Rhodium-catalyzed cyclohydrocarbonylation: Application to the synthesis of (+)-prosopinine and (-)-deoxoprosophylline

Article abstract of DOI:10.1021/jo9815608

Efficient convergent total syntheses of (+)-prosopinine (1) and (-)- deoxoprosophylline (4) were accomplished using Rh-BIPHEPHOS complex-catalyzed cyclohydrocarbonylation as the key step. The Rh-BIPHEPHOS complex-catalyzed cyclohydrocarbonylation of I, derived from (R)-serine, at 65 °C and 4 atm of CO and H₂ (1:1) in ethanol afforded 6-ethoxypiperidine II, which was transformed to enantiopure (+)-prosopinine (1) in 3 steps. In a similar manner, (-)-deoxoprosophylline was synthesized through cyclohydrocarbonylation of IV derived from (S)-serine, giving 6- ethoxypiperidine V. The key intermediate V was transformed to enantiopure (- )-deoxoprosophylline (4) in 4 steps. These two short total syntheses clearly demonstrate the usefulness of the extremely regioselective cyclohydrocarbonylation process developed in these laboratories for the concise syntheses of piperidine alkaloids and related compounds.

Full text of DOI:10.1021/jo9815608

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J . Org. Chem. 1998, 63, 7999-8003
7999
Rh od iu m -Ca ta lyzed Cycloh yd r oca r bon yla tion : Ap p lica tion to th e
Syn th esis of (+)-P r osop in in e a n d (-)-Deoxop r osop h yllin e†
Iwao Ojima* and Ephraim S. Vidal
Department of Chemistry, State University of New York at Stony Brook,
Stony Brook, New York 11794-3400
Received August 3, 1998
Efficient convergent total syntheses of (+)-prosopinine (1) and (-)-deoxoprosophylline (4) were
accomplished using Rh-BIPHEPHOS complex-catalyzed cyclohydrocarbonylation as the key step.
The Rh-BIPHEPHOS complex-catalyzed cyclohydrocarbonylation of I, derived from (R)-serine, at
65 °C and 4 atm of CO and H2 (1:1) in ethanol afforded 6-ethoxypiperidine II, which was transformed
to enantiopure (+)-prosopinine (1) in 3 steps. In a similar manner, (-)-deoxoprosophylline was
synthesized through cyclohydrocarbonylation of IV derived from (S)-serine, giving 6-ethoxypiperidine
V. The key intermediate V was transformed to enantiopure (-)-deoxoprosophylline (4) in 4 steps.
These two short total syntheses clearly demonstrate the usefulness of the extremely regioselective
cyclohydrocarbonylation process developed in these laboratories for the concise syntheses of
piperidine alkaloids and related compounds.
Multifunctionalized piperidine alkaloids are found
abundantly in nature, and many of them exhibit biologi-
cal activity of medicinal interest.1 Among these various
naturally occurring compounds are (+)-prosopinine (1)
and (-)-prosophylline (2), which are isolated from the
leaves of Prosopis africana Taub (Figure 1).2 These
alkaloids possess antibiotic and anesthetic properties and
have attracted considerable interest as synthetic targets.3
The reduction analogues of prosopinine and prosophyl-
line, i.e., (+)-deoxoprosopinine (3)4 and (-)-deoxoproso-
phylline (4),5 also exhibit similar biological properties,
and thus, a variety of syntheses have been reported. We
describe here new and efficient syntheses of enantiopure
F igu r e 1.
1 and 4, bearing 2,3-trans-3,6-cis and 2,3-trans-3,6-trans
configurations, respectively, featuring the Rh-catalyzed
cyclohydrocarbonylation of functionalized homoallylic
amine intermediates, which was recently developed in
these laboratories.6
Our syntheses of these two alkaloids consists of an
efficient synthesis of enantiopure piperidine intermedi-
ates using our cyclohydrocarbonylation protocol and the
subsequent diastereoselective introduction of long alkyl
chains at the C-6 position of the piperidine.
The convergent total synthesis of 1 started with the
preparation of Garner’s aldehydes7 (6) from (R)-serine (5)
(Scheme 1). The aldehyde 6 contains the R configuration
that is required for the C-2 position of the key intermedi-
ate piperidine 11. Stereoselective addition of vinylmag-
nesium bromide to 6 afforded a 6:1 mixture of (S)-allylic
alcohol 7 and (R)-allylic alcohol 8, which were separated
by column chromatography to give the desired 7 in 77%
isolated yield.8 Alternatively, a mixture of 7 and 8 was
† This paper is dedicated to the late Dr. Maria Tzamarioudaki, a
pioneer of cyclohydrocarbonylation processes, who lost her life in the
Swissair flight 111 crash.
(1) (a) J ones, T. H.; Blum, M. S.; Robertson, H. G. J . Nat. Prod. 1990,
53, 429. (b) Numata, A.; Ibuka, T. In The Alkaloids; Brossi, A., Ed.;
Academic Press: New York, 1987; Vol. 31, Chapter 6, pp 193-315 and
references cited therein. (c) Fleet, G. W. J .; Fellow, L. E.; Winchester,
B. In Bioactive Compounds from Plants, Wiley: Chichester, U.K., 1990;
Ciba Foundation symposium Vol. 154.
(2) Cook, G. R.; Beholz, L. G.; Stille, J . R. Tetrahedron Lett. 1994,
35, 1669-1672 and reference cited therein.
(3) Previous synthesis of 1: (a) Reference 2. (b) Hirai, Y.; Watanabe,
J .; Nozaki, T.; Yokoyama, H.; Yamaguchi, S. J . Org. Chem. 1997, 62,
776. Previous synthesis of 2: Natsume, M. Ogawa, M. Heterocycles
1981, 16, 973.
(4) Previous synthesis of 3: (a) Saitoh, Y.; Moriyama, Y.; Takahashi,
T.; Khuong-Huu, Q. Tetrahedron Lett. 1980, 21, 75. (b) Saitoh, Y.;
Moriyama, Y.; Horita, H.; Takahashi, T.; Khuong-Huu, Q. Bull. Chem.
Soc. J pn. 1981, 54, 488. (c) Holmes, A. B.; Thompson, J .; Baxter, A. J .
G.; Dixon, J . J . Chem. Soc., Chem. Commun. 1985, 37. (d) Ciufolini,
M. A.; Hermann, C. W.; Whitmire, K. H.; Byrne, N. E. J . Am Chem.
Soc. 1989, 111, 3473. (e) Terakado, M.; Murai, K.; Miyazawa, M.;
Yamamoto, K. Tetrahedron 1994, 50, 5705. (f) Yuasa, Y.; Ando, J .;
Shibuya, S. Tetrahedron: Asymmetry 1995, 6, 1525. (g) Yuasa, Y.;
Ando, J .; Shibuya, S. J . Chem. Soc., Perkin Trans 1 1996, 793. (h)
Kadota, I.; Kawada, M.; Muramatsu, Y.; Yamamoto, Y. Tetrahedron
Lett. 1997, 38, 7469.
(6) Ojima, I.; Tzamarioudaki, M.; Eguchi, M. J . Org. Chem. 1995,
60, 7078.
(7) (a) Garner, P.; Park, J . M. J . Org. Chem 1987, 52, 2361. (b)
Garner, P.; Park, J . M. Org. Synth. 1991, 70, 18. Alternate preparation
of Garner’s aldehyde: (c) Avenoza, A.; Cativiela, C.; Corzana, F.;
Peregrina, J . M.; Zurbano, M. M. Synthesis 1997, 1146 and references
therein. (d) Roush, W. R.; Hunt, J . A. J . Org. Chem. 1995, 60, 798. (e)
Guibourdenche, C.; Roumestant, M. L.; Viallefont, Ph. Tetrahedron:
Asymmetry 1993, 4, 2041.
(8) The stereochemistry of 7 was unambiguously assigned on the
basis of 1H NMR analysis by converting 7 to 19 (2,3-trans (ax-ax), J
) 7.2 Hz). Compound 8 was also converted to the corresponding
(2R,3R)-1-Boc-2-TBSO-methyl-3-TBSO-piperidine in the same manner,
which showed 2,3-cis (ax-eq) relations (J ) 1.3 Hz).
(5) Previous synthesis of 4: (a) Takao, K.; Nigawara, Y.; Nishino,
E.; Tagaki, I.; Maeda, K.; Tadano, K.; Ogawa, O. Tetrahedron 1994,
50, 5681. (b) Reference 4b. (c) Reference 4c. (d) Luker, T.; Hiemstra,
H.; Speckamp, W. N. J . Org. Chem. 1997, 62, 3592.
10.1021/jo9815608 CCC: $15.00 © 1998 American Chemical Society
Published on Web 10/09/1998

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8000 J . Org. Chem., Vol. 63, No. 22, 1998
Sch em e 1
Ojima and Vidal
Sch em e 3
Sch em e 4
Sch em e 2
Sch em e 5
carried over to the next two steps and the diastereomers
of 10 were separated by column chromatography. Re-
moval of the acetonide group afforded N-Boc-diol 9 which
was protected as bis(tert-butyldimethylsilyl) ether to give
10. Rh-BIPHEPHOS9 complex-catalyzed cyclohydro-
carbonylation of 10 at 65 °C and 4 atm of CO and H2
(1:1) in ethanol afforded 5,6-trans-2-ethoxypiperidine 11
in 92% yield, which is the key intermediate in this total
synthesis.
The introduction of a 10-oxo-n-dodecanyl chain at C-6
of 11 was carried out through the chelation-controlled
addition of alkylcopper(I) 16 to the acyliminium ion
generated in situ by the reaction of 11 with BF3, which
gave the desired 2,6-trans product 17 (Scheme 2). 1-Bro-
mo-10-oxo-decane ketal 14, the key precusor of the
alkylcopper 16, was prepared in 5 steps from decane-1,-
10-diol (12) via 10-bromodecan-1-al (13).2
Lithiation of 14 followed by transmetalation to copper
and the subsequent addition of BF3 etherate generated
the alkylcopper‚BF3 complex 16 in situ.10 The addition
of 2-ethoxypiperidine 11 to the ether solution of 16 gave
the fully protected (+)-prosopinine 17 in 42% for 4 steps
(Scheme 2). Deprotection of TBS ethers using n-Bu4NF
as well as removal of the ketal and Boc groups by treating
with TFA in dichloromethane afforded (+)-prosopinine
(1) in 48% yield.
An alternative route to 17 was also examined (Scheme
3), which included the cyclohydrocarbonylation of 10
using THF as the solvent,5 giving 5,6-didehydropiperidine
18 in 96% yield, followed by hydrogenation on Rh/C,
yielding piperidine 19 quantitatively. The C-6 side chain
was introduced to 19 through stereoselective alkylation
using alkyl bromide 14 using Beak’s directed-lithiation
protocol11 to afford 17 in 36% yield.
The convergent total synthesis of 4 (Schemes 4 and 5)
also features a highly efficient synthesis of 6-ethoxypi-
peridine 23 through cyclohydrocarbonylation of N-Boc-
homoallylic amine 22 that was prepared from (S)-serine
(20) in a manner similar to the synthesis of 10 mentioned
above. The introduction of the C-6 side chain requires
2,6-cis stereochemistry in this case. Thus, Speckamp’s
protocol,4d i.e., a Lewis acid-promoted allylsilane addi-
(9) Billig, E.; Abatjoglou, A. G.; Bryant, D. R. (Union Carbide Corp.)
U.S. Patent (CIP) 4769498, 1988.
(10) Ludwig, C.; Wistrand, L.-G. Acta Chem. Scand. 1994, 48, 367.
(11) (a)Wu, S.; Lee, S.; Beak, P. J . Am. Chem. Soc. 1996, 118, 715.
(b) Beak, P.; Lee, W. K. J . Org. Chem. 1993, 58, 1109.

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Rhodium-Catalyzed Cyclohydrocarbonylation
J . Org. Chem., Vol. 63, No. 22, 1998 8001
over anhydrous MgSO4. The solvent was removed on a rotary
evaporator and the residue chromatographed on a silica gel
column using ethyl acetate as the eluant to yield 9 as a clear
colorless oil (0.845 g, 3.89 mmol, 95%): TLC, one spot (AcOEt);
1H NMR (300 MHz, CDCl3) δ 1.44 (s, 9 H), 3.62-4.44 (m, 4
H), 5.19-5.41 (m, 2 H), 5.84-5.98 (m, 1 H); 13C NMR (75.45
MHz, CDCl3) δ 28.26, 62.39, 64.18, 74.80, 116.57, 137.53; IR
tion to an acyliminium ion intermediate generated in situ
from 23 and BF3, was employed. The reaction of 23 with
allylsilane 2412 in the presence of BF3‚Et2O in dichlo-
romethane at -78 °C gave 25, the TIPS protection of
which was removed by adding n-Bu4NF in THF at room
temperature to afford dehydrodeoxoprosophylline 26 in
38% for two steps. Hydrogenation of the olefin moiety
using Pd/C and deprotection of the Boc group with TFA
gave 4 in 77% yield.
(neat) 3306, 1690, 1594 cm-1
. HRMS: calcd for C10H19NO4
(MH+), m/e 218.1395; found (CI), m/e 218.1392 (∆ ) 1.1 ppm).
P r ep a r a tion of (3S,4R)-4-(ter t-Bu toxyca r bon yla m in o)-
3,5-bis(ter t-bu tyld im eth ylsiloxy)p en t-1-en e (10). To a
solution of 9 (1.15 g, 3.5 mmol) and imidazole (0.95 g, 14 mmol)
in THF (20 mL) was added chloro(tert-butyl)dimethylsilane
(1.31 g, 8.75 mmol) in 5 mL of THF at 0 °C with stirring. The
mixture was stirred for 2 h while warming to room tempera-
ture. The progress of the reaction was periodically checked
by TLC. The reaction was quenched with saturated NH4Cl
solution (20 mL). The resulting two layers were separated and
the aqueous layer extracted with ether (20 mL × 4). The
organic layers were combined, washed with brine, and dried
over anhydrous Na2SO4. The solvent was removed on a rotary
evaporator and the residue chromatographed on a silica gel
column using hexane/EtOAc (4/1) as the eluant to yield 10 as
a colorless oil (1.27 g, 2.9 mol, 83%): TLC, one spot (hexane/
AcOEt ) 4/1); 1H NMR (250 MHz, CDCl3) δ 0.05 (s, 12 H),
0.88-0.89 (m, 18 H), 1.42 (s, 9 H), 3.51-3.60 (m, 2 H), 4.27-
4.43 (m, 1 H), 4.51-4.76 (m, 1 H), 5.08-5.27 (m, 2 H), 5.77-
5.90 (m, 1 H); 13C NMR (62.7 MHz, CDCl3) δ -5.3, -5.0, 18.1,
25.8, 28.4, 56.4, 61.3, 73.0, 79.1, 115.4, 138.3, 156.0; IR (neat)
3451,1701, 1684 cm-1. HRMS: calcd for C22H47NO4Si2 (MH+),
m/e 46.3121; found (CI), m/e 446.3117 (∆ ) 1.1 ppm). Anal.
Calcd for C22H47NO4Si2: C, 59.29, H, 10.64. Found: C, 59.50;
H, 10.37.
In summary, we have demonstrated the usefulness of
our Rh-catalyzed cyclohydrocarbonylation process in the
concise syntheses of piperidine alkaloids. Further studies
on the applications of this protocol are actively underway.
Exp er im en ta l Section
Gen er a l Meth od s a n d Ma ter ia ls. The 1H NMR, 13C
NMR, COSY, NOSY, and HETCOR NMR spectra were re-
1
corded at 250 MHz for H and 62.5 MHz for 13C or at 300 MHz
1H and 75 MHz for 13C using CDCl3 as the internal standard.
The IR spectra were measured with an FT-IR spectrophotom-
eter using samples as neat oils or as KBr disks. High-
resolution mass spectra were obtained at the Mass Spectrom-
etry Facility, University of California at Riverside. Analytical
gas chromatography was performed with a gas chromatograph
equipped with FID detectors using a 30 m DB-17 or a 15 m
DB-1 capillary column. Elemental Analyses were performed
at the M-H-W Laboratories, Phoenix, AZ. All solvents were
reagent grade and distilled before used. Rhodium complex,
Rh(acac)(CO)2, was obtained from the Mitsubishi Chemical
Corp. and used as received. Silica gel used for chromatogra-
phy, MN-Kieselgel 60, was purchased from Brinkman Instru-
ments Inc.
P r ep a r a tion of (2R,3S)-2-((ter t-bu tyld im eth ylsiloxy)-
m e t h yl)-3-(t er t -b u t yld im e t h ylsiloxy)-6-e t h oxyp ip e r i-
d in e (11). A solution of 10 (142 mg, 0.32 mmol) in ethanol (1
mL) was transferred via syringe to a 10 mL round-bottomed
flask with a magnetic stirring bar, containing a solution of Rh-
(acac)(CO)2 (0.82 mg, 0.0032 mmol) and BIPHEPHOS (4.92
mg, 0.0064 mmol) in ethanol (1 mL) under nitrogen. The
reaction flask was placed in a 300 mL stainless steel autoclave
and pressurized with 2 atm of carbon monoxide and 2 atm of
hydrogen. The autoclave was heated to 65 °C with stirring in
an oil bath for 14 h. Then, the autoclave was cooled to room
temperature and carefully depressurized. The solvent was
removed on a rotary evaporator and the residue chromato-
graphed on a silica gel column using hexane/EtOAc (8/1) as
the eluant to yield 11 as a colorless oil (148.1 mg, 0.294 mmol,
92%): TLC, one spot (hexane/AcOEt ) 8/1); 1H NMR (300
MHz, CDCl3) δ 0.02-0.11 (m, 12 H), 0.87-0.93 (m, 18 H),
1.12-1.21(m, 2H),1.26 (t, J ) 7.2 Hz, 3 H),1.50 (s, 9 H), 1.94-
2.26 (m, 2 H), 3.74 (q, J ) 7.2 Hz, 2 H), 3.35-3.62 (m, 2 H),
3.99-4.33 (m, 2 H), 5.34-5.50 (m, 1 H); 13C NMR (62.7 MHz,
CDCl3) δ -5.4, -4.9, 15.1, 18.0, 21.5, 23.8,24.0, 28.4, 59.5, 62.4,
63.1, 63.9, 78.9, 157.2; IR (neat) 1697 cm-1. HRMS: calcd for
P r ep a r a tion of 3-(ter t-Bu toxyca r bon yl)-2,2-d im eth yl-
4(R)-[(S)-1-h yd r oxyp r op -2-en yl)oxa zolid in e (7). To a so-
lution of Garner’s aldehyde (R)-67 (0.921 g, 4.3 mmol) in 20
mL of THF at -30 °C was added vinylmagnesium bromide
(0.94 M in THF, 9.1 mL, 8.6 mmol) dropwise over a period of
30 min. The solution was then gradually warmed over a period
of 1 h to 0 °C and then cooled again to -20 °C. A saturated
aqueous solution of NH4Cl (20 mL) was added and the mixture
gradually warmed to room temperature. The mixture was
extracted with ethyl acetate (3 × 20 mL), and the combined
organic layers were washed with brine and dried over anhy-
drous Na2SO4. The solvent was removed on a rotary evapora-
tor and the residue chromatographed on a silica gel column
using hexane/EtOAc (8:1) as the eluant to give a 6:1 mixture
of 7 and 8 as a clear colorless oil (1.057 g, 4.1 mmol, 95%).
Compounds 7 and 8 were separated further by column chro-
matography on silica gel using hexane/EtOAc (16:1) as the
eluant. Compound 7 thus obtained was in high purity, i.e.,
one spot on TLC and one peak in GC (15 m DB-1 capillary
column) analysis.
7: 1H NMR (300 MHz, CDCl3) δ 1.31-1.59 (m, 15 H), 3.87-
4.26 (m, 4 H), 5.18-5.38 (m, 2 H), 5.79-5.90 (m, 1 H); 13C NMR
(75.45 MHz, CDCl3) δ 18.41, 26.15, 28.22, 61.92, 64.74, 74.17,
74.50, 94.49, 117.90, 134.90, 155.24; IR (neat): 3347, 1694,
1504 cm-1. HRMS: calcd for C13H23NO4 (MH+), m/e 258.1705;
found (CI), m/e 258.1703 (∆ ) 0.9 ppm).
C
25H54NO5Si2 (MH+), m/e 504.3540; found (CI), 504.3536 (∆ )
0.9 ppm). Anal. Calcd for C25H53NO5Si2: C, 59.60; H, 10.61.
Found: C, 59.78; H, 10.42.
Syn t h esis of 2-et h yl-2-(9-b r om on on yl)-1,3-d ioxola n e
(14). P r ep a r a tion of 12-Br om od od eca n -3-ol. To a mag-
netically stirred solution of 9-bromodecanal13 (4.75 g, 19.7
mmol) in THF (20 mL) at -5 °C was added dropwise a 1.3 M
ethylmagnesium bromide solution in THF (30 mL, 39.4 mmol).
The solution was warmed to room temperature and stirred for
30 min. The reaction mixture was then cooled to 0 °C, and
saturated NH4Cl solution (20 mL) was added dropwise. The
resulting two layers were separated and the aqueous layer
extracted with 3 × 20 mL portions ether. The combined
organic extracts were dried over anhydrous Na2SO4 and the
solvent removed in vacuo. The residue was purified by column
chromatography on silica gel using hexane/EtOAc (4/1) as the
8: 1H NMR (300 MHz, CDCl3) δ 1.28-1.57 (m, 15 H), 3.85-
4.23 (m, 4 H), 5.15-5.36 (m, 2 H), 5.74-5.85 (m, 1 H); 13C NMR
(75.45 MHz, CDCl3) δ 18.62, 27.12, 28.01, 60.32, 63.67, 73.33,
74.63, 92.11, 116.31, 134.95, 158.23.
P r ep a r a tion of (3S,4R)-4-(ter t-Bu toxyca r bon yla m in o)-
3,5-d ih yd r oxyp en t-1-en e (9). To a solution of 7 (1.057 g,
4.1 mmol) in methanol (20 mL) was added p-toluenesulfonic
acid (25 mg). The solution was refluxed for 1 h and then cooled
to room temperature. Water (50 mL) was added to the reaction
mixture and extracted with ether (50 mL × 2). The combined
ethereal layers were combined, washed with brine, and dried
(12) Hoshi, M.; Masuda, Y.; Arase, A. Bull. Chem. Soc. J pn. 1992,
65, 685.
(13) Chuit, P.; Boelsing, F.; Hausser, J .; Malet, G. Helv. Chim. Acta
1926, 9, 1076.

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8002 J . Org. Chem., Vol. 63, No. 22, 1998
Ojima and Vidal
eluant to give 12-bromododecan-3-ol as a colorless oil (4.7 g,
17.8 mmol, 90% yield): TLC, one spot (hexane/AcOEt ) 4/1);
1H NMR (300 MHz, CDCl3) δ 0.935 (t, J ) 7.35, 3 H), 1.30-
1.56 (m, 14 H), 1.80-1.89 (m, 4 H), 3.40 (t, J ) 6.8 Hz, 2 H),
3.48-3.56 (m, 1 H); 13C NMR (75 MHz, CDCl3) δ 9.76, 25.52,
28.05, 21.63, 29.26, 29.38, 29.54, 30.05, 32.72, 33.94, 36.84,
73.3; IR (neat) 3376, 1055 cm-1. HRMS: calcd for C12H25BrO
(M+), m/e 264.1089; found, m/e 264.1431 (∆ ) +0.5 ppm).
P r ep a r a tion of 12-Br om od od eca n -3-on e. To a mixture
of pyridinium chlorochromate (9.58 g, 44.5 mmol), Celite (10
g), and dichloromethane (200 mL) in a 500 mL round-bottomed
flask fitted with a magnetic stirring bar and rubber septa was
added via syringe a solution 12-bromododecan-3-ol (4.76 g, 17.8
mmol) in 50 mL of dichloromethane at room temperature.
After the mixture was stirred for 3 h, the reaction mixture
was filtered through a 3 in. Celite pad and the residue washed
with dichloromethane. The filtrates was combined and the
solvent removed in vacuo. The residue was then purified by
column chromatography on silica gel using hexane/EtOAc (8/
1) as the eluent to give 12-bromododecan-3-one as a clear
colorless oil (2.67 g, 10.15 mmol, 57% yield): TLC, one spot
(hexane/AcOEt ) 8/1); 1H NMR (300 MHz, CDCl3) δ 1.04 (t, J
) 7.4 Hz, 3 H), 1.24-1.31 (m, 8 H), 1.39-1.43 (m, 2 H), 1.54-
1.61 (m, 2 H), 1.80-1.89 (m, 2 H), 2.3-2.45 (m, 4 H), 3.40 (t,
J ) 6.9 Hz, 2 H); 13C NMR (75 MHz, CDCl3) δ 7.7, 23.8, 28.6,
29.1, 29.13, 29.2, 32.7, 33.9, 35.8, 42.32, 212.1; IR (neat) 1714
cm-1 HRMS: calcd for C12H23BrO (M+), m/e 262.0932; found,
m/e 263.1024 (∆ ) -5.1 ppm).
0.03-0.08 (m, 12 H), 0.84-0.92 (m, 21 H), 1.21-1.37 (m, 16H),
1.43 (s, 9 H), 1.55-1.66 (m, 6 H), 1.78-2.03 (m, 2 H), 2.60-
2.81 (m, 1H), 3.56-3.68 (m, 2 H), 3.92 (s, 4 H), 4.06 (bs, 2 H);
13C NMR (62.89 MHz, CDCl3) δ -5.39, -4.99, 8.11, 14.10,
18.87, 22.67, 23.80, 25.76, 25.84, 27.24, 28.44, 29.32, 29.42,
29.54, 29.65, 29.78, 29.87, 29.96, 31.88, 36.69, 39.34, 59.13,
61.09, 64.52, 64.93, 112.114; IR (neat) 1693 cm-1
calcd for
37H75NO6Si2 (MH+), m/e 685.5132; found, m/e
685.5119 (∆ ) 2.0 ppm).
. HRMS:
C
P r ep a r a tion of (+)-P r osop in in e (1).3a,b To a solution of
17 (50.1 mg, 108 mmol) in THF (1 mL) was added n-Bu4NF
(1M in THF, 0.435 mL, 0.435 mmol) at room temperature. The
solution was allowed to stir overnight, and then an aqueous
NH4Cl solution (5 mL) was added. The mixture was extracted
with ether (10 mL × 3). The combined ethereal extracts were
washed with brine and dried over anhydrous MgSO4. The
solvent was removed on a rotary evaporator and the residue
dissolved in dichloromethane (1 mL). The solution was then
cooled to 0 °C and trifluoroacetic acid (1 mL) added. The
mixture was stirred for 30 min, and then the reaction was
quenched by adding saturated NaHCO3 solution until the pH
of the reaction mixture became pH 8. The reaction mixture
was extracted with dichloromethane, the extracts were dried
over anhydrous Na2SO4, and the solvent was removed under
reduced pressure. The residue was chromatographed on a
silica gel column using hexane/EtOAc (8/1) as the eluant to
afford 1 as a pale yellow oil (16.2 mg, 0.052 mmol, 48% yield):
1H NMR (300 MHz, CDCl3) δ 0.84 (t, J ) 7.1 Hz, 3H), 1.21-
1.37 (m, 13H), 1.54-1.66 (m, 5 H), 1.78-1.83 (m, 2 H), 2.06-
2.15 (m, 3H), 2.56-2.68 (m, 2 H), 2.92-3.33 (m, 4 H), 3.43-
3.59 (m, 3 H); 13C NMR (62.89 MHz, CDCl3) δ 8.14, 22.66,
23.79, 25.74, 27.26, 28.45, 29.38, 29.41, 29.55, 29.83, 29.92,
31.85, 41.66, 49.33, 59.16, 61.18, 64.83, 211.13
To a solution of 12-bromododecan-3-one (2.67 g, 8.72 mmol)
in toluene (150 mL) was added p-toluenesulfonic acid (0.2 g)
and 1,2-ethanediol (2.2 g, 38.88 mmol). The mixture was
heated under reflux using a Dean-Stark apparatus overnight.
The reaction mixture was then cooled to room temperature
and washed with a 10% solution of NaHCO3 (100 mL). The
organic layer was separated and dried over anhydrous Na2-
SO4, and the solvent was removed in vacuo. The residue was
purified by column chromatography on silica gel using hexane/
EtOAc (16/1) as the eluent to afford 14 as a clear colorless oil
(2.54 g, 8.28 mmol, 95% yield): TLC, one spot (hexane/AcOEt
) 16/1); GC, one peak (15 m DB-1 capillary column); 1H NMR
(300 MHz, CDCl3) δ 0.89 (t, J ) 7.5 Hz, 3 H), 1.21-1.43 (m,
12 H), 1.56-1.66 (m, 4 H), 1.82 (p, J ) 7.2 Hz, 2 H), 3.40 (t, J
) 6.9 Hz, 2H), 3.92 (s, 4 H); 13C NMR (75 MHz, CDCl3) δ 8.0,
23.7, 28.0, 28.6, 29.2, 29.4, 29.7, 29.8, 32.7, 33.9, 36.6, 64.9,
P r ep a r a tion of (2R,3S)-5,6-Did eh yd r o-2-((ter t-bu tyld i-
m eth ylsiloxy)m eth yl)-3-(ter t-bu tyld im eth ylsiloxy)p ip e-
r id in e (18). A solution of 10 (142 mg, 0.32 mmol) in THF (1
mL) under nitrogen was transferred via syringe to a 10 mL
round-bottomed flask with a magnetic stirring bar, containing
a solution of Rh(acac)(CO)2 (0.82 mg, 0.0032 mmol) and
BIPHEPHOS (4.92 mg, 0.0064 mmol) in THF (1 mL) under
nitrogen. The reaction flask was placed in a 300 mL stainless
steel autoclave and pressurized with 2 atm of carbon monoxide
and 2 atm of hydrogen. The autoclave was heated to 65 °C
with stirring in an oil bath for 14 h. Then, the autoclave was
cooled to room temperature and gases were carefully released.
The solvent was removed on a rotary evaporator and the
residue chromatographed on a silica gel column using hexane/
EtOAc (8/1) as the eluant to yield 18 as a colorless oil (140.4
mg, 0.307 mmol, 96% yield): TLC, one spot (hexane/AcOEt )
8/1); GC, one peak (15 m DB-1 capillary column); 1H NMR (300
MHz, CDCl3) δ 0.00-0.06 (m, 12 H) 0.84-0.88 (m, 18 H), 1.48
(s, 9 H), 1.89-2.28 (m, 2 H), 3.54-4.30 (m, 4 H), 4.60-4.80
(m, 1 H), 6.65-6.81 (m, 1 H); 13C NMR (62.7 MHz, CDCl3) δ
-5.4, -4.9, 18.0, 25.8, 28.3, 25.9, 56.9, 61.0, 66.0, 80.3, 101.6,
112.1; IR (neat) 1204 (νBr-C) cm-1. HRMS: calcd for C14H27
-
BrO2 (MH+), m/e 307.1273; found, m/e 307.1287 (∆ ) -4.7
ppm). Anal. Calcd for C14H27BrO2: C, 54.72; H, 8.86. Found:
C, 54.86; H, 8.47.
Syn t h esis of (2R,3S,6R)-1-(ter t-Bu t oxyca r b on yl)-2-
((ter t-bu tyld im eth ylsiloxy)m eth yl)-3-(ter t-bu tyld im eth -
ylsiloxy)-6-((2-eth yld ioxola n -2-yl)n on yl)p ip er id in e (17).
To a suspension of lithium powder (301 mg, 90.3 mg Li)
(Aldrich Chem Co., 30% suspension in mineral oil, the mineral
oil was removed by washing with hexane under N2) in ether
at -30 °C was added a solution of 14 (0.792 g, 2.58 mmol in
ether (10 mL). The mixture was stirred for 2 h, warmed to 0
°C, and stirred for additional 30 min. Then, the stirring was
stopped and unreacted lithium was allowed to settle at the
bottom. The solution was carefully transferred via cannula
under nitrogen atmosphere to a dry 100 mL round-bottomed
flask containing CuBr‚Me2S (1.06 g, 5.16 mmol) in ether (10
mL), and the mixture was cooled to -78 °C. To this mixture
was added dropwise BF3‚Et2O (366 mg, 0.32 mL, 2.58 mmol)
and the solution stirred for 30 min. Then, a solution of 11
(325 mg, 0.645 mmol) in ether (5 mL) was added, and the
mixture was stirred for 2 h at -78 °C followed by gradual
warming to 0 °C. The reaction was quenched by the addition
of 20 mL saturated aqueous solution of NH4Cl. The mixture
was warmed to room temperature and extracted with ether
(20 mL × 4). The ethereal layers were combined and dried
over anhydrous MgSO4. The solvent was removed on a rotary
evaporator and the residue chromatographed on a silica gel
column using hexane/EtOAc (8/1) as the eluant to afford 17
as a pale yellow oil (185.1 mg, 0.27 mmol, 42% yield): TLC,
one spot (hexane/AcOEt ) 8/1); 1H NMR (250 MHz, CDCl3) δ
124.5, 138.3, 156.5; IR (neat) 1691 cm-1
23H47NO4 (MH+), m/e 458.3121; found (CI), m/e 458.3122 (∆
) 1.7 ppm).
. HRMS: calcd for
C
P r ep a r a tion of (2R,3S)-2-((ter t-Bu tyld im eth ylsiloxy)-
m eth yl)-3-(ter t-bu tyld im eth ylsiloxy)p ip er id in e (19). To
5% Rh on carbon (145.1 mg) in a 50 mL reaction flask
connected to the standard ambient pressure hydrogenation
apparatus equipped with a gas bullet with hydrogen was added
a solution of 18 (705.2 mg, 1.54 mmol) in EtOAc/MeOH (1:1)
(10 mL). The mixture was stirred at room temperature for 4
h. The reaction mixture was filtered through a Celite pad and
the residue washed with ethyl acetate. The filtrates were
collected and the solvent removed on a rotary evaporator. The
residue was chromatographed on a silica gel column using
hexane/EtOAc (8/1) as the eluant to afford 19 as a clear
colorless oil (0.631 g, 1.37 mmol, 89%): TLC, one spot (hexane/
AcOEt ) 8/1)); GC, one peak (15 m DB-1 capillary column);
1H NMR (300 MHz, CDCl3) δ 0.03-0.07 (m, 12 H), 0.87-0.88
(m, 18 H), 1.42-1.45 (m, 9 H), 1.61-1.65 (m, 2 H), 2.61-2.97
(m, 2 H), 3.52-4.15 (m, 6 H); 13C NMR (75.45 MHz, CDCl3) δ
-5.09, -5.49, 24.18, 25.69, 25.76 25.87, 28.37, 29.59, 57.83,