Stereoselective synthesis of the C31-C41 spirolactam fragment of sanglifehrin a

Article abstract of DOI:10.1002/ejoc.201201684

A stereoselective synthesis of the spirolactam fragment (C31-C41) of a highly-potent immunosuppressant sanglifehrin A is described. The key steps involved in this synthesis are a desymmetrization protocol, Sharpless asymmetric epoxidation, Crimmins syn aldol reaction, Barton-McCombie deoxygenation, and acid-mediated spirolactamization. Copyright

Full text of DOI:10.1002/ejoc.201201684

Job/Unit: O21684
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Date: 09-04-13 17:01:43
Pages: 11
FULL PAPER
DOI: 10.1002/ejoc.201201684
Stereoselective Synthesis of the C31–C41 Spirolactam Fragment of
Sanglifehrin A
J. S. Yadav,*[a] K. V. Raghavendra Rao,[a] Aala Kavita,[a] and Debendra K. Mohapatra*[a]
Keywords: Synthetic methods / Asymmetric synthesis / Medicinal chemistry / Natural products / Spiro compounds /
Lactams
A stereoselective synthesis of the spirolactam fragment (C31–
C41) of a highly-potent immunosuppressant sanglifehrin A
is described. The key steps involved in this synthesis are a
desymmetrization protocol, Sharpless asymmetric epoxid-
ation, Crimmins syn aldol reaction, Barton–McCombie de-
oxygenation, and acid-mediated spirolactamization.
higher affinity than cyclosporin) and immunosuppressive
activity (10-fold less potent than cyclosporin). It has a com-
Introduction
The highly-potent immunosuppressive natural product san- plex molecular structure consisting of a 22-membered
glifehrin A (1) (Figure 1), isolated from Streptomyces flav- macrocyclic ring in combination with a highly-substituted
eolus (A92-308110), was found in soil samples collected at spirobicyclic [5.5] spirolactam subunit, and an unusual
Dembo-Bridge, Malawi, by a group of scientists from Nov- peptidic backbone.[3] Its molecular structure has been fully
artis. Sanglifehrin A acts as a potent inhibitor of the mito- elucidated by spectroscopic and X-ray crystallographic
chondrial permeability transition and reperfusion injury of techniques.[4] Unusual structural features, seventeen ste-
the heart through binding to cyclophilin D at a different reogenic centers, and sensitive functionalities coupled with
site from cyclosporine A.[1] It has high affinity towards cy- its important biological activity make sanglifehrin A at-
clophilin A and also inhibits nitrogen-induced B-cell prolif- tractive to synthetic- and medicinal-chemistry research
eration without influencing T-cell receptor-mediated cyto- groups worldwide. Its first total synthesis was achieved by
kine production.[2] It was found to exhibit significant bio- Nicolaou and co-workers in 1999 by using 3-pentanone as
logical properties like strong cyclophilin A binding (20-fold the starting material for the spirolactam fragment,[5] and
Figure 1. Structure of sanglifehrin A.
then Paquette et al.[6] reported the second total synthesis.
[a] Natural Products Chemistry Division, CSIR-Indian Institute of
Chemical Technology,
Many other groups have also made attempts towards the
synthesis of sanglifehrinA.[7] As part of our ongoing inter-
est in the synthesis of spirocyclic natural products[8] and
macrolides containing polypropionates by means of desym-
metrization strategies,[9] the synthesis of sanglifehrin A (1)
was chosen for investigation and this report describes a
Hyderabad 500007, India
E-mail: yadavpub@iict.res.in
mohapatra@iict.res.in
Homepage: www.iictindia.org
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201684
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J. S. Yadav, D. K. Mohapatra et al.
FULL PAPER
highly-stereoselective synthesis of the C31–C41 segment free hydroxy group from a Swern oxidation reaction fol-
starting from bicyclic olefin 5 and substrate-controlled ster- lowed by condensation with Ph3P=CHCO2Et in benzene
eoselective transformations to create contiguous stereocen- furnished compound 9 in 90% yield. The α,β-unsaturated
ters.
ester upon treatment with diisobutylaluminium hydride
The retrosynthetic analysis of sanglifehrin A, shown in (DIBAL-H) afforded allyl alcohol compound 10 in 88%
Figure 2, explains the overall strategy involved in the pres- yield. Allylic alcohol 10 under Sharpless asymmetric epox-
ent synthesis. Fragment 2 could be synthesized through in- idation reaction conditions was smoothly converted into ep-
tramolecular spirolactamization of key fragment 3 embed- oxide 11 (92% yield, 97% de), which was regioselectively
ded with all of the required stereocenters of the spirolactam opened with sodium bis(2-methoxyethoxy)aluminium hy-
fragment. Fragment 3 in turn could be prepared starting dride (Red-Al) in tetrahydrofuran (THF) to afford 1,3-diol
from known triol 4, which in turn could be easily obtained product 12 exclusively in 89% yield.[14] The primary hy-
from 5.
droxy group was selectively silylated with tert-butyldiphen-
ylsilyl chloride (TBDPSCl), and the secondary alcohol fur-
ther protected as its tert-butyldimethylsilyl (TBDMS) ether
[15]
by using TBDMS trifluoromethanesulfonate (OTf)
and
2,6-lutidine to furnish fully-protected compound 14 in 77%
yield over two steps.
Selective deprotection of the acetonide group of 14 in the
presence of silyl groups by using CuCl2·2H2O in CH3CN at
0 °C gave 15 in 90% yield.[16] The 1,3-diol was protected as
its p-methoxybenzyl ether (PMB) acetal with anisaldehyde
dimethyl acetal in the presence of a catalytic amount of
CSA to furnish 16 in 92% yield, which on subsequent re-
gioselective acetal cleavage with DIBAL-H at –15 °C in
CH2Cl2 afforded 17 in 94%.[17] Further, the alcohol, on oxi-
dation with Dess–Martin periodinane[18] at 0 °C, furnished
an aldehyde that after aldol reaction with the chlorotita-
nium enolate of N-acyloxazolidinethione, (–)-sparteine at
0 °C gave aldol adduct 18 in 85% yield (Ͼ 98:2).[19] The
chiral auxiliary was reductively removed with NaBH4 to
form 1,3-diol 19 in 89% yield (Scheme 2).[20] The primary
alcohol was protected as triethylsilyl (TES) ether 20 in 86%
yield, and the secondary alcohol was converted into xan-
thate 21 in 94% yield by using NaH, CS2 and MeI. The
xanthate was treated with Bu3SnH and a catalytic amount
of azobisisobutyronitrile (AIBN) in toluene under Barton–
McCombie deoxygenation reaction conditions to obtain re-
quired compound 22 in 87% yield.[21] The selective depro-
tection of the TES group was successfully achieved with p-
toluenesulfonic acid (p-TSA; catalytic amount) in CH2Cl2
to give 23 in 84% yield. Alcohol 23 was converted into the
corresponding acid by following a two-step sequence. The
alcohol was converted into an aldehyde by Dess–Martin
Figure 2. Retrosynthetic analysis.
Results and Discussion
As mentioned in Scheme 1, key fragment 3, which con- periodinane followed by a Pinnick oxidation to furnish de-
tains all the required stereocenters of spirolactam 2, was sired acid 24 in 85% yield over two steps.[22]
prepared mainly through desymmetrization of bicyclic ole-
Our next task was spirolactamization of compound 3,
fin 5 by using Brown’s chiral hydroboration with (+)-diiso- which could be obtained from acid 24 (Scheme 3). Further-
pinocamphenylborane.[10] Chiral bicyclic alcohol 6 was con- more, the acid was converted into amide 25 in 85% yield
verted into exo-alkylated bicyclic lactone 7 by pyridinium- by using ethyl chloroformate followed by aqueous NH3.
chlorochromate-mediated oxidation reaction, Baeyer-Vil- The PMB group was selectively deprotected by using 2,3-
liger reaction,[11] and alkylation reaction with MeI. The re- dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) under stan-
ductive opening of exo-alkylated bicyclic lactone 7 with dard conditions to afford secondary alcohol 26 in 96%
lithium aluminium hydride afforded triol 4,[12] which has yield. Oxidation of the secondary alcohol with Dess–Mar-
been used as a main building block in the synthesis of many tin periodinane afforded keto compound 3 in 83% yield.
natural products containing polypropionate units in our The cleavage of the silyl group present in the keto com-
laboratory.[9] Triol 4 was converted into corresponding acet- pound with HF in CH3CN followed by cyclization fur-
onide 8 by using 2,2-dimethoxypropane and a catalytic nished spirolactam fragment 27 with the natural configura-
amount of camphor sulfonic acid (CSA).[13] The resulting tion at C37 with high fidelity in 80% yield. Finally, depro-
2
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The C31–C41 Spirolactam Fragment of Sanglifehrin A
Scheme 1. Synthesis of intermediate 14.
tection of the benzyl ether with Pd(OH)2 in MeOH under
a hydrogen atmosphere provided diol 2 in 86% yield. The
spectral (1H, 13C NMR, and IR) and analytical data {[α]2D7
= –57.4 (c = 0.45, CHCl3)} of spiro fragment 2 were in
good agreement with the reported values.[5c]
Experimental Section
General Remarks: Air- and/or moisture-sensitive reactions were
carried out in anhydrous solvents under an atmosphere of argon in
oven- or flame-dried glassware. All anhydrous solvents were dis-
tilled prior to use: THF, benzene, toluene, and diethyl ether from
Na and benzophenone; CH2Cl2, dimethyl sulfoxide (DMSO), di-
methylformamide (DMF), and hexane from CaH2; MeOH and
EtOH from Mg cake. Commercial reagents were used without puri-
fication. Column chromatography was carried out by using silica
gel (60–120 mesh). TOF analyzer technique was used for the
HRMS measurement. 1H and 13C NMR chemical shifts are re-
ported relative to tetramethylsilane. The following abbreviations are
used to designate signal multiplicity: s = singlet, d = doublet, t =
triplet, q = quartet, m = multiplet, br. = broad.
Conclusions
In conclusion, we have developed an efficient and highly-
stereoselective synthesis for the spirolactam segment of the
extremely potent immunosuppressant sanglifehrin A. The
synthesis of the C31–C41 fragment of sanglifehrin A (1)
was successfully accomplished by following our own desym-
metrization strategy, followed by Sharpless asymmetric
epoxidation reaction, Crimmins syn aldol reaction, Barton–
McCombie deoxygenation reaction, and spirolactamization
under aqueous HF conditions in a 21-step longest linear
sequence with 6.3% overall yield starting from known triol
4. Attempts toward the peptide macrolactone core and cou-
pling with the spirolactam segment to synthesize sangli-
fehrin A is in progress and will be reported in due course.
(2S,3S,4R,5S,6S)-5-(Benzyloxy)-2,4,6-trimethylheptane-1,3,7-triol
(4): To an ice-cooled suspension of LiAlH4 (5.1 g, 134.38 mmol)
in THF (60 mL) at 0 °C, was added methylated lactone 7 (13.0 g,
44.82 mmol) in THF (50 mL) under a nitrogen atmosphere. The
reaction mixture was allowed to stir at room temperature. After
complete conversion of the reaction (confirmed by TLC), it was
again cooled to 0 °C and quenched with a saturated solution of
Na2SO4 (60 mL). After stirring at room temperature for 5 h, the
solid was filtered off through a pad of Celite and washed with ethyl
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Scheme 2. Synthesis of intermediate 24.
acetate (3ϫ 50 mL). The filtrate was dried with Na2SO4 and evapo-
rated under reduced pressure. The crude product was purified by
column chromatography with silica gel (hexane/ethyl acetate = 1:1)
to afford triol 4 (12.2 g, 92%) as a viscous liquid. [α]2D7 = –3.1 (c =
(2S,3S,4S)-3-(Benzyloxy)-2-methyl-4-[(4S,5S)-2,2,5-trimethyl-1,3-di-
oxan-4-yl]pentan-1-ol (8): To a stirred solution of triol 4 (11.0 g,
37.16 mmol) in CH2Cl2 (80 mL) was added 2,2-dimethoxy propane
(13.7 mL, 111.48 mmol) followed by a catalytic amount of CSA
1.3, CHCl ). IR (neat): ν = 3508, 1462, 1036 cm–1 1H NMR (100 mg). The mixture was stirred at ambient temperature for
.
˜
3
(CDCl3, 300 MHz): δ = 7.38–7.24 (m, 5 H), 4.67 (ABq, J = 10.6 Hz,
2 H), 3.87–3.73 (m, 2 H), 3.70–3.50 (m, 4 H), 2.07–1.97 (m, 1 H),
30 min. The reaction mixture was quenched with saturated sodium
hydrogen carbonate solution (60 mL). The organic layer was sepa-
1.92–1.77 (m, 2 H), 1.13 (d, J = 6.8 Hz, 3 H), 0.96 (d, J = 6.8 Hz, rated and the aqueous layer extracted with CH2Cl2 (3ϫ 50 mL).
3 H), 0.73 (d, J = 6.8 Hz, 3 H) ppm. 13C NMR (CDCl3, 75 MHz): The combined organic layer was washed with brine (2ϫ 70 mL),
δ = 137.4, 128.7, 128.2, 127.9, 88.7, 69.2, 65.4, 37.9, 37.3, 35.5,
14.7, 13.3, 11.6 ppm. HRMS: calcd. for C17H28NaO4 [M + Na]+
319.1885; found 319.1874.
dried with anhydrous Na2SO4 and the solvent evaporated under
reduced pressure. The residue was purified by column chromatog-
raphy with silica gel (hexane/ethyl acetate = 9:1) to furnish pro-
4
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The C31–C41 Spirolactam Fragment of Sanglifehrin A
Scheme 3. Accomplishment of the C31–C41 spirolactam fragment 2 of sanglifehrin A.
tected diol 8 (11.2 g, 89%) as a white solid, m.p. 96–98 °C. [α]2D7
=
the reaction (monitored by TLC), the solvent was removed under
reduced pressure and the residue purified by column chromatog-
raphy with silica gel (hexane/ethyl acetate = 10:1) to obtain Wittig
+26.0 (c = 1.0, CHCl ). IR (neat): ν = 3453, 2962, 2928, 1457,
˜
3
1382, 1199, 1098, 1064 cm–1. 1H NMR (CDCl3, 300 MHz): δ =
7.38–7.22 (m, 5 H), 4.65 (ABq, J = 11.3 Hz, 2 H), 3.93–3.81 (m, 2 product 9 (10.3 g, 90%) as a pale yellow liquid. [α]2D7 = –9.0 (c =
1
H), 3.73–3.42 (m, 4 H), 2.95–2.49 (br. s, 1 H), 2.06–1.80 (m, 3 H),
1.0, CHCl ). IR (neat): ν = 2975, 2932, 1718, 1651, 1456 cm–1. H
˜
3
1.37 (s, 3 H), 1.36 (s, 3 H), 1.21 (d, J = 7.1 Hz, 3 H), 0.88 (d, J = NMR (CDCl3, 300 MHz): δ = 7.39–7.23 (m, 5 H), 7.09 (dd, J =
6.8 Hz, 3 H), 0.72 (d, J = 6.6 Hz, 3 H) ppm. 13C NMR (CDCl3,
75 MHz): δ = 138.3, 128.4, 127.5, 126.9, 97.9, 85.5, 75.3, 73.3, 66.1,
64.1, 37.3, 36.1, 30.2, 29.7, 19.4, 16.3, 12.4, 9.8 ppm. HRMS: calcd.
for C20H32NaO4 [M + Na]+ 359.2198; found 359.2185.
15.8, 8.5 Hz, 1 H), 5.83 (d, J = 15.8 Hz, 1 H), 4.64 (ABq, J =
12.0 Hz, 2 H), 4.19 (q, J = 7.1 Hz, 2 H), 3.88 (dd, J = 10.4, 0.9 Hz,
1 H), 3.66 (dd, J = 11.5, 5.0 Hz, 1 H), 3.52–3.39 (m, 2 H), 2.74–
2.62 (m, 1 H), 1.92–1.55 (m, 2 H), 1.37 (s, 3 H), 1.35 (s, 3 H), 1.30
(t, J = 7.1 Hz, 3 H), 1.21 (d, J = 6.9 Hz, 3 H), 0.82 (d, J = 6.9
HZ Hz, 3 H), 0.68 (d, J = 6.6 Hz, 3 H) ppm. 13C NMR (CDCl3,
75 MHz): δ = 166.6, 150.5, 138.8, 128.2, 127.2, 126.8, 121.4, 97.9,
83.0, 74.6, 73.2, 66.1, 60.1, 39.6, 37.5, 30.1, 29.8, 19.4, 17.6, 14.2,
12.3, 9.3 ppm. HRMS: calcd. for C24H36NaO5 [M + Na]+
427.2455; found 427.2445.
Ethyl (4S,5S,6S,E)-5-(Benzyloxy)-4-methyl-6-[(4S,5S)-2,2,5-tri-
methyl-1,3-dioxan-4-yl]hept-2-enoate (9): To a solution of oxalyl
chloride (7.1 g, 56.54 mmol) in CH2Cl2 (30 mL), was added DMSO
(8.8 g, 113.09 mmol) at –78 °C. After 20 min, alcohol (9.5 g,
28.27 mmol) in CH2Cl2 (30 mL) was added to the reaction mixture
and stirred at –78 °C for 45 min. Triethylamine (22.8 g,
226.19 mmol) was added to the reaction mixture and stirred at the
same temperature for a further 45 min. Saturated aqueous NH4Cl
solution (40 mL) was added to the reaction mixture and the layers
were separated. The aqueous layer was extracted with CH2Cl2 (2ϫ
75 mL). The combined organic layer was washed with water
(100 mL) and brine (100 mL), dried with anhydrous Na2SO4 and
concentrated. The crude aldehyde was used for the next reaction
without further purification.
(4S,5S,6S,E)-5-(Benzyloxy)-4-methyl-6-[(4S,5S)-2,2,5-trimethyl-1,3-
dioxan-4-yl]hept-2-en-1-ol (10): To a solution of compound 9
(10.0 g, 24.75 mmol) in CH2Cl2 (50 mL), was added DIBAL-H
(20% in toluene, 35.3 mL, 49.5 mmol) dropwise down the walls of
the flask at –20 °C. After completion of the reaction (monitored
by TLC), it was quenched by addition of methanol (15 mL) at 0 °C
followed by a saturated solution of sodium potassium tartrate
(40 mL), and was stirred at room temperature for 6 h. The organic
layer was separated and the aqueous layer extracted with CH2Cl2
(3ϫ 60 mL). The combined organic layer was washed with brine
(2ϫ 75 mL), dried with anhydrous Na2SO4 and the solvent evapo-
rated under reduced pressure. The crude product was purified by
To a solution of ethyl 2-(triphenylphosphoranylidene)ethanoate
(11.87 g, 34.13 mmol) in benzene (60 mL) at 70 °C, was added the
crude aldehyde in benzene (40 mL). After complete addition, the
reaction mixture was heated to reflux for 3 h. After completion of
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column chromatography with silica gel (hexane/ethyl acetate = 4:1)
138.3, 128.4, 127.6, 127.1, 97.9, 86.0, 75.4, 75.2, 73.1, 66.2, 62.1,
41.7, 39.0, 35.8, 30.2, 29.8, 19.3, 17.1, 12.4, 9.9 ppm. HRMS: calcd.
for C22H36NaO5 [M + Na]+ 403.2455; found 403.2445.
to give allyl alcohol 10 (7.9 g, 88%) as a colorless viscous liquid.
[α]2D7 = +22.0 (c = 1.0, CHCl ). IR (neat): ν = 3384, 2970, 2934,
˜
3
1690, 1456, 1383 cm–1. 1H NMR (CDCl3, 200 MHz): δ = 7.42–7.20
(m, 5 H), 5.87–5.56 (m, 2 H), 4.62 (ABq, J = 11.5 Hz, 2 H), 4.09
(d, J = 4.9 Hz, 2 H), 3.88 (dd, J = 10.6, 1.6 Hz, 1 H), 3.66 (dd, J
= 11.5, 4.9 Hz, 1 H), 3.47 (t, J = 11.5 Hz, 1 H), 3.34 (dd, J = 9.8,
1.6 Hz, 1 H), 2.60–2.42 (m, 1 H), 1.98–1.56 (m, 2 H), 1.37 (s, 6 H),
1.17 (d, J = 6.5 Hz, 3 H), 0.83 (d, J = 7.3 Hz, 3 H), 0.68 (d, J =
6.5 Hz, 3 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 139.0, 133.9,
129.4, 128.2, 127.2, 126.9, 97.9, 83.3, 74.7, 73.3, 66.1, 63.7, 39.3,
37.3, 30.1, 29.8, 19.5, 18.9, 12.3, 9.3 ppm. HRMS: calcd. for
C22H34NaO4 [M + Na]+ 385.2349; found 385.2350.
(3S,4S,5S,6S)-5-(Benzyloxy)-1-(tert-butyldiphenylsilyloxy)-4-
methyl-6-[(4S,5S)-2,2,5-trimethyl-1,3-dioxan-4-yl]heptan-3-ol (13):
Imidazole (1.16 g, 17.10 mmol) and TBDPSCl (4.4 mL,
17.10 mmol) were added to a solution of diol 12 (6.5 g,
17.10 mmol) in CH2Cl2 (50 mL), and the reaction was stirred at
room temperature for 1 h. The reaction was quenched with satu-
rated NaHCO3 solution (40 mL), the aqueous phase was extracted
with CH2Cl2 (3ϫ 20 mL). The combined organic layer was washed
with brine (2ϫ 50 mL), dried with Na2SO4 and the solvents evapo-
rated. Purification of this residue by column chromatography with
silica gel (hexane/ethyl acetate = 9:1) furnished 13 (9.6 g, 90%) as
((2R,3R)-3-{(2R,3R,4S)-3-(Benzyloxy)-4-[(4S,5S)-2,2,5-trimethyl-
1,3-dioxan-4-yl]pentan-2-yl}oxiran-2-yl)methanol (11): To a stirred
mixture of 4 Å molecular sieves (5.0 g) in CH2Cl2 (40 mL),
Ti(OiPr)4 (0.7 mL, 2.5 mmol) and d-(–)-diethyl tartrate (0.5 mL,
3.2 mmol) were added at –20 °C. The reaction mixture was stirred
vigorously for 30 min. Allyl alcohol (7.8 g, 21.54 mmol) dissolved
in CH2Cl2 (30 mL) was added to the reaction mixture at the same
temperature and stirred again for 30 min, followed by addition of
tert-butyl hydroperoxide (4.26 g, 9.4 mL, 47.4 mmol). The reaction
mixture was stirred at –20 °C for an additional 48 h. After comple-
tion of the reaction (monitored by TLC), the reaction mixture was
filtered through Celite and washed with CH2Cl2 (3ϫ 40 mL). The
filtrate was quenched by the addition of water (14 mL), followed
by addition of 30% NaOH solution (6.0 mL) that was then satu-
rated with NaCl. The reaction mixture was stirred at room tem-
perature for 2 h. The organic layer was separated and the aqueous
phase extracted with CH2Cl2 (3ϫ 50 mL). The combined organic
layer was washed with brine (100 mL), dried with anhydrous
Na2SO4 and concentrated under reduced pressure. The residue was
purified by column chromatography with silica gel (hexane/ethyl
acetate = 5:2) to afford epoxy alcohol 11 (7.5 g, 92%) as a colorless
a colorless liquid. [α]2D7 = –15.0 (c = 1.0, CHCl ). IR (neat): ν =
˜
3
3444, 2924, 2854, 1462 cm–1. 1H NMR (CDCl3, 300 MHz): δ =
7.76–7.74 (m, 4 H), 7.46–7.21 (m, 11 H), 4.63 (ABq, J = 11.5 Hz,
2 H), 4.10–3.99 (m, 1 H), 3.96–3.79 (m, 3 H), 3.68 (dd, J = 11.5,
5.0 Hz, 1 H), 3.54–3.40 (m, 2 H), 2.09–1.79 (m, 4 H), 1.75–1.56 (m,
1 H), 1.38 (s, 3 H), 1.34 (s, 3 H), 1.13–1.0 (m, 12 H), 0.95 (d, J =
6.8 Hz, 3 H), 0.67 (d, J = 6.6 Hz, 3 H) ppm. 13C NMR (CDCl3,
75 MHz): δ = 138.9, 135.5, 129.6, 128.2, 127.6, 127.2, 126.8, 97.9,
84.3, 74.7, 73.2, 71.6, 66.2, 62.7, 41.1, 37.9, 36.0, 30.2, 29.8, 26.7,
19.3, 19.0, 15.0, 12.3, 9.9 ppm. HRMS: calcd. for C38H54NaO5Si
[M + Na]+ 641.3632; found 641.3633.
(S)-5-{(2R,3R,4S)-3-(Benzyloxy)-4-[(4S,5S)-2,2,5-trimethyl-1,3-di-
oxan-4-yl]pentan-2-yl}-2,2,3,3,10,10-hexamethyl-9,9-diphenyl-4,8-di-
oxa-3,9-disilaundecane (14): To an ice-cooled solution of 13 (8.0 g,
12.94 mmol) in CH2Cl2 (60 mL), tert-butyldimethylsilyl trifluoro-
methanesulfonate (TBSOTf; 4.4 mL, 19.41 mmol) and 2,6-lutidine
(2.25 mL, 19.41 mmol) were added and the reaction mixture was
slowly warmed to ambient temperature. After stirring for 1 h at the
same temperature the reaction was quenched with saturated NH4Cl
(40 mL). The organic layer was separated and the aqueous layer
extracted with CH2Cl2 (3ϫ 40 mL). The combined organic layer
was washed with brine (75 mL), dried with Na2SO4 and the sol-
vents evaporated. The resulting residue was purified by column
chromatography with silica gel (hexane/ethyl acetate = 20:1) to af-
viscous liquid. [α]2D7 = +48.0 (c = 3.0, CHCl ). IR (neat): ν = 3380,
˜
3
2972, 1450, and 1199 cm–1. 1H NMR (CDCl3, 300 MHz): δ = 7.38–
7.22 (m, 5 H), 4.65 (ABq, J = 11.7 Hz, 2 H), 3.99–3.82 (m, 2 H),
3.67 (dd, J = 11.3, 5.1 Hz, 1 H), 3.62–3.35 (m, 3 H), 3.13 (dd, J =
7.9, 2.0 Hz, 1 H), 2.89–2.83 (m, 1 H), 2.19–2.06 (m, 1 H), 1.98–
1.62 (m, 2 H), 1.37 (s, 3 H), 1.36 (s, 3 H), 1.09 (d, J = 7.1 Hz, 3
H), 0.88 (d, J = 6.8 Hz, 3 H), 0.75 (d, J = 6.8 Hz, 3 H) ppm. 13C
NMR (CDCl3, 75 MHz): δ = 138.9, 128.2, 127.2, 126.7, 97.8, 82.8,
74.7, 73.2, 66.1, 62.1, 56.3, 38.0, 37.3, 30.1, 29.8, 19.4, 15.0, 12.3,
9.6 ppm. HRMS: calcd. for C22H34NaO5 [M + Na]+ 401.2298;
found 401.2296.
ford 14 (8.1 g, 85%) as a colorless liquid. [α]2D7 = –10.0 (c = 1.2,
1
CHCl ). IR (neat): ν = 2921, 2851, 1219 cm–1. H NMR (CDCl ,
˜
3
3
300 MHz): δ = 7.81–7.71 (m, 4 H), 7.54–7.27 (m, 11 H), 4.63 (ABq,
J = 10.6 Hz, 2 H), 3.99–3.68 (m, 5 H), 3.58–3.48 (m, 1 H), 3.43
(dd, J = 9.8, 3.0 Hz, 1 H), 2.29–2.09 (m, 1 H), 2.07–1.69 (m, 4 H),
1.46 (s, 3 H), 1.40 (s, 3 H), 1.22–1.09 (m, 12 H), 1.03–0.85 (m, 15
H), 0.13 (s, 3 H), 0.10 (s, 3 H) ppm. 13C NMR (CDCl3, 75 MHz):
δ = 137.4, 135.5, 135.4, 129.5, 128.5, 127.9, 127.5, 98.6, 88.2, 77.1,
76.1, 69.4, 69.3, 61.9, 42.3, 37.2, 34.9, 30.6, 29.8, 26.8, 25.8, 19.1,
17.9, 13.3, 11.8, 11.0, –4.3, –4.7 ppm. HRMS: calcd. for
C44H68NaO5Si2 [M + Na]+ 755.4502; found 755.4508.
(3S,4S,5S,6S)-5-(Benzyloxy)-4-methyl-6-[(4S,5S)-2,2,5-trimethyl-
1,3-dioxan-4-yl]heptane-1,3-diol (12): To a stirred solution of epox-
ide 11 (7.3 g, 19.31 mmol) in THF (40 mL) was added Red-Al (70%
w/w in toluene, 33.5 mL, 57.93 mmol) dropwise at –20 °C. The re-
action mixture was slowly allowed to warm to room temperature
and stirred for 2 h. After complete conversion (monitored by TLC),
the reaction mixture was quenched with saturated NH4Cl (30 mL)
at 0 °C, and the aqueous phase was extracted with ethyl acetate
(3ϫ 30 mL). The combined organic layer was washed with brine
(2ϫ 30 mL), dried with Na2SO4 and evaporated, and the residue
was purified by column chromatography with silica gel (hexane/
(2S,3S,4R,5R,6R,7S)-5-(Benzyloxy)-7-(tert-butyldimethylsilyloxy)-
9-(tert-butyldiphenylsilyloxy)-2,4,6-trimethylnonane-1,3-diol (15):
To a stirred solution of 14 (8.0 g, 10.92 mmol) in CH3CN (50 mL)
at 0 °C, was added CuCl2·2H2O (2.95 g, 16.39 mmol). The reaction
mixture was allowed to stir for 30 min at the same temperature.
After complete conversion (monitored by TLC), the reaction was
ethyl acetate = 2:1) to give 12 (6.6 g, 89%) as a viscous yellow quenched by a saturated NaHCO3 solution (30 mL). The organic
liquid. [α]2D7 = +5.0 (c = 1.0, CHCl ). IR (neat): ν = 3408, 2952,
solvent was removed under reduced pressure and the aqueous
˜
3
2927, 1457, 1383 cm–1. 1H NMR (CDCl3, 300 MHz): δ = 7.43–7.25 phase extracted with ethyl acetate (3ϫ 60 mL). The combined or-
(m, 5 H), 4.67 (s, 2 H), 3.98–3.64 (m, 5 H), 3.57–3.45 (m, 1 H), ganic layer was washed with brine (100 mL), dried with Na2SO4
3.43–3.36 (m, 1 H), 3.29–3.16 (br. s, 1 H), 2.10–1.78 (m, 4 H), 1.74–
1.59 (m, 1 H), 1.38 (s, 3 H), 1.35 (s, 3 H), 0.97 (t, J = 7.3 Hz, 6 H), by column chromatography with silica gel (hexane/ethyl acetate =
0.70 (d, J = 6.8 Hz, 3 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 4:1) to give 15 (6.8 g, 90%) as a colorless viscous liquid. [α]2D7
and evaporated under reduced pressure. The residue was purified
=
6
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O21684
/KAP1
Date: 09-04-13 17:01:43
Pages: 11
The C31–C41 Spirolactam Fragment of Sanglifehrin A
–35.2 (c = 1.1, CHCl ). IR (neat): ν = 3450, 2956, 2928, 1463,
135.4, 133.9, 130.7, 129.4, 129.3, 128.2, 127.5, 127.4, 127.3, 113.6,
˜
3
1253 cm–1. H NMR (CDCl3, 300 MHz): δ = 7.81–7.71 (m, 4 H), 85.3, 83.2, 75.0, 73.8, 68.8, 66.1, 61.7, 55.1, 42.2, 39.4, 38.9, 35.0,
1
7.56–7.34 (m, 9 H), 7.33–7.25 (m, 2 H), 4.62 (ABq, J = 11.3 Hz, 2 26.8, 25.8, 19.1, 18.0, 15.2, 13.0, 11.2, –4.1, –4.6 ppm. HRMS:
H), 4.27–4.15 (m, 2 H), 3.99–3.87 (m, 2 H), 3.83–3.69 (m, 4 H),
3.45 (dd, J = 10.6, 1.5 Hz, 1 H), 2.28–2.13 (m, 1 H), 2.04–1.71 (m,
4 H), 1.25 (d, J = 7.5 Hz, 3 H), 1.12 (s, 9 H), 0.94 (s, 9 H), 0.90 (d,
J = 6.8 Hz, 3 H), 0.82 (d, J = 6.8 Hz, 3 H), 0.12 (s, 3 H), 0.03 (s,
3 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 137.4, 135.6, 135.5,
133.9, 133.8, 129.5, 128.5, 127.9, 127.5, 88.2, 77.1, 76.1, 69.4, 69.2,
61.9, 42.3, 37.3, 34.9, 26.9, 25.8, 19.1, 17.9, 13.3, 11.8, 11.0, –4.3,
–4.7 ppm. HRMS: calcd. for C41H64NaO5Si2 [M + Na]+ 715.4184;
found 715.4186.
calcd. for C49H72NaO6Si2 [M + Na]+ 835.4759; found 835.4749.
(2S,3R,4S,5S,6R,7R,8R,9S)-1-[(S)-4-Benzyl-2-thioxothiazolidin-3-
yl]-7-(benzyloxy)-9-(tert-butyldimethylsilyloxy)-11-(tert-butyldi-
phenylsilyloxy)-2-ethyl-3-hydroxy-5-(4-methoxybenzyloxy)-4,6,8-tri-
methylundecan-1-one (18): To a stirred solution of alcohol 16 (6.5 g,
8.0 mmol) in CH2Cl2 (60 mL), Dess–Martin periodinane (5.09 g,
12.0 mmol) was added at 0 °C under a nitrogen atmosphere. Stir-
ring was continued for 2 h at room temperature. After complete
conversion of the starting material (monitored by TLC) the reac-
tion was quenched with a saturated NaHCO3 solution (30 mL) and
diluted with CH2Cl2 (20 mL). The organic layer was separated and
the aqueous layer extracted with CH2Cl2 (2ϫ 50 mL). The com-
bined organic layer was washed with brine (2ϫ 75 mL), dried with
anhydrous Na2SO4 and concentrated under reduced pressure to get
a crude product that was quickly purified by column chromatog-
raphy with silica gel (hexane/ethyl acetate = 10:1) to obtain alde-
hyde 18 (6.4 g) as a colorless liquid that was immediately used for
the next reaction.
(5S)-5-{(2R,3R,4S)-3-(Benzyloxy)-4-[(4S,5S)-2-(4-methoxyphenyl)-
5-methyl-1,3-dioxan-4-yl]pentan-2-yl}-2,2,3,3,10,10-hexamethyl-9,9-
diphenyl-4,8-dioxa-3,9-disilaundecane (16): To a stirred solution of
diol 15 (6.6 g, 9.53 mmol) in CH2Cl2 (60 mL), p-methoxyphenyl
(PMP)-CH(OMe)2 (1.9 mL, 11.44 mmol) was added followed by a
catalytic amount of CSA (48 mg). The reaction mixture was stirred
at room temperature for 1 h and then quenched by the addition
of a saturated NaHCO3 solution (30 mL). The organic layer was
separated and the aqueous layer extracted with CH2Cl2 (3 ϫ
50 mL). The combined organic layer was washed with brine (2ϫ
20 mL), dried with Na2SO4, and evaporated under reduced pres-
sure. The crude product was purified by column chromatography
with silica gel (hexane/ethyl acetate = 20:1) to give 16 (7.2 g, 92%)
TiCl4 (0.83 mL, 7.65 mmol) was added slowly to a solution of (R)-
1-(4-benzyl-2-thioxothiazolidin-3-yl) propan-1-one (1.94 g,
6.953 mmol) in CH2Cl2 (15 mL) at 0 °C and stirred for 5 min. To
this yellow suspension, (–)-sparteine (4.0 mL, 17.38 mmol) was
added. After stirring for 20 min, to the dark red enolate, freshly
prepared aldehyde (6.4 g) dissolved in CH2Cl2 (20 mL) was added
slowly at 0 °C. After stirring for 2 h at the same temperature, the
reaction mixture was quenched with saturated NH4Cl (25 mL). The
organic layer was separated and the aqueous layer extracted with
CH2Cl2 (3ϫ 60 mL). The combined organic layer was washed with
brine (100 mL), dried with Na2SO4, evaporated under reduced
pressure, and purified by column chromatography over silica gel
(hexane/ethyl acetate = 9:1) to afford 18 (7.4 g, 85%) as a pale
as a colorless liquid. [α]2D7 = +10.7 (c = 0.5, CHCl ). IR (neat): ν =
˜
3
2957, 2931, 1615, 1462, 1250 cm–1. 1H NMR (CDCl3, 300 MHz):
δ = 7.70–7.60 (m, 4 H), 7.43–7.20 (m, 13 H), 6.88 (d, J = 8.5 Hz,
2 H), 5.28 (s, 1 H), 4.56 (ABq, J = 11.7 Hz, 2 H), 4.26–4.19 (m, 1
H), 4.02 (dd, J = 11.1, 4.5 Hz, 1 H), 3.83–3.71 (m, 6 H), 3.49 (dd,
J = 9.8, 3.4 Hz, 1 H), 3.37 (t, J = 10.9 Hz, 1 H), 2.23–1.91 (m, 4
H), 1.69–1.53 (m, 1 H), 1.10–0.98 (m, 15 H), 0.83 (s, 9 H), 0.51 (d, J
= 6.6 Hz, 3 H), 0.04 (s, 3 H), 0.01 (s, 3 H) ppm. 13C NMR (CDCl3,
75 MHz): δ = 159.7, 139.5, 135.5, 135.4, 134.1, 131.5, 129.4, 129.3,
128.1, 127.5, 127.3, 126.9, 126.6, 113.5, 100.7, 82.9, 81.7, 75.1, 73.2,
67.8, 61.2, 55.2, 41.2, 36.7, 35.8, 30.3, 26.9, 25.8, 19.2, 18.0, 11.8,
11.4, 10.5, –4.1, –4.5 ppm. HRMS: calcd. for C49H70NaO6Si2 [M
+ Na]+ 833.4603; found 833.4596.
yellow liquid. [α]2D7 = +32.2 (c = 1.0, CHCl ). IR (neat): ν = 3456,
˜
3
2924, 2853, 1702, 1513, 1462 cm–1. 1H NMR (CDCl3, 300 MHz):
δ = 7.78–7.68 (m, 4 H), 7.54–7.28 (m, 16 H), 7.09 (d, J = 8.3 Hz,
2 H), 6.85 (d, J = 8.3 Hz, 2 H), 4.94–4.81 (m, 1 H), 4.73–4.52 (m,
4 H), 4.39 (d, J = 9.0 Hz, 1 H), 4.28 (d, J = 10.5 Hz, 2 H), 3.96–
3.82 (m, 5 H), 3.80–3.67 (m, 2 H), 3.32–3.20 (m, 2 H), 3.16–3.05
(m, 1 H), 2.88 (d, J = 11.3 Hz, 1 H), 2.33–2.19 (m, 1 H), 2.17–1.72
(m, 6 H), 1.29 (d, J = 6.8 Hz, 3 H), 1.18–1.05 (m, 12 H), 1.02 (d,
J = 7.5 Hz, 3 H), 0.91 (t, J = 6.8 Hz, 3 H), 0.86 (s, 9 H), 0.10 (s, 3
H), 0.08 (s, 3 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 201.0,
175.9, 158.9, 138.6, 136.6, 135.5, 135.4, 133.9, 130.3, 129.4, 128.7,
128.2, 127.5, 127.3, 127.0, 113.6, 85.1, 83.4, 74.7, 73.9, 73.8, 70.2,
68.6, 61.3, 55.1, 49.0, 41.9, 40.9, 39.5, 36.6, 35.3, 26.8, 25.8, 19.1,
18.0, 16.6, 14.7, 12.5, 12.4, 11.3, –4.1, –4.5 ppm. HRMS: calcd. for
C63H87NNaO7S2Si2 [M + Na]+ 1112.5360; found 1112.5357.
(2S,3S,4R,5R,6R,7S)-5-(Benzyloxy)-7-(tert-butyldimethylsilyloxy)-
9-(tert-butyldiphenylsilyloxy)-3-(4-methoxybenzyloxy)-2,4,6-tri-
methylnonan-1-ol (17): DIBAL-H (20 % in toluene, 18.5 mL,
25.92 mmol) was added to a stirred solution of PMP-acetal 15
(7.0 g, 8.64 mmol) in CH2Cl2 (70 mL) at –20 °C under an argon
atmosphere. The reaction mixture was allowed to stir for 30 min at
the same temperature. After complete conversion (monitored by
TLC) the reaction was quenched by the addition of methanol
(10 mL), followed by a saturated solution of sodium potassium tar-
trate (40 mL) and stirred for 5 h. The organic layer was separated
and the aqueous phase extracted with CH2Cl2 (3ϫ 50 mL). The
combined organic layer was washed with brine (100 mL), dried
with Na2SO4, filtered and evaporated under reduced pressure. The
crude product was purified by column chromatography with silica
(2R,3S,4S,5S,6R,7R,8R,9S)-7-(Benzyloxy)-9-(tert-butyldimethylsil-
yloxy)-11-(tert-butyldiphenylsilyloxy)-2-ethyl-5-(4-methoxybenz-
gel (hexane/ethyl acetate = 7:1) to obtain alcohol 16 (6.6 g, 94%) yloxy)-4,6,8-trimethylundecane-1,3-diol (19): To a stirred solution
as a colorless liquid. [α]2D7 = +3.5 (c = 0.5, CHCl ). IR (neat): ν =
of aldol adduct 18 (7.0 g, 6.42 mmol) in MeOH (40 mL) at 0 °C
˜
3
3485, 2957, 2926, 1464, 1249 cm–1. 1H NMR (CDCl3, 300 MHz): NaBH4 (475 mg, 12.85 mmol) was added portion wise. The reac-
δ = 7.75–7.66 (m, 4 H), 7.49–7.34 (m, 6 H), 7.33–7.28 (m, 5 H), tion mixture was allowed to stir for 1 h at room temperature and
7.12 (d, J = 8.3 Hz, 2 H), 6.83 (d, J = 8.3 Hz, 2 H), 4.59 (ABq, J then quenched with saturated aqueous NH4Cl (20 mL). The sol-
= 11.3 Hz, 2 H), 4.50 (ABq, J = 10.6 Hz, 2 H), 4.30–4.22 (m, 1 H),
3.90–3.79 (m, 4 H), 3.78–3.57 (m, 3 H), 3.33–3.26 (dd, J = 7.5,
vent was removed under reduced pressure and the resulting residue
was diluted with water (20 mL). The organic layer was separated
5.3 Hz, 1 H), 2.99–2.91 (m, 1 H), 2.17–1.81 (m, 4 H), 1.80–1.65 (m, and the aqueous layer extracted with ethyl acetate (3ϫ 60 mL).
1 H), 1.20 (d, J = 6.8 Hz, 3 H),1.07 (s, 9 H), 0.97 (d, J = 6.8 Hz, 3
H), 0.94 (d, J = 6.8 Hz, 3 H), 0.89 (s, 9 H), 0.08 (s, 3 H), 0.01 (s,
3 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 159.0, 138.6, 135.5,
The combined organic layers were washed with brine (100 mL),
dried with Na2SO4 and evaporated under reduced pressure. The
crude product was purified by column chromatography with silica
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O21684
/KAP1
Date: 09-04-13 17:01:43
Pages: 11
J. S. Yadav, D. K. Mohapatra et al.
FULL PAPER
gel (hexane/ethyl acetate = 4:1) to afford 19 (5.1 g, 89%) as a vis-
7.55–7.34 (m, 11 H), 7.28 (d, J = 8.3 Hz, 2 H), 6.93 (d, J = 8.3 Hz,
2 H), 4.74–4.54 (m, 4 H), 4.29–4.20 (m, 1 H), 3.96–3.77 (m, 7 H),
cous colorless liquid. [α]2D7 = +5.2 (c = 1.0, CHCl ). IR (neat): ν =
˜
3
3442, 2956, 2930, 1513, 1463, 1250 cm–1
.
1H NMR (CDCl3, 3.70 (dd, J = 10.5, 3.7 Hz, 1 H), 3.61 (dd, J = 9.8, 5.2 Hz, 1 H),
300 MHz): δ = 7.72–7.64 (m, 4 H), 7.47–7.23 (m, 11 H), 7.11 (d, J 3.41 (t, J = 6.8 Hz, 1 H), 2.65 (s, 3 H), 2.30–2.01 (m, 3 H), 1.94–
= 8.3 Hz, 2 H), 6.83 (d, J = 8.3 Hz, 2 H), 4.71–4.62 (m, 2 H), 4.55– 1.67 (m, 3 H), 1.63–1.36 (m, 2 H), 1.21 (d, J = 6.8 Hz, 3 H), 1.15
4.37 (m, 4 H), 4.30–4.21 (m, 1 H), 3.86–3.69 (m, 5 H), 3.65 (d, J (s, 9 H), 1.11 (d, J = 7.5 Hz, 3 H), 1.09–1.0 (m, 12 H), 0.95–0.87
= 7.5 Hz, 1 H), 3.42–3.15 (m, 2 H), 2.17–1.61 (m, 6 H), 1.43–1.25 (m, 12 H), 0.66 (q, J = 7.5 Hz, 6 H), 0.15–0.10 (m, 6 H) ppm. 13C
(m, 2 H), 1.13 (d, J = 6.8 Hz, 3 H), 1.05 (s, 9 H), 1.01 (d, J =
NMR (CDCl3, 75 MHz): δ = 214.3, 158.6, 139.1, 135.5, 134.1,
6.7 Hz, 3 H), 0.94 (t, J = 6.8 Hz, 3 H), 0.87 (s, 9 H), 0.68 (d, J = 133.9, 129.4, 128.6, 128.0, 127.5, 127.2, 127.0, 113.4, 87.5, 85.2,
6.0 Hz, 3 H), 0.07 (s, 3 H), 0.01 (s, 3 H) ppm. 13C NMR (CDCl3,
75 MHz): δ = 158.9, 135.5, 133.9, 129.5, 129.2, 128.8, 128.5, 127.5,
78.5, 74.7, 71.6, 68.9, 62.2, 61.7, 55.2, 44.7, 42.0, 38.5, 37.9, 35.1,
26.8, 25.8, 19.8, 19.1, 14.8, 12.3, 12.1, 11.0, 6.8, 4.3, –4.1, –4.7 ppm.
113.6, 84.2, 74.6, 74.4, 68.8, 66.0, 55.2, 41.9, 38.9, 38.0, 33.3, 31.9, HRMS: calcd. for C61H96NaO7S2Si3 [M + Na]+ 1111.5802; found
26.8, 26.0, 19.2, 18.3, 17.4, 13.9, 13.3, 12.2, –3.3, –4.0 ppm. HRMS: 1111.5805.
calcd. for C53H80NaO7Si2 [M + Na]+ 907.5340; found 907.5335.
(7S,8R,9R,10R,11S,12S,14S)-9-(Benzyloxy)-7-(tert-butyldimethylsil-
(6R,7S,8S,9S,10R,11R,12R,13S)-11-(Benzyloxy)-13-(tert-butyldi- yloxy)-14,17,17-triethyl-11-(4-methoxybenzyloxy)-2,2,8,10,12-penta-
methylsilyloxy)-3,3,6-triethyl-9-(4-methoxybenzyloxy)-
8,10,12,18,18-pentamethyl-17,17-diphenyl-4,16-dioxa-3,17-disila-
nonadecan-7-ol (20): TES-Cl (0.9 mL, 5.42 mmol) and imidazole
(615 mg, 9.04 mmol) were added to a solution of diol 19 (4.0 g,
4.52 mmol) in CH2Cl2 (40 mL). After stirring for 1 h, the reaction
was quenched with saturated NaHCO3 solution (25 mL). The or-
ganic layer was separated and the aqueous layer extracted with
CH2Cl2 (2ϫ 40 mL). The combined organic layer was washed with
brine (2ϫ 50 mL), dried with Na2SO4 and evaporated under re-
duced pressure. The residue was purified by column chromatog-
raphy with silica gel (hexane/ethyl acetate = 9:1) to afford 20 (3.9 g,
methyl-3,3-diphenyl-4,16-dioxa-3,17-disilanonadecane (22): Bu3SnH
(0.9 mL, 3.44 mmol) followed by a catalytic amount of AIBN
(20 mg) were added to a stirred solution of xanthate 21 (2.5 g,
2.29 mmol) in toluene (30 mL) and the reaction mixture was heated
to reflux under an incandescent lamp for 8 h. After completion of
the reaction (monitored by TLC), the solvent was evaporated under
reduced pressure. The residue was purified by column chromatog-
raphy with silica gel (hexane/ethyl acetate = 11:1) to obtain 22
(2.0 g, 87%) as a pale yellow liquid. [α]2D7 = –11.5 (c = 1.0, CHCl3).
IR (neat): ν = 2956, 2930, 1513, 1462, 1248 cm–1 1H NMR
.
˜
(CDCl3, 300 MHz): δ = 7.80–7.69 (m, 4 H), 7.53–7.37 (m, 8 H),
7.36–7.28 (m, 3 H), 7.20 (d, J = 8.3 Hz, 2 H), 6.88 (d, J = 8.3 Hz,
2 H), 4.61 (ABq, J = 11.3 Hz, 2 H), 4.51 (ABq, J = 10.6 Hz, 2 H),
86%) as a pale yellow liquid. [α]2D7 = –6.0 (c = 1.0, CHCl3). IR
1
(neat): ν = 3499, 2956, 2928, 1463, 1219 cm–1. H NMR (CDCl ,
˜
3
300 MHz): δ = 7.77–7.69 (m, 4 H), 7.51–7.36 (m, 7 H), 7.34–7.27 4.32–4.24 (m, 1 H), 3.95–3.82 (m, 4 H), 3.79–3.60 (m, 2 H), 3.49–
(m, 4 H), 7.20 (d, J = 9.0 Hz, 2 H), 6.87 (d, J = 9.0 Hz, 2 H), 4.63 3.38 (m, 2 H), 3.26 (dd, J = 7.5, 3.7 Hz, 1 H), 2.15–1.64 (m, 5 H),
(ABq, J = 11.3 Hz, 2 H), 4.55 (ABq, J = 10.6 Hz, 2 H), 4.32–4.23 1.57–1.34 (m, 5 H), 1.21 (d, J = 7.5 Hz, 3 H), 1.12 (s, 9 H), 1.08–
(m, 1 H), 3.94–3.80 (m, 7 H), 3.78–3.67 (m, 2 H), 3.33 (dd, J = 7.5, 0.94 (m, 15 H), 0.93–0.88 (m, 12 H), 0.66 (q, J = 7.5 Hz, 6 H), 0.10
5.3 Hz, 1 H), 2.20–1.89 (m, 4 H), 1.81–1.68 (m, 2 H), 1.60–1.33 (m, (s, 6 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 158.6, 139.0, 135.5,
2 H), 1.21 (d, J = 6.8 Hz, 3 H), 1.10 (s, 9 H), 1.07–0.96 (m, 15 H),
0.89 (s, 9 H), 0.84 (d, J = 6.8 Hz, 3 H), 0.68 (q, J = 7.5 Hz, 6 H),
134.1, 134.0, 131.8, 129.4, 128.7, 128.0, 127.5, 127.2, 127.0, 113.4,
85.9, 82.1, 74.6, 72.4, 68.9, 64.7, 62.1, 55.2, 42.2, 39.7, 37.8, 35.1,
0.09 (s, 3 H), 0.01 (s, 3 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 34.8, 33.2, 31.4, 26.9, 25.8, 19.1, 17.9, 16.7, 13.7, 11.2, 11.1, 6.8,
158.8, 139.1, 135.5, 135.4, 134.0, 131.1, 129.4, 128.8, 128.0, 127.5,
127.1, 127.0, 113.5, 85.9, 81.7, 74.4, 74.3, 72.6, 68.9, 64.1, 61.9,
55.2, 43.8, 41.8, 39.5, 38.1, 35.0, 26.8, 25.8, 19.1, 18.0, 16.3, 13.8,
13.1, 12.6, 10.9, 6.7, 4.3, –4.1, –4.7 ppm. HRMS: calcd. for
C59H94NaO7Si3 [M + Na]+ 1021.6199; found 1021.6197.
4.4, –4.2, –4.6 ppm. HRMS: calcd. for C59H94NaO6Si3 [M + Na]+
1005.6250; found 1005.6255.
(2S,4S,5S,6R,7R,8R,9S)-7-(Benzyloxy)-9-(tert-butyldimethylsilyl-
oxy)-11-(tert-butyldiphenylsilyloxy)-2-ethyl-5-(4-methoxybenzyl-
oxy)-4,6,8-trimethylundecan-1-ol (23): To a stirred solution of 22
(1.5 g, 1.52 mmol) in CH2Cl2 (30 mL) at 0 °C, was added a catalytic
amount of p-TSA (30 mg) and the reaction was allowed to stir for
30 min at the same temperature. After completion of the reaction
(monitored by TLC), it was quenched with saturated NaHCO3
solution (20 mL). The organic layer was separated and the aqueous
phase extracted with ethyl acetate (3ϫ 20 mL). The combined or-
ganic layer was washed with brine (2ϫ 40 mL), dried with Na2SO4,
and then evaporated under reduced pressure. The crude product
was purified by column chromatography with silica gel (hexane/
ethyl acetate = 9:1) to give TES-deprotected 23 as viscous colorless
(6R,7S,8R,9R,10R,11R,12R,13S)-11-(Benzyloxy)-13-(tert-butyldi-
methylsilyloxy)-3,3,6-triethyl-9-(4-methoxybenzyloxy)-
8,10,12,18,18-pentamethyl-17,17-diphenyl-4,16-dioxa-3,17-disila-
nonadecan-7-yl S-Methyl Carbonodithioate (21): Alcohol 20 (3.5 g,
3.50 mmol) in THF (25 mL) was added to a suspension of NaH
(252 mg, 10.52 mmol) in THF (10 mL) under a nitrogen atmo-
sphere at 0 °C. Carbon disulfide (5 mL) was added to the reaction
mixture and heated to 60 °C and stirring continued at the same
temperature for 5 h. After cooling the reaction mixture to room
temperature, MeI (1.7 mL, 28.05 mmol) was added dropwise to the
reaction mixture and stirred at same temperature for 1 h. After
completion of the reaction (monitored by TLC), it was cooled to
0 °C and quenched with saturated aqueous NH4Cl solution
(30 mL). The reaction mixture was diluted with ethyl acetate
(40 mL) and the organic layer separated. The aqueous layer was
extracted with ethyl acetate (3ϫ 40 mL) and the combined organic
layer washed with brine (2ϫ 75 mL), dried with anhydrous Na2SO4
and evaporated under reduced pressure. The residue was purified
by column chromatography with silica gel (hexane/ethyl acetate =
liquid (1.1 g, 84%). [α]2D7 = –23.3 (c = 1.5, CHCl ). IR (neat): ν =
˜
3
3453, 2950, 2928, 1461, 1382, 1251 cm–1
.
1H NMR (CDCl3,
500 MHz): δ = 7.78–7.72 (m, 4 H), 7.51–7.40 (m, 6 H), 7.38–7.30
(m, 5 H), 7.22 (d, J = 7.9 Hz, 2 H), 6.90 (d, J = 7.9 Hz, 2 H), 4.66–
4.44 (m, 4 H), 4.31–4.26 (m, 1 H), 3.93–3.87 (m, 4 H), 3.80–3.73
(m, 1 H), 3.62 (dd, J = 10.9, 4.9 Hz, 1 H), 3.55–3.48 (m, 2 H), 3.31
(dd, J = 7.9, 4.9 Hz, 1 H), 2.15–2.06 (m, 2 H), 2.04–195 (m, 1 H),
1.90–1.74 (m, 2 H), 1.69–1.56 (m, 2 H), 1.56–1.44 (m, 1 H), 1.39–
1.29 (m, 2 H), 1.22 (d, J = 7.9 Hz, 3 H), 1.13 (s, 9 H), 1.02 (d, J =
6.9 Hz, 3 H), 0.98 (d, J = 6.9 Hz, 3 H), 0.95 (t, J = 6.9 Hz, 3 H),
0.92 (s, 9 H), 0.11 (s. 3 H), 0.02 (s, 3 H) ppm. 13C NMR (CDCl3,
10:1) to furnish xanthate 21 (3.6 g, 94%) as a brown liquid. [α]2D7
–6.5 (c = 1.2, CHCl ). IR (neat): ν = 2955, 1710, 1513, and
=
˜
3
1219 cm–1. H NMR (CDCl3, 300 MHz): δ = 7.82–7.73 (m, 4 H), 75 MHz): δ = 158.6, 138.7, 135.2, 133.8, 133.7, 131.2, 129.2, 128.8,
1
8
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O21684
/KAP1
Date: 09-04-13 17:01:43
Pages: 11
The C31–C41 Spirolactam Fragment of Sanglifehrin A
127.9, 127.3, 127.0, 126.9, 113.3, 85.1, 82.2, 74.3, 72.7, 68.8, 64.2,
61.9, 54.9, 41.9, 39.3, 37.3, 34.7, 34.4, 33.2, 26.6, 25.6, 24.7, 18.9,
17.7, 16.8, 12.9, 11.0, 10.7, –4.4, –4.9 ppm. HRMS: calcd. for
C53H80NaO6Si2 [M + Na]+ 891.5391; found 891.5396.
3.0 Hz, 1 H), 3.33 (dd, J = 7.5, 4.5 Hz, 1 H), 2.31–2.18 (m, 1 H),
2.16–1.96 (m, 2 H), 1.92–1.49 (m, 6 H), 1.44–1.28 (m, 1 H), 1.20
(d, J = 7.5 Hz, 3 H), 1.16–1.11 (m, 12 H), 1.06–0.95 (m, 6 H), 0.91
(s, 9 H), 0.11 (s, 3 H), 0.01 (s, 3 H) ppm. 13C NMR (CDCl3,
75 MHz): δ = 178.1, 158.8, 138.8, 135.4, 134.7, 133.9, 131.2, 129.4,
129.1, 128.1, 128.0, 127.5, 127.4, 127.2, 113.5, 84.9, 82.0, 74.6, 73.0,
68.9, 62.0, 55.2, 46.2, 42.2, 37.6, 35.2, 34.9, 34.6, 26.9, 25.8, 24.8,
22.6, 19.1, 17.1, 13.0, 11.8, 10.9, –4.2, –4.6 ppm. HRMS: calcd. for
C53H80NO6Si2 [M + H]+ 882.5518; found 882.5512.
(2S,4S,5S,6R,7R,8R,9S)-7-(Benzyloxy)-9-(tert-butyldimethylsilyl-
oxy)-11-(tert-butyldiphenylsilyloxy)-2-ethyl-5-(4-methoxybenzyl-
oxy)-4,6,8-trimethylundecanoic Acid (24): A solution of alcohol 19
(0.8 g, 0.92 mmol) in CH2Cl2 (20 mL) was added to a suspension
of Dess–Martin periodinane (0.59 g, 1.38 mmol) in CH2Cl2
(10 mL) at 0 °C and stirred for 1 h. The reaction mixture was then
diluted with CH2Cl2 (15 mL) and washed with saturated aqueous
NaHCO3 (2ϫ 25 mL). The organic layer was dried with Na2SO4,
evaporated under reduced pressure. The crude aldehyde (0.81 g)
was immediately used for the next reaction. To a solution of alde-
hyde in a mixture of tert-butanol and water (3:1, 16 mL) at 0 °C
was added NaH2PO4 (221 mg, 1.84 mmol) followed by 2-methyl-2-
butene (0.2 mL, 1.84 mmol) and stirred for 5 min. NaClO2
(166 mg, 1.84 mmol) was added and the reaction mixture was
stirred at 0 °C. After completion of the reaction, the organic sol-
vent was evaporated under reduced pressure and the residue was
diluted with ethyl acetate. The organic layer was separated and the
aqueous layer extracted with ethyl acetate (3ϫ 20 mL). The com-
bined organic layer was washed with brine (50 mL) and dried with
Na2SO4 and concentrated. The residue was purified by column
chromatography with silica gel (hexane/ethyl acetate = 4:1) to af-
(2S,4S,5S,6R,7R,8R,9S)-7-(Benzyloxy)-9-(tert-butyldimethylsilyl-
oxy)-11-(tert-butyldiphenylsilyloxy)-2-ethyl-5-hydroxy-4,6,8-tri-
methylundecanamide (26): To a ice-cold mixture of amide 25
(250 mg, 0.283 mmol) in CH2Cl2/H2O (9:1; 15 mL), DDQ (128 mg,
0.567 mmol) was added in one portion. The resulting mixture was
stirred at the same temperature for 30 min. After completion of
the reaction (monitored by TLC), it was quenched with saturated
NaHCO3 solution (10 mL). The organic layer was separated and
the aqueous layer extracted with CH2Cl2 (3ϫ 10 mL). The com-
bined organic layer was washed with brine (3ϫ 15 mL), dried with
Na2SO4, and concentrated to afford a residue that was purified by
column chromatography with silica gel (hexane/ethyl acetate = 1:4)
to furnish alcohol 26 (205 mg, 96%) as a pale yellow liquid. [α]2D7
= +5.1 (c = 0.9, CHCl ). IR (neat): ν = 3450, 2923, 2853, 1690,
˜
3
1219 cm–1. H NMR (CDCl3, 300 MHz): δ = 7.77–7.70 (m, 4 H),
1
7.54–7.33 (m, 9 H), 7.31–7.25 (m, 2 H), 6.53 (br. s, 1 H), 5.37 (br.
s, 1 H), 4.61 (s, 2 H), 4.22–4.13 (m, 2 H), 3.96–3.85 (m, 1 H), 3.79–
3.68 (m, 1 H), 3.62 (d, J = 9.0 Hz, 1 H), 3.42 (dd, J = 10.5, 1.5 Hz,
ford 24 (700 mg, 85% yield) as a colorless viscous liquid. [α]2D7
–7.1 (c = 0.5, CHCl ). IR (neat): ν = 3250, 2924, 2854, 1709, 1462,
=
˜
3
1219 cm–1. H NMR (CDCl3, 300 MHz): δ = 7.89–7.78 (m, 4 H), 1 H), 2.45–2.31 (m, 1 H), 2.24–2.08 (m, 2 H), 2.04–1.94 (m, 1 H),
1
7.62–7.37 (m, 1 H), 7.33 (d, J = 8.5 Hz, 2 H), 6.99 (d, J = 8.5 Hz, 1.86–1.60 (m, 4 H), 1.46–1.29 (m, 2 H), 1.16 (d, J = 7.5 Hz, 3 H),
2 H), 4.76–4.54 (m, 4 H), 4.28–4.19 (m, 1 H), 4.01–3.83 (m, 5 H),
3.58–3.52 (m, 1 H), 3.41 (dd, J = 7.7, 3.6 Hz, 1 H), 2.65–2.47 (m,
1 H), 2.35–2.22 (m, 1 H), 2.14–1.98 (m, 3 H), 1.93–1.76 (m, 2 H),
1.10 (s, 9 H), 1.04 (t, J = 7.5 Hz, 3 H), 0.94–0.87 (m, 15 H), 0.10
(s, 6 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 178.6, 137.5, 135.5,
135.4, 129.5, 128.4, 128.1, 127.7, 127.5, 127.3, 127.0, 126.9, 88.1,
1.73–1.61 (m, 1 H), 1.56–1.43 (m, 2 H), 1.30 (d, J = 6.9 Hz, 3 H), 76.0, 74.8, 69.2, 61.9, 46.6, 42.3, 35.3, 34.8, 34.4, 26.8, 25.8, 24.7,
1.23 (s, 9 H), 1.17 (d, J = 6.7 Hz, 3 H), 1.12 (t, J = 7.3 Hz, 3 H), 22.6, 19.0, 16.1, 11.6, 11.4, 10.9, –4.3, –4.7 ppm. HRMS: calcd. for
1.06 (d, J = 6.9 Hz, 3 H), 0.95 (s, 9 H), 0.14 (s, 3 H), 0.01 (s, 3
H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 178.7, 158.8, 139.0,
135.5, 133.4, 133.3, 129.6, 129.0, 128.0, 127.6, 127.3, 127.0, 113.5,
83.7, 77.1, 74.0, 73.5, 69.1, 63.0, 55.2, 44.8, 42.3, 38.5, 34.7, 33.5,
26.8, 26.7, 25.7, 22.6, 17.8, 17.2, 12.9, 11.9, 10.3, –4.3, –4.8 ppm.
HRMS: calcd. for C53H79O7Si2 [M + H]+ 883.5364; found
883.5359.
C45H71NNaO5Si2 [M + Na]+ 784.4768; found 784.4775.
(2S,4S,6S,7S,8R,9S)-7-(Benzyloxy)-9-(tert-butyldimethylsilyloxy)-
11-(tert-butyldiphenylsilyloxy)-2-ethyl-4,6,8-trimethyl-5-oxoun-
decanamide (3): To a stirred solution of alcohol 17 (90 mg,
0.118 mmol) in CH2Cl2 (10 mL), Dess–Martin periodinane (75 mg,
0.177 mmol) was added at 0 °C under a nitrogen atmosphere. Stir-
ring was continued for 2 h at room temperature. After complete
conversion of the starting material (monitored by TLC), the reac-
tion was quenched with saturated NaHCO3 solution (10 mL) and
diluted with CH2Cl2 (10 mL). The organic layer was separated and
the aqueous layer extracted with CH2Cl2 (2ϫ 20 mL). The com-
bined organic layer was washed with brine (2ϫ 30 mL), dried with
anhydrous Na2SO4 and concentrated under reduced pressure. The
crude product was rapidly purified by flash column chromatog-
raphy with silica gel (hexane/ethyl acetate = 3:2) to obtain keto 3
(2S,4S,5S,6R,7R,8R,9S)-7-(Benzyloxy)-9-(tert-butyldimethylsilyl-
oxy)-11-(tert-butyldiphenylsilyloxy)-2-ethyl-5-(4-methoxybenzyl-
oxy)-4,6,8-trimethylundecanamide (25): To a solution of acid 24
(400 mg, 0.453 mmol) in CH2 Cl2 (10 mL), Et3N (91 μL,
0.906 mmol) was added at 0 °C and stirred for 20 min, followed by
addition of ethyl chloroformate (64 μL, 0.680 mmol), followed by
further stirring for 30 min at the same temperature. To this reaction
mixture aqueous ammonia (30%, 2.0 mL) was added slowly at 0 °C
and slowly warmed to room temperature. After complete conver-
sion of the reaction (monitored by TLC), it was quenched with
saturated NH4Cl solution (10 mL) and was extracted with CH2Cl2
(3ϫ 10 mL). The combined organic layer was washed with brine
(2ϫ 30 mL), dried with Na2SO4, and evaporated under reduced
pressure. The crude product was purified by column chromatog-
raphy with silica gel (hexane/ethyl acetate = 1:1) to give amide 25
(350 mg, 88%) as a colorless viscous liquid. [α]2D7 = –15.2 (c = 1.2,
(75 mg, 83%) as a colorless liquid. [α]2D7 = +11.1 (c = 0.6, CHCl3).
IR (neat): ν = 3361, 2923, 2853, 1659, 1463, 1219 cm–1. H NMR
1
˜
(CDCl3, 300 MHz): δ = 7.72–7.64 (m, 4 H), 7.46–7.22 (m, 11 H),
5.45 (br. s, 2 H), 4.47 (ABq, J = 11.3 Hz, 2 H), 4.22–4.13 (m, 1 H),
3.83–3.76 (m, 2 H), 3.71 (dd, J = 8.3, 4.5 Hz, 1 H), 3.12 (dd, J =
8.3, 6.8 Hz, 1 H), 2.62–2.52 (m, 1 H), 2.40–2.30 (m, 1 H), 2.19–
1.88 (m, 2 H), 1.75–1.54 (m, 3 H), 1.47–1.23 (m, 2 H), 1.11–1.05
(m, 12 H), 1.01 (d, J = 7.5 Hz, 3 H), 0.95–0.87 (m, 6 H), 0.85 (s, 9
H), 0.06 (s, 3 H), 0.02 (s, 3 H) ppm. 13C NMR (CDCl3, 75 MHz):
CHCl ). IR (neat): ν = 3410, 2923, 2853, 1692, 1461, 1219 cm–1.
˜
3
1H NMR (CDCl3, 300 MHz): δ = 7.81–7.72 (m, 4 H), 7.53–7.39 δ = 216.2, 177.5, 138.8, 135.4, 134.0, 133.9, 129.5, 128.1, 127.6,
(m, 6 H), 7.38–7.32 (m, 5 H), 7.21 (d, J = 8.3 Hz, 2 H), 6.90 (d, J
127.5, 127.1, 83.4, 74.5, 68.3, 61.4, 47.1, 46.0, 44.2, 41.3, 35.6, 35.0,
26.9, 25.8, 24.7, 22.6, 19.2, 15.6, 13.7, 12.0, 10.9, –4.1, –4.5 ppm.
= 8.3 Hz, 2 H), 5.61–5.55 (br. s, 1 H), 5.37–5.28 (br. s, 1 H), 4.65
(ABq, J = 10.6 Hz, 2 H), 4.49 (ABq, J = 11.3 Hz, 2 H), 4.30–4.22 HRMS: calcd. for C45H69NNaO5Si2 [M + Na]+ 782.4606; found
(m, 1 H), 3.96–3.85 (m, 4 H), 3.84–3.73 (m, 1 H), 3.48 (dd, J = 5.3,
782.4605.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
9

Job/Unit: O21684
/KAP1
Date: 09-04-13 17:01:43
Pages: 11
J. S. Yadav, D. K. Mohapatra et al.
FULL PAPER
[3] a) T. Fehr, L. Oberer, Intern. Patent Appl. WO97/02285, Jan.
23, 1997; b) T. Fehr, L. Oberer, R. V. Quesniaux, J. J. Sanglier,
W. Schuler, R. Sedrani, Intern. Patent. Appl. WO98/07743,
March 3, 1998.
(2S,3S,4S,5S,6R,9R,11S)-4-(Benzyloxy)-9-ethyl-2-(2-hydroxyethyl)-
3,5,11-trimethyl-1-oxa-7-azaspiro[5.5]undecan-8-one (27): To a
stirred solution of 3 (50 mg, 0.065 mmol) in acetonitrile (6 mL) and
water (0.6 mL), HF (0.2 mL, 40% in water) was added at 0 °C.
The reaction mixture was allowed to stir at room temperature for
overnight. After complete conversion of the starting material (mon-
itored by TLC), the reaction was quenched by saturated aqueous
solution of NaHCO3 (10 mL). The organic solvent was removed
under reduced pressure and the aqueous phase extracted with ethyl
acetate (3ϫ 20 mL). The combined organic layer was washed with
brine (30 mL), dried with anhydrous Na2SO4, and concentrated un-
der reduced pressure to get a residue, which on purification by col-
umn chromatography over silica gel (hexane/ethyl acetate = 1:1),
furnished spirolactam 27 (20 mg, 80%) as a viscous pale yellow
[4] a) T. Fehr. L. Oberer, V. Q. Ryffel, J. J. Sanglier, W. Schuler, R.
Sedrani, (Sandoz Ltd.), WO-A 9702285A/970123, 1997; b) J. J.
Sanglier, V. Quesniaux, T. Fehr, H. Hofmann, M. Mahnke, K.
Memmert, W. Schuler, G. Zenke, L. Gschwind, C. Mauer, W.
Schilling, J. Antibiot. 1999, 52, 466; c) T. Fehr, J. Kallen, L.
Oberer, J. J. Sanglier, W. Schilling, J. Antibiot. 1999, 52, 474.
[5] a) K. C. Nicolaou, T. Ohshima, F. Murphy, S. Barluenga, J.
Xu, N. Winssinger, Chem. Commun. 1999, 809; b) K. C. Nico-
laou, J. Xu, F. Murphy, S. Barluenga, O. Baudoin, H.-X. Wei,
D. L. F. Gray, T. Ohshima, Angew. Chem. 1999, 111, 2599; An-
gew. Chem. Int. Ed. 1999, 38, 2447; c) K. C. Nicolaou, F. Mur-
phy, S. Barluenga, T. Ohshima, H. Wei, J. Xu, D. L. F. Gray,
O. Baudoin, J. Am. Chem. Soc. 2000, 122, 3830.
[6] a) M. Duan, L. A. Paquette, Angew. Chem. 2001, 113, 3744;
Angew. Chem. Int. Ed. 2001, 40, 3632; b) L. A. Paquette, M.
Duan, I. Konetzki, C. Kempmann, J. Am. Chem. Soc. 2002,
124, 4257.
[7] a) L. C. Dias, A. G. Salles Jr., Tetrahedron Lett. 2006, 47, 2213;
b) M. K. Gurjar, S. R. Chaudhuri, Tetrahedron Lett. 2002, 43,
2435; c) R. Metternich, D. Denni, B. Thai, R. Sedrani, J. Org.
Chem. 1999, 64, 9632; d) R. Biinteli, I. Brun, P. Hail, R. Met-
ternich, Tetrahedron Lett. 1999, 40, 2109.
liquid. [α]2D7 = –45.0 (c = 0.95, CHCl ). IR (neat): ν = 3460, 2972,
˜
3
1645, 1455 cm–1. 1H NMR (CDCl3, 300 MHz): δ = 7.96 (br. s, 1
H), 7.41–7.33 (m, 4 H), 7.32–7.28 (m, 1 H), 4.67 (ABq, J = 11.0 Hz,
2 H), 3.98–3.92 (m, 1 H), 3.73 (t, J = 5.5 Hz, 2 H), 3.60 (t, J =
3.3 Hz, 1 H), 2.37–2.30 (m, 1 H), 2.27–2.18 (m, 1 H), 2.05–1.80 (m,
4 H), 1.73–1.49 (m, 4 H), 1.03 (d, J = 7.7 Hz, 3 H), 0.97–0.89 (m,
9 H) ppm. 13C NMR (CDCl3, 125 MHz): δ = 175.2, 137.5, 128.6,
128.0, 127.7, 87.7, 83.8, 70.3, 60.8, 42.0, 40.8, 38.4, 34.5, 33.9, 33.4,
24.3, 14.7, 13.9, 13.4, 10.6 ppm. HRMS: calcd. for C23H35NNaO4
[M + Na]+ 412.2458; found 412.2452.
[8] a) J. S. Yadav, L. Chetia, Org. Lett. 2007, 9, 4587; b) J. S. Yadav,
V. Rajender, Y. G. Rao, Org. Lett. 2010, 12, 348.
(2S,3R,4S,5S,6R,9R,11S)-9-Ethyl-4-hydroxy-2-(2-hydroxyethyl)-
[9] a) J. S. Yadav, C. S. Rao, S. Chandrasekhar, A. V. Rama Rao,
Tetrahedron Lett. 1995, 36, 7717; b) J. S. Yadav, S. Abraham,
M. M. Reddy, G. Sabitha, A. R. Sanker, A. C. Kunwar, Tetra-
hedron Lett. 2001, 42, 4713; c) J. S. Yadav, M. M. Ahmed, Tet-
rahedron Lett. 2002, 43, 7147; d) J. S. Yadav, R. Srinivas, K.
Sathaiah, Tetrahedron Lett. 2006, 47, 1603; e) J. S. Yadav, T. V.
Pratap, V. Rajender, J. Org. Chem. 2007, 72, 5882.
[10] a) H. C. Brown, J. V. N. Varaprasad, J. Am. Chem. Soc. 1986,
108, 2049; b) H. C. Brown, M. C. Desai, P. K. Jadav, J. Org.
Chem. 1982, 47, 5065; c) H. M. R. Hoffmann, Angew. Chem.
1984, 96, 29; Angew. Chem. Int. Ed. Engl. 1984, 23, 1.
[11] E. J. Corey, N. M. Weinshenker, T. F. Schoff, W. J. Hubber, J.
Am. Chem. Soc. 1969, 91, 5675.
3,5,11-trimethyl-1-oxa-7-azaspiro[5.5]undecan-8-one (2): To
a
stirred solution of 27 (15.0 mg, 0.038 mmol) in MeOH/THF
(2.0 mL, 5:1) was added Pd(OH)2 (20%, 10.0 mg) under an argon
atmosphere. The reaction mixture was stirred under H2 overnight
at room temperature. After completion of the reaction (monitored
by TLC), the reaction mixture was filtered through a short pad of
Celite and the filtrate was concentrated under reduced pressure.
The residue was purified by column chromatography with silica gel
(ethyl acetate) to afford 2 (10.0 mg, 86%) as a white solid, m.p.
137–139 °C. [α]2D7 = –57.4 (c = 0.45, CHCl ). IR (neat): ν = 3395,
˜
3
2949, 2873, 1691, 1456, 1219 cm–1. 1H NMR (CDCl3, 500 MHz):
δ = 8.28 (br. s, 1 H), 3.98 (t, J = 8.7 Hz, 1 H), 3.82–3.72 (m, 3 H),
2.39–2.19 (m, 1 H), 2.08–1.95 (m, 1 H), 1.94–1.81 (m, 3 H), 1.75–
1.50 (m, 5 H), 1.07 (d, J = 6.7 Hz, 3 H), 0.98 (t, J = 6.7 Hz, 3 H),
0.95–0.85 (m, 6 H) ppm. 13C NMR (CDCl3, 125 MHz): δ = 177.1,
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Received: December 13, 2012
Published Online: ᭿
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O21684
/KAP1
Date: 09-04-13 17:01:43
Pages: 11
The C31–C41 Spirolactam Fragment of Sanglifehrin A
Asymmetric Synthesis
J. S. Yadav,* K. V. Raghavendra Rao,
A. Kavita,
D. K. Mohapatra* ........................... 1–12
Stereoselective Synthesis of the C31–C41
Spirolactam Fragment of Sanglifehrin A
Keywords: Synthetic methods / Asymmetric
synthesis / Medicinal chemistry / Natural
products / Spiro compounds / Lactams
An efficient and highly-stereoselective syn-
thesis for the spirolactam segment of the
extremely potent immunosuppressant
metrization strategy, followed by Sharpless
asymmetric epoxidation, Crimmins syn
aldol reaction, Barton–McCombie deoxy-
genation, and spirolactamization as key re-
actions.
sanglifehrin A
was
successfully
ac-
complished by following our own desym-
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
11