Total synthesis of desoxoprosophylline: Application of a lactam-derived enol triflate to natural product synthesis

Article abstract of DOI:10.1021/jo962347j

The total synthesis of desoxoprosophylline 1 from a piperidinone-derived enol triflate 8 has been realized and is one of the first applications of such lactam-derived triflates to natural product synthesis. Palladium-catalyzed methoxycarbonylation of 8 followed by 1,2-reduction and protection introduces the required C2 hydroxymethyl group, affording 10. The C3 hydroxy function is stereoselectively added by a novel N-tosylenamide hydroboration (de 88%), and the final C6 dodecyl chain is incorporated with complete stereocontrol, in a single step, via an N-tosyliminium ion-allylsilane coupling. Deprotection gives the natural product in an efficient 7.5% yield over nine steps.

Full text of DOI:10.1021/jo962347j

3592
J . Org. Chem. 1997, 62, 3592-3596
Tota l Syn th esis of Desoxop r osop h yllin e: Ap p lica tion of a
La cta m -Der ived En ol Tr ifla te to Na tu r a l P r od u ct Syn th esis
Tim Luker, Henk Hiemstra* and W. Nico Speckamp*
Laboratory of Organic Chemistry, Amsterdam Institute of Molecular Studies, University of Amsterdam,
Nieuwe Achtergracht 129, 1018 WS Amsterdam, The Netherlands
Received December 16, 1996X
The total synthesis of desoxoprosophylline 1 from a piperidinone-derived enol triflate 8 has been
realized and is one of the first applications of such lactam-derived triflates to natural product
synthesis. Palladium-catalyzed methoxycarbonylation of 8 followed by 1,2-reduction and protection
introduces the required C2 hydroxymethyl group, affording 10. The C3 hydroxy function is
stereoselectively added by a novel N-tosylenamide hydroboration (de 88%), and the final C6 dodecyl
chain is incorporated with complete stereocontrol, in a single step, via an N-tosyliminium ion-
allylsilane coupling. Deprotection gives the natural product in an efficient 7.5% yield over nine
steps.
Sch em e 1
In tr od u ction
In contrast to the numerous reports describing the
formation and functionalization of enol triflates derived
from aldehydes, ketones, lactones,1a and thiolactones,1b
there have been relatively few publications concerning
extension of this methodology to include lactam-derived
variants. Isobe2a,b and Comins2c have reported the
preparation of such lactam-derived triflates; however to
the best of our knowledge only a single report of their
use in natural product synthesis exists.2c We recently
disclosed a high-yielding route to N-tosyl-R-ethoxypyr-
rolidinone and -piperidinone derived enol triflates (such
as 8, Scheme 1) and some preliminary studies on the
stability and reactivity of these molecules.3 Triflate 8 is
also a precursor to iminium ions, which are now widely
regarded as powerful intermediates for organic synthe-
sis.4 We hoped that molecules such as 8, which allow
access to these two extremely productive areas of syn-
thetic methodology, should be useful in the construction
of natural products.
Herein we show that our piperidinone-derived enol
triflate 8 is indeed a useful building block for the
stereocontrolled synthesis of polysubstituted piperidines,
a nucleus present in a wide range of natural products.5
Desoxoprosophylline 1, a racemic alkaloid derivative
isolated from Prosopis africana,5a has attracted recent
interest as a synthetic target.6 Scheme 1 summarizes
the two previous total syntheses of this molecule, both
of which used similar strategies. Tadano utilized an
aminopalladation reaction (5 f 4) to close the piperidine
ring,6a an approach which initially gave the incorrect
a
b
Reference 6a. References 6b,c.
product stereochemistry (later corrected via a fortuitous
epimerization). Takahashi had earlier reported ring
closure via a conceptually similar aminomercuration
reaction6b (3 f 2).
Our retrosynthetic strategy is also shown in Scheme
1. In contrast to the previous routes, we begin with a
cyclic starting material, triflate 8, and hoped that the
three reactive moieties present would allow the ste-
reospecific incorporation of the three required piperidine
ring substituents. The triflate moiety would allow in-
troduction of the C2 hydroxymethyl group3 of 7, hydrobo-
ration of the resulting enamide3 would functionalize C3
affording 6, and finally N-tosyliminium ion generation
(from the R-ethoxysulfonamide) would permit introduc-
tion of the C6 dodecyl chain.
X Abstract published in Advance ACS Abstracts, May 1, 1997.
(1) (a) Review: Ritter, K. Synthesis 1993, 735. (b) O’Neil, I. O.;
Hamilton, K. M.; Miller, J . A.; Young, R. J . Synlett 1995, 151.
(2) (a) Okita, T.; Isobe, M. Synlett 1994, 589. (b) Okita, T.; Isobe,
M. Tetrahedron 1995, 51, 3737. (c) Foti, C. J .; Comins, D. L. J . Org.
Chem. 1995, 60, 2656.
(3) Luker, T.; Hiemstra, H.; Speckamp, W. N. Tetrahedron Lett.
1996, 37, 8257.
(4) Hiemstra, H.; Speckamp, W. N. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford,
1991; Vol. 2, pp 1047-1082.
(5) (a) Khuong-Huu, Q.; Ratle, G.; Monseur, X.; Goutarel, R. Bull.
Soc. Chim. Belg. 1972, 81, 443. (b) Khuong-Huu, Q.; Ratle, G.;
Monseur, X.; Goutarel, R. Bull. Soc. Chim. Belg. 1972, 81, 425. (c)
Fodor, G. B.; Colasanti, B. In Alkaloids: Chemical and Biological
Perspectives; Pelletier, S. W., Ed.; Wiley: New York, 1985; Vol. 3, p 1.
(d) Strunz, G. M.; Findlay, J . A. In The Alkaloids; Brossi, A., Ed;
Academic Press: San Diego, 1986; Vol. 26, p 89.
Resu lts a n d Discu ssion
The synthesis of 1 started with triflate 8 which was
prepared from the corresponding N-tosyl-6-ethoxy-2-
(6) (a) Takao, K.; Nigawara, Y.; Nishino, E.; Tagaki, I.; Maeda, K.;
Tadano, K.; Ogawa, O. Tetrahedron 1994, 50, 5681. (b) Saitoh, Y.;
Moriyama, Y.; Hirota, H.; Takahashi, T.; Khuong-Huu, Q. Bull. Chem.
Soc. J pn. 1981, 54, 488. (c) Saitoh, Y.; Moriyama, Y.; Takahashi, T.;
Khuong-Huu, Q. Tetrahedron Lett. 1980, 21, 75.
S0022-3263(96)02347-X CCC: $14.00 © 1997 American Chemical Society

Total Synthesis of Desoxoprosophylline
J . Org. Chem., Vol. 62, No. 11, 1997 3593
Sch em e 2a
Sch em e 3a
a
Conditions: (a) 15, BF3‚Et2O, -78 f -30 °C 55%; (b) Pd/C,
H2, MeOH; (c) HCl (0.4 M in MeOH) 75% (two steps); (d) Na/NH3
75%.
failed to react with 11, even after protracted reaction
times or elevated temperatures. We eventually found
that reaction of 11 with excess borane-THF at low
temperature (-10 °C) resulted in slow but clean hydrobo-
ration; however, upon warming to rt, the resulting
organoborane was unstable, giving a plethora of uniden-
tified products. Fortunately, at 0 °C the reaction pro-
ceeded both smoothly and at a reasonable rate. Oxidative
workup with alkaline hydrogen peroxide gave complex
product mixtures. Pleasingly, oxidation with trimethyl-
amine N-oxide12 afforded the desired alcohol 12 in a high-
yielding, stereocontrolled process (15:1 mixture, de 88%).
Thus we had efficiently introduced the second of the ring
substituents required for the natural product. A 3,6-
trans product was expected as the major isomer,11c
resulting from the transition state shown in Scheme 2.
A(1,3) strain from the N-tosyl group imposes an axial
orientation on the C6-ethoxy group, and hydroboration
from the least hindered face affords the 3,6-trans product.
Unfortunately, this relative stereochemistry could not be
proven (noncrystallinity prevented X-ray analysis, and
a
Conditions: (a) Pd(AsPh3)4, CO, MeOH, DMF 61%; (b) DIBALH,
THF 70%; (c) SEMCI, iPr2EtN, CH2Cl2 80%; (d) BH3‚THF, -78
f 0 °C then Me3NO, 0 f 65 °C 83%; (e) TBDMSOTf, 2,6-lutidine,
CH2Cl2 92%.
piperidinone (9)3 as shown in Scheme 2. We quickly
found that the potassium enolate of 9 reacted more
satisfactorily with triflating agents than the correspond-
ing lithium variant. Enolate trapping with triflic anhy-
dride did afford the desired triflate product, albeit in poor
yield (ca. 35%). Switching to Comins’ N-(5-chloro-2-
pyridyl)triflimide7 increased the yield to ca. 60%. Finally
we found that Kugelrohr distillation of the commercially
obtained Comins’ reagent before use (distilled material
was stable for >3 months at 0 °C) dramatically increased
the yield of 8 to an excellent 97%.
The first challenge was introduction of the C2-hydroxy-
methyl substituent. Attempts to introduce this substitu-
ent in one step via reaction of 8 with lithium bis((meth-
oxymethoxy)methyl) cuprate8 ((MOMOCH2)2CuLi) failed
to give the desired coupling product, and so an alternative
strategy was sought. Palladium-catalyzed methoxy-
carbonylation2c,9 using the previously reported conditions
(Pd(OAc)2, PPh3) gave a moderate yield of ester 10. The
reaction was improved both in terms of yield and rate
by switching to an in situ generated tetrakis(triphenyl-
arsine)palladium(0) catalyst known to accelerate Stille
couplings.10 Selective 1,2-reduction of ester 10 gave an
allylic alcohol which was only stable for moderate periods
at rt. It was therefore immediately protected as the SEM
((â-(trimethylsilyl)ethoxy)methyl) ether 11. Thus the
first of the required piperidine substituents had been
efficiently introduced.
1
overlapping proton resonances in the H NMR spectra
inhibited NOE studies). As a new C6-substituent was
to be introduced shortly, the uncertain stereochemistry
of the ethoxy group was viewed of minor importance and
not pursued further. Protection of the secondary alcohol
under standard conditions gave TBDMS ether 13,13 and
so the final challenge remaining was the stereospecific
introduction of the C6-dodecyl substituent.
We intended to generate the N-tosyliminium ion14 14
from 13 and introduce the 12-carbon chain in one step
via allylsilane 15 (Scheme 3). The synthesis of 15 was
surprisingly straightforward. Using the conditions de-
scribed by Arase,15 hydroboration of 3-chloro-1-(trimeth-
ylsilyl)-1-propyne with dinonylborane followed by reac-
With quantities of 11 in hand, we were now in a
position to attempt the novel hydroboration of the trisub-
stituted N-tosylenamide moiety. Only a few reports have
appeared concerning the hydroboration of cyclic enecar-
bamates11a,b and enamides.11c All contained disubstituted
double bonds, and in all but one case11c the diastereose-
lection was poor. Hindered boranes such as 9-BBN-H
(11) (a) Shono, T.; Matsumura, Y.; Tsubata, K.; Sugihara, Y.;
Yamane, S.; Kanazawa, T.; Aoki, T. J . Am. Chem. Soc. 1982, 104, 6697.
(b) Plehiers, M.; Hootele´, C. Tetrahedron Lett. 1993, 34, 7569. (c)
Oppolzer, W.; Bochet, C. G. Tetrahedron Lett. 1995, 36, 2959.
(12) Kabalka, G. W.; Hedgecock, H. C., J r. J . Org. Chem. 1975, 40,
1776.
(13) The Lewis acidity of the TBDMSOTf occasionally caused partial
elimination of EtOH from 13, affording an N-tosylenamide byproduct
(ca. 5-15%). However, this was of little consequence as both 13 and
the byproduct reacted with silane 15 in the next step.
(14) Åhman, J .; Somfai, P. Tetrahedron 1992, 48, 9537 and refer-
ences therein.
(7) Comins, D. L.; Dehghani, A. Tetrahedron Lett. 1992, 33, 6299.
(8) Phillips, D.; O’Neill, B. T. Tetrahedron Lett. 1990, 31, 3291.
(9) Cacchi, S.; Morera, E.; Ortar, G. Tetrahedron Lett. 1985, 26, 1109.
(10) Farina, V.; Krishman, B. J . Am. Chem. Soc. 1991, 113, 9585.

3594 J . Org. Chem., Vol. 62, No. 11, 1997
Luker et al.
THF (3 mL) was added rapidly in one portion. After 45 min
of stirring, the reaction mixture was warmed to ca. 0 °C.
Saturated ammonium chloride solution (15 mL) followed by
dichloromethane (20 mL) and water (15 mL) were added, and
the organic layer was separated. The aqueous layer was
extracted with dichloromethane (2 × 25 mL), the combined
organic solutions were dried, and the solvent was removed in
vacuo. Column chromatography (1:5 f 1:1 dichloromethane/
tion with MeLi gave, after quenching, 15 in 56% yield
from a one-pot process. Coupling of 13 and 15 proceeded
in reasonable yield, mediated by boron trifluoride ether-
ate, affording 16 as a single diastereomer (no traces of
1
diastereomeric impurities were detected in either the H-
or 13C-NMR spectra of the crude reaction product).
Although the relative stereochemistry at the newly
formed stereocenter was not known until the last step of
the synthesis (NOE studies proved fruitless), we pre-
dicted 16 to have the correct natural product stereochem-
istry from analysis of the possible transition states. Due
to a strong A(1,2) strain between the C2-hydroxymethyl
substituent and the N-tosyl group of the iminium ion,
transition state 14a was expected to be less stable than
14b, which contains the axial C2-hydroxymethyl.16 Ste-
reoelectronically preferred axial attack17 by the silane
nucleophile on 14b would account for the 2,6-cis-sub-
stituted piperidine isolated. Interestingly, but for less
obvious reasons, the C3-hydroxyl group is also known to
direct such incoming nucleophiles, but in a trans
manner,16b further reinforcing the observed stereoselec-
tivity.
light petroleum ether, on SiO2
) afforded triflate 8 as white
crystals (1.660 g, 96%): mp 67-70 °C from light petroleum
ether; IR 3413, 1677 cm-1; 1H NMR (400 MHz) δ 7.76 (2 H, d,
J ) 8.3), 7.36 (2 H, d, J ) 8.2), 5.41 (1 H, t, J ) 4.6), 5.40 (1
H, t, J ) 2.6), 3.81 (1 H, dq, J ) 9.3, 7.1), 3.51 (1 H, dq, J )
9.3, 7.0), 2.46 (3 H, s), 2.32 (1 H, dddd, J ) 18.9, 12.1, 7.3,
3.6), 2.02 (1 H, ddd, J ) 18.6, 6.4, 4.3), 1.81 (1 H, ddd, J )
13.6, 6.6, 1.4), 1.16 (1 H, m), 1.16 (3 H, t, J ) 7.0); 13C NMR
(50 MHz) δ 145.1 (s), 137.2 (s), 135.1 (s), 130.2 (2d), 128.0 (2d),
118.7 (s; q J ) 321.1), 108.7 (d), 86.4 (d), 64.2 (t), 25.4 (t), 21.8
(q), 18.4 (t), 11.6 (q); MS 429 M+ (58); HRMS calcd for
C15H18NO6F3S2 429.0528, found 429.0512. Anal. Calcd for
C15H18NO6F3S2: C, 41.95; H, 4.23; N, 3.26. Found: C, 42.42;
H, 4.60; N, 3.42.
2-Ca r bom eth oxy-6-eth oxy-1-p-tolu en esu lfon yl-1,4,5,6-
tetr a h yd r op yr id in e (10). A solution of triflate 8 (0.324 g,
0.755 mmol), Pd2dba3 (0.017 g, 0.018 mmol, 0.03 equiv), and
triphenylarsine (0.046 g, 0.151 mmol, 0.20 equiv) in DMF (3.5
mL) was flushed with carbon monoxide for 10 min. Triethyl-
amine (0.42 mL, 3.02 mmol, 4 equiv) and methanol (1.22 mL,
30.21 mmol, 40 equiv) were added, and the solution was
attached to a balloon of carbon monoxide and stirred for 12 h.
After the solution was flushed with nitrogen, ethyl acetate (10
mL) and water (6 mL) were added and the organic phase was
separated. The aqueous phase was extracted with ethyl
acetate (2 × 10 mL), the combined organics were washed with
brine (2 × 10 mL) and dried, and the solvent was removed in
vacuo. Column chromatography (1:5 ethyl acetate/light pe-
troleum ether, on SiO2) afforded ester 10 as a colorless oil
which occasionally partially crystallized to a waxy white solid
(0.155 g, 61%): IR 1727, 1645 cm-1; 1H NMR (400 MHz) δ 7.83
(2 H, d, J ) 8.3), 7.30 (2 H, d, J ) 8.2), 6.33 (1 H, t, J ) 3.6),
4.99 (1 H, t, J ) 2.7), 3.83 (3 H, s), 3.59 (1 H, dq, J ) 9.7, 7.1),
3.20 (1 H, dq, J ) 9.7, 7.0), 2.42 (3 H, s), 2.23 (1 H, dddd, J )
19.8, 11.6, 7.6, 3.6), 2.03 (1 H, dddd, J ) 19.8, 7.3, 4.1, 0.8),
1.77 (1 H, ddt, J ) 13.8, 7.6, 1.2), 1.35 (1 H, dddd, J ) 13.8,
10.5, 7.4, 3.0), 1.01 (3 H, t, J ) 7.1); 13C NMR (100 MHz) δ
166.3 (s), 144.4 (s), 135.5 (s), 129.8 (2d), 128.2 (2d), 127.7 (s),
127.4 (d), 82.0 (d), 63.3 (t), 52.4 (q), 25.2 (t), 21.8 (q), 19.0 (t),
14.7 (q); MS 339 M+ (96); HRMS calcd for C16H21NO5S
339.1140, found 339.1138.
6-E t h oxy-1-p -t olu en esu lfon yl-2-(((â-(t r im et h ylsilyl)-
eth oxy)m eth oxy)m eth yl)-1,4,5,6-tetr a h ydr opyr id in e (11).
To a solution of ester 10 (0.630 g, 1.858 mmol) in THF (12
mL) at 0 °C was added DIBALH (9.29 mL of a 1 M solution in
THF, 9.29 mmol, 5 equiv), and the solution was warmed to rt.
After 5 h, the reaction was carefully quenched with saturated
aqueous Rochelle’s salt. Water (25 mL) was added, and the
solution was extracted with ethyl acetate (4 × 35 mL). The
combined extracts were dried, and the solvent was removed
in vacuo. Column chromatography (1:4 f 1:3 ethyl acetate/
light petroleum ether, on SiO2) afforded an allylic alcohol
product (0.407 g, 70%) as a colorless oil. This compound was
of low thermal stability and so was immediately protected as
its SEM ether before full characterization: 1H NMR (400 MHz)
δ 7.67 (2 H, d, J ) 8.3), 7.31 (2 H, d, J ) 8.1), 5.41 (1 H, t, J
) 3.5), 5.35 (1 H, t, J ) 5.3), 4.54 (1 H, dd, J ) 13.2, 7.0), 4.13
(1 H, dd, J ) 13.2, 8.3), 3.83 (1 H, dq, J ) 9.8, 7.2), 3.62 (1 H,
dq, J ) 9.8, 7.0), 3.16 (1 H, dd, J ) 8.2, 7.0), 2.43 (3 H, s), 2.17
(1 H, m), 1.73 (2 H, m), 1.20 (3 H, t, J ) 7.0), 0.96 (1 H, m).
To a solution of this alcohol (0.353 g, 1.135 mmol) in
dichloromethane (5 mL) were added diisopropylethylamine
(0.58 mL, 3.41 mmol, 3 equiv) and SEMCl (0.54 mL, 3.07
mmol, 2.7 equiv). After 12 h, the volatiles were removed in
vacuo. Column chromatography (1:6 f 1:4 ethyl acetate/light
petroleum ether, on SiO2) afforded SEM ether 11 as a colorless
oil which slowly crystallized upon standing (0.399 g, 80%): mp
67-69 °C from ethyl acetate/light petroleum ether; IR 3023,
Hydrogenation of olefin 16, followed by deprotection
of the hydroxy and amino groups, afforded desoxoproso-
phylline 1 in excellent yield. Mp and NMR data were
identical with those previously reported.5a,6a,b
In conclusion, the synthesis of desoxoprosophylline has
been achieved in nine steps and 7.5% overall yield from
N-tosyl-6-ethoxy-2-piperidinone. Our route to 1 has lead
to the development of novel methodology including a
highly diastereoselective trisubstituted enamide hydro-
boration and a completely stereoselective “internal” al-
lylsilane-N-tosyliminium ion coupling. The work pre-
sented should go some way toward establishing lactam-
derived enol triflates as useful synthetic intermediates.
Exp er im en ta l Section
Gen er a l. Unless otherwise noted, materials were obtained
from commercial suppliers and used without further purifica-
tion. Dichloromethane, triethylamine, diisopropylethylamine,
2,6-lutidine, and DMF were distilled from CaH2 prior to use
and stored under nitrogen. THF was distilled from Na/
benzophenone. N-(5-Chloro-2-pyridyl)triflimide was Kugelrohr
distilled before use and could be stored at 0 °C for 3 months.
All reaction mixtures were stirred under a nitrogen atmo-
sphere unless otherwise indicated. During workup, where
drying of the organic solutions is indicated, Na2SO4 was used
with subsequent filtration in all cases. IR spectra were
recorded as CHCl3 solutions. NMR spectra were measured
in CDCl3 and are reported in units of ppm. J values are in
hertz. Carbon resonances are reported as q (CH3), t (CH2), d
(CH), or s (C) as determined by APT (attached proton test) or
DEPT experiments. Mass spectra were determined using the
electron-impact method unless otherwise indicated, with data
reported as m/z (relative intensity).
6-Eth oxy-1-p-tolu en esu lfon yl-2-((tr iflu or om eth an esu lfo-
n yl)oxy)-1,4,5,6-tetr a h yd r op yr id in e (8). To a stirred solu-
tion of N-tosyl-6-ethoxy-2-piperidinone3 (1.200 g, 4.04 mmol)
in THF (24 mL) at -78 °C was added KHMDS (10.1 mL of a
0.5 M solution in toluene, 5.05 mmol, 1.25 equiv), and the pale
yellow solution was stirred for 45 min. A solution of N-(5-
chloro-2-pyridyl)triflimide (1.983 g, 5.05 mmol, 1.25 equiv) in
(15) Hoshi, M.; Masuda, Y.; Arase, A. Bull. Chem. Soc. J pn. 1992,
65, 685.
(16) For similar results with N-acyliminium ions, see: (a) Ludwig,
C.; Wistrand, L.-G. Acta Chem. Scand. 1994, 48, 367 and references
therein. (b) Shono, T.; Matsumura, Y.; Onomura, O.; Sato, M. J . Org.
Chem. 1988, 53, 4118.
(17) Deslongchamps, P. Stereoelectronic Effects in Organic Chem-
istry; Pergamon: New York, 1983; Chapter 6.

Total Synthesis of Desoxoprosophylline
J . Org. Chem., Vol. 62, No. 11, 1997 3595
1
1683 cm-1; H NMR (400 MHz) δ 7.67 (2 H, d, J ) 8.0), 7.29
(250 MHz) δ 5.61 (1 H, dt, J ) 16.9, 9.4), 4.87 (1 H, d, J )
10.1), 4.81 (1 H, d, J ) 17.1), 1.57-1.27 (17 H, m), 0.89 (3 H,
t, J ) 5.8), -0.02 (9 H, s); 13C NMR (100 MHz) δ 140.5 (d),
111.6 (t), 34.9 (d), 31.9 (t), 29.7 (t), 29.6 (t), 29.5 (t), 29.4 (t),
29.3 (t), 28.4 (t), 22.7 (t), 14.1 (q), -3.3 (3q).
(2 H, d, J ) 8.2), 5.38 (1 H, d, J ) 3.7), 5.26 (1 H, t, J ) 2.4),
4.72 (1 H, d, J ) 6.7), 4.67 (1 H, d, J ) 6.7), 4.59 (1 H, d, J )
13.1), 4.31 (1 H, d, J ) 13.1), 3.75 (1 H, dq, J ) 9.6, 7.0), 3.69
(1 H, q, J ) 8.9), 3.62 (1 H, q, J ) 8.8), 3.51 (1 H, dq, J ) 9.6,
6.9), 2.42 (3 H, s), 2.16 (1 H, dt, J ) 18.1, 9.6), 1.71 (2 H, m),
1.14 (3 H, t, J ) 7.0), 1.05 (1 H, m), 0.956 (2 H, t, J ) 8.6),
0.03 (9 H, s); 13C NMR (100 MHz) δ 143.8 (s), 136.3 (s), 130.7
(s), 129.8 (2d), 127.4 (2d), 118.7 (d), 93.3 (t), 83.6 (d), 68.5 (t),
65.4 (t), 63.1 (t), 25.5 (t), 21.7 (q), 18.5 (t), 18.3 (t), 14.9 (q),
-1.2 (3q); MS 368 (M - TMS)+ (11), 296 (M - OCH2O-
(CH2)2TMS)+ (16). Anal. Calcd for C21H35NO5SSi: C, 57.12;
H, 7.99; N, 3.17. Found: C, 56.70; H, 8.09; N, 3.04.
(2S*,3R*,6S*)-3-((ter t-Bu tyld im eth ylsilyl)oxy)-6-(2(E)-
d od ecen yl)-1-p -t olu en esu lfon yl-2-(((â-(t r im et h ylsilyl)-
eth oxy)m eth oxy)m eth yl)p ip er id in e (16). To a solution of
R-ethoxy sulfonamide 13 (0.120 g, 0.209 mmol) and allylsilane
15 (0.251 g, 1.047 mmol, 5 equiv) in dichloromethane (3 mL)
at -78 °C was added boron trifluoride etherate (77 µL, 0.63
mmol, 3 equiv) dropwise, and the solution was stirred at this
temperature for 30 min before being warmed to -30 °C
(freezer) over 2.5 h. Saturated sodium bicarbonate solution
(3 mL) was added, and the reaction mixture was warmed to
rt. The organic layer was separated and the aqueous layer
extracted with dichloromethane (2 × 5 mL). The combined
organics were dried, and the solvent was removed in vacuo.
Column chromatography (0:1 f 1:10 ethyl acetate/light pe-
troleum ether, on SiO2) afforded alkene 16 as a colorless oil
(0.080 g, 55%): IR 2955, 2928, 1602 cm-1; 1H NMR (400 MHz)
δ 7.85 (2 H, d, J ) 8.3), 7.23 (2 H, d, J ) 8.1), 5.42 (1 H, dt, J
) 15.4, 6.5), 5.26 (1 H, dt, J ) 15.3, 8.1), 4.71 (1 H, d, J )
6.6), 4.68 (1 H, d, J ) 6.6), 4.09 (1 H, dd, J ) 10.0, 4.5), 4.05
(1 H, t, J ) 1.2), 3.63 (4 H, m), 3.55 (1 H, m), 2.40 (3 H, s),
2.40-2.24 (2 H, m), 1.98 (2 H, m), 1.76 (2 H, m), 1.27 (16 H,
m), 0.97 (2 H, m), 0.88 (3 H, t, J ) 6.2), 0.86 (9 H, s), 0.05 (9
H, s), 0.03 (3 H, s), 0.02 (3 H, s); 13C NMR (100 MHz) δ 142.5
(s), 138.4 (s), 133.8 (d), 129.3 (2d), 127.4 (2d), 126.5 (d), 94.8
(t), 69.5 (t), 65.4 (t), 65.2 (d), 59.2 (d), 52.3 (d), 38.5 (t), 32.5
(t), 31.9 (t), 29.6 (t), 29.5 (t), 29.4 (t), 29.3 (t), 29.1 (t), 25.9
(3q), 22.7 (t), 22.0 (t), 21.5 (q), 18.4 (t), 18.2 (s), 18.1 (t), 14.1
(q), -1.4 (3q), -4.8 (q), -5.0 (q); MS 638 (M - t-Bu)+ (12);
HRMS calcd for C33H69NO5SSi2 638.3731, found 638.3766.
N-p-Tolu en esu lfon yld esoxop r osop h yllin e. Alkene 16
(0.080 g, 0.115 mmol) and 10% Pd/C (0.020 g) in MeOH (5 mL)
were stirred under a balloon of hydrogen for 15 h. The solution
was filtered through Celite and solvent removed in vacuo to
yield a pale yellow oil (0.080 g). This was analyzed by 1H NMR
to confirm complete alkene reduction (disappearance of reso-
nances at δ 5.42 and 5.26 ppm) and then dissolved in HCl (0.4
M in MeOH, 5 mL) and stirred at 40 °C for 15 h. Saturated
sodium bicarbonate solution (4 mL) and dichloromethane (5
mL) were then added. The organic phase was separated, and
the aqueous phase was extracted with dichloromethane (2 ×
8 mL). The combined organics were dried, and the solvent
was removed in vacuo. Column chromatography (1:6 f 3:1
ethyl acetate/light petroleum ether, on SiO2) afforded the title
(2S*,3R*)-6-E t h oxy-3-h yd r oxy-1-p -t olu en esu lfon yl-2-
(((â-(tr im eth ylsilyl)eth oxy)m eth oxy)m eth yl)p ip er id in e
(12). To a solution of SEM ether 11 (0.150 g, 0.340 mmol) in
THF (16 mL) at -78 °C was added a borane-THF complex
(1.1 mL of a 1 M solution in THF, 1.1 mmol, 3.4 equiv)
dropwise. After 5 min of stirring, the flask was sealed and
placed in a refrigerator at 0 °C for 16 h. Trimethylamine
N-oxide (0.450 g, 4.049 mmol) was added to the vigorously
stirred hydroboration mixture at 0 °C, a reflux condenser was
quickly attached, and the reaction mixture was transferred
to a preheated oil bath at 65 °C (maintain vigorous stirring
while heating). After 2 h the reaction mixture was cooled to
rt and ethyl acetate (30 mL) added. The organic solution was
washed with brine (2 × 15 mL) and dried and the solvent
removed in vacuo. Column chromatography (1:3 f 1:2 ethyl
acetate/light petroleum ether, on SiO2) afforded alcohol 12 as
a colorless oil (0.108 g, 83%): 16:1 mixture of inseparable
diastereomers by 1H NMR (integration of proton resonances
at 5.27 and 5.18 ppm, respectively); IR 3588, 2954 cm-1; H
1
NMR (400 MHz) δ (major only) 7.75 (2 H, d, J ) 8.3), 7.29 (2
H, d, J ) 8.0), 5.27 (1 H, t, J ) 3.1), 4.63 (1 H, d, J ) 6.7), 4.60
(1 H, d, J ) 6.7), 3.98 (1 H, br s), 3.80 (2 H, m), 3.69 (1 H, dq,
J ) 9.7, 7.2), 3.63-3.56 (3 H, m), 3.49 (1 H, dq, J ) 9.7, 7.1),
2.41 (3 H, s), 2.02 (1 H, tt, J ) 13.8, 2.9), 1.84 (1 H, tt, J )
13.6, 4.0), 1.67 (1 H, m), 1.49 (1 H, m), 1.24 (1 H, br s), 1.18 (3
H, t, J ) 7.0), 0.94 (1 H, q, J ) 7.2), 0.92 (1 H, q, J ) 7.2), 0.03
(9 H, s); 13C NMR (100 MHz) δ 143.6 (s), 137.7 (s), 129.8 (2d),
127.4 (2d), 95.2 (t), 81.8 (d), 68.6 (t), 65.5 (t), 64.2 (d), 63.0 (t),
58.7 (d), 24.3 (t), 21.8 (q), 20.7 (t), 18.3 (t), 15.0 (q), -1.2 (3q);
MS (FAB) 482 MNa+ (40); HRMS calcd for C21H37NO6SSiNa
482.2008, found 482.2054.
(2S*,3R*)-3-((ter t-Bu tyld im eth ylsilyl)oxy)-6-eth oxy-1-
p-tolu en esu lfon yl-2-(((â-(tr im eth ylsilyl)eth oxy)m eth oxy)-
m eth yl)p ip er id in e (13). To a solution of alcohol 12 (0.108
g, 0.235 mmol) in dichloromethane (2 mL) at 0 °C were added
2,6-lutidine (164 µL, 1.41 mmol, 6 equiv) and TBDMSOTf (108
µL, 0.471 mmol, 2 equiv), and the solution was warmed to rt
over 12 h. Saturated aqueous sodium bicarbonate (1 mL),
water (5 mL), and dichloromethane (5 mL) were then added.
The organic phase was separated, and the aqueous phase was
extracted with dichloromethane (2 × 5 mL). The combined
organics were dried, and the solvent was removed in vacuo.
Column chromatography (1:10 f 1:8 ethyl acetate/light pe-
troleum ether, on SiO2) afforded TBDMS ether 13 as a colorless
oil (0.124 g, 92%) (contaminated with small amounts of an
uncharacterized enamide byproduct): IR 2955, 2930 cm-1; 1H
NMR (400 MHz) δ 7.73 (2 H, d, J ) 8.0), 7.72 (2 H, d, J )
8.0), 5.15 (1 H, t, J ) 2.6), 4.66 (1 H, d, J ) 6.6), 4.63 (1 H, d,
J ) 6.6), 4.03 (1 H, s), 3.73 (4 H, m), 3.60 (1 H, t, J ) 8.6),
3.60 (1 H, t, J ) 8.1), 3.48 (1 H, dq, J ) 9.6, 7.0), 2.38 (3 H, s),
2.05 (1 H, tt, J ) 13.8, 3.0), 1.90 (1 H, tt, J ) 13.2, 3.2), 1.61
(1 H, m), 1.39 (1 H, m), 1.16 (3 H, t, J ) 6.8), 0.95 (2 H, m),
0.72 (9 H, s), 0.03 (9 H, s), -0.09 (3 H, s), -0.13 (3 H, s); 13C
NMR (100 MHz) δ 143.0 (s), 138.4 (s), 129.6 (2d), 127.5 (2d),
94.9 (t), 81.9 (d), 68.6 (t), 65.4 (t), 64.8 (d), 62.9 (t), 59.2 (d),
26.1 (3q), 24.4 (t), 21.6 (q), 21.5 (t), 18.4 (s), 18.3 (t), 15.1 (q),
-1.2 (3q), -4.8 (q), -4.9 (q).
1
diol as a colorless oil (0.039 g, 75%): IR 3503, 2927 cm-1; H
NMR (400 MHz) δ 7.81 (2 H, d, J ) 8.3), 7.27 (2 H, d, J )
8.2), 4.00 (1 H, t, J ) 8.8), 3.93 (1 H, br s), 3.81 (1 H, br s),
3.70 (1 H, dd, J ) 11.0, 7.1), 3.64 (1 H, dd, J ) 10.9, 8.3), 2.73
(1 H, br s), 2.40 (3 H, s), 2.00 (1 H, br s), 1.75 (2 H, m), 1.60 (1
H, m), 1.44 (2 H, m), 1.25 (21 H, m), 0.877 (3 H, t, J ) 6.6);
13C NMR (100 MHz) δ 143.2 (s), 137.7 (s), 129.6 (2d), 127.3
(2d), 64.3 (d), 64.2 (t), 61.4 (d), 52.5 (d), 35.5 (t), 31.9 (t), 29.7
(t), 29.6 (3t), 29.5 (t), 29.4 (t), 29.3 (t), 27.2 (t), 22.7 (t), 22.0
(t), 21.5 (q), 20.2 (t), 14.1 (q); MS 422 (M - CH2OH)+ (10);
HRMS calcd for C24H40NO3S 422.2729, found 422.2694.
Desoxop r osop h yllin e (1). Small pieces of sodium metal
were periodically added to a solution of N-p-toluenesulfo-
nyldesoxoprosophylline (0.027 g, 0.060 mmol) in THF (0.5 mL)
and liquid ammonia (10 mL) at -78 °C, such that a blue color
persisted for 5 h. Solid ammonium chloride was then added
to discharge the blue color, and the solution was warmed to
room temperature while the ammonia was evaporated under
a stream of nitrogen. The residue was taken up in HCl (2 M,
5 mL) and extracted with dichloromethane (3 × 8 mL). The
acidic aqueous phase was neutralized by the addition of
saturated aqueous sodium bicarbonate (ca. 8 mL, pH ca. 10),
and the now basic aqueous phase was extracted with dichlo-
romethane (4 × 10 mL). These latter organics were combined
and dried, and the solvent was removed in vacuo to afford pale
yellow crystals. NMR analysis showed them to be virtually
pure desoxoprosophylline. A single recrystallization afforded
the natural product in pure form (0.013 g, 75%): mp 83-83.5
3-(Tr im eth ylsilyl)-1-d od ecen e (15). The title compound
was prepared from nonene and 3-chloro-1-(trimethylsilyl)-1-
propyne by an identical route to that reported by Arase for
the preparation of the 3-(trimethylsilyl)-1-heptene homo-
logue.15 The reaction afforded silane 15 as a colorless oil (56%)
after column chromatography (pentane, on SiO2): 1H NMR

3596 J . Org. Chem., Vol. 62, No. 11, 1997
Luker et al.
°C from ethyl acetate [lit mp 83 °C,5a 83-83.5 °C6b]; 1H NMR
(400 MHz) δ 3.84 (1 H, dd, J ) 10.7, 5.0), 3.70 (1 H, dd, J )
10.8, 5.4), 3.46 (1 H, ddd, J ) 10.9, 9.1, 4.6), 2.57 (1 H, dt, J
) 9.0, 5.2), 2.52 (1 H, m), 2.04 (1 H, dq, J ) 12.3, 4.1), 2.03 (3
H, v br s), 1.74 (1 H, dq, J ) 13.2, 3.1), 1.44-1.25 (23 H, m),
1.12 (1 H, tdd, J ) 13.4, 11.1, 3.7), 0.88 (3 H, t, J ) 6.6); 13C
NMR (100 MHz) δ 70.92 (d), 64.96 (t), 63.18 (d), 55.93 (d), 36.64
(t), 34.01 (t), 31.91 (t), 31.23 (t), 29.79 (t), 29.66 (t), 29.65 (t),
29.64 (t), 29.59 (t), 29.57 (t), 29.34 (t), 26.19 (t), 22.68 (t), 14.11
(q).
fellowship) are acknowledged for generous financial
support.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
compounds 8, 10, 11, 12, 13, 16, and N-p-toluenesulfonyldes-
1
oxoprosophylline and H and 13C NMR spectra of desoxoproso-
phylline (9 pages). This material is contained in libraries on
microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
Ack n ow led gm en t. The European Union (TMR fel-
lowship) and the Royal Society (Science Exchange
J O962347J