3. Results Obtained for the Preparation of 1-Alkyl
gem-Difluoromethylenated Dihydroxyindolizidines
a
products (% yield)
entry
RM
R
24
25
26
CONCLUSION
■
1
2
3
EtMgCl
Et
24a (50)
24b (43)
24c (−)
25a (22)
25b (16)
25c (−)
26a (−)
26b (14)
26c (48)
In conclusion, we have demonstrated the synthetic utilities of
PhSCF2SiMe3 as a useful gem-difluoromethylene building block
for an asymmetric synthesis of gem-difluoromethylenated
dihydroxypyrrolizidine and indolizidine derivatives. The present
work started from readily available chiral starting imides and
involved sequential stereoselective fluoride-catalyzed addition
of PhSCF2SiMe3 to chiral imide, intramolecular radical cycliza-
tion, reduction of the hydroxy functionality and organometallic
addition followed by hydrogenolysis. The method provides a
n-BuMgCl
iPrMgCl
n-Bu
iPr
a
Isolated yields.
Finally, the conversions of dibenzyl protected compounds
21a−c and 24a,b to the corresponding dihydroxy derivatives
27a−c and 28a,b were straightforward and successfully
performed by treatment with H2/PdCl2 in methanol at room
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(500 MHz, CDCl3) δ 5.80 (ddt, J = 6.1, 10.1, 16.7 Hz, 1H), 5.29−5.18
(m, 2H), 4.50 (s, 2H), 4.14−4.06 (m, 2H), 0.96 (s, 18H), 0.24 (s,
6H), 0.19 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 172.9 (2 × CO),
130.3 (CH), 119.0 (CH2), 76.9 (2 × CH), 40.8 (CH2), 25.6 (6 ×
CH3), 18.2 (2 × C), −4.5 (2 × CH3), −5.0 (2 × CH3); IR (neat) νmax
1727s, 1371m, 1254s, 1112s, 838s cm−1; MS m/z (%) relative intensity
399 (M+, 2), 342 (100), 314 (58), 231 (13), 155 (55), 149 (16), 133
(14), 111 (5), 73 (37); HRMS (ESI-TOF) calcd for C19H38NO4Si2
[M + H]+ 400.2339, found 400.2322.
Scheme 13. Preparation of gem-Difluoromethylenated
Pyrrolizidines 27 and Indolizidines 28
(3R,4R)-1-(But-3-enyl)-3,4-bis(tert-butyldimethylsilyloxy)-
pyrrolidine-2,5-dione (3). The reaction of L-tartaric acid (4.51 g,
30 mmol) with p-methoxybenzylamine (3.9 mL, 30.6 mmol) in xylene
(30 mL) gave a white solid of (3R,4R)-3,4-dihydroxy-1-(4-
methoxybenzyl) pyrrolidine-2,5-dione7a,b (7.02 g, 93% yield): mp
193−194 °C; [α]26 +89.0° (c 1, MeOH); 1H NMR (300 MHz,
D
acetone-d6) δ 7.24 (d, J = 8.5 Hz, 2H), 6.85 (d, J = 8.5 Hz, 2H), 5.43−
5.41 (br s, 2H), 4.57 (s, 2H), 4.48 (s, 2H), 3.76 (s, 3H); 13C NMR (75
MHz, acetone-d6) δ 174.6 (2 × CO), 160.2 (C), 130.5 (2 × CH),
129.2 (C), 114.6 (2 × CH), 76.0 (2 × CH), 55.5 (OCH3) 41.9 (CH2);
IR (KBr) νmax 3285br, 1710s, 1615m, 1513s, 1352s, 813w cm−1
;
MS m/z (%) relative intensity 251 (M+, 2), 136 (100), 121 (83),
109 (18), 91 (23), 77 (20), 65 (5). The reaction of (3R,4R)-3,4-
dihydroxy-1-(4-methoxybenzyl)pyrrolidine-2,5-dione (5.05 g, 20.1
mmol) with TBSCl (7.88 g, 52.3 mmol) and imidazole (4.11 g, 60.4
mmol) in dry DMF (40 mL) gave a colorless oil of (3R,4R)-3,4-
bis(tert-butyldimethylsilyloxy)-1-(4-methoxybenzyl)pyrrolidine-2,5-di-
general access to chiral gem-difluoromethylenated dihydroxy-
pyrrolizidines and indolizidines and may be applied for syn-
thesis of analogues of some pyrrolizidine and indolizidine
natural products.
EXPERIMENTAL SECTION
■
one7d,e (9.52 g, 99% yield) after column chromatography (SiO2, 10%
General Procedures. 1H NMR spectra were recorded on 300 and
500 MHz spectrometers and are reported in ppm. NMR data are
reported as follows: s = singlet, d = doublet, t = triplet, q = quartet,
m = multiplet, br = broad, dd = doublet of doublets; coupling
constant(s) in Hz; integration; assignment. Proton decoupled 13C
NMR spectra were recorded on 75 and 125 MHz spectrometers and
are reported in ppm. 19F NMR spectra were recorded on a 470 MHz
spectrometer and are reported in ppm.
1
EtOAc in hexanes): [α]26 +102.9° (c 1, CHCl3); H NMR (300
D
MHz, CDCl3) δ 7.33 (d, J = 8.6 Hz, 2H), 6.83 (d, J = 8.6 Hz, 2H),
4.56 (s, 2H), 4.45 (s, 2H), 3.78 (s, 3H), 0.93 (s, 18H), 0.21 (s, 6H),
0.16 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 173.0 (2 × CO), 159.3
(C), 130.5 (2 × CH), 127.6 (C), 114.0 (2 × CH), 76.9 (2 × CH),
55.2 (OCH3), 41.8 (CH2), 25.6 (6 × CH3), 18.2 (2 × C), −4.5 (2 ×
CH3), −5.0 (2 × CH3); IR (neat) νmax 1724s, 1612m, 1514s, 1250s,
1135s, 838s cm−1; MS m/z (%) relative intensity 479 (M+, trace),
421 (6), 121 (100), 91 (9), 77 (7); HRMS (ESI-TOF) calcd for
C24H42NO5Si2 [M + H]+ 480.2602, found 480.2607. A solution of
(3R,4R)-3,4-bis(tert-butyldimethylsilyloxy)-1-(4-methoxybenzyl) pyr-
rolidine-2,5-dione (2.40 g, 5 mmol) in CH3CN (20 mL) cooled at
0 °C was treated with a solution of ceric ammonium nitrate (10.96 g,
20 mmol) in water (30 mL) over 20 min. The mixture was stirred at
0 °C for 5 h, diluted with water (50 mL) and extracted with EtOAc
(3 × 50 mL). The organic phase was washed with saturated aqueous
NaHCO3 (50 mL), brine (50 mL) and dried over anhydrous Na2SO4.
After solvent removal, a crude product was purified by gradient
column chromatography (SiO2, 3−5% EtOAc in hexanes) to give a
colorless oil of (3R,4R)-3,4-bis(tert-butyldimethylsilyloxy)pyrrolidine-
Reactions were monitored by thin layer chromatography and
visualized by UV and solution of KMnO4. Tetrahydrofuran (THF) was
distilled from sodium-benzophenone ketyl. Dichloromethane
(CH2Cl2), toluene and N,N-dimethylformamide (DMF) were distilled
over calcium hydride and were stored over activated molecular sieves
(4 Å). All glass wares and syringes were oven-dried and kept in a
desiccator before use. Purification of reaction products were carried
out by preparative TLC plates, column chromatography or flash
column chromatography.
(3R,4R)-1-Allyl-3,4-bis(tert-butyldimethylsilyloxy)pyrrolidine-
2,5-dione (2).7a−c A mixture of L-tartaric acid (4.51 g, 30 mmol)
and allylamine (2.3 mL, 30.7 mmol) in xylene (30 mL) was heated
at reflux by using a Dean−Stark apparatus for 15 h. The result-
ing solution was cooled to room temperature and concentrated in
vacuo. The obtained solid material was coevaporated with ethanol
to remove traces of xylene. The suspension was cooled to room
temperature, and the resulting precipitates were filtered and washed
with cold CH2Cl2 to give a pale yellow crystal of (3R,4R)-1-allyl-3,4-
2,5-dione7d,e (0.94 g, 52% yield): [α]26 +196.1° (c 1, CHCl3); H
1
D
NMR (500 MHz, CDCl3) δ 8.63−8.61 (br s, 1H), 4.54 (s, 2H), 0.96
(s, 18H), 0.23 (s, 6H), 0.10 (s, 6H); 13C NMR (125 MHz, CDCl3) δ
173.2 (2 × CO), 77.5 (2 × CH), 25.6 (6 × CH3), 18.2 (2 × C), −4.5
(2 × CH3), −5.0 (2 × CH3); IR (neat) νmax 3263br, 2930s, 1732s,
1135s, 839s cm−1; MS m/z (%) relative intensity 359 (M+, trace),
344 (21), 274 (100), 147 (6), 117 (8), 73 (36). A mixture of (3R,4R)-
3,4-bis(tert-butyldimethylsilyloxy)pyrrolidine-2,5-dione (0.32 g,
0.9 mmol), 4-bromobut-1-ene (0.1 mL, 1 mmol) and anhydrous
potassium carbonate (0.15 g, 1.1 mmol) in acetone (3 mL) was heated
at reflux for 6 h. After cooling to 20 °C, the mixture was filtered and
the solvent was evaporated to give a yellow oil, which was purified by
dihydroxypyrrolidine-2,5-dione (2.57 g, 50% yield): mp 154−155 °C;
1
[α]26 +134.6° (c 1, MeOH); H NMR (500 MHz, acetone-d6) δ
D
5.81−5.74 (m, 1H), 5.63−5.52 (br s, 2H), 5.15−5.04 (m, 2H), 4.49 (s,
2H), 4.02 (s, 2H); 13C NMR (125 MHz, acetone-d6) δ 174.6 (2 ×
CO), 132.3 (CH), 117.5 (CH2), 75.9 (2 × CH), 40.9 (CH2); IR
(KBr) νmax 3387br, 1707s, 1333s, 1089s, 993m cm−1; MS m/z (%)
relative intensity 172 (M+ + 1, 58), 171 (M+, 6), 153 (18), 142 (25),
128 (10), 125 (41), 114 (20), 96 (39), 83 (12), 69 (45), 58 (100);
HRMS (ESI-TOF) calcd for C7H10NO4 [M + H]+ 172.0610, found
172.0642. A mixture of (3R,4R)-1-allyl-3,4-dihydroxypyrrolidine-2,5-
dione (1.30 g, 7.6 mmol), TBSCl (2.98 g, 19.8 mmol) and imidazole
(1.55 g, 22.8 mmol) in dry DMF (15 mL) was allowed to stir at room
temperature for 1 h, quenched with ice water, and extracted with
CH2Cl2 (3 × 25 mL). The organic phase was washed successively with
water (25 mL), brine (25 mL), and dried over anhydrous Na2SO4.
After solvent removal, a crude product was purified by column
column chromatography (SiO2, 3% EtOAc in hexanes) to provide a
1
colorless oil of 3 (0.33 g, 89% yield): [α]26 +503° (c 1, CHCl3); H
D
NMR (500 MHz, CDCl3) δ 5.72 (ddt, J = 7.4, 10.2, 17.0 Hz, 1H),
5.09−5.04 (m, 2H), 4.45 (s, 2H), 3.61−3.49 (m, 2H), 2.39−2.33 (m,
2H), 0.95 (s, 18H), 0.23 (s, 6H), 0.18 (s, 6H); 13C NMR (125 MHz,
CDCl3) δ 173.3 (2 × CO), 134.0 (CH), 117.6 (CH2), 76.8 (2 × CH),
37.7 (CH2), 31.8 (CH2), 25.6 (6 × CH3), 18.2 (2 × C), −4.5 (2 ×
CH3), −5.1 (2 × CH3); IR (neat) νmax 1727s, 1361m, 1109s cm−1; MS
m/z (%) relative intensity 414 (M+ + 1, 4), 398 (28), 356 (100), 340
(15), 328 (75), 231 (41), 129 (11), 73 (52); HRMS (ESI-TOF) calcd
for C20H40NO4Si2 [M + H]+ 414.2496, found 414.2471.
chromatography (SiO2, 10% EtOAc in hexanes) to give a colorless
1
oil of 2 (2.99 g, 99% yield): [α]26 +102.2° (c 1, CHCl3); H NMR
D
8470
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Article
(3R,4R)-1-Allyl-3,4-bis(benzyloxy)pyrrolidine-2,5-dione (4).
Ethanol (35.2 mL, 0.6 mol) and DOWEX 50 WX8 (H⊕-form
(30 g) were added to a solution of L-tartaric acid (15.1 g, 0.1 mol) in
benzene (63 mL). The reaction mixture was heated at reflux by using a
Dean−Stark apparatus to remove water. After stirring for 24 h, the
reaction mixture was allowed to cool to room temperature, filtered and
evaporated in vacuo to give a colorless oil of (2R,3R)-diethyl 2,3-
dihydroxysuccinate7f (19.76 g, 95% yield) after distillation under
reduced pressure (0.4 Torr, bp 110 °C): [α]25D +7.4° (c 1.6, EtOAc);
1H NMR (500 MHz, CDCl3) δ 4.54 (s, 2H), 4.29 (dq, J = 1.8, 7.2 Hz,
4H), 1.31 (dd, J = 7.2, 7.2 Hz, 6H); 13C NMR (125 MHz, CDCl3) δ
171.5 (2 × CO), 72.1 (2 × CH), 62.2 (2 × CH2), 14.0 (2 × CH3); IR
(neat) νmax 3445s, 1732s, 1280m, 1131m, 1093m, 1019w cm−1; MS
m/z (%) relative intensity 207 (M+ + 1, 5), 206 (M+, 5), 201(25), 178
(100), 167 (39), 149 (85), 99 (23), 97 (26); HRMS (ESI-TOF) calcd
for C8H14O6Na [M + Na]+ 229.0688, found 229.0705. A suspension of
NaH (60% in mineral oil, 0.8 g, 20 mmol) in dry DMF (40 mL) was
added dropwise to a solution of (2R,3R)-diethyl 2,3-dihydroxysucci-
nate (2.06 g, 10 mmol) in dry DMF (30 mL) at −20 °C. The reaction
mixture was allowed to stir for 30 min and was added BnBr (3.6 mL,
30.3 mmol) in DMF (10 mL). After stirring at this temperature for
40 min, the mixture was allowed to warm to 0 °C and stir for 1 h. The
reaction mixture was cautiously quenched by adding water (50 mL)
and extracted with EtOAc (3 × 50 mL). The combined extracts were
washed with brine (50 mL), dried over anhydrous Na2SO4, filtered,
and concentrated in vacuo. The residue was purified by column
chromatography (SiO2, 5% EtOAC in hexanes) to give (2R,3R)-
(d, J = 11.6 Hz, 2H), 4.78 (d, J = 11.6 Hz, 2H), 4.65 (d, J = 14.0 Hz,
1H), 4.61 (d, J = 14.0 Hz, 1H), 4.40 (s, 2H), 3.81 (s, 3H); 13C NMR
(125 MHz, CDCl3): δ 172.4 (2 × CO), 159.4 (C), 136.5 (2 × C),
130.4 (2 × CH), 128.5 (4 × CH), 128.2 (5 × CH), 127.2 (C), 114.0
(3 × CH), 78.8 (2 × CH), 73.4 (2 × CH2), 55.2 (OCH3), 41.7
(CH2); IR (KBr) νmax 1728s, 1717s, 1514m, 1385w, 1251w, 1106m,
750w, 700w cm−1; MS m/z (%) relative intensity 432 (M+ + 1, trace),
325 (3), 220 (12), 219 (86), 162 (16), 121 (100), 91 (12), 65 (1);
HRMS (ESI-TOF) calcd for C26H25NO5Na [M + Na]+ 454.1630,
found 454.1644. A mixture of (3R,4R)-3,4-bis(benzyloxy)-1-(4-
methoxybenzyl)pyrrolidine-2,5-dione (4.31 g, 10 mmol) and ceric
ammonium nitrate (27.41 g, 50 mmol) in a mixture of MeCN−H2O
(9:1, 100 mL) was stirred at 0 °C for 1 h. The reaction mixture was
allowed to warm to room temperature and stirred for 3 h to give
(3R,4R)-3,4-bis(benzyloxy)pyrrolidine-2,5-dione7i (2.64 g, 85% yield)
as a white solid after column chromatography (SiO2, 15% EtOAc in
1
hexanes): mp 58 °C; [α]25 +144.8° (c 0.5, EtOAc); H NMR (500
D
MHz, CDCl3) δ 8.49−8.47 (br s, 1H), 7.41−7.35 (m, 10H), 5.00 (d,
J = 11.6 Hz, 2H), 4.77 (d, J = 11.6 Hz, 2H), 4.67 (s, 2H); 13C NMR
(125 MHz, CDCl3) δ 172.5 (2 × CO), 136.4 (2 × C), 128.5 (4 ×
CH), 128.3 (2 × CH), 128.2 (4 × CH), 79.4 (2 × CH), 73.5 (2 ×
CH2); IR (KBr) νmax 3508w, 3243br, 1800m, 1732s, 1455m, 1322s,
1266m, 1176m, 1114s, 740m, 699s cm−1; MS m/z (%) relative
intensity 311 (M+, 1), 144 (56), 107 (94), 99 (60), 92 (24), 91 (100),
77 (8), 65 (9); HRMS (ESI-TOF) calcd for C18H17NO4Na [M + Na]+
334.1055, found 334.1039. A mixture of (3R,4R)-3,4-bis(benzyloxy)-
pyrrolidine-2,5-dione (1.55 g, 5 mmol), triphenylphosphine (1.31 g,
5 mmol) and allyl alcohol (0.3 mL, 4.5 mmol) in dry THF (20 mL)
was treated with diisopropyl azodicarboxylate (1.1 mL, 5.6 mmol) at
0 °C. The resulting yellow solution was allowed to stir at room
temperature for 16 h, and then it was quenched with a saturated
aqueous NaHCO3 (50 mL) and extracted with EtOAc (3 × 50 mL).
The combined extracts were washed with brine (50 mL) and dried
over anhydrous Na2SO4. Filtration followed by evaporation gave a
crude product, which was purified by gradient column chromatography
diethyl 2,3-bis(benzyloxy)succinate7g,h (3.28 g, 85% yield) as a color-
1
less liquid: [α]25 +122.9° (c 0.8, CH2Cl2); H NMR (500 MHz,
D
CDCl3) δ 7.35−7.29 (m, 10H), 4.91 (d, J = 12.0 Hz, 2H), 4.49 (d, J =
12.0 Hz, 2H), 4.43 (s, 2H), 4.23 (dq, J = 7.3, 10.7 Hz, 2H), 4.10 (dq,
J = 7.3, 10.7 Hz, 2H), 1.21 (dd, J = 7.2, 7.2 Hz, 6H); 13C NMR
(125 MHz, CDCl3) δ 169.0 (2 × CO), 136.9 (2 × C), 128.2 (8 ×
CH), 127.8 (2 × CH), 78.4 (2 × CH), 73.1 (2 × CH2), 61.2 (2 ×
CH2), 14.0 (2 × CH3); IR (neat) νmax 1755s, 1623m, 1455m, 1271m,
1193s, 1152s, 1105s, 740m, 699s cm−1; MS m/z (%) relative intensity
386 (M+, trace), 278 (27), 250 (30), 207 (25), 205 (38), 197 (38),
189 (38), 105 (16), 91 (100), 65 (4); HRMS (ESI-TOF) calcd for
C22H26O6Na [M + Na]+ 409.1627, found 409.1605. A mixture of
(2R,3R)-diethyl 2,3-bis(benzyloxy)succinate (3.86 g, 10 mmol) and
LiOH·H2O (1.68 g, 40 mmol) in a mixture of EtOH−H2O (3:1,
20 mL) was stirred at 0 °C for 24 h. After removal of ethanol under
reduced pressure, the residue was acidified with HCl to reach pH 2,
and the resultant mixture was extracted with ethyl acetate (3 ×
50 mL). The combined organic extracts were washed with brine (50 mL),
dried over anhydrous Na2SO4, and filtered. The solvent was removed
under reduced pressure to give (2R,3R)-2,3-bis(benzyloxy)succinic
acid7g,h (3.29 g, 100% yield) as a colorless oil, which was used in the
(SiO2, 2−5% EtOAc in hexanes) to give a white solid of 4 (1.29 g,
1
82% yield): mp 60−62 °C; [α]26 +139.7° (c 0.6, EtOAc); H NMR
D
(500 MHz, CDCl3) δ 7.42−7.36 (m, 10H), 5.82 (ddt, 6.0, 10.2, 17.1
Hz, 1H), 5.29 (dd, J = 1.1, 17.1 Hz, 1H), 5.25 (dd, J = 1.1, 10.2 Hz,
1H), 5.04 (d, J = 11.6 Hz, 2H), 4.81 (d, J = 11.6 Hz, 2H), 4.44 (s, 2H),
4.19−4.11 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 172.2 (2 × CO),
136.5 (2 × C), 130.0 (CH), 128.5 (4 × CH), 128.2 (6 × CH), 119.0
(CH2), 78.8 (2 × CH), 73.4 (2 × CH2), 40.6 (CH2); IR (KBr) νmax
1715s, 1643w, 1350m, 1194m, 1139w, 1104s, 738m, 698s cm−1; MS
m/z (%) relative intensity 352 (M+ + 1, trace), 140 (9), 139 (100),
111 (30), 107 (8), 96 (29), 91 (33), 77 (2), 65 (3); HRMS (ESI-
TOF) calcd for C21H21NO4Na [M + Na]+ 374.1368, found 374.1341.
(3R,4R)-3,4-Bis(benzyloxy)-1-(but-3-enyl)pyrrolidine-2,5-
dione (5).7i The reaction of (3R,4R)-3,4-bis(benzyloxy)pyrrolidine-
2,5-dione (3.11 g, 10 mmol) with triphenylphosphine (2.62 g, 10 mmol),
3-buten-1-ol (0.78 mL, 9 mmol) and diisopropyl azodicarboxylate
(2.2 mL, 11.2 mmol) in dry THF (40 mL) gave 5 (2.83 g, 86% yield) as
a colorless oil after column chromatography (SiO2, 2−5% EtOAc in
hexanes): [α]24D +129.7° (c 0.5, EtOAc); 1H NMR (500 MHz, CDCl3)
δ 7.40−7.35 (m, 10H), 5.74 (ddt, J = 7.0, 10.2, 17.0 Hz, 1H), 5.12−5.04
(m, 2H), 5.02 (d, J = 11.6 Hz, 2H), 4.79 (d, J = 11.6 Hz, 2H), 4.40 (s,
2H), 3.68−3.57 (m, 2H), 2.44−2.34 (m, 2H); 13C NMR (125 MHz,
CDCl3) δ 172.6 (2 × CO), 136.6 (2 × C), 133.9 (CH), 128.5 (5 × CH),
128.2 (5 × CH), 117.9 (CH2), 78.7 (2 × CH), 73.4 (2 × CH2), 37.7
(CH2), 31.7 (CH2); IR (neat) νmax 1715s, 1644w, 1455m, 1398m,
1348m, 1100s, 921m, 739s, 699s cm−1; MS m/z (%) relative intensity 365
(M+, trace), 153 (86), 111 (15), 105 (28), 99 (29), 91 (100), 77 (11), 65
(21); HRMS (ESI-TOF) calcd for C22H23NO4Na [M + Na]+ 388.1525,
found 388.1520.
next step without further purification: [α]24 +29.8° (c 1.0, EtOAc);
D
1H NMR (500 MHz, CDCl3) δ 7.34−7.29 (m, 10H), 4.84 (d, J = 11.6
Hz, 2H), 4.56 (d, J = 11.6 Hz, 2H), 4.52 (s, 2H); 13C NMR (125
MHz, CDCl3) δ 173.0 (2 × CO), 135.8 (2 × C), 128.6 (5 × CH),
128.5 (5 × CH), 78.0 (2 × CH), 74.1 (2 × CH2); IR (neat) νmax
3472s, 3131br, 1715s, 1634m, 1463s, 1377m, 1219m, 950m, 892s, 821m
cm−1; MS m/z (%) relative intensity 330 (M+, 1), 205 (43), 188 (21),
181 (20), 150 (12), 116 (5), 92 (9), 91 (100), 65 (24); HRMS (ESI-
TOF) calcd for C18H18O6Na [M + Na]+ 353.1001, found 353.1019.
A mixture of (2R,3R)-2,3-bis(benzyloxy)succinic acid (4.95 g, 15
mmol) and acetyl chloride (15 mL) was heated at reflux for 4 h. After
concentrating under reduced pressure, the residue was dissolved in
CH2Cl2 (15 mL), to which was added a solution of p-methoxybenzyl-
amine (2.4 mL, 18.4 mmol) in CH2Cl2 (15 mL) at 0 °C. The resulting
mixture was heated at reflux for 5 h and then concentrated in vacuo.
The residue was dissolved in acetyl chloride (15 mL) and refluxed
for 5 h. After concentration of the reaction mixture in vacuo, the
residue was purified by column chromatography (SiO2, 10% EtOAc
in hexanes) to give (3R,4R)-3,4-bis(benzyloxy)-1-(4-methoxybenzyl)-
(3R,4R,5R)- and (3R,4R,5S)-1-Allyl-3,4-bis(tert-butyldimethyl-
silyloxy)-5-(difluoro(phenylthio)methyl)-5-hydroxypyrrolidin-
2-one (syn-6 and anti-6). General Procedure A. A mixture of
PhSCF2TMS (1) (3.71 g, 16 mmol) and 2 (3.20 g, 8 mmol) in dry
DMF (25 mL) was treated with a solution of 10 mol % TBAT (0.86 g,
1.6 mmol) in dry DMF (15 mL) at 0 °C for 2 h. The reaction mixture
pyrrolidine-2,5-dione7g,h (5.82 g, 90% yield) as a white crystal:
1
mp 127−128 °C; [α]25 +200.3° (c 0.8, CH2Cl2); H NMR (500
D
MHz, CDCl3) δ 7.40−7.35 (m, 12H), 6.88−6.86 (m, 2H), 5.02
8471
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Article
was quenched with water (25 mL) and the resulting mixture was
stirred at room temperature for 30 min and then extracted with
CH2Cl2 (3 × 25 mL). The organic phase was washed successively with
brine (25 mL) and dried over anhydrous Na2SO4. After solvent
removal, the crude product was purified by gradient column
chromatography (SiO2, 5−10% EtOAc in hexanes) to give a white
solid of syn-6 (3.22 g, 72% yield) and a pale yellow liquid of anti-6
7.43−7.40 (m, 2H), 5.80 (ddt, J = 6.4, 10.2, 17.2 Hz, 1H), 5.12−5.08
(m, 1H), 5.05−5.03 (m, 1H), 4.52 (s, 1H), 4.47 (d, J = 2.8 Hz, 1H),
4.11 (d, J = 2.8 Hz, 1H), 3.66 (ddd, J = 6.4, 9.3, 15.0 Hz, 1H), 3.39
(ddd, J = 6.4, 9.3, 15.0 Hz, 1H), 2.56−2.49 (m, 1H), 2.45−2.38 (m,
1H), 0.97 (s, 9H), 0.93 (s, 9H), 0.26 (s, 3H), 0.25 (s, 3H), 0.23 (s,
3H), 0.20 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 171.6 (CO), 136.8
(2 × CH), 135.4 (CH), 130.1 (CH), 129.1 (2 × CH), 128.8 (t, J =
287.8 Hz, CF2), 125.1 (C), 116.6 (CH2), 89.4 (t, J = 25.9 Hz, C), 76.7
(CH), 75.9 (CH), 41.0 (CH2), 32.4 (CH2), 25.8 (3 × CH3), 25.7 (3 ×
CH3), 18.2 (C), 17.9 (C), −3.8 (CH3), −4.2 (CH3), −4.9 (CH3),
−5.2 (CH3); 19F NMR (470 MHz, CDCl3) δ −84.00 (d, J = 211.0 Hz,
1F), −81.89 (d, J = 211.0 Hz, 1F); IR (neat) νmax 3296br, 2960m,
1686s, 1642w, 1472m, 1391m, 1362m, 1250m, 1150s, 910m, 842s
cm−1; MS m/z (%) relative intensity 574 (M+ + 1, 3), 516 (100),
496 (24), 386 (8), 310 (10), 277 (11), 255 (15), 184 (12), 155 (12), 151
(15), 77 (14), 73 (63); HRMS (ESI-TOF) calcd for C27H45F2NO4SSi2Na
[M + Na]+ 596.2474, found 596.2450.
(0.35 g, 8% yield). syn-6: mp 122−123 °C; [α]26 +74.0° (c 1,
D
1
CHCl3); H NMR (500 MHz, CDCl3) δ 7.64−7.59 (m, 2H), 7.49−
7.44 (m, 1H), 7.43−7.38 (m, 2H), 5.89 (ddt, J = 5.9, 10.2, 17.1 Hz,
1H), 5.23 (dd, J = 1.3, 17.1 Hz, 1H), 5.14 (dd, J = 1.3, 10.2 Hz, 1H),
4.52 (d, J = 6.8 Hz, 1H), 4.25 (d, J = 6.8 Hz, 1H), 4.16 (dd, J = 5.9,
15.7 Hz, 1H), 3.84−3.81 (br s, 1H), 3.81 (dd, J = 5.9, 15.7 Hz, 1H),
0.99 (s, 9H), 0.97 (s, 9H), 0.27 (s, 3H), 0.22 (s, 3H), 0.21 (s, 3H),
0.19 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 171.1 (CO), 136.8 (2 ×
CH), 133.6 (CH), 130.1 (CH), 129.1 (2 × CH), 128.3 (dd, J = 287.6,
287.6 Hz, CF2), 125.3 (C), 117.3 (CH2), 90.9 (t, J = 24.2 Hz, C), 82.9
(CH), 75.2 (CH), 43.0 (CH2), 26.0 (3 × CH3), 25.9 (3 × CH3), 18.2
(C), 17.9 (C), −4.0 (CH3), −4.1 (CH3), −4.5 (CH3), −4.6 (CH3);
19F NMR (470 MHz, CDCl3) δ −79.76 (d, J = 216.2 Hz, 1F), −78.85
(d, J = 216.2 Hz, 1F); IR (KBr) νmax 3375br, 2931m, 1697s, 1474m,
1397m, 1361m, 1253m, 1158m, 1057m, 981m, 842s, 750m cm−1; MS
m/z (%) relative intensity 559 (M+, 2), 518 (43), 502 (100), 482 (17),
314 (43), 277 (14), 239 (12), 170 (13), 143 (17), 73 (55); HRMS
(3R,4R,5R)- and (3R,4R,5S)-1-Allyl-3,4-bis(benzyloxy)-5-
(difluoro(phenylthio)methyl)-5-hydroxypyrrolidin-2-one (syn-
8 and anti-8). According to the general procedure A, the reaction of 1
(1.39 g, 6 mmol) with 4 (1.06 g, 3 mmol) in dry THF (10 mL) in the
presence of 10 mol % TBAT (0.32 g, 0.6 mmol) in dry THF (5 mL) at
−78 °C for 8 h followed by gradient chromatography (SiO2, 5−10%
EtOAc in hexanes) gave syn-8 (0.73 g, 48% yield) and anti-8 (0.47 g,
31% yield) as pale yellow oils. syn-8: [α]25D +90.1° (c 0.7, CH2Cl2); 1H
NMR (500 MHz, CDCl3) δ 7.62−7.58 (m, 2H), 7.42−7.33 (m, 13H),
5.85 (ddt, J = 6.2, 10.2, 17.0, 1H), 5.24 (dd, J = 1.4, 17.0 Hz, 1H), 5.14
(dd, J = 1.4, 10.2 Hz, 1H), 5.12 (d, J = 11.4 Hz, 1H), 4.97 (d, J = 12.0
Hz, 1H), 4.78 (d, J = 11.4 Hz, 1H), 4.75 (d, J = 12.0 Hz, 1H), 4.71−
4.65 (br s, 1H), 4.50 (d, J = 7.8 Hz, 1H), 4.27 (dd, J = 1.8, 7.8 Hz,
1H), 4.15−4.10 (m, 1H), 3.85 (dd, J = 6.6, 15.7 Hz, 1H); 13C NMR
(125 MHz, CDCl3) δ 170.6 (CO), 137.4 (C), 137.2 (C), 136.8 (2 ×
CH), 133.1 (CH), 130.1 (CH), 129.0 (2 × CH), 128.4 (4 × CH),
128.3 (dd, J = 288.7, 288.7 Hz, CF2), 128.1 (2 × CH), 128.0 (2 ×
CH), 127.9 (CH), 127.8 (CH), 125.3 (C), 117.7 (CH2), 90.5 (dd, J =
23.0, 27.9 Hz, C), 87.5 (CH), 78.7 (d, J = 3.0 Hz, CH), 74.2 (CH2),
73.3 (CH2), 42.9 (CH2); 19F NMR (470 MHz, CDCl3) δ −81.13. (d,
J = 217.1 Hz, 1F), −80.24 (d, J = 217.1 Hz, 1F); IR (neat) νmax
3307br, 1694s, 1455m, 1442m, 1330w, 1138m, 1094m, 750m, 699m
cm−1; MS m/z (%) relative intensity 512 (M+ + 1, 1), 314 (14), 296
(24), 294 (14), 224 (17), 217 (32), 216 (100), 181 (28), 172 (29),
161 (52), 91 (91), 65 (5); HRMS (ESI-TOF) calcd for
C28H27F2NO4SNa [M + Na]+ 534.1527, found 534.1531. anti-8:
[α]25D +68.8° (c 0.7, CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 7.63−
7.58 (m, 2H), 7.51−7.47 (m, 1H), 7.46−7.36 (m, 10H), 7.33−7.30
(m, 2H), 5.93 (ddt, J = 6.7, 10.3, 17.1, 1H), 5.30 (dd, J = 1.3, 17.1 Hz,
1H), 5.20 (dd, J = 1.3, 10.3 Hz, 1H), 5.10 (d, J = 11.7 Hz, 1H), 4.86
(d, J = 11.7 Hz, 1H), 4.75 (d, J = 11.1 Hz, 1H), 4.69 (d, J = 11.1 Hz,
1H), 4.44 (d, J = 4.7 Hz, 1H), 4.41 (s, 1H), 4.27 (dd, J = 6.1, 15.6 Hz,
1H), 4.18 (d, J = 4.7 Hz, 1H), 4.02 (dd, J = 6.1, 15.6 Hz, 1H); 13C
NMR (125 MHz, CDCl3) δ 171.4 (CO), 137.1 (C), 136.8 (2 × CH),
136.0 (C), 133.0 (CH), 130.2 (CH), 129.1 (2 × CH), 128.6 (3 ×
CH), 128.5 (6 × CH), 128.2 (dd, J = 254.6, 254.6 Hz, CF2), 128.1
(CH), 124.7 (C), 117.6 (CH2), 88.6 (t, J = 25.8 Hz, C), 78.3 (CH),
78.0 (CH), 73.6 (CH2), 72.6 (CH2), 44.0 (CH2); 19F NMR (470
MHz, CDCl3) δ −84.78 (d, J = 210.4 Hz, 1F), −82.10 (d, J = 210.4
Hz, 1F); IR (neat) νmax 3390br, 1732s, 1606w, 1455s, 1359m, 1328m,
1206m, 1155m, 924m, 741m, 699s cm−1; MS m/z (%) relative
intensity 511 (M+, trace), 314 (3), 299 (11), 246 (4), 217 (32), 216
(100), 181 (12), 131 (10), 91 (33), 65 (2); HRMS (ESI-TOF) calcd
for C28H27F2NO4SNa [M + Na]+ 534.1527, found 534.1526.
(ESI-TOF) calcd for C26H43F2NO4SSi2Na [M + Na]+ 582.2317, found
1
582.2314. anti-6: [α]24 −1.0° (c 1, CHCl3); H NMR (500 MHz,
D
CDCl3) δ 7.63 (d, J = 7.4 Hz, 2H), 7.51−7.45 (m, 1H), 7.42 (t, J = 7.4
Hz, 2H), 5.90 (ddt, J = 5.9, 10.3, 17.2 Hz, 1H), 5.25 (dd, J = 1.4, 17.2
Hz, 1H), 5.16 (dd, J = 1.4, 10.3 Hz, 1H), 4.57 (s, 1H), 4.51 (d, J = 2.6
Hz, 1H), 4.19 (dd, J = 5.9, 15.8 Hz, 1H), 4.13 (d, J = 2.6 Hz, 1H), 3.99
(dd, J = 5.9, 15.8 Hz, 1H), 0.97 (s, 9H), 0.93 (s, 9H), 0.27 (s, 6H),
0.23 (s, 3H), 0.20 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 171.5
(CO), 136.8 (2 × CH), 133.1 (CH), 130.1 (CH), 129.1 (2 × CH),
128.7 (dd, J = 287.7, 287.7 Hz, CF2), 125.1 (C), 117.0 (CH2), 89.4 (t,
J = 26.0 Hz, C), 76.7 (CH), 75.9 (CH), 43.8 (CH2), 25.8 (3 × CH3),
25.7 (3 × CH3), 18.2 (C) 18.0 (C), −3.8 (CH3), −4.2 (CH3), −5.0
(CH3), −5.1 (CH3); 19F NMR (470 MHz, CDCl3) δ −83.90 (d, J =
211.0 Hz, 1F), −81.87 (d, J = 211.0 Hz, 1F); IR (neat) νmax 3372br,
2931s, 1695s, 1473m, 1391m, 1361m, 1252s, 1150s, 1098s, 981w, 842s,
749m, 691m cm−1; MS m/z (%) relative intensity 560 (M+ + 1, 0.8),
516 (100), 502 (98), 482 (23), 155 (19), 151 (28), 73 (83); HRMS
(ESI-TOF) calcd for C26H43F2NO4SSi2Na [M + Na]+ 582.2317, found
582.2312.
(3R,4R,5R)- and (3R,4R,5S)-1-(But-3-enyl)-3,4-bis(tert-butyl-
dimethylsilyloxy)-5-(difluoro(phenylthio)methyl)-5-hydroxy-
pyrrolidin-2-one (syn-7 and anti-7). According to the general
procedure A, the reaction of 1 (2.32 g, 10 mmol) with 3 (2.07 g,
5 mmol) in the presence of 10 mol % TBAT (0.54 g, 1 mmol)
followed by gradient column chromatography (SiO2, 2−10% EtOAc in
hexanes) gave a white solid of syn-7 (2.18 g, 76% yield) and a pale
yellow liquid of anti-7 (0.12 g, 4% yield). syn-7: mp 132−134 °C;
1
[α]26 +54.3° (c 1, CHCl3); H NMR (500 MHz, CDCl3) δ 7.65−
D
7.59 (m, 2H), 7.50−7.44 (m, 1H), 7.43−7.38 (m, 2H), 5.79 (ddt, J =
6.9, 10.2, 17.2 Hz, 1H), 5.13−5.03 (m, 2H), 4.43 (d, J = 6.3 Hz, 1H),
4.17 (d, J = 6.3 Hz, 1H), 3.68 (s, 1H), 3.54 (ddd, J = 6.2, 9.5, 14.7 Hz,
1H), 3.27 (ddd, J = 6.2, 9.5, 14.7 Hz, 1H), 2.53−2.44 (m, 1H), 2.43−
2.34 (m, 1H), 0.98 (s, 9H), 0.97 (s, 9H), 0.26 (s, 3H), 0.22 (s, 3H),
0.21 (s, 3H), 0.19 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 171.4
(CO), 136.7 (2 × CH), 135.6 (CH), 130.1 (CH), 129.1 (2 × CH),
128.3 (t, J = 288.5 Hz, CF2), 125.4 (C), 116.9 (CH2), 90.9 (t, J = 24.9
Hz, C), 82.7 (CH), 75.2 (CH), 40.2 (CH2), 32.5 (CH2), 25.9 (3 ×
CH3), 25.8 (3 × CH3), 18.2 (C), 17.9 (C), −4.1 (CH3), −4.2 (CH3),
−4.5 (2 × CH3); 19F NMR (470 MHz, CDCl3) δ −80.14 (d, J =
215.5 Hz, 1F), −79.48 (d, J = 215.5 Hz, 1F); IR (KBr) νmax 3370br,
1686s, 1642w, 1473m, 1390w, 1361w, 1251m, 1150s, 1105s, 842s, 748w
cm−1; MS m/z (%) relative intensity 573 (M+, 1), 517 (37), 516
(100), 496 (15), 277 (9), 255 (13), 185 (11), 151 (11), 147 (10), 73
(38); HRMS (ESI-TOF) calcd for C27H45F2NO4SSi2Na [M + Na]+
(3R,4R,5R)- and (3R,4R,5S)-3,4-Bis(benzyloxy)-1-(but-3-enyl)-
5-(difluoro(phenylthio)methyl)-5-hydroxypyrrolidin-2-one
(syn-9 and anti-9). According to the general procedure A, the reaction
of 1 (1.86 g, 8 mmol) with 5 (1.47 g, 4 mmol) in dry THF (15 mL) in
the presence of 10 mol % TBAT (0.44 g, 0.8 mmol) in dry THF (5
mL) at −78 °C for 10 h, followed by gradient chromatography (SiO2,
5−10% EtOAc in hexanes) gave a pale yellow oil of syn-9 (0.84 g,
596.2474, found 596.2480. anti-7: [α]24 +2.8° (c 1, CHCl3); 1H
40% yield) and a pale yellow solid of anti-9 (0.65 g, 31% yield).
D
1
NMR (500 MHz, CDCl3) δ 7.65−7.62 (m, 2H), 7.50−7.45 (m, 1H),
syn-9: [α]24 +107.7° (c 2.0, CH2Cl2); H NMR (500 MHz, CDCl3)
D
8472
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The Journal of Organic Chemistry
Article
δ 7.69−7.58 (m, 2H), 7.48−7.31 (m, 13H), 5.78 (ddt, J = 7.0, 10.3,
17.2 Hz, 1H), 5.12 (d, J = 11.3 Hz, 1H), 5.09 (dd, J = 1.3, 17.2 Hz,
1H), 5.06 (dd, J = 1.3, 10.3 Hz, 1H), 4.97 (d, J = 11.7 Hz, 1H), 4.78
(d, J = 11.3 Hz, 1H), 4.76 (d, J = 11.7 Hz, 1H), 4.46 (d, J = 7.9 Hz,
1H), 4.37−4.26 (br s, 1H), 4.19 (dd, J = 2.1, 7.9 Hz, 1H), 3.53 (ddd,
J = 5.0, 9.3, 14.1 Hz, 1H), 3.30−3.24 (m, 1H), 2.51−2.39 (m, 2H);
13C NMR (125 MHz, CDCl3) δ 170.7 (CO), 137.5 (C), 137.1 (C),
136.8 (2 × CH), 135.6 (CH), 130.1 (CH), 129.0 (2 × CH), 128.5
(t, J = 288.8 Hz, CF2), 128.4 (4 × CH), 128.1 (2 × CH), 128.0 (2 ×
CH), 127.9 (CH), 127.8 (CH), 125.4 (d, J = 3.4 Hz, C), 117.1
(CH2), 90.2 (dd, J = 22.7, 28.4 Hz, C), 87.6 (CH), 78.7 (d, J = 3.1 Hz,
CH), 74.2 (CH2), 73.3 (CH2), 40.2 (CH2), 32.3 (CH2); 19F NMR
(470 MHz, CDCl3) δ −81.57 (d, J = 216.7 Hz, 1F), −80.43 (d, J =
216.7 Hz, 1F); IR (neat) νmax 3272br, 1694s, 1683s, 1456s, 1360m,
1148m, 1097m, 1069s, 749m, 693s cm−1; MS m/z (%) relative intensity
525 (M+, trace), 290 (6), 230 (21), 181 (11), 91 (100), 77 (6), 65 (14);
HRMS (ESI-TOF) calcd for C29H29F2NO4SNa [M + Na]+ 548.1683,
found 548.1697. anti-9: mp 57−58 °C; [α]24D +60.9° (c 1, CH2Cl2); 1H
NMR (500 MHz, CDCl3) δ 7.63−7.60 (m, 2H), 7.52−7.48 (m, 1H),
7.46−7.35 (m, 10H), 7.33−7.31 (m, 2H), 5.82 (ddt, J = 6.9, 10.2,
17.1 Hz, 1H), 5.15−5.05 (m, 2H), 5.10 (d, J = 11.8 Hz, 1H), 4.85 (d,
J = 11.8 Hz, 1H), 4.75 (d, J = 11.1 Hz, 1H), 4.69 (d, J = 11.1 Hz, 1H),
4.42 (d, J = 4.9 Hz, 1H), 4.39 (s, 1H), 4.17 (d, J = 4.9 Hz, 1H), 3.76
(ddd, J = 5.7, 9.5, 14.2 Hz, 1H), 3.42 (ddd, J = 5.7, 9.5, 14.2 Hz, 1H),
2.59−2.40 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 171.5 (CO), 137.2
(C), 136.7 (3 × CH), 136.0 (C), 135.2 (CH), 130.2 (CH), 129.2 (3 ×
CH), 128.7 (t, J = 287.9 Hz, CF2), 128.6 (3 × CH), 128.5 (4 × CH),
128.1 (CH), 124.7 (C), 116.7 (CH2), 88.7 (t, J = 26.0 Hz, C), 78.3
(CH), 78.0 (CH), 73.6 (CH2), 72.6 (CH2), 40.9 (CH2), 32.6 (CH2);
19F NMR (470 MHz, CDCl3) δ −84.91 (d, J = 209.9 Hz, 1F), −82.08
25.6 (3 × CH3), 18.1 (C), 17.9 (C), 9.5 (d, J = 8.9 Hz, CH3), −4.2
(CH3), −4.7 (CH3), −5.0 (2 × CH3); 19F NMR (470 MHz, CDCl3)
δ −129.38 (dd, J = 23.0, 230.8 Hz, 1F), −125.89 (d, J = 230.8 Hz, 1F);
IR (KBr) νmax 3375br, 2930m, 1693s, 1473m, 1252m, 1110s, 838s
cm−1; MS m/z (%) relative intensity 451 (M+, trace), 394 (100), 346
(31), 234 (37), 212 (26), 206 (14), 73 (19); HRMS (ESI-TOF) calcd
for C20H39F2NO4Si2Na [M + Na]+ 474.2283, found 474.2256.
(1R,2R,7S,8aR)- and (1R,2R,7R,8aR)-1,2-Bis(tert-butyldime-
thylsilyloxy)-8,8-difluoro-8a-hydroxy-7-methylhexahydroin-
dolizin-3(5H)-one (trans-11, cis-11). According to the general
procedure B, radical cyclization of syn-7 (3.44 g, 6 mmol) followed by
the removal of tin byproduct and flash column chromatography (SiO2,
10% EtOAc in hexanes) gave trans-11 (0.95 g, 34% yield) and cis-11
(0.33 g, 12% yield) as white solids. trans-11: mp 211−212 °C; [α]24
D
+28.5° (c 1, CHCl3); 1H NMR (500 MHz, CDCl3) δ 4.33 (dd, J = 2.7,
7.0 Hz, 1H), 4.19 (dd, J = 1.1, 7.0 Hz, 1H), 3.95 (dd, J = 5.1, 13.3 Hz,
1H), 3.00 (dt, J = 3.4, 13.3 Hz, 1H), 2.83 (s, 1H), 2.46−2.38 (m, 1H),
1.66−1.59 (m, 1H), 1.53 (dq, J = 5.1, 13.3 Hz, 1H), 1.07 (d, J = 6.8
Hz, 3H), 0.95 (s, 9H), 0.94 (s, 9H), 0.24 (s, 3H), 0.19 (s, 3H), 0.17 (s,
3H), 0.16 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 169.7 (CO), 120.5
(dd, J = 247.5, 258.9 Hz, CF2), 85.5 (dd, J = 26.4, 35.1 Hz, C), 84.2
(CH), 76.8 (d, J = 4.3 Hz, CH), 34.9 (CH2), 33.9 (t, J = 22.3 Hz,
CH), 30.2 (d, J = 6.3 Hz, CH2), 25.8 (3 × CH3), 25.7 (3 × CH3), 18.2
(C), 17.8 (C), 11.9 (t, J = 3.8 Hz, CH3), −4.1 (CH3), −4.3 (CH3),
−4.6 (CH3), −4.7 (CH3); 19F NMR (470 MHz, CDCl3) δ −130.04
(dd, J = 26.8, 251.3 Hz, 1F), −117.89 (d, J = 251.3 Hz, 1F); IR (KBr)
νmax 3411br, 2930m, 1686s, 1463w, 1361w, 1252m, 1137m, 1094m,
838s cm−1; MS m/z (%) relative intensity 465 (M+, trace), 408 (100),
360 (26), 248 (22), 226 (11), 198 (11), 151 (10), 73 (15); HRMS
(ESI-TOF) calcd for C21H41F2NO4Si2Na [M + Na]+ 488.2440, found
1
488.2455. cis-11: mp 248−249 °C; [α]25 +1.9° (c 0.5, CHCl3); H
(d, J = 209.9 Hz, 1F); IR (KBr) νmax 3441br, 1715s, 1641w, 1455m,
1410m, 1353m, 1000s, 1018m, 749s, 698s cm−1; MS m/z (%) relative
intensity 525 (M+, trace), 400 (28), 385 (11), 302 (31), 181 (45), 91
(100), 77 (6), 65 (12); HRMS(ESI-TOF) calcd for C29H29F2NO4SNa
[M + Na]+ 548.1683, found 548.1697.
D
NMR (500 MHz, CDCl3) δ 4.30 (dd, J = 2.7, 6.3 Hz, 1H), 4.11 (dd,
J = 1.0, 6.3 Hz, 1H), 3.94−3.90 (m, 1H), 3.17 (dt, J = 3.7, 12.9 Hz,
1H), 2.82 (s, 1H), 2.42−2.35 (m, 1H), 2.05−1.97 (m, 1H), 1.54−1.51
(m, 1H), 1.29 (d, J = 7.4 Hz, 3H), 0.94 (s, 18H), 0.23 (s, 3H), 0.18 (s,
3H), 0.17 (s, 3H), 0.15 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 170.1
(CO), 120.0 (dd, J = 244.4, 261.1 Hz, CF2), 87.1 (dd, J = 26.4, 36.4
Hz, C), 84.3 (CH), 76.8 (d, J = 3.6 Hz, CH), 35.8 (t, J = 23.1 Hz,
CH), 31.3 (CH2), 28.2 (d, J = 5.6 Hz, CH2), 25.8 (3 × CH3), 25.7
(3 × CH3), 18.2 (C), 17.8 (C), 13.3 (dd, J = 3.9, 7.9 Hz, CH3), −4.1
(CH3), −4.3 (CH3), −4.6 (CH3), −4.7 (CH3); 19F NMR (470 MHz,
CDCl3) δ −116.14 (dd, J = 6.6, 256.2 Hz, 1F), −109.25 (dd, J = 14.1,
256.2 Hz, 1F); IR (KBr) νmax 3387br, 2961s, 1709s, 1453m, 1388m,
1260s, 1156s, 1067s, 844s cm−1; MS m/z (%) relative intensity 466
(M+ + 1, 2), 448 (12), 408 (100), 360 (24), 248 (23), 200 (24), 73
(25); HRMS (ESI-TOF) calcd for C21H41F2NO4Si2Na [M + Na]+
488.2440, found 488.2424.
(1R,2R,6R,7aR)- and (1R,2R,6S,7aR)-1,2-Bis(tert-butyldime-
thylsilyloxy)-7,7-difluoro-7a-hydroxy-6-methyltetrahydro-1H-
pyrrolizin-3(2H)-one (cis-10 and trans-10). General Procedure B.
An argon gas was bubbled through a solution of syn-6 (2.24 g, 4 mmol)
in dry toluene (25 mL) for 30 min, and then a mixture of Bu3SnH
(1.9 mL, 7.1 mmol) and AIBN (0.10 g, 0.6 mmol) in dry toluene
(15 mL) was added dropwise at reflux over a 1 h period. After the com-
pletion of the reaction, volatiles were evaporated and the tin byproduct
were removed by column chromatography (SiO2, hexanes (300 mL)
then EtOAc) to give a crude product, which was then purified by flash
column chromatography (SiO2, 10% EtOAc in hexanes) to afford cis-10
(0.67 g, 37% yield) as a white solid and trans-10 (0.27 g, 15% yield) as
a pale yellow solid. cis-10: mp 211−212 °C; [α]25D +2.8° (c 1, CHCl3);
1H NMR (500 MHz, CDCl3) δ 4.14 (d, J = 2.1 Hz, 1H), 4.03 (d, J =
(1R,2R,6R,7aR)- and (1R,2R,6S,7aR)-1,2-Bis(benzyloxy)-7,7-
difluoro-7a-hydroxy-6-methyltetrahydro-1H-pyrrolizin-3(2H)-
one (cis-12 and trans-12). According to the general procedure B,
radical cyclization of syn-8 (2.05 g, 4 mmol) followed by the removal
of tin byproduct and preparative thin-layer chromatography (SiO2,
10% EtOAc in hexanes ×6) gave cis-12 (0.63 g, 39% yield) as a
2.1 Hz, 1H), 3.97 (dd, J = 8.1, 11.5 Hz, 1H), 3.96 (s, 1H), 2.95 (t, J =
11.5 Hz, 1H), 2.54−2.45 (m, 1H), 1.15 (d, J = 6.9 Hz, 3H), 0.92 (s,
9H), 0.89 (s, 9H), 0.20 (s, 3H), 0.19 (s, 3H), 0.13 (s, 6H); 13C NMR
(125 MHz, CDCl3) δ 174.5 (CO), 125.0 (t, J = 258.4 Hz, CF2), 95.1
(dd, J = 32.1, 20.9 Hz, C), 79.1 (CH), 78.9 (CH), 45.7 (d, J = 5.9 Hz,
CH2), 41.5 (t, J = 23.4 Hz, CH), 25.6 (3 × CH3), 25.5 (3 × CH3), 17.9
(C), 17.8 (C), 9.5 (d, J = 7.1 Hz, CH3), −4.7 (CH3), −4.9 (CH3), −5.1
(d, J = 1.8, CH3), −5.2 (CH3); 19F NMR (470 MHz, CDCl3)
δ −121.59 (dd, J = 19.3, 241.6 Hz, 1F), −119.13 (dd, J = 12.7, 241.6 Hz,
1F); IR (KBr) νmax 3354br, 2930s, 1694s, 1464m, 1261s, 1123s, 1059s,
844s cm−1; MS m/z (%) relative intensity 452 (M+ + 1, 1), 451 (M+,
trace), 394 (100), 346 (21), 234 (83), 212 (14), 206 (25), 73 (29);
HRMS (ESI-TOF) calcd for C20H39F2NO4Si2Na [M + Na]+ 474.2283,
colorless crystal and trans-12 (0.21 g, 13% yield) as a colorless oil. cis-
1
12: mp 145−146 °C; [α]23 +33.4° (c 2.0, CH2Cl2); H NMR (500
D
MHz, CDCl3) δ 7.38−7.31 (m, 10H), 4.88 (d, J = 11.5 Hz, 1H), 4.75
(d, J = 11.6 Hz, 1H), 4.68 (d, J = 11.5 Hz, 1H), 4.47 (d, J = 11.6 Hz,
1H), 4.19−4.16 (m, 2H), 4.10 (dd, J = 9.0, 11.9 Hz, 1H), 4.01 (s, 1H),
2.97 (dd, J = 6.3, 11.9 Hz, 1H), 2.66−2.50 (m, 1H), 1.28−1.26
(m, 3H); 13C NMR (125 MHz, CDCl3) δ 172.4 (CO), 137.1 (C),
136.7 (C), 128.5 (2 × CH), 128.4 (2 × CH), 128.2 (3 × CH), 128.0
(CH), 127.9 (2 × CH), 125.1 (dd, J = 248.9, 269.8 Hz, CF2),
92.1 (dd, J = 24.6, 34.7 Hz, C), 84.7 (CH), 81.6 (CH), 73.2 (CH2),
73.0 (CH2), 46.8 (CH2), 40.5 (t, J = 23.7 Hz, CH), 13.7 (CH3); 19F
NMR (470 MHz, CDCl3) δ −125.59 (d, J = 236.9 Hz, 1F), −107.72
(dd, J = 23.0, 236.9 Hz, 1F); IR (KBr) νmax 3262br, 1728s, 1702m,
1457m, 1338m, 1203s, 1095s, 1062s, 756s, 701s cm−1; MS m/z (%)
relative intensity 404 (M+ + 1, trace), 191 (93), 171 (23), 151 (14),
136 (18), 111 (17), 91 (100), 77 (5), 65 (24); HRMS (ESI-TOF)
calcd for C22H23F2NO4Na [M + Na]+ 426.1493, found 426.1495.
found 474.2253. trans-10: mp 176−177 °C; [α]24 +97.4° (c 1,
D
CHCl3); 1H NMR (500 MHz, CDCl3) δ 4.29 (d, J = 4.6 Hz, 1H), 4.14
(dd, J = 1.9, 4.6 Hz, 1H), 3.56 (dd, J = 9.2, 11.5 Hz, 1H), 3.41−3.33
(br s, 1H), 3.24 (dd, J = 8.5, 11.5 Hz, 1H), 3.04−2.93 (m, 1H), 1.16
(d, J = 7.0 Hz, 3H), 0.93 (s, 18H), 0.22 (s, 3H), 0.18 (s, 6H), 0.16 (s,
3H); 13C NMR (125 MHz, CDCl3) δ 173.1 (CO), 123.6 (dd, J = 252.4,
266.6 Hz, CF2), 91.8 (dd, J = 24.8, 32.2 Hz, C), 80.9 (CH), 79.7 (CH),
46.1 (d, J = 7.3 Hz, CH2), 38.0 (t, J = 22.9 Hz, CH), 25.7 (3 × CH3),
8473
dx.doi.org/10.1021/jo301327s | J. Org. Chem. 2012, 77, 8465−8479

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Article
trans-12: [α]23D +63.0° (c 1, CH2Cl2); 1H NMR (500 MHz, CDCl3) δ
7.41−7.29 (m, 10H), 4.89 (d, J = 11.5 Hz, 1H), 4.80 (d, J = 11.7 Hz,
1H), 4.69 (d, J = 11.5 Hz, 1H), 4.46 (d, J = 11.7 Hz, 1H), 4.29−4.23
(br s, 1H), 4.22 (s, 2H), 3.54 (t, J = 10.5 Hz, 1H), 3.28 (dd, J = 8.1,
10.5 Hz, 1H), 3.15−2.99 (m, 1H), 1.16 (d, J = 7.0 Hz, 3H); 13C NMR
(125 MHz, CDCl3) δ 172.7 (CO), 137.4 (C), 136.9 (C), 128.5 (2 ×
CH), 128.4 (2 × CH), 128.2 (2 × CH), 128.1 (CH), 127.9 (3 × CH),
124.0 (dd, J = 250.0, 268.9 Hz, CF2), 91.3 (dd, J = 25.2, 33.6 Hz, C),
85.0 (CH), 82.0 (CH), 73.3 (CH2), 73.2 (CH2), 47.0 (d, J = 7.4 Hz,
CH2), 37.5 (t, J = 22.9 Hz, CH), 9.6 (d, J = 9.4 Hz, CH3); 19F NMR
(470 MHz, CDCl3) δ −129.70 (dd, J = 23.5, 229.4 Hz, 1F), −127.95
(dd, J = 7.1, 229.4 Hz, 1F); IR (neat) νmax 3230br, 1708s, 1692s,
1455m, 1416m, 1234s, 1148s, 1026m, 1003m, 801m, 731s, 694s cm−1;
MS m/z (%) relative intensity 403 (M+, trace), 191 (100), 174 (10),
171 (25), 151 (17), 136 (15), 111 (24), 91 (99), 77 (10), 65 (30);
HRMS (ESI-TOF) calcd for C22H23F2NO4Na [M + Na]+ 426.1493,
found 426.1490.
purified by column chromatography (SiO2, 10% EtOAc in hexanes) to
give trans-15 (160 mg, 71% yield) as a white solid: mp 153−155 °C;
[α]25D +55.3° (c 0.7, EtOAc); 1H NMR (500 MHz, CDCl3) δ 4.50 (d,
J = 7.6 Hz, 1H), 4.39 (d, J = 7.6 Hz, 1H), 4.17 (s, 1H), 3.52 (t, J = 10.2
Hz, 1H), 3.10 (t, J = 10.2 Hz, 1H), 3.02−2.84 (m, 1H), 1.18 (d, J = 6.9
Hz, 3H), 0.97 (s, 9H), 0.96 (s, 9H), 0.22 (s, 6H), 0.18 (s, 3H), 0.14 (s,
3H); 13C NMR (125 MHz, CDCl3) δ 170.8 (CO), 122.4 (dd, J =
251.0, 262.5 Hz, CF2), 88.3 (dd, J = 27.5, 34.0 Hz, C), 77.9 (CH), 73.4
(d, J = 4.5 Hz, CH), 44.4 (d, J = 7.0 Hz, CH2), 36.6 (t, J = 22.5 Hz,
CH), 25.8 (3 × CH3), 25.6 (3 × CH3), 18.3 (C), 17.7 (C), 8.5 (d, J =
7.0 Hz, CH3), −4.2 (CH3), −4.3 (CH3), −4.7 (CH3), −5.3 (CH3);
19F NMR (470 MHz, CDCl3) δ −127.96 (dd, J = 26.3, 221.7 Hz, 1F),
−125.96 (dd, J = 4.7, 221.7 Hz, 1F); IR (KBr) νmax 3391br, 1721s,
1704s, 1473m, 1385m, 1256s, 1166m, 1145s, 1001s, 897m, 869m, 839s,
783s cm−1; MS m/z (%) relative intensity 451 (M+, 1), 436 (4), 396
(17), 395 (33), 394 (100), 234 (26), 212 (13), 206 (57), 186 (11),
75 (6), 73 (13); HRMS (ESI-TOF) calcd for C20H39F2NO4Si2Na
[M + Na]+ 474.2283, found 474.2261.
Preparation of (1S,2R,6R,7aR)-1,2-Bis(tert-butyldimethylsily-
loxy)-7,7-difluoro-6-methyltetrahydro-1H-pyrrolizin-3(2H)-one
(14), (1S,2R,6R,7aR)-1-(tert-Butyldimethylsilyloxy)-7,7-difluoro-
2-hydroxy-6-methyltetrahydro-1H-pyrrolizin-3(2H)-one (16)
and (1S,2R,6R,7aR)-7,7-Difluoro-1,2-dihydroxy-6-methyltetra-
hydro-1H-pyrrolizin-3(2H)-one (17). The reaction of cis-10
(451.4 mg, 1 mmol) with Et3SiH (1.6 mL, 10 mmol) and BF3·OEt2
(0.38 mL, 3 mmol) in dry CH2Cl2 (10 mL) at reflux for 24 h gave 14
(87 mg, 20% yield), 16 (39 mg, 12% yield) and 17 (27 mg, 13% yield)
(1R,2R,7S,8aR)- and (1R,2R,7R,8aR)-1,2-Bis(benzyloxy)-8,8-
difluoro-8a-hydroxy-7-methylhexahydroindolizin-3(5H)-one
(trans-13 and cis-13). According to the general procedure B, radical
cyclization of syn-9 (3.15 g, 6 mmol) followed by the removal of
tin byproduct and preparative thin-layer chromatography (SiO2, 15%
EtOAc in hexanes ×5) gave trans-13 (1.08 g, 43% yield) as a colorless
oil and cis-13 (0.38 g, 15% yield) as a colorless crystal. trans-13: [α]25
D
+16.3° (c 0.6, EtOAc); 1H NMR (500 MHz, CDCl3) δ 7.39−7.26 (m,
10H), 4.94 (d, J = 11.7 Hz, 1H), 4.81 (d, J = 11.6 Hz, 1H), 4.73 (d, J =
11.7 Hz, 1H), 4.45−4.35 (br s, 1H), 4.38 (d, J = 11.6 Hz, 1H), 4.35
(dd, J = 2.5, 7.6 Hz, 1H), 4.19 (dd, J = 0.9, 7.6 Hz, 1H), 3.86 (dd, J =
4.2, 13.3 Hz, 1H), 3.08 (dt, J = 4.2, 13.3 Hz, 1H), 2.61−2.44 (m, 1H),
1.67−1.62 (m, 1H), 1.49 (ddt, J = 5.0, 13.2, 13.2 Hz, 1H), 1.07 (d, J =
6.8 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 169.3 (CO), 137.7 (C),
137.0 (C), 128.4 (2 × CH), 128.3 (2 × CH), 128.2 (2 × CH), 128.1
(CH), 127.8 (2 × CH), 127.7 (CH), 120.6 (dd, J = 244.1, 261.1 Hz,
CF2), 87.9 (CH), 85.9 (dd, J = 26.7, 35.7 Hz, C), 80.4 (d, J = 3.6 Hz,
CH), 73.7 (CH2), 73.6 (d, J = 3.3 Hz, CH2), 34.9 (CH2), 33.4 (t, J =
after gradient chromatography (SiO2, 10−30% EtOAc in hexanes). 14:
1
a white solid; mp 170−172 °C; [α]25 +37.2° (c 0.5, EtOAc); H
D
NMR (500 MHz, CDCl3) δ 4.46 (d, J = 8.1 Hz, 1H), 4.39 (dd, J = 6.5,
8.1 Hz, 1H), 3.78 (ddd, J = 3.9, 6.5, 18.3 Hz, 1H), 3.46 (t, J = 10.5 Hz,
1H), 3.23 (t, J = 10.5 Hz, 1H), 2.77−2.62 (m, 1H), 1.16 (d, J = 6.9 Hz,
3H), 0.97 (s, 6H), 0.96 (s, 3H), 0.93 (s, 6H), 0.92 (s, 3H), 0.22 (s,
3H), 0.15 (s, 6H), 0.14 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 171.8
(CO), 123.8 (t, J = 253.8 Hz, CF2), 79.6 (CH), 75.4 (d, J = 7.4 Hz,
CH), 66.4 (dd, J = 26.3, 32.5 Hz, CH), 46.1 (d, J = 6.8 Hz, CH2), 40.2
(t, J = 23.8 Hz, CH), 25.8 (s, 3 × CH3), 25.6 (s, 3 × CH3), 18.3 (C),
17.8 (C), 9.1 (d, J = 7.6 Hz, CH3), −4.3 (2 × CH3), −4.7 (CH3), −5.2
(CH3); 19F NMR (470 MHz, CDCl3) δ −126.13 (td, J = 21.6, 225.5
Hz, 1F), −115.64 (dd, J = 4.9, 225.5 Hz, 1F); IR (KBr) νmax 1731s,
1713s, 1391m, 1345m, 1261s, 1238m, 1177m, 1130s, 919m, 867m,
835s, 781s cm−1; MS m/z (%) relative intensity 435 (M+, trace), 380
(12), 379 (32), 378 (100), 216 (8), 128 (13), 73 (12); HRMS (ESI-
TOF) calcd for C20H40F2NO3Si2 [M + H]+ 436.2515, found 436.2498.
16: a white solid; mp 193−195 °C; [α]24D +30.8° (c 0.5, CH2Cl2); 1H
NMR (500 MHz, CDCl3) δ 4.44−4.37 (m, 2H), 3.86−3.80 (m, 1H),
3.49 (dd, J = 9.1, 11.0 Hz, 1H), 3.42−3.35 (br s, 1H), 3.23 (t, J = 11.0
Hz, 1H), 2.80−2.61 (m, 1H), 1.15 (d, J = 6.9 Hz, 3H), 0.91 (s, 9H),
0.16 (s, 3H), 0.14 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 172.9
(CO), 123.5 (t, J = 253.8 Hz, CF2), 78.5 (CH), 75.3 (d, J = 7.8 Hz,
CH), 66.8 (dd, J = 26.3, 32.1 Hz, CH), 46.3 (d, J = 6.5 Hz, CH2), 40.3
(t, J = 23.8 Hz, CH), 25.5 (3 × CH3), 17.9 (C), 9.1 (d, J = 7.5 Hz,
CH3), −4.7 (CH3), −5.4 (CH3); 19F NMR (470 MHz, CDCl3) δ
−126.56 (ddd, J = 9.4, 21.2, 225.6 HZ, 1F), −116.44 (ddd, J = 4.4, 9.4,
225.6 Hz, 1F); IR (KBr) νmax 3325br, 1710s, 1687m, 1385m, 1259m,
1238m, 1120s, 917m, 842s, 783m cm−1; MS m/z (%) relative intensity
321 (M+, 1), 265 (14), 264 (100), 204 (17), 188 (19), 170 (11), 128
(85), 100 (19), 80 (18), 73 (31); HRMS (ESI-TOF) calcd for
22.2 Hz, CH), 30.2 (d, J = 6.5 Hz, CH2), 11.8 (t, J = 3.7 Hz, CH3); 19
F
NMR (470 MHz, CDCl3) δ −130.0 (dd, J = 27.7, 249.4 Hz, 1F),
−119.7 (d, J = 249.4 Hz, 1F); IR (neat) νmax 3297br, 1673s, 1456s,
1358s, 1136s, 1006m, 742s, 730s, 696s cm−1; MS m/z (%) relative
intensity 418 (M+ + 1, trace), 417 (M+, trace), 205 (100), 188 (26),
150 (39), 105 (6), 91 (79), 77 (6), 65 (18); HRMS (ESI-TOF) calcd
for C23H25F2O4NNa [M + Na]+ 440.1649, found 440.1675. cis-13: mp
1
180−182 °C; [α]25 +27.8° (c 0.6, EtOAc); H NMR (500 MHz,
D
CDCl3) δ 7.40−7.26 (m, 10H), 4.94 (d, J = 11.7 Hz, 1H), 4.84 (d, J =
11.6 Hz, 1H), 4.72 (d, J = 11.6 Hz, 1H), 4.39 (d, J = 11.7 Hz, 1H),
4.32 (dd, J = 2.8, 7.6 Hz, 1H), 4.26−4.21 (br s, 1H), 4.09 (d, J = 7.6
Hz, 1H), 3.83−3.79 (m, 1H), 3.22 (dt, J = 3.8, 13.7 Hz, 1H), 2.44−
2.40 (m, 1H), 2.02−1.91 (m, 1H), 1.51 (d, J = 13.7 Hz, 1H), 1.35 (d,
J = 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 169.5 (CO), 137.6
(C), 137.1 (C), 128.4 (2 × CH), 128.3 (2 × CH), 128.1 (2 × CH),
128.0 (CH), 127.8 (2 × CH), 127.7 (CH), 120.0 (dd, J = 239.9, 264.8
Hz, CF2), 88.7 (CH), 87.0 (dd, J = 27.3, 36.8 Hz, C), 80.3 (d, J = 4.5
Hz, CH), 73.6 (CH2), 73.5 (d, J = 3.1 Hz, CH2), 36.0 (t, J = 33.7 Hz,
CH), 31.4 (CH2), 28.6 (d, J = 6.0 Hz, CH2), 13.5 (t, J = 4.4 Hz, CH3);
19F NMR (470 MHz, CDCl3) δ −116.7 (d, J = 254.3 Hz, 1F), −108.7
(dd, J = 15.0, 254.3 Hz, 1F); IR (KBr) νmax 3304br, 1672s, 1455m,
1173s, 1097s, 1068s, 917s, 697s cm−1; MS m/z (%) relative intensity
418 (M+ + 1, 1), 206 (10), 205 (100), 188 (27), 177 (12), 150 (46),
91 (79), 77 (3), 65 (18); HRMS (ESI-TOF) calcd for C23H25F2O4NNa
[M + Na]+ 440.1649, found 440.1661.
C14H25F2NO3SiNa [M + Na]+ 344.1469, found 344.1481. 17: a
1
colorless oil; [α]24 +17.3° (c 1.0, CH2Cl2); H NMR (500 MHz,
D
CDCl3) δ 5.28−5.06 (br s, 1H), 4.99−4.80 (br s, 1H), 4.52 (d, J = 7.7
Hz, 1H), 4.38 (t, J = 7.7 Hz, 1H), 3.85 (ddd, J = 5.4, 5.4, 17.2 Hz, 1H),
3.42 (t, J = 10.4 Hz, 1H), 3.20 (t, J = 10.4 Hz, 1H), 2.76−2.56 (m,
1H), 1.07 (d, J = 6.9 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 172.8
(CO), 123.5 (t, J = 253.6 Hz, CF2), 78.2 (CH), 74.1 (CH), 65.7 (dd,
J = 26.0, 32.6 Hz, CH), 46.3 (d, J = 6.0 Hz, CH2), 40.2 (t, J = 23.3 Hz,
CH), 9.3 (d, J = 7.0 Hz, CH3); 19F NMR (470 MHz, CDCl3) δ
−126.98 (td, J = 19.3, 225.4 Hz, 1F), −116.60 (d, J = 225.4 Hz, 1F);
IR (CHCl3) νmax 3382br, 1708s, 1459m, 1234s, 1119s, 981s cm−1;
MS m/z (%) relative intensity 207 (M+, 12), 206 (100), 174 (17),
(1R,2R,6R,7aS)-1,2-Bis(tert-butyldimethylsilyloxy)-7,7-di-
fluoro-7a-hydroxy-6-methyltetrahydro-1H-pyrrolizin-3(2H)-
one (trans-15). To a cooled solution of cis-10 (226 mg, 0.5 mmol) in
dry CH2Cl2 (5 mL) at −78 °C was added dropwise Et3SiH (0.80 mL,
5 mmol) and BF3·OEt2 (0.19 mL, 1.5 mmol) under an argon
atmosphere. The mixture was slowly warmed up to room temperature,
stirred for 24 h, quenched with saturated aqueous NaHCO3 (10 mL)
and extracted with CH2Cl2 (3 × 10 mL). The combined extracts were
washed with brine (10 mL) and dried over anhydrous Na2SO4.
Filtration followed by evaporation gave a crude product, which was
8474
dx.doi.org/10.1021/jo301327s | J. Org. Chem. 2012, 77, 8465−8479

The Journal of Organic Chemistry
Article
134 (24), 94 (5); HRMS (ESI-TOF) calcd for C8H11F2NO3Na
[M + Na]+ 230.0605, found 230.0624.
The filtrate was evaporated to dryness followed by lyophilization to
give 17 (28 mg, 68% yield) and (32 mg, 77% yield), respectively.
To a suspension of LiAlH4 (455 mg, 12 mmol) in dry THF (2 mL)
was added a solution of 17 (83 mg, 0.4 mmol) in dry THF (2 mL).
The mixture was heated at reflux overnight and quenched at 0 °C
by careful addition of water (1 mL) followed by 1 M NaOH (1 mL).
The resulting mixture was filtered through a Celite pad, and the filtrate
was concentrated under reduced pressure. Purification by column
chromatography (SiO2, a mixture of 1% NH3 and 5% MeOH in
CH2Cl2) gave 20 (55 mg, 72% yield) as a white solid: mp 215−
216 °C; [α]24D +13.4° (c 0.5, EtOAc); 1H NMR (500 MHz, CD3OD)
δ 4.78−4.52 (br s, 2H), 4.23 (t, J = 6.1 Hz, 1H), 4.18−4.14 (m, 1H),
3.47 (ddd, J = 6.6, 6.6, 21.8 Hz, 1H), 3.35−3.32 (m, 1H), 3.26−3.23
(m, 1H), 2.71−2.47 (m, 3H), 1.10 (d, J = 6.6 Hz, 3H); 13C NMR (125
MHz, CD3OD) δ 127.4 (t, J = 252.7 Hz, CF2), 79.6 (CH), 75.4 (d, J =
9.1 Hz, CH), 74.4 (dd, J = 22.9, 28.8 Hz, CH), 60.4 (d, J = 8.1 Hz,
CH2), 59.9 (CH2), 42.6 (dd, J = 22.1, 23.6 Hz, CH), 8.4 (d, J = 6.1 Hz,
CH3); 19F NMR (470 MHz, CD3OD) δ −120.96 (td, J = 22.1, 225.4
Hz, 1F), −115.04 (d, J = 225.4 Hz, 1F); IR (KBr) νmax 3372br, 1396m,
1384m, 1145s, 1117s, 1024s, 976m, 605m cm−1; MS m/z (%) relative
intensity 194 (M+ + 1, 47), 167 (30), 151 (35), 129 (35), 105 (47),
104 (55), 91 (100), 81 (39), 67 (53); HRMS (ESI-TOF) calcd for
C8H14F2NO2 [M + H]+ 194.0993, found 194.1007.
(2R,5S,6S,7S,7aR)-6,7-Bis(benzyloxy)-5-ethyl-1,1-difluoro-2-
methylhexahydro-1H-pyrrolizine (21a). EtMgCl (2 M in THF,
0.5 mL, 1 mmol) was slowly added to a solution of 18 (77 mg, 0.2
mmol) in dry THF (5 mL) at 0 °C for 30 min. To the reaction
mixture was added 4 M HCl-dioxane in MeOH (4 M HCl-dioxane/
MeOH, 1:29, 5 mL), followed by the addition of excess NaBH3CN
for an additional 1 h. To the mixture was added 10% aqueous NaOH
solution (5 mL), and the mixture was extracted with CH2Cl2 (3 ×
10 mL). The combined extracts were washed with brine (10 mL) and
dried over anhydrous Na2SO4. Filtration followed by evaporation gave
a crude product, which was purified by chromatography (SiO2, 5%
EtOAc in hexanes) to afford 21a (45 mg, 56% yield) as a colorless oil:
[α]25D +17.9° (c 1.7, CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 7.41−
7.29 (m, 10H), 4.83 (d, J = 11.5 Hz, 1H), 4.68 (d, J = 11.6 Hz, 1H),
4.64 (d, J = 11.5 Hz, 1H), 4.49 (d, J = 11.6 Hz, 1H), 4.34 (t, J = 7.3
Hz, 1H), 3.94 (t, J = 7.3 Hz, 1H), 3.66 (ddd, J = 5.7, 5.7, 24.4 Hz, 1H),
3.40 (t, J = 9.5 Hz, 1H), 2.67−2.61 (m, 2H), 2.37 (t, J = 9.5 Hz, 1H),
1.67−1.61 (m, 1H), 1.54−1.48 (m, 1H), 1.13 (d, J = 6.7 Hz, 3H), 0.95
(t, J = 7.5 Hz, 3H); 13C NMR (500 MHz, CDCl3) δ 138.4 (C), 137.9
(C), 128.4 (2 × CH), 128.3 (2 × CH), 128.0 (2 × CH), 127.8 (2 ×
CH), 127.7 (CH), 127.6 (CH), 126.0 (dd, J = 256.4, 266.1 Hz, CF2),
87.7 (CH), 80.6 (d, J = 8.1 Hz, CH), 72.7 (CH2), 72.3 (d, J = 1.8 Hz,
CH2), 71.5 (dd, J = 22.3, 28.4 Hz, CH), 69.9 (CH), 59.5 (d, J = 8.3
Hz, CH2), 41.3 (t, J = 22.9 Hz, CH), 26.0 (CH2), 10.2 (CH3), 8.3
(CH3); 19F NMR (470 MHz, CDCl3) δ −120.12 (td, J = 24.2, 220.9
Hz, 1F), −116.48 (d, J = 220.9 Hz, 1F); IR (CHCl3) νmax 1604m,
1497m, 1455s, 1360m, 1185s, 1150s, 1093s, 1074s, 700s cm−1; MS m/z
(%) relative intensity 372 (M+−Et, 9), 310 (17), 164 (11), 161 (25),
146 (56) 91 (100), 77 (12), 65 (22); HRMS (ESI-TOF) calcd for
C24H29F2O2NNa [M + Na]+ 424.2064, found 424.2071.
(1S,2R,6R,7aR)-1,2-Bis(benzyloxy)-7,7-difluoro-6-methylte-
trahydro-1H-pyrrolizin-3(2H)-one (18). The reaction of cis-12
(1.21 g, 3 mmol) with Et3SiH (2.4 mL, 15 mmol) and BF3·OEt2
(1.1 mL, 9 mmol) in dry CH2Cl2 (30 mL) at room temperature for
48 h gave 18 (0.85 g, 73% yield) as a colorless oil after preparative
thin-layer chromatography (SiO21, 5% EtOAc, 15% hexanes in CH2Cl2):
[α]23 +69.3° (c 1.0, CH2Cl2); H NMR (500 MHz, CDCl3) δ 7.31−
D
6.34 (m, 10H), 5.05 (d, J = 11.8 Hz, 1H), 4.81 (d, J = 11.8 Hz, 1H), 4.70
(d, J = 11.6 Hz, 1H), 4.57 (d, J = 11.6 Hz, 1H), 4.50 (d, J = 8.0 Hz, 1H),
4.43 (dd, J = 5.9, 8.0 Hz, 1H), 3.92 (ddd, J = 5.9, 5.9, 18.1 Hz, 1H), 3.53
(t, J = 10.5 Hz, 1H), 3.32 (t, J = 10.5 Hz, 1H), 2.84−2.68 (m, 1H), 1.19
(d, J = 6.9 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 171.1 (CO), 137.4
(C), 137.0 (C), 128.5 (2 × CH), 128.4 (2 × CH), 128.1 (2 × CH), 128.0
(CH), 127.9 (CH), 127.8 (2 × CH), 123.4 (t, J = 253.9 Hz, CF2),
82.4 (CH), 79.1 (d, J = 6.9 Hz, CH), 72.7 (CH2), 72.3 (CH2), 65.9
(dd, J = 25.8, 33.6 Hz, CH), 46.6 (d, J = 6.3 Hz, CH), 40.0 (t, J =
23.4 Hz, CH2), 9.4 (d, J = 7.6 Hz, CH3); 19F NMR (470 MHz, CDCl3)
δ −125.96 (td, J = 20.1, 225.6 Hz, 1F), −116.56 (dd, J = 9.4, 225.6 Hz,
1F); IR (CHCl3) νmax 1715s, 1456m, 1360m, 1278m, 1215s, 1121s,
997m, 699m cm−1; MS m/z (%) relative intensity 387 (M+, trace), 175
(100), 174 (34), 120 (11), 96 (43), 91 (64), 68 (23), 65 (25); HRMS
(ESI-TOF) calcd for C22H23F2NO3Na [M + Na]+ 410.1544, found
410.1522.
(1R,2R,6S,7aS)- and (1R,2R,6R,7aS)-1,2-Bis(benzyloxy)-7,7-
difluoro-7a-hydroxy-6-methyltetrahydro-1H-pyrrolizin-3(2H)-
one (cis-19 and trans-19). Radical cyclization of anti-8 (1.02 g,
2 mmol), followed by the removal of tin byproduct and preparative
thin-layer chromatography (SiO2, 10% EtOAc in hexanes ×6) gave
cis-19 (0.31 g, 38% yield) as a colorless crystal and trans-19 (0.12 g,
15% yield) as a colorless oil. cis-19: mp 154−155 °C; [α]23 +108.0°
D
(c 0.8, CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 7.43−7.33 (m, 10H),
5.04 (d, J = 11.8 Hz, 1H), 4.78 (d, J = 11.8 Hz, 1H), 4.74 (d, J = 11.4
Hz, 1H), 4.60 (d, J = 11.4 Hz, 1H), 4.47 (d, J = 7.7 Hz, 1H), 4.39 (d,
J = 7.7 Hz, 1H), 4.24 (s, 1H), 3.96 (dd, J = 8.4, 11.7 Hz, 1H), 3.08
(ddd, J = 1.3, 3.4, 11.7 Hz, 1H), 2.76−2.64 (m, 1H), 1.35 (dd, J = 1.3,
7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 169.7 (CO), 137.2 (C),
136.1 (C), 128.5 (2 × CH), 128.4 (CH), 128.3 (2 × CH), 128.1 (2 ×
CH), 128.0 (2 × CH), 127.9 (CH), 123.6 (dd, J = 248.2, 265.8 Hz,
CF2), 88.6 (dd, J = 28.6, 34.1 Hz, C), 80.8 (CH), 77.8 (d, J = 5.1 Hz,
CH), 73.1 (CH2), 72.9 (CH2), 45.7 (d, J = 2.8 HZ, CH2), 38.9 (dd, J =
22.5, 25.1 Hz, CH), 14.6 (t, J = 6.1 Hz, CH3); 19F NMR (470 MHz,
CDCl3) δ −125.55 (d, J = 228.0 Hz, 1F), −103.78 (dd, J = 22.1, 228.0
Hz, 1F); IR (KBr) νmax 3228br, 1708s, 1692s, 1455m, 1416m, 1234m,
1148s, 1035m, 1026m, 731s, 694m cm−1; MS m/z (%) relative
intensity 404 (M+ + 1, trace), 192 (8), 191 (100), 171 (22), 151 (16),
136 (38), 111 (23), 92 (8), 91 (83), 73 (10), 65 (25); HRMS (ESI-
TOF) calcd for C22H23F2NO4Na [M + Na]+ 426.1493, found
1
426.1463. trans-19: [α]23 +61.2.0° (c 0.6, CH2Cl2); H NMR (500
D
MHz, CDCl3) δ 7.42−7.34 (m, 10H), 5.04 (d, J = 11.8 Hz, 1H), 4.78
(d, J = 11.8 Hz, 1H), 4.73 (d, J = 11.4 Hz, 1H), 4.60 (d, J = 11.4 Hz,
1H), 4.47 (d, J = 7.9 Hz, 1H), 4.39 (d, J = 7.9 Hz, 1H), 4.17 (s, 1H),
3.58 (t, J = 10.7 Hz, 1H), 3.15 (t, J = 10.7 Hz, 1H), 3.09−2.90 (m,
1H), 1.25 (d, J = 6.9 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 170.0
(CO), 137.2 (C), 136.1 (C), 128.6 (2 × CH), 128.5 (CH), 128.4 (3 ×
CH), 128.2 (CH), 128.1 (2 × CH), 127.9 (CH), 122.1 (t, J = 259 Hz,
CF2), 88.3 (t, J = 30.8 Hz, C), 80.7 (CH), 77.0 (CH), 73.2 (CH2),
72.9 (CH2), 44.8 (CH2), 36.5 (t, J = 22.9 Hz, CH), 8.6 (CH3); 19F
NMR (470 MHz, CDCl3) δ −127.26 (s, 1F), −127.22 (d, J = 6.1 Hz,
1F); IR (neat) νmax 3231br, 1708s, 1692s, 1455m, 1362m, 1234m,
1148s, 1035m, 1003m, 731s, 694s cm−1; MS m/z (%) relative intensity
404 (M+ + 1, trace), 191 (21), 167 (32), 149 (100), 91 (22), 77 (5),
65 (9); HRMS (ESI-TOF) calcd for C22H23F2NO4Na [M + Na]+
426.1493, found 426.1494.
(2R,5S,6S,7S,7aR)-6,7-Bis(benzyloxy)-5-butyl-1,1-difluoro-2-
methylhexahydro-1H-pyrrolizine (21b). The reaction of 18 (155 mg,
0.4 mmol) with n-BuMgCl (2 M in THF, 1.0 mL, 2 mmol) gave 21b
(100 mg, 58% yield) as a colorless oil after column chromatography
(SiO2, 5% EtOAc in hexanes): [α]25D +20.0° (c 0.7, EtOAc); 1H NMR
(500 MHz, CDCl3) δ 7.42−7.29 (m, 10H), 4.83 (d, J = 11.5, 1H),
4.68 (d, J = 11.6, 1H), 4.64 (d, J = 11.5, 1H), 4.49 (d, J = 11.6, 1H),
4.33 (t, J = 7.1 Hz, 1H), 3.92 (t, J = 7.1 Hz, 1H), 3.67 (ddd, J = 5.7,
5.7, 24.2 Hz, 1H), 3.39 (t, J = 8.4 Hz, 1H), 2.69−2.54 (m, 2H), 2.36
(t, J = 10.6 Hz, 1H), 1.61−1.55 (m, 1H), 1.50−1.43 (m, 1H), 1.37−
1.25 (m, 4H), 1.13 (d, J = 6.7 Hz, 3H), 0.90 (t, J = 7.0 Hz, 3H); 13C
NMR (500 MHz, CDCl3) δ 138.3 (C), 137.8 (C), 128.4 (2 × CH),
128.3, (2 × CH), 127.9 (2 × CH), 127.8 (2 × CH), 127.7 (CH),
127.6 (CH), 125.9 (t, J = 246.8 Hz, CF2), 88.2 (CH), 80.5 (d, J = 8.0
Hz, CH), 72.7 (CH2), 72.2 (d, J = 1.8 Hz, CH2), 71.5 (dd, J = 22.1,
28.4 Hz, CH), 68.8 (CH), 59.7 (d, J = 8.6 Hz, CH2), 41.2 (t, J =
23.0 Hz, CH), 33.5 (CH2), 28.2 (CH2), 23.1 (CH2), 14.0 (CH3),
(1S,2S,6R,7aR)-7,7-Difluoro-6-methylhexahydro-1H-pyrroli-
zine-1,2-diol (20). A mixture of 14 (87 mg, 0.2 mmol) or 16 (64 mg,
0.2 mmol) with a cation exchange resin, DOWEX 50 WX8 (H⊕-form)
(600 mg) in MeOH (5 mL) was stirred at room temperature for 24 h.
The resin was filtered off and washed with 10% NH4OH (20 mL).
8475
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Article
8.5 (d, J = 6.0 Hz, CH3); 19F NMR (470 MHz, CDCl3) δ −126.12
(ddd, J = 18.8, 21.9, 225.3 Hz, 1F), −115.67 (dd, J = 4.7, 225.3 Hz,
1F); IR (neat) νmax 1605s, 1497s, 1455s, 1363s, 1309s, 1157s, 1124s,
1100s, 737s, 698s cm−1; MS m/z (%) relative intensity 430 (M+ + 1, 2),
338 (23), 266 (12), 188 (16), 160 (34), 147 (25), 134 (15), 91 (100), 77
(9), 65 (24); HRMS (ESI-TOF) calcd for C26H34F2NO2 [M + H]+
430.2558, found 430.2565.
1408m, 1361m, 1180m, 1149m, 800m, 738s, 699s cm−1; MS m/z (%)
relative intensity 283 (M+, trace), 267 (10), 251 (6), 239 (13), 237
(6), 193 (6), 191 (7), 155 (21), 125 (43), 111 (64), 97 (75), 91 (22),
71 (73), 65 (12), 57 (100), 55 (80); HRMS (ESI-TOF) calcd for
C18H21O2NNa [M + Na]+ 306.1470, found 306.1495.
(1S,2R,7S,8aR)- and (1S,2R,7S,8aS)-1,2-Bis(benzyloxy)-8,8-
difluoro-7-methylhexahydro-indolizin-3(5H)-one (cis-23 and
trans-23). The reaction of trans-13 (417 mg, 1 mmol) with Et3SiH
(0.8 mL, 5 mmol) and BF3·OEt2 (0.38 mL, 3 mmol) in refluxing
CH2Cl2 (10 mL) for 24 h gave cis-23 (160 mg, 40% yield) as a
colorless oil and trans-23 (88 mg, 22% yield) as a white solid after
preparative thin-layer chromatography (SiO2, 5% EtOAc, 25% hexanes
in CH2Cl2 × 2). cis-23: [α]24D +101.0° (c 0.5, CH2Cl2); 1H NMR (500
MHz, CDCl3) δ 7.45−7.31 (m, 10H), 5.06 (d, J = 11.7 Hz, 1H), 4.84
(d, J = 11.7 Hz, 1H), 4.66 (d, J = 11.5 Hz, 1H), 4.56 (d, J = 11.5 Hz,
1H), 4.44 (t, J = 5.0 Hz, 1H), 4.28 (dd, J = 1.1, 5.0 Hz, 1H), 4.11−4.07
(m, 1H), 3.74 (ddd, J = 1.1, 4.0, 23.0 Hz, 1H), 2.93 (dt, J = 4.3, 13.6
Hz, 1H), 2.52−2.47 (m, 1H), 2.06−1.96 (m, 1H), 1.67−1.58 (m, 1H),
1.21 (d, J = 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 169.5 (CO),
137.4 (C), 137.2 (C), 128.4 (4 × CH), 128.3 (2 × CH), 128.0 (CH),
127.9 (3 × CH), 119.9 (t, J = 246.9 Hz, CF2), 80.8 (CH), 76.8 (d, J =
6.4 Hz, CH), 72.4 (CH2), 72.2 (d, J = 1.8 Hz, CH2), 59.2 (dd, J = 24.6,
35.8 Hz, CH), 34.7 (dd, J = 20.1, 24.3 Hz, CH), 33.2 (CH2), 27.1 (d,
J = 6.4 Hz, CH2), 12.2 (dd, J = 2.3, 8.0 Hz, CH3); 19F NMR (470
MHz, CDCl3) δ −112.80 (d, J = 242.0 Hz, 1F), −110.58 (ddd, J =
11.3, 23.4, 242.0 Hz, 1F); IR (CHCl3) νmax 1716s, 1456m, 1293m,
1278m, 1121s, 997w, 699m cm−1; MS m/z (%) relative intensity 402
(M+ + 1, trace), 189 (100), 188 (74), 174 (18), 168 (14), 91 (47), 77
(6), 65 (15); HRMS (ESI-TOF) calcd for C23H25F2NO3Na [M +
Mixture of (2R,5S,6S,7S,7aR)-6,7-Bis(benzyloxy)-5-butyl-1,1-
difluoro-2-methylhexahydro-1H-pyrrolizine (21b) and (S)-6-
(Benzyloxy)-1-butyl-2-methyl-2H-pyrrolizin-5(3H)-one (22b).
To a solution of CeCl3 (745 mg, 2 mmol) in THF (5 mL) was
added n-BuLi (1.5 mL, 2 mmol, 1.35 M solution in hexane) at −78 °C.
After stirring at −78 °C for 1 h, a solution of 18 (155 mg, 0.4 mmol)
in THF (5 mL) was added. The mixture was stirred at −78 °C for 1 h
and then gradually warmed to −20 °C, and quenched by the addition
of 4 M HCl-dioxane in MeOH (6 mL) followed by the addition of an
excess amount of NaBH3CN. The resulting reaction mixture was
stirred at 0 °C for 1 h, and 10% aqueous NaOH solution (6 mL) was
then added. The mixture was diluted and extracted with CH2Cl2 (3 ×
20 mL). The combined extracts were washed with brine (20 mL) and
dried over anhydrous Na2SO4. Filtration followed by evaporation gave
a crude product, which was purified by preparative thin-layer
chromatography (SiO2, 5% EtOAc in hexanes × 2) to afford colorless
oils of 21b (26 mg, 15% yield) and 22b (51 mg, 43% yield): [α]25
D
+8.9° (c 0.3, CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 7.43−7.34 (m,
5H), 6.39 (s, 1H), 5.01 (s, 2H), 4.39 (dd, J = 7.7, 11.4 Hz, 1H), 3.72
(dd, J = 4.2, 11.4 Hz, 1H), 3.06−3.03 (m, 1H), 2.67 (t, J = 7.5 Hz,
2H), 1.61 (quint., J = 7.5 Hz, 2H), 1.40−1.34 (m, 5H), 0.96 (t, J = 7.5
Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 191.2 (CO), 149.9 (C),
137.3 (C), 128.5 (2 × CH), 127.9 (CH), 127.4 (2 × CH), 125.5 (C),
124.9 (C), 93.7 (CH), 72.8 (CH2), 49.0 (CH2), 43.4 (CH), 30.5
(CH2), 23.3 (CH2), 22.4 (CH2), 15.9 (CH3), 13.8 (CH3); IR (neat)
νmax 1682s, 1548w, 1455m, 1373m, 1171m, 1079m, 1024m, 770w, 738s,
699m cm−1; MS m/z (%) relative intensity 298, (M+ + 1, 9), 232 (43),
219 (80), 203 (57), 189 (100), 149 (60), 147 (90), 91 (27), 65 (8);
HRMS (ESI-TOF) calcd for C19H23O2NNa [M + Na]+ 320.1626,
found 320.1640.
Na]+ 424.1700, found 424.1704. trans-23: mp 75−76 °C; [α]24
D
+63.7° (c 1.2, CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 7.42−7.30 (m,
10H), 5.11 (d, J = 11.8 Hz, 1H), 4.82 (d, J = 11.8 Hz, 2H), 4.62 (d, J =
11.8 Hz, 1H), 4.44 (dd, J = 3.5, 7.6 Hz, 1H), 4.40 (t, J = 7.6 Hz, 1H),
4.28−4.20 (m, 1H), 3.78 (dd, J = 7.6, 27.4 Hz, 1H), 2.70 (dt, J = 3.0,
13.3 Hz, 1H), 2.10−1.99 (m, 1H), 1.68−1.63 (m, 1H), 1.56 (ddt, J =
5.0, 5.0, 13.3 Hz, 1H), 1.13 (d, J = 6.6 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ 170.3 (CO), 137.8 (C), 137.5 (C), 128.4 (2 × CH), 128.3
(2 × CH), 128.0 (2 × CH), 127.8 (CH), 127.7 (3 × CH), 120.5 (t, J =
251.5 Hz, CF2), 79.8 (d, J = 1.9 Hz, CH), 78.7 (CH), 72.9 (CH2),
72.8 (CH2), 58.8 (dd, J = 25.8, 30.2 Hz, CH), 39.1 (CH2), 38.2 (t, J =
Mixture of (2R,5S,6S,7S,7aR)-6,7-Bis(benzyloxy)-1,1-di-
fluoro-5-isopropyl-2-methyl-hexahydro-1H-pyrrolizine (21c)
and (S)-6-(Benzyloxy)-1-isopropyl-2-methyl-2H-pyrrolizin-
5(3H)-one (22c). The reaction of 18 (77 mg, 0.2 mmol) with
iPrMgCl (2 M in THF, 0.5 mL, 1 mmol) gave 21c (42 mg, 51% yield)
as a colorless oil and 22c (7 mg, 12% yield) as a yellow oil after pre-
22.6 Hz, CH), 30.1 (d, J = 6.9 Hz, CH2), 11.9 (t, J = 3.9 Hz, CH3); 19
F
NMR (470 MHz, CDCl3) δ −130.21 (td, J = 26.7, 244.2 Hz, 1F),
−112.69 (d, J = 244.2 Hz, 1F); IR (CHCl3) νmax 1716s, 1456m,
1278m, 1153m, 1121s, 996s, 699m cm−1; MS m/z (%) relative
intensity 401 (M+, 1), 205 (52), 189 (100), 188 (74), 179 (23), 165
(24), 105 (28), 91 (74), 77 (20), 65 (18); HRMS (ESI-TOF) calcd
for C23H25F2NO3Na [M + Na]+ 424.1700, found 424.1678.
parative thin-layer chromatography (SiO2, 5% EtOAc in hexanes × 2).
1
21c: [α]23 +48.2° (c 1.0, CH2Cl2); H NMR (500 MHz, CDCl3)
D
δ 7.42−7.29 (m, 10H), 4.81 (d, J = 11.4 Hz, 1H), 4.67 (d, J = 11.5 Hz,
1H), 4.62 (d, J = 11.4 Hz, 1H), 4.50 (d, J = 11.5 Hz, 1H), 4.36 (t, J =
6.5 Hz, 1H), 4.04 (t, J = 8.1 Hz, 1H), 3.65 (ddd, J = 6.2, 6.2, 23.1 Hz,
1H), 3.33 (t, J = 8.2 Hz, 1H), 2.70−2.50 (m, 2H), 2.38 (t, J = 10.5 Hz,
1H), 1.83−1.77 (m, 1H), 1.12 (d, J = 6.7 Hz, 3H), 0.96 (d, J = 7.0 Hz,
3H), 0.93 (d, J = 6.9 Hz, 3H); 13C NMR (500 MHz, CDCl3) δ 138.3
(C), 137.9 (C), 128.4 (2 × CH), 128.3 (2 × CH), 128.0 (2 × CH),
127.9 (2 × CH), 127.7 (CH), 127.6 (CH), 126.1 (t, J = 253.7 Hz,
CF2), 86.2 (CH), 81.2 (d, J = 8.6 Hz, CH), 73.9 (CH), 72.4 (CH2),
72.3 (d, J = 1.6 Hz, CH2), 71.9 (dd, J = 22.5, 28.6 Hz, CH), 60.6 (d,
J = 8.5 Hz, CH2), 41.4 (t, J = 22.8 Hz, CH), 30.4 (CH), 19.6 (CH3),
18.3 (CH3), 8.4 (d, J = 6.3 Hz, CH3); 19F NMR (470 MHz, CDCl3)
δ −119.30 (d, J = 220.9 Hz, 1F), −115.29 (d, J = 220.9 Hz, 1F); IR
(CHCl3) νmax 1603w, 1497m, 1456s, 1362m, 1150s, 1093s, 700s cm−1;
MS m/z (%) relative intensity 416 (M+ + 1, 21), 415 (2), 372 (35),
160 (14), 91 (100), 77 (6), 65 (18); HRMS (ESI-TOF) calcd for
Mixture of (1S,2S,3R,7S,8aR)- and (1S,2S,3S,7S,8aR)-1,2-
Bis(benzyloxy)-3-ethyl-8,8-difluoro-7-methyloctahydroindoli-
zine (24a and 25a). The reaction of cis-23 (161 mg, 0.4 mmol) with
EtMgCl (2 M in THF, 0.4 mL, 0.8 mmol) gave 24a (83 mg, 50%
yield) and 25a (37 mg, 22% yield) as colorless oils after preparative
thin-layer chromatography (SiO2, 5% EtOAc in hexanes × 2). 24a:
[α]25D −55.0° (c 0.6, CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 7.40−
7.30 (m, 10H), 4.68 (d, J = 11.4 Hz, 1H), 4.63 (d, J = 12.0 Hz, 1H),
4.56 (d, J = 11.4 Hz, 1H), 4.42 (d, J = 12.0 Hz, 1H), 4.16 (d, J = 6.1
Hz, 1H), 3.82 (d, J = 5.0 Hz, 1H), 2.98−2.88 (m, 1H), 2.59 (ddd, J =
6.1, 8.3, 16.4 Hz, 1H), 2.44−2.38 (m, 2H), 2.21−2.13 (m, 2H), 1.78−
1.69 (m, 1H), 1.63−1.52 (m, 2H), 1.14 (d, J = 7.4 Hz, 3H), 0.87 (t, J =
7.4 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 138.1 (C), 138.0 (C),
128.4 (2 × CH), 128.2 (4 × CH), 127.9 (2 × CH), 127.8 (CH), 127.7
(CH), 121.9 (t, J = 244.6 Hz, CF2), 82.7 (CH), 81.2 (CH), 72.2
(CH2), 71.2 (CH2), 69.1 (CH), 69.0 (dd, J = 25.0, 27.1 Hz, CH), 44.1
(CH2), 35.2 (t, J = 22.4 Hz, CH), 29.2 (d, J = 4.1 Hz, CH2), 18.9
(CH2), 13.6 (t, J = 6.2 Hz, CH3), 10.7 (CH3); 19F NMR (470 MHz,
CDCl3) δ −108.95−(−108.89) (m, 2F); IR (neat) νmax 1606w,
1497m, 1455s, 1360m, 1340m, 1186s, 1120s, 1074m, 737s, 698s cm−1;
MS m/z (%) relative intensity 416 (M+ + 1, 3), 386 (17), 203 (25),
181 (24), 174 (22), 160 (29), 134 (15), 91 (100), 77 (3), 65 (14);
HRMS (ESI-TOF) calcd for C25H32O2F2N [M + H]+ 416.2401, found
C25H32F2NO2 [M + H]+ 416.2401, found 416.2385. 22c: [α]23
+16.7° (c 0.5, CH2Cl2); H NMR (500 MHz, CDCl3) δ 7.43−7.32
D
1
(m, 5H), 6.40 (s, 1H), 5.01 (s, 2H), 4.44 (dd, J = 7.7, 11.4 Hz, 1H),
3.77 (dd, J = 4.2, 11.4 Hz, 1H), 3.15 (quint., J = 7.1 Hz, 1H), 3.08−
3.01 (m, 1H), 1.38 (d, J = 7.4 Hz, 3H), 1.36 (d, J = 7.1 Hz, 6H); 13C
NMR (125 MHz, CDCl3) δ 191.2 (CO), 149.3 (C), 137.3 (C), 130.0
(C), 128.5 (2 × CH), 127.9 (CH), 127.4 (2 × CH), 124.7 (C), 93.9
(CH), 72.7 (CH2), 49.8 (CH2), 43.4 (CH), 25.4 (CH), 20.9 (CH3),
20.8 (CH3), 15.8 (CH3); IR (neat) νmax 1694s, 1682s, 1485m, 1456s,
8476
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1
416.2423. 25a: [α]25 +35.0° (c 0.7, EtOAc); H NMR (500 MHz,
125.4 (C), 99.1 (CH), 72.7 (CH2), 41.1 (CH2), 39.3 (CH), 31.2
(CH2), 30.9 (CH2), 22.9 (CH2), 22.4 (CH2), 15.3 (CH3), 13.8
(CH3); IR (neat) νmax 1728m, 1651m, 1644s, 1463s, 1455s, 1381s,
1162s, 1017s, 792m, 722m, 698s cm−1; MS m/z (%) relative intensity
312 (M+ + 1, 36), 311 (20), 220 (45), 179 (21), 178 (100), 91 (87),
77 (5), 65 (17); HRMS (ESI-TOF) calcd for C20H25O2NNa [M +
Na]+ 334.1783, found 334.1780.
(S)-2-(Benzyloxy)-8-isopropyl-7-methyl-6,7-dihydroindoli-
zin-3(5H)-one (26c). The reaction of cis-23 (161 mg, 0.4 mmol) with
iPrMgCl (2 M in THF, 0.4 mL, 0.8 mmol) gave 26c (57 mg, 48%
D
CDCl3) δ 7.41−7.29 (m, 10H), 4.65 (d, J = 11.9 Hz, 1H), 4.53 (d, J =
11.9 Hz, 1H), 4.49 (d, J = 11.7 Hz, 1H), 4.44 (d, J = 11.7 Hz, 1H),
4.26 (d, J = 2.0 Hz, 1H), 3.75 (d, J = 2.0 Hz, 1H), 3.39−3.31 (m, 1H),
3.13−3.09 (m, 1H), 2.97 (t, J = 10.3 Hz, 1H), 2.86−2.63 (m, 1H),
2.47−2.25 (m, 1H), 2.18−2.11 (m, 1H), 1.78−1.70 (m, 1H), 1.47−
1.36 (m, 2H), 1.16 (d, J = 7.3 Hz, 3H), 0.91 (t, J = 7.4 Hz, 3H); 13C
NMR (125 MHz, CDCl3) δ 138.5 (C), 138.1 (C), 128.5 (2 × CH),
128.3 (2 × CH), 128.2 (2 × CH), 127.9 (2 × CH), 127.8 (CH), 127.7
(CH), 121.9 (t, J = 244.2 Hz, CF2), 82.7 (CH), 81.3 (CH) 72.2 (d, J =
1.6 Hz, CH2), 71.2 (CH2), 69.1 (CH), 69.0 (dd, J = 25.0, 27.1 Hz,
CH), 44.7 (CH2), 40.2 (d, J = 22.4 Hz, CH), 29.2 (d, J = 4.3 Hz,
CH2), 23.6 (t, J = 5.8 Hz, CH3), 18.9 (CH2), 10.7 (CH3); 19F NMR
(470 MHz, CDCl3) δ −107.00 (d, J = 246.8 Hz, 1F), −104.54 (d, J =
246.8 Hz, 1F); IR (neat) νmax 1497m, 1455s, 1360m, 1340m, 1186s,
1148s, 1120s, 831m, 737s, 698s cm−1; MS m/z (%) relative intensity
416 (M+ + 1, 17), 415 (1), 386 (15), 203 (26), 181 (18), 174 (23),
91 (100), 77 (3), 65 (13); HRMS (ESI-TOF) calcd for C25H32O2F2N
[M + H+] 416.2401, found 416.2414.
yield) as a yellow oil after column chromatography (SiO2, 5% EtOAc
1
in hexanes): [α]23 −22.4° (c 0.8, CH2Cl2); H NMR (500 MHz,
D
CDCl3) δ 7.44−7.31 (m, 5H), 6.71 (s, 1H), 4.99 (s, 2H), 4.11 (ddd,
J = 4.2, 4.2, 12.6 Hz, 1H), 3.89 (ddd, J = 4.2, 10.5, 12.6 Hz, 1H), 3.06
(quint., J = 7.1 Hz, 1H), 2.60−2.51 (m, 1H), 2.33 (ddd, J = 4.7, 8.7,
13.5 Hz, 1H), 2.10−2.02 (m, 1H), 1.38 (d, J = 3.9 Hz, 3H), 1.36 (d,
J = 3.9 Hz, 3H), 1.29 (d, J = 7.0 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ 188.2 (CO), 145.6 (C), 137.6 (C). 129.9 (C), 128.4 (2 ×
CH), 127.7 (CH), 127.3 (2 × CH), 125.1 (C), 99.6 (CH), 72.5
(CH2), 41.3 (CH2), 39.0 (CH), 31.2 (CH2), 25.3 (CH), 20.9 (2 ×
CH3), 15.2 (CH3); IR (neat) νmax 1712m, 1651s, 1645s, 1471s, 1455s,
1417s, 1372s, 1185s, 738m, 698m cm−1; MS m/z (%) relative intensity
298 (M+ + 1, 6), 297 (29), 207 (30), 206 (100), 194 (34), 178 (55),
164 (26), 91 (89), 77 (6), 65 (21); HRMS (ESI-TOF) calcd for
C19H23O2NNa [M + Na]+ 320.1626, found 320.1595.
Mixture of (1S,2S,3R,7S,8aR)- and (1S,2S,3S,7S,8aR)-1,2-
Bis(benzyloxy)-3-butyl-8,8-difluoro-7-methyloctahydroindoli-
zine (24b and 25b) and (S)-2-(Benzyloxy)-8-butyl-7-methyl-
6,7-dihydroindolizin-3(5H)-one (26b). The reaction of cis-23
(80 mg, 0.2 mmol) with n-BuMgCl (2 M in THF, 0.5 mL, 1 mmol)
gave 24b (38 mg, 43% yield), 25b (14 mg, 16% yield) and 26b (9 mg,
14% yield) after preparative thin-layer chromatography (SiO2, 5%
(1S,2S,3S,6R,7aR)-3-Ethyl-7,7-difluoro-6-methylhexahydro-
1H-pyrrolizine-1,2-diol (27a). To a solution of 21a (40 mg,
0.1 mmol) in dry MeOH (2 mL) was added PdCl2 (36 mg, 0.2 mmol).
The reaction mixture was stirred at room temperature under an
atmosphere of H2 (balloon) for 24 h. The mixture was filtered through
a Celite pad, and the solids were washed with MeOH. The combined
filtrates were evaporated in vacuo, and the residue was purified by
column chromatography (SiO2, a mixture of 1% NH3 and 3% MeOH
EtOAc in hexanes ×3). 24b: a colorless oil; [α]25 −38.9° (c 0.5,
D
1
CH2Cl2); H NMR (500 MHz, CDCl3) δ 7.40−7.29 (m, 10H), 4.68
(d, J = 11.4 Hz, 1H), 4.64 (d, J = 12.0 Hz, 1H), 4.57 (d, J = 11.4 Hz,
1H), 4.40 (d, J = 12.0 Hz, 1H), 4.16 (d, J = 5.4 Hz, 1H), 3.79 (d, J =
5.4 Hz, 1H), 2.86−2.87 (m, 1H), 2.58 (ddd, J = 5.8, 9.5, 15.2 Hz, 1H),
2.47−2.36 (m, 2H), 2.24−2.11 (m, 2H) 1.78−1.68 (m, 1H), 1.60−
1.55 (m, 1H), 1.54−1.46 (m, 1H), 1.40−1.26 (m, 3H), 1.20−1.16 (m,
1H), 1.14 (d, J = 7.4 Hz, 3H), 0.89 (t, J = 7.3 Hz, 3H); 13C NMR (125
MHz, CDCl3) δ 138.1 (2 × CO), 128.4 (2 × CH), 128.3 (2 × CH),
128.2 (2 × CH), 127.9 (2 × CH), 127.8 (CH), 127.7 (CH), 121.9 (t,
J = 244.6 Hz, CF2), 82.7 (CH), 81.3 (CH), 72.1 (CH2), 71.1 (CH2),
69.1 (t, J = 25.9 Hz, CH), 67.6 (CH), 44.1 (CH2), 35.2 (t, J = 22.3 Hz,
CH), 29.2 (d, J = 2.9 Hz, CH2), 28.4 (CH2), 25.7 (CH2), 23.1 (CH2),
13.9 (CH3), 13.6 (t, J = 6.2 Hz, CH3); 19F NMR (470 MHz, CDCl3) δ
−109.44−(−108.39) (m, 2F); IR (neat) νmax 1497m, 1455s, 1364m,
1184m, 1122s, 736s, 698s cm−1; MS m/z (%) relative intensity 444
(M+ + 1, 5), 280 (24), 202 (10), 181 (51), 174 (43), 91 (100), 77 (5),
65 (10); HRMS (ESI-TOF) calcd for C27H36O2F2N [M + H]+
in CH2Cl2) to give 27a (21 mg, 95% yield) as a pale yellow solid: mp
1
211−212 °C; [α]25 +11.4° (c 0.6, EtOAc); H NMR (500 MHz,
D
CD3OD) δ 4.74−4.48 (br s, 2H), 4.15 (t, J = 7.8 Hz, 1H), 3.66 (t, J =
8.3 Hz, 1H), 3.38 (ddd, J = 6.9, 6.9, 21.5 Hz, 1H), 3.35 (t, J = 8.2 Hz,
1H), 2.62−2.46 (m, 1H), 2.42−2.35 (m, 1H), 2.32 (t, J = 10.8 Hz,
1H), 1.70−1.62 (m, 1H), 1.51−1.42 (m, 1H), 1.07 (d, J = 6.7 Hz,
3H), 0.98 (t, J = 7.4 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 126.0
(t, J = 253.6 Hz, CF2), 82.3 (CH), 73.8 (d, J = 10.3 Hz, CH), 70.9
(CH), 70.5 (dd, J = 22.5, 27.9 Hz, CH), 59.6 (d, J = 8.5 Hz, CH2),
41.4 (t, J = 22.8 Hz, CH), 26.1 (CH2), 10.5 (CH3), 8.3 (d, J = 5.8 Hz,
CH3); 19F NMR (470 MHz, CD3OD) δ −121.96 (d, J = 224.2 Hz,
1F), −117.21 (d, J = 224.2 Hz, 1F); IR (Nujol-mull) νmax 3502br,
1463s, 1456s, 1377m, 1134m, 1062m cm−1; MS m/z (%) relative
intensity 222 (M+ + 1, 7), 221 (M+, 14), 207 (29), 192 (17), 191 (43),
178 (100), 161 (72), 149 (95), 133 (27), 95 (62), 67 (57); HRMS
(ESI-TOF) calcd for C10H18F2NO2 [M + H]+ 222.1306, found
222.1296.
444.2714, found 444.2703. 25b: a colorless oil; [α]24 +29.2° (c 0.2,
D
EtOAc); 1H NMR (500 MHz, CDCl3) δ 7.29−7.12 (m, 10H), 4.55 (d,
J = 11.8 Hz, 1H), 4.41 (d, J = 12.9 Hz, 1H), 4.40 (d, J = 12.9 Hz, 1H),
4.37 (d, J = 11.8 Hz, 1H), 4.15−4.14 (m, 1H), 3.64−3.62 (m, 1H),
3.25−3.19 (m, 1H), 3.08−3.04 (m, 1H), 2.83 (t, J = 11.3 Hz, 1H),
2.65−2.63 (m, 1H), 2.36−2.18 (m, 1H), 2.12−2.04 (m, 1H), 1.78−
1.66 (m, 1H), 1.56−1.41 (m, 2H), 1.38−1.28 (m, 2H), 1.25−1.09 (m,
5H), 0.80 (t, J = 6.8 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 137.1
(2 × C), 128.4 (2 × CH), 128.3 (2 × CH), 128.2 (2 × CH), 127.9
(2 × CH), 127.8 (CH), 127.7 (CH), 122.6 (t, J = 244.8 Hz, CF2), 82.7
(CH), 81.4 (CH), 72.5 (CH2), 71.0 (CH2), 68.6 (CH2), 65.1 (t, J =
26.5 Hz, CH), 42.1 (CH), 35.2 (t, J = 22.1 Hz, CH), 29.2 (d, J =
2.9 Hz, CH2), 28.4 (CH2), 25.7 (CH2), 23.1 (CH2), 13.9 (CH3), 13.6
(t, J = 6.3 Hz, CH3); 19F NMR (470 MHz, CDCl3) δ −107.06 (d, J =
241.0 Hz, 1F), −104.81 (ddd, J = 14.6, 27.5, 241.0 Hz, 1F); IR (neat)
νmax, 1497m, 1455s, 1364m, 1183m, 1122s, 736s, 698s; MS m/z (%)
relative intensity 444 (M+ + 1, 8), 352 (12), 280 (28), 181 (72), 174
(49), 165 (22), 91 (100), 77 (7), 65 (12); HRMS (ESI-TOF) calcd
(1S,2S,3S,6R,7aR)-3-Butyl-7,7-difluoro-6-methylhexahydro-
1H-pyrrolizine-1,2-diol (27b). The reaction of 21b (129 mg, 0.3
mmol) with PdCl2 gave 27b (69 mg, 92% yield) as a white solid after
column chromatography (SiO2, a mixture of 1% NH3 and 2% MeOH
in CH2Cl2): mp 217−218 °C; [α]25D +12.9° (c 0.6, EtOAc); 1H NMR
(500 MHz, CD3OD) δ 4.74−4.52 (br s, 2H), 4.17 (t, J = 7.9 Hz, 1H),
3.68 (t, J = 8.7 Hz, 1H), 3.42 (ddd, J = 7.0, 7.0, 21.1 Hz, 1H), 3.38 (t,
J = 8.1 Hz, 1H), 2.65−2.51 (m, 1H), 2.51−2.44 (m, 1H), 2.38−2.34
(m, 1H), 1.69−1.63 (m, 1H), 1.51−1.34 (m, 5H), 1.10 (d, J = 6.7 Hz,
3H), 0.95 (t, J = 7.1 Hz, 3H); 13C NMR (500 MHz, CD3OD) δ 127.3
(t, J = 253.1 Hz, CF2), 83.8 (CH), 74.2 (d, J = 10.0 Hz, CH), 72.1 (t,
J = 25.6 Hz, CH), 71.5 (CH), 60.9 (d, J = 8.5 Hz, CH2), 42.6 (t, J =
22.9 Hz, CH), 34.4 (CH2), 29.7 (CH2), 24.1 (CH2), 14.3 (CH3), 8.5
(d, J = 6.3 Hz, CH3); 19F NMR (470 MHz, CD3OD) δ −123.02 (td,
J = 23.0, 224.0 Hz, 1F), −117.74 (d, J = 224.0 Hz, 1F); IR (KBr) νmax
3390br, 1462m, 1394m, 1382m, 1223s, 1139s, 1044m, 981m, 806m
cm−1; MS m/z (%) relative intensity 250 (M+ + 1, 3), 249, (M+, 12),
192 (100), 174 (20), 160 (66), 147 (77), 132 (53), 120 (86), 80 (15);
HRMS (ESI-TOF) calcd for C12H22F2NO2 [M + H]+ 250.1619, found
250.1620.
for C27H36O2F2N [M + H]+ 444.2714, found 444.2713. 26b: a yellow
oil; [α]23 −28.6° (c 0.6, CH2Cl2); H NMR (500 MHz, CDCl3) δ
1
D
7.43−7.31 (m, 5H), 6.68 (s, 1H), 4.99 (s, 2H), 4.07 (ddd, J = 4.2, 4.2,
12.6 Hz, 1H), 3.88 (ddd, J = 4.2, 10.4, 12.6 Hz, 1H), 2.70−2.51 (m,
2H), 2.32 (ddd, J = 4.6, 8.8, 13.5 Hz, 1H), 2.09−2.01 (m, 1H), 1.59−
1.52 (m, 2H), 1.42−1.34 (m, 3H), 1.29 (d, J = 9.1 Hz, 3H), 0.95 (t, J =
7.3 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 188.1 (CO), 145.7 (C),
137.5 (C), 128.3 (2 × CH), 127.8 (CH), 127.4 (2 × CH), 126.0 (C),
8477
dx.doi.org/10.1021/jo301327s | J. Org. Chem. 2012, 77, 8465−8479

The Journal of Organic Chemistry
Article
(1S,2S,3S,6R,7aR)-7,7-Difluoro-3-isopropyl-6-methylhexahy-
dro-1H-pyrrolizine-1,2-diol (27c). The reaction of 21c (42 mg,
0.1 mmol) with PdCl2 gave 27c (22 mg, 93% yield) as a pale yellow
solid after column chromatography (SiO2, a mixture of 1% NH3 and
AUTHOR INFORMATION
Corresponding Author
*E-mail: manat.poh@mahidol.ac.th.
Notes
■
1% MeOH in CH2Cl2): mp 193−195 °C; [α]25 +18.9° (c 0.7,
D
EtOAc); 1H NMR (500 MHz, CD3OD) δ 4.74−4.52 (br s, 2H), 4.12
(t, J = 8.1 Hz, 1H), 3.80 (t, J = 8.7 Hz, 1H), 3.36 (ddd, J = 7.7, 7.7,
20.6 Hz, 1H), 3.31−3.28 (m, 1H), 2.63−2.46 (m, 1H), 2.35−2.30 (m,
2H), 1.83−1.72 (m, 1H), 1.05 (d, J = 6.7 Hz, 3H), 0.98 (d, J = 7.0 Hz,
3H), 0.96 (d, J = 6.9 Hz, 3H); 13C NMR (500 MHz, CD3OD) δ 127.7
(t, J = 252.3 Hz, CF2), 81.5 (CH), 76.4 (CH), 74.8 (d, J = 10.8 Hz,
CH), 72.3 (dd, J = 23.3, 28.0 Hz, CH), 62.0 (d, J = 8.3 Hz, CH2) 42.8
(t, J = 23.0, CH), 31.5 (CH), 20.0 (CH3), 18.7 (CH3), 8.5 (d, J = 6.6
Hz, CH3); 19F NMR (470 MHz, CD3OD) δ −122.48 (td, J = 21.6,
225.1 Hz, 1F), −115.46 (d, J = 225.1 Hz, 1F); IR (CHCl3) νmax
3401br, 1473s, 1462s, 1391s, 1230s, 1122s, 1078s, 1045s, 983m cm−1;
MS m/z (%) relative intensity 236 (M+ + 1, 6), 235 (M+, 1), 192
(100), 164 (12), 160 (15), 146 (20), 44 (11), 126 (13), 120 (69), 80
(10); HRMS (ESI-TOF) calcd for C11H20F2NO2 [M + H]+ 236.1462,
found 236.1437.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the Center of Excellence for Innovation
in Chemistry (PERCH-CIC), the Office of Higher Education
Commission and Mahidol University under the National
Research Universities Initiative and the Thailand Research
Fund (to M.P., BRG5380019, and to P.K., DBG5480015) is
gratefully acknowledged.
REFERENCES
■
(1) For selected recent references, see: (a) Ojima, I. Fluorine in
Medicinal Chemistry and Chemical Biology; Blackwell: Oxford, 2009.
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(1S,2S,3R,7S,8aR)-3-Ethyl-8,8-difluoro-7-methyloctahydroin-
dolizine-1,2-diol (28a). The reaction of 24a (42 mg, 0.1 mmol) with
PdCl2 gave 28a (23 mg, 98% yield) as a pale yellow solid after column
chromatography (SiO2, a mixture of 1% NH3 and 2% MeOH in
(2) (a) Qing, F.-L.; Zheng, F. Synlett 2011, 1052. (b) Chernykh, Y.;
Hlat-Glembova, K.; Klepetarova, B.; Beier, P. Eur. J. Org. Chem. 2011,
́ ́ ̌ ́
1
CH2Cl2): mp 222−223 °C; [α]25 −35.7° (c 0.5, MeOH); H NMR
D
(500 MHz, CD3OD) δ 4.60−4.63 (br s, 2H), 4.10 (dd, J = 1.6, 6.9 Hz,
1H), 3.83 (dd, J = 1.6, 5.4 Hz, 1H), 2.86−2.82 (m, 1H), 2.39 (ddd, J =
1.3, 6.8, 23.8 Hz, 1H), 2.34−2.23 (m, 2H), 2.20−2.15 (m, 1H), 2.03−
1.95 (m, 1H), 1.61−1.51 (m, 3H), 1.09 (d, J = 7.4 Hz, 3H), 0.95 (t, J =
7.4 Hz, 3H); 13C NMR (125 MHz, CD3OD) δ 123.4 (t, J = 243.8 Hz,
CF2), 79.0 (CH), 77.8 (d, J = 2.1 Hz, CH), 70.5 (CH), 70.0 (dd, J =
22.9, 28.4 Hz, CH), 45.1 (CH2), 36.5 (dd, J = 20.3, 24.3 Hz, CH), 30.2
(d, J = 6.6 Hz, CH2), 19.9 (CH2), 13.6 (dd, J = 4.3, 8.1 Hz, CH3), 10.9
(CH3); 19F NMR (470 MHz, CD3OD) δ −113.04 (d, J = 240.2 Hz,
1F), −111.36 (ddd, J = 13.3, 23.1, 240.2 Hz, 1F); IR (KBr) νmax 3504s,
1472m, 1385s, 1218m, 1134m, 1062s, 1040m cm−1; MS m/z (%)
relative intensity 236 (M+ + 1, trace), 207 (3), 167 (40), 150 (11), 149
(100), 104 (5), 146 (20), 44 (11), 126 (13), 120 (69), 80 (10);
HRMS (ESI-TOF) calcd for C11H20F2NO2 [M + H]+ 236.1462, found
236.1451.
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(1S,2S,3R,7S,8aR)-3-Butyl-8,8-difluoro-7-methyloctahydroin-
dolizine-1,2-diol (28b). The reaction of 24b (89 mg, 0.2 mmol)
with PdCl2 gave 28b (48 mg, in 91% yield) as a yellow crystal after
column chromatography (SiO2, a mixture of 1% NH3 and 2% MeOH
1
in CH2Cl2): mp 205−207 °C; [α]25 −70.4° (c 0.5, CD3OD); H
D
NMR (500 MHz, CD3OD) δ 4.70−4.52 (s, 2H), 4.09 (d, J = 6.8 Hz,
1H), 3.80 (d, J = 5.1 Hz, 1H), 2.89−2.80 (m, 1H), 2.41−2.31 (m,
2H), 2.31−2.22 (m, 1H), 2.19−2.14 (m, 1H), 2.05−1.93 (m, 1H),
1.63−1.53 (m, 2H), 1.53−1.41 (m, 2H), 1.41−1.31 (m, 2H), 1.31−
1.21 (m, 1H), 1.09 (d, J = 7.3 Hz, 3H), 0.85 (t, J = 7.2 Hz, 3H); 13C
NMR (125 MHz, CD3OD) δ 123.5 (t, J = 243.7 Hz, CF2), 79.2 (CH),
77.8 (d, J = 1.8 Hz, CH), 70.0 (dd, J = 22.7, 28.4 Hz, CH), 69.0 (CH),
45.1 (CH2), 36.5 (dd, J = 20.2, 24.4 Hz, CH), 30.2 (d, J = 6.6 Hz,
CH2), 29.6 (CH2), 26.8 (CH2), 24.1 (CH2), 14.4 (CH3), 13.6 (dd, J =
4.0, 8.3 Hz, CH3); 19F NMR (470 MHz, CD3OD) δ −113.03 (d, J =
240.5 Hz, 1F), −111.32 (ddd, J = 13.3, 22.9, 240.5 Hz, 1F); IR
(CHCl3) νmax 3403br, 1458m, 1386m, 1186m, 1159m, 1121s, 1088s,
1067s cm−1; MS m/z (%) relative intensity 264 (M+ + 1, 3), 207 (12),
206 (100), 174 (25), 160 (14), 134 (40), 57 (1); HRMS (ESI-TOF)
calcd for C13H24F2NO2 [M + H]+ 264.1775, found 264.1775.
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ASSOCIATED CONTENT
■
S
* Supporting Information
̌ ̌ ̌
́
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Characterization data for all compounds and CIF data for single
crystal X-ray analyses of cis-10, trans-11, cis-13, cis-19, and 28b.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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(17) We thank one of the reviewers for suggesting an alternative
mechanism pathway B for the formation of compounds 22 and 26.
8479
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