Efficient synthesis of the γ-amino-β-hydroxy acid subunit of hapalosin

Full text of DOI:10.1021/jo990200x

J . Org. Chem. 1999, 64, 4551-4554
4551
Sch em e 1
Efficien t Syn th esis of th e
γ-Am in o-â-h yd r oxy Acid Su bu n it of
Ha p a losin
Godwin C. G. Pais and Martin E. Maier*
Institut fu¨r Organische Chemie, Universita¨t Tu¨bingen,
Auf der Morgenstelle 18, D-72076 Tu¨bingen, Germany
Received February 2, 1999
In tr od u ction
The 1,2-amino alcohol substructure represents an
important replacement of the peptide bond in a number
of peptidomimetics.1,2 Enantiomerically pure 1,2-amino
alcohols allow the formation of heterocycles which rank
among the most popular chiral auxiliaries. Moreover, this
structural element can be found in amino sugars,3
sphingosins,4 and also some acids. Representative ex-
amples for the latter include statine and (3S,4S)-4-amino-
3-hydroxy-5-phenylpentanoic acid, which are the key
constituents of renin inhibitors.5-7 Furthermore, the
3-hydroxy-4-amino acid related to 3 is part of the cyclic
depsipeptide hapalosin (1) (Scheme 1).8-12 This natural
product turned out to be quite active in reversing
multidrug resistance caused by overexpression of the
P-glycoprotein. To synthesize analogues of hapalosin,13,14
an efficient and flexible synthesis of the acid 3 was
sought. The requirements to incorporate this substruc-
ture into hapalosin fragment 2 are protecting groups at
the 3-hydroxy and the 4-N-methylamino function. Amino
acids of type 3 are usually prepared by elongation of
phenylalanine.9-12 Other routes to the amino alcohol
group involve the asymmetric hydrogenation of an enam-
inoketone,15 the Sharpless aminohydroxylation reaction,16
and the Lewis acid promoted coupling reactions of
oxazins with nucleophiles.17
Recognizing that the amino function might originate
from a carboxylic group through a Curtius rearrange-
ment,3,18,19 we devised an aldol reaction/Curtius rear-
rangement strategy for compound 3 (Scheme 1). The
realization of this route is presented in this paper.
Resu lts
The two stereocenters of the target molecule were
established by an Evans aldol reaction.20 Thus, enoliza-
tion of the acylated oxazolidinone 4 with di-n-butylboron
triflate21 in the presence of diisopropylethylamine at 0
°C followed by the addition of acrolein at -78 °C gave
rise to the aldol product 5.22 The use of the Hu¨nig’s base
proved to be crucial since with triethylamine the yield
dropped to 10%. Subsequent hydrolysis with lithium
hydroxide and hydrogen peroxide23 furnished the acid 6.
With acid 6 being somewhat unstable, although it can
be stored at -25 °C, it was used immediately in the next
step. Treatment of 6 with diphenylphosphoryl azide and
triethylamine and heating to 80 °C induced Curtius
rearrangement19 and intramolecular trapping24 of the
isocyanate to the oxazolidinone 7. The vicinal coupling
constant J 4,5 ) 6.7 Hz is in accord with a syn-orientation
of the two substituents.25 To facilitate the hydrolysis of
the oxazolidinone 7, it was converted to the corresponding
BOC derivative 8.26 Stirring of 8 with cesium carbonate
in methanol provided the N-protected amino alcohol 9
in 76% yield. The melting point as well as the optical
rotation matched the reported values.27,28 Both of these
(1) For a review on 1,2-amino alcohols, see: Ager, D. J .; Prakash,
I.; Schaad, D. R. Chem. Rev. 1996, 96, 835-875.
(2) For a review on γ-amino-â-hydroxy acids, see: Yokoyama, T.;
Yuasa, Y.; Shibuya, S. Heterocycles 1992, 33, 1051-1078.
(3) Sibi, M. P.; Lu, J .; Edwards, J . J . Org. Chem. 1997, 62, 5864-
5872.
(4) Somfai, P.; Olsson, R. Tetrahedron 1993, 49, 6645-6650.
(5) Greenlee, W. J . Pharmacol. Res. 1987, 4, 364-374.
(6) Weidmann, B. Chimia 1991, 45, 367-376.
(7) Shinozaki, K.; Mizuno, K.; Oda, H.; Masaki, Y. Chem. Lett. 1992,
2265-2268.
(8) Stratmann, K.; Burgoyne, D. L.; Moore, R. E.; Patterson, G. M.
L.; Smith, C. D. J . Org. Chem. 1994, 59, 7219-7226.
(9) Dinh, T. Q.; Du, X.; Armstrong, R. W. J . Org. Chem. 1996, 61,
6606-6616.
(18) Ghosh, A. K.; Liu, W. J . Org. Chem. 1996, 61, 6175-6182.
(19) Ghosh, A. K.; Hussain, K. A.; Fidanze, S. J . Org. Chem. 1997,
62, 6080-6082.
(20) Gage, J . R.; Evans, D. A. Org. Synth. 1989, 68, 83-91.
(21) Inoue, T.; Mukaiyama, T. Bull. Chem. Soc. J pn. 1980, 53, 174-
178.
(10) Ghosh, A. K.; Liu, W.; Xu, Y.; Chen, Z. Angew. Chem. 1996,
108, 73-75.
(11) Wagner, B.; Beugelmans, R.; Zhu, J . Tetrahedron Lett. 1996,
37, 6557-6560.
(12) Okuno, T.; Ohmori, K.; Nishiyama, S.; Yamamura, S.; Naka-
mura, K.; Houk, K. N.; Okamoto, K. Tetrahedron 1996, 52, 14723-
14734.
(22) Heathcock, C. H.; Finkelstein, B. L.; J arvi, E. T.; Radel, P. A.;
Hadley, C. R. J . Org. Chem. 1988, 53, 1922-1942.
(23) Evans, D. A.; Britton, T. C.; Ellman, J . A. Tetrahedron Lett.
1987, 28, 6141-6144.
(13) Dinh, T. Q.; Smith, C. D.; Armstrong, R. W. J . Org. Chem. 1997,
62, 790-791.
(24) Wittenberger, S. J .; Baker, W. R.; Donner, B. G. Tetrahedron
1993, 49, 1547-1556.
(14) Dinh, T. Q.; Du, X.; Smith, C. D.; Armstrong, R. W. J . Org.
Chem. 1997, 62, 6773-6783.
(25) Sakaitani, M.; Ohfune, Y. J . Am. Chem. Soc. 1990, 112, 1150-
(15) Doi, T.; Kokubo, M.; Yamamoto, K.; Takahashi, T. J . Org. Chem.
1998, 63, 428-429.
1158.
(26) Ishizuka, T.; Kunieda, T. Tetrahedron Lett. 1987, 28, 4185-
4188.
(27) Hanson, G. J .; Lindberg, T. J . Org. Chem. 1985, 50, 5399-5401.
(28) Ito, H.; Ikeuchi, Y.; Taguchi, T.; Hanzawa, Y.; Shiro, M. J . Am.
Chem. Soc. 1994, 116, 5469-5470.
(16) Reddy, K. L.; Sharpless, K. B. J . Am. Chem. Soc. 1998, 120,
1207-1217.
(17) Aoyagi, Y.; Williams, R. M. Tetrahedron 1998, 54, 10419-
10433.
10.1021/jo990200x CCC: $18.00 © 1999 American Chemical Society
Published on Web 05/22/1999

4552 J . Org. Chem., Vol. 64, No. 12, 1999
Notes
Sch em e 2
Sch em e 3
In summary, we could show that the aldol reaction
with acrolein followed by a Curtius rearrangement and
conversion of the double bond to a terminal carboxylic
function allows the stereocontrolled synthesis of γ-amino-
â-hydroxy acids such as the one in hapalosin. Moreover,
this strategy should open up a new route to optically
active nitrogen heterocycles.30
Exp er im en ta l Section
All melting points were recorded on a Bu¨chi melting point
B-540 apparatus. Optical rotations were recorded on a J ASCO
P-1020 polarimeter. IR spectra were recorded on a J asco FT/
IR-430 spectrometer. 1H (250 MHz) and 13C (62.5 MHz) spectra
were recorded in CDCl3. Unless mentioned, all the reactions
were carried out under an argon atmosphere. Anhydrous
solvents were obtained as follows: diethyl ether, tetrahydro-
furan, and toluene by distillation from sodium and benzophe-
none; methylene chloride by distillation from calcium hydride;
dimethylformamide was first stirred over calcium hydride,
decanted, and distilled under reduced pressure. Tributylborane
was prepared from boron trifluoride etherate and butylmagne-
sium bromide in dry ether under argon.31 Di-n-butylboron triflate
was prepared according to Mukaiyama’s procedure.21 The chiral
auxiliary 4 was prepared according to the literature proce-
dure.32,33 Aqueous sodium hypochlorite (13% active chlorine,
ACROS) was diluted to 0.43 M. Hu¨nig’s base was distilled from
KOH before use. Triethylamine was distilled from calcium
hydride prior to use. Column chromatography was performed
with E. Merck 40-63 µm silica gel. Thin-layer chromatography
was carried out with Polygram Sil G/UV254 from Macherey-
Nagel.
(3R,4S)-4-[N-(ter t-Bu t oxyca r b on yl)-N-m et h yla m in o]-3-
(m eth oxym eth oxy)-5-p h en ylp en ta n oic Acid (3). Compound
12 (1.80 g, 5.10 mmol) was dissolved in acetone (40 mL) and
added to an aqueous 5% NaHCO3 solution (13.5 mL). This
magnetically stirred heterogeneous mixture was cooled to 0 °C
and treated sequentially with KBr (62 mg, 0.52 mmol) and
TEMPO (0.84 g, 5.39 mmol). Sodium hypochlorite (15 mL, 6.45
mmol) was then added dropwise, while the mixture was vigor-
ously stirred and maintained at 0 °C. After 1 h, additional NaOCl
(5.8 mL, 2.50 mmol) was added, and stirring was continued at
0 °C for an another hour followed by addition of a 5% NaHCO3
solution (19 mL). Following evaporation of the acetone, the
aqueous layer was washed with ether (2 × 50 mL, to remove
TEMPO impurities), acidified to pH 6 with 10% aqueous citric
acid, and extracted with ethyl acetate (3 × 100 mL). The
combined organic phases were washed with water and brine,
dried over NaSO4, and concentrated to give the crude acid. Pure
acid 3 (1.5 g, 80%) was obtained by flash chromatography
(petroleum ether/ethyl acetate, 1:1): TLC (40% ethyl acetate in
petrol ether): Rf ) 0.37; [R]22D ) -39.8 (c 0.6, CHCl3); IR (neat)
papers describe the synthesis of 9 by an addition of
vinylmagnesium bromide to an R-amino aldehyde. How-
ever, this approach produces a mixture of both diaster-
eomers which have to be separated. In the next step the
hydroxyl group was protected with chloromethyl methyl
ether (MOM chloride) to give compound 10. This protect-
ing group was chosen over a silicon-based one because
the N-methylation conditions can cause cleavage of a
neighboring silicon protecting group. Having the ether
10 in hand, N-methylation to the alkene 11 was achieved
using sodium hydride (NaH) and methyl iodide (MeI).9
The final steps served to establish the carboxylic function
from the double bond. This was initiated by hydrobora-
tion of 11 using 9-borabicyclo[3.3.1]nonane (9-BBN)
followed by oxidative workup.25
The resulting primary alcohol 12 was then oxidized to
the carboxylic acid 3 by the use of sodium hypochlorite
and TEMPO (Scheme 2).16 These conditions proved to be
superior in comparison to the oxidation with pyridinium
dichromate (PDC) in DMF.
With a view to the synthesis of functionalized pyrro-
lidines, we investigated the conversion of the double bond
to the carboxylic function with a free NH group in the
molecule. This route was studied with the alkene 13
which is available by silylation of the alcohol 9. As
described above, hydroboration delivered the primary
alcohol 14. Oxidation of this compound with PDC in DMF
gave directly the lactam 15.29 This could be opened under
mild conditions to the methyl ester 16 (Scheme 3).
(30) Yoda, H.; Yamazaki, H.; Kawauchi, M.; Takabe, K. Tetrahe-
dron: Asymmetry 1995, 6, 2669-2672.
(31) J ohnson, J . R.; Snyder, H. R.; Van Campen, M. G., J r. J . Am.
Chem. Soc. 1938, 60, 115-121.
(32) Evans, D. A.; Britton, T. C.; Dorow, R. L.; Dellaria, J . F., J r.
Tetrahedron 1988, 44, 5525-5540.
(29) Ishibuchi, S.; Ikematsu, Y.; Ishizuka, T.; Kunieda, T. Tetrahe-
dron Lett. 1991, 32, 3523-3526.
(33) Gage, J . R.; Evans, D. A. Org. Synth. 1989, 68, 77-82.

Notes
J . Org. Chem., Vol. 64, No. 12, 1999 4553
3449-2622 (br), 1733 (s), 1692 (s) cm-1; 1H NMR (both rotamers)
δ 1.19 (br s, 9 H, minor), 1.25 (s, 9 H, major), 2.43-2.62 (complex,
6 H), 3.17 (dd, J ) 11.1, 13.5, 2.7 Hz, 1H), 3.35 (s, 3 H, minor),
3.36 (s, 3 H, major), 4.04-4.15 (br m, 2 H), 4.66 (d, J ) 7.1 Hz,
1H), 4.75 (d, J ) 7.1 Hz, 1 H), 7.07-7.22 (m, 5 H); 13C NMR
(both rotamers) δ 28.1, 28.3, 34.5, 38.0, 56.2, 56.3, 76.5, 77.3,
97.1, 97.3, 126.2, 126.4, 128.3, 128.4, 129.0, 138.5, 155.7, 175.8;
the reaction mixture to room temperature, the toluene was
removed under reduced pressure. The residue was partitioned
between ethyl acetate and saturated aqueous NaHCO3. The
organic layer was washed with brine, dried (Na2SO4), filtered,
and concentrated under reduced pressure to give a black residue,
which was purified by flash chromatography (40% ethyl acetate
in petroleum ether) providing 7 (1.58 g, 80%) as light yellow oil:
MS (EI), m/z (%) 368 [M+ + 1] (10); HRMS (EI) calcd for C19H29
-
TLC (40% ethyl acetate in petroleum ether) Rf ) 0.33; [R]23
)
D
NO6 367.19948, found 367.20129.
-118.5 (c 1.04, CHCl3); IR (neat) 3278 (s), 1750 (s) cm-1; 1H NMR
δ 2.54 (dd, J ) 2.5, 11.0 Hz, 1 H), 2.74 (dd, J ) 9.6, 4.0 Hz, 1 H),
3.96-4.08 (m, 1 H), 5.06 (dd, J ) 6.7, 1.2 Hz, 1 H), 5.10 (dd, J
) 1.2, 0.9 Hz, 1 H), 5.38 (dt, J ) 10.4, 1.2 Hz, 1 H), 5.47 (dt, J
) 17.4, 1.3 Hz, 1 H), 5.84-5.97 (m, 1 H), 7.07-7.10 (m, 2 H),
7.15-7.30 (m, 3 H); 13C NMR δ 37.5, 57.2, 80.1, 120.4, 127.2,
(4S)-4-Ben zyl-3-[(2S,3R)-2-ben zyl-3-h ydr oxy-4-pen ten oyl]-
1,3-oxa zolid in -2-on e (5). To a solution of 432 (5.80 g, 18.7 mmol)
in CH2Cl2 (38 mL) at 0 °C was added di-n-butylboron triflate
(22.9 mL, 22.9 mmol, 1 M in CH2Cl2) dropwise. This was followed
by the dropwise addition of Hu¨nig’s base (4.20 mL, 24.4 mmol).
After 1 h at 0 °C, the solution was cooled to -78 °C and freshly
distilled acrolein (1.9 mL, 28.1 mmol) was added over 2 min.
After being stirred for 1 h at -78 °C, the reaction mixture was
allowed to warm to room temperature over 1 h and kept at this
temperature for 2 h. The mixture was poured into pH 7 buffer
(42 mL), and then ether (55 mL) was added. The layers were
separated, and the aqueous layer was extracted with ether (2 ×
50 mL). The combined layers were washed with brine (30 mL),
and the solvent was removed with a rotary evaporator. The
residue was dissolved in methanol (55 mL), cooled to 0 °C, and
treated dropwise with H2O2 (18.75 mL of a 30% aqueous
solution). After 60 min at 0 °C, the mixture was diluted with
water (55 mL), and most of the methanol was removed with a
rotary evaporator. The aqueous layer was extracted with ether
(3 × 50 mL). The combined organic layers were washed with
cold 5% HCl (7 mL), saturated aqueous NaHCO3 (15 mL), and
brine (15 mL), dried (Na2SO4), filtered, and concentrated in
vacuo. The residue was purified by flash chromatography
(petroleum ether/ethyl acetate, 3:2) to give 5 as a colorless oil
(5.4 g, 79%) which solidifies upon standing, mp 45.8-46.8 °C:
129.0, 129.1, 130.78, 136.8, 158.3; MS (EI), m/z (%) 204 [M+
1] (5.9); HRMS (EI) calcd for C12H13NO2 203.09463, found
203.09147.
+
(4S,5R)-4-Ben zyl-3-(ter t-bu toxyca r bon yl)-5-vin yl-1,3-ox-
a zolid in -2-on e (8). A solution of oxazolidinone 7 (1.3 g, 6.40
mmol) in tetrahydrofuran (30 mL) was treated with (Boc)2O (1.82
g, 8.34 mmol) and triethylamine (1.07 mL, 7.68 mmol) in the
presence of DMAP (0.16 g, 1.28 mmol) and the mixture stirred
at room temperature for 5.30 h. Excess (Boc)2O was quenched
by the addition of N,N-diethylenediamine (0.17 mL, 1.28 mmol)
and the mixture stirred for 10 min. Then ether (100 mL) was
added to the reaction mixture which was washed successively
with a 1 M aqueous KHSO4 solution, water, a saturated aqueous
NaHCO3 solution, water, and brine. The organic layer was dried
(Na2SO4), filtered, and concentrated under reduced pressure. The
residue was purified by flash chromatography (30% ethyl acetate
in petroleum ether) to give 8 (1.84 g, 95%) as colorless needles,
mp 72-73 °C: TLC (30% ethyl acetate in petroleum ether) Rf )
0.65; [R]21 ) -13.5 (c 1.0, CHCl3); IR (KBr) 3606 (w), 3429 (w),
D
3059 (s), 1803 (s), 1719 (s) cm-1; H NMR δ 1.41 (s, 9 H), 2.85
1
TLC (petroleum ether/ethyl acetate, 3:2): Rf ) 0.46; [R]23
(d, J ) 2.1 Hz, 1 H), 2.87 (s, 1 H), 4.54 (q, J ) 6.8 Hz, 1 H),
4.92-4.98 (m, 1 H), 5.29 (dt, J ) 10.7, 1.2 Hz, 1 H), 5.44 (dt, J
) 17.1, 1.2 Hz, 1 H), 5.62-5.75 (m, 1 H), 7.10-7.25 (m, 5 H);
13C NMR δ 27.8, 35.6, 59.5, 78.1, 83.9, 120.4, 126.9, 128.7, 129.6,
129.7, 136.4, 148.9, 151.6; MS (EI), m/z (%) 247 [M+ + 1 - t-Bu]
(7).
D
+11.75 (c 1.22, CHCl3); IR (neat) 3821 (s), 1777 (s), 1698 (s) cm-1
;
1H NMR δ 2.17 (ddd, J ) 4.3, 9.2, 4.0 Hz, 1 H), 2.80 (dd, J )
10.1, 3.4 Hz, 1 H), 2.91-3.09 (m, 2 H), 3.92 (dd, J ) 6.1, 3.0 Hz,
1 H), 4.03 (dd, J ) 1.2, 7.9 Hz, 1 H), 4.39-4.43 (m, 1 H), 4.52-
4.62 (m, 2 H), 5.20 (dt, J ) 10.4, 1.5 Hz, 1 H), 5.30 (dt, J ) 17.1,
1.2 Hz, 1 H), 5.91 (ddd, J ) 6.5, 4.2, 6.1 Hz, 1 H), 6.83-6.87 (m,
2 H), 7.10-7.21 (m, 8 H); 13C NMR δ 33.8, 37.4, 49.8, 55.0, 65.8,
73.9, 117.1, 126.6 127.3, 128.5, 128.9, 129.4, 129.5, 135.1, 137.4,
138.8, 153.5, 174.0; MS (EI), m/z (%) 365 [M] (1); HRMS (EI)
calcd for C22H23NO4 365.16273, found 365.16983.
(3R,4S)-N-(ter t-Bu t oxyca r b on yl)-4-a m in o-3-h yd r oxy-5-
p h en ylp en t-1-en e (9). A mixture of the oxazolidinone 8 (1.80
g, 5.94 mmol) in methanol (80 mL) and cesium carbonate (0.774
g, 2.38 mmol) was stirred for 25 h at room temperature. Then
the reaction was quenched with citric acid, and the product was
extracted with ethyl acetate, dried (Na2SO4), filtered, and
concentrated in vacuo. Purification of the residue by flash
chormatography (20% ethyl acetate in petroleum ether) gave
1.26 g (76%) of 9 as colorless needles, mp 124.5 °C, lit.27 125-
(2S,3R)-2-Ben zyl-3-h yd r oxy-4-p en ten oic Acid (6). To a
solution of the oxazolidinone 5 (5.0 g, 13.7 mmol) in tetra-
hydrofuran-distilled water (3:1, v/v, 205 mL) was added H2O2
(30% aqueous solution, 7.75 mL, 68.42 mmol) at 0 °C via syringe
over a 5-min period. This was followed by the addition of lithium
hydroxide (1.15 g, 27.37 mmol), dissolved in water (27 mL). Some
gas evolved from the clear solution. After stirring for 1 h at 0
°C and for 15 h at room temperature, the excess H2O2 was
quenched by the addition of sodium sulfite (8.62 g, 68.4 mmol)
in distilled water (41 mL). The bulk of the tetrahydrofuran was
removed by rotary evaporation at a bath temperature of 25-30
°C, and the resulting mixture was extracted with dichlo-
romethane (3 × 60 mL) to remove the oxazolidinone auxiliary.
The aqueous layer was cooled in an ice bath and acidified to pH
2 with aqueous 1 N hydrochloric acid. The resulting cloudy
solution was then extracted with ether (5 × 60 mL). The
combined ether extracts were dried (MgSO4), filtered, and
concentrated. The residue was purified by flash chromatography
(50% ethyl acetate in petroleum ether) to give 6 (2.4 g, 85%) as
a colorless oil: TLC (petroleum ether/ethyl acetate, 1:1) Rf )
126.5 °C: TLC (hexane/ethyl acetate, 2:1): Rf ) 0.65; [R]23
)
D
-23.9 (c 0.5, CHCl3), lit.27 [R]25 ) -23 (c 1.0, CHCl3); IR (KBr)
D
1
3356 (s), 1686 (s) cm-1; H NMR δ 1.29 (s, 9 H), 2.61-2.82 (m,
1 H), 2.78 (dd, J ) 8.9, 5.5 Hz, 1 H), 3.00 (br s, 1 H), 3.90 (br s,
1 H), 4.16 (s, 1 H), 4.53 (br d, J ) 6.4 Hz, 1 H), 5.22 (dt, J )
10.4, 1.6 Hz, 1 H), 5.30 (dt, J ) 17.4, 1.6 Hz, 1 H), 5.87 (dddd,
J ) 1.3, 5.5, 4.9, 5.8 Hz, 1 H), 7.11-7.26 (m, 5 H); 13C NMR δ
28.3, 36.0, 56.5, 74.6, 79.778, 116.9, 126.4, 128.4, 129.3, 137.0,
138.1, 156.4; MS (EI), m/z (%) 278 [M+ + 1] (3.7).
(3R ,4S )-N -(t er t -B u t o x y c a r b o n y l)-4-a m in o -3-(m e t h -
oxym eth oxy)-5-p h en ylp en t-1-en e (10). Chloromethyl methyl
ether (4.00 mL, 49.6 mmol) was added dropwise to a cooled (0
°C) solution of the alcohol 9 (3.00 g, 10.8 mmol) and diisoprop-
ylethylamine (17 mL, 100 mmol) of CH2Cl2 (15 mL). The reaction
mixture was stirred at this temperature for 1 h and then at room
temperature for 8 h. Water was added, the two phases were
separated, and the aqueous phase was extracted with CH2Cl2
(3 × 100 mL). The combined organic phases were washed with
1 N HCl (3 × 50 mL), water, and brine, dried (Na2SO4), filtered,
and concentrated under reduced pressure. The residue was
purified by flash chromatography (30% ethyl acetate in petro-
leum ether as eluent) to give the ether 10 (3.3 g, 95%) as colorless
crystals, mp 93-94 °C: TLC (30% ethyl acetate in petroleum
0.38; [R]25 ) -12.85 (c 0.16, CHCl3); IR (neat) 3412-2056 (br),
D
1
1709 (s) cm-1; H NMR δ 2.77-3.01 (m, 3 H), 4.30 (td, J ) 3.2,
1.4 Hz, 1 H), 5.18 (dt, J ) 10.4, 1.2 Hz, 1 H), 5.27 (dt, J ) 17.4,
1.3 Hz, 1 H), 5.78-5.91 (m, 1 H), 6.64 (br s, 2 H), 7.07-7.26 (m,
5 H); 13C NMR δ 33.0, 52.8, 73.0, 117.7, 126.6, 128.6, 128.9,
136.7, 138.8, 178.7; MS (EI), m/z (%) 206 [M+] (35), 188 (50),
143 (82).
(4S,5R)-4-Ben zyl-5-vin yl-1,3-oxa zolid in -2-on e (7). The hy-
droxy acid 6 (2.00 g, 9.66 mmol) was dissolved in dry toluene
(21 mL), diphenylphosphoryl azide (3.13 mL, 14.49 mmol)
followed by triethylamine (3.16 mL, 22.71 mmol) was added, and
the resulting mixture was heated at 80 °C for 4 h. After cooling
ether): Rf ) 0.5; [R]21 ) -82.2 (c 1.0, CHCl3); IR (KBr) 3382
D
(s), 3083 (m), 3058 (m), 1687 (s), 1032 (s) cm-1; H NMR δ 1.25
1
(s, 9 H), 2.63 (dd, J ) 3.4, 10.7 Hz, 1 H), 2.89 (dd, J ) 9.5, 4.6
Hz, 1 H), 3.32 (s, 3 H), 3.91 (br s, 1 H), 4.11 (dd, J ) 4.2, 6.7 Hz,
1 H), 4.62 (d, J ) 6.7 Hz, 1 H), 5.23 (d, J ) 15.6 Hz, 1 H), 5.26

4554 J . Org. Chem., Vol. 64, No. 12, 1999
Notes
(dt, J ) 17.5, 1.2 Hz, 1 H), 5.64-5.78 (m, 1 H), 7.08-7.23 (m, 5
H); 13C NMR δ 28.3, 35.7, 54.9, 55.8, 79.2, 94.6, 119, 126.2, 128.3,
129.3, 135.1, 138.4, 155.4; MS (EI), m/z (%) 322 [M + 1] (0.1),
266 (0.2).
(3R ,4S)-N -(t er t -Bu t oxyca r b on yl)-4-a m in o-3-(t er t -b u t -
yld im eth ylsilyloxy)-1-h yd r oxy-5-p h en ylp en ta n e (14). To a
solution of 13 (1.50 g, 3.84 mmol) in THF (33 mL) was added
9-borabicyclo[3.3.1]nonane (11.2 mL, 0.5 M solution in hexane,
5.60 mmol) at room temperature. The reaction mixture was
stirred for 20 h before it was treated successively with EtOH (7
mL), 6 N NaOH (2.4 mL), and 30% H2O2 (4.7 mL). The mixture
was heated at 50 °C for 1 h, cooled to room temperature, and
extracted with ethyl acetate several times. The combined organic
layers were washed with water and brine, dried (Na2SO4),
filtered, and concentrated in vacuo. Pure 14 (1.13 g, 72%) was
obtained by flash chromatography (25% ethyl acetate in petro-
leum ether) as colorless oil: TLC (30% ethyl acetate in petroleum
(3R,4S)-4-[N-(ter t-Bu t oxyca r b on yl)-N-m et h yla m in o]-3-
(m eth oxym eth oxy)-5-p h en ylp en t-1-en e (11). To a cooled (0
°C, ice bath) solution of 10 (2.50 g, 7.79 mmol) and MeI (1.0 mL,
15.6 mmol) in DMF (30 mL) was added NaH (0.405 g, 10.12
mmol, 60% in mineral oil) in portions. After complete addition,
the ice bath was removed, and the mixture was stirred at room
temperature for 15 h. The reaction was quenched with saturated
aqueous NH4Cl, and much of the DMF was removed in vacuo.
The mixture was extracted with ethyl acetate (3 × 30 mL), and
the organic layers were washed with water, dried, filtered, and
concentrated. The resulting thick liquid was purified by flash
chromatography (15% ethyl acetate in petroleum ether) to give
11 (2.50 g, 96%) as a colorless oil: TLC (20% ethyl acetate in
ether): Rf ) 0.45, [R]23 ) -24.9 (c 1.0, CHCl3); IR (neat) 3453
D
1
(s), 1699 (s) cm-1; H NMR δ -0.01 (d, J ) 2.43 Hz, 6 H), 0.85
(t, J ) 3.1 Hz, 9 H), 1.25 (s, 9 H), 1.71 (dd, J ) 6.4, 6.1 Hz, 2 H),
2.48-2.66 (m, 2 H), 2.80-2.89 (m, 1 H), 3.66 (br d, J ) 6.7 Hz,
1 H), 3.69 (br d, J ) 5.5 Hz, 1 H), 3.81 (br s, 1 H), 3.90 (br s, 1
H), 4.51 (d, J ) 8.6 Hz, 1 H), 7.17-7.23 (m, 2 H), 7.08-7.14 (m,
3 H); 13C NMR δ -4.5, -4.6, 18.1, 25.9, 28.3, 36.1, 55.6, 59.4,
72.1, 79.4, 126.3, 128.4, 129.2, 138.7, 155.7; MS (EI), m/z (%)
410 [M+ + 1] (6); HRMS (EI) calcd for C22H40NO4Si 410.272663,
found 410.26828.
petroleum ether): Rf ) 0.63; [R]22 ) -154.4 (c 0.3, CHCl3); IR
D
(neat) 1694 (s) cm-1; 1H NMR (both rotamers, 1:1.4) δ 1.18 (s, 9
H, minor), 1.24 (s, 9 H, major), 2.46 (br s, 3 H, minor), 2.59 (br
s, 3 H, major), 2.77-2.83 (complex, 1 H), 3.15 (ddd, J ) 14.4,
5.2, 3.7 Hz, 1 H), 3.34 (s, 3 H, minor), 3.35 (s, 3 H, major), 4.03
(br s, 1 H), 4.18 (br s, 1 H), 4.50 (d, J ) 6.7 Hz, 1 H), 4.69 (dd,
J ) 1.6, 5.1 Hz, 1 H), 5.16-5.25 (complex, 2 H), 5.51-5.72 (m,
1 H), 7.08-7.21 (m, 5 H); 13C NMR (both rotamers) δ 28.2, 28.3,
34.3, 34.6, 55.9, 56.0, 78.6, 79.07, 79.13, 79.5, 93.8, 94.0, 119.2,
119.8, 126.0, 126.2, 128.2, 128.3, 129.0, 135.4, 136.0, 138.9, 155.6;
MS (EI), m/z (%) 336 [M+ + 1] (7); HRMS calcd for C19H29NO4
335.20965, found 335.21414.
ter t-Bu t yl (2S,3R)-2-Ben zyl-3-[ter t-b u t yl(d im et h yl)sil-
yloxy]-5-oxo-1-p yr r olid in eca r boxyla te (15). A mixture of the
alcohol 14 (0.500 g, 1.23 mmol), PDC (1.73 g, 4.60 mmol), and
DMF (5.5 mL) was stirred at room temperature for 18 h. The
resulting mixture was poured into water (35 mL) and extracted
with CH2Cl2 (3 × 50 mL). The extract was washed with 5% HCl
(1 × 50 mL) and brine (1 × 50 mL), dried with MgSO4, filtered,
and evaporated under reduced pressure. The residue was
purified by flash chromatography (25% ethyl acetate in petro-
leum ether) to give compound 15 (0.37 g, 75%) as a colorless oil
which solidified, mp 71-72 °C: TLC (25% ethyl acetate in
(3R,4S)-4-[N-(ter t-Bu t oxyca r b on yl)-N-m et h yla m in o]-3-
(m eth oxym eth oxy)-1-h yd r oxy-5-p h en ylp en ta n e (12). To a
solution of the alkene 11 (2.00 g, 5.97 mmol) in THF (50 mL)
was added 9-borabicyclo[3.3.1]nonane (35.8 mL, 0.5 M solution
in hexane, 17.9 mmol) at room temperature. The reaction
mixture was stirred for 20 h before it was treated successively
with EtOH (11 mL), 6 N NaOH (3.7 mL), and 30% H2O2 (7.3
mL). The mixture was heated at 50 °C for 1 h, cooled to room
temperature, and extracted several times with ethyl acetate. The
combined organic layers were washed with water and brine,
dried (Na2SO4), filtered, and concentrated in vacuo. The pure
alcohol 12 (1.58 g, 75%) was obtained by flash chromatography
(50% ethyl acetate in petroleum ether) as colorless oil: TLC (50%
petroleum ether): Rf ) 0.57; [R]21 ) +10.7 (c 1.0, CHCl3); IR
D
1
(neat) 1788 (s), 1703 (s) cm-1; H NMR δ -0.31 (d, J ) 4.3 Hz,
6 H), 0.66 (t, J ) 3.1 Hz, 9 H), 1.52 (s, 9 H), 2.22 (d, J ) 17.7
Hz, 1 H), 2.43 (dd, J ) 3.1, 10.4 Hz, 1 H), 2.57 (dd, J ) 12.2, 5.5
Hz, 1 H), 3.11 (dd, J ) 10.1, 3.5 Hz, 1 H), 3.99 (d, J ) 4.9 Hz, 1
H), 4.08 (dd, J ) 6.7, 3.7 Hz, 1 H), 7.11-7.30 (m, 5 H); 13C NMR
δ -5.2, 17.7, 25.6, 28.2, 38.0, 41.4, 66.9, 69.2, 83.1, 127.1, 128.9,
129.3, 136.7, 150.1, 172.8; MS (EI), m/z (%) 406 [M+ + 1] (3.7);
HRMS (EI) calcd for C22H35NO4Si 405.23353, found 405.23498.
Meth yl (3R,4S)-4-[(ter t-Bu toxyca r bon yl)a m in o]-3-[ter t-
bu tyl(d im eth yl)silyloxy]-5-p en ta n oa te (16). To a stirred
solution of 15 (0.500 g, 1.23 mmol) in methanol (15 mL) was
added cesium carbonate (0.081 g, 0.25 mmol) at 0 °C, and the
reaction mixture was stirred at room temperature for 2 h. Then
it was quenched with citric acid, and the product was extracted
with ethyl acetate, dried (Na2SO4), filtered, and concentrated
in vacuo. Purification of the residue by flash chromatography
(15% ethyl acetate in petroleum ether) gave 0.271 g (50%) of
the ester 16 as colorless oil: TLC (20% ethyl acetate in petroleum
ether): Rf ) 0.64; [R]22D ) -19.7 (c 0.38, CHCl3); IR (neat) 1741
ethyl acetate in petroleum ether): Rf ) 0.3; [R]25 ) -17.8 (c
D
0.9, CHCl3); IR (neat) 3445 (s), 1689 (s) cm-1; 1H NMR (CDCl3)
(both rotamers) δ 1.15 (s, 3 H, minor), 1.25 (s, 3 H, major), 1.44-
1.97 (m, 2 H), 2.21 (br s, 1 H), 2.49 (s, 3 H, minor), 2.61 (br s, 3
H, major), 2.76-2.81 (complex, 1 H), 3.07 (td, J ) 13.7, 3.1 Hz,
1 H), 3.38 (s, 3 H, minor), 3.41 (s, 3 H, major), 3.61-3.83 (m, 2
H), 3.88 (br s, 1 H), 4.19 (br s, 1 H), 4.67 (deformed t, J ) 6.3,
4.6 Hz, 1 H), 4.73 (deformed t, J ) 4.0, 6.7 Hz, 1 H), 7.07-7.22
(m, 5 H); 13C NMR (both rotamers) δ 28.1, 28.3, 31.1, 34.1, 34.6,
56.2, 56.4, 58.8, 79.6, 79.8, 97.4, 97.7, 126.1, 126.3, 128.4, 128.9,
129.0, 138.8, 155.5, 155.9; MS (EI), m/z (%) 354 [M+ + 1] (2.2);
HRMS (EI) calcd for C19H31NO5 353.22022, found 353.22531.
(3R ,4S)-N -(t er t -Bu t oxyca r b on yl)-4-a m in o-3-(t er t -b u t -
yld im eth ylsilyloxy)-5-p h en ylp en t-1-en e (13). A mixture of
9 (1.20 g, 4.33 mmol), tert-butyldimethylsilyl chloride (2.24 g,
9.53 mmol), and imidazole (1.29 g, 19.06 mmol) in DMF (7 mL)
was stirred under an argon atmosphere for 2 h. After dilution
with ether (50 mL), the mixture was washed with water (5 ×
10 mL), dried over Na2SO4, filtered, and concentrated under
reduced pressure to give a pale yellow oil which was purified by
flash chromatography (5% ethyl acetate in petroleum ether) to
give 1.52 g (90%) of 13 as colorless crystals, mp 50-51 °C: TLC
(10% ethyl acetate in petroleum ether) Rf ) 0.74; [R]22D ) -18.9
(c 0.6, CHCl3); IR (neat) 3454 (m), 3370 (m), 3275 (m), 1705 (s),
1
(s), 1703 (s) cm-1; H NMR δ 0.00 (s, 3 H), 0.06 (d, J ) 1.5 Hz,
3 H), 0.85-0.89 (complex, 9 H), 1.27 (s, 9 H), 2.47 (d, J ) 2.8
Hz, 1 H), 2.50 (d, J ) 1.5 Hz, 1 H), 2.92 (dd, J ) 9.5, 4.6 Hz, 1
H), 2.53-2.56 (m, 1 H), 3.81 (s, 3 H), 4.07 (br s, 1 H), 4.24 (br s,
2 H), 4.40 (br s, 1 H), 7.13-7.28 (m, 5 H); 13C NMR δ -4.7, 18.1,
25.9, 28.3, 35.9, 39.9, 51.7, 56.3, 71.4, 79.3, 126.3, 128.4, 129.2,
138.3, 155.2, 171.7; MS (EI), m/z (%) 364 [M+ - OtBu]; HRMS
(EI) calcd for C23H39NO5Si - OtBu 364.19441, found 364.19110.
Ack n ow led gm en t. Financial support by the Deut-
sche Forschungsgemeinschaft and the Fonds der Che-
mischen Industrie is gratefully acknowledged. G. C. G.
Pais thanks the Alexander von Humboldt foundation
for a postdoctoral fellowship.
1
1699 (s) cm-1; H NMR δ 0.02 (d, J ) 8.2 Hz, 6 H), 0.91 (t, J )
3.1 Hz, 9 H), 1.33 (s, 9 H), 2.63 (dd, J ) 14.0, 10.1 Hz, 1 H), 2.87
(dd, J ) 9.7, 4.7 Hz, 1 H), 3.86 (br s, 1 H), 4.33 (br s, 1 H), 4.48
(br d, J ) 8.5 Hz, 1 H), 5.18 (br d, J ) 10.4 Hz, 1 H), 5.31 (dt,
J ) 17.4, 1.7 Hz, 1 H), 5.80-5.92 (m, 1 H), 7.13-7.28 (m, 5 H);
13C NMR δ -5.0, -4.4, 18.3, 25.9, 28.4, 34.9, 56.3, 74.8, 79.1,
116.2, 126.1, 128.3, 129.2, 138.1, 138.8, 155.4; MS (EI), m/z (%)
392 [M + 1] (16); HRMS (EI) calcd for C22H37NO3Si 391.25427,
found 391.25229.
Su p p or t in g In for m a t ion Ava ila b le: NMR spectra of
compounds prepared. This material is available free of charge
via the Internet at http://pubs.acs.org.
J O990200X