Formal total synthesis of stevastelins B and B3

Article abstract of DOI:10.1002/hlca.201300255

The formal total synthesis of stevastelins B and B3 (2 and 4, resp.) have been accomplished employing a highly enantiomerically controlled Lewis acid catalyzed non-aldol approach to obtain the syn aldol product and temperature controlled hydroboration oxidation reaction to construct four consecutive stereogenic centers. The other key reactions include Sharpless asymmetric epoxidation, macrolactonization, and macrolactamization towards building the core skeleton 2 and 4. Copyright

Full text of DOI:10.1002/hlca.201300255

Helvetica Chimica Acta – Vol. 97 (2014)
669
Formal Total Synthesis of Stevastelins B and B3
by Jhillu Singh Yadav*, Satadru Sekhar Mandal, and Pabbaraja Srihari
Division of Natural Products Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad-
500007, India (phone: þ 91-40-27193737; fax: þ 91-40-27160512; e-mail: yadavpub@iict.res.in)
The formal total synthesis of stevastelins B and B3 (2 and 4, resp.) have been accomplished
employing a highly enantiomerically controlled Lewis acid catalyzed non-aldol approach to obtain the
syn aldol product and temperature controlled hydroboration oxidation reaction to construct four
consecutive stereogenic centers. The other key reactions include Sharpless asymmetric epoxidation,
macrolactonization, and macrolactamization towards building the core skeleton 2 and 4.
Introduction. – In recent years, several new immunosuppressive agents have
entered clinical trials, while cyclosporine A, calcinuerin, and FK506 have already been
clinically used in organ transplantations. In 1994, the stevastelins A, B, A3, B3 and C3
(1 – 5, resp.) were isolated from a culture broth of penicillium sp. NK374186 [1] (Fig.).
It has been reported that stevastelins show potent immunosuppressive activities by
blocking human T-cell activation without affecting the phosphatase activity of
calcineurin [2] and inhibiting dual specificity phosphatase, VHR [3]. With such a
novel mode of action, stevastelins represent a new class of natural cyclic depsipeptides
which differ from that of well-known immunosuppressant FK506 [4], cyclosporine A
[5], and sanglifehrin A [6].
The structural study by spectroscopy, degradation, and synthetic considerations
revealed that stevastelin B (2) consists of (2S,3S,4S,5R)-3,5-dihydroxy-2,4-dimethyloc-
tadecanoic acid, O-acetyl-l-serine, l-threonine, and l-valine, and possesses a 15-
membered ring structure [6]. Based on spectroscopic analyses of other stevastelins, it
has been proposed that stevastelin B3 (4) is an isomer of stevastelin B (2) with a 13-
Figure. Structures of stevastelins A, B, A3, B3, and C3 (1 – 5, resp.)
ꢀ 2014 Verlag Helvetica Chimica Acta AG, Zꢁrich

670
Helvetica Chimica Acta – Vol. 97 (2014)
membered ring structure. The pronounced biological activities of stevastelins and their
unique structures have attracted the attention of synthetic organic chemists, as
evidenced by several contributions on the total synthesis of stevastelins B [7] and B3 [8]
(2 and 4, resp.), along with other synthetic approaches [2][8c]. In continuation of our
efforts on total synthesis of biologically active natural products [9], we herein describe
our efforts for a formal total synthesis of 2 and 4 by employing a non-aldol approach for
an aldol product to synthesize the key lipid fragment for the target synthesis.
Results and Discussion. – Our retrosynthetic analysis suggested that stevastelin B
(2), possessing a 15-membered ring structure, could be obtained by macrolactamiza-
tion, followed by debenzylation and acetylation of the amino carboxylic acid obtained
from 6 through allyl deprotection and Boc (tBuOCO) deprotection (Scheme 1). The
key intermediate 6 was envisioned to be synthesized by condensation of the peptide
moiety with the fatty-acid precursor 7. The synthesis by a macrolactonization-based
strategy could lead to the 13-membered ring-containing stevastelin B3 (4) from the
precursor 8 or 9, respectively, after deallylation and cyclization. These two key
intermediates, 8 and 9, were envisioned to be obtained by condensation of the peptide
moiety with the fatty-acid precursors 10 and 11, respectively. While the precursor 12,
C(1)ꢀC(18) fragment common to both stevastelin B and B3 (2 and 4, resp.) could be
obtained using the non-aldol transformation from chiral epoxy alcohol 13, generated
through Sharpless asymmetric epoxidation from the readily available inexpensive
starting material tetradecan-1-ol (14), the peptide chain could be easily prepared from
commercially available protected serine, threonine, and valine derivatives (Scheme 1).
Our synthesis was initiated with the preparation of key intermediate 12. Thus, we
started with commercialy available tetradecan-1-ol (14) which was converted to epoxy
alcohol 13. Swern oxidation, followed by C2-Wittig reaction of 14 provided a,b-
unsaturated ester 15. Compound 15 upon reduction with diisobutylaluminium hydride
(DIBAL-H) [10], followed by Sharpless asymmetric epoxidation [11], provided 13.
Rearrangement of the epoxy alcohol on treatment with trimethylsilyl triflate
(trimethylsilyl trifluoromethanesulfonate; TMSOTf) in the presence of Hꢀnigꢂs base
[12] afforded the syn-aldol product 16 as a single diastereoisomer in 89% yield
(Scheme 2).
Deprotection of the silyl moiety with 1n HCl followed by Wittig reaction [10] with
[1-(ethoxycarbonyl)ethylidene](triphenyl)phosphorane, provided an unseparable mix-
ture of (E)- and (Z)-a,b-unsaturated hydroxy ester 12 (91.3%; Scheme 2).
Chemoselective reduction of the ester function in the presence of the C¼C bond in
12 was achieved with DIBAL-H at ꢀ108 to furnish the allylic alcohol 17 in 93% yield
(Scheme 3). Hydroboration of 17 with borane dimethylsulfide (BH3 · DMS) [13] at
ꢀ 108, followed by alkaline H2O2 workup, yielded the triol 18 along with its
diasteroisomer 18a in a minor amount (95 :5). The spectroscopic data and specific
rotation of 18 was in good agreement with the data reported in literature [3a]. The
origin of the stereospecificity observed might be related to the conformational
preference of allylic alcohol 17, based on Houkꢂs transition-state model [14], which
minimizes the allylic 1,3-strains. Therefore, hydroboration would take place preferen-
tially from the sterically less hindered a-face to yield alcohol 18 as the major isomer.
The configuration of the polyol chain of 18 was also confirmed based on the

Helvetica Chimica Acta – Vol. 97 (2014)
671
Scheme 1. Retrosynthetic Analysis for Stevastelins B and B3 (2 and 4, resp.)
Scheme 2. Synthesis of the Key Intermediate 12 ((ꢀ)-d-DET, (ꢀ)-d-diethyl tartrate; TBHP, tBuOOH)

672
Helvetica Chimica Acta – Vol. 97 (2014)
conformational property of 1,3-diol acetonide (Scheme 3). Towards this, the triol was
subjected to primary-alcohol protection as the corresponding benzyl ether 19 and then
to acetonide protection with with 2,2-dimethoxypropane (DMP) and a catalytic
amount of camphorsulfonic acid (CSA) to yield 20 in 94% yield (Scheme 3). The 13C-
NMR spectrum of 20 displayed the Me signals at 19.4 and 30.1 ppm, confirming the
syn-configuration for the 3,5-diol function [15].
Having established the route to advanced common precursor 18 for the synthesis of
stevastelins, the total synthesis of stevastelin B (2), possessing a 15-membered cyclic
depsipeptide structure, was first investigated. Compound 18 was treated with DMP in
the presence of CSA [16] to afford the masked product 21 in 82% yield (Scheme 4).
Initially, direct esterification of the alcohol with amino acid residue Boc-Val-Thr-
Ser(Bzl) was attempted without any success [17]. The poor reactivity of the OH group
in 21, probably due to steric hindrance, led us to employ the stepwise introduction of
the amino acid moiety. The condensation of 21 with Boc-Ser(Bn)ꢀOH (22) using N,N’-
dicyclohexylcarbodimide (DCC) [18] and 4-(dimethylamino)pyridine (DMAP) yield-
ed the acylated product 23 in 73% yield. Acetonide deprotection with aqueous AcOH
gave the diol 24 in 76% yield. The primary alcohol in 24 was selectively oxidized
with (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) and [bis(acetoxy)iodo]benzene
(BAIB) [19] to give the aldehyde which was further oxidized by NaClO2 to afford the
carboxylic acid 7 in 75% yield (Scheme 4).
The synthesis of the peptide residue 26 (two amino acid residue) was achieved by a
conventional method starting from the corresponding commercially available protect-
ed amino acid 25 in 83% yield (Scheme 5) [20].
The coupling of acid 7 with the amino salt (obtained after treating allyl-Thr-Val (26)
with TFA) in the presence of 1-[3-(dimethylamino)propyl]-3-ethylcarbodimide hydro-
chloride (WSC · HCl) and 1-hydroxybenzotriazole (HOBt) provided the condensed
Scheme 3. Synthesis of Triol 18 and Confirmation of syn-Geometry of 3,5-Diol

Helvetica Chimica Acta – Vol. 97 (2014)
673
Scheme 4. Synthesis of the Fatty-Acid Precursor 7
Scheme 5. Synthesis of the Peptide Fragment 26
product 6 in 84% yield (Scheme 6). The allyl ester 6 was converted to the acid 27 with
Pd(PPh3)4 and morpholine [21]. Treatment of 27 with CF3COOH (TFA) provided the
amino carboxylic acid as its corresponding TFA salt 28. The crucial step, the
macrolactamization, was successfully carried out according to the protocol of by Shioiri
et al. [22] using diethylphosphoryl cyanide (DEPC) in DMF under high dilution
condition (0.01m) to provide the 15-membered macrocycle 29 in 25% yield from 28.
Compound 29 was converted to stevastelin B (2) as reported in [7a][7c].
Synthesis of Stevastelin B3 (4). We then proceeded toward the synthesis of 4,
possessing a 13-membered cyclic depsipeptide, employing the macrolactonization
strategy. Initially, keeping in mind the robustness of the methoxymethyl (MOM)
moiety, we protected the free secondary alcohol 12 as the corresponding MOM ether 30
(Scheme 7). Chemoselective reduction of the ester functionality in the presence of the
C¼C bond in 30 was achieved with DIBAL-H to furnish allyl alcohol 32 in 93% yield.
Hydroboration of 32 with BH3 · DMS in THF, followed by alkaline H2O2 workup,
yielded the alcohol 34 along with a small amount of its diastereoisomer 34a that was
easily separable by column chromatography. The primary alcohol group in 34 was
selectively oxidized with TEMPO and BAIB to give the corresponding aldehyde, which
was further oxidized with NaClO2 to afford the carboxylic acid 10 (Scheme 7).
The peptide segment 36 was synthesized from commercially available protected
amino acid 37 in three steps as reported in [7c](Scheme 8).
The peptide salt obtained after treatment of 36 with TFAwas coupled with 10 in the
presence of WSC · HCl and HOBt to furnish the amide 8 in 90% yield. The acid
precursor for esterification the hydroxy acid 37 was obtained from the reaction of 8
with Pd(PPh3)4 in the presence of morpholine. The acid 37 was subjected to several

674
Helvetica Chimica Acta – Vol. 97 (2014)
Scheme 6. Formal Synthesis of Stevastelin B (2)
t
Scheme 7. Synthesis of the Lipid-Chain Precursor 10 (TBS, BuMe2Si)
Scheme 8. Synthesis of the Peptide Fragment 36

Helvetica Chimica Acta – Vol. 97 (2014)
675
macrolactonization conditions, e.g., Yamaguchi methodology, under high dilution
conditions and also with a variety of coupling reagents [23], such as DEPC [24],
diphenylphosphoryl azide (DPPA) [25], ꢃ1-ethyl-3-[3-(dimethylamino)propyl]carbo-
diimideꢂ (EDCI)/HOBt, and pentafluorophenol/EDCI, in different solvents (CH2Cl2,
THF, DMF, MeCN). All these attempts were not successfull. Finally, after several
attempts, we succeeded in lactonization by applying conditions reported by Yonemitsu
and co-workers [26] wherein the amino acid 37 underwent lactonization to yield the
corresponding depsipeptide 39 (Scheme 9).
With the basic macrolide skeleton in hand after lactonization, we proceeded
towards removal of the Bn and MOM moieties, and acetylation of the primary alcohol.
Unfortunately, all our attempts to remove the MOM moiety under acidic conditions to
provide 41 did not succeed and resulted in decomposition of the starting material. Thus,
the best option left was to start the whole sequence by changing the protecting group
that could be easily removed at the end stage. Hence, we chose a silyl protective group,
Scheme 9. Synthesis of the Depsipeptide 39

676
Helvetica Chimica Acta – Vol. 97 (2014)
tBuMe2Si in place of the MOM moiety. Compound 11 was synthesized starting from 12
via a similar set of reactions as performed for 10 (Scheme 7). Thus, 12 was protected as
the corresponding TBS ether 31 and subjected to ester hydrolysis with DIBAL-H to
obtain 33. Hydroboration, followed by treatment with H2O2 under basic conditions,
provided easily separable diastereoisomers 35 and 35a, respectively. The primary OH
group in 35 was oxidized to aldehyde and then to acid with TEMPO and BAIB,
followed by Pinnick oxidation conditions, to furnish acid 11. Compound 11 was then
coupled with 36 to afford 9, which, upon reaction with Pd(PPh3)4 in the presence of
morpholine, gave acid 38 (Scheme 9). The acid 38 was subjected to macrolactonization
to prepare 40 following Yamaguchiꢂs methodology under high-dilution conditions,
or with a variety of coupling reagents in different solvents, but the reaction was not
successful (Scheme 9). Reasoning this outcome due to bulkiness of the TBS moiety
adjacent to the OH group, we opted to proceed further by removal of TBS moiety at
this stage. Thus, compound 9 was converted to diol 42 by treating with CSA in MeOH,
and then reacted with Pd(PPh3)4 in the presence of morpholine to give the known
precursor 43, which was utilized earlier for the total synthesis of stevastalin B3 (4) [8b]
(Scheme 10).
Scheme 10. Synthesis of the Key Precursor Diol 43
Conclusions. – In conclusion, we have accomplished the formal total synthesis of
stevastelin B and B3 (2 and 4, resp.) in an enantioselective manner. The highlights of
our synthesis include the preparation of the lipid chain through a ꢃnon-aldol aldolꢂ
reaction, and employing Sharpless epoxidation, Wittig reaction, hydroboration/
oxidation, macrolactonization, and macrolactamization as other key steps. Further
investigations are currently under progress to accomplish the cyclization reaction and
explore it further for the synthesis of several analogs for biological studies.

Helvetica Chimica Acta – Vol. 97 (2014)
677
S. S. M. thanks CSIR, New Delhi, for financial assistance in the form of fellowship. J. S. Y. thanks
CSIR, New Delhi, for CSIR-Bhatnagar Award. The authors thank CSIR, New Delhi, for partial funding
through XII Five Year Plan Project ORIGIN (CSC-108).
Experimental Part
General. All reactions were carried out under Ar or N2 using standard syringe, septa, and cannula
techniques unless otherwise mentioned. Commercial reagents were used without further purification. All
solvents were purified by standard techniques. Column chromatography (CC): silica gel (SiO2 , 60 –
120 mesh); elution with AcOEt/petroleum ether mixtures. Visualization of the spots on TLC plates
was achieved either by exposure to I2 vapor or UV light, or by dipping the plates to ethanolic
anisaldehyde/H2SO4/AcOH or to phosphomolybdic acid/H2SO4 soln., and heating the plates at 1208.
Optical rotations: PerkinElmer 241 polarimeter in 1.0-dm and 1.0-ml cells. IR Spectra: PerkinElmer 683
spectrometer using NaCl optics; ˜n in cmꢀ1; spectra were calibrated against the polystyrene absorption at
1
1610 cmꢀ1. Samples were scanned neat, in KBr wafers, or in CHCl3 as a thin film. H- and 13C-NMR
spectra: Bruker 300 NMR spectrometer (13C: 75 MHz); in CDCl3; d in ppm rel. to Me4Si as internal
standard, J in Hz. MS: Finnigan MAT1020B or micromass VG 70-70 H spectrometer; at 70 eV using a
direct inlet system; in m/z.
Ethyl (2E)-2-Methylhexadec-2-enoate (15). To the soln. of oxalyl chloride (8.1 ml, 93.3 mmol) in dry
CH2Cl2 at ꢀ 788 was slowly added a soln. of DMSO (13.3 ml, 186.6 mmol) in CH2Cl2 (80 ml). After
stirring for 1 h at ꢀ 788, tetradecan-1-ol (14; 10.0 g, 46.6 mmol) in dry CH2Cl2 (100 ml) was slowly added.
After 45 min., Et3N (38.9 ml, 279.9 mmol) was introduced via a syringe. The mixture was then stirred at
ꢀ 788 for 10 – 15 min, and further at ꢀ 508 for 20 min, prior to the addition of aq. sat. NH4Cl (50.0 ml)
soln. The org. phase was separated and then washed with CH2Cl2 (2 ꢁ 15 ml). The combined org. layer
was dried (Na2SO4) and passed through a short pad of SiO2. The filtrate was concentrated to give
tetradecanal (9.11 g, 92%) as pale-yellow syrup, which was used as such for the next step without further
purification. Rf (10% AcOEt/hexane) 0.8. 1H-NMR (300 MHz, CDCl3): 0.88 (t, J ¼ 6.8, 3 H); 1.20 – 1.38
(m, 20 H); 1.54 – 1.70 (m, 2 H); 2.28 – 2.45 (m, 2 H); 9.74 (s, 1 H). 13C-NMR (75 MHz, CDCl3): 13.9; 21.9;
22.5; 24.6; 29.01; 29.2; 29.3; 29.4; 29.5 (2 C); 31.8; 33.8; 43.7; 202.2.
Tetradecanal (2.6 g, 12.3 mmol, 1.0 equiv.) was dissolved in benzene (25 ml), and to this soln. [1-
(ethoxycarbonyl)ethylidene](triphenyl)phosphorane (6.67 g, 18.4 mmol, 1.5 equiv.) was added at r.t. The
mixture was heated at reflux until the reaction was complete as judged by TLC (ca. 12 h). The solvents
were removed by concentration under reduced pressure. The resulting crude residue was purified by CC
(1% AcOEt/hexane) to give 15 (3.15 g, 87%) exclusively (LC/MS). Colorless liquid. Rf (2% AcOEt/
hexane) 0.4. IR (neat): 1033, 1250, 1513, 1737, 2901, 3285. 1H-NMR (300 MHz, CDCl3): 0.88 (t, J ¼ 6.8,
3 H); 1.20 – 1.38 (m, 20 H); 1.30 (t, J ¼ 6.8, 3 H); 1.38 – 1.50 (m, 2 H); 1.81 (s, 3 H); 2.15 (q, J ¼ 7.6, 2 H);
4.17 (q, J ¼ 7.6, 2 H); 6.70 (t, J ¼ 7.6, 1 H). 13C-NMR (75 MHz, CDCl3): 12.2; 14.0; 14.2; 22.6; 28.5; 28.6;
29.3; 29.4; 29.5 (2 C); 29.6 (4 C); 31.8; 60.2; 127.5; 142.3; 168.1. ESI-MS: 297 ([M þ H]þ). HR-ESI-MS:
296.2622 (C19H36Oþ2 ; calc. 296.2625).
[(3R)-2-Methyl-3-tridecyloxiran-2-yl]methanol (13). A soln. of 15 (4.6 g, 15.5 mmol) in 50 ml of
CH2Cl2 was cooled to ꢀ 108. DIBAL-H (22.1 ml, 31.1 mmol; 20% soln. in toluene) was then added
dropwise during 5 min. The resulting mixture was stirred for 2 h before quenching the reaction with sat
aq. sodium potassium tartrate soln. (30 ml). The mixture was warmed to r.t. and stirred for 5 h. Org. layer
was separated, and aq. layer was extracted with CH2Cl2 (2 ꢁ 15 ml). Combined org. layer was dried
(Na2SO4) and evaporated. CC (SiO2; AcOEt/hexane (8%)) of the crude product afforded the allyl
alcohol (3.51 g, 89%). Colorless liquid. Rf (20% AcOEt/hexane) 0.7. 1H-NMR (300 MHz, CDCl3): 0.88
(t, J ¼ 6.8, 3 H); 1.20 – 1.38 (m, 22 H); 1.65 (s, 3 H); 2.01 (q, J ¼ 6.8, 2 H); 3.95 (s, 2 H); 5.36 (t, J ¼ 6.8,
1 H). 13C-NMR (75 MHz, CDCl3): 13.8; 14.0; 22.4; 28.3; 28.4; 29.1; 29.2; 29.3; 29.4; 31.7; 60.0; 127.3;
142.1. ESI-MS: 277 ([M þ Na]þ).
Finely powdered activated molecular sieves (4 ꢄ, 28.0 g) were placed in a 500-ml two-neck round-
bottom flask equipped with a septum and N2 inlet, and a magnetic bar. CH2Cl2 (120 ml) was cannulated,
and the flask was then cooled to ꢀ 258. (ꢀ)-d-diethyl tartrate ((ꢀ)-d-DET; 1.8 ml, 10.5 mmol) and

678
Helvetica Chimica Acta – Vol. 97 (2014)
Ti(OiPr)4 (2.5 ml, 8.4 mmol) were added sequentially, and resulting mixture was stirred for 30 – 40 min
before adding a soln. of the above allyl alcohol (10.7 g, 42.12 mmol) in 40 ml of dry CH2Cl2. After stirring
for another 50 min at ꢀ 258, tBuOOH (6.3m in toluene, 13.4 ml, 84.3 mmol) was added dropwise during
30 min period. The resulting mixture was stirred for 1.5 h, and the reaction was quenched with 50 ml H2O.
The resulting mixture was stirred for 30 min at r.t. After stirring 30 min at r.t., 12.5 g of NaOH (20%
NaOH soln. in brine) was added at r.t. The mixture was stirred for another 4 h at r.t. The soln. was then
filtered through a small pad of Celite, and the residue was washed with CH2Cl2 (at least 20 times). The
combined CH2Cl2 layer was evaporated under reduced pressure. CC (SiO2; AcOEt/hexane (10%) of the
crude product afforded 13 (10.5 g, 92%; 94% ee by HPLC analysis). Colorless liquid. Rf (20% AcOEt/
hexane) 0.4. [a]D30 ¼ þ9.2 (c ¼ 1.4, CHCl3). IR (neat): 1033, 1248, 1513, 1611, 2925, 3452. 1H-NMR
(300 MHz, CDCl3): 0.88 (t, J ¼ 6.8, 3 H); 1.20 – 1.38 (m, 24 H); 1.44 – 1.61 (m, 2 H); 1.83 – 1.93 (m, 1 H);
2.97 (t, J ¼ 6.0, 1 H); 3.51 (q, J ¼ 8.7, 1 H); 3.63 (q, J ¼ 4.5, 1 H). 13C-NMR (75 MHz, CDCl3): 13.9; 22.5;
26.3; 28.0; 29.2 (2 C); 29.3 (2 C); 29.4 (2 C); 29.5 (3 C); 31.8; 60.2; 61.0; 65.5. ESI-MS: 293 ([M þ Na]þ).
HR-ESI-MS: 293.2468 (C17H34NaOþ2 ; calc. 293.2456).
(2S,3R)-2-Methyl-3-[(trimethylsilyl)oxy]hexadecanal (16). Finely powdered activated molecular
sieves (4 ꢄ; 8.0 g) were placed in a 50-ml two-neck round-bottom flask. The alcohol 13 (3.0 g, 11.1 mmol)
in CH2Cl2 (30 ml) and EtNiPr2 (3.4 ml, 19.4 mmol) were added sequentially, and the mixture was stirred
for 5 – 10 min. The resulting mixture was cooled to ꢀ 458 and treated with TMSOTf (2.9 ml, 16.1 mmol).
The mixture was stirred at ꢀ 458 for 3 h, and then the reaction was quenched with H2O (15 ml). Org.
layer was separated, and the aq. layer was extracted with CH2Cl2 (2 ꢁ 5 ml). Combined org. layer was
dried (Na2SO4) and evaporated. CC (SiO2; AcOEt/hexane (4%) afforded 16 (3.4 g, 89%). Colorless
liquid. Rf (10% AcOEt/hexane) 0.3. 1H-NMR (300 MHz, CDCl3): 0.09 (s, 9 H); 0.88 (t, J ¼ 6.8, 3 H); 1.06
(d, J ¼ 7.2, 3 H); 1.20 – 1.37 (m, 23 H); 1.39 – 1.52 (m, 1 H); 2.31 – 2.42 (m, 1 H); 4.01 – 4.09 (m, 1 H); 9.70
(s, 1 H).
Ethyl (2E,4R,5R)-5-Hydroxy-2,4-dimethyloctadec-2-enoate (12). Compound 16 (3.2 g, 9.35 mmol)
was dissolved in THF (30 ml), and 5 ml of 1n HCl were added at 08. The mixture was stirred at r.t. for
30 min, and then the reaction was quenched with solid NaHCO3 and filtered. The filtrate was
concentrated in vacuum. CC (SiO2; AcOEt/hexane (12%)) of the crude product gave the hydroxy
aldehyde (2.32 g, 92%). Colorless oil. Rf (20% AcOEt/hexane) 0.4. 1H-NMR (300 MHz, CDCl3): 0.88 (t,
J ¼ 6.8, 3 H); 1.14 (d, J ¼ 7.2, 3 H); 1.20 – 1.38 (m, 23 H); 1.39 – 1.58 (m, 1 H); 2.36 – 2.47 (m, 1 H); 4.01 –
4.09 (m, 1 H); 9.70 (s, 1 H).
The hydroxy aldehyde obtained above (2.2 g, 8.1 mmol, 1.0 equiv.) was dissolved in benzene (25 ml),
and [1-(ethoxycarbonyl)ethylidene](triphenyl)phosphorane (4.16 g, 11.5 mmol, 1.5 equiv.) was added at
r.t. The mixture was heated at reflux until the reaction was complete as judged by TLC (ca. 12 h). The
solvents were removed by concentration under reduced pressure. The resulting crude residue was
purified by CC (SiO2; AcOEt/hexane (5%)) to give 12 (2.63 g, 91.3%). Colorless liquid (in 95 :5 ratio as
determined by 1H-NMR and LC/MS). Rf (10% AcOEt/hexane) 0.5. A small portion of the sample was
purified to measure the optical rotation. [a]2D9 ¼ þ22.6 (c ¼ 1.6, CHCl3). IR (neat): 1035, 1175, 1248, 1370,
1721, 2927. 1H-NMR (300 MHz, CDCl3): 0.88 (t, J ¼ 6.8, 3 H); 1.05 (d, J ¼ 6.8, 3 H); 1.19 – 1.38 (m, 23 H);
1.31 (t, J ¼ 6.8, 3 H); 1.39 – 1.51 (m, 1 H); 1.51 – 1.65 (br. s, OH); 1.85 (s, 3 H); 2.45 – 2.60 (m, 1 H); 3.39 –
3.52 (m, 1 H); 4.18 (q, J ¼ 6.8, 2 H); 6.56 (d, J ¼ 9.8, 1 H). 13C-NMR (75 MHz, CDCl3): 12.6; 14.0; 14.2;
15.2; 22.6; 25.9; 29.3; 29.6 (7 C); 31.9; 34.9; 39.6; 60.5; 75.2; 127.6; 144.0; 168.2. ESI-MS: 377 ([M þ
Na]þ). HR-ESI-MS: 377.3041 (C22H42NaOþ3 ; calc. 377.3031).
(2E,4R,5R)-2,4-Dimethyloctadec-2-ene-1,5-diol (17). A soln. of 12 (2.0 g, 5.64 mmol) in 25 ml of
CH2Cl2 was cooled to ꢀ 108. DIBAL-H (8.1 ml, 11.3 mmol; 20% soln. in toluene) was then added
dropwise during 5 min. The resulting mixture was stirred for 2 h before quenching the reaction with sat.
aq. KNaC4H4O6 · 4 H2O soln. (15 ml). The mixture was warmed to r.t. and stirred for 5 h. Org. layer was
separated, and aq. layer was extracted with CH2Cl2 (2 ꢁ 10 ml). Combined org. layer was dried (Na2SO4)
and evaporated. CC (SiO2; AcOEt/hexane (10%) of the crude product afforded 17 (1.64 g, 93%).
Colorless liquid. Rf (20% AcOEt/hexane) 0.5. [a]3D0 ¼ þ19.2 (c ¼ 1.4, CHCl3). IR (neat): 1246, 1513, 1615,
2853, 2925, 3256. 1H-NMR (300 MHz, CDCl3): 0.88 (t, J ¼ 6.8, 3 H); 0.97 (d, J ¼ 6.8, 3 H); 1.22 – 1.33 (m,
23 H); 1.42 – 1.49 (m, 1 H); 1.68 (s, 3 H); 2.41 – 2.52 (m, 1 H); 3.35 – 3.42 (m, 1 H); 3.97 (s, 2 H); 5.26 (d,

Helvetica Chimica Acta – Vol. 97 (2014)
679
J ¼ 10.2, 1 H). 13C-NMR (75 MHz, CDCl3): 14.1; 15.7; 22.6; 26.1; 29.3; 29.6 (7 C); 31.9; 34.1; 37.9; 68.6;
75.8; 128.4; 135.1. ESI-MS: 335 ([M þ Na]) þ. HR-ESI-MS: 335.2932 (C20H40NaOþ2 ; calc. 335.2926).
(2S,3S,4S,5R)-2,4-Dimethyloctadecane-1,3,5-triol (18). To the soln. of 17 (3.0 g, 9.6 mmol) in dry
THF (30 ml) was added BH3 · DMS (1.36 ml, 14.4 mmol) during 15 min. maintaining the temp. at ꢀ 108.
The mixture was then allowed to warm to 08 and stirred for 4 h. The soln. was cooled to ꢀ 108, and 3m
NaOH (until the mixture was basic, maintaining the temp. at ꢀ 108.) and H2O2 (9 ml, 30% soln. in H2O
were added;) and then the mixture was further stirred for 3 h and diluted with AcOEt (20 ml). The org.
layers were separated and washed with brine (1 ꢁ 15 ml), dried (Na2SO4), and evaporated to give the
crude product, which was purified by CC (SiO2; AcOEt/hexane (5%)) to give 18 (2.63 g, 83%) as a
colorless liquid, along with minor diastereomer 18a (0.136 g, 4.3%) as colorless liquid.
Data for 18. Rf (30% AcOEt/hexane) 0.3. [a]D30 ¼ þ9.2 (c ¼ 1.4, CHCl3). IR (neat): 1078, 1461, 2385,
2922, 3251. 1H-NMR (300 MHz, CDCl3): 0.75 (d, J ¼ 6.8, 3 H); 0.88 (t, J ¼ 7.6, 3 H); 0.92 (d, J ¼ 6.8, 3 H);
1.16 – 1.35 (m, 23 H); 1.36 – 1.48 (m, 1 H); 1.55 – 1.66 (m, 1 H); 1.80 – 1.96 (m, 1 H); 3.60 – 3.87 (m, 3 H);
3.81 – 3.90 (m, 1 H). 13C-NMR (75 MHz, CDCl3): 4.1; 13.1; 14.1; 22.7; 26.0; 29.3, 29.6 (7 C); 31.9; 35.4;
37.1; 37.7; 68.9; 77.6; 83.2. ESI-MS: 353 ([M þ Na]þ). HR-ESI-MS: 353.3032 (C20H42NaO3þ ; calc.
353.3055).
(2S,3S,4S,5R)-1-(Benzyloxy)-2,4-dimethyloctadecane-3,5-diol (19). NaH (25 mg, 0.61 mmol) was
slowly added in portions to a soln. of 18 (200 mg, 0.61 mmol) in anh. THF (5 ml) at 08, and the mixture
was stirred for 15 min. Then, BnBr (0.8 ml, 0.66 mmol) and cat. amount Bu4NI were added at 08, and the
mixture was allowed to stir at r.t. for 4 h. After completion the reaction was quenched by slow addition of
H2O (5 ml), and the mixture was extracted with AcOEt (10 ml). The org. layer was separated, and
washed with H2O (5 ml) and brine (5 ml). The org. solvent was evaporated, and the crude product was
purified by CC (SiO2; AcOEt/hexane (15%)) to yield 19 (221 mg, 87%). Colorless liquid. Rf (30%
AcOEt/hexane) 0.7. 1H-NMR (300 MHz, CDCl3): 0.76 (d, J ¼ 7.0, 3 H); 0.87 (d, J ¼ 7.0, 3 H); 0.91 (d, J ¼
7.0, 3 H); 1.20 – 1.47 (m, 23 H); 1.49 – 1.70 (m, 2 H); 1.93 – 2.09 (m, 1 H); 3.47 (t, J ¼ 4.2, 1 H); 3.61 (dd,
J ¼ 5.1, 9.4, 1 H); 3.72 (dd, J ¼ 2.1, 9.4, 1 H); 3.80 – 3.87 (m, 1 H); 4.53 (s, 2 H); 7.28 – 7.41 (m, 5 H).
13C-NMR (75 MHz, CDCl3): 4.2; 13.0; 14.1; 22.7; 26.2; 29.3; 29.6; 29.7 (6 C); 31.9; 35.1; 35.9; 38.1; 73.6;
76.8; 78.1; 82.9; 127.7; 128.0; 128.5; 137.4.
(4S,5S,6R)-4-[(2S)-1-(Benzyloxy)propan-2-yl]-2,2,5-trimethyl-6-tridecyl-1,3-dioxane (20). To a soln.
of 19 (200 mg, 0.48 mmol) in CH2Cl2 (5 ml) at r.t. was added DMP (0.09 ml, 0.95 mmol), followed by
CSA (12 mg), and the mixture was stirred at r.t. for 5 min. Solid NaHCO3 was added at 08, and the
mixture was again stirred for 10 min. The mixture was filtered through a pad of neutral alumina, and the
filtrate was concentrated in vacuum. CC (SiO2; AcOEt/hexane (8%)) gave the acetonide-protected
compound 20 (205.9 mg, 94%). Colorless liquid. Rf (20% AcOEt/hexane) 0.7. 1H-NMR (300 MHz,
CDCl3): 0.82 (d, J ¼ 6.8, 3 H); 0.88 (t, J ¼ 7.0, 3 H); 0.93 (d, J ¼ 7.0, 3 H); 1.18 – 1.34 (m, 23 H); 1.37 (s,
3 H); 1.39 – 1.53 (m, 1 H); 1.56 (s, 3 H); 1.77 – 1.93 (m, 1 H); 3.45 (dd, J ¼ 6.0, 8.9, 1 H); 3.55 (dd, J ¼ 3.0,
8.9, 1 H); 3.69 (dd, J ¼ 1.9, 10.0, 1 H); 3.77 – 3.85 (m, 1 H); 4.50 (q, J ¼ 12.1, 2 H); 7.27 – 7.38 (m, 5 H).
13C-NMR (75 MHz, CDCl3): 4.4; 12.6; 14.1; 19.7; 22.7; 25.4; 29.3; 29.7 (7 C); 30.1; 32.0; 32.3; 32.9; 35.3;
72.4; 73.2; 73.7; 74.0; 98.7; 127.3; 127.5; 128.2; 139.0.
(2S,3R)-2-[(4R,5S)-2,2,5-Trimethyl-1,3-dioxan-4-yl]hexadecan-3-ol (21). To a soln. of 18 (267 mg,
0.808 mmol) in CH2Cl2 (28 ml) at r.t. were added DMP (0.155 ml, 1.62 mmol) and CSA (19 mg,
0.081 mmol), and the mixture was stirred at r.t. for 5 min. To this mixture at 08 was added Et3N (4 ml),
and the mixture was diluted with AcOEt. The org. layer was washed with a sat. aq. NaHCO3 soln. (5 ml)
and brine (5 ml), and then dried (Na2SO4). Removal of the solvent left a residue, which was purified by
CC (SiO2; AcOEt/hexane (8%)) to give 21 (1.62 g, 82%). Colorless liquid. Rf (20% AcOEt/hexane) 0.7.
[a]3D0 ¼ þ36.3 (c ¼ 1.5, CHCl3). IR (neat): 1033, 1094, 1250, 1513, 1610, 2901, 3285, 3439. 1H-NMR
(300 MHz, CDCl3): 0.71(d, J ¼ 6.8, 3 H); 0.88 (t, J ¼ 6.8, 3 H); 0.91 (d, J ¼ 6.8, 3 H), 1.21 – 1.32 (m, 23 H);
1.35 (s, 3 H); 1.46 (s, 3 H); 1.47 – 1.54 (m, 1 H); 1.59 – 1.65 (m, 1 H); 1.84 – 1.94 (m, 1 H); 3.08 (br. s, OH);
3.48 (t, J ¼ 11.6, 1 H); 3.62 – 3.71 (m, 3 H). 13C-NMR (75 MHz, CDCl3): 4.8; 12.0; 14.1; 19.2; 22.7; 26.2;
29.3; 29.6 (7 C); 29.7; 30.5; 31.9; 34.9; 36.8; 66.1; 76.7; 81.4; 98.2. ESI-MS: 393 ([M þ Na]þ).
(2S,3R)-2-[(4S,5S)-2,2,5-Trimethyl-1,3-dioxan-4-yl]hexadecan-3-yl (2S)-3-(Benzyloxy)-2-{[(tert-bu-
toxy)carbonyl]amino}propanoate (23). To a soln. of Boc-Ser(Bn)ꢀOH 22 (1.43 g, 4.86 mmol) in CH2Cl2
(20 ml) were added N,N’-dicyclohexylcarbodimide (DCC; 2.51 g, 12.15 mmol) and 4-(dimethylamino)-

680
Helvetica Chimica Acta – Vol. 97 (2014)
pyridine (DMAP; 99 mg, 0.81 mmol). After stirring for 30 min at 08, under Ar at 08 a soln. of 21 (1.5 mg,
4.05 mmol) in CH2Cl2 (5 ml) was added under Ar at 08, and the resulting mixture was further stirred at 08
for 2.5 h. To the mixture was added H2O (10 ml) at 08, and the products were extracted with CH2Cl2. The
org. layer was washed with brine and then dried (Na2SO4). Removal of the solvent left a residue, which
was purified by CC (SiO2; AcOEt/hexane (8%)) to furnish 23 (1.91 g, 73%). Sticky colorless liquid. Rf
(20% AcOEt/hexane) 0.7. [a]3D2 ¼ ꢀ26.5 (c ¼ 1.5, CHCl3). IR (neat): 1256, 1510, 1726, 2863, 2920, 3436.
1H-NMR (300 MHz, CDCl3): 0.66 (t, J ¼ 6.2, 3 H); 0.82 – 0.94 (m, 6 H); 1.21 – 1.29 (m, 23 H); 1.30 (d, J ¼
5.1, 3 H); 1.36 (d, J ¼ 7.3, 3 H); 1.44 (s, 9 H); 1.47 – 1.56 (m, 1 H); 1.71 – 1.88 (m, 2 H); 3.36 – 3.48 (m, 1 H);
3.49 – 3.72 (m, 3 H); 3.81 – 3.92 (m, 1 H); 4.28 – 4.40 (m, 1 H); 4.50 (s, 2 H); 4.87 – 5.03 (m, 1 H); 5.29 (t,
J ¼ 9.9, 1 H); 7.11 – 7.33 (m, 5 H). 13C-NMR (75 MHz, CDCl3): 9.1; 12.1; 14.1; 18.7; 22.6; 28.3; 29.3 (3 C);
29.4; 29.5; 29.6 (6 C); 30.5; 31.1; 31.9; 36.8; 54.2; 66.2; 70.3; 73.3; 74.3; 78.3; 79.7; 97.9; 127.6; 127.7 (2 C);
128.3 (2 C); 137.5; 155.3; 170.2. ESI-MS: 670 ([M þ Na]þ). HR-ESI-MS: 670.4725 (C38H65NaNO7þ ; calc.
670.4732).
(2S,3S,4R,5R)-1,3-Dihydroxy-2,4-dimethyloctadecan-5-yl (2S)-3-(Benzyloxy)-2-{[(tert-butoxy)car-
bonyl]amino}propanoate (24). The soln. of 23 (1.8 g, 2.8 mmol) in AcOH (7.5 ml) and H2O (2.5 ml)
was stirred at r.t. for 10 h. The mixture was diluted with H2O, and to this soln. was added solid NaHCO3
(6.8 g) at 08. The products were extracted with AcOEt, and the org. layer was washed with a sat. aq.
NaHCO3 soln. and brine, and then dried (Na2SO4). Removal of the solvent left a residue, which was
purified by CC (SiO2; AcOEt/hexane (30%)) to yield 24 (1.18 g, 76%). Colorless liquid. Rf (40% AcOEt/
hexane) 0.4. [a]D30 ¼ ꢀ12.6 (c ¼ 0.51, CHCl3). IR (neat): 1168, 1347, 1499, 1720, 2857, 2926, 3445. 1H-NMR
(300 MHz, CDCl3): 0.78 (t, J ¼ 6.6, 3 H); 0.88 (t, J ¼ 6.8, 3 H); 0.95 (d, J ¼ 7.2, 3 H); 1.15 – 1.38 (m, 23 H);
1.44 (s, 9 H); 1.52 – 1.70 (m, 1 H); 1.71 – 1.85 (m, 1 H); 1.96 – 2.15 (m, 1 H); 3.45 – 3.73 (m, 4 H); 3.82 –
4.02 (m, 1 H); 4.23 – 4.40 (m, 1 H); 4.51 (s, 2 H); 4.96 – 5.11 (m, 1 H); 5.23 – 5.38 (m, 1 H); 7.17 – 7.37
(m, 5 H). 13C-NMR (75 MHz, CDCl3): 6.8; 7.2; 14.0; 22.6; 25.3; 28.2; 29.3; 29.4; 29.6 (10 C); 31.8; 32.2;
32.5; 37.8; 38.4; 53.9; 68.1; 69.8; 73.4; 79.1; 79.6; 80.1; 127.6; 127.9 (2 C); 128.4 (2 C); 137.0; 155.6; 170.6.
ESI-MS: 630 ([M þ Na]þ). HR-ESI-MS: 630.4360 (C35H61NaNOþ7 ; calc. 630.4345).
(2R,3R,4R,5R)-5-[((2S)-3-(Benzyloxy)-2-{[(tert-butoxy)carbonyl]amino}propanoyl)oxy]-3-hy-
droxy-2,4-dimethyloctadecanoic Acid (7). To the soln. of 24 (1.1 g, 1.81 mmol) in CH2Cl2 (12 ml) at 08
were added TEMPO (28.3 mg, 0.002 mmol), and BAIB (641.9 mg, 1.99 mmol). After stirring at 08 for
2 h, a 20% aq. Na2S2O3 soln was added. The products were extracted with CHCl3, and the org. layer was
washed with a 20% aq. Na2S2O3 soln. and then dried (Na2SO4). Removal of the solvent gave a crude
aldehyde (1.12 g). The aldehyde was dissolved in MeCN (10 ml) and H2O (2.5 ml). To this soln. were
added 2-methylbut-2-ene (0.08 ml, 0.95 mmol), NaH2PO4 · 2 H2O (722 mg, 4.62 mmol), and NaClO2
(333.2 mg, 3.70 mmol), and the mixture was stirred at r.t. for 20 min. To this mixture at 08 was added a 1m
aq. citric acid soln., and the products were extracted with CHCl3. The org. layer was washed with a 1m aq.
citric acid soln. and then dried (Na2SO4). Removal of the solvent left a residue, which was purified by CC
(SiO2; AcOEt/hexane (40%)) gave 7 (860 mg, 75%). Colorless liquid. Rf (40% AcOEt/hexane) 0.2. IR
(neat): 1036, 1248, 1372, 1731, 2924, 3445. 1H-NMR (300 MHz, CDCl3): 0.88 (t, J ¼ 7.7, 3 H); 0.94 (t, J ¼
6.8, 3 H); 1.01 (t, J ¼ 7.7, 3 H); 1.19 – 1.32 (m, 23 H); 1.44 (s, 9 H); 1.51 – 1.70 (m, 1 H); 1.77 – 1.96 (m,
1 H); 2.60 – 2.83 (m, 1 H); 3.60 – 3.75 (m, 2 H); 3.82 – 3.98 (m, 1 H); 4.35 – 4.58 (m, 3 H); 5.01 – 5.17 (m,
1 H); 5.31 – 5.50 (m, 1 H); 7.20 – 7.40 (m, 5 H). 13C-NMR (75 MHz, CDCl3): 9.0; 14.1; 16.1; 18.0; 22.6;
25.5; 28.2; 29.3; 29.5; 29.6 (6 C); 31.0; 32.2; 39.6; 43.1; 58.2; 69.8; 70.8; 73.3; 73.9; 74.7; 127.6; 127.8 (2 C);
128.4 (2 C); 137.6; 155.6; 169.8; 176.2. ESI-MS: 644 ([M þ Na]þ).
Prop-2-en-1-yl (2R)-3-(Benzyloxy)-2-[(2-{[(tert-butoxy)carbonyl]amino}-3-methylbutanoyl)ami-
no]butanoate (26). To a soln. of the Boc-Thr(allyl) (3.12 g, 8.95 mmol) in CH2Cl2 (15 ml) under Ar at
08 was added TFA (3.5 ml). After stirring at 08 for 1 h, the mixture was concentrated to give a crude
amine, which was dissolved in CH2Cl2 (25 ml). To this soln. at 08 were added the 1-[3-(dimethylami-
no)propyl]-3-ethylcarbodimide hydrochloride (WSC · HCl; 2.15 g, 11.2 mmol), HOBt (1.0 g, 7.46 mmol),
and Boc-Val (1.5 g, 7.46 mmol), and the mixture was stirred for 10 min. To this was added EtNiPr2 (until
the mixture was basic, maintaining the temp. at 08), and the whole mixture was further stirred at r.t. for
4 h. The mixture was diluted with CH2Cl2 and washed successively with a 1m aq. citric acid soln., a sat. aq.
NaHCO3 soln., and brine, and then dried (Na2SO4). Removal of the solvent left a residue, which was
purified by CC (SiO2; acetone/hexane (15%)) to provide 26 (3.07 g, 92%). Colorless liquid. Rf (30%

Helvetica Chimica Acta – Vol. 97 (2014)
681
1
acetone/hexane) 0.6. H-NMR (300 MHz, CDCl3): 0.91 (d, J ¼ 6.8, 3 H); 0.96 (d, J ¼ 6.8, 3 H); 1.22 (d,
J ¼ 6.4, 3 H); 1.42 (s, 9 H); 2.08 – 2.21 (m, 1 H); 3.60 (dd, J ¼ 3.4, 9.4, 1 H); 3.88 (dd, J ¼ 3.4, 9.4, 1 H);
4.10 – 4.24 (m, 1 H); 4.37 (d, J ¼ 12.3, 1 H); 4.40 (d, J ¼ 12.3, 1 H); 4.58 – 4.60 (m, 2 H); 5.07 (br. d, J ¼ 7.9,
1 H); 5.17 – 5.35 (m, 2 H); 5.76 – 5.93 (m, 1 H); 6.89 (bd, J ¼ 6.2, 1 H); 7.23 – 7.33 (m, 5 H). 13C-NMR
(75 MHz, CDCl3): 14.6; 17.6; 19.2; 28.2 (3 C); 31.0; 52.8; 59.9; 66.0; 69.3; 71.4; 74.2; 118.6; 127.5; 127.6
(2 C); 128.3 (2 C); 131.5; 137.9; 155.7; 169.2; 171.6. ESI-MS: 471 ([M þ Na]þ).
Prop-2-en-1-yl (6S,12R)-18-[(1S)-1-(Benzyloxy)ethyl]-6-[(benzyloxy)methyl]-11-hydroxy-2,2,10,
12-tetramethyl-4,7,13,16-tetraoxo-15-(propan-2-yl)-9-tridecyl-3,8-dioxa-5,14,17-triazanonadecan-19-oate
(6). To a soln. of 26 (807 mg, 2.32 mmol) in CH2Cl2 (15 ml) under Ar at 08 was added TFA (1.1 ml). After
stirring at 08 for 1 h, the mixture was concentrated to give a crude amino TFA salt, which was dissolved in
CH2Cl2 (15 ml). To this soln. at 08 were added the WSC · HCl (370.5 mg, 1.93 mmol), HOBt (174 mg,
1.29 mmol), and acid compound 7 (800 mg, 1.29 mmol), and the mixture was stirred for 10 min. To this
was added EtNiPr2 (until the mixture was basic, maintaining the temp. at 08), and the whole mixture was
further stirred at r.t. for 4 h. The mixture was diluted with CH2Cl2 and washed successively with a 1m aq.
citric acid soln., a sat. aq. NaHCO3 soln., and brine, and then dried (Na2SO4). Removal of the solvent left
a residue, which was purified by CC (SiO2; acetone/hexane (25%)) to give 6 (1.03 g, 84%). Colorless
liquid. Rf (40% acetone/hexane) 0.6. [a]3D0 ¼ ꢀ16.3 (c ¼ 1.0, CHCl3). IR (neat): 745, 1166, 1456, 1662,
1734, 2856, 2925, 3439. 1H-NMR (300 MHz, CDCl3): 0.87 (t, J ¼ 7.2, 3 H); 0.89 (d, J ¼ 6.0, 3 H); 0.96 (t,
J ¼ 7.2, 3 H); 0.98 (d, J ¼ 6.0, 3 H), 1.11 (d, J ¼ 7.2, 3 H); 1.18 (d, J ¼ 6.8, 3 H); 1.20 – 1.32 (m, 23 H); 1.44
(s, 9 H); 1.53 – 1.66 (m, 1 H); 1.68 – 1.81 (m, 1 H); 2.08 – 2.23 (m, 1 H); 2.46 – 2.61 (m, 1 H); 3.33 – 3.53 (m,
2 H); 3.57 – 3.72 (m, 1 H); 3.79 – 3.93 (m, 1 H); 4.08 – 4.19 (m, 1 H); 4.23 – 4.40 (m, 2 H); 4.43 – 4.67 (m,
6 H); 5.01 – 5.13 (m, 1 H); 5.15 – 5.26 (m, 1 H); 5.27 – 5.36 (m, 1 H); 5.71 – 5.89 (m, 1 H); 6.55 – 6.72 (m,
2 H); 7.16 – 7.35 (m, 11 H). 13C-NMR (75 MHz, CDCl3): 8.7; 14.1; 15.6; 16.1; 18.0; 19.2; 22.6; 25.5;
28.3(3 C); 29.3; 29.5; 29.6 (7 C); 31.0; 31.9; 32.2; 39.6; 40.1; 43.1; 43.5; 54.2; 56.7; 58.3; 66.1; 69.8; 70.8;
73.3; 73.9; 74.7; 77.3; 79.9; 119.0; 127.6; 127.7; 127.8 (2 C); 128.4 (2 C); 131.4; 137.2; 137.6; 155.6; 169.8;
170.5; 171.4; 176.2. ESI-MS: 974 ([M þ Na]þ). HR-MS: 974.6102 (C54H85NaN3O1þ1 ; calc. 974.6081).
(6S,12R)-18-[(1S)-1-(Benzyloxy)ethyl]-6-[(benzyloxy)methyl]-11-hydroxy-2,2,10,12-tetramethyl-
4,7,13,16-tetraoxo-15-(propan-2-yl)-9-tridecyl-3,8-dioxa-5,14,17-triazanonadecan-19-oic Acid (27). To a
soln. of 6 (950 mg, 0.99 mmol) in THF (10.0 ml) were added morpholine (0.44 ml, 4.5 mmol) and
Pd(PPh3)4 (115.4 mg, 0.1 mmol) at 258. After 30 min, the mixture was diluted with Et2O and treated with
a 0.5m aq. soln. of citric acid. Separation of both phases was followed by extraction of the aq. layer with
Et2O, and the combined org. extracts were washed with H2O and brine, dried (NaSO4), filtered, and
concentrated under reduced pressure. The resulting crude residue was purified by CC (SiO2; MeOH/
CHCl3 (10%)) to furnish 27 (693 mg, 75%). Colorless liquid. Rf (10% MeOH/CHCl3) 0.8. [a]3D1 ¼ ꢀ12.6
(c ¼ 1.6, CHCl3). IR (neat): 1028, 1461, 1645, 1710, 1732, 3311. 1H-NMR (300 MHz, CDCl3): 0.86 (t, J ¼
7.2, 3 H); 0.88 (d, J ¼ 6.0, 3 H); 0.95 (t, J ¼ 7.2, 3 H); 0.97 (d, J ¼ 6.0, 3 H); 1.09 (d, J ¼ 7.2, 3 H); 1.16 (d,
J ¼ 6.8, 3 H); 1.18 – 1.33 (m, 23 H); 1.42 (s, 9 H); 1.52 – 1.65 (m, 1 H); 1.67 – 1.79 (m, 1 H); 2.07 – 2.20 (m,
1 H); 2.44 – 2.58 (m, 1 H); 3.31 – 3.39 (m, 1 H); 3.57 – 3.68 (m, 1 H); 3.78 – 3.91 (m, 1 H); 4.08 – 4.18 (m,
1 H); 4.22 – 4.33 (m, 1 H); 4.42 – 4.61 (m, 6 H); 5.17 (d, J ¼ 10.5, 1 H); 6.52 – 6.71 (m, 2 H); 7.15 – 7.34 (m,
11 H). 13C-NMR (75 MHz, CDCl3): 9.5; 14.5; 16.0; 16.5; 18.4; 19.7; 23.1; 25.9; 28.7 (3 C); 29.7 (6 C);
29.9; 30.0; 31.4; 32.3; 32.7; 40.0; 40.5; 43.5; 44.0; 54.6; 57.1; 58.7; 70.3; 71.2; 73.8; 74.3; 75.2; 77.6; 80.3;
128.0; 128.1; 128.2; 128.4; 128.6 (2 C); 128.8 (2 C); 137.7; 138.0; 156.0; 170.3; 171.0; 171.8; 176.6. ESI-MS:
934 ([M þ Na]þ). HR-ESI-MS: 934.5754 (C51H81NaN3O1þ1 ; calc. 934.5768).
(3S,6S,9S)-6-[1-(Benzyloxy)ethyl]-3-[(benzyloxy)methyl]-13-hydroxy-12,14-dimethyl-9-(propan-2-
yl)-15-tridecyl-1-oxa-4,7,10-triazacyclopentadecane-2,5,8,11-tetrone (29). To a soln. of 27 (85 mg,
0.09 mmol) in anh. CH2Cl2 (2 ml) was added TFA (1 ml) at 08. The mixture was stirred for 3 h at r.t.,
then, the solvents were evaporated under reduced pressure, and the crude product was diluted with
toluene (2 ml) and concentrated again, repeating this operation twice. The resulting salt 28 was used for
the macrocyclization step without any further purification.
A soln. of the TFA salt 28 in DMF (400 ml, 2.4 mm) was treated with DEPC (0.07 ml, 0.47 mmol) at
258, and, after 30 min, with EtNiPr2 (0.09 ml, 0.51 mmol). The mixture was allowed to react at this temp.
for 48 h, after which DMF was removed by distillation under vacuum (0.5 mm Hg) at 508. The crude
mixture was purified by CC (SiO2; AcOEt/hexane (10%)) to provide 29 (18.5 mg, 25%). Clear oil. Rf

682
Helvetica Chimica Acta – Vol. 97 (2014)
(40% acetone/toluene) 0.5. IR (neat): 1074, 1214, 1441, 1646, 1738, 2853, 2924, 3457. 1H-NMR (300 MHz,
CDCl3): 0.85 (d, J ¼ 8.3, 3 H); 0.88 (d, J ¼ 9.8, 3 H); 0.90 (d, J ¼ 9.8, 3 H); 1.03 (d, J ¼ 6.8, 3 H); 1.09 (d,
J ¼ 6.0, 3 H); 1.18 (d, J ¼ 6.0, 3 H); 1.20 – 1.37 (m, 23 H); 1.38 – 1.62 (m, 1 H); 1.90 – 2.04 (m, 1 H); 2.05 –
2.32 (m, 1 H); 2.41 – 2.61 (m, 1 H); 3.47 – 3.69 (m, 1 H); 3.71 – 3.90 (m, 2 H); 3.93 – 4.13 (m, 1 H); 4.35 (d,
J ¼ 11.3, 1 H); 4.43 (d, J ¼ 11.3, 1 H); 4.50 – 4.65 (m, 3 H); 4.66 – 4.81 (m, 2 H); 5.10 – 5.24 (m, 1 H); 6.94
(br. d, J ¼ 8.3, 1 H); 7.05 – 7.34 (m, 10 H); 7.53 (br. d, J ¼ 7.6, 1 H); 7.72 (br. d, J ¼ 8.3, 1 H). 13C-NMR
(75 MHz, CDCl3): 14.1; 15.0; 16.1; 16.2; 16.6; 17.4; 17.9; 19.0; 22.6; 26.6; 29.1; 29.3; 29.4; 29.5; 29.6 (3 C);
31.9; 40.2; 44.0; 53.2; 56.7; 63.5; 68.2; 71.5; 72.0; 73.1; 74.3; 75.6; 81.0; 127.4; 127.5; 127.7; 127.8; 127.9;
128.1; 136.9; 137.7; 168.7; 169.8; 171.3; 178.2. ESI-MS: 816 ([M þ Na]þ). HR-ESI-MS: 816.5118
(C46H71N3NaOþ8 ; calc. 816.5138).
Ethyl (2E,4R,5R)-5-(Methoxymethoxy)-2,4-dimethyloctadec-2-enoate (30). To 12 (2.6 g, 7.3 mmol)
in anh. CH2Cl2 (30 ml) at 08 was added EtNiPr2 (7.7 ml, 44.0 mmol) and cat. amount of DMAP. After
15 min. chloromethyl methyl ether (MOMCl) (2.22 ml, 29.4 mmol) was added dropwise during 10 min,
and stirring was continued for further 12 h. The mixture was diluted with H2O (30 ml) and extracted with
CH2Cl2 (2 ꢁ 15 ml). The combined org. extracts were washed with brine, dried (Na2SO4), and
concentrated in vacuum. The obtained crude product was purified by CC (SiO2; AcOEt/hexane (4%)) to
afford 30 (2.54 g, 87%). Clear oil. Rf (10% AcOEt/hexane) 0.7. [a]3D1 ¼ þ23.2 (c ¼ 1.0, CHCl3). IR (neat):
1
1035, 1248, 1514, 1734, 2934. H-NMR (300 MHz, CDCl3): 0.88 (t, J ¼ 6.8, 3 H); 1.02 (d, J ¼ 6.8, 3 H);
1.21 – 1.36 (m, 23 H); 1.30 (t, J ¼ 6.8, 3 H); 1.41 – 1.56 (m, 1 H); 1.48 (s, 3 H); 2.62 – 2.77 (m, 1 H); 3.35 (s,
3 H); 3.41 (q, J ¼ 6.0, 1 H); 4.17 (q, J ¼ 6.8, 1 H); 4.58 (d, J ¼ 6.8, 1 H); 4.62 (d, J ¼ 6.8, 1 H); 6.62 (d, J ¼
9.8, 1 H). 13C-NMR (75 MHz, CDCl3): 12.5; 14.1; 14.2; 15.3; 22.7; 25.3; 29.3; 29.5; 29.6 (5 C); 29.7; 31.8;
31.9; 36.7; 55.8; 60.4; 81.0; 96.1; 127.3; 144.1; 168.2. ESI-MS: 421 ([M þ Na]þ). HR-ESI-MS: 421.3341
(C24H46NaOþ4 ; calc. 421.3328).
Ethyl (2E,4R,5R)-5-{[(tert-Butyl)(dimethyl)silyl]oxy}-2,4-dimethyloctadec-2-enoate (31). To a stir-
red soln. of 12 (2.0 g, 5.65 mmol) in anh. CH2Cl2 (20 ml) and 2,6-lutidine (1.0 ml, 7.91 mmol) at 08 was
added (tert-butyl)(dimethyl)silyl TBSOTf; (1.68 ml, 7.34 mmol) dropwise and stirred for 2 h at r.t. The
reaction was quenched with H2O, and the mixture was extracted with CH2Cl2 (3 ꢁ 5 ml). The combined
org. layers were washed with brine, dried (Na2SO4), and concentrated under reduced pressure. CC (SiO2;
AcOEt/hexane (2%)) of the crude product afforded 31 (2.35 g, 89%). Colorless liquid. Rf (10% AcOEt/
hexane) 0.7. [a]D30 ¼ þ19.2 (c ¼ 1.4, CHCl3). IR (neat): 1028, 1238, 1528, 1730, 2930, 3346. 1H-NMR
(300 MHz, CDCl3): 0.04 (s, 6 H); 0.87 – 0.94 (m, 12 H); 0.99 (d, J ¼ 6.6, 3 H); 1.18 – 1.38 (m, 26 H); 1.39 –
1.54 (m, 1 H); 1.84 (s, 3 H); 2.49 – 2.67 (m, 1 H); 3.56 (q, J ¼ 5.3, 1 H); 4.18 (q, J ¼ 6.8, 2 H); 6.64 (d, J ¼
10.0, 1 H). 13C-NMR (75 MHz, CDCl3): ꢀ 4.2; ꢀ 4.6; 12.5; 14.1; 14.3; 14.5; 18.1; 22.7; 24.8; 25.7; 25.9
(3 C); 29.3; 29.6 (5 C); 29.8; 31.9; 35.1; 37.9; 60.4; 75.1; 126.3; 145.6; 168.3. ESI-MS: 491 ([M þ Na]þ).
HR-ESI-MS: 491.3811 (C28H56NaO3Siþ; calc. 491.3821).
(2E,4R,5R)-5-(Methoxymethoxy)-2,4-dimethyloctadec-2-en-1-ol (32). A soln. of 30 (2.32 g,
5.83 mmol) in 30 ml of CH2Cl2 was cooled to ꢀ 108. DIBAL-H (8.3 ml, 2.0 mmol; 20% soln. in toluene)
was then added dropwise during 5 min. The resulting mixture was stirred for 2 h before quenching the
reaction with sat. aq. KNaC4H4O6 · 4 H2O soln. (10 ml). The mixture was warmed to r.t. and stirred for
5 h. Org. layer was separated, and aq. layer was extracted with CH2Cl2 (2 ꢁ 10 ml). Combined org. layer
was dried (Na2SO4) and evaporated. CC (SiO2; AcOEt/hexane (10%)) of the crude product afforded 32
(1.93 g, 93%). Colorless liquid. Rf (20% AcOEt/hexane) 0.4. [a]3D0 ¼ þ16.2 (c ¼ 1.5, CHCl3). IR (neat):
1
1163, 1273, 1638, 2987, 3274, 3454. H-NMR (300 MHz, CDCl3): 0.88 (t, J ¼ 6.8, 3 H); 0.96 (d, J ¼ 6.8,
3 H); 1.21 – 1.36 (m, 23 H); 1.40 – 1.51 (m, 1 H); 1.67 (s, 3 H); 2.53 – 2.66 (m, 1 H); 3.35 (s, 3 H); 3.30 –
3.40 (m, 1 H); 3.96 (s, 2 H); 5.29 (d, J ¼ 9.8, 1 H). 13C-NMR (75 MHz, CDCl3): 13.9; 14.1; 16.4; 22.6;
25.4; 29.3; 29.6; 29.8; 31.6; 31.9; 35.5; 55.7; 68.8; 82.0; 96.1; 128.5; 134.6. ESI-MS: 379 ([M þ Na]þ). HR-
ESI-MS: 379.3243 (C22H44NaOþ3 ; calc. 379.3251).
(2E,4R,5R)-5-{[tert-Butyl(dimethyl)silyl]oxy}-2,4-dimethyloctadec-2-en-1-ol (33). A soln. of unsat-
urated ester 31 (2.20 g, 4.7 mmol) in 10 ml of CH2Cl2 was cooled to ꢀ 108. DIBAL-H (8.4 ml,
11.75 mmol; 20% soln. in toluene) was then added dropwise during 5 min. The resulting mixture was
stirred for 2 h before quenching the reaction with sat. aq. KNaC4H4O6 · 4 H2O soln. (15 ml). The mixture
was warmed to r.t. and stirred for 5 h. Org. layer was separated, and aq. layer was extracted with CH2Cl2
(2 ꢁ 10 ml). Combined org. layer was dried (Na2SO4) and evaporated. CC (SiO2; AcOEt/hexane (8%))

Helvetica Chimica Acta – Vol. 97 (2014)
683
of the crude product furnish 33 (1.86 g, 93%). Colorless liquid. Rf (20% AcOEt/hexane) 0.4. [a]D30
¼
þ18.2 (c ¼ 1.5, CHCl3). IR (neat): 1166, 1284, 1652, 2980, 3253, 3447. 1H-NMR (300 MHz, CDCl3):
0.02 (s, 6 H); 0.83 – 0.95 (m, 15 H); 1.18 – 1.33 (m, 23 H); 1.35 – 1.45 (m, 1 H); 1.66 (s, 3 H); 2.49 – 2.53 (m,
1 H); 3.47 (q, J ¼ 5.3, 1 H); 3.95 (s, 2 H); 5.27 (d, J ¼ 8.7, 1 H). 13C-NMR (75 MHz, CDCl3): ꢀ 4.2; ꢀ 4.4;
13.8; 14.1; 15.9; 18.2; 22.7; 24.8; 25.9 (3 C); 29.3; 29.5; 29.6 (5 C); 29.7; 29.9; 31.9; 34.7; 69.1; 76.0; 130.1;
133.5. ESI-MS: 449 ([M þ Na]þ).
(2S,3S,4R,5R)-5-(Methoxymethoxy)-2,4-dimethyloctadecane-1,3-diol (34). To the soln. of 32 (1.8 g,
5.05 mmol) in dry THF (20 ml) was added BH3 · DMS (0.72 ml, 7.58 mmol) during 15 min, maintaining
the temp. at ꢀ 108. The mixture was then allowed to warm to 08 and stirred during 4 h. The soln. was
cooled to ꢀ 108, and 3n NaOH (until the mixture was basic, maintaining the temp. at ꢀ 108.) and H2O2
(5 ml, 30% soln. in H2O) were added, and the mixture was further stirred during 1 h and diluted with
AcOEt (30 ml). The org. layers were separated and washed with brine (1 ꢁ 20 ml), dried (Na2SO4), and
to give a crude product, which was purified by CC (SiO2; AcOEt/hexane (5%)) to afford 34 (1.51 g,
80%). Colorless liquid. Rf (30% AcOEt/hexane) 0.5. 1H-NMR (300 MHz, CDCl3): 0.78 (d, J ¼ 7.0, 3 H);
0.88 (t, J ¼ 7.0, 3 H); 0.95 (d, J ¼ 7.0, 3 H); 1.16 – 1.39 (m, 23 H); 1.36 – 1.50 (m, 1 H); 1.51 – 1.63 (m, 1 H);
1.64 – 1.75 (m, 1 H); 1.82 (br. s, OH); 3.40 (s, 3 H); 3.49 – 4.04 (m, 4 H); 4.64 (d, J ¼ 6.4, 1 H); 4.76 (d, J ¼
6.4, 1 H). 13C-NMR (75 MHz, CDCl3): 5.5; 13.7; 14.0; 22.6; 25.5; 29.3; 29.5; 29.6; 29.7 (5 C); 31.4; 31.9;
36.5; 37.4; 56.0; 68.7; 82.1; 83.4; 95.4. ESI-MS: 397 ([M þ Na]þ). HR-ESI-MS: 397.3350 calc.
(C22H46NaOþ4 ; calc.397.3364).
(2S,3S,4R,5R)-5-{[(tert-Butyl)(dimethyl)silyl]oxy}-2,4-dimethyloctadecane-1,3-diol (35). To the
soln. of 33 (1.7 g, 3.99 mmol) in dry THF (20 ml) was added BH3 · DMS (0.57 ml, 5.98 mmol) during
15 min maintaining the temp. at 08. The mixture was then allowed to warm to r.t. and stirred during 4 h.
The soln. was cooled to 08, and 3n NaOH (until the mixture was basic, maintaining the temp. at 08.) and
H2O2 (5 ml, 30% soln. in H2O) were added, and the mixture was further stirred during 1 h and diluted
with AcOEt (20 ml). The org. layers were separated and washed with brine (1 ꢁ 15 ml), dried (Na2SO4)
and evaporated to give a crude product, which was purified by CC (SiO2; AcOEt/hexane (5%)) to give 35
(1.38 g, 78%). Colorless liquid. Rf (30% AcOEt/hexane) 0.4. 1H-NMR (300 MHz, CDCl3): 0.04 (s, 6 H);
0.70 (d, J ¼ 6.8, 3 H); 0.74 – 0.88 (m, 15 H); 1.10 – 1.29 (m, 23 H); 1.34 – 1.55 (m, 1 H); 1.57 – 1.80 (m,
1 H); 1.71 – 1.86 (m, 1 H); 3.25 (br. s, OH); 3.41 – 3.65 (m, 3 H); 3.70 – 3.88 (m, 1 H). 13C-NMR (75 MHz,
CDCl3): ꢀ 3.5; ꢀ 4.6; 4.7; 13.6; 14.1; 22.7; 25.4; 25.8 (3 C); 29.3; 29.5; 29.6 (6 C); 29.7; 31.9; 34.9; 36.2;
37.5; 68.9; 79.0; 82.7. ESI-MS: 467 ([M þ Na]þ).
(2R,3R,4R,5R)-3-Hydroxy-5-(methoxymethoxy)-2,4-dimethyloctadecanoic Acid (10). To a soln. of
34 (1.4 g, 3.74 mmol) in CH2Cl2 (20 ml) at 08 were added (2,2,6,6-tetramethylpiperidin-1-yl)oxyl
(TEMPO; 58.5 mg, 0.37 mmol) and bis(acetoxy)iodobenzene (BAIB; 1.32 g, 4.11 mmol). After stirring
at 08 for 2 h, a 20% aq. Na2S2O3 (5 ml) soln. was added. The products were extracted with CHCl3, and the
org. layer was washed with a 20% aq. Na2S2O3 soln. and then dried (Na2SO4). Removal of the solvent
under reduced pressure gave a crude aldehyde (1.4 g). The crude aldehyde was dissolved in MeCN
(12 ml) and H2O (4 ml). To this soln. were added 2-methylbut-2-ene (0.08 ml, 0.95 mmol), NaH2PO4 ·
2 H2O (1.47 g, 9.4 mmol), and NaClO2 (677 mg, 7.52 mmol), and the mixture was stirred at r.t. for
20 min. To the mixture at 08 was added a 1m aq. citric acid soln., and the products were extracted with
CHCl3. The org. layer was washed with a 1m aq. citric acid soln. and then dried. Removal of the solvent
left a residue, which was purified by CC (SiO2; AcOEt/hexane (30%)) to give 10 (1.05 g, 72%). Colorless
liquid. Rf (40% AcOEt/hexane) 0.5. IR (neat): 1033, 1250, 1513, 1739, 3285, 3439. 1H-NMR (300 MHz,
CDCl3): 0.88 (t, J ¼ 7.0, 3 H); 0.96 (d, J ¼ 7.2, 3 H); 1.02 (d, J ¼ 7.2, 3 H); 1.19 – 1.38 (m, 23 H); 1.40 – 1.84
(m, 2 H); 2.50 – 2.65 (m, 1 H); 3.39 (s, 3 H); 3.68 – 3.76 (m, 1 H); 3.94 (dd, J ¼ 1.9, 8.9, 1 H); 4.64 (d, J ¼
6.6, 1 H); 4.74 (d, J ¼ 6.6, 1 H). 13C-NMR (75 MHz, CDCl3): 6.0; 10.7; 14.1; 22.6; 25.6; 29.3; 29.5; 29.6
(7 C); 31.4; 31.9; 49.4; 56.0; 76.2; 82.8; 95.5; 205.6. ESI-MS: 411 ([M þ Na]þ).
(2R,3R,4R,5R)-5-{[tert-Butyl(dimethyl)silyl]oxy}-3-hydroxy-2,4-dimethyloctadecanoic Acid (11).
To a soln. of 35 (1.20 g, 2.7 mmol) in CH2Cl2 (15 ml) at 08 were added TEMPO (42.3 mg, 0.27 mmol)
and BAIB (956.3 mg, 2.97 mmol). After stirring at 08 for 2 h, a 20% aq. Na2S2O3 soln. was added. The
products were extracted with CHCl3, and the org. layer was washed with a 20% aq. Na2S2O3 soln. and
then dried (Na2SO4). Removal of the solvent gave a crude aldehyde (1.2 g).

684
Helvetica Chimica Acta – Vol. 97 (2014)
The aldehyde was dissolved in MeCN (10 ml) and H2O (2.5 ml). To this soln. were added 2-
methylbut-2-ene (0.07 ml, 0.95 mmol), NaH2PO4 · 2 H2O (1.26 g, 8.06 mmol), and NaClO2 (581 mg,
6.45 mmol), and the mixture was stirred at r.t. for 20 min. To the mixture at 08 was added a 1m aq. citric
acid soln., and the products were extracted with CHCl3. The org. layer was washed with a 1m aq. citric
acid soln. and then dried (Na2SO4). Removal of the solvent left a residue, which was purified by CC
(SiO2; AcOEt/hexane (30%)) to furnish 11 (940 mg, 76%). Colorless liquid. Rf (30% AcOEt/hexane)
0.3. IR (neat): 1031, 1256, 1518, 1731, 3282, 3437. 1H-NMR (300 MHz, CDCl3): 0.09 (s, 6 H); 0.87 – 0.93
(m, 15 H); 1.17 (d, J ¼ 7.3, 3 H); 1.23 – 1.34 (m, 22 H); 1.43 – 1.63 (m, 2 H); 1.66 – 1.75 (m, 1 H); 2.57 – 2.67
(m, 1 H); 3.81 – 3.89 (m, 2 H). 13C-NMR (75 MHz, CDCl3): ꢀ 3.7; ꢀ 4.5; 5.7; 14.0; 14.1; 18.0; 22.7; 25.3;
25.8 (3 C); 29.3; 29.5; 29.6 (5 C); 29.7; 31.9; 34.6; 36.8; 43.1; 76.5; 77.3; 180.0. ESI-MS: 481 ([M þ Na]þ).
Prop-2-en-1-yl (6S)-9-[(1R)-1-(Benzyloxy)ethyl]-12-[(benzyloxy)methyl]-2,2-dimethyl-4,7,10-tri-
oxo-6-(propan-2-yl)-3-oxa-5,8,11-triazatridecan-13-oate (36). To a soln. of the Boc-Ser(allyl) (3.12 g,
8.95 mmol) obtained from 37 in CH2Cl2 (15 ml) under Ar at 08, was added TFA (3.5 ml). After stirring at
08 for 1 h, the mixture was concentrated to give a crude amine, which was dissolved in CH2Cl2 (25 ml). To
this soln. at 08 were added WSC · HCl (2.15g, 11.2 mmol), HOBt (1.0, 7.46 mmol), and Boc-
Thr(Bzl)ꢀOH (1.5 g, 7.46 mmol), and the mixture was stirred during of 10 min. To this was added
EtNiPr2 (until the mixture was basic, maintaining the temp. at 08), and the whole mixture was further
stirred at r.t. for 4 h. The mixture was diluted with CH2Cl2 and washed successively with a 1m aq. citric
acid soln., sat. aq. NaHCO3 soln., and brine, and then dried (Na2SO4). Removal of the solvent left a
residue, which was purified by CC (SiO2; acetone/hexane (12%)) to afford compound Boc-Thr-Ser(allyl)
(3.13 g, 92%). Colorless liquid. Rf (30% acetone/hexane) 0.5. 1H-NMR (300 MHz, CDCl3): 1.24 (d, J ¼
6.4, 3 H); 1.45 (s, 9 H); 3.61 (dd, J ¼ 3.2, 9.4, 1 H); 3.89 (dd, J ¼ 3.2, 9.4, 1 H); 4.10 – 4.25 (m, 1 H); 4.30 –
4.49 (m, 3 H); 4.53 – 4.69 (m, 4 H); 4.70 – 4.84 (m, 1 H); 5.17 – 5.35 (m, 2 H); 5.52 (bd, J ¼ 6.0, 1 H);
5.77 – 5.94 (m, 1 H); 7.13 – 7.37 (m, 10 H); 7.52 (bd, J ¼ 7.7, 1 H ) . 13C-NMR (75 MHz, CDCl3): 15.0; 28.2
(3 C); 52.8; 57.3; 66.0; 69.4; 71.4; 73.1; 74.9; 80.0; 118.6; 127.5; 127.6; 127.7; 128.2; 128.3; 131.4; 137.3;
138.0; 155.6; 169.4; 169.8. ESI-MS: 549 ([M þ Na]þ).
To a soln. of the Boc-Thr-Ser(allyl) (3.12 g, 7.16 mmol) in CH2Cl2 (25 ml) under Ar at 08 was added
TFA (3.5 ml). After stirring at 08 for 1 h, the mixture was concentrated to give a crude salt, which was
dissolved in CH2Cl2 (25 ml). To this soln. at 08 were added WSC · HCl (1.72 g, 8.95 mmol), HOBt
(806.6 mg, 5.97 mmol), and Boc-Val (1.2 g, 5.97 mmol), and the mixture was stirred during of 10 min. To
this was added EtNiPr2 (until the mixture was basic, maintaining the temp. at 08), and the whole mixture
was further stirred at r.t. for 4 h. The mixture was diluted with CH2Cl2 and washed successively with a 1m
aq. citric acid soln., sat. aq. NaHCO3 soln., and brine, and then dried (Na2SO4). Removal of the solvent
left a residue, which was purified by CC (SiO2; using acetone/hexane (10%)) to give 36 (3.36 g, 90%).
Colorless liquid. Rf (30% acetone/hexane) 0.6. 1H-NMR (300 MHz, CDCl3): 0.9 (d, J ¼ 6.8, 3 H); 0.96 (d,
J ¼ 6.8, 3 H); 1.22 (d, J ¼ 6.4, 3 H); 1.42 (s, 9 H); 2.06 – 2.22 (m, 1 H); 3.60 (dd, J ¼ 3.4, 9.4, 1 H); 3.89 (dd,
J ¼ 3.4, 9.4, 1 H); 3.94 – 4.06 (m, 1 H); 4.10 – 4.23 (m, 1 H); 4.37 (d, J ¼ 12.3, 1 H); 4.44 (d, J ¼ 12.3, 1 H);
4.57 – 4.82 (m, 6 H); 5.06 (br. d, J ¼ 7.9, 1 H); 5.17 – 5.35 (m, 2 H); 5.77 – 5.93 (m, 1 H); 6.89 (br. d, J ¼ 6.2,
1 H); 7.13 – 7.40 (m, 10 H); 7.56 (br. d, J ¼ 8.3, 1 H). 13C-NMR (75 MHz, CDCl3): 14.7; 17.6; 19.2; 28.2
(3 C); 30.9; 52.8; 55.8; 59.9; 66.0; 69.3; 71.4; 73.1; 73.8; 74.2; 79.8; 118.5; 127.5 (4 C); 127.6; 127.7; 128.3
(4 C); 131.5; 137.3; 137.9; 155.7; 169.2; 169.3; 171.6. ESI-MS: 648 ([M þ Na]þ).
Prop-2-en-1-yl (5R,6R,7R,8R,11S,14S,17S)-14-[1-(Benzyloxy)ethyl]-17-[(benzyloxy)methyl]-7-hy-
droxy-6,8-dimethyl-9,12,15-trioxo-11-(propan-2-yl)-5-tridecyl-2,4-dioxa-10,13,16-triazaoctadecan-18-oate
(8). To a soln. of 36 (1.46 g, 2.78 mmol) in CH2Cl2 (15 ml) under Ar at 08 was added TFA (1.5 ml). After
stirring at 08 for 1 h, the mixture was concentrated to give a crude amine salt, which was dissolved in
CH2Cl2 (1.9 ml). To this soln. at 08 were added the WSC · HCl (667 mg, 3.48 mmol), HOBt (313.4 mg,
2.78 mmol), and 10 (900 mg, 2.78 mmol), and the whole mixture was stirred at r.t. for 4 h. The mixture
was diluted with CH2Cl2 and washed successively with a 1m aq. citric acid soln., sat. aq. NaHCO3 soln.,
and brine, and then dried (Na2SO4). Removal of the solvent left a residue, which was purified by CC
(SiO2; acetone/hexane (20%)) to afford 8 (1.87 g, 90%). Colorless liquid. Rf (40% acetone/hexane) 0.5.
[a]3D0 ¼ ꢀ14.3 (c ¼ 1.0, CHCl3). IR (neat): 1101, 1213, 1547, 1636, 1743, 2856, 2926, 3276. 1H-NMR
(300 MHz, CDCl3): 0.88 (t, J ¼ 7.1, 3 H); 0.92 (dd, J ¼ 2.4, 7.1, 3 H); 0.95 (d, J ¼ 7.8, 3 H); 0.97 (d, J ¼ 7.1,
3 H); 1.09 (t, J ¼ 7.8, 3 H); 1.19 (d, J ¼ 7.1, 3 H); 1.20 – 1.35 (m, 23 H); 1.38 – 1.51 (m, 1 H); 1.52 – 1.76 (m,

Helvetica Chimica Acta – Vol. 97 (2014)
685
1 H); 2.11 – 2.26 (m, 1 H); 2.40 – 2.50 (m, 1 H); 3.34 (s, 3 H); 3.54 – 3.65 (m, 1 H); 3.67 – 3.77 (m, 2 H);
3.83 – 3.91 (m, 1 H); 4.08 – 4.20 (m, 1 H); 4.23 – 4.34 (m, 1 H); 4.38 (d, J ¼ 11.7, 1 H); 4.46 (d, J ¼ 11.7,
1 H); 4.51 – 4.78 (m, 8 H); 5.19 (dd, J ¼ 5.5, 9.4, 1 H), 5.28 (d, J ¼ 17.2, 1 H); 5.77 – 5.90 (m, 1 H); 6.61 –
6.67 (m, 1 H); 7.06 (dd, J ¼ 7.8, 18.6, 1 H); 7.18 – 7.35 (m, 10 H); 7.48 (dd, J ¼ 8.3, 18.6, 1 H). 13C-NMR
(75 MHz, CDCl3): 6.5; 14.1; 14.8; 15.8; 17.8; 19.3; 22.6; 25.7; 29.0; 29.3; 29.6 (6 C); 29.8; 30.6; 31.4; 31.8;
37.2; 44.0; 52.7; 55.8; 56.2; 58.6; 66.0; 69.3; 71.4; 73.0; 74.2; 82.2; 95.5; 118.5; 127.5 (4 C); 127.6; 127.7; 128.3
(4 C); 131.5; 137.3; 137.8; 169.2; 171.3; 176.1; 176.3. ESI-MS: 918 ([M þ Na]þ). HR-ESI-MS: 918.5790
(C51H81N3NaOþ10 ; calc. 918.5819).
(5R,6R,7R,8S,11S,14S,17S)-14-[1-(Benzyloxy)ethyl]-17-[(benzyloxy)methyl]-7-hydroxy-6,8-di-
methyl-9,12,15-trioxo-11-(propan-2-yl)-5-tridecyl-2,4-dioxa-10,13,16-triazaoctadecan-18-oic Acid (37).
To a soln. of 8 (250 mg, 0.28 mmol) in THF (10.0 ml) were added morpholine (0.02 ml, 0.28 mmol)
and Pd(PPh3)4 (33 mg, 0.028 mmol) at 258. After 3 h, the mixture was diluted with Et2O and treated with
a 0.5m aq. soln. of citric acid. Separation of both phases was followed by extraction of the aq. layer with
Et2O, and the combined org. extracts were washed with H2O (8 ml) and brine (10 ml), dried (Na2SO4),
filtered, and concentrated under reduced pressure. The resulting crude residue was purified by CC (SiO2;
acetone/hexane (50%)) to give 37 (176.7 mg, 74%). Colorless liquid. Rf (40% acetone/hexane) 0.2.
[a]3D0 ¼ ꢀ20.1 (c ¼ 1.6, CHCl3). IR (neat): 1036, 1248, 1372, 1731, 2924, 3445. 1H-NMR (300 MHz,
CDCl3): 0.80 – 0.99 (m, 12 H); 1.07 (t, J ¼ 5.7, 3 H); 1.18 (d, J ¼ 6.2, 3 H); 1.20 – 1.35 (m, 23 H); 1.41 – 1.80
(m, 2 H); 1.96 – 2.17 (m, 1 H); 2.35 – 2.54 (m, 1 H); 3.35 (s, 3 H); 3.36 – 3.43 (m, 1 H); 3.60 – 3.74 (m,
2 H); 3.75 – 3.93 (m, 1 H); 4.02 – 4.20 (m, 1 H); 4.38 – 4.46 (m, 2 H); 4.47 – 4.78 (m, 7 H); 6.99 (bd, J ¼ 8.1,
1 H); 7.14 – 7.36 (m, 10 H); 7.48 (bd, J ¼ 7.6, 1 H); 7.60 (bd, J ¼ 8.9, 1 H). 13C-NMR (75 MHz, CDCl3): 6.5;
11.4; 14.1; 14.8; 17.8; 19.3; 20.4; 22.6; 25.7; 29.0; 29.3; 29.6 (6 C); 30.8; 31.6 (2 C); 31.9; 37.2; 44.1; 52.8;
55.8; 58.7; 60.4; 69.3; 71.5; 73.1; 74.2; 82.4; 95.6; 127.5 (4 C); 127.6; 127.7; 128.3 (4 C); 137.4; 137.9; 169.2;
169.4; 171.3; 176.1. ESI-MS: 856 (M þ H)þ.
(3S,6S,9S,12R,13R)-6-[1-(Benzyloxy)ethyl]-3-[(benzyloxy)methyl]-13-[(2S,3R)-3-(methoxyme-
thoxy)hexadecan-2-yl]-12-methyl-9-(propan-2-yl)-1-oxa-4,7,10-triazacyclotridecane-2,5,8,11-tetrone
(39). A soln. of 37 (50 mg, 0.06 mmol) in toluene (2 ml) was treated at 08 with Et3N (0.02 ml, 0.13 mmol)
and 2,4,6-trichlorobenzoyl chloride (0.02 ml, 0.08 mmol). To this mixture under Ar at 08 was added a
soln. of DMAP (16 mg, 0.13 mmol) in toluene (2 ml), and the resulting mixture was further stirred at 08
for 40 min. The mixture was allowed to warm to r.t. and stirred for 1 h. To the mixture was added 1m aq.
citric acid soln. Then, Et2O (10 ml) was added, and the resulting mixture was sequentially washed with
H2O (5 ml) and brine (5 ml), and the org. phase was separated, dried (Na2SO4), filtered, and
concentrated under reduced pressure. CC (SiO2; acetone/hexane (10%)) of the crude product gave 39
(10.7 mg, 22%). Colorless liquid. Rf (40% acetone/hexane) 0.8. IR (neat): 1084, 1248, 1371, 1514, 1614,
1734, 2986, 3455. 1H-NMR (300 MHz, CDCl3): 0.88 (t, J ¼ 7.0, 3 H); 0.89 (d, J ¼ 6.2, 3 H); 0.93 (d, J ¼ 7.0,
3 H); 0.97 (d, J ¼ 7.0, 3 H); 1.00 (d, J ¼ 6.9, 3 H); 1.15 (d, J ¼ 6.9, 3 H); 1.20 – 1.34 (m, 23 H); 1.51 – 1.66
(m, 1 H); 1.70 – 1.82 (m, 1 H); 1.99 – 2.30 (m, 1 H); 2.29 – 2.53 (m, 1 H); 3.36 (s, 3 H); 3.63 – 3.70 (m, 1 H);
3.76 – 3.83 (m, 1 H); 4.19 (d, J ¼ 6.2, 1 H); 4.37 – 4.48 (m, 4 H); 4.50 – 4.59 (m, 4 H); 4.62 (d, J ¼ 7.0, 1 H);
4.70 (d, J ¼ 7.0, 1 H); 5.22 (dd, J ¼ 2.2, 8.8, 1 H); 6.63 (d, J ¼ 8.8, 1 H); 6.71 (d, J ¼ 8.8, 1 H); 7.17 – 7.41 (m,
11 H). 13C-NMR (75 MHz, CDCl3): 7.0; 14.2; 15.0; 16.5; 18.1; 19.3; 22.7; 25.8; 29.4; 29.6; 29.7 (2 C); 29.9
(4 C); 31.3; 31.6; 32.0; 37.5; 44.3; 52.2; 55.9; 58.4; 61.9; 71.4; 72.3; 74.7; 82.2; 95.6; 121.2; 127.5 (4 C); 127.6;
127.7 (4 C); 128.3; 133.1; 137.6; 137.7; 146.1; 156.4; 159.9; 171.4; 175.7. ESI-MS: 838 ([M þ H])þ.
Prop-2-en-1-yl (5S,6R,7R,8R,11S,14S,17S)-14-[1-(Benzyloxy)ethyl]-17-[(benzyloxy)methyl]-7-hy-
droxy-2,2,3,3,6,8-hexamethyl-9,12,15-trioxo-11-(propan-2-yl)-5-tridecyl-4-oxa-10,13,16-triaza-3-silaocta-
decan-18-oate (9). To a soln. of 36 (1.24 g, 2.35 mmol) in CH2Cl2 (15 ml) under Ar at 08 was added TFA
(1.5 ml). After stirring at 08 for 3 h, the mixture was concentrated to give a crude salt, which was
dissolved in CH2Cl2 (5 ml). To this soln. at 08 were added the WSC · HCl (565.1 mg, 2.94 mmol), HOBt
(264.8 mg, 1.96 mmol), and 11 (900 mg, 1.96 mmol), and the whole mixture was stirred at r.t. for 4 h. The
mixture was diluted with CH2Cl2 and washed successively with 1m aq. citric acid soln., sat. aq. NaHCO3
soln., and brine, and then dried (Na2SO4). Removal of the solvent left a residue, which was purified by
CC (SiO2; acetone/hexane (12%)) to furnish 9 (1.58 g, 90%). Colorless liquid. Rf (40% acetone/hexane)
0.5. [a]3D0 ¼ ꢀ10.6 (c ¼ 1.0, CHCl3). IR (neat): 1211, 1540, 1637, 1736, 2851, 2925, 3270. 1H-NMR
(300 MHz, CDCl3): 0.08 (s, 6 H); 0.88 (s, 9 H); 0.92 (d, J ¼ 7.2, 3 H); 0.96 (d, J ¼ 6.8, 3 H); 1.05 (d, J ¼ 6.4,

686
Helvetica Chimica Acta – Vol. 97 (2014)
3 H); 1.07 (d, J ¼ 6.8, 3 H); 1.11 (d, J ¼ 6.4, 3 H); 1.20 (d, J ¼ 6.4, 3 H); 1.21 – 1.37 (m, 23 H); 1.41 – 1.58
(m, 1 H); 1.62 – 1.74 (m, 1 H); 2.12 – 2.27 (m, 1 H); 2.33 – 2.47 (m, 1 H); 3.58 (dd, J ¼ 3.4, 9.4, 1 H); 3.65 –
3.77 (m, 2 H); 3.78 – 3.92 (m, 2 H); 4.06 – 4.21 (m, 1 H); 4.28 – 4.48 (m, 2 H); 4.53 – 4.66 (m, 5 H); 4.67 –
4.80 (m, 1 H); 5.19 (dd, J ¼ 3.4, 10.2, 1 H); 5.28 (d, J ¼ 17.4, 1 H); 5.74 – 5.92 (m, 1 H); 6.80 (dd, J ¼ 8.3,
12.8, 1 H); 7.08 (t, J ¼ 7.9, 1 H); 7.11 – 7.37 (m, 10 H); 7.52 (dd, J ¼ 7.9, 8.3, 1 H). 13C-NMR (75 MHz,
CDCl3): ꢀ 4.7; ꢀ 3.7; 5.4; 14.0; 14.8; 15.8; 17.5; 17.9; 19.3; 22.6; 25.3; 25.7 (3 C); 29.3 (2 C); 29.5; 29.6
(4 C); 29.7; 30.7; 31.8; 34.7; 36.8; 44.0; 52.7; 55.8; 58.6; 66.0; 69.2; 71.4; 73.0; 74.2; 77.5; 118.4; 127.5 (4 C);
127.6; 127.7; 128.2 (4 C); 131.5; 137.3; 137.9; 169.3; 171.5; 176.0; 176.3. ESI-MS: 988 ([M þ Na]þ). HR-
ESI-MS: 988.6394 (C55H91N3NaO9Siþ; calc. 988.6422).
(5R,6R,7R,8S,11S,14S,17S)-14-[1-(Benzyloxy)ethyl]-17-[(benzyloxy)methyl]-7-hydroxy-2,2,3,3,6,8-
hexamethyl-9,12,15-trioxo-11-(propan-2-yl)-5-tridecyl-4-oxa-10,13,16-triaza-3-silaoctadecan-18-oic Acid
(38). To a soln. of 9 (300 mg, 0.31 mmol) in THF (8 ml) were added morpholine (0.03 ml, 0.31 mmol)
and Pd(PPh3)4 (36 mg, 0.03 mmol) at 258. After 4 h, the mixture was diluted with E2O (10 ml) and
treated with a 0.5m aq. soln. of citric acid (4 ml). Separation of both phases was followed by extraction of
the aq. layer with E2O (2 ꢁ 10 ml), and the combined org. extracts were washed with H2O (8 ml) and
brine (8 ml), dried (Na2SO4), filtered, and concentrated under reduced pressure. The resulting crude
residue was purified by CC (SiO2; acetone/hexane (40%)) to yield 38 (230.3 mg, 80%). Colorless liquid.
Rf (50% acetone/hexane) 0.3. [a]3D1 ¼ ꢀ19.2 (c ¼ 1.5, CHCl3). IR (neat): 1056, 1241, 1376, 1738, 2934,
3415. 1H-NMR (300 MHz, CDCl3): 0.08 (s, 6 H); 0.80 – 0.98 (m, 21 H); 1.05 (d, J ¼ 6.4, 3 H); 1.16 (d, J ¼
6.4, 3 H); 1.20 – 1.36 (m, 23 H); 1.40 – 1.58 (m, 1 H); 1.60 – 1.74 (m, 1 H); 2.04 – 2.22 (m, 1 H); 2.36 – 2.52
(m, 1 H); 3.66 (d, J ¼ 8.8, 1 H); 3.75 (d, J ¼ 7.6, 1 H); 3.79 – 3.91 (m, 2 H); 4.00 – 4.24 (m, 1 H); 4.40 (s,
2 H); 4.44 – 4.50 (m, 1 H); 4.52 (d, J ¼ 4.9, 1 H); 4.58 (d, J ¼ 6.6, 1 H); 4.62 – 4.77 (m, 2 H); 7.01 – 7.35 (m,
11 H); 7.43 (dd, J ¼ 6.3, 17.2, 1 H); 7.64 (dd, J ¼ 7.6, 17.0, 1 H). 13C-NMR (75 MHz, CDCl3): ꢀ 4.7; ꢀ 3.6;
5.4; 14.0; 14.8; 15.8; 17.5; 17.9; 19.3; 22.6; 25.3; 25.7 (3 C); 29.3; 29.5; 29.6 (4 C); 29.7; 30.7; 31.8; 34.7;
36.8; 44.0; 52.7; 55.8; 58.6; 69.2; 71.4; 73.0; 74.2; 77.5; 127.5 (4 C); 127.6; 127.8; 128.2 (4 C); 137.3; 137.9;
169.3; 171.5; 171.6; 176.1. ESI-MS: 948 ([M þ Na]þ). HR-ESI-MS: 948.6138 (C52H87NaN3O9Siþ;
calc.948.6109).
Prop-2-en-1-yl (2S)-3-(Benzyloxy)-2-{[(2S)-3-(benzyloxy)-2-{[(2S)-2-{[(2R,3R,4S,5R)-3,5-dihy-
droxy-2,4-dimethyloctadecanoyl]amino}-3-methylbutanoyl]amino}butanoyl]amino}propanoate (42). To
a soln. of 9 (400 mg, 0.42 mmol) in MeOH (5 ml) at 08 was added anh. CSA (52 mg, 0.21 mmol). The
mixture was stirred at r.t. for 3 h, and then the reaction was quenched with solid NaHCO3, and the
mixture was filtered. The filtrate was concentrated in vacuum. CC (SiO2; acetone/hexane (40%)) of the
crude product gave 42 (211.6 mg, 60%). Colorless liquid. Rf (40% acetone/hexane) 0.2. [a]3D0 ¼ ꢀ13.6
(c ¼ 1.5, CHCl3). IR (neat): 1036, 1248, 1372, 1731, 2924, 3445. 1H-NMR (300 MHz, CDCl3): 0.85 (d, J ¼
8.3, 3 H); 0.88 (t, J ¼ 9.8, 3 H); 0.90 (d, J ¼ 9.8, 3 H); 1.03 (d, J ¼ 6.8, 3 H); 1.09 (d, J ¼ 6.0, 3 H); 1.18 (d,
J ¼ 6.0, 3 H); 1.20 – 1.36 (m, 23 H); 1.38 – 1.60 (m, 1 H); 1.89 – 2.36 (m, 2 H); 2.40 – 2.60 (m, 1 H); 3.54
(dd, J ¼ 3.0, 9.0, 1 H); 4.37 – 4.45 (m, 1 H); 3.59 – 3.69 (m, 1 H); 3.70 – 3.91 (m, 2 H); 3.93 – 4.13 (m, 1 H);
4.27 – 4.46 (m, 2 H); 4.49 – 4.64 (m, 5 H); 4.65 – 4.80 (m, 2 H); 5.17 (d, J ¼ 10.6, 1 H); 5.27 (d, J ¼ 16.6,
1 H); 5.73 – 5.90 (m, 1 H); 6.94 (bd, J ¼ 8.3, 1 H); 7.06 – 7.35 (m, 10 H); 7.53 (bd, J ¼ 7.6, 1 H); 7.72 (bd,
J ¼ 8.3, 1 H). 13C-NMR (75 MHz, CDCl3): 4.8; 12.2; 14.1; 14.5; 14.8; 19.3; 22.6; 26.1; 29.3; 29.5; 29.6
(4 C); 30.8; 31.9; 35.2; 36.9; 44.2; 52.8; 56.0; 58.9; 66.1; 69.3; 71.5; 74.3; 78.4; 118.6; 127.5 (4 C); 127.7;
127.8; 128.3 (4 C); 131.5; 137.4; 137.9; 169.3; 171.3; 173.8; 176.1. ESI-MS: 874 ([M þ Na]þ). HR-ESI-MS:
874.5544 (C49H77N3NaOþ9 ; calc. 874.5557).
(2S)-3-(Benzyloxy)-2-{[(2S)-3-(benzyloxy)-2-{[(2S)-2-{[(2R,3R,4S,5R)-3,5-dihydroxy-2,4-dime-
thyloctadecanoyl]amino}-3-methylbutanoyl]amino}butanoyl]amino}propanoic Acid (43). To a soln. of
42 (180 mg, 0.21 mmol) in THF (5.0 ml) were added morpholine (0.09 ml, 1.06 mmol) and Pd(PPh3)4
(25 mg, 0.02 mmol) at r.t. After 3 h, the mixture was diluted with Et2O (8 ml) and treated with a 0.5m aq.
soln. of citric acid (5 ml). Separation of both phases was followed by extraction of the aq. layer with Et2O,
and the combined org. extracts were washed with H2O and brine, dried (Na2SO4), filtered, and
concentrated under reduced pressure. The resulting crude residue was purified by CC (SiO2; acetone/
1
hexane (40%)) to give 43 (108.5 mg, 63%). Colorless liquid. Rf (50% acetone/hexane) 0.2. H-NMR
(300 MHz, CDCl3): 0.87 (d, J ¼ 7.0, 3 H); 0.88 (t, J ¼ 7.0, 3 H); 0.92 (dd, J ¼ 2.3, 7.0, 3 H), 0.96 (dd, J ¼ 4.7,
7.0, 3 H), 1.09 (t, J ¼ 7.8, 3 H); 1.19 (d, J ¼ 6.2, 3 H); 1.21 – 1.35 (m, 23 H); 1.35 – 1.50 (m, 1 H); 1.53 – 1.77

Helvetica Chimica Acta – Vol. 97 (2014)
687
(m, 1 H); 2.19 (q, J ¼ 7.0, 1 H); 2.45 (q, J ¼ 7.0, 1 H); 3.57 (dd, J ¼ 3.1, 9.3, 1 H); 3.63 (d, J ¼ 7.0, 1 H);
3.67 – 3.77 (m, 2 H); 3.87 (dt, J ¼ 3.1, 9.3, 1 H); 4.37 – 4.45 (m, 1 H); 4.53 – 4.63 (m, 4 H); 4.64 – 4.68 (m,
1 H); 4.70 – 4.77 (m, 1 H); 6.60 – 6.67 (m, 1 H); 7.06 (dd, J ¼ 7.8, 17.0, 1 H); 7.18 – 7.35 (m, 10 H); 7.48 (dd,
J ¼ 8.5, 17.0, 1 H). 13C-NMR (75 MHz, CDCl3): 10.1; 12.2; 14.1; 14.8; 18.0; 19.3; 22.6; 25.4; 29.3; 29.5; 29.6
(5 C) ; 30.8; 31.9; 35.2; 38.1; 44.2; 52.8;56.3; 58.9; 69.3; 71.5; 73.1; 74.3; 78.2; 127.5 (4 C); 127.7; 127.8;
128.3 (4 C); 137.4; 137.9; 169.3; 171.3; 176.1; 176.3. ESI-MS: 835 ([M þ Na]þ).
REFERENCES
[1] T. Morino, A. Masuda, M. Yamada, M. Nishimoto, T. Nishikiori, S. Saito, N. Shimada, J. Antibiot.
1994, 47, 1341.
[2] T. Hamaguchi, A. Masuda, T. Morino, H. Osada, Chem. Biol. 1997, 4, 279.
[3] a) T. Morino, K. Shimada, A. Masuda, N. Yamashita, M. Nishimoto, T. Nishikiori, S. Saito, S. J.
Antibiot. 1996, 49, 564; b) K. Shimada, T. Morino, A. Masuda, M. Sato, M. Kitagawa, S. Saito, J.
Antibiot. 1996, 49, 569.
[4] H. Tanaka, A. Kuroda, H. Marusawa, H. Hatanaka, T. Kino, T. Goto, M. Hashimoto, T. Taga, J. Am.
Chem. Soc. 1987, 109, 5031; M. J. Tocci, D. A. Matkovich, K. A. Collier, P. Kwok, F. Dumont, S. Lin,
S. Degudicibus, J. J. Siekerka, J. Chin, N. I. Hutchinson, J. Immunol. 1989, 143, 718; M. W. Harding,
A. Golat, D. E. Uehling, S. L. Schreiber, Nature 1989, 341, 758; C. S. Lin, R. C. Boltz, J. J. Siekierka,
N. H. Sigal, Cell. Immunol. 1991, 133, 269; B. E. Bierer, Curr. Opin. Hematol. 1993, 1, 149; S. L.
Schreiber, Science 1991, 251, 283.
[5] M. Dreyfuss, E. Harri, H. Hofmann, Eur. J. Appl. Microbiol. 1976, 3, 125; H. F. Stahelin, Experientia
1996, 52, 5; J. F. Elliott, Y. Lin, S. B. Mizel, R. C. Bleackley, D. G. Harnish, V. Paetkau, Science 1984,
226, 1439; M. Bickel, P. Amstad, V. Evequoz, S. E. Mergenhagen, D. H. Pluznik, H. Tsuda, S. M.
Wahl, Proc. Natl. Acad. Sci. U.S.A. 1987, 84, 3274.
[6] J. J. Sanglier, V. Quesniaux, T. Fehr, H. Hofmann, M. Mahnke, K. Memmert, W. Schuler, G. Zenke,
L. Gschwind, C. Maurer, W. Schilling, J. Antibiot. 1999, 52, 474; R. Sedrani, J. Kallen, L. M.
Martin Cabrejas, C. D. Papageorgiou, F. Senia, S. Rohrbach, D. Wagner, B. Thai, A. M. Jutzi Eme, J.
France, L. Oberer, G. Rihs, G. Zenke, J. Wagner, J. Am. Chem. Soc. 2003, 125, 3849.
[7] a) K. Kurosawa, T. Nagase, N. Chida, Chem. Commun. 2002, 1280; b) N. Kohyama, Y. Yamamoto,
´
Synlett. 2001, 694; c) F. Sarabia, S. Chammaa, F. J. Lopez-Herrera, Tetrahedron Lett. 2002, 43, 2961;
d) K. Kurosawa, K. Matsuura, T. Nagase, N. Chida, Bull. Chem. Soc. Jpn. 2006, 79, 921; e) F. Sarabia,
S. Chammaa, J. Org. Chem. 2005, 70, 7846.
[8] a) K. Kurosawa, K. Matsuura, N. Chida, Tetrahedron Lett. 2005, 46, 389; b) T. K. Chakraborty, S.
Ghosh, P. Laxman, S. Dutta, R. Samanta, Tetrahedron Lett. 2005, 46, 5447; c) T. K. Chakraborty, S.
Ghosh, S. Dutta, Tetrahedron Lett. 2001, 42, 5085; d) N. Bisek, S. Wetzel, H. D. Arndt, H. Waldmann,
Chem. – Eur. J. 2008, 14, 8847.
[9] J. S. Yadav, S. S. Mandal, J. S. S. Reddy, P. Srihari, Tetrahedron 2011, 67, 4620; P. Srihari, K.
Satyanarayana, B. Ganganna, J. S. Yadav, J. Org. Chem. 2011, 76, 1922; J. S. Yadav, J. S. S. Reddy,
S. S. Mandal, P. Srihari, Synlett 2010, 2636; P. Srihari, B. Kumaraswamy, G. Maheshwara Rao, J. S.
Yadav, Tetrahedron: Asymmetry 2010, 106.
[10] A. J. Mancuso, S. L. Huang, D. Swern, J. Org. Chem. 1978, 43, 2480; B. E. Maryanoff, A. B. Reitz,
Chem. Rev. 1989, 89, 863.
[11] T. Katsuki, K. B. Sharpless, J. Am. Chem. Soc. 1980, 102, 5974.
[12] M. E. Jung, D. C. DꢂAmico, J. Am. Chem. Soc. 1993, 115, 12208; M. E. Jung, D. C. DꢂAmico, J. Am.
Chem. Soc. 1997, 119, 12150; P. Srihari, K. Ravindar, R. Somaiah, J. S. Yadav, Synth. Commun. 2008,
38, 1389.
[13] G. Schmid, T. Fukuyama, K. Akasaka, Y. Kishi, J. Am. Chem. Soc. 1979, 101, 259.
[14] K. N. Houk, N. G. Rondan, Y. D. Wu, J. T. Metz, M. N. Paddon-Row, Tetrahedron 1984, 40, 2257.
[15] S. D. Rychnovsky, D. J. Skalitzy, Tetrahedron Lett. 1990, 31, 945; D. A. Evans, D. L. Rieger, J. R.
Gage, Tetrahedron Lett. 1990, 31, 7099.
[16] E. Fanton, J. Gelas, D. Horton, J. Chem. Soc., Chem. Commun. 1980, 21.

688
Helvetica Chimica Acta – Vol. 97 (2014)
[17] J. Inanaga, K. Hirata, H. Saeki, T. Katsuki, M. Yamaguchi, Bull. Chem. Soc. Jpn. 1979, 52, 1989.
[18] E. P. Boden, G. E. Keck, J. Org. Chem. 1985, 50, 2394.
[19] P. L. Anelli, C. Biffi, F. Montanari, S. Quici, J. Org. Chem. 1987, 52, 2559; T. Inokuchi, S. Matsumoto,
T. Nishiyama, S. Torii, J. Org. Chem. 1990, 55, 462.
[20] J. Jones, in ꢃAmino Acid and Peptide Synthesisꢂ, Oxford Chemistry Primers Series 7, Oxford
University Press, New York, 1992.
[21] H. Kogen, T. Kiho, M. Nakayama Y. Furukawa, T. Kinoshita, M. Inukai, J. Am. Chem. Soc. 2000,
122, 10214.
[22] T. Shioiri, Y. Yokoyama, Y. Kasai, S. Yamada, Tetrahedron 1976, 32, 2211.
[23] K. J. Hale, G. S. Bhatia, M. Frigerio, in ꢃThe Chemical Synthesis of Natural Productsꢂ, Ed. K. J. Hale,
Sheffield Academic Press, Sheffield, 2000, pp. 349 – 415.
[24] S. Yamada, S. Kasai, Y. Shioiri, T. Tetrahedron Lett. 1973, 14, 1595; S. Takuma, Y. Hamada, T. Shioiri,
Chem. Pharm. Bull. 1982, 30, 3147.
[25] W. R. Li, W. R. Ewing, B. D. Harris, M. M. Joullie, J. Am. Chem. Soc. 1990, 112, 7659.
[26] M. Hikota, H. Tone, K. Horita, O. Yonemitsu, J. Org. Chem. 1990, 55, 7.
Received June 25, 2013