The formal total synthesis of FR252921-An immunosuppressant

Article abstract of DOI:10.1002/ejoc.201201097

The formal total synthesis of FR252921 is described. The key steps include the preparation of three fragments starting from 1,4-butanediol, (R)-malic acid, and prenol, respectively, followed by two consecutive peptide couplings of the three fragments. Other key steps involve an allene-type rearrangement or enyne isomerization to install the triene moiety, a Seebach methylation, a Julia olefination to construct the trisubstituted diene unit, and an enzymatic resolution strategy to generate the C-18 stereocenter.

Full text of DOI:10.1002/ejoc.201201097

FULL PAPER
DOI: 10.1002/ejoc.201201097
The Formal Total Synthesis of FR252921 – An Immunosuppressant
J. S. Yadav*[a] and Sandip Sengupta[a]
Keywords: Total synthesis / Natural products / Macrocycles / Kinetic resolution / Alkylation / Olefination
The formal total synthesis of FR252921 is described. The key
steps include the preparation of three fragments starting
from 1,4-butanediol, (R)-malic acid, and prenol, respectively,
followed by two consecutive peptide couplings of the three
fragments. Other key steps involve an allene-type rearrange-
ment or enyne isomerization to install the triene moiety, a
Seebach methylation, a Julia olefination to construct the tri-
substituted diene unit, and an enzymatic resolution strategy
to generate the C-18 stereocenter.
Unlike other immunosuppressants, FR252921 inhibits
both lipopolysaccharide (LPS)-stimulated and anti-CD3
mAb-stimulated splenocyte proliferations in vitro without
blocking T-cell activation.[3b] Further studies show that
FR252921 decreases transcription activity regulated by an
activating protein 1 (AP-1) and acts dominantly against an
antigen presenting cell (APC) rather than a T-cell. To exam-
ine the possibility of FR252921 to act as a concomitant
drug of FK506, a T-cell specific inhibitor was evaluated
and, thus, shows a synergy with FK506 in immunosup-
pressive activity, both in splenic proliferation and in murine
skin transplantation.[3c]
Introduction
Immunosuppressive natural products such as cyclospo-
rin A, FK506, rapamycin, deoxyspergualin, and di-
demnin B have proven to be useful tools for the dissection
of cell signaling pathways,[1] and have also led to a signifi-
cant increase in the success of organ and bone marrow
transplants.[2] In 2003, three new immunosuppressive agents
FR252921 (1a), FR252922 (1b), and FR256523 (1c), which
have an unusual 19-membered lactone-dilactam structure,
were isolated from the culture broth of Pseudomonas fluo-
rescens no. 408813 by Fujine et al. (see Figure 1).[3]
Although the overall gross structure of FR252921 was
established by Fujina et al. through NMR studies, its abso-
lute configuration was unknown for some time. In 2005, it
was very exciting that the antimicrobial substance pseu-
dotrenic acid B was isolated from the same strains by Po-
hanka et al., which upon treatment with TFA (trifluoro-
acetic acid) provided macrolactone FR252921.[4] Through
this biomimetic transformation, the configurations at C-12
and C-13 were assumed as (S) and (R), respectively, but still
the configuration of C-18 was unknown. In 2007, Falck et
al. assigned the absolute configuration of FR252921 as
(12S,13R,18R) through the total syntheses of all of its dia-
stereomers.[5] The molecular architecture of macrolactone
FR252921 includes the presence of an (E,E,E) trienic conju-
gated double bond, two amide bonds, and a trisubstituted
conjugated (E,E) diene moiety.
Our continuing interest in the total syntheses of various
biologically active natural products and the unique bio-
logical profile and challenging structural features of
FR252921 prompted us to explore the synthesis of this mo-
lecule.[5,6] In planning our approach, we developed a con-
vergent, straightforward route to provide a platform from
which entry to analogues of biological interest could ulti-
mately be realized. A detailed account of our successful en-
deavors towards the formal synthesis of FR252921 is pre-
sented in this paper.
Figure 1. Structure of macrolactones FR252921 (1a), FR252922
(1b), FR256523 (1c).
[a] CSIR – Indian Institute of Chemical Technology,
Tarnaka, Hyderabad 500607, India
Fax: +91-40-27160512
E-mail: yadavpub@iict.res.in
Homepage: http://www.iictindia.org/jsy/index.html
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201097.
376
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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The Formal Total Synthesis of FR252921 – An Immunosuppressant
tected as mono-THP (tetrahydropyran-2-yl) ether 9 by the
aid of a catalytic amount of pTSA (para-toluenesulfonic
acid). Bromination of the other free hydroxy group by treat-
ment with CBr4/TPP (triphenylphosphine) in anhydrous
CH2Cl2 gave bromide 10 in 52% yield over the two steps.
Compound 10 was coupled with propargyl alcohol using
LiNH2 in liquid NH3 to yield acetylenic alcohol 11 in 82%
yield, which then underwent consecutive Swern oxidation
and C-2 Wittig reactions to furnish the desired enyne ester
12 in 85% yield over the two steps. Isomerization[7] of 12
using TPP and phenol as effective cocatalysts installed the
(E,E,E) configuration of trienic ester 13 with Ͼ95% selec-
Results and Discussion
Recognizing the importance of developing a convergent
synthesis for 1a, we describe a retrosynthetic plan based
on the macrocyclization of the seco acid 2, as depicted in
Scheme 1. Furthermore, the formation of seco acid 2 was
envisaged to occur through two consecutive peptide cou-
plings of the three key fragments 3, 4, and 5.
1
tivity (by H and 13C NMR) in 71% yield. Deprotection
of the THP ether was achieved by treatment with PPTS
(pyridinium p-toluenesulfonate) in ethanol under refluxing
conditions to obtain primary alcohol 14 in 95% yield. The
resulting free hydroxy group of 14 was converted into azide
derivative 15, through a mesyl protection step, in 83% yield
over two steps. The Staudinger reaction[8] was employed to
convert azide 15 into its amine derivative, which was then
protected to give the trienic Boc (tert-butoxycarbonyl)-pro-
tected amino ester fragment 3 in 95% yield over two steps
(see Scheme 2).
Although the synthesis of fragment 3 was efficiently
achieved in 8 steps with an overall 19.5% yield, we have
demonstrated an alternate route to deliver fragment 3 from
the same starting material. Accordingly, 6 was monopro-
tected as TBS (tert-butyldimethylsilyl) ether 16 in 84%
yield, which was then subsequently oxidized to the corre-
sponding aldehyde 17 by PCC (pyridinium chlorochromate)
oxidation. The addition of lithiated methyl propiolate to
aldehyde 17 provided propargylic alcohol[9] 18 in 75% yield
over the two steps. The TPP-mediated allene-type re-
arrangement of 18 yielded (E,E)-diene 19 in 75% yield.[10]
Diene ester 19 then underwent DIBAL-H (diisobutylalumi-
Scheme 1. Biomimetic transformation of FR252921 from pseu-
dotrienic acid B and the retrosynthetic analysis of FR252921.
Our synthesis began with the construction of aminotri- num hydride) reduction to obtain alcohol 20 in 95% yield.
enic ester fragment 3 from the commercially available start- Consecutive Swern oxidation and C-2 Wittig reactions were
ing material 1,4-butanediol (6), which was initially pro- incorporated successfully to obtain trienic ester 21 in 92%
Scheme 2. Synthesis of fragment 3.
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377

J. S. Yadav, S. Sengupta
FULL PAPER
Scheme 3. Alternate route for the synthesis of fragment 3.
yield over the two steps with excellent (E,E,E) selectivity ane) and pTsOH in acetone at 0 °C followed by the silyl
1
(by H and 13C spectroscopy). Silyl deprotection of 21 was deprotection with TBAF, to provide primary alcohol 29
done by treatment with TBAF (tetra-n-butylammonium (75% yield over two steps), which was then converted into
fluoride) at 0 °C to obtain 14 in 95% yield, which was then carboxylic acid fragment 4 in 80% yield over two steps. IBX
converted into target fragment 3 by using the same se- (2-iodoxybenzoic acid) oxidation of 29 followed by conver-
quence of reactions as described earlier. The alternate pro- sion of the resulting aldehyde to an acid under Pinnick con-
cess gave us a comparatively better yield of 31% in the same ditions[14] (NaClO2/NaH2PO4, tBuOH/H2O) yielded acid
number of steps (see Scheme 3).
fragment 4 in 8 steps and 28% overall yield (see Scheme 4).
The β-hydroxy dienic acid fragment 5, possessing the (R)
Next, we turned our attention towards the synthesis of
carboxylic acid fragment 4, starting from (R)-dimethyl mal- configuration, was synthesized by an enzymatic resolution
ate (7), which was easily accessible from (R)-malic acid. We strategy. The synthesis was initiated from commercially
prepared the (2S,3R) stereoisomer by using the Seebach available prenol (8) as the starting material, which upon
alkylation as the key step. (R)-malic acid was subjected to protection of the hydroxy group as its TBDPS (tert-butyldi-
esterification by treatment with BF3·Et2O in MeOH to give phenylsilyl) ether gave protected prenol 30 in 98% yield.
dimethyl malonate in 98% yield. Accordingly, employing Allylic oxidation[15] of 30 was achieved regioselectively by
the procedure reported by Seebach,[11] dimethyl (R)-malate using SeO2 and tBuOOH in CH2Cl2 to obtain a mixture of
(7) was alkylated with MeI and LDA (lithium diisoprop- the trans allylic alcohol and the aldehyde (3:2). Subsequent
ylamide) in THF (tetrahydrofuran) to give alcohol 22 along oxidation of the mixture by PCC yielded allylic aldehyde 31
with its syn diastereomer (anti/syn, 8:2). We observed that as the sole product in 45% yield over the two steps. Alde-
using LHMDS (lithium hexamethyldisilazide) in place of hyde 31 was then converted into β-hydroxy ester 32 in 95%
LDA as the base led to a slightly improved diastereoselec- yield by
a
Reformatsky reaction,[16] which used
tivity (anti/syn, 9:1, combine yield 80%). The reduction of BrCH2CO2Et and Zn(Cu) couple in THF. Ester 32 was
22 using LiAlH4 provided triol 23 in excellent yield,[12] and then protected as silyl ether 33 by treatment with TBSCl in
triol 23 was selectively protected, through a dibutyltin ketal CH2Cl2. Selective deprotection of the primary TBDPS
intermediate, to give TBS ether 24 in 70% yield over the ether in presence of the secondary TBS ether moiety was
three steps.[13] In the presence of tosyl imidazole and NaH achieved by using NH4F in MeOH at room temperature to
at 0 °C, the resulting diol 24 was then converted into epox- give primary allylic alcohol 34 in 95% yield over the two
ide 25 in 88% yield. The regioselective epoxide ring opening steps. Primary allylic alcohol 34 was oxidized to its corre-
of 25 was achieved with NaN3/DMF (N,N-dimethylform- sponding aldehyde by treatment with IBX in DMSO (di-
amide) at 70 °C to afford azido alcohol 26 in 95% yield. methyl sulfoxide), and the resulting aldehyde was then used
Azido alcohol 26 underwent a Staudinger reaction[8] by directly in the Julia olefination[17] with sulfone 35.[18] This
treatment with TPP and then was subsequently protected delivered trisubstituted dienic ester 36 in 65% yield over the
as its carbamate by using (Boc)2O to yield 27 in quantitative two steps with a selectivity of (E,E)/(Z,E), 94:6 (by wt.-%,
yield. It is noteworthy that the separation of the minor dia- separated by column chromatography). Among the bases
stereomer was completely achieved in this step. Subsequent (NaHMDS, KHMDS, LiHMDS) used for this Julia ole-
protection of the resulting amino alcohol as N,O-acetonide fination, KHMDS was found to be the best with regard to
28 was achieved, by using 2,2-DMP (2,2-dimethoxyprop- the yield. Silyl deprotection of 36 was done by employing
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The Formal Total Synthesis of FR252921 – An Immunosuppressant
Scheme 4. Synthesis of carboxylic acid fragment 4.
TBAF in THF at 0 °C to obtain β-hydroxy ester 37 in 95% Table 1. Lipase-mediated resolution of compound 37.
yield. Our next step involved the resolution of β-hydroxy
ester 37 through a chemical as well as enzymatic process.
Although the Sharpless resolution[19] was found to be effec-
tive for resolving the alcohol, a satisfactory yield was ob-
tained from a lipase resolution process.[20] Among the sev-
eral lipases screened for this resolution, Amano lipase PS-
C with the solvent hexane was found to be most effective
(see Table 1). Studying 0.6 equiv. (w/w) of lipase PS-C and
6 equiv. of vinyl acetate at different temperatures showed
that beyond 30 °C there was not much difference in the iso-
lated yield of the product. Racemic β-hydroxy ester 37 was
exposed to an enzymatic acylation reaction using Amano
lipase PS-C in hexane in presence of vinyl acetate as the
acylating agent at 25 °C for 30 h to provide enantioenriched
acetate (R)-38 in 45% yield and 92%ee.[21] After careful[22]
hydrolysis of 38 by treatment with K2CO3 in CH3OH, β-
hydroxy ester (R)-39 was formed in 92% yield. Hydrolysis
of (R)-39 with LiOH in THF/MeOH/H2O (2:2:1) gave us
the third and final fragment 5 in 12% overall yield (see
Scheme 5).
Entry
Lipases[a]
Time [h]
% Yield[b]
% ee[c]
1
2
3
4
5
6
7
PS
PS-C
PPL
CRL
AK-Amano
PS-D
wheat germ
72
30
96
24
72
72
96
22
45
2
62
19
–
76
92
–
28
62
–
–
–
[a] Pseudomonas cepacia (PS) was obtained from the Amano Phar-
maceutical Company, Japan; P. cepacia lipase was immobilized on
modified ceramic particles (PS-C); P. cepacia lipase was immobi-
lized on diatomite (PS-D); Candida rugosa lipase (CRL) and Pseu-
domonas fluorescence (AK) lipase were from the Amano Pharma-
ceutical Company; porcine pancreas lipase, type II (PPL) was from
Sigma. [b] Isolated yield. [c] Determined by HPLC (chiral AD-H
column, Daicel) employing hexane/isopropyl alcohol (85:15) as
mobile phase at a flow rate of 1 mL/min and monitored by UV
(254 nm).
40 in 95% yield over the two steps. Successful cleavage of
At this stage, to assemble the core structure of 1a, we both the N,O-acetonide and tert-butyloxycarbonyl protect-
started to connect the fragments with each other (see ing group was achieved with 40% TFA in CH2Cl2 and
Scheme 6). For this purpose, the Boc group present in frag- MeOH at room temperature, and the resulting free amino
ment 3 was cleaved by treatment with TFA in CH2Cl2 alcohol was condensed with β-hydroxy acid fragment 5 un-
(30%), and the resulting free amine was united with carbox- der classic peptide coupling conditions {HOBT, HBTU [O-
ylic acid fragment 4 by using a suspension of N-(3-dimeth- (benzotriazol-1-yl)-N,N,NЈ,NЈ-tetramethyluronium
hexa-
ylaminopropyl)-N-ethyl carbodiimide (EDCI) and 1-hy- fluorophosphate], NMM (N-methylmorpholine), CH3CN},
droxybenzotriazole (HOBT) in CH2Cl2 to produce peptide to afford bis(amide) 41 in 90% yield over the two steps.
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J. S. Yadav, S. Sengupta
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Scheme 5. Synthesis of fragment 5.
Saponification of the bis(amide) 41 with LiOH in THF/ FR252921. The spectral and analytical data of 2 were in
MeOH/H2O (2:2:1) yielded the corresponding seco acid 2 full agreement with those previously reported by Falck
quantitatively. This constitutes the formal synthesis of et al.[5]
Scheme 6. Formal synthesis of FR252921.
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The Formal Total Synthesis of FR252921 – An Immunosuppressant
TPP (29.6 g, 112.8 mmol) in dry CH2Cl2 (100 mL) at –30 °C. The
mixture was stirred for an additional 30 min at –30 °C, and then a
solution of alcohol 9 (10.0 g, 56.4 mmol) and imidazole (7.70 g,
112.8 mmol) in dry CH2Cl2 (100 mL) was added dropwise success-
ively to the resultant red solution. The reaction mixture was
warmed to 30 °C over a period of 3 h. The solvent was concen-
trated to a small volume, and petroleum ether was added. The re-
sultant precipitate was filtered, and the filtrate was concentrated in
vacuo to give the crude product, which was purified by column
chromatography on silica gel (60–120 mesh, 10% EtOAc/hexane)
to afford compound 10 (10.2 g, 75%) as a yellow liquid; Rf = 0.85
(30% EtOAc/hexane). In the next step, to liquid ammonia (150 mL)
was added small finely cut pieces of lithium metal (1.76 g), and the
reaction mixture was stirred for 30 min, followed by the addition
of ferric nitrate (catalytic amount). The deep blue solution turned
grey, indicating the formation of the lithium amide. Propargyl
alcohol (4 mL, 63.0 mmol) was then added dropwise, and the reac-
tion mixture was stirred for 2 h at liquid ammonia temperature.
Then, bromo compound 10 (10.0 g, 42 mmol), which was dissolved
in anhydrous THF (20 mL), was added dropwise, and the reaction
mixture was stirred at liquid ammonia temperature for 8 h. Solid
NH4Cl (5 g) was added portionwise, and the ammonia was allowed
to evaporate. Ether (100 mL) was added to the solid residue, and
the mixture was filtered. The filtrate was concentrated, and after
column chromatography on silica gel (60–120 mesh, 20% EtOAc/
hexane), compound 11 (7.33 g, 82%) was obtained as a colorless
Conclusions
In summary, we have disclosed a concise, efficient, and
convergent formal total synthesis of FR252921 by synthe-
sizing and coupling three key fragments prepared from
commercially available starting materials. The key features
include an allene-type rearrangement or enyne isomeriza-
tion to install the trienic moiety, a Seebach methylation, a
Julia olefination to construct the trisubstituted dienic unit,
and an enzymatic resolution strategy to generate the C-18
stereocenter. The formal synthesis consists of 12 steps in its
longest linear sequence with a 10% overall yield.
Experimental Section
General Methods: 1H and 13C NMR spectroscopic data were re-
corded at ambient temperature in CDCl3 or CD3OD with a 200,
300, or 500 MHz spectrometer. The coupling constant J is given in
Hz. The chemical shifts are reported in ppm on scale downfield
from TMS, which was used as the internal standard. The signal
patterns are s (singlet), d (doublet), t (triplet), q (quartet), sext (sex-
tet), m (multiplet), and br. (broad). FTIR spectra were recorded
using KBr pellets and CHCl3/neat (as mentioned) and are reported
in wavenumbers (cm–1). Optical rotations were measured with a
digital polarimeter using a 1 mL cell with a 1 dm path length. For
low MS and HRMS, m/z ratios are reported as values in atomic
mass units. Mass spectrometric analyses were done in the ESI
mode. All of the reagents were reagent grade and used without
further purification, unless specified otherwise. The solvents for the
reactions were distilled prior to use. THF, toluene, and diethyl ether
were distilled from Na and benzophenone ketyl. MeOH was dis-
tilled from Mg and I2, and CH2Cl2 was distilled from CaH2. All
air- or moisture-sensitive reactions were conducted under nitrogen
or argon in flame-dried or oven-dried glassware, using magnetic
stirring. Column chromatography was carried out with silica gel
(60–120 mesh or 100–200 mesh) packed in glass columns. Technical
grade ethyl acetate and petroleum ether used for column
chromatography were distilled prior to use.
liquid; R = 0.3 (30% EtOAc/hexane). IR (KBr): ν = 3432, 2939,
˜
f
2866, 2223, 1732, 1444, 1271, 1129, 1071, 1024, 901, 572 cm–1. H
1
NMR (300 MHz, CDCl3): δ = 4.56–4.54 (m, 1 H), 4.18 (br. s, 2
H), 3.85–3.69 (m, 2 H), 3.48–3.33 (m, 2 H), 2.26–2.22 (m, 2 H), 2.14
(s, 1 H), 1.86–1.42 (m, 10 H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 98.5, 85.3, 78.7, 66.7, 62.0, 50.7, 30.4, 28.6, 25.2, 25.1, 19.3,
18.3 ppm. MS (ESI): m/z = 235 [M + Na]+. HRMS (ESI): calcd.
for C12H20O3Na [M + Na]+ 235.1310; found 235.1311.
Ethyl (E)-10-(Tetrahydro-2H-pyran-2-yloxy)dec-2-en-5-ynoate (12):
To a cold (–78 °C) solution of oxalyl chloride (3.08 mL, 35.3 mmol)
in CH2Cl2 (50 mL) was added DMSO (3.01 mL, 42.5 mmol). After
stirring for 10 min at –78 °C, a solution of propargylic alcohol 11
(5.0 g, 23.6 mmol) was added dropwise to the reaction mixture. The
solution was stirred for 15 min at the same temperature, and then
Et3N (19.7 mL, 141.6 mmol) was added dropwise. The reaction
mixture was stirred at that same temperature for 45 min and then
poured into an aqueous saturated NH4Cl solution (20 mL). The
organic phase was separated and washed with aqueous saturated
NaHCO3 solution (20 mL). The organic phase was dried, filtered,
and concentrated in vacuo to give the crude aldehyde, which was
used in the C-2 Wittig reaction without any further purification.
The C-2 Wittig ylide (13.1 g, 37.7 mmol) was added to a solution
of the crude aldehyde in CH2Cl2 (100 mL), and the reaction was
allowed to continue for 6 h at room temperature. After the comple-
tion of the reaction, checked by TLC, column chromatography on
silica gel (60–120 mesh, 5% EtOAc/hexane) gave ester compound
12 (5.6 g, 85% over two steps) as a colorless liquid; Rf = 0.8 (20%
4-(Tetrahydro-2H-pyran-2-yloxy)butan-1-ol (9): To a stirred solu-
tion of 1,4-butanediol (10.0 g, 110.9 mmol) in dry CH2Cl2
(300 mL) at 0 °C was added DHP (dihydropyran, 10 mL,
109.8 mmol) dropwise. After the addition was complete, a catalytic
amount of pTSA was added, and the resulting mixture was stirred
for 15 min and then checked by TLC. Then the reaction mixture
was quenched with saturated Na2CO3 solution (50 mL) at 0 °C,
and the resulting mixture was extracted with CH2Cl2 (3ϫ150 mL).
The organic extracts were washed with brine (20 mL) and dried
with anhydrous Na2SO4, and the solvent was evaporated under re-
duced pressure to give the crude residue, which was purified by
column chromatography on silica gel (60–120 mesh, 30% EtOAc/
hexane) to afford compound 9 (13.5 g, 70%) as a colorless liquid;
EtOAc/hexane). IR (neat): ν = 3421, 2942, 2869, 2214, 1716, 1619,
˜
R = 0.5 (60% EtOAc/hexane). IR (KBr): ν = 3424, 2951, 2140,
˜
f
1448, 1300, 1267, 1156, 1033, 956, 867, 812 cm–1. 1H NMR
(400 MHz, CDCl3): δ = 6.69 (dd, J = 16.1, 2.1 Hz, 1 H), 6.10 (d,
J = 16.1 Hz, 1 H), 4.54 (m, 2 H), 4.17 (q, J = 7.3 Hz, 2 H), 3.82–
3.70 (m, 2 H), 3.48–3.34 (m, 2 H), 2.42 (t, J = 5.1 Hz, 2 H), 1.85–
1.50 (m, 10 H), 1.29 (t, J = 7.3 Hz, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 166.0, 129.3, 125.9, 100.3, 98.7, 78.0, 66.7, 62.2, 60.5,
30.6, 28.8, 25.4, 25.1, 24.6, 19.5, 14.1 ppm. MS (ESI): m/z = 303
[M + Na]+. HRMS (ESI): calcd. for C16H24O4Na [M + Na]+
303.1572; found 303.1568.
1641, 1453, 1018, 665 cm–1. 1H NMR (300 MHz, CDCl3): δ = 4.51
(t, J = 2.9 Hz, 1 H), 3.82–3.62 (m, 2 H), 3.55 (t, J = 5.8 Hz, 2 H),
3.47–3.28 (m, 2 H), 2.66 (br. s, 1 H), 1.82–1.43 (m, 10 H) ppm. 13
C
NMR (75 MHz, CDCl3): δ = 98.2, 66.8, 61.6, 30.1, 29.1, 25.7, 24.9,
18.9 ppm. MS (ESI): m/z = 197 [M + Na]+.
7-(Tetrahydro-2H-pyran-2-yloxy)hept-2-yn-1-ol (11): To a solution
of CBr4 (18.7 g, 56.4 mmol) in dry CH2Cl2 (50 mL) under nitrogen
was slowly added dropwise over a period of 30 min a solution of
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Ethyl (2E,4E,6E)-9-(Tetrahydro-2H-pyran-2-yloxy)nona-2,4,6-tri-
enoate (13): To the solution of ester 12 (5.0 g, 17.8 mmol) in benz-
ene (17.8 mL) were added TPP (4.7 g, 17.8 mmol) and phenol
(1.7 g, 17.8 mmol). The resulting mixture was warmed to 55 °C and
stirred for 12–14 h, and then the solution was cooled to ambient
temperature and then diluted with diethyl ether (50 mL) and
NaOH (1 n solution, 10 mL). The layers were separated, and the
aqueous layer was extracted with diethyl ether (2ϫ20 mL). The
combined organic layers were washed with water (5 mL) and brine
solution (5 mL), dried, and concentrated under reduced pressure.
Purified of the residue by flash chromatography on silica gel (60–
120 mesh, 5% EtOAc/hexane) afforded triene ester compound 13
The organic layer was washed with water (5 mL) and brine solution
(5 mL), dried with Na2SO4, and concentrated under reduced pres-
sure. Purification of the residue by flash chromatography on silica
gel (60–120 mesh, 5% EtOAc/hexane) afforded compound 15
(2.80 g, 83% over two steps) as a yellow liquid; Rf = 0.8 (20%
EtOAc/hexane). IR (KBr): ν = 3450, 2982, 2932, 2097, 1707, 1618,
˜
1455, 1301, 1260, 1135, 1005, 767 cm–1. 1H NMR (200 MHz,
CDCl3): δ = 7.23 (dd, J = 15.4, 11.0 Hz, 1 H), 6.49 (dd, J = 14.7,
10.3 Hz, 1 H), 6.30–6.15 (m, 2 H), 5.87 (dt, J = 15.4, 7.3 Hz, 1 H),
5.83 (d, J = 15.4 Hz, 1 H), 4.16 (q, J = 7.3 Hz, 2 H), 3.34 (t, J =
7.3 Hz, 2 H), 2.41 (m, 2 H), 1.30 (t, J = 7.3 Hz, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 166.7, 144.1, 139.8, 134.3, 132.2,
(3.55 g, 71%) as a colorless liquid; Rf = 0.8 (20% EtOAc/hexane). 129.0, 120.8, 60.0, 50.2, 27.6, 14.1 ppm. MS (ESI): m/z = 244 [M
IR (KBr): ν = 3423, 2941, 2870, 1710, 1617, 1444, 1300, 1262, 1133,
+ Na]+, 222 [M + H]+. HRMS (ESI): calcd. for C11H15N3O2Na
[M + Na]+ 244.1061; found 244.1062.
˜
1071, 1032, 977, 869, 755, 698 cm–1. 1H NMR (300 MHz, CDCl3):
δ = 7.23 (dd, J = 15.8, 11.3 Hz, 1 H), 6.50 (dd, J = 14.3, 10.5 Hz,
1 H), 6.28–6.14 (m, 2 H), 5.98–5.89 (m, 1 H), 5.79 (d, J = 15.8 Hz,
1 H), 4.56 (m, 1 H), 4.16 (q, J = 6.7 Hz, 2 H), 3.89–3.70 (m, 2 H),
3.48–3.38 (m, 2 H), 2.41 (q, J = 6.7 Hz, 2 H), 1.85–1.49 (m, 6 H),
1.29 (t, J = 6.7 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
167.0, 144.5, 140.7, 136.2, 131.4, 128.3, 120.3, 98.7, 66.4, 62.2, 60.1,
33.3, 30.6, 25.3, 19.5, 14.2 ppm. MS (ESI): m/z = 303 [M + Na]+.
HRMS (ESI): calcd. for C16H24O4Na [M + Na]+ 303.1572; found
303.1583.
4-(tert-Butyldimethylsilyloxy)butan-1-ol (16): To a stirred suspen-
sion of NaH (60% w/v dispersion in mineral oil, 3.91 g, 97.7 mmol)
in dry THF (60 mL) was added dropwise a solution of 1,4-butane-
diol (6, 8.0 g, 88.8 mmol) in anhydrous THF (100 mL) at 0 °C. The
stirring was continued for 1 h at room temperature. After 1 h,
TBSCl (13.4 g, 88.8 mmol) was added slowly at room temperature.
The reaction was completed within 8 h. Then, the reaction mixture
was quenched with saturated NH4Cl solution (20 mL) at 0 °C, and
the resulting mixture was extracted with EtOAc (3ϫ20 mL). The
combined organic extracts were washed with brine (10 mL) and
Ethyl (2E,4E,6E)-9-Hydroxynona-2,4,6-trienoate (14): To a solution
of compound 13 (5.0 g, 17.8 mmol) in EtOH (30 mL) was added dried with anhydrous Na2SO4. The solvent was evaporated under
PPTS (catalytic amount), and the resulting mixture was heated to
reflux for 1–2 h. After completion of the reaction (checked by
TLC), the mixture was cooled to room temperature, and a satu-
rated NaHCO3 solution (10 mL) was added. The EtOH was re-
moved with a rotary evaporator, and the residue was diluted with
EtOAc (50 mL). The layers were separated, and the aqueous layer
was extracted with EtOAc (2ϫ30 mL). The combined organic lay-
ers were washed with water and then brine solution, dried, and
concentrated under reduced pressure. Purification of the residue
by flash chromatography on silica gel (60–120 mesh, 20% EtOAc/
hexane) afforded compound 14 (3.30 g, 95%) as a colorless liquid;
reduced pressure to give a crude residue, which was purified by
column chromatography on silica gel (60–120 mesh, 10% EtOAc/
hexane) to afford compound 16 (15.2 g, 84%) as a colorless liquid;
R = 0.5 (20% EtOAc/hexane). IR (KBr): ν = 3368, 2932, 2859,
˜
f
1468, 1388, 1254, 1188, 1101, 1063, 837, 776, 662 cm–1. H NMR
1
(300 MHz, CDCl3): δ = 3.68–3.58 (m, 4 H), 2.88 (br. s, 1 H), 1.64–
1.57 (m, 4 H), 0.87 (s, 9 H), 0.04 (s, 6 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 63.1, 62.0, 29.5, 29.4, 25.7, 18.1, –5.5 ppm. MS (ESI):
m/z = 205 [M + Na]+. HRMS (ESI): calcd. for C10H24O2Si [M +
H]+ 205.1623; found 205.1634.
Methyl 7-(tert-Butyldimethylsilyloxy)-4-hydroxyhept-2-ynoate (18):
To a stirred solution of Celite (47.0 g) in CH2Cl2 (200 mL) at 0 °C
was added PCC (31.6 g, 147.0 mmol). After 10 min, alcohol 16
(15.0 g, 73.5 mmol) and NaOAc (12.0 g, 147.0 mmol) were added
successively to the reaction at the same temperature, and the mix-
ture was stirred for 2 h at 0 °C. After completion of the reaction,
the reaction mass was filtered, and the filtrate was concentrated in
vacuo to give crude aldehyde 17, which was used in the next step
without any further purification. To a stirred solution of methyl
propiolate (5.03 g, 59.9 mmol) in THF (150 mL) at –78 °C was
slowly added LiHMDS (1.0 m solution in hexane, 80 mL,
80.0 mmol), and the resulting mixture was stirred at –78 °C for 1 h.
Then, aldehyde 17 (10.13 g, 49.9 mmol) in THF (150 mL) was
R = 0.2 (20% EtOAc/hexane). IR (KBr): ν = 3423, 2936, 1708,
˜
f
1620, 1370, 1267, 1184, 1141, 1047, 871, 753 cm–1. 1H NMR
(500 MHz, CDCl3): δ = 7.23 (dd, J = 14.8, 10.8 Hz, 1 H), 6.49 (dd,
J = 15.8, 10.8 Hz, 1 H), 6.25–6.18 (m, 2 H), 5.90–5.80 (m, 1 H),
5.80 (d, J = 14.8 Hz, 1 H), 4.17 (q, J = 6.9 Hz, 2 H), 3.68 (t, J =
5.9 Hz, 2 H), 2.39 (q, J = 6.9 Hz, 2 H), 1.45 (br. s, 1 H), 1.29 (t, J
= 6.9 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 166.9, 144.4,
140.5, 135.9, 131.5, 128.0, 120.0, 61.1, 59.9, 35.9, 13.9 ppm. MS
(ESI): m/z = 219 [M + Na]+. HRMS (ESI): calcd. for C11H16O3Na
[M + Na]+ 219.0997; found 219.0993.
Ethyl (2E,4E,6E)-9-Azidonona-2,4,6-trienoate (15): To a solution of
compound 14 (3.0 g, 15.3 mmol) in CH2Cl2 (50 mL) at 0 °C was
added Et3N (4.3 mL, 30.6 mmol), and the resulting mixture was added dropwise to the reaction mixture at –78 °C, and the stirring
stirred for 10 min. Then, MsCl (1.8 mL, 22.9 mmol) and DMAP
[4-(dimethylamino)pyridine, catalytic amount] were added to the
reaction mixture, which was then stirred for 30 min. After comple-
tion, the reaction was quenched with water (5 mL), and the re-
sulting solution was diluted with EtOAc (50 mL). The layers were
separated, and the aqueous layer was extracted with EtOAc
(2ϫ20 mL). The combined organic layers were washed with water
and brine solution, dried, and concentrated under reduced pres-
sure. Purification of the residue by flash chromatography afforded
the crude mesylated compound. To this mesylated compound in
dry DMF (10 mL) was added NaN3 (3.0 g, 46.0 mmol), and the
reaction mixture was stirred at 60–70 °C for 12 h. The reaction was
checked by TLC, cooled, and then diluted with EtOAc (20 mL).
was continued for 30 min. The reaction mixture was quenched with
aqueous saturated NH4Cl solution (20 mL), and the resulting solu-
tion was warmed to room temperature. The mixture was diluted
with water (10 mL), and the solution was extracted with diethyl
ether (2ϫ50 mL). The combined organic layers were washed with
brine (10 mL), dried with Na2SO4, and concentrated in vacuo. The
residue was purified by column chromatography (silica gel,
5Ǟ10% EtOAc in hexane) to give alkynol 18 (15.7 g, 75% yield
for two steps) as a colorless oil; Rf = 0.5 (10% EtOAc/hexane). IR
(neat, KBr): ν = 3424, 2954, 2928, 2056, 2236, 1718, 1436, 1253,
˜
1097, 836, 776, 752, 664 cm–1. 1H NMR (300 MHz, CDCl3): δ =
4.56–4.44 (m, 1 H), 3.75 (s, 3 H), 3.73–3.59 (m, 2 H), 1.92–1.65 (m,
4 H), 0.89 (s, 9 H), 0.07 (d, J = 1.5 Hz 6 H) ppm. 13C NMR
382
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 376–388

The Formal Total Synthesis of FR252921 – An Immunosuppressant
(75 MHz, CDCl3): δ = 153.9, 88.4, 76.0, 63.1, 61.6, 52.7, 34.7, 28.2,
25.8, 18.2, –5.5 ppm. MS (ESI): m/z = 309 [M + Na]+.
121.3, 62.3, 60.0, 31.0, 25.8, 18.1, 14.2, –5.4 ppm. MS (ESI): m/z =
310 [M + Na]+.
Methyl
(2E,4E)-7-(tert-Butyldimethylsilyloxy)hepta-2,4-dienoate
Ethyl (2E,4E,6E)-9-(tert-Butoxycarbonylamino)nona-2,4,6-trienoate
(3): TPP (2.80 g, 10.8 mmol) was added to a solution of compound
15 (2.0 g, 9.0 mmol) in THF/H2O (4:1, 25 mL) at room tempera-
ture. After 20 h, the reaction mixture was quenched with HCl (1 n
solution, pH = 1–2), and the resulting solution was washed with
(19): A mixture of alkynol 18 (4.0 g, 13.9 mmol) and TPP (4.48 g,
16.7 mmol) in benzene (30 mL) was stirred at room temperature.
After completion of the reaction (2 h, monitored by TLC), the sol-
vent was removed under vacuum, and the crude mixture was puri-
fied by column chromatography (silica gel, 2Ǟ5% EtOAc in hex- toluene and then basified with NaOH (10% solution, 5 mL). The
ane) to give conjugated diene ester 19 (2.80 g, 75%) as a colorless
mixture was extracted with CH2Cl2 (3ϫ50 mL). The combined ex-
tracts were dried with Na2SO4 and then concentrated to give the
crude amine. To the crude amine in THF (20 mL) were added Et3N
liquid; R = 0.8 (10% EtOAc/hexane). IR (neat, KBr): ν = 3448,
˜
f
2954, 2930, 2857, 1728, 1654, 1467, 1437, 1359, 1256, 1173, 1097,
1
836, 777, 722 cm–1. H NMR (300 MHz, CDCl3): δ = 7.21 (dd, J (2.5 mL, 18 mmol) and (Boc)2O (3.1 mL, 13.5 mmol) successively
= 14.8, 10.5 Hz, 1 H), 6.19 (dd, J = 14.8, 10.5 Hz, 1 H), 6.13–6.07
at 0 °C, and the reaction mixture was allowed to come to room
(m, 1 H), 5.76 (d, J = 15.8 Hz 1 H), 3.72 (s, 3 H), 3.67 (t, J = temperature for 2–3 h. After completion of the reaction, EtOAc
6.3 Hz, 2 H), 2.35 (q, J = 6.3 Hz, 2 H), 0.88 (s, 9 H), 0.03 (s, 6
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 167.5, 145.0, 140.9,
129.9, 119.1, 62.0, 51.3, 36.4, 25.8, 18.2, –5.4 ppm. MS (ESI): m/z
= 293 [M + Na]+.
(20 mL) was added to dilute the mixture. The organic layer was
washed with water (5 mL) and brine solution (5 mL), dried with
Na2SO4, and concentrated under reduced pressure. Purification of
the residue by flash chromatography on silica gel (60–120 mesh,
20% EtOAc/hexane) afforded fragment 3 (2.50 g, 95% over two
steps) as a yellow liquid; Rf = 0.5 (30% EtOAc/hexane). IR (KBr):
(2E,4E)-7-(tert-Butyldimethylsilyloxy)hepta-2,4-dien-1-ol (20): To
conjugated diene ester 19 (4.0 g, 14.8 mmol) in dry CH2Cl2 (50 mL)
was added DIBAL-H (25% solution in toluene, 26 mL, 46.3 mmol)
at –78 °C, and the mixture was stirred for 30 min at the same tem-
perature. Then, the reaction mixture was quenched by adding a
saturated potassium sodium tartrate solution (10 mL). The result-
ant mixture was extracted with CH2Cl2 (3ϫ20 mL). The combined
organic layers were washed with brine (20 mL), dried with Na2SO4,
and filtered. The solvents were evaporated, and the resulting crude
product was purified by column chromatography on silica gel (60–
120 mesh, 10% EtOAc/hexane) to afford compound 20 (3.40 g,
95%) as a colorless liquid; Rf = 0.4 (20% EtOAc/hexane). IR
ν = 3371, 2978, 2932, 1709, 1618, 1518, 1452, 1367, 1254, 1173,
˜
1140, 1038, 1004, 865, 779 cm–1. 1H NMR (200 MHz, CDCl3): δ =
7.24 (dd, J = 15.3, 11.5 Hz, 1 H), 6.48 (dd, J = 14.7, 10.8 Hz, 1
H), 6.26–6.13 (m, 2 H), 5.83 (d, J = 15.3 Hz, 1 H), 5.79 (m, 1 H),
4.51 (br. s, 1 H, NH), 4.19 (q, J = 7.2 Hz, 2 H), 3.21 (m, 2 H), 2.34
(m, 2 H), 1.42 (s, 9 H), 1.30 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 167.0, 155.8, 144.3, 140.2, 135.9, 131.8,
128.6, 120.6, 79.2, 60.2, 39.6, 33.5, 28.3, 14.2 ppm. MS (ESI): m/z
= 318 [M + Na]+. HRMS (ESI): calcd. for C16H25NO4Na [M +
Na]+ 318.1618; found 318.1613.
(KBr): ν = 3358, 3020, 2954, 2930, 2858, 1717, 1467, 1384, 1254, Dimethyl (2R,3S)-2-Hydroxy-3-methylsuccinate (22): To a stirred
˜
1
1099, 989, 936, 837, 777, 663 cm–1. H NMR (300 MHz, CDCl3):
solution of dimethyl malate (7, 4.0 g, 24.7 mmol) in dry THF
δ = 6.21–6.01 (m, 2 H), 5.74–5.60 (m, 2 H), 4.12 (d, J = 6.0 Hz, 2 (40 mL) at –78 °C was slowly added LHMDS (1 m solution in THF,
H), 3.62 (t, J = 6.8 Hz, 2 H), 2.27 (q, J = 6.8 Hz, 2 H), 0.88 (s, 9 54.3 mL, 54.3 mmol), and the reaction mixture was stirred for 1 h
H), 0.03 (s, 6 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 131.6,
131.3, 131.2, 130.0, 63.2, 62.8, 36.2, 29.6, 25.9, –5.3 ppm. MS
(ESI): m/z = 265 [M + Na]+.
at the same temperature. Methyl iodide (2.31 mL, 37.0 mmol) in
THF (7 mL) was added slowly, and the mixture was stirred at
–78 °C for 3 h. Then, the temperature was gradually increased to
0 °C over 20 h. After completion of the reaction, the reaction mix-
ture was quenched with aqueous NH4Cl solution (10 mL). Later,
the mixture was acidified with dilute HCl, and the THF was evapo-
rated. The resulting solution was extracted with EtOAc
(2ϫ60 mL), and the combined organic layers were dried with an-
hydrous Na2SO4 and concentrated in vacuo. The residue was puri-
fied by column chromatography (silica gel, 60–120 mesh, EtOAc/
hexane, 10:90) to afford a diastereomeric mixture (9:1) of com-
pound 22 (3.75 g, 80%) as a yellow oil; Rf = 0.4 (50% EtOAc/
Ethyl (2E,4E,6E)-9-(tert-Butyldimethylsilyloxy)nona-2,4,6-trienoate
(21): To a stirred solution of IBX (3.80 g, 13.4 mmol) in dry DMSO
(9 mL) under nitrogen was added alcohol 20 (2.17 g, 8.96 mmol) in
dry CH2Cl2 (30 mL) at room temperature. The reaction mixture
was stirred for 2 h and then diluted with an excess amount of ether
(50 mL), and the resulting mixture was filtered through Celite. The
filtrate was washed with saturated aqueous NaHCO3 solution
(10 mL), water (10 mL), and then brine solution (10 mL). The or-
ganic layer was dried with Na2SO4 and concentrated to dryness
under reduced pressure. The residue was purified by flash column
chromatography (5% ethyl acetate in hexane) to give the aldehyde,
which was then dissolved in benzene. To this stirring and refluxing
solution was added the C-2 Wittig ylide (5.53 g, 16.0 mmol) por-
tionwise to obtain the crude trienic ester. The resulting crude prod-
uct was purified by column chromatography on silica gel (60–
hexane). IR (KBr): ν = 3487, 2955, 1740, 1440, 1213, 1104, 1007,
˜
1
838 cm–1. H NMR (300 MHz, CDCl3): δ = 4.20 (t, J = 4.5 Hz, 1
H), 3.78 (s, 3 H), 3.67 (s, 3 H), 3.07 (br. d, J = 6.0 Hz, 1 H), 3.01–
2.93 (m, 1 H), 1.26 (d, J = 7.5 Hz, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 173.2, 173.0, 72.1, 52.1, 51.5, 42.9, 12.5 ppm. MS
(ESI): m/z = 177 [M + H]+.
120 mesh, 10% EtOAc/hexane) to afford compound 21 (2.55 g, (2R,3R)-4-(tert-Butyldimethylsilyloxy)-3-methylbutane-1,2-diol (24):
92% for two steps) as a colorless liquid; Rf = 0.5 (10% EtOAc/ To a suspension of LiAlH4 (5.38 g, 141.7 mmol) in THF (100 mL)
hexane). IR (KBr): ν = 3448, 2954, 2931, 2897, 2858, 1719, 1650, was slowly added a solution of the diastereomeric mixture (9:1)
˜
1467, 1388, 1366, 1256, 1203, 1176, 1099, 1042, 835 cm–1. 1H NMR
(300 MHz, CDCl3): δ = 7.28 (dd, J = 15.8, 12.1 Hz, 1 H), 6.98 (dt, (50 mL). The mixture was heated at reflux for 2 h and then cooled
of methylated dimethyl (R)-malate 22 (6.24 g, 35.4 mmol) in THF
J = 15.8, 6.8 Hz, 1 H), 6.52 (dd, J = 15.1, 10.6 Hz, 1 H), 6.19 (ddd,
J = 15.1, 11.3, 10.5 Hz, 1 H), 5.97–5.79 (m, 2 H), 4.18 (q, J =
6.8 Hz, 2 H), 3.65 (dt, J = 14.3, 6.8 Hz, 2 H), 2.39–2.23 (m, 2 H),
1.28 (t, J = 6.8 Hz, 3 H), 0.89 (s, 9 H), 0.04 (s, 6 H) ppm. 13C NMR
to room temperature. Water (5.54 mL) and NaOH (15% aqueous
solution, 5.54 mL) were added at 0 °C, sequentially and slowly with
care. The mixture was filtered through Celite, which was washed
with Et2O (300 mL). The filtrate was concentrated in vacuo to give
(75 MHz, CDCl3): δ = 166.9, 144.5, 140.7, 136.3, 131.4, 128.1, a diastereomeric mixture (9:1) of triol 23 (3.47 g). A solution of the
Eur. J. Org. Chem. 2013, 376–388
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
383

J. S. Yadav, S. Sengupta
FULL PAPER
crude triol in MeOH (150 mL) was treated with nBu2SnO (7.211 g,
28.97 mmol). The mixture was heated at reflux overnight to give a
clear solution. The solution was concentrated under high vacuum
to give a white solid. A solution of the solid in CHCl3 (150 mL)
was treated with TBSCl (5.25 g, 34.7 mmol) for 20 min. Acetoni-
trile (150 mL) was then added, and the solution was concentrated
to about 50 mL. Hexane (150 mL) was added, and the mixture was
extracted with CH3CN (3ϫ100 mL). The combined acetonitrile
extracts were concentrated. Flash chromatography (hexane/EtOAc,
2:1) gave a diastereomeric mixture (9:1) of 1,2-diol 24 (5.80 g, 70%
yield from the dimethyl ester) as a colorless liquid; Rf = 0.6 (20%
with HCl (1 n solution, pH = 1–2), and the resulting solution was
washed with toluene and basified with NaOH (10% solution,
5 mL). The mixture was extracted with CH2Cl2 (3ϫ10 mL). The
combined extracts were dried with Na2SO4 and then concentrated
to give the crude amine. To the crude amine in THF (5 mL) were
added successively Et3N (0.538 mL, 3.86 mmol) and (Boc)2O
(0.76 mL, 3.47 mmol) at 0 °C, and the mixture was allowed to come
to room temperature over 2–3 h. After completion of the reaction,
the mixture was diluted with EtOAc (20 mL). The organic layer
was washed with water (5 mL) and brine solution (5 mL), dried
with Na2SO4, and concentrated under reduced pressure. Purifica-
tion by flash chromatography on silica gel (60–120 mesh, 20%
EtOAc/hexane). IR (KBr): ν = 3384, 2959, 2928, 2866, 1650, 1462,
˜
1254, 1075, 1026, 837, 775 cm–1. 1H NMR (300 MHz, CDCl3): δ = EtOAc/hexane) afforded compound 27 (0.76 g, quantitative as
3.86 (br. s, 1 H), 3.71 (dd, J = 10.0, 4.1 Hz, 1 H), 3.67–3.48 (m, 4
H), 2.47 (br. s, 1 H), 1.88–1.74 (m, 1 H), 0.91 (s, 9 H), 0.86 (d, J =
7.0 Hz, 3 H), 0.09 (s, 6 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
76.6, 76.3, 64.7, 64.6, 37.1, 37.0, 26.9, 25.7, 25.6, 13.6, 13.4, –5.4,
–5.7 ppm. MS (ESI): m/z = 353 [M + Sn + H]+.
combined yield for two steps) as a yellow liquid; Rf = 0.5 (20%
EtOAc/hexane). [α]2D4 = –13.9 (c = 2.52, CHCl ). IR (KBr): ν =
˜
3
3448, 2957, 2930, 2859, 1693, 1513, 1366, 1253, 1171, 1094, 839,
1
777 cm–1. H NMR (300 MHz, CDCl3): δ = 4.98 (br. s, 1 H), 4.03
(br. s, 1 H), 3.75 (dd, J = 10.6, 4.5 Hz, 1 H), 3.61–3.51 (m, 2 H),
3.38–3.31 (m, 1 H), 3.10–3.02 (m, 1 H), 1.81–1.70 (m, 1 H), 1.44
(s, 9 H), 0.90 (s, 9 H), 0.84 (d, J = 7.5 Hz, 3 H), 0.08 (s, 6 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 156.3, 79.0, 75.8, 68.3, 44.5, 37.6,
28.3, 25.7, 18.0, 13.0, –5.7 ppm. MS (ESI): m/z = 356 [M + Na]+.
HRMS (ESI): calcd. for C16H35O4NSiNa [M + Na]+ 356.2233;
found 356.2227.
tert-Butyldimethyl{(R)-2-[(R)-oxiran-2-yl]propoxy}silane (25): To a
solution of the diastereomeric mixture (9:1) of 1,2-diol 24 (8.0 g,
34.2 mmol) in THF (200 mL) at 0 °C was added NaH (60% in
mineral oil, 0.90 g, 37.6 mmol). The mixture was stirred at 0 °C for
20 min. Then 1-(p-tolylsulfonyl)imidazole (8.45 g, 37.6 mmol) was
added slowly with caution. Then, the cooling bath was removed,
and the mixture was stirred at room temperature for 14 h. The reac-
tion was quenched by the addition of a saturated aqueous NH4Cl
solution (20 mL). The mixture was extracted with Et2O
(3ϫ50 mL), and the combined organic extracts were washed with
water (10 mL) and brine solution (5 mL), dried with MgSO4, and
concentrated. Column chromatography (hexane/EtOAc, 20:1) gave
a diastereomeric mixture (9:1) of epoxide 25 (6.50 g, 88%); Rf =
tert-Butyl (R)-5-[(R)-1-(tert-Butyldimethylsilyloxy)propan-2-yl]-2,2-
dimethyloxazolidine-3-carboxylate (28): To a stirred solution of
compound 27 (0.87 g, 2.60 mmol) in CH2Cl2/Et2O (9:1, 20 mL)
were added successively 2,2-dimethoxypropane (1.9 mL,
15.63 mmol) and CSA (camphorsulfonic acid, catalytic amount) at
room temperature. The reaction mixture was stirred for 1 h at the
same temperature and then checked by TLC. After the completion
of the reaction, the mixture was quenched with saturated NaHCO3
solution (5 mL), and the resulting solution was extracted with
CH2Cl2 (3ϫ20 mL). The combined extracts were dried with
Na2SO4 and then concentrated under reduced pressure. Purifica-
tion of the residue by flash chromatography (4% EtOAc/hexane)
afforded compound 28 (0.77 g, 80%) as a colorless liquid; Rf = 0.6
0.6 (10% EtOAc/hexane). IR (KBr): ν = 2956, 2929, 2857, 1466,
˜
1254, 1096, 1035, 838, 776, 667 cm–1. 1H NMR (300 MHz, CDCl3):
δ = 3.63 (d, J = 5.3 Hz, 2 H), 2.83–2.74 (m, 1 H), 2.71–2.66 (m, 1
H), 2.46 (ddd, J = 8.3, 5.3, 3.0 Hz, 1 H), 1.54–1.40 (m, 1 H), 0.95
(d, J = 6.8 Hz, 3 H), 0.89 (s, 9 H), 0.04 (d, J = 1.5 Hz, 6 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 65.1, 53.7, 45.5, 38.6, 29.6, 25.7,
12.5, –5.6 ppm. MS (ESI): m/z = 217 [M + H]+.
(10% EtOAc/hexane). [α]2D4 = –6.7 (c = 1.2, CHCl ). IR (KBr): ν =
˜
3
3451, 2958, 2932, 2892, 2860, 1702, 1467, 1392, 1255, 1175, 1097,
1
1049, 838 cm–1. H NMR (300 MHz, CDCl3): δ = 3.96–3.88 (m, 1
(2R,3R)-1-Azido-4-(tert-butyldimethylsilyloxy)-3-methylbutan-2-ol
(26): To a solution of the diastereomeric mixture (9:1) of epoxide 25
(1.40 g, 6.48 mmol) in MeOH/H2O (8:2, 30 mL) were added NaN3
(1.40 g, 21.5 mmol) and NH4Cl (0.58 g, 10.7 mmol). The mixture
was stirred at 80 °C for 2 h. After the completion of the reaction,
the mixture was cooled to room temperature. The MeOH was re-
moved in vacuo, and the residue was diluted with EtOAc (20 mL).
Then, the reaction mixture was extracted with Et2O (3ϫ30 mL).
The combined organic extracts were washed with water (5 mL) and
brine solution (5 mL), dried with MgSO4, and concentrated. Col-
umn chromatography (hexane/EtOAc, 10:1) gave a diastereomeric
mixture (9:1) of azide 26 (1.59 g, 95% yield); Rf = 0.4 (20% EtOAc/
H), 3.66–3.46 (m, 3 H), 3.07 (t, J = 9.4 Hz, 1 H), 1.77 (m, 1 H),
1.52–1.45 (m, 15 H), 0.93–0.89 (m, 12 H), 0.04 (s, 6 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 152.3, 152.0, 93.0, 92.7, 79.8, 79.1,
74.9, 74.4, 64.5, 48.9, 39.0, 38.6, 28.5, 27.1, 26.1, 25.9, 25.1, 24.1,
18.2, 12.3, 12.1, –5.5 ppm. MS (ESI): m/z = 396 [M + Na]+. HRMS
(ESI): calcd. for C19H39O4NSiNa [M + Na]+ 396.2546; found
396.2548.
tert-Butyl (R)-5-[(R)-1-Hydroxypropan-2-yl]-2,2-dimethyloxazolid-
ine-3-carboxylate (29): To an ice cooled solution of silyl ether 28
(0.94 g, 2.53 mmol) in dry THF (10 mL) was added TBAF
(2.60 mL, 1 m solution in THF, 2.60 mmol). After 15 min of stir-
ring, the reaction mixture was warmed to room temperature and
then stirred for another 2 h. After completion the reaction, the mix-
ture was cooled and then quenched with an ammonium chloride
solution (5 mL). The resulting solution was extracted with EtOAc
(3ϫ10 mL), dried with anhydrous Na2SO4, and concentrated in
vacuo. The residue was purified by silica gel chromatography (20%
EtOAc/hexane) to give alcohol 29 (0.62 g, 95%) as a colorless oil;
Rf = 0.5 (20% EtOAc/hexane). [α]2D4 = –16.8 (c = 1.15, CHCl3). IR
hexane). IR (KBr): ν = 3448, 2921, 2851, 2101, 1732, 1399, 1088,
˜
776 cm–1. 1H NMR (300 MHz, CDCl3): δ = 3.77 (dd, J = 10.0,
4.0 Hz, 1 H), 3.70–3.64 (m, 1 H), 3.59 (dd, J = 9.8, 7.5 Hz, 1 H),
3.41–3.32 (m, 1 H), 3.26–3.18 (m, 1 H), 1.91–1.83 (m, 1 H), 0.91
(s, 9 H), 0.87 (d, J = 6.8 Hz, 3 H), 0.09 (s, 6 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 75.8, 67.7, 55.0, 37.4, 37.2, 25.7, 13.2, –5.7,
–5.8 ppm. MS (ESI): m/z = 282 [M + Na]+. HRMS (ESI): calcd.
for C11H25O2N3SiNa [M + Na]+ 282.1613; found 282.1607.
tert-Butyl (2R,3R)-4-(tert-Butyldimethylsilyloxy)-2-hydroxymeth-
ylbutylcarbamate (27): TPP (0.60 g, 2.31 mmol) was added to a
solution of compound 26 (0.50 g, 1.93 mmol) in THF/H2O (4:1,
5 mL) at room temperature. After 20 h, the reaction was quenched
(KBr): ν = 3459, 2975, 2931, 1695, 1467, 1399, 1255, 1096, 1045,
˜
871, 766 cm–1. 1H NMR (300 MHz, CDCl3): δ = 3.89 (q, J =
9.5 Hz, 1 H), 3.79–3.49 (m, 3 H), 3.18–3.03 (m, 1 H), 2.37 (br. s, 1
H), 1.92–1.77 (m, 1 H), 1.61–1.37 (m, 15 H), 0.87 (d, J = 6.6 Hz,
384
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 376–388

The Formal Total Synthesis of FR252921 – An Immunosuppressant
3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 152.1, 151.8, 93.7,
93.4, 80.1, 79.5, 77.8, 66.6, 49.9, 39.0, 28.3, 27.1, 26.0, 25.0, 24.2,
12.7 ppm. MS (ESI): m/z = 282 [M + Na]+. HRMS (ESI): calcd.
for C13H25O4NNa [M + Na]+ 282.1681; found 282.1679.
(150 mL). Then, the solution was washed with KOH (10% solution,
30 mL) portionwise and with brine solution (1ϫ20 mL) and then
dried with anhydrous Na2SO4. Removal of solvent was done in
vacuo to afford a crude mixture (alcohol/aldehyde, 1:4), which
without any further purification underwent PCC oxidation in the
next step. To a stirred solution of Celite (14.5 g) in CH2Cl2 (90 mL)
at 0 °C was added PCC (9.60 g, 45.0 mmol). After 10 min, the
crude mixture of the alcohol and aldehyde was added at the same
temperature, and the reaction mixture was stirred for 2 h at 0 °C.
After the reaction was completed, the reaction mass was filtered,
and the filtrate was concentrated in vacuo to get the crude alde-
hyde. Purification by column chromatography on silica gel (60–
120 mesh, 10 % EtOAc/hexane) afforded compound 31 (16.6 g,
45% for two steps) as a colorless liquid; Rf = 0.5 (10% EtOAc/
(S)-2-[(R)-3-(tert-Butoxycarbonyl)-2,2-dimethyloxazolidin-5-yl]-
propanoic Acid (4): To a stirred solution of IBX (0.88 g, 3.08 mmol)
in anhydrous DMSO (4 mL) under nitrogen was added alcohol 29
(0.50 g, 1.93 mmol) in dry CH2Cl2 (12 mL) at room temperature.
The reaction mixture was stirred for 2 h and then diluted with an
excess amount of ether (20 mL). The resulting mixture was filtered
through Celite, and the filtrate was washed with saturated aqueous
NaHCO3 solution (5 mL), water (5 mL), and then brine solution
(5 mL). The organic layer was dried with Na2SO4 and concentrated
to dryness under reduced pressure. The residue was used for next
step without any further purification. To a solution of the aldehyde
(0.44 g, 1.73 mmol) in tert-butyl alcohol (10 mL) was added 2-
methyl-2-butene (2 m solution in THF, 1.08 mL, 2.16 mmol) at
room temperature. Sodium dihydrogenphosphate (0.88 g,
5.67 mmol) and sodium chlorite (255 g, 2.83 mmol) were dissolved
in water (5 mL) to make a clear solution, which was subsequently
added to the above-mentioned reaction mixture at 0 °C. The reac-
tion mixture was allowed to stir for an additional 3 h at room tem-
perature and then was extracted with ethyl acetate (3ϫ10 mL). The
combined organic layers were washed with brine (5 mL), dried with
anhydrous Na2SO4, and concentrated under reduced pressure. The
crude product was purified by column chromatography (EtOAc/
hexane, 3:7) to afford acid fragment 4 (0.38 g, 80%) as a colorless
oil; Rf = 0.3 (30% EtOAc/hexane). [α]2D4 = –19.3 (c = 0.93, CHCl3).
hexane). IR (KBr): ν = 3457, 3067, 2933, 2858, 1733, 1467, 1380,
˜
1
1267, 1162, 1110, 1060, 823 cm–1. H NMR (300 MHz, CDCl3): δ
= 9.37 (s, 1 H), 7.64 (d, J = 7.0 Hz, 4 H), 7.38 (m, 6 H), 6.52 (t, J
= 5.0 Hz, 1 H), 4.47 (d, J = 5.0 Hz, 2 H), 1.55 (s, 3 H), 1.06 (s, 9
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 194.4, 152.4, 137.7,
135.4, 132.9, 129.8, 127.7, 61.1, 26.6, 19.0, 9.2 ppm. MS (ESI): m/z
= 361 [M + Na]+. HRMS (ESI): calcd. for C21H26O2SiNa [M +
Na]+ 361.1600; found 361.1584.
Ethyl (E)-6-(tert-Butyldiphenylsilyloxy)-3-hydroxy-4-methylhex-4-
enoate (32): To a stirred solution of 31 (15.0 g, 44.2 mmol) in anhy-
drous THF (150 mL) was added ethyl bromoacetate (10.2 mL,
110.5 mmol), and the reaction mixture was cooled to –10 °C. After
that, the Zn–Cu couple (20.0 g) was added portionwise at the same
temperature, and the reaction was stirred for an additional 1 h. The
metallic Zn–Cu couple was removed by filtration and washed with
dry petroleum ether (50 mL). The solvent was removed until the
solution became turbid. At this stage, water (20 mL) was added to
the reaction mixture. The white precipitate of zinc hydroxide, thus
formed, was removed by filtration and washed with ethyl acetate
(4ϫ50 mL). The organic layer was separated and dried with anhy-
drous Na2SO4. Removal of the solvent in vacuo and purification
of the residue by silica gel column chromatography (10% ethyl acet-
ate in hexane) afforded 32 (17.8 g, 95% yield) as a colorless liquid;
IR (KBr): ν = 3452, 2977, 2927, 1699, 1508, 1460, 1392, 1252, 1172,
˜
1
1103, 1048, 870, 640 cm–1. H NMR (300 MHz, CDCl3): δ = 4.28
(m, 1 H), 3.79–3.58 (m, 1 H), 3.20–3.12 (m, 1 H), 2.69–2.63 (m, 1
H), 1.54–1.46 (m, 15 H), 1.19 (d, J = 6.9 Hz, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 179.0, 152.4, 151.8, 93.8, 93.5, 80.5, 79.7,
74.3, 48.4, 48.1, 43.0, 42.8, 28.3, 27.0, 26.0, 25.1, 24.2, 12.8,
12.6 ppm. MS (ESI): m/z = 296 [M + Na]+. HRMS (ESI): calcd.
for C13H23O5NNa [M + Na]+ 296.1473; found 296.1463.
tert-Butyl(3-methylbut-2-enyloxy)diphenylsilane (30): To a stirred
solution of prenol (8, 10.0 g, 116.3 mmol) in dry CH2Cl2 (300 mL)
were added imidazole (11.8 g, 174.4 mmol) and TBDPSCl (35.0 g,
127.9 mmol) at 0 °C. The reaction mixture was stirred at room tem-
perature for 30 min. After completion of the reaction, the mixture
was diluted with CH2Cl2 (100 mL), and the resulting solution was
washed with water (20 mL) and brine (20 mL) and then dried with
anhydrous Na2SO4. Removal of solvent in vacuo and purification
by silica gel column chromatography (5% ethyl acetate in hexane)
afforded 30 (37.0 g, 98% yield) as a colorless liquid; Rf = 0.5 (5%
R = 0.2 (10% EtOAc/hexane). IR (KBr): ν = 3457, 3069, 2933,
˜
f
2858, 1734, 1468, 1380, 1267, 1161, 1110, 1061, 941, 823, 704 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.64 (d, J = 7.5 Hz, 4 H), 7.39–
7.32 (m, 6 H), 5.64 (t, J = 6.0 Hz, 1 H), 4.34 (m, 1 H), 4.20 (d, J
= 6.0 Hz, 2 H), 4.14 (q, J = 6.8 Hz, 2 H), 2.66 (br. s, 1 H), 2.43
(dd, J = 6.8, 3.0 Hz, 2 H), 1.44 (s, 3 H), 1.27 (t, J = 6.8 Hz, 3 H),
1.03 (s, 9 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 171.7, 135.5,
129.7, 129.5, 127.7, 127.6, 125.9, 70.5, 62.3, 60.8, 37.6, 26.7, 19.1,
14.1, 13.3 ppm. MS (ESI): m/z = 449 [M + Na]+. HRMS (ESI):
calcd. for C25H34O4SiNa [M + Na]+ 449.2124; found 449.2107.
EtOAc/hexane). IR (KBr): ν = 3449, 3067, 2959, 2932, 2858, 1893,
˜
Ethyl (E)-3-(tert-Butyldimethylsilyloxy)-6-(tert-butyldiphenyl-
silyloxy)-4-ethylhexenoate (33): To an ice cooled solution of 32
(6.0 g, 14.1 mmol) in CH2Cl2 (40 mL), was added imidazole
(1.50 g, 22.5 mmol) followed by TBDMSCl (2.50 g, 16.9 mmol).
The reaction mixture was stirred for 4 h and then was quenched
with NH4Cl solution (5 mL). The reaction mixture was extracted
with CH2Cl2 (3ϫ10 mL). The combined organic layers were dried
with anhydrous Na2SO4 and concentrated to dryness under re-
duced pressure. The crude mixture was purified by silica gel column
chromatography (5% ethyl acetate/hexane) to afford compound 33
(7.40 g, 98%) as a colorless liquid; Rf = 0.8 (10% EtOAc/hexane).
1
1673, 1474, 1429, 1193, 1111, 822, 739 cm–1. H NMR (300 MHz,
CDCl3): δ = 7.66–7.63 (m, 4 H), 7.37–7.30 (m, 6 H), 5.36–5.30 (m,
1 H), 4.13 (d, J = 6.8 Hz, 2 H), 1.68 (s, 3 H), 1.45 (s, 3 H), 1.03 (s,
9 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 135.6, 134.0, 133.6,
129.4, 127.5, 124.2, 61.0, 26.8, 25.6, 19.1, 17.8 ppm. MS (ESI): m/z
= 347 [M + Na]+. HRMS (ESI): calcd. for C21H28OSiNa [M +
Na]+ 347.1807; found 347.1800.
(E)-4-(tert-Butyldiphenylsilyloxy)-2-methylbut-2-enal (31): A 70%
solution of TBHP (tert-butyl hydroperoxide, 53.6 mL, 391.2 mmol,
3.6 equiv.) was added to SeO2 (0.63 g, 5.70 mmol, 0.15 equiv.) in
CH2Cl2 (40 mL) at 0 °C. After stirring for some time, compound
30 (35.3 g, 108.6 mmol) in CH2Cl2 (150 mL) was added dropwise
at the same temperature, and the reaction was left for 7 h at 25 °C.
After the completion of the reaction (checked by TLC), the CH2Cl2
was evaporated, and the residue was diluted with diethyl ether
IR (KBr): ν = 2955, 2932, 2893, 2858, 1738, 1468, 1254, 1167, 1109,
˜
1075, 833, 703, 613 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.64
(d, J = 6.8 Hz, 4 H), 7.39–7.33 (m, 6 H), 5.64 (t, J = 6.0 Hz, 1 H),
4.47 (q, J = 4.5 Hz, 1 H), 4.19 (m, 2 H), 4.09 (q, J = 6.8 Hz, 2 H),
2.47 (dd, J = 13.6, 9.0 Hz, 1 H), 2.28 (dd, J = 14.3, 4.5 Hz, 1 H),
Eur. J. Org. Chem. 2013, 376–388
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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385

J. S. Yadav, S. Sengupta
FULL PAPER
1.45 (s, 3 H), 1.26 (t, J = 6.8 Hz, 3 H), 1.03 (s, 9 H), 0.86 (s, 9 H),
perature. The reaction mixture was stirred for 2 h and then diluted
0.01 (d, J = 10.6 Hz, 6 H) ppm. 13C NMR (75 MHz, CDCl3): δ = with an excess amount of ether (30 mL). The resulting mixture was
171.3, 137.6, 135.6, 133.8, 127.6, 125.8, 74.9, 60.6, 60.3, 42.4, 26.7,
25.7, 19.1, 18.0, 14.2, 11.3, –5.3, –4.7 ppm. MS (ESI): m/z = 563
[M + Na]+. HRMS (ESI): calcd. for C31H48O4Si2Na [M + Na]+
563.2988; found 563.2999.
filtered through Celite. The filtrate was washed with saturated
aqueous NaHCO3 solution (5 mL), water (5 mL), and brine solu-
tion (5 mL). The organic layer was dried with Na2SO4 and concen-
trated to dryness under reduced pressure. The residue was purified
by flash column chromatography (20% ethyl acetate in hexane) to
give the pure aldehyde (3.70 g, 90%) as a colorless liquid. To a
solution of the aldehyde (3.50 g, 11.6 mmol) and sulfone 35 (2.60 g,
8.30 mmol) in dry THF (60 mL) was bubbled argon for 30 min to
degas the reaction mixture. The mixture was then cooled at –78 °C,
and KHMDS (0.5 m in toluene, 18.2 mL, 9.12 mmol) was added
dropwise. The reaction was warmed to 0 °C, stirred for 1 h at room
temperature, and then quenched with a saturated NH4Cl solution
(10 mL). The layers were separated, and the aqueous layer was ex-
tracted with EtOAc (2ϫ50 mL). The combined organic layers were
washed with brine (5 mL), dried with Na2SO4, and concentrated
to a residue. Purification by flash column chromatography on silica
gel (5% EtOAc/Hexane) afforded Julia product 36 (3.29 g, 72%) as
Ethyl (E)-3-(tert-Butyldimethylsilyloxy)-6-hydroxy-4-methylhex-4-
enoate (34): To a stirred solution of 33 (5.0 g, 9.2 mmol) in anhy-
drous MeOH (30 mL) was added NH4F (1.70 g, 46.0 mmol) at
25 °C, and the reaction was stirred for 12 h. After complete removal
of the tert-butyldiphenylsilyl group (checked by TLC), saturated
NH4Cl solution (10 mL) was added, and the MeOH was removed
under vacuum. The crude reaction mixture was diluted with EtOAc
(30 mL), and the organic layer was washed with brine (5 mL), dried
with Na2SO4, and concentrated in vacuo. The residue was purified
by column chromatography (silica gel, 10Ǟ20% EtOAc in hexane)
to yield 34 (2.70 g, 97% yield) as a colorless oil; Rf = 0.3 (20%
EtOAc/hexane). IR (KBr): ν = 3429, 2933, 2895, 2858, 1734, 1466,
˜
1374, 1255, 1081, 835, 777, 669 cm–1. 1H NMR (300 MHz, CDCl3):
δ = 5.61 (t, J = 6.8 Hz, 1 H), 4.47 (q, J = 4.5 Hz, 1 H), 4.12 (d, J
= 6.8 Hz, 2 H), 4.08 (q, J = 6.8 Hz, 2 H), 2.50 (dd, J = 14.3, 8.3 Hz,
1 H), 2.34 (dd, J = 13.6, 4.5 Hz, 1 H), 1.65 (s, 3 H), 1.43 (br. s, 1
H), 1.26 (t, J = 6.8 Hz, 3 H), 0.85 (s, 9 H), 0.02 (d, J = 11.3 Hz, 6
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 171.3, 139.2, 125.1, 74.8,
60.4, 58.7, 42.3, 25.5, 17.9, 14.0, 11.1, –5.5, –4.8 ppm. MS (ESI):
m/z = 325 [M + Na]+. HRMS (ESI): calcd. for C15H30O4SiNa [M
+ Na]+ 325.1811; found 325.1800.
a yellow liquid; R = 0.9 (10% EtOAc/hexane). IR (KBr): ν = 2927,
˜
f
2857, 1739, 1633, 1372, 1254, 1167, 1077, 962, 835, 669 cm–1. 1H
NMR (300 MHz, CDCl3): δ = 6.13 (dd, J = 14.9, 10.7 Hz, 1 H),
5.92 (d, J = 10.7 Hz, 1 H), 5.66–5.56 (m, 1 H), 4.54–4.46 (m, 1 H),
4.09 (q, J = 6.8 Hz, 2 H), 2.53 (dd, J = 14.2, 9.0 Hz, 1 H), 2.35 (dt,
J = 14.3, 10.2, 4.1 Hz, 1 H), 2.17–2.05 (m, 2 H), 1.70 (s, 3 H), 1.42–
1.23 (m, 13 H), 0.89–0.85 (m, 12 H), 0.02 (d, J = 13.4 Hz, 6
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 171.3, 136.0, 135.2,
125.8, 125.7, 75.3, 60.2, 42.5, 32.9, 31.8, 29.6, 29.3, 29.1, 27.6, 25.6,
22.6, 14.1, 14.0, 11.4, –4.8, –5.4 ppm. MS (ESI): m/z = 419 [M +
Na]+. HRMS (ESI): calcd. for C23H44O3SiNa [M + Na]+ 419.2957;
found 419.2957.
2-(Octylsulfonyl)benzo[d]thiazole (35): To a stirred solution of octyl
bromide (5.0 g, 25.9 mmol, 1.0 equiv.) in THF (60 mL) were suc-
cessively added Et3N (5.42 mL, 38.8 mmol) and benzothiazole
(5.20 g, 31.1 mmol) at 0 °C, and the reaction mixture was allowed
to reach room temperature. After stirring for 2 h, the mixture was
quenched by the addition of water (20 mL), and the layers were
separated. The aqueous phase was extracted with EtOAc
(3ϫ10 mL). The combined organic layers were washed with brine
(10 mL), dried with MgSO4, filtered, and concentrated in vacuo.
The residue was purified by column chromatography (silica gel,
2Ǟ5% EtOAc in hexane) to give the sulfide (6.80 g, 95% yield) as
a yellow liquid. To a stirred solution of the sulfide (5.0 g,
17.92 mmol) in CH2Cl2 (50 mL) was added mCPBA (meta-chloro-
peroxybenzoic acid, 13.2 g, 53.7 mmol) portionwise at 0 °C for
10 min. The reaction mixture was stirred for 4 h at room tempera-
ture. After the completion of the reaction, saturated NaHCO3
(10 mL) and saturated NaHSO3 (10 mL) solutions were added suc-
cessively, and the solution was stirred for another 30 min at room
temperature. After the layers were separated, the aqueous phase
was extracted with CH2Cl2 (3ϫ20 mL). The combined organic lay-
ers were washed with brine (10 mL), dried with MgSO4, filtered,
and concentrated in vacuo. The residue was purified by column
chromatography (silica gel, 10Ǟ20% EtOAct in hexane) to give 35
(5.0 g, 90%) as a semisolid compound; Rf = 0.4 (20% EtOAc/hex-
Ethyl (4E,6E)-3-Hydroxy-4-methyltetradeca-4,6-dienoate (37): To
an ice cooled solution of silyl ether 36 (4.50 g, 11.4 mmol) in dry
THF (35 mL) was added TBAF (1 m solution in THF, 17 mL,
17.0 mmol). After 15 min of stirring, the reaction mixture was
warmed to room temperature and then stirred for another 2 h. Af-
ter completion, the reaction mixture was cooled and then quenched
with an ammonium chloride solution (5 mL). The resulting mixture
was extracted with EtOAc (3 ϫ 10 mL), dried with anhydrous
Na2SO4, and concentrated in vacuo. The residue was purified by
silica gel chromatography (10% EtOAc/hexane) to give alcohol 37
(3.0 g, 95%) as a yellow oil; Rf = 0.2 (20% EtOAc/hexane). IR
(KBr): ν = 3453, 2925, 2855, 1734, 1460, 1271, 1165, 1035, 888,
˜
770, 536 cm–1. 1H NMR (300 MHz, CDCl3): δ = 6.16 (dd, J = 14.9,
10.7 Hz, 1 H), 5.99 (d, J = 10.7 Hz, 1 H), 5.69–5.59 (m, 1 H), 4.48–
4.39 (m, 1 H), 4.15 (q, J = 7.2 Hz, 2 H), 2.53–2.48 (m, 2 H), 2.08
(q, J = 7.0 Hz, 2 H), 1.73 (s, 3 H), 1.40–1.24 (m, 13 H), 0.90–0.86
(m, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 172.4, 135.8,
133.1, 125.8, 125.6, 73.1, 60.6, 40.1, 32.9, 31.7, 29.6, 29.3, 29.1,
22.6, 14.1, 14.0, 12.3 ppm. MS (ESI): m/z = 305 [M + Na]+. HRMS
(ESI): calcd. for C17H30O3Na [M + Na]+ 305.2092; found 305.2095.
Ethyl (R,4E,6E)-3-Acetoxy-4-methyltetradeca-4,6-dienoate (38): To
a suspension of racemic alcohol 37 (3.0 g, 10.6 mmol) in hexane
(150 mL) were added Amano lipase PS-C (2.0 g) and molecular
sieves (4 Å, 5.50 g), followed by vinyl acetate (5.50 g, 63.6 mmol)
as the acylating agent. The reaction mixture was stirred at 30 °C
for 30 h, filtered through Celite, and concentrated. Purification by
chromatography on silica gel (5% ethyl acetate in hexane) yielded
allylic (R)-acetate 38 (1.50 g, 45% yield) and the unreacted (S)-
alcohol (1.80 g, 53 % yield); Rf = 0.3 (10 % EtOAc/hexane). 1H
NMR (300 MHz, CDCl3): δ = 6.18 (dd, J = 14.3, 10.6 Hz, 1 H),
6.06 (d, J = 10.6 Hz, 1 H), 5.78–5.67 (m, 1 H), 5.58 (dd, J = 9.1,
5.3 Hz, 1 H), 4.12 (q, J = 6.8 Hz, 2 H), 2.72 (dd, J = 15.1, 9.1 Hz,
1
ane). H NMR (300 MHz, CDCl3): δ = 8.24 (d, J = 8.9 Hz, 1 H),
8.02 (d, J = 8.9 Hz, 1 H), 7.68–7.57 (m, 2 H), 3.51 (tapp, J = 7.9 Hz,
2 H), 1.93–1.82 (m, 2 H), 1.46–1.24 (m, 10 H), 0.87–0.83 (m, 3
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 165.8, 152.5, 136.4,
127.8, 127.4, 125.0, 122.1, 54.4, 31.3, 28.5, 27.9, 22.2, 21.9,
13.8 ppm. MS (ESI): m/z = 312 [M + H]+. HRMS (ESI): calcd. for
C15H21O2NS2Na [M + Na]+ 334.0911; found 334.0902.
Ethyl (4E,6E)-3-(tert-Butyldimethylsilyloxy)-4-methyltetradeca-4,6-
dienoate (36): To a stirred solution of IBX (4.20 g, 14.6 mmol) in
anhydrous DMSO (9 mL) under nitrogen was added alcohol 34
(2.40 g, 7.97 mmol) in anhydrous CH2Cl2 (30 mL) at room tem-
386
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The Formal Total Synthesis of FR252921 – An Immunosuppressant
1
1 H), 2.57 (dd, J = 15.1, 5.3 Hz, 1 H), 2.13–2.04 (m, 2 H), 2.04 (s,
3 H), 1.74 (s, 3 H), 1.42–1.21 (m, 13 H), 0.88 (t, J = 6.8 Hz, 3
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 170.0, 169.7, 136.9,
134.2, 128.3, 125.2, 75.1, 60.6, 38.6, 32.9, 31.7, 29.6, 29.2, 29.1,
22.6, 21.0, 14.1, 14.0, 12.3 ppm. MS (ESI): m/z = 347 [M + Na]+.
1175, 1137, 1055, 1011, 767 cm–1. H NMR (300 MHz, CDCl3): δ
= 7.26 (m, 1 H), 6.49 (dd, J = 14.5, 10.8 Hz, 1 H), 6.27–6.09 (m, 2
H, NH), 5.85 (m, 1 H), 5.85 (d, J = 15.5 Hz, 1 H), 4.17 (q, J =
7.0 Hz, 2 H), 4.07 (m, 1 H), 3.67 (br. s, 1 H), 3.35 (m, 2 H), 3.07
(t, J = 9.6 Hz, 1 H), 2.35 (m, 3 H), 1.53 (br. s, 3 H), 1.46 (br. s, 3
H), 1.46 (s, 9 H), 1.30 (t, J = 7.2 Hz, 3 H), 1.12 (d, J = 6.8 Hz, 3
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 173.2, 167.0, 152.1,
151.8, 144.2, 140.1, 135.8, 131.8, 128.8, 120.8, 93.8, 93.7, 80.3, 80.0,
75.0, 60.2, 49.5, 49.3, 44.2, 44.0, 38.5, 33.0, 28.4, 27.2, 26.2, 25.2,
24.2, 14.2, 13.3 ppm. MS (ESI): m/z = 473 [M + Na]+. HRMS
(ESI): calcd. for C24H38O6N2Na [M + Na]+ 473.2627; found
473.2621.
Methyl (R,4E,6E)-3-Hydroxy-4-methyltetradeca-4,6-dienoate (39):
To a suspension of K2CO3 (0.21 g) in methanol (1.5 mL) was added
allylic (R)-acetate 38 (0.20 g, 0.62 mmol). The reaction mixture was
stirred for 15 min at –10 °C and then was filtered. EtOAc (10 mL)
was added. The combined filtrate was washed with water (2 mL)
and brine (2 mL) and then dried with Na2SO4. The solvents were
removed in vacuo, and the resulting residue was purified by
chromatography on silica gel (10% ethyl acetate in hexane) to give
allylic (R)-alcohol 39 (0.15 g, 92% yield) as a yellow oil; Rf = 0.15
Ethyl 9-(2E,4E,6E)-{(2S,3R)-3-Hydroxy-4-[(R,4E,6E)-3-hydroxy-4-
methyltetradeca-4,6-dienamido]-2-methylbutanamido}nona-2,4,6-tri-
enoate (41): A stirred solution of the amide 40 (0.05 g, 0.12 mmol)
in dry CH2Cl2/MeOH (1:1, 2 mL) at 0 °C under nitrogen was
treated with CF3COOH (0.8 mL), and the resulting mixture was
stirred at room temperature for 4 h. The reaction mixture was con-
centrated, and the residue was dried under high vacuum. The amine
salt was basified with DIPEA (0.03 mL, 0.18 mmol) in dry CH2Cl2
(2 mL) to generate the corresponding free amino alcohol. In an-
other round-bottomed flask, to the previously obtained carboxylic
acid 5 (0.03 g, 0.13 mmol) in dry CH3CN (2 mL) was added se-
quentially 1-hydroxybenzotriazole (0.02 g, 0.13 mmol, 1.1 equiv.),
O-(1H-benzotriazole-1-yl)-N,N,NЈ,NЈ-tetramethyluronium hexaflu-
orophosphate (0.05 g, 0.13 mmol, 1.1 equiv.), and N-methylmorph-
oline (40 μL, 0.36 mmol, 3.0 equiv.). The solution was warmed to
room temperature, and after stirring for 6 h, the resulting brown
mixture was hydrolyzed by the addition of water (2 mL). CH3CN
was removed under reduced pressure, and the resulting aqueous
layer was extracted with EtOAc (3ϫ5 mL). The combined organic
layers were successively washed with a saturated aqueous solution
of NaHCO3 (5 mL), a saturated aqueous solution of NH4Cl
(5 mL), and brine solution (5 mL). The organic layer was dried
with MgSO4 and filtered, and the solvents were evaporated to dry-
ness under reduced pressure. The residue, thus obtained, was puri-
fied by flash chromatography on silica gel (hexane/EtOAc, from
80:20 to 50:50), which provided the desired diamide 41 (0.06 g, 90%
over 2 steps) as a colorless oil; Rf = 0.35 (10% MeOH/CHCl3).
(20% EtOAc/hexane). [α]2D4 = +1.3 (c = 1.0, CHCl ). IR (KBr): ν
˜
3
= 3453, 2925, 2854, 1737, 1638, 1438, 1272, 1164, 965 cm–1. 1H
NMR (300 MHz, CDCl3): δ = 6.17 (dd, J = 14.7, 10.7 Hz, 1 H),
6.00 (d, J = 10.8 Hz, 1 H), 5.70–5.60 (m, 1 H), 4.43–4.40 (m, 1 H),
3.70 (s, 3 H), 2.69 (br. s, 1 H), 2.53–2.50 (m, 2 H), 2.08 (q, J =
6.8 Hz, 2 H), 1.74 (s, 3 H), 1.38–1.28 (m, 10 H), 0.90–0.86 (m, 3
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 172.9, 136.0, 134.8,
125.9, 125.6, 73.1, 51.7, 40.0, 32.9, 31.8, 29.6, 29.3, 29.1, 22.6, 14.0,
12.4 ppm. MS (ESI): m/z = 291 [M + Na]+. HRMS (ESI): calcd.
for C16H28O3Na [M + Na]+ 291.1936; found 291.1942.
(R,4E,6E)-3-Hydroxy-4-methyltetradeca-4,6-dienoic Acid (5): To a
stirred solution of the previously obtained methyl ester (R)-39
(0.11 g, 0.40 μmol, 1.0 equiv.) in a mixture of THF/MeOH/H2O
(2:2:1, 25 mL) was added solid LiOH (0.19 g, 8.10 mmol, 20 equiv.)
in one portion at 0 °C. The resulting yellow mixture was allowed
to reach room temperature, and the stirring was continued for 2 h.
The mixture was then concentrated under reduced pressure to re-
move the THF and MeOH, diluted with EtOAc (25 mL), and acidi-
fied with a saturated aqueous solution of NaH2PO4 (pH = 4.5,
15 mL). The layers were separated, and the aqueous phase was ex-
tracted with EtOAc (3ϫ 20 mL). The combined organic layers were
dried with MgSO4, filtered, and concentrated in vacuo to provide
the corresponding crude carboxylic acid fragment 5 (0.10 g, 100%),
which was used without further purification in the next step.
[α]2D4 = +4.2 (c = 0.985, CHCl ). IR (KBr): ν = 3430, 2926, 2857,
˜
3
tert-Butyl (R)-5-{(S)-1-[(3E,5E,7E)-9-Ethoxy-9-oxonona-3,5,7-tri-
enylamino]-1-oxopropan-2-yl}-2,2-dimethyloxazolidine-3-carb-
oxylate (40): A stirred solution of trienic ester fragment 3 (0.25 g,
0.85 mmol) in dry CH2Cl2 (3 mL) at 0 °C under nitrogen was
treated with CF3COOH (0.8 mL), and the resulting mixture was
stirred at room temperature for 45 min. The reaction mixture was
concentrated, and the residue was dried under high vacuum. The
amine salt was basified with DIPEA (N,N-diisopropylethylamine,
0.26 mL, 1.27 mmol) in dry CH2Cl2 (3 mL) to generate the corre-
sponding free amine. In another round-bottomed flask, to acid
fragment 4 (0.25 g, 0.90 mmol) in dry CH2Cl2 (3 mL) were added
sequentially HOBT (0.16 g, 1.04 mmol) and EDCI (0.20 g,
1.04 mmol) at 0 °C under nitrogen. After 15 min, the above-men-
tioned free amine in dry CH2Cl2 (3 mL) was added to the reaction
mixture. The reaction mixture was allowed to reach room tempera-
ture and stirred for an additional 4 h under nitrogen. The mixture
was diluted with CHCl3 (10 mL), and the resulting solution was
1641, 1558, 1438, 1259, 1140, 843, 756, 561 cm–1
.
1H NMR
(300 MHz, CDCl3): δ = 7.22 (dd, J = 15.1, 11.3 Hz, 1 H), 6.72 (br.
m, 1 H, NH), 6.57 (br. t, J = 6.0 Hz, 1 H, NH), 6.44 (dd, J = 15.1,
10.6 Hz, 1 H), 6.18 (dd, J = 15.1, 11.3 Hz, 1 H), 6.18–6.08 (m, 2
H), 5.97 (d, J = 10.6 Hz, 1 H), 5.78 (d, J = 15.1 Hz, 1 H), 5.77 (m,
1 H), 5.64 (dt, J = 14.3, 7.5 Hz, 1 H), 5.05 (m, 1 H, OH), 4.34 (dd,
J = 9.0, 3.7 Hz, 1 H), 4.12 (q, J = 6.8 Hz, 2 H), 3.62 (m, 1 H), 3.48
(m, 1 H), 3.34–3.25 (m, 2 H), 3.05 (m, 1 H), 2.40–2.18 (m, 5 H),
2.01 (m, 2 H), 1.66 (s, 3 H), 1.35–1.14 (m, 16 H), 0.81 (t, J = 6.8 Hz,
3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 175.6, 173.0, 167.1,
144.3, 140.1, 136.0, 135.5, 135.5, 132.1, 129.0, 125.6, 125.0, 120.8,
73.7, 73.0, 60.4, 60.3, 44.0, 43.3, 41.6, 38.5, 32.9, 31.8, 29.6, 29.4,
29.1, 22.6, 15.5, 14.2, 14.0, 12.6 ppm. MS (ESI): m/z = 569 [M +
Na]+. HRMS (ESI): calcd. for C31H50O6N2Na [M + Na]+
569.3566; found 569.3556.
(2E,4E,6E)-9-{(2S,3R)-3-Hydroxy-4-[(R,4E,6E)-3-hydroxy-4-
washed with HCl (1 n solution, 3 mL), water (2 mL), NaHCO3 (5% methyltetradeca-4,6-dienamido]-2-methylbutanamido}nona-2,4,6-tri-
aqueous solution, 2 mL), and brine solution (5 mL). The organic
layer was dried with Na2SO4 and concentrated in vacuo. Silica gel
column chromatography (ethyl acetate/hexane, 50:50) of the residue
gave the desired amide 40 (0.36 g, 95% yield) as a waxy solid; Rf
= 0.5 (50% EtOAc/hexane). [α]2D5 = –2.1 (c = 0.9, MeOH). IR
enoic Acid (2): To a stirred solution of 41 (0.05 g, 0.09 mmol,
1.0 equiv.) in a mixture of THF/MeOH/H2O (2:2:1, 12.5 mL) was
added solid LiOH (0.04 g, 1.82 mmol, 20 equiv.) in one portion at
0 °C, and the resulting yellow mixture was allowed to reach room
temp. After stirring for 12 h, the mixture was concentrated under
(KBr): ν = 3444, 2928, 2863, 1699, 1651, 1549, 1460, 1391, 1259, reduced pressure to remove the THF and MeOH, diluted with
˜
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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387

J. S. Yadav, S. Sengupta
FULL PAPER
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bined organic layers were washed with brine (10 mL), dried with
MgSO4, filtered, and concentrated in vacuo to provide the corre-
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MeOH). IR (KBr): ν = 3385, 2925, 2856, 1711, 1642, 1556, 1458,
˜
1
1376, 1257, 1096, 805, 406 cm–1. H NMR (500 MHz, CD3OD): δ
= 7.91–7.80 (m, 2 H, NH), 7.27 (dd, J = 14.8, 10.9 Hz, 1 H), 6.59
(dd, J = 15.8, 11.9 Hz, 1 H), 6.38–6.22 (m, 3 H), 6.02 (d, J =
10.9 Hz, 1 H), 5.96–5.91 (m, 1 H), 5.83 (d, J = 14.8 Hz, 1 H), 5.67
(dt, J = 14.8, 7.0 Hz, 1 H), 4.41 (dd, J = 8.0, 5.0 Hz, 1 H), 3.69
(m, 1 H), 3.40 (dd, J = 13.8, 3.0 Hz, 1 H), 3.30–3.24 (m, 2 H), 3.14
(dd, J = 12.8, 7.0 Hz, 1 H), 2.51–2.33 (m, 5 H), 2.10 (qapp, J =
7.0 Hz, 2 H), 1.74 (s, 3 H), 1.38 (m, 2 H), 1.35–1.24 (m, 8 H), 1.10
(d, J = 7.0 Hz, 3 H), 0.90 (t, J = 7.0 Hz, 3 H) ppm. 13C NMR
(75 MHz, CD3OD): δ = 177.5, 174.3, 170.6, 146.6, 142.2, 137.6,
137.3, 136.2, 133.1, 129.8, 127.3, 126.8, 121.6, 75.1, 73.3, 45.4, 44.5,
43.2, 39.7, 34.0, 33.0, 30.7, 30.6, 30.3, 23.7, 15.2, 14.5, 12.4 ppm.
MS (ESI): m/z = 541 [M + Na]+. HRMS (ESI): calcd. for
C29H46O6N2Na [M + Na]+ 541.3253; found 541.3241.
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Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectra for all new compounds and HPLC
chromatogram of compound 38.
Acknowledgments
S. S. thanks the Council of Scientific and Industrial Research
(CSIR), New Delhi, India for financial assistance.
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[22] The hydrolysis of compound 38 required very mild conditions,
as elimination to the conjugated diene occurred as a competing
reaction.
Received: August 13, 2012
Published Online: November 15, 2012
388
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Eur. J. Org. Chem. 2013, 376–388