Highly diastereoselective synthesis of pederic acid derivatives

Article abstract of DOI:10.1021/jo961841k

A highly diastereoselective synthesis of methyl pederate (2) is described. A critical feature of the successful route is the introduction of the key C(7)-stereocenter at the stage of 4 via an enantioselective, syn-selective aldol reaction of aldehyde 5 and the chiral acyl oxazolidinone 6. Aldehyde 5, in turn, was prepared from the readily available aldol derivative 7 via a chelate-controlled reaction with allyltrimethylsilane. Intermediate 4 was elaborated to 2 via the intermediacy of 7-O-(3,4-dimethoxybenzyl)pederic acid (3), an intermediate in Kishi's syntheses of mycalamides A and B and onnamide A, by way of methyl pyranoside 16 and the fully protected pederic acid derivative 11.

Full text of DOI:10.1021/jo961841k

474
J . Org. Chem. 1997, 62, 474-478
High ly Dia ster eoselective Syn th esis of P ed er ic Acid Der iva tives
William R. Roush,* Thomas G. Marron, and Lance A. Pfeifer
Department of Chemistry, Indiana University, Bloomington, Indiana 47405
Received September 26, 1996X
A highly diastereoselective synthesis of methyl pederate (2) is described. A critical feature of the
successful route is the introduction of the key C(7)-stereocenter at the stage of 4 via an
enantioselective, syn-selective aldol reaction of aldehyde 5 and the chiral acyl oxazolidinone 6.
Aldehyde 5, in turn, was prepared from the readily available aldol derivative 7 via a chelate-
controlled reaction with allyltrimethylsilane. Intermediate 4 was elaborated to 2 via the
intermediacy of 7-O-(3,4-dimethoxybenzyl)pederic acid (3), an intermediate in Kishi’s syntheses of
mycalamides A and B and onnamide A, by way of methyl pyranoside 10 and the fully protected
pederic acid derivative 11.
Mycalamides A and B are a pair of potent antiviral
require use of expensive (R,R)-2,3-epoxybutane24 as
starting material for the synthesis of the naturally
occurring enantiomer of 1. We therefore have developed
and report herein an enantioselective and highly dia-
stereoselective synthesis of methyl pederate (2) that
proceeds by way of 7-O-(3,4-dimethoxybenzyl)pederic acid
(3), an intermediate in Kishi’s syntheses of mycalamides
A, B and onnamide A.6,7
and antitumor agents isolated from a marine sponge of
the Mycale genus found in Otago Harbor, New Zealand.1,2
These compounds are sub-nanomolar inhibitors of protein
and DNA synthesis and, in addition to their promising
antiviral and antitumor activity,3,4 are reported also to
have immunosuppressive activity via inhibition of T-cell
activation.5 As a result, the mycalamides have attracted
considerable attention as targets for total synthesis.
Kishi reported pioneering total syntheses of mycalamides
A and B, as well as of the structurally related marine
sponge metabolite onnamide A,6,7 while Nakata has
completed a formal total synthesis of mycalamide A by
converging with one of Kishi’s advanced mycalamine
intermediates.8-10 In addition, studies on the synthesis
of the mycalamides have been reported from the labora-
tories of Kocienski11 and Hoffmann12,13 and our own
laboratory.14,15 Very recently, a total synthesis of 10-O-
methylmycalamide B was reported by Kocienski.16
In connection with our ongoing studies on the synthesis
of the mycalamides, we required a readily accessible
source of a suitably protected derivative of pederic acid,
1. Owing to the occurrence of pederic acid as a subunit
of the powerful insect vesicant pederin,17 several synthe-
ses of derivatives of 1 have been recorded.13,18-23 How-
ever, none of these prior syntheses was deemed suitable
for our purposes: several are quite lengthy, while others
X Abstract published in Advance ACS Abstracts, J anuary 1, 1997.
(1) Perry, N. B.; Blunt, J . W.; Munro, M. H. G.; Pannell, L. K. J .
Am. Chem. Soc. 1988, 110, 4850.
(2) Perry, N. B.; Blunt, J . W.; Munro, M. H. G.; Thompson, A. M. J .
Org. Chem. 1990, 55, 223.
(3) Burres, N. S.; Clement, J . J . Cancer Res. 1989, 49, 2935.
(4) Ogawara, H.; Higashi, K.; Uchino, K.; Perry, N. B. Chem. Pharm.
Bull. 1991, 39, 2152.
(5) Galvin, F.; Freeman, G. J .; Razi-Wolf, Z.; Benacerraf, B.; Nadler,
L.; Reiser, H. Eur. J . Immunol. 1993, 23, 283.
(6) Hong, C. Y.; Kishi, Y. J . Org. Chem. 1990, 55, 4242.
(7) Hong, C. Y.; Kishi, Y. J . Am. Chem. Soc. 1991, 113, 9693.
(8) Nakata, T.; Matsukura, H.; J ian, D.; Nagashima, H. Tetrahedron
Lett. 1994, 35, 8229.
(9) Nakata, T.; Fukui, H.; Nakagawa, T.; Matsukura, H. Heterocycles
1996, 42, 159.
(10) We refer to the right hand, amine component of the mycala-
mides as “mycalamine.”
In all but one of the previous syntheses of pederic acid
derivatives,13 the C(6)-C(7) bond was constructed with-
out control of the critical C(7)-(S) hydroxyl stereocenter.
This necessitated that several additional manipulations
(11) Davis, J .; Kocienski, P. J .; Boyle, T. Pol. J . Chem. 1994, 68,
2249.
(12) Hoffmann, R. W.; Schlapbach, A. Tetrahedron Lett. 1993, 34,
7903.
(17) Frank, J . H.; Kanamitsu, K. J . Med. Entomol. 1987, 24, 67 and
references cited therein.
(13) Hoffmann, R. W.; Breitfelder, S.; Schlapbach, A. Helv. Chim.
Acta 1996, 79, 346.
(14) Roush, W. R.; Marron, T. G. Tetrahedron Lett. 1993, 34, 5421.
(15) Marron, T. G.; Roush, W. R. Tetrahedron Lett. 1995, 36, 1581.
(16) Kocienski, P.; Raubo, P.; Davis, J . K.; Boyle, F. T.; Davies, D.
E.; Richter, A. J . Chem. Soc., Perkin Trans. 1 1996, 1797.
(18) Tsuzuki, K.; Watanabe, T.; Yanagiya, M.; Matsumoto, T.
Tetrahedron Lett. 1976, 4745.
(19) Adams, M. A.; Duggan, A. J .; Smolanoff, J .; Meinwald, J . J .
Am. Chem. Soc. 1979, 101, 5364.
(20) Isaac, K.; Kocienski, P.; Campbell, S. J . Chem. Soc., Chem.
Commun. 1983, 249.
S0022-3263(96)01841-5 CCC: $14.00 © 1997 American Chemical Society

Synthesis of Pederic Acid Derivatives
J . Org. Chem., Vol. 62, No. 3, 1997 475
be performed to establish the correct C(7) stereochemistry
via reduction of the corresponding ketone.13,18-23 The
plan that we have successfully reduced to practice
involves introduction of the C(7)-(S) stereocenter at the
stage of 4 via a syn-selective, enantioselective aldol
reaction of aldehyde 5 and the chiral acyloxazolidinone
6.25,26 Aldehyde 5, in turn, was prepared from the readily
available aldol derivative 7. Although the C(4)-(R)-
stereocenter of 4 has no long-term significance to this
synthesis, we anticipated that this center could influence
the stereoselectivity of the subsequent methyl hemiket-
alization step (cf., 4 f 10). Consequently, we elected to
use an alkyl ether protecting group in 7 to facilitate
control of the 1,3-anti diol relationship in 5 via a chelate-
controlled reaction of 7 with allyltrimethylsilane.27,28
Bu2BOTf, which provided the syn aldol 4 in 72% yield
for the two steps.25,26,34
The next stage of the synthesis took advantage of the
well-established low kinetic acidity of â-keto imides.29
Thus, oxidation of 4 by the Swern protocol32 provided the
corresponding â-keto imide (98% based on recovered 4).
The C(2)-benzyl ether was then selectively removed by
hydrogenation over 30% Pd/C in MeOH.35 The resulting
hemiacetal was treated with trimethyl orthoformate and
0.05 equiv of camphorsulfonic acid (CSA) in MeOH
overnight,36 which provided 10 in 77% overall yield from
4. Oxidation of 10 by the Swern protocol32 (92%) then
set the stage for introduction of the exo methylene unit
by using the Takai-Nozaki protocol (CH2I2, TiCl4, Zn,
THF, 86% yield).37 Finally, hydrolysis of the chiral imide
by using LiOH and H2O2 in THF-H2O (pH ) 6 work-
up)38,39 provided the very acid-sensitive pederic acid
1
derivative 3 (82% yield), the H NMR spectrum of which
was in excellent agreement with data kindly provided by
Prof. Kishi.6 For further proof of stereostructure, acid 3
was converted to the corresponding methyl ester by
treatment with Me3SiCHN2,40 and then the DMPM ether
was removed by treatment with DDQ in an 18:1 mixture
of CH2Cl2 and pH ) 7 phosphate buffer.6,35 This provided
methyl (+)-pederate 2 ([R]23 +115° (c ) 0.3, CH2Cl2)),
D
the stereostructure of which was unambiguously assigned
by comparison of the 1H NMR data with literature
values.18
Aldehyde 7 was synthesized in 76% yield from syn
aldol 821,29 by a three-step sequence involving treatment
of 8 with benzyl trichloroacetimidate and catalytic triflic
acid in cyclohexane-CH2Cl2 (87%),30 reduction of the
imide with LiBH4 in wet Et2O (92%),31 and oxidation of
the resulting primary alcohol via the usual Swern
protocol (DMSO, (COCl)2, CH2Cl2, -78 °C, then Et3N;
95% yield).32 Treatment of 7 with allyltrimethylsilane
and TiCl4 in CH2Cl2 at -78 °C provided the desired 4(R)-
homoallylic alcohol with >15:1 selectivity (58-74%),27,28
which was treated with tert-butyldimethylsilyl triflate
under standard conditions to give TBS ether 9 in 94%
yield. Cleavage of the vinyl group of 9 via a one-pot
OsO4-NaIO4 oxidation33 (91%) then set the stage for a
highly diastereoselective aldol reaction with the enol
borane prepared from the chiral glycolate imide 6 and
(21) Nakata, T.; Nagao, S.; Oishi, T. Tetrahedron Lett. 1985, 26,
6465.
(22) Willson, T. M.; Kocienski, P.; J arowicki, K.; Isaac, K.; Faller,
A.; Campbell, S. F.; Bordner, J . Tetrahedron 1990, 46, 1757.
(23) Kocienski, P.; J arowicki, K.; Marczak, S. Synthesis 1991, 1191.
(24) (R,R)-2,3-Epoxybutane ($120/g from Acros Organics) can be
synthesized in two steps from (R,R)-2,3-butanediol ($20/g, Aldrich) or
in seven steps from dimethyl (S,S)-tartrate: Byrstrom, S.; Hogberg,
H. E.; Norin, T. Tetrahedron 1981, 37, 2249.
(25) Evans, D. A.; Bartroli, J .; Shih, T. L. J . Am. Chem. Soc. 1981,
103, 2127.
(26) Evans, D. A.; Bender, S. L. Tetrahedron Lett. 1986, 27, 799.
(27) Heathcock, C. H.; Kiyooka, S.-i.; Blumenkopf, T. A. J . Org.
Chem. 1984, 4214.
(28) Reetz, M. T.; Kesseler, K.; J ung, A. Tetrahedron Lett. 1984, 25,
729.
(29) Evans, D. A.; Ennis, M. D.; Le, T.; Mandel, N.; Mandel, G. J .
Am. Chem. Soc. 1984, 106, 1154.
In summary, a highly diastereoselective synthesis of
pederic acid derivative 3, an intermediate in Kishi’s
(30) Widmer, U. Synthesis 1987, 568.
(31) Penning, T. D.; Djuric, S. W.; Haack, R. A.; Kalish, V. J .;
Miyashiro, J . M.; Rowell, B. W.; Yu, S. S. Synth. Commun. 1990, 20,
307.
(32) Mancusco, A. J .; Swern, D. Synthesis 1981, 165.
(33) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem.
Rev. 1994, 94, 2483 and references cited therein.
(34) Chiral glycolate imide 6 was prepared in 80% yield from (3,4-
dimethoxybenzyl)glycolic acid by using the procedure described for the
synthesis of the corresponding (p-methoxybenzyl)glycolate-derived
imide: Evans, D. A.; Kaldor, S. W.; J ones, T. K.; Clardy, J .; Stout, T.
J . J . Am. Chem. Soc. 1990, 112, 7001

476 J . Org. Chem., Vol. 62, No. 3, 1997
Roush et al.
mycalamide and onnamide syntheses,6,7 has been achieved.
Further progress on our total synthesis of the mycala-
mides will be reported in due course.
organic layer was washed with NaHSO4 (75 mL) and NaHCO3
(2 × 75 mL) and then dried (MgSO4), filtered, and concentrated
in vacuo. Purification of the crude product by flash chroma-
tography (silica gel, 9:1 to 3:1 hexanes-EtOAc) yielded alde-
hyde 7 (4.36 g, 95%) as a clear oil. This sensitive intermediate
was used directly in the next step without further purification.
To a -78 °C solution of aldehyde 7 (4.36 g, 22.7 mmol) in
CH2Cl2 (18.4 mL) was added TiCl4 (1.0 M in CH2Cl2, 27.2 mL,
27.2 mmol) followed immediately by allyltrimethylsilane (4.69
mL, 29.5 mmol). The reaction mixture was stirred at -78 °C
for 16 h and then quenched by addition of saturated NaOMe-
MeOH solution (5 mL). The reaction mixture was diluted with
CH2Cl2 (100 mL) and poured into saturated NH4Cl solution
(200 mL). The aqueous layer was separated and extracted
with CH2Cl2 (2 × 150 mL). The combined organic phases were
dried (MgSO4), filtered, and concentrated in vacuo. Purifica-
tion of the crude product by flash chromatography (silica gel,
9:1 to 3:1 hexanes-EtOAc) yielded the desired homoallylic
Exp er im en ta l Section 41
(2R,3R)-3-(Ben zyloxy)-2-m eth yl-1-bu ta n ol (12). To a
solution of aldol 821 (7.30 g, 31.9 mmol) in a mixture of
cyclohexane (42 mL) and CH2Cl2 (21 mL) was added benzyl
trichloroacetimidate (10.5 g, 41.4 mmol) followed by triflic acid
(0.422 mL). The mixture was stirred for 1 h and then filtered
through Celite. The solution was poured into saturated
aqueous NaHCO3 (100 mL), and the aqueous layer was
extracted with EtOAc (2 × 100 mL). The combined organic
phases were dried (MgSO4), filtered, and concentrated in
vacuo. Purification of the crude product by flash chromatog-
raphy (silica gel, 3:1 hexanes-EtOAc) yielded the desired
alcohol (3.09 g, 13.2 mmol, 58%)42 as a clear oil: [R]23 -32°
D
(c ) 1.4, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 7.32 (m, 5 H),
5.86-5.98 (m, 1 H), 5.08-5.13 (m, 2 H), 4.61 (A of AB, J AB
)
12.0 Hz, 1 H), 4.49 (B of AB, J AB ) 11.6 Hz, 1 H), 3.83 (dq, J
) 7.6, 6.6 Hz, 1 H), 3.71 (dt, J ) 7.6, 4.0 Hz, 1 H), 3.5 (s(br),
1 H), 2.31-2.38 (m, 1 H), 2.12-2.21 (m, 1 H), 1.82 (ddq, J )
7.6, 7.6, 4.0 Hz, 1 H), 1.23 (d, J ) 6.4 Hz, 3 H), 0.89 (d, J ) 6.8
Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 138.1, 135.2, 128.3,
127.6, 116.8, 77.4, 72.7, 70.5, 40.9, 39.6, 15.0, 12.3; IR (CDCl3)
3478, 3054, 2984 cm-1; HRMS for C15H23O2 (M+ + H) calcd
235.1691, found 235.1690. Anal. Calcd for C15H22O2: C, 76.88;
H, 9.46. Found: C, 77.57; H, 9.46.
benzyl ether (8.82 g , 87%) as a clear oil: [R]23 -43° (c 0.6,
D
1
CH2Cl2); H NMR (400 MHz, CDCl3) δ 7.31 (m, 5 H), 4.76 (A
of AB, J AB ) 11.6 Hz, 1 H), 4.49 (m, 1 H), 4.45 (B of AB, J AB
) 12.0 Hz, 1 H), 4.26 (dd, J ) 9.2, 8.8 Hz, 1 H), 4.18 (dd, J )
8.8, 2.8 Hz, 1 H), 4.02 (dq, J ) 7.2, 7.2 Hz, 1 H), 3.89 (dq, J )
5.6, 5.6 Hz, 1 H), 2.29 (m, 1 H), 1.27 (d, J ) 6.4 Hz, 3 H), 1.23
(d, J ) 6.4 Hz, 3 H), 0.88 (d, J ) 7.2 Hz, 3 H), 0.80 (d, J ) 6.8
Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 175.1, 153.8, 138.7,
128.2, 127.3, 76.5, 70.8, 62.9, 58.3, 43.0, 28.3, 17.9, 17.3, 14.5,
12.0; IR (CDCl3) 1776, 1697 cm-1; HRMS for C18H26O4N (M+
+ H) calcd 320.1855, found 320.1865.
To a solution of the homoallylic alcohol from the preceding
experiment (3.09 g, 13.2 mmol) in CH2Cl2 (27 mL) at -78 °C
was added 2,6-lutidine (3.09 mL, 26.5 mmol) followed by TBS-
OTf (3.95 mL, 17.2 mmol). The solution was stirred for 30
min at -78 °C, warmed to 0 °C for 30 min, and then diluted
with CH2Cl2 (100 mL) and poured into saturated NaHCO3 (100
mL). The aqueous layer was separated and extracted with
EtOAc (2 × 100 mL). The combined organic phases were dried
(MgSO4), filtered, and concentrated in vacuo. Purification of
the crude reaction mixture by flash chromatography (silica gel,
95 : 5 hexanes-EtOAc) yielded TBS ether 9 (4.32 g, 94%) as
To a 0 °C solution of the above benzyl ether (8.82 g, 27.7
mmol) in Et2O (553 mL) was added H2O (0.647 mL) followed
by LiBH4 (2 M in THF, 17.9 mL, 35.9 mmol). The solution
was stirred at 0 °C for 1 h and then at 23 °C for 1 h. NaOH
(1 N, 300 mL) was added dropwise, and the solution was
stirred at 23 °C for 1 h. The organic layer was removed, and
the aqueous layer was extracted with EtOAc (3 × 200 mL).
The combined organic layers were dried (MgSO4), filtered, and
concentrated in vacuo. Purification of the crude product by
flash chromatography (silica gel, 9:1 to 1:1 hexanes-EtOAc)
yielded the desired alcohol 12 (4.95 g, 92%) as a clear, volatile
a clear oil: [R]23 -25° (c ) 1.6, CH2Cl2); 1H NMR (400 MHz,
D
CDCl3) δ 7.34 (m, 5 H), 5.82-5.94 (m, 1 H), 5.02-5.08 (m, 2
H), 4.60 (A of AB, J AB ) 11.6 Hz, 1 H), 4.38 (B of AB, J AB
)
11.6 Hz, 1 H), 3.81 (q, J ) 6.0 Hz, 1 H), 3.64 (dq, J ) 5.4, 1.2
Hz, 1 H), 2.16-2.28 (m, 2 H), 1.58-1.68 (m, 1 H), 1.20 (d, J )
6.4 Hz, 3 H), 0.94 (d, J ) 6.4 Hz, 3 H), 0.89 (s, 9 H), 0.044 (s,
3 H), 0.023 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 139.3, 135.6,
128.2, 127.3, 127.2, 116.5, 75.4, 72.9, 70.4, 45.2, 37.6, 25.9, 17.6,
9.4, -4.2, -4.6; IR (CDCl3) 3054, 2962, 2892, 2856, 1422, 1278,
oil: [R]23 -32° (c ) 2.4, CH2Cl2); 1H NMR (400 MHz, CDCl3)
D
δ 7.1-7.3 (m, 5 H), 4.55 (A of AB, J AB ) 11.6 Hz, 1 H), 4.39 (B
of AB, J AB ) 12.0 Hz, 1 H), 3.62-3.66 (m, 2 H), 3.49 (dd, J )
11.2, 4.4 Hz, 1 H), 2.27 (s(br), 1 H), 1.94 (m, 1 H), 1.14 (d, J )
6.0 Hz, 3 H), 0.82 (d, J ) 7.2 Hz, 3 H); 13C NMR (100 MHz,
CDCl3) δ 138.4, 128.4, 127.6, 77.8, 70.6, 65.7, 39.2, 14.9, 11.9;
IR (CDCl3) 3499 cm-1; HRMS for C12H18O2 (M+ + H) calcd
195.1380, found 195.1385.
1249, 1052 cm-1; HRMS for C17H27O2Si (M+
291.1773, found 291.1772. Anal. Calcd for C21H36O2Si: C,
72.46; H, 10.40. Found: C, 70.46; H, 10.42.
-
tBu) calcd
(4R,5S,6R)-6-(Ben zyloxy)-4-(ter t-bu tyld im eth ylsiloxy)-
5-m eth yl-1-h ep ten e (9). To a -78 °C solution of (COCl)2
(3.35 g, 2.3 mL, 26.4 mmol) in CH2Cl2 (96 mL) was added
DMSO (3.74 mL). The solution was warmed to -40 °C for 15
min and then was recooled to -78 °C.32 To this solution was
added dropwise a solution of alcohol 12 (4.66 g, 24.0 mmol) in
CH2Cl2 (10 mL) followed by Et3N (16.7 mL, 120 mmol). The
reaction mixture was allowed to warm to 0 °C and then poured
into saturated aqueous NaHCO3 solution (150 mL). The
Meth yl [3,4-Dim eth oxyben zyl)oxy]a ceta te (13). A mix-
ture of (3,4-dimethoxyphenyl)methyl 2,2,2-trichloroacetimi-
date43 (8.00 g, 2.57 mmol), methyl glycolate (2.10 g, 23.4 mmol),
and pyridinium p-toluenesulfonate (0.294 g, 1.17 mmol) in
CH2Cl2 (46 mL) was stirred for 36 h. The solution was
concentrated in vacuo and filtered to give a yellow oil.
Purification of the crude product by flash chromatography
(silica gel, 50% hexanes-EtOAc) afforded DMPM ether 13
(35) Horita, K.; Yoshioka, T.; Tanaka, T.; Oikawa, Y.; Yonemitsu,
O. Tetrahedron 1986, 42, 3021.
(36) Formation of the methyl hemiketal is fast under these condi-
tions (<1 h). Cleavage of the TBS ether requires the overnight reaction
period.
(37) Hibino, J .; Okazoe, T.; Takai, K.; Nozaki, H. Tetrahedron Lett.
1985, 26, 5579.
1
(5.49 g, 98%) as a white solid: m.p. 60-61 °C; H NMR (400
MHz, CDCl3) δ 6.93 (d, J ) 2.0 Hz, 1 H), 6.88 (dd, J ) 2.0, 8.0
Hz, 1 H), 6.82 (d, J ) 8.0 Hz, 1 H), 4.56 (s, 2 H), 4.08 (s, 2 H),
3.88 (s, 3 H), 3.86 (s, 3 H), 3.75 (s, 3 H); 13C NMR (100 MHz,
CDCl3) δ 170.7, 149.0, 148.8, 129.4, 120.7, 111.3, 110.8, 73.1,
(38) Evans, D. A.; Britton, T. C.; Ellman, J . A. Tetrahedron Lett.
1987, 28, 6141.
(39) Use of a pH ) 6 aqueous phase is critical to the success of this
experiment. Substantial decomposition of 3 occurred in experiments
in which the pH of the aqueous phase was not carefully controlled.
(40) Aoyama, T.; Shioiri, T. Chem. Pharm. Bull. 1981, 29, 3249.
(41) For general experimental details, see: Roush, W. R.; Hunt, J .
A. J . Org. Chem. 1995, 60, 798. Unless otherwise noted, all compounds
purified by chromatography are sufficiently pure (>95% by 1H NMR
analysis) for use in subsequent reactions.
(42) The yield of the homoallylic alcohol was 74% when the allylation
was performed on a 1 g (5 mmol) scale.
(43) Wessel, H.-P.; Iversen, T.; Bundle, D. R. J . Chem. Soc., Perkin
Trans. 1 1985, 2247.

Synthesis of Pederic Acid Derivatives
J . Org. Chem., Vol. 62, No. 3, 1997 477
66.7, 55.8, 55.7, 51.7; IR (CDCl3) 3010, 1755, 1610 cm-1; HRMS
calcd for C12H16O5 (M+) 240.0993, found 240.1002. Anal.
Calcd for C12H16O5 C, 59.99; H, 6.71. Found: C, 59.75; H, 6.74.
3-[[(3,4-Dim et h oxyb en zyl)oxy)a cet yl]-4(S)-isop r op y-
loxa zolid in -2-on e (6). To a solution of methyl ester 13 (5.49
g, 22.9 mmol) in a solution of THF/H2O (60 mL, 60 mL) was
added NaOH (2.75 g, 69 mmol). The solution was stirred for
30 min, and then a solution of Et2O:hexanes (5 mL:50 mL)
was added and the layers were separated. The aqueous layer
was acidified to pH ) 4 with 1 N HCl and extracted with
EtOAc (2 × 50 mL). The aqueous layer was further acidified
to pH ) 2 and extracted with EtOAc (2 × 50 mL). The
combined organic extracts were washed with H2O (2 × 75 mL)
and brine (50 mL), dried (Na2SO4), and concentrated in vacuo.
The resulting acid (4.96 g, 96%) was dried by concentration
from benzene (2 × 10 mL) to remove residual H2O and then
used directly in the next step. 1H NMR (400 MHz, CDCl3)
data for carboxylic acid: δ 6.83-6.92 (m, 3 H), 4.59 (s, 2 H),
4.12 (s, 2 H), 3.89 (s, 3 H), 3.88 (s, 3 H).
To a -78 °C solution of the above carboxylic acid (6.45 g,
28.5 mmol) in THF (50 mL) was added n-BuLi (2.47 M in
hexanes, 12.3 mL, 30.4 mmol). The solution was stirred for
10 min, and then oxalyl chloride (2.49 mL, 28.5 mmol) was
added dropwise. The solution was warmed to 23 °C and stirred
for 1 h. The resulting solution of the acid chloride was used
immediately in the following step.
To a -78 °C solution of 4(S)-isopropyloxazolidinone25 (3.49
g, 27.0 mmol) in THF (40 mL) was added n-BuLi (10.9 mL,
27.0 mmol) dropwise. The resulting heterogeneous solution
was stirred for 20 min, at which time the acid chloride (see
preceding paragraph) was added. The solution was stirred for
15 min and then warmed to 0 °C and quenched with saturated
aqueous NH4Cl (50 mL). The solution was extracted with
EtOAc (3 × 50 mL), and the combined organic extracts were
washed with brine (50 mL), dried (Na2SO4), and concentrated
in vacuo. Purification of the crude reaction mixture by flash
h and then warmed to 0 °C and stirred for an additional 30
min. MeOH (15 mL), pH ) 7 buffer solution (20 mL), and
30% H2O2 (4 mL) were then added sequentially, and the
solution was warmed to 23 °C and stirred for 1 h. The aqueous
layer was then removed and extracted with CH2Cl2 (3 × 30
mL). The combined organic extracts were dried (Na2SO4) and
concentrated in vacuo. Purification of the crude product by
flash chromatography (silica gel, 2:1 hexanes-EtOAc) afforded
aldol 4 (1.19 g, 79%) as a white foam: [R]23D +8° (c ) 1.3, CH2-
1
Cl2); H NMR (400 MHz, CDCl3) δ 7.33 (m , 5 H), 6.70-6.90
(m, 3 H), 5.15 (d, J ) 3.2 Hz, 1 H), 4.58 (A of AB, J AB ) 11.6
Hz, 1 H), 4.58 (A′ of AB, J A′B′ ) 11.6 Hz, 1 H), 4.46 (B of AB,
J AB ) 12.0 Hz, 1 H), 4.39 (br q, J ) 4.4 Hz, 1 H), 4.35 (B′ of
AB, J A′B′ ) 12.0 Hz, 1 H), 4.21 (d, J ) 4.8 Hz, 1 H), 4.02-4.09
(m, 2 H), 3.84-3.87 (m, 1 H), 3.86 (s, 3 H), 3.84 (s, 3 H), 3.40
(dq, J ) 6.2, 6.0 Hz, 1 H), 2.42 (s (br), 1 H), 2.37 (m, 1 H), 1.76
(q, J ) 5.6 Hz, 1 H), 1.69 (ddd, J ) 14.2, 10.8, 2.0 Hz, 1 H),
1.53 (ddd, J ) 14.0, 8.8, 2.0 Hz, 1 H), 1.11 (d, J ) 6.0 Hz, 3
H), 0.96 (d, J ) 7.2 Hz, 3 H), 0.91 (d, J ) 6.0 Hz, 3 H), 0.86 (s,
9 H), 0.80 (d, J ) 7.2 Hz, 3 H), 0.038 (s, 3 H), 0.025 (s, 3 H);
13C (100 MHz, CDCl3) δ 170.7, 153.7, 148.9, 138.9,129.5, 128.2,
127.5, 127.3, 121.1, 111.7, 110.6, 79.3, 76.4, 73.0, 70.5, 70.1,
69.2, 63.9, 59.0, 55.8, 45.5, 35.5, 28.4, 25.8, 18.0, 14.4, 9.3, -4.6,
-4.7; IR (CDCl3) 3569, 2961, 1780, 1709 cm-1; FAB for
C37H57O9SiNNa (M+ + Na) calcd 710, found 710. Anal. Calcd
for C37H57O9SiN: C, 64.59; H, 8.35; N, 2.03. Found: C, 64.44;
H, 7.83; N, 1.94.
(4S)-[(2S,5R,6S,7R)-7-(Ben zyloxy)-5-(ter t-bu tyld im eth -
ylsiloxy)-3-oxo-2-[(3,4-d im e t h oxyb e n zyl)oxy]-6-m e t h -
ylocta n oyl]-4-isop r op yl-2-oxa zolid in on e (14). To a solu-
tion of (COCl)2 (0.188 mL, 2.16 mmol) in CH2Cl2 (20 mL) at
-78 °C was added DMSO (0.306 mL, 4.32 mmol). The solution
was warmed to -40 °C for 15 min and recooled to -78 °C,
and then a solution of alcohol 4 (1.35 g, 1.96 mmol) in CH2Cl2
(5 mL) was added dropwise followed by Et3N (1.37 mL, 9.83
mmol). The reaction mixture was allowed to warm to 0 °C
and poured into saturated aqueous NaHCO3 solution (100 mL).
The organic layer was washed with aqueous NaHSO4 (25 mL)
and aqueous NaHCO3 (2 × 25 mL) and then dried (MgSO4),
filtered, and concentrated in vacuo. Purification of the crude
product by flash chromatography (silica gel, 9:1 to 3:1 hex-
anes-EtOAc) yielded recovered alcohol 4 (300 mg, 22%) and
chromatography (silica gel, 1:1 hexanes-EtOAc) afforded
1
imide 6 (5.65 g, 62%) as a clear oil: [R]25 +58.6°; H NMR
D
(400 MHz, CDCl3) δ 6.97 (d, J ) 2.0 Hz, 1 H), 6.91 (dd, J )
2.0, 8.0 Hz, 1 H), 6.83 (d, J ) 8.0 Hz, 1 H), 4.67 (s, 2 H), 4.60
(s, 2 H), 4.44 (m, 1 H), 4.33 (dd, J ) 9.2, 8.0 Hz, 1 H), 4.25 (dd,
J ) 3.2, 9.2 Hz, 1 H), 3.89 (s, 3 H), 3.87 (s, 3 H), 2.43 (m, 1 H),
0.93 (d, J ) 6.8 Hz, 3 H), 0.87 (d, J ) 6.8 Hz, 3 H); 13C NMR
(100 MHz, CDCl3) δ 170.1, 153.9, 149.1, 148.9, 129.7, 120.8,
111.4, 110.9, 73.4, 69.3, 64.4, 58.2, 55.9, 55.8, 28.2, 17.8, 14.6;
IR (CDCl3) 3015, 1780, 1720, 1610, 1595; HRMS calcd for
C17H23NO6 (M+) 337.1519, found 337.1542. Anal. Calcd for
C17H23NO6: C, 60.52; H, 6.87; N, 4.15. Found: C, 60.42; H,
6.94; N, 4.01.
(4S)-[(2S,3R,5R,6S,7R)-7-(Ben zyloxy)-5-(ter t-b u t yld i-
m eth ylsiloxy)-3-h yd r oxy-2-[(3,4-d im eth oxyben zyl)oxy]-
6-m eth ylocta n oyl]-4-isop r op yl-2-oxa zolid in on e (4). To a
solution of TBS ether 9 (1.39 g, 3.97 mmol) in t-BuOH (14.3
mL), THF (4.3 mL), and H2O (1.4 mL) was added 4-methyl-
morpholine N-oxide (0.56 g, 4.77 mmol) followed by OsO4 (0.1
M in toluene, 2.0 mL, 0.2 mmol). The solution was stirred for
1.5 h, at which time additional H2O (6.5 mL) was added
followed by NaIO4 (2.54 g, 11.9 mmol). After being stirred for
an additional 30 min, the reaction mixture was diluted with
saturated aqueous Na2SO3 (25 mL). The resulting mixture
was stirred for 1 h and then extracted with Et2O (3 × 30 mL).
The combined organic extracts were washed with brine (50
mL), dried (Na2SO4), and concentrated in vacuo. Purification
of the crude reaction mixture by flash chromatography (silica
gel, 9:1 hexanes-EtOAc) afforded the intermediate aldehyde
(1.27 g, 91%) as a clear oil, which was stored at -78 °C until
it used in the subsequent aldol reaction.
To a -78 °C solution of Bu2BOTf (1.15 mL, 4.60 mmol) in
CH2Cl2 (4.6 mL) was added Et3N (0.66 mL, 4.82 mmol)
dropwise with stirring. After 1 min, a solution of chiral imide
6 (1.48 g, 4.38 mmol) in CH2Cl2 (7.7 mL) was added dropwise.
The resulting yellow solution was stirred at -78 °C for 3 h
and then warmed to 0 °C and stirred for an additional 30 min
to ensure complete enolization. The resulting light brown
solution was recooled to -78 °C, and then a solution of
aldehyde from the preceding experiment (0.77 g, 2.19 mmol)
in CH2Cl2 (3.4 mL) was added. The solution was stirred for 3
the desired â-keto imide 14 (1.03 g, 77%; >98% based on
1
recovered 4) as a clear oil: [R]23 +22° (c ) 2.1, CH2Cl2); H
D
NMR (400 MHz, CDCl3) δ 7.32 (m , 5 H), 6.70-6.90 (m, 3 H),
5.46 (s(br), 1 H), 4.64 (A of AB, J AB ) 11.6, 1 H), 4.59 (B of
AB, J AB ) 11.6, 1 H), 4.54 (A′ of AB′, J A′B′ ) 11.6, 1 H), 4.34
(B′ of A′B′, J A′B′ ) 11.6 Hz, 1 H), 4.30 (m, 2 H), 4.26 (t, J ) 8.4
Hz, 1 H), 4.18 (dd, J ) 8.8, 2.4 Hz, 1 H), 3.87 (s, 3 H), 3.84 (s,
3 H), 3.34 (dq, J ) 6.0, 6.0 Hz, 1 H), 2.75-2.90 (m, 2 H), 2.31
(m, 1 H), 1.73 (m, 1 H), 1.18 (d, J ) 6.4 Hz, 3 H), 0.909 (d, J
) 6.8 Hz, 3 H), 0.89 (d, J ) 6.8 Hz, 3 H), 0.83 (s, 9 H), 0.81 (d,
J ) 6.8 Hz, 3 H), 0.031 (s, 3 H), -0.028 (s, 3 H); 13C (100 MHz,
CDCl3) δ 203.5, 167.7, 153.7, 149.1, 144.0, 138.9, 128.7, 128.2,
127.8, 127.3, 121.5, 111.8, 110.7, 83.6, 76.5, 74.0, 70.7, 68.8,
64.1, 58.7, 55.8, 45.9, 42.7, 28.6, 25.8, 17.8, 17.7, 14.6, 9.4, -4.8,
-4.9; IR (CDCl3) 1782, 1710 cm-1; FAB mass spectrum for
C37H57O9SiNNa (M+ + Na), calcd 708, found 708. Anal. Calcd
for C37H57O9SiN: C, 64.78; H, 8.08; N, 2.04. Found: C, 64.70;
H, 7.77; N, 1.87.
(4S)-[(rS,2R,4R,5R,6R)-r-[(3,4-Dim eth oxyben zyl)oxy]-
2-m et h oxy-5,6-d im et h yl-4-h yd r oxy-2H -p yr a n yl]-4-iso-
p r op yl-2-oxa zolid in on e (10). A solution of the â-keto imide
14 (1.03 g, 1.50 mmol) in MeOH (30 mL) was flushed with a
stream of H2 for 1 min, and then 30% Pd/C (72 mg) was added.
The solution was stirred for 24 h at ambient temperature
under a steady stream of H2. The solution was then filtered
through silica gel and evaporated to give the crude product
that was used directly in the subsequent step.

478 J . Org. Chem., Vol. 62, No. 3, 1997
Roush et al.
A solution of the crude hemiketal in MeOH (10 mL) was
treated with HC(OMe)3 (0.250 mL) and catalytic camphorsul-
fonic acid (CSA) (17 mg). The mixture was stirred for 8 h,
and NaHCO3 (100 mg) was added.36 The reaction mixture was
concentrated in vacuo, and the crude product was purified by
flash chromatography (silica gel, 3:1 to 1:3 hexanes-EtOAc)
H), 1.01 (d, J ) 6.4 Hz, 3 H), 0.90 (d, J ) 7.2 Hz, 3 H), 0.84 (d,
J ) 6.8 Hz, 3 H), 0.81 (d, J ) 7.2 Hz, 3 H); 13C (100 MHz,
CDCl3) δ 171.5, 154.1, 148.9, 148.8, 146.4, 129.4, 121.4, 111.9,
110.6, 109.7, 101.2, 73.2, 68.6, 64.0, 59.5, 55.7, 48.6, 41.2, 32.3,
29.7, 17.9, 17.3, 15.0, 11.6; IR (CDCl3) 2971, 2938, 1782, 1701
cm-1; HRMS for C26H38O8N (M+ + H) calcd 492.2587, found
492.2583. Anal. Calcd for C25H35O8N: C, 65.05; H, 7.65; N,
2.89. Found: C, 64.73; H, 8.05; N, 3.89.
to yield ketal 10 (584 mg, 79%) as a clear oil: [R]23 +109° (c
D
) 1.6, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 6.78-6.96 (m, 3
H), 5.81 (s, 1 H), 4.55 (A of AB, J AB ) 12.4 Hz, 1 H), 4.51 (B of
AB, J AB ) 11.6 Hz, 1 H), 4.25-4.28 (m, 1 H), 4.07-4.18 (m, 3
H), 3.87 (s, 3 H), 3.85 (s, 3 H), 3.72 (dq, J ) 6.4, 2.0 Hz, 1 H),
3.12 (s, 3 H), 2.12-2.21 (m, 1 H), 1.96 (dd, J ) 13.6, 4.8 Hz, 1
H), 1.82 (dd, J ) 13.2, 11.6 Hz, 1 H), 1.73-1.80 (m, 1 H), 1.03
(d, J ) 6.4 Hz, 3 H), 0.89 (d, J ) 7.2 Hz, 3 H), 0.79 (d, J ) 6.8
Hz, 3 H), 0.68 (d, J ) 6.8 Hz, 3 H); 13C (100 MHz, CDCl3) δ
171.1, 154.0, 148.8, 148.7, 129.2, 121.4, 111.8, 110.5, 101.5,
73.0, 72.9, 67.8, 67.2, 63.9, 59.4, 55.7, 48.2, 38.3, 30.8, 29.6,
17.8, 17.4, 15.0, 3.5; IR (CDCl3) 2970, 1782, 1702 cm-1; HRMS
for C25H38O9N (M+ + H) calcd 496.2536, found 496.2537.
7-(3,4-Dim eth oxyben zyl)p ed er ic Acid (3). To a 0 °C
solution of imide 11 (55 mg, 0.112 mmol) in THF (1.8 mL) and
H2O (0.60 mL) was added 30% H2O2 (0.076 mL, 0.672 mmol)
followed by LiOH (5.4 mg, 0.224 mmol).38 The mixture was
stirred for 11 h at 23 °C and then diluted with EtOAc (2 mL)
and pH 7 buffer (1 mL). The Et2O layer, containing the
oxazolidinone chiral auxiliary, was removed and discarded.
The aqueous layer was diluted with pH ) 6 buffer (2 mL) and
extracted repeatedly with EtOAc (30 × 2 mL).39 The combined
organic phases were dried (MgSO4), filtered, and concentrated
in vacuo, giving 34 mg (82%) of acid 3 that was g95% pure by
1H NMR analysis. The instability of 3 precluded efforts to
obtain analytically pure samples by chromatographic methods.
The 1H NMR data for 3 were in complete agreement with data
provided by Professor Yoshi Kishi:6,7 1H NMR (400 MHz,
CDCl3) δ 6.80-7.0 (m, 3 H), 4.87 (s, 1 H), 4.86 (A of AB, J AB
)
11.6 Hz, 1 H), 4.77 (s, 1 H), 4.58 (B of AB, J AB ) 11.6 Hz, 1 H),
4.07 (s, 1 H), 3.99 (dq, J ) 6.4, 2.4 Hz, 1 H), 3.89 (s, 3 H), 3.88
(s, 3 H), 3.01 (s, 3 H), 2.54 (s, 2 H), 2.26 (dq, J ) 7.2, 2.8 Hz,
1 H), 1.78 (d, J ) 6.8 Hz, 3 H), 0.99 (d, J ) 7.2 Hz, 3 H); HRMS
for C18H25O6 (M+ - OMe) calcd 349.1644, found 349.1655.
Meth yl P ed er a te (2). To a solution of the sensitive acid 3
(15 mg, 0.039 mmol) in THF (1.0 mL) and MeOH (0.500 mL)
was added TMSCHN2 (0.059 mL, 2 M in hexane, 0.118
mmol).40 The solution was concentrated in vacuo, and the
crude reaction mixture was purified by flash chromatography
(silica gel, 1:1 hexanes-EtOAc) yielding the DMPM protected
methyl ester (11 mg, 71%).
(4S)-[(rS,2R,5R,6R)-r-[(3,4-Dim et h oxyb en zyl)oxy]-2-
m eth oxy-5,6-d im eth yl-4-oxo-2H-p yr a n yl]-4-isop r op yl-2-
oxa zolid in on e (15). To a solution of (COCl)2 (0.113 mL, 1.29
mmol) in CH2Cl2 (12 mL) at -78 °C was added DMSO (0.183
mL, 2.59 mmol). The solution was warmed to -40 °C for 15
min and then recooled to -78 °C. To this solution was added
dropwise a solution of alcohol 10 (0.584 g, 1.17 mmol) in CH2-
Cl2 (1 mL) followed by Et3N (0.822 mL, 5.89 mmol). The
reaction mixture was allowed to warm to 0 °C and poured into
saturated aqueous NaHCO3 solution (50 mL). The organic
layer was separated and washed with aqueous NaHSO4 (25
mL) and aqueous NaHCO3 (2 × 25 mL) and then dried
(MgSO4), filtered, and concentrated in vacuo. Purification of
the crude product by flash chromatography (silica gel, 9:1 to
To a solution of the above methyl ester (10 mg, 0.026 mmol)
in CH2Cl2 (0.246 mL) was added pH ) 7 aqueous buffer (0.013
mL) followed by DDQ (6.5 mg, 0.029 mmol).6,7 The mixture
was stirred for 30 min before additional DDQ was added (3
mg). The mixture was stirred for 1 h and then poured into
saturated aqueous NaHCO3 solution (10 mL). The aqueous
layer was extracted with EtOAc (2 × 10 mL), and the combined
organic phases were dried (MgSO4), filtered, and concentrated
in vacuo. Purification of the crude product by flash chroma-
tography (silica gel, 2% MeOH:CH2Cl2) yielded methyl peder-
1:1 hexanes-EtOAc) yielded ketone 15 (0.533 g, 92%) as a
1
clear oil: [R]23 +75° (c ) 1.0, CH2Cl2); H NMR (400 MHz,
D
CDCl3) δ 6.79-6.93 (m, 3 H), 5.95 (s, 1 H), 4.53 (s, 2 H), 4.32-
4.37 (m, 1 H), 4.16-4.24 (m, 2 H), 4.05 (dq, J ) 6.0, 3.2 Hz, 1
H), 3.87 (s, 3 H), 3.86 (s, 3 H), 3.14 (s, 3 H), 3.07 (d, J ) 16.0
Hz, 1 H), 2.52 (dd, J ) 16.0, 1.2 Hz, 1 H), 2.14-2.28 (m, 2 H),
1.10 (d, J ) 6.4 Hz, 3 H), 0.95 (d, J ) 7.2 Hz, 3 H), 0.91 (d, J
) 6.8 Hz, 3 H), 0.82 (d, J ) 6.4 Hz, 3 H); 13C (100 MHz, CDCl3)
δ 209.0, 171.2, 154.0, 148.9, 148.8, 144.0, 129.1, 121.3, 111.7,
110.6, 102.8, 72.9, 72.3, 67.3, 64.0, 59.3, 55.8, 48.7, 40.8, 29.5,
ate (2) as a clear oil (80%): [R]23 +115° (c ) 0.3, CH2Cl2); 1H
D
NMR (400 MHz, CDCl3) δ 4.84 (t, J ) 2.0 Hz, 1 H), 4.73 (t, J
) 1.6 Hz, 1 H), 4.36 (d, J ) 5.6 Hz, 1 H), 3.92 (dq, J ) 6.4, 2.4
Hz, 1 H), 3.83 (s, 3 H), 3.30 (s, 3 H), 2.91 (d, J ) 5.6 Hz, 1 H),
17.8, 16.5, 15.0, 9.8; IR (CDCl3) 2960, 2925, 1780, 1700 cm-1
;
HRMS for C25H36O9N (M+ + H) calcd 494.2380, found 494.2377.
Anal. Calcd for C25H35O9N: C, 60.84; H, 7.15; N, 2.84.
Found: C, 60.95; H, 7.37; N, 2.58.
2.37 (A of AB, dt, J ) 14.0, 2.0 Hz, 1 H), 2.31 (B of AB, J AB
)
14.4 Hz, 1 H), 2.22 (dq, J ) 7.2, 2.8 Hz, 1 H), 1.16 (d, J ) 6.4
Hz, 3 H), 0.94 (d, J ) 6.8 Hz, 3 H); 13C NMR (100 MHz, CDCl3)
δ 172.8, 146.0, 110.1, 99.5, 72.5, 69.4, 52.6, 48.8, 41.3, 33.5,
29.7, 17.7, 11.6; HRMS for C11H17O4 (M+ - OMe) calcd
213.1122, found 213.1089.
(4S)-[(rS,2R,5R,6R)-r-[(3,4-d im et h oxyb en zyl)oxy]-2-
m et h oxy-5,6-d im et h yl-4-m et h ylen e-2H -p yr a n yl]-4-iso-
p r op yl-2-oxa zolid in on e (11). A mixture of Zn (122 mg, 1.87
mmol) and CH2I2 (0.084 mL, 1.04 mmol) in THF (1.0 mL) was
stirred for 30 min at 23 °C. The solution was cooled to 0 °C,
and then TiCl4 (0.207 mL, 0.207 mmol) was added, and the
solution was allowed to warm to 23 °C and stirred for 30 min.
A solution of ketone 15 (96 mg, 0.207 mmol) in THF (1.6 mL)
was then added dropwise.37 The mixture was stirred for 2.5
h and then was poured into saturated aqueous NaHCO3
solution (5 mL). The aqueous layer was extracted with EtOAc
(2 × 20 mL), and the combined organic layers were dried
(MgSO4), filtered, and concentrated in vacuo. Purification of
the crude reaction mixture by flash chromatography (silica gel,
9:1 to 1:1 hexanes-EtOAc) yielded 11 (82 mg, 86%) as a clear
oil: [R]23D +260° (c ) 3.0, CH2Cl2); 1H NMR (400 MHz, CDCl3)
δ 6.75-7.00 (m, 3 H), 5.86 (s, 1 H), 4.79 (t, J ) 2.0 Hz, 1 H),
4.73 (t, J ) 2.0 Hz, 1 H), 4.57 (A of AB, J AB ) 12.0 Hz, 1 H),
4.53 (B of AB, J AB ) 12.0 Hz, 1 H), 4.28-4.32 (m, 1 H), 4.12-
4.20 (m, 2 H), 3.88 (s, 3 H), 3.85 (s, 3 H), 3.79 (dq, J ) 6.8, 2.8
Hz, 1 H), 3.16 (s, 3 H), 2.74 (dt, J ) 2.0, 2.4 Hz, 1 H), 2.72 (t,
J ) 2.0 Hz, 1 H), 2.33 (d, J ) 15.2 Hz, 1 H), 2.12-2.22 (m, 2
The 1H NMR data obtained for 2 were in excellent agree-
ment with literature values.18
Ack n ow led gm en t. This research was supported by
a grant from the National Institute of General Medical
Sciences (GM 38907). A graduate fellowship to T.G.M.
provided by General Electric is also gratefully acknowl-
edged.
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H NMR
spectra of intermediates 2, 3, 10, and 12 (4 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.
J O961841K