Studies on the preparation of protomycinolide IV: Enantioselective synthesis of the C3-C9 segment

Article abstract of DOI:10.1016/S0957-4166(97)00596-X

The C3-C9 segment, (-)-16, of the polyene macrolide antibiotic protomycinolide IV (1a) was prepared in optically pure form from commercially available methyl (S)-2-methyl-3-hydroxypropionate in 12 steps giving 17% yield.

Full text of DOI:10.1016/S0957-4166(97)00596-X

Pergamon
Tetrahedron: Asymmetry 9 (1998) 133–140
Studies on the preparation of protomycinolide IV:
Enantioselective synthesis of the C3–C9 segment
James T. Wasicak † and William A. Donaldson∗
Department of Chemistry, Marquette University, PO Box 1881, Milwaukee, WI 53201-1881, USA
Received 9 October 1997; accepted 3 November 1997
Abstract
The C3–C9 segment, (−)-16, of the polyene macrolide antibiotic protomycinolide IV (1a) was prepared in
optically pure form from commercially available methyl (S)-2-methyl-3-hydroxypropionate in 12 steps giving
17% yield. © 1998 Elsevier Science Ltd. All rights reserved.
1. Introduction
Protomycinolide IV and mycinolide IV (1a and 1b) are 16-membered polyene macrolides isolated
from the culture broth of Micromonospora griseorubida sp. nov.1a The configuration of 1b was deter-
mined by X-ray diffraction analysis1b Conversion of 1b into 1a (tosylation of the 1° alcohol followed
by reduction) demonstrated their structural association. While protomycinolide does not possess notable
antibacterial activity, it has been shown to be a biosynthetic intermediate for the mycinamycin family
of antibiotics which display significant activity against Gram-positive bacteria.1c Structural correlation
between protomycinolide IV and other 16-membered macrolides (e.g. chalcomycin,2a rosaramicin2b and
tylosin2c) has recently led to a proposed biosynthetic pathway for their formation.2a In support of this
mechanism, methyl mycinoate II (2a) and dicarboxymycinonic acid III (2b) have been isolated from the
culture broth of a mutant of Micromonospora griseorubida which is unable to produce 1a.1d The total
syntheses of 1a,3 2a and b4 have been reported.
We recently described a synthetic strategy for the preparation of dienolide 1 which relies on the
ability of an Fe(CO)3 moiety to control C–C bond formation adjacent and remote to a coordinated diene
(Scheme 1).5 To this end, we have reported the preparation of the C10–C17 segment 3 from (methyl
3,5-hexadienoate)Fe(CO)3 in a highly diastereoselective fashion, as well as model studies for generation
of the C9–C10 dienone bond via Friedel–Crafts acylation. The synthesis of 1a by this methodology
∗
†
Corresponding author. E-mail: donaldsonw@vms.csd.mu.edu
Current address: Pharmaceutical Discovery Div., Abbott Laboratories, Abbott Park, Chicago, IL 60064, USA.
0957-4166/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(97)00596-X

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requires the functionalized acyl halide 4. We herein report the preparation of the C3–C9 segment in an
enantioselective fashion.
Scheme 1.
1.1. Enantioselective preparation of the C3–C9 segment
The preparation of 17, in optically pure form, initially required preparation of the C4–C6 segment.
There are many possibilities for generation of this stereotriad6 and a double diastereoselective aldol
condensation was chosen as our point of inception. Aldehyde (+)-7 was prepared from commercially
available methyl (S)-2-methyl-3-hydroxypropionate by protection, reduction7 and oxidation7 (70% yield,
3 steps, Scheme 2). Aldol condensation of (+)-7 with N-propionyl-4(R)-methyl-5(S)-phenyloxazolidin-
2-one8 was effected by the use of dibutylboron triflate/NEt2iPr. The proton NMR spectrum of the crude
product revealed one major diastereomer and a trace amount of at least one other diastereomer; however,
the quantity of this very minor diastereomer was insufficient to determine its relative configuration
or to determine a diastereomeric ratio. Chromatographic purification gave pure (+)-8 as a crystalline
product (89%). The ‘anti-Felkin–syn-aldol’ stereochemistry, which was expected on the basis of literature
precedents,9 was confirmed by X-ray diffraction analysis (Fig. 1).10
Scheme 2. Reagents: (a) TBDPSCl/imidazole (93%); (b) DIBAL/THF (83%); (c) DMSO/(COCl)2/NEt3 (88%); (d)
(N)-propyl-4(R)-methyl-5(S)-phenyloxazolidinone/nBu2 BOTf (89%); (e) NaOMe/MeOH (78%)
Treatment of (+)-8 with NaOMe/MeOH gave the methyl ester (+)-9 (78%) along with the recovered
chiral auxilary (75%, Scheme 2). Protection of the secondary alcohol with methoxymethyl chloride
gave the ether (+)-10 (95%, Scheme 3). Reduction of ester (+)-10 with DIBAL (THF/toluene) gave
the alcohol (+)-11 (92%), which was protected as its benzyloxymethyl ether (+)-12 (69%). Removal of
the silyl protecting group with TBAF (83%) followed by Swern oxidation (84%) gave the aldehyde (−)-
14. Horner–Emmons olefination of (−)-14 with triethyl phosphonoacetate gave the unsaturated ester 15
(88%) which contains all of the carbons of the C3–C9 segment of 1. Brief (1 h) catalytic hydrogenation

J. T. Wasicak, W. A. Donaldson / Tetrahedron: Asymmetry 9 (1998) 133–140
135
Fig. 1. ORTEP view of (+)-8
of 15 resulted in saturation of the C6–C7 olefin without removal of the BOM protecting group (79%).
Hydrolysis of (−)-16 gave the carboxylic acid 17 (51%). The use of this segment in the synthesis of 1
will be reported in due course.
Scheme 3. Reagents: (a) MOMCl/iPr2NEt (95%); (b) DIBAL (92%); (c) BOMCl/iPr2NH (69%); (d) TBAF/THF (83%); (e)
DMSO/(COCl)2/NEt3 (84%); (f) (EtO)2P(O)CH2CO2Et/NaH (88%); (g) H2/10% Pd–C (79%); (h) KOH/H2O/EtOH (51%)
2. Experimental section
2.1. General data
Spectrograde solvents were used without purification with the exception of tetrahydrofuran which
was distilled from the sodium benzophenone ketyl. Aldrich sure-seal dichloromethane and DMSO
were used without further purification. Methyl (S)-3-hydroxy-2-methylpropionate and 4(R)-methyl-
5(S)-phenyloxazolidin-2-one were purchased from the Aldrich Chemical Company, Inc. Column chro-
matography was performed on silica gel 60 (0.04–0.063 mm, E. Merck or 60–200 mesh, Aldrich) and
‘flash’ chromatography was performed on silica gel 60 (230–400 mesh). Thin layer chromatography
was performed on Merck (Kieselgel 60 F254) or Kodak Chromagram (silica gel without fluorescent
indicator).
1
All H NMR and 13C NMR spectra were recorded at 300 and 75 MHz respectively. Melting points
were obtained on a Mel-Temp melting point apparatus and are uncorrected. Elemental analyses were
obtained from Robertson Microlit Laboratories, Inc., Madison, NJ and high resolution mass spectra (EI)
were obtained from the Washington University Resource for Mass Spectrometry.

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2.2. Methyl (S)-3-(tert-butyldiphenylsilyloxy)-2-methylpropionate ((+)-5)
This was prepared from (S)-3-hydroxy-2-methylpropionate in a fashion similar to the procedure of
Ley et al.7 (93%) and was identified by comparison to the literature 1H NMR spectral data: [α]D +17 (c
2.5, CHCl3), (lit.7 [α]D +23 (c 7.8, CH3OH)); Rf 0.38 (hexane:ethyl acetate=15:1).
2.3. (R)-3-(tert-Butyldiphenylsilyloxy)-2-methyl-1-propanol ((+)-6)
This was prepared by the reduction of (+)-5 with DIBAL in a fashion similar to the procedure of Ley
et al.7 (83%) and was identified by comparison to the literature 1H NMR spectral data: [α]D +6.1 (c 2.5,
CHCl3), (lit.7 [α]D +6.3 (c 1.0, CHCl3)); Rf 0.27 (CH2Cl2).
2.4. (S)-3-(tert-Butyldiphenylsilyloxy)-2-methylpropanal ((+)-7)
This was prepared by oxidation of (+)-6 with DMSO/(COCl)2 in a fashion similar to the procedure
of Roush et al.7 The crude product was passed through a 3.5 inch bed of SiO2 (CH2Cl2) to give (+)-7
1
as a waxy solid (88%) which was identified by comparison to the literature H NMR spectral data: mp
61–63°C (lit.7a mp 51–61°C); [α]D +22 (c 1.0, CHCl3); Rf 0.20 (hexanes:CH2Cl2=2:1).
2.5. Chiral aldol product ((+)-8)
To a solution of N-propionyl-4(R)-methyl-5(S)-phenyloxazolidin-2-one (36.6 g, 157 mmol) in CH2Cl2
(315 mL) cooled to 0°C was added dropwise freshly distilled dibutylboron triflate (47.3 g, 173 mmol)
followed immediately by diisopropylethylamine (32.8 mL, 188 mmol). The mixture was stirred for 30
min, then cooled to −78°C whereupon a solution of (+)-7 in CH2Cl2 (157 mL) was added to the reaction
mixture via a cannula transfer. The mixture was stirred for 30 min, warmed to rt, and stirred for an
additional 90 min. The mixture was cooled to 0°C and pH 7 buffer (225 mL), methanol (600 mL) and
30% H2O2:methanol (1:1, 225 mL) were added in succession. The mixture was warmed to rt and stirred
for 30 min, after which the phases separated. The aqueous layer was extracted twice with CH2Cl2, and
the combined organic phases were dried (MgSO4) and concentrated. The residue was purified by flash
chromatography (hexanes:ethyl acetate=12:1 to 8:1 gradient) to give (+)-8 as a colorless solid (78.4
1
g, 89%): mp 102–103°C; [α]D +22 (c 1.2, CHCl3); Rf 0.18 (hexanes:ethyl acetate=6:1); H NMR
(CDCl3/D2O) δ 7.70–7.66 (m, 4H), 7.44–7.37 (m, 9H), 7.33–7.30 (m, 2H), 5.68 (d, J=7.0 Hz, 1H),
4.78 (dq, 7.0, 6.6 Hz, 1H), 4.00–3.93 (m, 2H), 3.82 (dd, J=4.4, 9.9 Hz, 1H), 3.73 (d, J=6.6, 9.9 Hz, 1H),
1.90–1.80 (m, 1H), 1.25 (d, J=6.6 Hz, 3H), 1.06 (s, 9H), 0.93 (d, J=7.0 Hz, 3H), 0.91 (d, J=6.2 Hz,
3H); 13C NMR (CDCl3) δ 176.1, 152.6, 135.5, 133.2, 132.9, 132.8, 129.7, 128.6, 127.7, 125.5, 78.8,
75.1, 68.4, 55.0, 40.7, 37.5, 26.7, 19.1, 14.2, 13.2, 9.1; EI-HRMS m/z 560.2828 (calcd for C33H42NO5Si
(M+H)+ 560.2832); Anal. Calcd for C33H41NO5Si: C, 70.81; H, 7.38; N, 2.50. Found: C, 70.54; H, 7.35;
N, 2.45. A sample suitable for X-ray diffraction analysis10 was obtained by recrystallization from hot
methanol.
2.6. Methyl (2R,3S,4S)-5-t-butyldiphenylsilyloxy-3-hydroxy-2,4-dimethylpentanoate ((+)-9)
To a freshly prepared solution of methanolic sodium methoxide (1.9 g Na/350 mL MeOH) at 0°C was
slowly added a solution of (+)-8 (45.8 g, 81.8 mmol) in THF (250 mL). When 8 was no longer observed
by TLC monitoring (ca. 15 min), saturated aqueous NH4Cl was added and the heterogenous mixture

J. T. Wasicak, W. A. Donaldson / Tetrahedron: Asymmetry 9 (1998) 133–140
137
was partitioned between CH2Cl2/H2O. The layers were separated and the aqueous layer was extracted
with CH2Cl2. All of the CH2Cl2 phases were combined, dried (MgSO4) and concentrated. The residue
was purified by flash chromatography (hexanes:ethyl acetate=10:1) to give (+)-9 as a viscous oil (26.4 g,
78%): [α]D +6.8 (c 1.0, CHCl3); Rf 0.5 (hexanes:ethyl acetate=4:1); 1H NMR (CDCl3/D2O) δ 7.69–7.65
(m, 4H), 7.44–7.36 (m, 6H), 3.96 (dd, J=3.7, 8.4 Hz, 1H), 3.83 (d, J=4.2, 10.3 Hz, 1H), 3.70 (d, J=6.3,
10.3 Hz, 1H), 3.70 (s, 3H), 2.63 (dq, J=7.0, 3.7 Hz, 1H), 1.83–1.73 (m, 1H), 1.21 (d, J=7.0 Hz, 3H), 1.05
(s, 9H), 0.86 (d, J=7.0 Hz, 3H); MS (CI/NH3) m/z 415 (M+H)+, 432 (M+NH4)+.
2.7. Methyl (2R,3S,4S)-5-t-butyldiphenylsilyloxy-3-[methoxy(methoxy)]-2,4-dimethylpentanoate ((+)-
10)
To a solution of (+)-9 (26.1 g, 62.9 mmol) in freshly distilled diisopropylethylamine (125 mL) at 0°C
was slowly added, via a syringe, chloromethyl methyl ether (24.0 mL, 315 mmol). The reaction mixture
was warmed to rt, and then heated at 38°C for 18 h. After cooling to rt, the reaction mixture was diluted
with CH2Cl2 and washed with 0.25 N HCl (2×160 mL), followed by saturated aqueous NaHCO3, and
brine:H2O (1:1), dried (MgSO4) and concentrated. The residue was purified by flash chromatography
(hexanes:ethyl acetate=10:1) to give (+)-10 as a colorless oil which solidified upon storing in the freezer
1
(27.5 g, 95%): mp 54.5–55.5°C; [α]D +4 (c 0.9, CHCl3); Rf 0.60 (hexanes:ethyl acetate=4:1); H NMR
(CDCl3) δ 7.67–7.64 (m, 4H), 7.44–7.34 (m, 6H), 4.53 (d, J=6.6 Hz, 1H), 4.45 (d, J=6.6 Hz, 1H), 3.93
(dd, J=3.7, 7.8 Hz, 1H), 3.73 (d, J=4.2, 10.3 Hz, 1H), 3.66 (s, 3H), 3.61 (dd, J=6.0, 10.0 Hz, 1H), 3.19
(s, 3H), 2.70 (dq, J=7.0, 3.7 Hz, 1H), 1.90–1.80 (m, 1H), 1.14 (d, J=7.0 Hz, 3H), 1.07 (s, 9H), 0.99 (d,
J=7.0 Hz, 3H); MS (FAB) m/z 497 (M+K)+; Anal. Calcd for C26H38O5Si: C, 68.08; H, 8.35. Found: C,
67.93; H, 8.24.
2.8. (2S,3R,4S)-5-t-Butyldiphenylsilyloxy-3[(methoxy)methoxy]-2,4-dimethyl-1-pentanol ((+)-11)
To a solution of (+)-10 (26.7 g, 58.3 mmol) in THF (120 mL) at −78°C was added dropwise a solution
of DIBAL (128 mL, 1.0 M in toluene, 128 mmol). The mixture was stirred for 15 min, and then methanol
was cautiously added until gas evolution ceased. The mixture was warmed to rt and partitioned between
ethyl acetate and 1 M potassium sodium tartrate. The separated organic layer was washed with fresh
1 M potassium sodium tartrate, and the combined aqueous phases were extracted with CH2Cl2. All of
the organic phases were combined, dried (MgSO4), and concentrated. The residue was purified by flash
chromatography (hexanes:ethyl acetate=8:1 to 4:1 gradient) to give (+)-11 as a viscous oil (23.0 g, 92%):
1
[α]D +54 (c 1.0, CHCl3); Rf 0.25 (hexanes:ethyl acetate=4:1); H NMR (CDCl3/D2O) δ 7.66–7.62 (m,
4H), 7.45–7.34 (m, 6H), 4.68 (d, J=6.6 Hz, 1H), 4.43 (d, J=6.6 Hz, 1H), 3.75–3.67 (m, 3H), 3.61 (d,
J=7.7 Hz, 1H), 3.34 (s, 3H), 1.96–1.87 (m, 1H), 1.87–1.77 (m, 1H), 1.08 (s, 9H), 0.94 (d, J=7.0 Hz, 3H),
0.76 (d, J=7.0 Hz, 3H); HRMS (CI) m/z 431.2603 (calcd for C25H39O4Si (M+H)+ 431.2618; Anal. Calcd
for C25H38O4Si: C, 69.26; H, 8.90. Found: C, 69.72; H, 8.89.
2.9. (2S,3R,4S)-1-[(Benzyloxy)methoxy]-5-t-butyldiphenylsilyloxy-3[(methoxy)methoxy]-2,4-dimethyl-
1-pentane ((+)-12)
To a solution of (+)-11 (3.34 g, 7.76 mmol) in diisopropylamine (31 mL) at 0°C was added dropwise
benzyloxymethyl chloride (8.0 mL, 46.6 mmol). The reaction mixture was gradually warmed to rt and
stirred for 18 h. The mixture was then heated at a gentle reflux for 24 h. The mixture was cooled and
2 N aqueous HCl was carefully added. The mixture was extracted with ethyl acetate and the combined

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J. T. Wasicak, W. A. Donaldson / Tetrahedron: Asymmetry 9 (1998) 133–140
extracts washed with 2 N aqueous HCl, brine, dried (MgSO4), and concentrated. The residue was purified
by flash chromatography (hexanes:ethyl acetate=20:1) to give (+)-12 as an oil (2.95 g, 69%): [α]D +3.5
(c 1.4, CHCl3); Rf 0.17 (hexanes:ethyl acetate=15:1); 1H NMR (CDCl3) δ 7.67–7.63 (m, 4H), 7.43–7.27
(m, 11H), 4.97–4.49 (m, 6H), 3.74 (dd, J=3.9, 9.7 Hz, 1H), 3.64–3.44 (m, 4H), 3.20 (s, 3H), 2.30–1.84
(m, 2H), 1.07 (s, 9H), 0.98 (d, J=7.0 Hz, 3H), 0.88 (d, J=7.0 Hz, 3H); MS (CI/NH3) m/z 568 (M+NH4)+;
Anal. Calcd for C33H46O5Si: C, 71.96; H, 8.42. Found: C, 71.83; H, 8.26.
2.10. (2S,3S,4S)-5-[(Benzyloxy)methoxy]-3-[(methoxy)methoxy]-2,4-dimethyl-1-pentanol ((−)-13)
To a solution of (+)-12 (2.50 g, 4.65 mmol) in THF (18.5 mL) at 0°C was added a solution of
tetrabutylammonium fluoride in THF (1.0 M, 4.9 mL, 4.9 mmol). Thr reaction mixture was warmed
to rt and stirred for 3 h. The reaction mixture was poured into water and extracted with ether, the
combined extracts dried (MgSO4), and concentrated. The residue was purified by flash chromatography
(hexanes:ethyl acetate=4:1) to give (−)-13 as an oil (1.21 g, 83%): [α]D −42 (c 1.2, CHCl3); Rf 0.33
1
(hexanes:ethyl acetate=2:1); H NMR (CDCl3) δ 7.36–7.27 (m, 5H), 4.79–4.61 (m, 6H), 3.88–3.81 (m,
1H), 3.65 (dd, J=2.2, 9.2 Hz, 1H), 3.56–3.47 (m, 3H), 3.43 (s, 3H), 2.93 (t, J=6.8 Hz, OH), 2.07–1.97
(m, 1H), 1.88–1.79 (m, 1H), 0.96 (d, J=7.0 Hz, 3H), 0.88 (d, J=7.0 Hz, 3H); MS (CI/NH3) m/z 330
(M+NH4)+; Anal. Calcd for C17H28O5: C, 65.36; H, 9.03. Found: C, 65.17; H, 9.08.
2.11. (2R,3R,4S)-5-[(Benzyloxy)methoxy]-3-[(methoxy)methoxy]-2,4-dimethylpentanal ((−)-14)
To a solution of oxalyl chloride (1.4 mL, 16.5 mmol) in CH2Cl2 (25 mL) cooled to −78°C was added
DMSO (2.1 mL, 30 mmol), followed by dropwise addition of a solution of (−)-13 (4.7 g, 15 mmol) in
CH2Cl2 (30 mL). The reaction mixture was stirred for 15 min and then triethylamine (6.3 mL, 45 mmol)
was added. The reaction mixture was stirred at −78°C for 15 min, warmed to rt, and a solution of 1
N HCl was added. The phases were separated, and the organic phase washed with saturated aqueous
NaHCO3, brine, dried (MgSO4), and concentrated. The residue was purified by flash chromatography
(hexanes:ethyl acetate=8:1) to give (−)-14 as an oil (3.93 g, 84%): [α]D −27 (c 0.9, CHCl3); Rf 0.17
1
(hexanes:ethyl acetate=8:1); H NMR (CDCl3) δ 9.72 (d, J=2.9 Hz, 1H), 7.42–7.26 (m, 5H), 4.75 (s,
2H), 4.69 (d, J=6.8 Hz, 1H), 4.60 (d, J=6.8 Hz, 1H), 4.60 (m, 2H), 3.94 (dd, J=3.3, 7.4 Hz, 1H), 3.50
(d, J=7.0 Hz, 2H), 3.33 (s, 3H), 2.70–2.60 (m, 1H), 2.04–1.97 (m, 1H), 1.07 (d, J=7.0 Hz, 3H), 0.94 (d,
J=7.0 Hz, 3H); MS (CI/NH3) m/z 328 (M+NH4)+.
2.12. Ethyl (2E,4S,5S,6S)-7-[(benzyloxy)methoxy]-5-[(methoxy)methoxy]-4,6-dimethyl-2-heptenoate
(15)
To a slurry of NaH (415 mg, 13.8 mmol, 80% dispersion in mineral oil) in THF (25 mL) was added
dropwise triethyl phosphonoacetate (2.7 mL, 13.8 mmol). After 15 min, a solution of (−)-14 (3.9 g, 12.6
mmol) in THF (25 mL) was added. The reaction mixture was stirred for 18 h and then carefully quenched
with 1 N aqueous HCl (140 mL). The phases were separated, and the aqueous phase extracted with ether.
The combined organic phases were dried (MgSO4) and concentrated. The residue was purified by flash
chromatography (hexanes:ethyl acetate=12:1) to give 15 as an oil (4.2 g, 88%): Rf 0.42 (hexanes:ethyl
acetate=4:1); 1H NMR (CDCl3) δ 7.40–7.26 (m, 5H), 7.03 (dd, J=8.5, 15.5 Hz, 1H), 5.85 (d, J=15.5 Hz,
1H), 4.75 (s, 2H), 4.64 (d, J=6.7 Hz, 1H), 4.60 (s, 2H), 4.58 (d, J=6.7 Hz, 1H), 4.18 (q, J=7.0 Hz, 2H),
3.60–3.46 (m, 3H), 3.36 (s, 3H), 2.66–2.53 (m, 1H), 2.20–1.92 (m, 1H), 1.28 (t, J=7.0 Hz, 3H), 1.07 (s,
3H), 0.94 (d, J=7.0 Hz, 3H); MS (CI/NH3) m/z 398 (M+NH4)+.

J. T. Wasicak, W. A. Donaldson / Tetrahedron: Asymmetry 9 (1998) 133–140
139
2.13. Ethyl (4S,5S,6S)-7-[(benzyloxy)methoxy]-5-[(methoxy)methoxy]-4,6-dimethylheptanoate ((−)-16)
A solution of 15 (4.2 g, 11 mmol) and 10% Pd/C (360 mg) in ethyl acetate (22 mL) was stirred under
an atmosphere of H2 (1 atm) for 14 h. The reaction mixture was filtered and concentrated. The residue
was purified by flash chromatography (hexanes:ethyl acetate=15:1) to give 16 as an oil (3.3 g, 79%):
[α]D −9.2 (c 1.0, CHCl3); Rf 0.42 (hexanes:ethyl acetate=4:1); 1H NMR (CDCl3) δ 7.38–7.26 (m, 5H),
4.76 (s, 2H), 4.68 (d, J=6.6 Hz, 1H), 4.63 (d, J=6.6 Hz, 1H), 4.60 (s, 2H), 4.12 (q, J=7.0 Hz, 2H),
3.51–3.38 (m, 3H), 3.39 (s, 3H), 2.41 (ddd, J=5.5, 10.3, 15.6 Hz, 1H), 2.26 (ddd, J=6.4, 9.7, 15.6 Hz,
1H), 2.04–1.89 (m, 2H), 1.76–1.64 (m, 1H), 1.51–1.39 (m, H), 1.25 (t, J=7.0 Hz, 3H), 0.92 (d, J=7.0
Hz, 3H), 0.90 (d, J=7.0 Hz, 3H); 13C NMR (CDCl3) δ 173.9, 137.9, 128.4, 127.8, 127.6, 98.4, 94.8,
83.4, 71.1, 69.4, 60.2, 56.0, 35.4, 35.2, 32.2, 27.8, 16.0, 14.2, 11.3; MS (CI/NH3) m/z 400 (M+NH4)+;
EI-HRMS m/z 321.2057 (calcd for C19H29O4 (M–OCH2OCH3)+ 321.2066).
2.14. (4S,5S,6S)-7-[(Benzyloxy)methoxy]-5-[(methoxy)methoxy]-4,6-dimethylheptanoic acid (17)
A solution of KOH (245 mg, 4.3 mmol) in water (3 mL) and ethanol (9 mL) was added to 16 (1.38 g,
3.6 mmol). The reaction mixture was stirred for 5 h. The mixture was acidified with excess 2 N HCl and
extracted with CH2Cl2. All of the organic phases were combined, dried (MgSO4), and concentrated. The
residue was purified by flash chromatography (CHCl3:MeOH=98:2) to give 17 as an oil (650 mg, 51%):
1H NMR (CDCl3) δ 7.36–7.26 (m, 5H), 4.76 (s, 2H), 4.68 (d, J=6.6 Hz, 1H), 4.63 (d, J=6.6 Hz, 1H),
4.61 (s, 2H), 3.52–3.38 (m, 3H), 3.39 (s, 3H), 2.45 (ddd, J=5.5, 10.3, 16.0 Hz, 1H), 2.36 (ddd, J=6.9,
9.9, 16.0 Hz, 1H), 2.05–1.91 (m, 2H), 1.78–1.68 (m, 1H), 1.52–1.41 (m, H), 0.92 (d, J=6.7 Hz, 3H), 0.91
(d, J=6.6 Hz, 3H); 13C NMR (CDCl3) δ 179.7, 137.8, 128.4, 127.8, 127.6, 98.3, 94.8, 83.4, 71.0, 69.4,
65.8, 56.0, 35.2, 31.8, 27.5, 15.9, 15.2; MS (CI/NH3) m/z 372 (M+NH4)+; Anal. Calcd for C19H30O6: C,
64.38; H, 8.53. Found: C, 63.90; H, 8.49.
Acknowledgements
Financial support for this work was provided by the National Institutes of Health (GM-42641). The
high resolution mass-spectral determination for (−)-16 was made at the Washington University Resource
for Mass Spectrometry. The authors thank Mr Rodger Henry for obtaining the X-ray crystal structure of
(+)-8 and Mr Bireshwar Dasgupta for obtaining the 13C NMR spectra of 8, 16, and 17.
References
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H.; Young, S. D.; Hagen, J. P.; Pilli, R.; Badertscher, U. J. Org. Chem. 1985, 50, 2095–2105; (b) Roush, W. R.; Palkowitz,
A. D.; Ando, K. J. Am. Chem. Soc. 1990, 112, 6348–59.
8. Evans, D. A.; Dow, R. L.; Shih, T. L.; Takacs, J. M.; Zahler, R. J. Am. Chem. Soc. 1990, 112, 5290–5313.
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Chem. 1991, 56, 4151–7. This stereotriad has been previously prepared by aldol condensation of (S)-3-benzyloxy-2-
methylpropanal with N-propionyl-4(R)-isopropyloxazolidin-2-one: Seebach, D.; Chow, H.-F.; Jackson, R. F. W.; Lawson,
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10. Crystal data for (+)-8: MW=559.8, C33H41NO5Si, crystal dimensions 0.700×0.700×0.100 mm, monoclinic, P21 (#4),
a=13.836(3), b=7.2965(6), c=16.358(3) Å, β=108.14(2)°, V=1569.5(5) Å3, Z=2, Dcalc=1.184 g cm−3. Crystallographic
data were collected with a Rigaku AFC5R diffractometer using Cu Kα radiation (λ=1.54178 Å). Refinement of the
structure using full matrix least squares refinement of 360 parameters on 2363 reflections with I>3.00σ (I) gave R=0.053,
Rw=0.064(15). We thank Mr Rodger Henry, Abbott Laboratories, for performing this X-ray diffraction analysis.