Synthetic studies toward (+)-spongidepsin

Article abstract of DOI:10.1002/hlca.201200519

A convergent enantiomerically controlled synthetic effort toward (+)-spongidepsin is reported. The synthesis benefits from the use of readily available and inexpensive starting materials like D-mannitol and (-)-β-citronellene. Key transformations include Evans asymmetric methylation, Mitsunobu esterification, (1H-benzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate (PyBOP)-mediated amide formation for the preparation of a fully functionalized acyclic precursor, and ring-closing metathesis (RCM). Copyright

Full text of DOI:10.1002/hlca.201200519

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Helvetica Chimica Acta – Vol. 96 (2013)
Synthetic Studies Toward (þ)-Spongidepsin
by Guvvala Venkateswar Reddy, Rotte Satish Chandra Kumar, Gundeti Shankaraiah, Katragadda
Suresh Babu*, and Janaswamy Madhusudana Rao*
Division of Natural Product Chemistry, Indian Institute of Chemical Technology, Hyderabad, 500007,
India (phone: +91-49-27191880/1881; fax: +91-40-27160512; e-mail: suresh@iict.res.in)
A convergent enantiomerically controlled synthetic effort toward (þ)-spongidepsin is reported. The
synthesis benefits from the use of readily available and inexpensive starting materials like d-mannitol
and (ꢀ)-b-citronellene. Key transformations include Evans asymmetric methylation, Mitsunobu
esterification, (1H-benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP)-
mediated amide formation for the preparation of a fully functionalized acyclic precursor, and ring-
closing metathesis (RCM).
Introduction. – Marine organisms have been a rich source of biologically active
cyclic peptides with unique structural features. (ꢀ)-Spongidepsin is a macrolide
isolated from a Spongia species, collected from the Vanuatu Islands, Australia, by
Riccio and co-workers [1], with cytotoxic and antiproliferative activities against
J774.A1, WEHI-164, and HEK-293 cancer cell lines. (ꢀ)-Spongidepsin is a 13-
membered macrolactam with five stereogenic centers. Its structure was established by
spectroscopic analysis, and the N-methylphenylalanine residue with l configuration has
been identified by isolation. The absolute configurations at the other four stereogenic
centers were determined by total synthesis [2]. While biological studies are severely
limited by the scarcity of these natural products, the unprecedented structural features
and remarkable biological activity have provided the impetus for additional total
syntheses [3]. In continuation of our synthesis work on bioactive macrolides [4], we
present herein an enantioselective synthesis of the unnatural (þ)-spongidepsin (1).
Results and Discussion. – We report here a highly convergent synthesis of (þ)-
spongidepsin (1) using a ring-closing metathesis (RCM) to from the 13-membered
macrocycle [2][3]. In analogy to the described syntheses of the natural (ꢀ)-
spongidepsin, we envisioned in our retrosynthetic analysis the preparation of three
nonracemic components, 3 – 5, for the convergent assembly of the target macrolactam
(Scheme 1).
Efforts towards the construction of fragment 4 started with the inexpensive and
readily available d-mannitol (7; Scheme 2), which was converted to the a,b-
unsaturated ester 9 by a known procedure [5]. The alkene 9 was reduced selectively
with NiCl2/NaBH4 [6] to give the saturated ester 10 in 97% yield, and this was
subsequently hydrolyzed to give acid 11, which was coupled with the Evans
oxazolidinone (R)-4-benzyloxazolidin-2-one ((R)-20), by forming the activated ester
with pivaloyl chloride [7], leading to imide 12 in 75% yield. Asymmetric methylation of
ꢀ 2013 Verlag Helvetica Chimica Acta AG, Zꢁrich

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Scheme 1
12 according to the Evans protocol (NaHMDS, THF, ꢀ 788, and then MeI) [8] afforded
13 in 86% yield as a single stereoisomer. The optimal conditions entailed dropwise
addition of 3 equiv. of MeI over 30 min, and the temperature was kept at ꢀ 78 for 4 h
to minimize the formation of the a-dimethylated by-product. Reductive removal [9] of
the chiral auxiliary by treatment with LiBH4 furnishedthe primary alcohol 14 in 83%
yield. This alcohol was converted to its pivalate [10] with 2,2-dimethylpropanoyl
chloride (pivaloyl chloride; PivCl) and pyridine in CH2Cl2, and the crude pivalate was
exposed to Dowex 50WX8 in MeOH to afford diol 15 in 80% yield. The latter was
converted to epoxide 16 as described in [11] (NaH, 1-tosyl-1H-imidazole) in good yield
(96%). Opening of epoxide 16 with the acetylide anion, derived from benzyl propargyl
ether, under Yamaguchi conditions [12] gave 17. Removal of the Piv group in 17 with
DIBAL, followed by oxidation of 18 with PhI(OAc)2 and TEMPO [13], gave lactone
19 in 92% yield, which was then reduced with DIBAL-H and olefinated by the Wittig
reaction to give 4 in 73% yield (two steps).
Construction of the acid 5 started with commercially available (ꢀ)-b-citronellene
(8), which, via the reported ozonolysis [14], furnished the known aldehyde, which, on
exposure to Jones oxidation [15], gave acid 21 in 85% yield. Coupling of 21 with (S)-4-
benzyloxazolidin-2-one ((S)-20) (PivCl, Et3N, THF, ꢀ 208; then LiCl, (S)-20, room
temperature) furnished imide 22 in 72% yield. Asymmetric methylation of 22
according to the Evans protocol (NaHMDS, THF, ꢀ 788; then MeI, ꢀ 78 to ꢀ 408)
afforded 23 in 80% yield as an 8 :2 mixture of diastereoisomers (1H-NMR). Reductive
removal of the chiral auxiliary by treatment with NaBH4 [16] gave 24, which, on further
treatment with Jones reagent, provided the desired acid 5 (Scheme 3).
The amino acid moiety 3 was synthesized in analogy to [2] from the unnatural
amino acid d-phenylalanine (6). Boc Protection with (Boc)2O in 20% aq. NaOH in

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Helvetica Chimica Acta – Vol. 96 (2013)
Scheme 2
a) NiCl2 · H2O, NaBH4, MeOH, 08, 1 h; 97%. b) LiOH, THF/H2O/MeOH 4 :4 :2, 08 to r.t., 10 h; 91%. c)
Pivaloyl chloride (PivCl), Et3N, LiCl, Evans oxazolidinone (R)-20, 08, 4 h; 75%. d) Sodium bis-
(trimethylsilyl)amide (NaHMDS), MeI, THF, ꢀ 788, 3 h; 86%. e) LiBH4, MeOH, Et2O, ꢀ 108, 1 h;
83%. f) 1. PivCl, pyridine, 4-(dimethylamino)pyridine (DMAP; cat.), CH2Cl2, 08 to r.t., 2 h; 2. Dowex
50WX8, MeOH, r.t., 48 h; 80% (2 steps). g) NaH, 1-tosyl-1H-imidazole, THF, 08, 1.5 h; 96%. h) Benzyl
propargyl ether (HCCCH2OCH2Ph), BuLi, THF, ꢀ 788, BF3 · OEt2, 40 min; 93% diisobutylaluminium
hydride (DIBAL-H), ꢀ 788, 40 min; 90%. j) (2,2,6,6-Tetramethylpiperidin-1-yl)oxyl (TEMPO),
PhI(OAc)2, CH2Cl2 þ H2O 1:1, r.t., 3 h; 92%. k) 1. DIBAL-H, CH2Cl2, ꢀ 788, 30 min; 2. Ph3P(Me)3I,
NaHMDS, ꢀ 788 to 08, 5 h; 73% (2 steps).
THF afforded N-Boc-d-phenylalanine (25) in 90% yield, which was N-methylated [17]
with NaH and MeI in THF at 08 to room temperature to give compound 3 as two
rotamers in 98% yield (Scheme 4).
Having three fragments in our hand, we focused on the completion of the synthesis
of (þ)-spongidepsin as outlined in Scheme 5. A Mitsunobu esterification (Ph3P,
diisopropyl azodicarboxylate, Et2O, room temperature) [18] of 3 with the secondary
alcohol 4 led to 26 containing minor amounts of isomers. After separation by flash

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Scheme 3
a) 1. O3, CH2Cl2 , then Me2S, ꢀ 788, 30 min; 88%; 2. Jones oxidation, acetone, 08, 2 h; 85%. b) PivCl,
Et3N, LiCl, Evans oxazolidinone (S)-20, 08, 4 h; 72%. c) NaHMDS, MeI, THF, ꢀ 788, 3 h; 80%. d)
NaBH4, THF/H2O (5 :1), 08 to r.t., 12 h; 80%. e) Jones oxidation, acetone, 08, 1 h; 86%.
Scheme 4
a) (Boc)2O, 20% NaOH, THF; 90%. b) NaH, MeI, THF, 08 to r.t., 12 h; 98% (in [2]).
chromatography on SiO2, 26 was isolated in 65% yield. Removal of the Boc protecting
group by treatment with TFA (CH2Cl2, room temperature) [19] afforded the free
amine 27, which was coupled with the unsaturated acid 5 by using PyBOP and DIPEA
in CH2Cl2 [20] to furnish diene 28 in 70% yield (overall yield for the two steps). RCM
of this diene 28 using second-generation Grubbs catalyst, 29, was attempted as reported
in [2][3], but unfortunately we were unable to obtain cyclized product under a variety
of RCM conditions (Table).
Table. Reaction Conditions for RCM
Entry
Catalyst
mol-%
Solvent
Temp. [8]
Time [h]
Outcome
Recovered 28 [%]
1
2
3
4
5
6
29
29
29
29
30
30
15
15
50
50
10
40
CH2Cl2
Toluene
CH2Cl2
Toluene
CH2Cl2
Toluene
40
100
40
100
40
20
12
20
12
16
10
No reaction
No reaction
No reaction
No reaction
No reaction
No reaction
95
90
60
40
80
40
100
Then, assuming that the CꢁC bond may be creating problems due to the linearity of
the system, which may prevent RCM, we blocked the CꢁC bond by using [Co2(CO)6]
[21] and with the cobalt compound 31, and we investigated the RCM [22] by using
catalyst 29 and obtained the Co-free ring-closed product 32 (Scheme 6).

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Scheme 5
a) Ph3P, Diisopropyl azodicarboxylate, THF, 08 to r.t., 10 h; 65%. b) CF3COOH (TFA), CH2Cl2, 08, 3 h;
90%. c) (1H-benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), Et-
N(iPr)2 (DIPEA), acid 5, CH2Cl2, 08 to r.t., 12 h; 70%.
Scheme 6
a) [(Co)2(CO)8], Toluene, r.t., 30 min; 90%. b) Second-generation Grubbs catalyst (29; 30 mol-%),
toluene, reflux, 10 h; 30%.
In summary, we have developed an efficient, and highly enantio- and diastereo-
selective route for the synthesis of 32, starting from simple and commercially available
chiral materials such as d-mannitol and (ꢀ)-b-citronellene. Key steps involved in this
synthesis are the Evans asymmetric methylation, Mitsunobu esterification, PyBOP-
mediated amide formation (for the formation of a fully functionalized acyclic
precursor), and ring-closing metathesis. Extension of the above strategy to a total
synthesis of spongidepsin and structural activity investigation is currently underway in
our laboratory.

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Experimental Part
General. All commercially available reagents were used without further purification unless
otherwise stated. The solvents used were all of anal.-reagent grade and were distilled under N2 where
necessary. All reactions were performed in pre-dried apparatus under N2 unless otherwise stated. The
progress of the reactions was monitored by anal. TLC performed on Merck Silica Gel 60F254 plates.
Visualization was performed using 5% H2SO4 soln. followed by heating. Column chromatography (CC):
silica gel 60 – 120 mesh (SiO2; Qingdao Marine Chemical, P. R. China). Yields were of purified
compounds and were not optimized. Optical rotations: JASCO DIP 300 digital polarimeter at 258. NMR
Spectra: Bruker 300 MHz spectrometers, with TMS as an internal standard, in CDCl3, the chemical shifts
in ppm; and the coupling constants, J, in Hz. High-resolution (HR) MS: LC-MSD-Trap-SL instrument.
Ethyl 3-[(2S)-1,4-Dioxaspiro[4.5]dec-2-yl]propanoate (10). NiCl2 · 6 H2O (4.9 g, 20.97 mmol) and
then portionwise NaBH4 (3.24 g, 85.8 mmol) were added to a stirred soln. of the unsaturated ester 9
(10.0 g, 41.3 mmol) in MeOH (100 ml) at 08. After 1 h, the solvent was evaporated, and the residue was
filtered through Celite using Et2O as an eluent (60 ml). The org. phase was concentrated, and the residue
was purified by FCC (AcOEt/hexane 1:9) to yield 9.76 g of 10 (97%). Colorless oil. [a]2D5 ¼ ꢀ4.6 (c ¼ 1,
CHCl3). IR (KBr): 2938, 2862, 1735, 1148, 1219, 1164, 1105, 1037, 771. 1H-NMR: 4.09 – 3.99 (m, 3 H); 3.94
(t, J ¼ 7.5, 1 H); 3.45 (t, J ¼ 7.5, 1 H); 2.44 – 2.22 (m, 2 H); 1.85 – 1.70 (m, 2 H); 1.58 – 1.40 (m, 8 H); 1.35 –
1.23 (m, 2 H); 1.16 (t, J ¼ 6.7, 3 H). 13C-NMR: 172.8; 109.1; 74.3; 68.4; 60.0; 36.3; 34.9; 30.2; 28.6; 24.9;
23.7; 23.5; 13.9. ESI-MS: 265 ([M þ Na]þ). HR-MS: 265.1420 ([M þ Na]þ, C13H22NaOþ4 ; calc. 265.1416).
3-[(2S)-1,4-Dioxaspiro[4.5]dec-2-yl)propanoic Acid (11). To a stirred soln. of 10 (5 g, 20.6 mmol) in
THF (20 ml), H2O (20 ml), and MeOH (10 ml) was added LiOH (0.715 g, 30.976 mmol), and the
mixture was stirred at r.t. for 10 h. After completion of the reaction (TLC), the mixture was extracted
with Et2O, the aq. layer was acidified to pH 2 with 2n HCl, and extracted with AcOEt (4 ꢂ 40 ml). The
combined org. layer was washed with brine (40 ml), dried (Na2SO4), and concentrated. Purification of
the crude product by CC (SiO2; AcOEt/hexane, 4 :6) afforded 11 (4.02 g, 91%). Colorless oil. [a]D25
¼
1
ꢀ6.6 (c ¼ 1, CHCl3). H-NMR: 4.16 – 3.98 (m, 2 H); 3.56 – 3.48 (m, 1 H); 2.58 – 2.38 (m, 2 H); 1.95 –
1.75 (m, 2 H); 1.63 – 1.51 (m, 10 H). 13C-NMR: 179.2; 109.6; 74.3; 68.5; 36.6; 35.1; 30.2; 28.6; 25.1;
23.9; 23.8. ESI-MS: 237 ([M þ Na]þ). HR-MS: 237.1107 ([M þ Na]þ, C11H18NaOþ4 ; calc. 237.1103).
(4R)-4-Benzyl-3-{3-[(2S)-1,4-dioxaspiro[4.5]dec-2-yl]propanoyl}-1,3-oxazolidin-2-one (12). To a
soln. of 11 (4 g, 18.6 mmol) in THF (90 ml) were added Et3N (6.5 ml, 46.8 mmol) and PivCl (1.59 ml,
18.6 mmol) in sequence at ꢀ 208. After stirring for 1 h, LiCl (1.19 g, 28.2 mmol) and (R)-20 (3.31 g,
18.6 mmol) were added. The mixture was stirred for 1 h at ꢀ 208 and warmed to 08. After stirring for 4 h
at 08, the reaction was quenched by addition of sat. NH4Cl soln. (30 ml). The resulting mixture was
extracted with Et2O (2 ꢂ 50 ml). The combined org. extracts were washed with brine (50 ml), dried
(MgSO4), filtered, and concentrated. FCC (hexane/AcOEt 8 :2) provided 12 (5.2 g, 75%). [a]2D5 ¼ ꢀ43.3
1
(c ¼ 1, CHCl3). IR (KBr): 3383, 2934, 1782, 1700, 1449, 1387, 1214, 1102, 765. H-NMR: 7.39 – 7.13 (m,
5 H); 4.65 – 4.54 (m, 1 H); 4.20 – 4.08 (m, 3 H); 4.03 (t, J ¼ 8.3, 1 H); 3.55 (t, J ¼ 8.3, 1 H); 3.37 – 3.27 (m,
1 H); 3.11 – 2.94 (m, 2 H); 2.77 – 2.64 (m, 1 H); 1.90 (dd, J ¼ 6.7, 14.4, 2 H); 1.63 – 1.50 (m, 8 H); 1.44 – 1.33
(m, 2 H). 13C-NMR: 172.3; 152.9; 135.4; 129.4; 129.0; 127.3; 109.4; 74.5; 68.8; 65.9; 55.2; 38.1; 36.8; 35.3;
31.9; 28.4; 25.3; 24.0; 23.9. ESI-MS: 396 ([M þ Na]þ). HR-MS: 396.1783 ([M þ Na]þ, C21H27NNaO5þ ;
calc. 396.1787).
(4R)-4-Benzyl-3-{(2R)-3-[(2S)-1,4-dioxaspiro[4.5]dec-2-yl]-2-methylpropanoyl}-1,3-oxazolidin-2-
one (13). NaHMDS (1.0m soln. in THF, 16 ml, 16 mmol) was added to a soln. of 12 (4 g, 10.7 mmol) in
THF (42 ml) at ꢀ 788. After stirring for 30 min, MeI (1.98 ml, 32.1 mmol) was added. This mixture was
stirred at ꢀ 788 for 3 h, and then treated with sat. NH4Cl soln. (20 ml) and extracted with Et2O (2 ꢂ
50 ml). The combined org. extracts were washed with brine (50 ml), dried (MgSO4), filtered, and
concentrated. The residue was purified by FCC (hexane/AcOEt 85 :15) to give 13 (3.56 g, 86%). [a]D25
¼
ꢀ66.9 (c ¼ 1, CHCl3). IR (KBr): 3451, 2934, 2858, 1781, 1697, 1452, 1386, 1215, 1102, 1037, 762. 1H-NMR:
7.38 – 7.18 (m, 5 H); 4.68 – 4.59 (m, 1 H); 4.23 – 4.13 (m, 2 H); 4.11 – 4.04 (m, 1 H); 4.02 – 3.97 (m, 1 H);
3.94 – 3.84 (m, 1 H); 3.51 (t, J ¼ 6.9, 1 H); 3.33 – 3.27 (m, 1 H); 2.78 – 2.72 (m, 1 H); 2.08 – 2.00 (m, 1 H);
1.71 – 1.64 (m, 1 H); 1.61 – 1.50 (m, 8 H); 1.43 – 1.35 (m, 2 H); 1.29 (d, J ¼ 6.9, 3 H). 13C-NMR: 176.3;

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Helvetica Chimica Acta – Vol. 96 (2013)
152.7; 135.2; 129.4; 128.9; 127.3; 109.4; 73.5; 69.0; 66.0; 55.3; 37.9; 36.8; 36.7; 35.2; 34.9; 25.1; 24.0; 23.8;
18.1. ESI-MS: 410 ([M þ Na]þ). HR-MS: 410.1949 ([M þ Na]þ, C22H29NNaOþ5 ; calc. 410.1943).
(2R)-3-[(2S)-1,4-Dioxaspiro[4.5]dec-2-yl]-2-methylpropan-1-ol (14). LiBH4 (2.0m soln. in THF,
22.6 ml, 45.2 mmol) was dropwise added to a soln. of 13 (3.5 g, 9.0 mmol) and MeOH (0.93 ml,
16.0 mmol) in Et2O (16 ml) at ꢀ 108. After stirring for 1 h at ꢀ 108, the resulting mixture was treated
with 1n NaOH soln. (28 ml), stirred for 20 min at 08, and extracted with CH2Cl2 (2 ꢂ 70 ml). The
combined org. extracts were washed with brine (40 ml), dried (MgSO4), filtered, and concentrated. The
residue was purified by flasch CC (hexane/AcOEt 75 :25) to give 14 (1.6 g, 83%). [a]2D5 ¼ þ2.2 (c ¼ 1,
CHCl3). IR (KBr): 3384, 2935, 2871, 1219, 1037, 772. 1H-NMR: 4.26 – 4.14 (m, 1 H); 4.08 – 4.02(m, 1 H);
3.57 – 3.42 (m, 3 H); 2.91 (s, 1 H); 1.90 – 1.76 (m, 1 H); 1.69 – 1.51(m, 10 H); 1.44 – 1.34 (m, 2 H); 0.98 (d,
J ¼ 6.8, 3 H). 13C-NMR: 109.2; 73.4; 69.2; 67.1; 37.1; 36.6; 35.2; 33.1; 25.1; 24.0; 23.8; 23.7; 16.8. ESI-MS:
237 ([M þ Na]þ). HR-MS: 237.1459 ([M þ Na]þ, C12H22NaOþ3 ; calc. 237.1467).
(2R,4S)-4,5-Dihydroxy-2-methylpentyl 2,2-Dimethylpropanoate (15). To a cooled 08 soln. of 14
(2.5 g, 11.6 mmol) in CH2Cl2 (30 ml) were successively added pyridine (9.3 ml, 116 mmol), PivCl (2.8 ml,
23.2 mmol), and DMAP (70 mg, 0.58 mmol). The mixture was allowed to warm to r.t. and stirred for 2 h.
H2O was added, and the resulting soln. was extracted with Et2O. The extracts were washed with H2O and
brine, then dried (MgSO4), and concentrated under reduced pressure to give the corresponding crude
pivalate, which was used in the next step without further purification.
To a soln. of the crude pivalate (3.40 g) in MeOH (113 ml) was added Dowex 50WX8 (16 g). After
stirring for 48 h at r.t., the mixture was basicified with Et3N (6 ml). The resulting mixture was filtered
through a Celite pad eluting with MeOH, and the filtrate was extracted with hexane (3 ꢂ , to remove 1,1-
dimethoxycyclohexane). The MeOH layer was concentrated under reduced pressure to give a yellow oil.
The oil was dissolved in dry toluene (5 ml), and the solvent was removed in vacuo (azeotropic MeOH
removal) to give 15 (2.03 g, 80%). [a]2D5 ¼ ꢀ9.2 (c ¼ 1, CHCl3). IR (KBr): 3379, 2965, 2935, 1725, 1462,
1287, 1287, 1166, 1033, 772. 1H-NMR: 4.08 – 3.99 (m, 1 H); 3.95 – 3.86, (m, 1 H); 3.80 (s, 1 H); 3.67 – 3.56
(m, 1 H); 3.47 – 3.29 (m, 1 H); 3.16 (s, 1 H); 1.20 – 1.95 (m, 1 H); 1.45 – 1.35 (m, 1 H); 1.20 (s, 9 H); 1.01
(d, J ¼ 6.8, 3 H). 13C-NMR: 178.8; 69.8; 68.4; 66.7; 38.8; 36.5; 29.3; 27.1; 17.8. ESI-MS: 241 ([M þ Na]þ).
HR-MS: 241.1421 ([M þ Na]þ, C11H22NaO4þ ; calc. 241.1416).
(2R)-2-Methyl-3-[(2S)-oxiran-2-yl]propyl 2,2-Dimethylpropanoate (16). To a soln. of 15 (2 g,
9.17 mmol) in THF (30 ml) at 08 was added NaH (60 wt.-% in mineral oil, 1.0 g, 27.4 mmol). The mixture
was then warmed to r.t. and stirred for 40 min. The mixture was then cooled to 08, 1-tosyl-1H-imidazole
(3.2 g, 9.6 mmol) was added in one portion, the mixture was allowed to warm to ambient temp., and was
stirred for 30 min. The reaction was quenched with H2O (30 ml), and the mixture was extracted with
Et2O (3 ꢂ 50 ml). The combined org. layers were washed with brine (30 ml), dried (anh. MgSO4),
filtered, and concentrated in vacuo. Flash CC (SiO2, AcOEt/hexane 10 :90) provided 16 (1.75 g, 96%
yield). Colorless oil. [a]2D5 ¼ ꢀ11.7 (c ¼ 1, CHCl3). IR (KBr): 2967, 2932, 1729, 1480, 1284, 1159, 1033, 772.
1H-NMR: 3.93 (d, J ¼ 6.0, 2 H); 2.96 – 2.89 (m, 1 H); 2.77 – 2.71 (m, 1 H); 2.43 – 2.38 (m, 1 H); 2.08 – 1.99
(m, 1 H); 1.64 – 1.55(m, 1 H); 1.42 – 1.33 (m, 1 H); 1.17 (s, 9 H); 1.01 (d, J ¼ 7.0, 3 H). 13C-NMR: 178.4;
68.4; 50.7; 46.8; 36.4; 31.2; 27.1; 17.2. ESI-MS: 223 ([M þ Na]þ). HR-MS: 223.1312 ([M þ Na]þ,
C11H20NaOþ3 ; calc. 223.1310).
(2R,4S)-8-(Benzyloxy)-4-hydroxy-2-methyloct-6-yn-1-yl 2,2-Dimethylpropanoate (17). To a stirred
ꢀ 788 soln. of benzyl propargyl ether (2.57 g, 17.5 mmol) in THF (30 ml) was added BuLi (10.3 ml of a
1.60m soln. in hexane, 16.6 mmol). The resulting soln. was stirred for 15 min before being added via
cannula to a soln. of 16 (1.75 g, 8.7 mmol) in THF (20 ml) at ꢀ 788. Freshly dist. BF3 · Et2O (1.25 ml,
8.7 mmol) was added dropwise, and the resulting soln. was stirred at ꢀ 788 for 40 min, sat. aq. NaHCO3
(20 ml) was added, and THF was removed by rotary evaporation. The residue was diluted with AcOEt,
and the resulting emulsion was filtered under vacuum. The separated aq. residue was extracted with
AcOEt (3 ꢂ 50 ml), and the combined org. layers were washed with H2O and sat. aq. NaCl (75 ml each),
dried (Na2SO4), filtered, and concentrated. The residue was purified by CC (hexane/AcOEt 80 :20) to
yield 17 (2.8 g, 93%) as a clear, colorless oil. [a]2D5 ¼ ꢀ0.8 (c ¼ 1, CHCl3). IR (KBr): 3453, 2932, 2237, 1727,
1
1455, 1219, 1071, 771. H-NMR: 7.38 – 7.28 (m, 5 H); 4.58 (s, 2 H); 4.19 – 4.14 (m, 2 H); 4.05 – 3.85 (m,
3 H); 2.55 – 2.31 (m, 2 H); 2.10 – 1.97 (m, 1 H); 1.66 – 1.39 (m, 2 H); 1.20 (s, 9 H); 1.00 (d, J ¼ 6.8, 3 H).

Helvetica Chimica Acta – Vol. 96 (2013)
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13C-NMR: 178.5; 137.3; 128.3; 127.9; 127.8; 83.0; 78.6; 71.5; 68.3; 67.7; 57.5; 39.9; 29.5; 28.1; 27.1; 17.7. ESI-
MS: 369 ([M þ Na]þ). HR-MS: 369.2047 ([M þ Na]þ, C21H30NaO4þ ; calc. 369.2042).
(2R,4S)-8-(Benzyloxy)-2-methyloct-6-yne-1,4-diol (18). To a cooled (ꢀ 788) soln. of 17 (2 g,
5.7 mmol) in CH2Cl2 (12 ml) was added DIBAL-H (17.3 ml, 17.3 mmol) in hexane (1.0m). After
40 min at ꢀ 78, the reaction was quenched with MeOH (16 ml) and sat. aq. Rochelle salt (40 ml), and the
mixture was stirred at r.t. for 1 h vigorously and extracted with AcOEt (4 ꢂ 50 ml). Combined extracts
were washed with brine (40 ml), dried (Na2SO4), filtered, and concentrated to give alcohol. Flash CC
(SiO2, AcOEt/hexane 30 :70) gave 18 (1.36 g, 90% yield). Colorless oil. [a]2D5 ¼ þ4.5 (c ¼ 1, CHCl3). IR
1
(KBr): 3367, 2925, 2872, 2234, 1714, 1454, 1355, 1261, 1069, 699. H-NMR: 7.40 – 7.27 (m, 5 H); 4.58 (s,
2 H); 4.16 (s, 2 H); 4.00 – 3.89 (m, 1 H); 3.58 – 3.40 (m, 2 H); 2.47 – 2.39 (m, 2 H); 1.99 – 1.84 (m, 1 H);
1.61 (t, J ¼ 6.0, 2 H); 0.94 (d, J ¼ 7.6, 3 H). 13C-NMR: 162.5; 137.3; 128.3; 127.9; 127.7; 83.8; 77.9; 71.4; 67.4;
57.5; 40.6; 31.9; 27.6; 17.1. ESI-MS: 285 ([M þ Na]þ). HR-MS: 285.1458 ([M þ Na]þ, C16H22NaO3þ ; calc.
285.1467).
(3R,5S)-5-[4-(Benzyloxy)but-2-yn-1-yl]-3-methyldihydrofuran-2(3H)-one (19). To a soln. of 18
(1.3 g, 4.9 mmol) in H2O/CH2Cl2 1:1 (20 ml) were added TEMPO (231.5 mg, 1.48 mmol) and PhI(OAc)2
(4.7 g, 14.7 mmol). After stirring at r.t. for 3 h, the mixture was diluted with CHCl3 and then washed with
sat. aq. Na2S2O3. The org. layer was dried (Na2SO4), filtered, and concentrated under reduced pressure.
Purification by flash CC (20% AcOEt/hexane) afforded 19 (1.17 g, 92%). Clear oil. [a]2D5 ¼ þ0.7 (c ¼ 1,
CHCl3). IR (KBr): 2928, 2854, 2240, 1770, 1715, 1454, 1355, 1261, 1190, 1016, 700. 1H-NMR: 7.36 – 7.20
(m, 5 H); 4.63 – 4.49 (m, 3 H); 4.08 (s, 2 H); 2.81 – 2.66 (m, 1 H); 2.64 – 2.25 (m, 2 H); 2.41 – 2.29 (m,
1 H); 2.09 – 1.96 (m, 1 H); 1.27 (d, J ¼ 7.6, 3 H). 13C-NMR: 179.5; 137.2; 128.3; 127.9; 127.8; 80.8; 78.9;
75.2; 71.6; 57.4; 34.2; 33.6; 25.3; 15.9. ESI-MS: 276 ([M þ NH4]þ).
(3R,5S)-9-(Benzyloxy)-3-methylnon-1-en-7-yn-5-ol (4). To a soln. of 19 (1 g, 3.87 mmol) in 20 ml of
CH2Cl2 under Ar was added dropwise 1.0m soln. of DIBAL-H (7.75 ml, 7.75 mmol) in CH2Cl2 at ꢀ 788.
After stirring for 30 min at ꢀ 788, the reaction was quenched with 20 ml of MeOH. The resulting mixture
was allowed to warm to 238 over 1 h until a white precipitate appeared. The residue was filtered on a pad
of Celite, washed with Et2O, and concentrated to give the crude lactol, which was directly used in the next
step.
To a soln. of Ph3P(Me)I (6.1 g, 17.6 mmol) in 50 ml of THF under Ar was added 1.6m soln. of
NaHMDS (11 ml, 17.6 mmol) in toluene at ꢀ 788. After stirring at ꢀ 788 for 30 min, the crude lactol in
10 ml of THF was added. After stirring for further 5 h at 08, the reaction was quenched with sat. aq.
NH4Cl, and the mixture was extracted with Et2O, washed with brine, dried (anh. MgSO4), and
concentrated. Purification by CC (hexane/AcOEt 80 :20) gave 4 (730 mg, 73%). Colorless oil. [a]D25
¼
ꢀ6.6 (c ¼ 1, CHCl3). IR (KBr). 3469, 3071, 2970, 2236, 1720, 1641, 1452, 1261, 1112, 914, 698.
1H-NMR: 7.31 – 7.20 (m, 5 H); 5.75 – 5.54 (m, 1 H); 5.02 – 4.85 (m, 2 H); 4.51 (s, 2 H); 4.11 (s, 2 H); 3.79 –
3.69 (m, 1 H); 2.45 – 2.23 (m, 3 H); 1.62 – 1.33 (m, 2 H); 0.97 (d, J ¼ 6.7, 3 H). 13C-NMR: 143.6; 137.4;
128.4; 128.0; 127.8; 113.7; 83.3; 78.4; 71.5; 67.9; 57.6; 43.1; 34.6; 28.2; 21.1. ESI-MS: 276 ([M þ NH4]þ).
HR-MS: 276.1960 ([M þ NH4]þ, C17H26NO2þ ; calc. 276.1964).
(4R)-4-Methylhex-5-enoic Acid (21). (ꢀ)-b-Citronellene (8; 6 g, 43.4 mmol) was dissolved in dry
CH2Cl2 (50 ml) and cooled to ꢀ 788. O3 was bubbled through the soln. until a persistent and
homogeneous blue color appeared. At this point, N2 was bubbled instead of O3 until disappearance of the
blue color. Me2S (6.4 ml, 86.8 mmol) was then added, and the soln. was allowed to warm to r.t. for 2 h
under stirring. Washed with brine, dried (Na2SO4), and concentrated at low temp. under reduced
pressure to give aldehyde which was used in the next step without any further purification.
To a soln. of aldehyde in acetone (50 ml) was added Jones reagent (4.2 ml) at 08, and the mixture was
stirred at the same temp. for 2 h. iPrOH was added, and the resulting mixture was filtered, concentrated
in vacuo, the residue was dissolved in 30 ml of AcOEt, washed with brine (3 ꢂ 5 ml), dried (Na2SO4), and
concentrated in vacuo. The residue was purified by CC (hexane/AcOEt 75 :25) to afford 21 (4.0 g, 85%).
Colorless oil. [a]2D5 ¼ ꢀ6.1 (c ¼ 1, CHCl3). 1H-NMR: 11.36 – 10.57 (s, 1 H); 5.68 – 5.58 (m, 1 H); 5.05 – 4.92
(m, 2 H); 2.41 – 2.27 (m, 2 H); 2.24 – 2.11 (m, 1 H); 1.77 – 1.54 (m, 2 H); 1.02 (d, J ¼ 6.4, 3 H). 13C-NMR:
180.3; 143.1; 113.8; 37.2; 32.0; 31.2; 19.8.
(4S)-4-Benzyl-3-[(4R)-4-methylhex-5-enoyl]-1,3-oxazolidin-2-one (22). To a soln. of 21 (1.22 g,
5.5 mmol) in THF (28 ml) were added Et3N (1.92 ml, 13.8 mmol) and PivCl (0.47 ml, 5.5 mmol) in

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Helvetica Chimica Acta – Vol. 96 (2013)
sequence at ꢀ 208. After stirring for 1 h, LiCl (352 mg, 8.3 mmol) and imide (S)-20 (975 mg, 5.5 mmol)
were added. The mixture was stirred for 1 h at ꢀ 208 and warmed to 08. After stirring for 3 h at 08, the
reaction was quenched by addition of sat. NH4Cl soln. (10 ml). The resulting mixture was extracted with
Et2O (2 ꢂ 50 ml). The combined org. extracts were washed with brine (30 ml), dried (MgSO4), filtered,
and concentrated. Flash CC (hexane/AcOEt 8 :2) provided 22 (1.51 g, 72%). [a]2D5 ¼ þ43.3 (c ¼ 1,
1
CHCl3). IR (KBr): 2962, 2926, 1782, 1699, 1386, 1210, 1098, 703. H-NMR: 7.34 – 7.12 (m, 5 H); 5.77 –
5.55 (m, 1 H); 5.06 – 4.89 (m, 2 H); 4.66 – 4.53 (m, 1 H); 4.13 – 4.02 (m, 2 H); 3.28 – 3.16 (m, 1 H);
2.96 – 2.65 (m, 3 H); 2.28 – 2.12 (m, 1 H); 1.78 – 1.55 (m, 2 H); 1.04 (d, J ¼ 6.8, 3 H). 13C-NMR: 172.4;
152.6; 143.0; 135.0; 128.9; 128.3; 126.7; 113.2; 65.5; 54.5; 37.3; 37.0; 32.9; 30.3; 19.8. ESI-MS: 288 ([M þ
H]þ). HR-MS: 288.1604 ([M þ H]þ, C17H22NOþ3 ; calc. 288.1600).
(4S)-4-Benzyl-3-[(2S,4R)-2,4-dimethylhex-5-enoyl]-1,3-oxazolidin-2-one (23). NaHMDS (1.0m soln.
in THF, 6.3 ml, 6.3 mmol) was added to a soln. of 22 (1.62 g, 4.2 mmol) in THF (21 ml) at ꢀ 788. After
stirring for 30 min, MeI (0.78 ml, 12.6 mmol) was added. This mixture was stirred at ꢀ 788 for 4 h, and
then treated with sat. NH4Cl soln. (10 ml) and extracted with Et2O (2 ꢂ 50 ml). The combined org.
extracts were washed with brine (30 ml), dried (MgSO4), filtered, and concentrated. The residue was
purified by flash CC (hexane/acetone 85 :15) to give 23 (1.3 g, 80%). [a]2D5 ¼ þ57.7 (c ¼ 1, CHCl3). IR
(KBr): 2967, 1780, 1696, 1386, 1210, 1100, 702. 1H-NMR: 7.39 – 7.16 (m, 5 H); 5.74 – 5.54 (m, 1 H); 5.04 –
4.83 (m, 2 H); 4.73 – 4.53 (m, 1 H); 4.20 – 4.09 (m, 2 H); 3.85 – 3.65 (m, 1 H); 3.30 – 3.17 (m, 1 H); 2.84 –
2.69 (m, 1 H); 2.30 – 2.11 (m, 1 H); 1.92 – 1.75 (m, 1 H); 1.46 – 1.31 (m, 1 H); 1.21 (d, J ¼ 6.8, 3 H); 1.00 (d,
J ¼ 6.8, 3 H). 13C-NMR: 177.2; 152.8; 143.7; 135.2; 129.3; 128.7; 127.1; 112.9; 65.8; 55.1; 39.8; 37.7; 36.6;
35.9; 35.5; 20.9; 17.6. ESI-MS: 302 ([M þ H]þ). HR-MS: 302.1759 ([M þ H]þ, C18H24NOþ3 ; calc.
302.1756).
(2S,4R)-2,4-Dimethylhex-5-en-1-ol (24). To a cooled 08 soln. of 23 (1.2 g, 3.9 mmol) in THF/H2O
(5 :1, 20ml) was added portionwise NaBH4 (0.67 g, 19.9 mmol). After 10 h at r.t., the reaction was
quenched with sat. NH4Cl (10 ml), and the mixture was stirred at r.t. for 1 h vigorously and extracted with
AcOEt (4 ꢂ 10 ml). Combined extracts were washed with brine (20 ml), dried (Na2SO4), filtered, and
concentrated. Purification of the product by CC (SiO2; hexane/AcOEt 70 :30) afforded 24 (411 mg, 80%)
Colorless oil. [a]D25 ¼ ꢀ30.2 (c ¼ 1, CHCl3). IR (KBr): 3351, 2925, 2856, 1640, 1459, 1219, 1033, 910, 772.
1H-NMR: 5.64 – 5.54 (m, 1 H); 4.99 – 4.85 (m, 2 H); 3.43 – 3.29 (m, 2 H); 2.96 – 2.85 (m, 1 H); 2.28 – 2.16
(m, 1 H); 1.71 – 1.58 (m, 1 H); 1.41 – 1.23 (m, 2 H); 1.0 (d, J ¼ 7.0, 3 H); 0.88 (d, J ¼ 7.0, 3 H). 13C-NMR:
144.2; 112.6; 68.1; 40.2; 35.3; 33.1; 21.3; 16.1.
(2S,4R)-2,4-Dimethylhex-5-enoic Acid (5). To a soln. of 24 (400 mg, 3.1 mmol) in acetone (10 ml)
was added Jones reagent (4.0 ml) at 08, and the mixture was stirred at the same temp. for 1 h. iPrOH was
added, and the resulting mixture was filtered, concentrated in vacuo, and the residue was dissolved in
30 ml of AcOEt, washed with brine (3 ꢂ 5 ml), dried (anh. Na2SO4), and concentrated in vacuo. The
residue was purified by CC (hexane/AcOEt 80 :20) to afford 5 (381 mg, 86%). Colorless oil. [a]2D5 ¼ þ8.5
(c ¼ 1, CHCl3). IR (KBr): 3450, 3050, 1707, 1460, 1417, 1243, 914. 1H-NMR: 5.69 – 5.54 (m, 1 H); 5.04 –
4.88 (m, 2 H); 2.56 – 2.44 (m, 1 H); 2.26 – 2.13 (m, 1 H); 1.79 – 1.66 (m, 1 H); 1.40 – 1.27 (m, 1 H); 1.15 (d,
J ¼ 6.9, 3 H); 1.01 (d, J ¼ 6.9, 3 H). 13C-NMR: 183.7; 143.3; 113.5; 39.9; 37.2; 35.7; 20.5; 16.5. EI-MS: 142
(Mþ).
N-[(tert-Butoxy)carbonyl]-N-methyl-d-phenylalanine (3). NaH (60% in mineral oil; 633 mg,
26.4 mmol, 14 equiv.) was added slowly in portions over a period of 2 h to a cooled (08) soln. of N-
Boc-phenylalanine (25 500 mg, 1.88 mmol) and MeI (1.1 ml, 18.8 mmol) in anh. THF (2 ml) under N2.
The mixture was stirred at r.t. for 24 h under N2 and then diluted with Et2O (20 ml), and the reaction was
quenched with H2O (30 ml). The layers were separated, and the aq. layer was extracted with Et2O (2 ꢂ
15 ml), acidified to pH 3 with a 20% aq. soln. of citric acid, and extracted with AcOEt (3 ꢂ 20 ml). The
combined org. phase was dried (Na2SO4) and evaporated to afford 3 (515 mg, 98%). Thick colorless oil.
[a]2D5 ¼ þ60.2 (c ¼ 1, CHCl3). 1H-NMR: 7.37 – 7.14 (m, 5 H); 4.91 – 4.81 (m, 0.5 H); 4.69 – 4.58 (m, 0.5 H);
3.40 – 3.25 (m, 1 H); 3.18 – 2.95 (m, 1 H); 2.76 (s, 1.5 H); 2.68 (s, 1.5 H); 1.39 (s, 4.5 H); 1.34 (s, 4.5 H).
13C-NMR: 176.3; 156.4; 137.5; 129.1; 128.7; 126.8; 80.8; 61.5; 35.3; 32.9; 28.3. ESI-MS: 302 ([M þ Na]þ).
HR-MS: 302.1364 ([M þ Na]þ, C15H21NNaO4þ ; calc. 302.1368).
(3R,5R)-9-(Benzyloxy)-3-methylnon-1-en-7-yn-5-yl N-[(tert-Butoxy)carbonyl]-N-methyl-d-phenyl-
alaninate (26). To a flask containing 4 (450 mg1.74 mmol) was added THF (20 ml) under Ar. Ph3P (1.58 g,

Helvetica Chimica Acta – Vol. 96 (2013)
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6.12 mmol), and 3 (1.7 g, 6.12 mmol) were added at r.t. The mixture was cooled to 08, followed by
dropwise addition of diisopropyl azodicarboxylate (0.96 ml, 4.87 mmol). The combined pale-yellow
mixture was stirred at r.t. overnight and directly concentrated under reduced pressure. Further
purification by flash CC (20% AcOEt/hexane) gave 26 (588 mg, 65%). Colorless oil. [a]2D5 ¼ þ2.5 (c ¼ 1,
1
CHCl3). IR (KBr): 2936, 2862, 1735, 1697, 1451, 1366, 11219, 1165, 1098, 761. H-NMR: 7.44 – 7.12 (m,
10 H); 5.74 – 5.53 (m, 1 H); 5.07 – 4.78 (m, 3 H); 4.51 (s, 2 H); 4.16 (s, 2 H); 3.41 – 3.25 (m, 1 H); 3.06 –
2.85 (m, 1 H); 2.77 (s, 3 H); 2.62 – 2.49 (m, 2 H); 2.30 – 2.11 (m, 1 H); 1.83 – 1.58 (m, 3 H); 1.36 (s, 9 H);
1.07 – 0.95 (m, 3 H). 13C-NMR: 170.6; 170.4; 155.0; 155.6; 142.8; 137.4; 128.8; 128.3; 127.9; 127.7; 126.5;
126.4; 114.0; 82.1; 81.7; 80.1; 78.5; 71.3; 71.1; 60.6; 59.6; 57.5; 39.9; 35.0; 34.9; 34.5; 34.4; 31.8; 31.0; 28.1;
24.6; 20.8. ESI-MS: 542 ([M þ Na]þ). HR-MS: 542.2886 ([M þ Na]þ, C32H41NNaOþ5 ; calc. 542.2882).
(3R,5R)-9-(Benzyloxy)-3-methylnon-1-en-7-yn-5-yl N-Methyl-d-phenylalaninate (27). To a soln. of
26 (400 mg, 0.77 mmol) in 3 ml of dry CH2Cl2 under Ar was added CF3CO2H (0.61 ml, 7.7 mmol) at 08.
After stirring for 3 h at 238, the reaction was quenched with sat. aq. NaHCO3, and the mixture was
extracted with AcOEt, washed with brine, dried (Na2SO4), and concentrated. Purification by CC (SiO2;
hexane/AcOEt 60 :40) gave 27 (289 mg, 90%). Colorless oil. [a]2D5 ¼ ꢀ21.5 (c ¼ 1, CHCl3). IR (KBr):
1
3030, 2924, 2854, 2232, 1736, 1642, 1453, 1260, 1195, 1073, 1026, 772. H-NMR: 7.44 – 7.12 (m, 10 H);
5.61 – 5.47 (m, 1 H); 4.93 – 4.78 (m, 3 H); 4.51 (s, 2 H); 4.01 (s, 2 H); 3.41 (t, J ¼ 6.8, 1 H); 2.89 (d, J ¼ 6.8,
2 H); 2.53 – 2.39 (m, 2 H); 2.32 (s, 3 H); 1.93 – 1.85 (m, 1 H); 1.61 – 1.43 (m, 2 H); 0.89 (d, J ¼ 6.8, 3 H).
13C-NMR: 173.4; 142.4; 136.7; 128.7; 128.0; 127.5; 127.3; 126.2; 113.5; 81.7; 77.9; 70.9; 70.4; 64.2; 57.1; 39.6;
39.0; 34.2; 33.6; 24.3; 20.4. ESI-MS: 420 ([M þ H]þ). HR-MS: 420.2545 ([M þ H]þ, C27H34NO3þ ; calc.
420.2539).
(3R,5R)-9-(Benzyloxy)-3-methylnon-1-en-7-yn-5-yl N-[(2S,4R)-2,4-Dimethylhex-5-enoyl]-N-meth-
yl-d-phenylalaninate (28). DIPEA (0.16 ml, 0.94 mmol) was added to a soln. of 27 (200 mg, 0.47 mmol)
and 5 (81.2 mg, 0.57 mmol) in CH2Cl2 at 08. PyBOP (297 mg, 0.57 mmol) was added at 08, and the
resulting mixture was stirred for 10 h at r.t., and the reaction was quenched with sat. aq. NH4Cl, and the
mixture was extracted with AcOEt, washed with brine, dried (Na2SO4), and concentrated. Purification
by CC (SiO2; hexane/AcOEt 20 :80) gave 28 (181 mg, 70%). Colorless oil. [a]2D5 ¼ þ30.4 (c ¼ 1, CHCl3).
IR (KBr): 3066, 2961, 2924, 2239, 1951, 1737, 1647, 1455, 1261, 1090, 1022, 800, 699. 1H-NMR: 7.43 – 7.11
(m, 10 H); 5.71 – 5.35 (m, 2 H); 5.08 – 4.77 (m, 5 H); 4.57 (s, 2 H); 4.15 (s, 2 H); 3.47 – 3.27 (m 1 H); 3.05 –
2.87 (m, 2 H); 2.81 (s, 3 H); 2.59 – 2.48 (m, 2 H); 2.27 – 2.07 (m, 3 H); 1.88 – 1.50 (m, 4 H); 1.06 – 0.87 (m,
6 H); 0.69 (d, J ¼ 6.8, 2.4 H); 0.58 (d, J ¼ 6.8, 0.6 H). 13C-NMR: 177.0; 170.9; 144.0; 143.1; 137.5; 137.0;
129.8; 128.3; 128.4; 127.9; 126.6; 113.2; 112.8; 82.1; 79.1; 72.9; 71.2; 65.0; 57.5; 40.0; 36.9; 34.7; 34.4; 33.2;
32.2; 24.6; 20.8; 20.1. ESI-MS: 544 ([M þ H]þ). HR-MS: 544.3432 ([M þ H]þ, C35H46NOþ4 ; calc.
544.3427).
Cobalt Complex (31). To a soln. of 28 (30 mg, 0.05 mmol) in toluene (5 ml) was added [Co2(CO)8]
(26.4 mg, 0.77 mmol). The mixture was stirred at r.t. for 30 min, and the solvent was removed under
reduced pressure. The dark residue was purified by flash CC (5% AcOEt in hexane) to give 31 (46 mg,
98%) as a red oil, an inseparable mixture of diastereoisomers, which was used immediately in the next
step.
(3R,6S,8R,11R,13R)-3-Benzyl-13-[4-(benzyloxy)but-2-yn-1-yl]-4,6,8,11-tetramethyl-1-oxa-4-azacy-
clotridec-9-ene-2,5-dione (32). To a soln. of 31 (20 mg, 0.024 mmol) in dry toluene (120 ml) was added
second-generation Grubbs catalyst (6.1 mg, 0.0072 mmol). The resulting soln. was heated to 1108 for
10 h, then cooled to r.t. and filtered through a plug of SiO2. The solvent was removed under reduced
pressure. The residue was purified by flash CC (20% AcOEt/hexane) to give 32 (3.5 mg, 30%). Brown
oil. [a]2D5 ¼ þ70.0 (c ¼ 1, CHCl3). IR (KBr): 2959, 2923, 2234, 1737, 1705, 1649, 1454, 1405, 1374, 1260,
1
1219, 1087, 1019, 772. H-NMR: 7.43 – 7.13 (m, 10 H); 5.02 – 4.72 (m, 3 H); 4.54 (s, 2 H); 4.18 (s, 2 H);
3.49 – 3.31 (m, 1 H); 3.11 – 2.97 (m, 1 H); 2.81 (s, 3 H); 2.66 – 2.51 (m, 1 H); 2.28 – 1.97 (m, 5 H); 1.72 –
1.42 (m, 4 H); 1.32 – 1.27 (m, 4 H); 1.06 (d, J ¼ 6.6, 3 H); 0.80 (d, J ¼ 6.7, 2 H). 13C-NMR: 176.4; 170.1;
138.0; 136.3; 135.5; 133.2; 129.0; 128.3; 128.2; 127.8; 125.6; 83.2; 81.5; 73.0; 72.0; 60.7; 46.5; 40.0; 39.7;
38.9; 36.8; 34.8; 33.8; 29.8; 20.5; 19.8; 19.3; 18.5. ESI-MS: 516 ([M þ H]þ). HR-MS: 516.3119 ([M þ H]þ,
C33H42NOþ4 ; calc. 516.3114).

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Helvetica Chimica Acta – Vol. 96 (2013)
The authors gratefully acknowledge keen interest shown by Dr. J. S. Yadav, Director, IICT,
Hyderabad. G. V. R. thanks UGC, New Delhi, for financial support.
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Received September 12, 2012