Asymmetric synthesis of a cytotoxic amide of Telesto riisei

Article abstract of DOI:10.1016/S0957-4166(98)00091-3

An efficient synthesis of both the enantiomers of N-(2-phenylethyl)-8- hydroxypentadecacarboxamide using the cytotoxic principles of Telesto riisei has been formulated using cyclohexylideneglyceraldehyde 1 as the chiral template. A non-stereoselective Grignard addition to the aldehyde 1 gave the C-3 epimers of the required chiron, 3-alkylglycerol which were converted to the title compound via a standard sequence of reactions.

Full text of DOI:10.1016/S0957-4166(98)00091-3

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 1345–1350
Asymmetric synthesis of a cytotoxic amide of Telesto riisei
Sivaraman Sankaranarayanan and Subrata Chattopadhyay∗
Bio-organic Division, Bhabha Atomic Research Centre, Mumbai-400 085, India
Received 29 December 1997; accepted 2 March 1998
Abstract
An efficient synthesis of both the enantiomers of N-(2-phenylethyl)-8-hydroxypentadecacarboxamide using the
cytotoxic principles of Telesto riisei has been formulated using cyclohexylideneglyceraldehyde 1 as the chiral
template. A non-stereoselective Grignard addition to the aldehyde 1 gave the C-3 epimers of the required chiron,
3-alkylglycerol which were converted to the title compound via a standard sequence of reactions. © 1998 Published
by Elsevier Science Ltd. All rights reserved.
1. Introduction
The search for new bioactive organic compounds has led to an explosive growth of marine chemistry
in the last decade.1 This has also provided compounds with novel structural features which probably owe
their origin to several factors in the marine kingdom such as the salty environment, unusual metabolisms
and involvement of symbiotic relationships acting individually or in combination. To this end, numerous
species of soft corals and gorgonians which abound in tropical reefs have been the major focus of
attention leading to a vast array of secondary metabolites.2 In contrast, the octocoral order, Telestaceae
contains few members and their chemical investigation is also rather scarce. Only one of these viz.
Telesto riisei has so far been investigated leading to the isolation of two new pregnane derivatives3
and several highly functionalized prostanoids.4,5 The chemical constituents of the octocoral were found
to be totally environment dependent and varied according to their habitation. Recently, from T. riisei,
collected at Chuuk Atoll, Federated States of Micronesia, two new bioactive amides were isolated.6
These were identified as N-(2-phenylethyl)-8-hydroxypentadecacarboxamide I and the corresponding
8-oxo compound. Both compounds showed cytotoxicity to murine leukemia cells (P-388) with ED50
(µg/ml) values 2.2 and 2.1 respectively. Although, the amide I was optically active, the stereochemistry
of its C-8 centre is still obscure.
In view of the promising bioassay result, compound I seems to be a good candidate in cancer
therapy research. At the same time, the importance of chirality on bioactivity warrants availability of
∗
Corresponding author. E-mail: bod@magnum.barct1.ernet.in
0957-4166/98/$19.00 © 1998 Published by Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00091-3

1346
S. Sankaranarayanan, S. Chattopadhyay / Tetrahedron: Asymmetry 9 (1998) 1345–1350
its enantiomers in homochiral forms. This would not only provide an insight into its mechanism of
action but also lead to better therapeutic formulation. In addition, the hitherto unknown configuration of
the natural compound could also be determined by its synthesis. With this aim, we developed the first
enantiomeric synthesis of I in its antipodal forms.
The synthetic strategy (Scheme 1) was based on an asymmetric strategy recently developed7 from our
laboratory for the preparation of chiral 3-alkylglycerols. Reaction of various organo–metallic reagents
to various glyceraldehyde derivatives is known to proceed with modest to poor enantioselectivity.
However, it was found7 that using cyclohexylideneglyceraldehyde8 1 as the chiral template, the resultant
carbinol enantiomers obtained by Grignard addition could be separated easily by normal column
chromatography. Owing to their homochirality and varied functionality, the resultant triol derivatives
are suitable for the asymmetric syntheses of a diverse array of complex natural products. In spite of
modest enantioselectivity, the above process thus provides the epimeric 3-alkylglycerols in homochiral
forms. This aspect seemed attractive in the present case, as we were interested in the synthesis of both
the enantiomers of I.
Scheme 1.
2. Results and discussion
Consequently, for the synthesis, the aldehyde 1 was reacted with n-heptylmagnesium bromide to
furnish the epimeric alcohols 2a and 2b which were individually isolated by normal column chro-
1
matography over silica gel. Their syn- and anti-stereochemistry were confirmed by comparing the H
NMR resonances of the –CH2O and –CHO groups with those reported in the literature.9a,b In contrast

S. Sankaranarayanan, S. Chattopadhyay / Tetrahedron: Asymmetry 9 (1998) 1345–1350
1347
1
to the three multiplets shown for the above protons in the high field (500 MHz) H NMR spectrum
of 2a, compound 2b exhibited four well separated multiplets at δ 3.77–3.83 (1H), 3.86–3.89 (1H),
3.93–3.96 (1H) and 3.98–4.04 (1H) respectively. Both the synthons were tailor-made for the synthesis of
I antipodes. For the synthesis of (S)-I, 2b was benzylated to furnish 3 which on acidic hydrolysis gave
the triol derivative 4. Cleavage of its diol function with NaIO4 afforded the desired chiron 5.
The other component 9 required for the synthesis, was prepared from cyclohexanone 6. Thus,
compound 6 was subjected to a Baeyer–Villiger oxidation10 with performic acid to give the hydroxy
acid 7. Its bromination furnished the known compound 811 which was converted to the phosphonium salt
9 by heating with Ph3P. A Wittig reaction12 between the aldehyde 5 and 9 in the presence of n-BuLi as
the base afforded the acid 10. Since the olefin geometry was of no consequence to the synthesis, we did
not analyze its composition. To check if there was any racemisation during the Wittig reaction, the acid
10 was converted to its methyl ester with diazomethane and subjected to HPLC analysis on CHIRALCEL
OJ (Daicel Chemical Industries) column using 15% 2-propanol/hexane as the eluent and a flow rate of
0.5 ml/min. Two peaks with retention times of 45 min (99%) and 48 min (1%) established its ee to be
98%. The acid was then converted to the amide 11 by reacting with 2-phenylethylamine in the presence
of DCC-DMAP. This on catalytic hydrogenation over 10% Pd–C in EtOH led to (S)-I.
Following an identical procedure, (R)-I was also synthesized starting from the syn-triol derivative 2a.
Their spectral data were in conformity with those reported.6 Both the antipodes of synthetic I should be
enantiomerically pure as their respective precursors viz. 2a and 2b were homochiral as suggested by their
1
high field H NMR spectra. Since the natural compound showed a negative specific rotation similar to
that of (R)-I, prepared by us, its configuration also must be (R).
3. Experimental
All the boiling points were uncorrected. The IR spectra were scanned with a Perkin–Elmer spectro-
photometer model 837 and only the pertinent bands are mentioned. The 1H NMR spectra were recorded
in CDCl3 with a Bruker AC-200 (200 MHz) instrument. The optical rotations were measured with a
Jasco DIP 360 polarimeter. Anhydrous reactions were carried out under Ar using freshly dried solvents.
The organic extracts were dried over anhydrous Na2SO4.
3.1. 1,2-Cyclohexylidenedecane-3-ol 2b
To a stirred solution of n-heptylmagnesium bromide [prepared from 1-bromoheptane (10.74 g, 0.06
mol) and Mg (1.75 g, 0.072 mol)] in anhydrous THF (60 ml) was added 1 (5.1 g, 0.03 mol) in THF
(15 ml) at 0°C. After 3 h, the reaction was quenched with aqueous saturated NH4Cl and the mixture
extracted with ether. The ether layer was washed with water and brine and finally dried. Removal
of the solvent under reduced pressure followed by column chromatography of the residue over silica
gel gave pure 2a (with 8% EtOAc/hexane) followed by a mid-fraction of the diastereomeric mixture
(with 8–10% EtOAc/hexane) and finally pure 2b (with 12% EtOAc/hexane). The mid-fraction was again
column chromatographed, as above, to obtain the second batch of 2a and 2b. 2a: Yield: 2.35 g (29%);
[α]D +9.76 (c 0.41, CHCl3); IR: 3380, 1030, 880, 810 cm−1; 1H NMR: δ 0.87 (dist. t, 3H), 1.24–1.38
22
(m, 12H), 1.4–1.6 (m, 10H), 2.3 (br. s, D2O exchangeable, 1H), 3.44–3.47 (m, 1H), 3.68–3.71 (m, 1H),
3.93–4.0 (m, 2H). Anal. calcd for C16H30O3: C 71.07, H 11.18; found: C 70.88, H 11.48. 2b: Yield:
22
1
4.1 g (50.6%); [α]D +8.75 (c 0.32, CHCl3); IR: 3400, 1030, 880, 810 cm−1; H NMR: δ 0.88 (dist.

1348
S. Sankaranarayanan, S. Chattopadhyay / Tetrahedron: Asymmetry 9 (1998) 1345–1350
t, 3H), 1.2–1.39 (m, 12H), 1.41–1.65 (m, 10H), 2.84 (br. s, D2O exchangeable, 1H), 3.77–3.83 (m, 1H),
3.86–3.89 (m, 1H), 3.93–3.96 (m, 1H), 3.98–4.04 (m, 1H).
3.2. (2R,3S)-1,2-Cyclohexylidene-3-benzyloxydecane 3
A solution of 2b (2.0 g, 7.4 mmol) in THF (20 ml) was added dropwise to a magnetically stirred
suspension of hexane washed NaH (0.391 g, 8.15 mmol, 50% dispersion in oil) in THF (20 ml) at room
temperature. The mixture was heated to 60°C for 1 h to ensure complete anion generation. After cooling
to room temperature, BnBr (1.4 g, 8.15 mmol) in THF (10 ml) was added and stirring continued for 18 h.
The mixture was then poured into cold water and extracted with ether. The ether extract was washed with
water and brine and dried. Removal of solvent followed by column chromatography (silica gel, 0–10%
EtOAc/hexane) of the residue gave pure 3. Yield: 2.39 g (90%); [α]D22 +7.48 (c 1.47, CHCl3); IR: 3065,
1
3030, 1600, 1440, 700 cm−1; H NMR: δ 0.88 (dist. t, 3H), 1.24–1.38 (m, 12H), 1.4–1.62 (m, 10H),
3.75–3.81 (m, 1H), 3.93–3.96 (m, 1H), 4.01–4.1 (m, 2H), 4.55 (s, 1H), 4.63 (s, 1H), 7.35 (s, 5H). Anal.
calcd for C23H36O3: C 76.62, H 10.07; found: C 76.57, H 10.16.
3.3. (2R,3S)-3-Benzyloxydecane-1,2-diol 4
A solution of 3 (2.3 g, 6.4 mmol) in trifluoroacetic acid (10 ml) and water (1 ml) was stirred at room
temperature for 72 h. Most of the solvent was removed in vacuo, the residue suspended in CHCl3 and
washed successively with water, 10% aqueous NaHCO3, water and brine. After drying, the extract was
concentrated in vacuo and the residue chromatographed (silica gel, 0–5% MeOH/CHCl3) to furnish 4.
Yield: 1.5 g (83.7%); [α]D +8.95 (c 0.38, CHCl3); IR: 3390, 3065, 3030, 1650, 1020, 697 cm−1; 1H
22
NMR: δ 0.88 (dist. t, 3H), 1.3–1.6 (m containing a br. s at δ 1.32, 12H), 3.1 (br. s, D2O exchangeable,
2H), 3.45–3.55 (m, 2H), 3.6–3.8 (m, 1H), 4.05–4.2 (m, 1H), 4.55 (s, 1H), 4.63 (s, 1H), 7.35 (s, 5H). Anal.
calcd for C17H28O3: C 72.82, H 10.07; found: C 72.77, H 10.31.
3.4. (2S)-2-Benzyloxynonanal 5
To a cooled (0°C) and stirred solution of 4 (1.5 g, 5.36 mmol) in CH3CN:H2O (50 ml, 3:2) was added
NaIO4 (2.2 g, 10.3 mmol) in portions. After stirring for 1.5 h, the reaction mixture was filtered and the
filtrate concentrated in vacuo. The residue was dissolved in ether, the ether layer washed successively
with water, aqueous Na2SO3, water, aqueous Na2S2O3, water and brine and finally dried. Removal of
solvent gave pure 5 (cf. TLC) which was used as such for the next step. Yield: 1.12 g (84%); IR: 3065,
3030, 2715, 1735, 1030 cm−1; 1H NMR: δ 0.9 (dist. t, 3H), 1.25–1.6 (m containing a br. s at δ 1.3, 12H),
4.5 (s, 2H), 4.6–4.9 (m, 1H), 7.35 (s, 5H), 9.8 (d, J=1.5 Hz, 1H).
3.5. 6-Bromohexanoic acid 8
To a stirred solution of HCO3H [prepared from H2O2 (120 ml, 30%) and HCO2H (360 ml)] was added
cyclohexanone 6 (31 ml) over a period of 1 h. After stirring for 24 h, water (200 ml) was added and
the mixture extracted with CHCl3 by continuous liquid–liquid solvent extraction. The solvent and excess
HCO2H was removed first at normal pressure and subsequently under reduced pressure (0.1 mmHg)
1
to furnish the hydroxy acid 7. Yield: 30.2 g (75%); IR: 3500–2500, 1710, 1420 cm−1; H NMR: δ
1.45 (br. s, partially D2O exchangeable, 7H), 2.4 (t, J=6 Hz, 2H), 3.6 (t, J=6 Hz, 2H), 10.2 (br. s, D2O
exchangeable, 1H).

S. Sankaranarayanan, S. Chattopadhyay / Tetrahedron: Asymmetry 9 (1998) 1345–1350
1349
To a stirred and cooled (0°C) aqueous solution 48% HBr (37.0 g) was slowly added conc. H2SO4 (12
ml). Subsequently, compound 7 (30.2 g, 0.23 mol) was carefully introduced to the above acid mixture.
The mixture was then refluxed for 8 h, brought to room temperature, diluted with water and extracted
with ether. The organic extract was washed with water and brine, dried and concentrated. The crude
product was purified by vacuum distillation to give 8. Yield: 28.7 g (64%); bp: 104–106°C/0.2 mmHg
(lit.11 bp: 142–143°C/11 mmHg); IR: 3500–2500, 1710 cm−1; 1H NMR: δ 1.3–1.9 (m, 6H), 2.4 (t, J=6
Hz, 2H), 3.43 (t, J=6 Hz, 2H), 11.3 (br. s, D2O exchangeable, 1H). Anal. calcd for C6H11O2Br: C 36.96,
H 5.68; found: C 36.77, H 5.59.
3.6. 5-Carboxypentyltriphenylphosphonium bromide 9
A mixture of 8 (27.7 g, 0.142 mol) and Ph3P (38.0 g, 0.144 mol) in CH3CN (150 ml) was refluxed
for 48 h. Most of the solvent was removed in vacuo and the residue titurated with solvent ether. The
precipitated pale yellow solid was filtered, washed thoroughly with ether and dried in vacuo over P2O5
to get 9. Yield: 61.4 g (94%); mp: 205°C, (lit.10 mp: 200–203°C).
3.7. (8S)-(6E/Z)-8-Benzyloxypentadec-6-enoic acid 10
To a stirred suspension of 9 (2.23 g, 4.88 mmol) in THF (20 ml) at −25°C was added n-BuLi (6.1
ml, 1.6 M in hexane, 9.77 mmol). After stirring for 1 h at the same temperature, it was cooled to −30°C
and the aldehyde 5 (1.1 g, 4.4 mmol) in THF (20 ml) was added to it. Stirring was continued for 4 h
at −30°C and 12 h at room temperature. It was treated with aqueous saturated NH4Cl, the organic part
separated and the aqueous portion extracted with ether. The combined organic extract was washed with
water and brine and finally dried. Removal of solvent and subsequent column chromatography of the
product over silica gel (0–5% MeOH/CHCl3) gave 10 as a mixture of geometrical isomers. Yield: 0.96 g
22
(63%); [α]D +3.71 (c 1.54, CHCl3); IR: 3550–3250, 3065, 3030, 1710 cm−1; 1H NMR: δ 0.9 (dist. t,
3H), 1.2–1.7 (m, 16H), 2.0–2.4 (m, 4H), 4.5 (s, 2H), 4.6–4.8 (m, 1H), 5.5–5.6 (m, 2H), 7.16 (br. s, 5H),
9.1 (br. s, D2O exchangeable, 1H). Anal. calcd for C22H34O3: C 76.26, H 9.89; found: C 76.42, H 10.12.
3.8. (8S)-8-Hydroxypentadecanoic acid 2-phenylethyl amide I
A solution of compound 10 (0.24 g, 0.7 mmol), 2-phenylethylamine (0.085 g, 0.7 mmol), DCC (0.144
g, 0.7 mmol) and DMAP (0.05 g) in CH2Cl2 (10 ml) was stirred for 16 h. The precipitated solid was
removed by filtration, the filtrate washed with aqueous dil. HCl (2 N), water and brine and dried. Solvent
removal followed by column chromatography of the residue (silica gel, 0–10% EtOAc/hexane) gave 11.
Yield: 0.14 g (45%); [α]D22 +2.56 (c 0.52, CHCl3); IR: 3335, 1690 cm−1; 1H NMR: δ 0.88 (dist. t, 3H),
1.2–1.6 (m, 14H), 1.7–2.0 (m, 4H), 2.55 (t, J=7 Hz, 2H), 3.3 (t, J=7 Hz, 2H), 4.51 (br. s, 1H), 4.6–4.7 (m
containing an s at δ 4.62, 3H), 5.3–5.5 (m, 2H), 7.16 (s, 10H).
A mixture of 11 (0.14 g, 0.31 mmol) and 10% Pd–C (0.05 g) in EtOH (10 ml) was shaken under a slight
a positive pressure of hydrogen until the required uptake of H2. The reaction mixture was diluted with
EtOAc and the supernatant passed through a pad (2 inches) of silica gel. The eluent was concentrated in
vacuo and the residue purified by preparative TLC (silica gel, 15% EtOAc/hexane) to furnish I. Yield:
0.089 g (79%); mp: 77°C (lit.6 mp: 78°C); [α]D +3.68 (c 0.46, CHCl3), (lit.6 [α]D −2.68 (c 0.41,
CHCl3)); IR: 3335, 1690 cm−1; 1H NMR: δ 0.88 (dist. t, 3H), 1.32 (br. s, 22H), 1.7–1.8 (m, 2H), 2.55
(t, J=7 Hz, 2H), 3.3–3.35 (m, 2H), 3.45–3.59 (m, 1H), 4.51 (br. s, 1H), 7.35 (s, 5H). Anal. calcd for
C23H39O2N: C 76.40, H 10.87; found: C 76.22, H 10.62.
22
25

1350
S. Sankaranarayanan, S. Chattopadhyay / Tetrahedron: Asymmetry 9 (1998) 1345–1350
3.9. (2R,3R)-1,2-Cyclohexylidene-3-benzyloxydecane 3
[α]D +4.32 (c 0.78, CHCl3); IR: 3065, 3030, 1610, 1460, 720 cm−1; 1H NMR: δ 0.86 (dist. t, 3H),
22
1.22–1.35 (m, 12H), 1.4–1.6 (m, 10H), 3.48–3.56 (m, 1H), 3.78–3.84 (m, 1H), 3.88–3.96 (m, 2H), 4.55
(s, 1H), 4.6 (s, 1H), 7.35 (s, 5H).
3.10. (2R,3R)-3-Benzyloxydecane-1,2-diol 4
22
1
[α]D +3.88 (c 0.68, CHCl3); IR: 3440, 3065, 3030, 1630, 1010, 700 cm−1; H NMR: δ 0.9 (dist.
t, 3H), 1.32 (br. s, 12H), 2.68 (br. s, D2O exchangeable, 2H), 3.51–3.55 (m, 2H), 3.63–3.72 (m, 1H),
4.1–4.6 (m, 3H), 7.35 (s, 5H).
3.11. (8R)-(6Z)-8-Benzyloxypentadec-6-enoic acid 10
22
[α]D −3.34 (c 1.4, CHCl3); IR: 3500–3200, 3065, 3030, 1715 cm−1; 1H NMR: δ 0.9 (dist. t, 3H),
1.2–1.63 (m, 16H), 2.1–2.45 (m, 4H), 4.55 (s, 2H), 4.64–4.78 (m, 1H), 5.5–5.6 (m, 2H), 7.26 (br. s, 5H),
8.9 (br. s, D2O exchangeable, 1H).
3.12. (8R)-8-Hydroxypentadecanoic acid 2-phenylethyl amide I
24
25
[α]D −3.36 (c 0.88, CHCl3), (lit.6 [α]D −2.68 (c 0.41, CHCl3)); mp: 73°C (lit.6 mp: 78°C); IR:
3340, 1685 cm−1; 1H NMR: δ 0.87 (dist. t, 3H), 1.30 (br. s, 22H), 1.74–1.83 (m, 2H), 2.59 (t, J=7 Hz,
2H), 3.31–3.39 (m, 2H), 3.4–3.51 (m, 1H), 4.48 (br. s, 1H), 7.35 (s, 5H).
References
1. Scheuer, P. J. J. Nat. Prod., 1995, 58, 335 and references cited therein.
2. Faulkner, D. J. Nat. Prod. Rept., 1995, 12, 223.
3. Ross, R. A.; Scheuer, P. J. Tetrahedron Lett., 1979, 49, 4701.
4. Baker, B. J.; Okuda, R. C.; Yu, P. T. K.; Scheuer, P. J. J. Am. Chem. Soc., 1985, 107, 2976.
5. Baker, B. J.; Scheuer, P. J. J. Nat. Prod., 1994, 57, 1346.
6. Liyanage, G. K.; Schmitz, F. J. J. Nat. Prod., 1996, 59, 148.
7. Chattopadhyay, A.; Mamdapur, V. R. J. Org. Chem., 1995, 60, 585.
8. Sugiyama, T.; Sugawara, H.; Watanabe, M.; Yamashita, K. Agric. Biol. Chem., 1984, 48, 1841.
9. (a) Mukaiyama, T.; Harda, T. Chem. Lett., 1981 1101. (b) Machiya, K.; Ichimoto, I.; Karihata, M.; Ueda, M. Agric. Biol.
Chem., 1985, 49, 643.
10. Robinson, R.; Smiff, L. H. J. Chem. Soc., 1937, 371.
11. Kaga, H.; Miura, M.; Orito, K. J. Org. Chem., 1989, 54, 3477.
12. Cadogan, J. I. G. Organophosphorus Reagents in Organic Synthesis, Academic Press, 1979.