Stereoselective Synthesis of a Key Precursor of Halicholactone and Neohalicholactone

Article abstract of DOI:10.1021/jo971564x

An efficient synthesis of a known precursor of halicholactone (1a) and neohalicholactone (1b) has been developed using the strategically functionalized key cyclopropane intermediate 2, which in turn has been synthesized via stereoselective cyclopropanation of trans-cinnamyl alcohol in the presence of the chiral dioxaborolane ligand 4. Elaboration of the above bifunctional cyclopropane to the target molecule was achieved in a relatively short reaction sequence and in good overall yield, representing a formal synthesis of the title compounds.

Full text of DOI:10.1021/jo971564x

642
J . Org. Chem. 1998, 63, 642-646
Ster eoselective Syn th esis of a Key P r ecu r sor of Ha lich ola cton e
a n d Neoh a lich ola cton e†
Debendra K. Mohapatra and Apurba Datta*
Organic III, Indian Institute of Chemical Technology, Hyderabad-500 007, India
Received August 21, 1997
An efficient synthesis of a known precursor of halicholactone (1a ) and neohalicholactone (1b) has
been developed using the strategically functionalized key cyclopropane intermediate 2, which in
turn has been synthesized via stereoselective cyclopropanation of trans-cinnamyl alcohol in the
presence of the chiral dioxaborolane ligand 4. Elaboration of the above bifunctional cyclopropane
to the target molecule was achieved in a relatively short reaction sequence and in good overall
yield, representing a formal synthesis of the title compounds.
Sch em e 1
In tr od u ction
Cyclopropyl and lactone containing oxylipins are a
growing class of natural products, isolated from a wide
spectrum of marine organisms. Among these compounds,
constanolactones,1 halicholactone, and neohalicholactone2
possess a linear C20 carbon skeleton, derived from
eicosanoid precursors, while solandelactones,3 having a
C22 carbon skeleton, are thought to be of docosanoid
origin. Because of their important physiological proper-
ties2,3 and the presence of interesting structural features,
such as a trans-substituted cyclopropane subunit and
saturated or unsaturated lactones of various ring size,
these compounds have attracted the attention of a
number of synthetic organic chemists worldwide. In the
approaches reported so far for the syntheses of the above
eicosanoid oxylipins, the central cyclopropyl core and the
lactone ring are generally constructed from an intermedi-
ate of appropriate carbon chain at a fairly advanced stage
of the synthesis.4-6 This strategy renders these methods
specific only to a particular target molecule, thereby
limiting their scope as a general approach for synthesiz-
ing the above-mentioned class of oxylipins. Our own
endeavor toward the synthesis of this class of compounds
was thus motivated by the need to establish a general
route that will be sufficiently flexible and practical to
allow the synthesis of all or a majority of these com-
pounds and their analogues from an advanced common
intermediate.
Our strategy involved (i) stereoselective synthesis of a
pivotal trans-substituted bifunctional cyclopropane ring
and (ii) utilization of this intermediate for synthesizing
the above-mentioned class of oxylipins. The present
report describes the synthesis of a versatile cyclopropane
intermediate 2 (Scheme 1) and its elaboration to a known
precursor of halicholactone (1a ) and neohalicholactone
(1b).
Resu lts a n d Discu ssion
Cyclopropanation of trans-cinnamyl alcohol (3) accord-
ing to Charette’s protocol,7 in the presence of the diox-
aborolane chiral ligand 4 [derived from (S,S)-(-)-
N,N,N′,N′-tetramethyltartaric acid diamide], cleanly
afforded the (1R,2R)-cyclopropyl alcohol 5 with good
enantioselectivity8 and high yield (Scheme 2). Acetyla-
tion of the hydroxy group followed by oxidative degrada-
tion of the phenyl moiety to a carboxylic acid under
standard conditions provided the key cyclopropane in-
termediate 2 in high overall yield. The carboxylic acid
carbonyl and the acetate protected latent aldehyde
functionality in this molecule allows for rapid construc-
tion of the target compounds, as has been illustrated
below. Conversion of acid 2 to the corresponding Weinreb
amide 7 and its reaction with allylmagnesium bromide
yielded the allyl ketone 8. Protection of the free hydroxy
group as its TBDMS ether and stereoselective reduction
† IICT communication No. 3824.
(1) (a) Nagle, D. G.; Gerwick, W. H. Tetrahedron Lett. 1990, 31,
2995-2998. (b) Nagle, D. G.; Gerwick, W. H. J . Org. Chem. 1994, 59,
9, 7227-7237.
(2) (a) Niwa, H.; Wakamatsu, K.; Yamada, K. Tetrahedron Lett.
1989, 30, 4543-4546. (b) Kigoshi, H.; Niwa, H.; Yamada, K.; Stout, T.
J .; Clardy, J . Tetrahedron Lett. 1991, 32, 2427-2430.
(3) Seo, Y.; Cho, K. W.; Rho, J .-R.; Shin, J .; Kwon, B.-M.; Bok, S.-
H.; Song, J .-I. Tetrahedron, 1996, 52, 10583-10596.
(4) (a) Synthesis of constanolactones A and B: White, J . D.; J ensen,
M. S. J . Am. Chem. Soc. 1995, 117, 6224-6233. (b) Synthesis of
constanolactone E: Miyaoka, H.; Shigemoto, T.; Yamada, Y. Tetrahe-
dron Lett. 1996, 37, 7407-7408.
(5) Synthesis of halicholactone and neohalicholactone: Crichter, D.
J .; Connoly, S.; Wills, M. Tetrahedron Lett. 1995, 36, 3763-3766.
(6) Synthesis of related eicosanoids: (a) White, J . D.; J ensen, M. S.
J . Am. Chem. Soc. 1993, 115, 2970-2971. (b) Nagasawa, T.; Handa,
Y.; Onoguchi, Y.; Suzuki, K. Bull. Chem. Soc. J pn. 1996, 69, 31-39.
(7) Charette, A. B.; Prescott, S.; Brochu, C. J . Org. Chem. 1995, 60,
1081-1083.
(8) The enantiomeric excess was determined by comparison of the
specific rotation of 5 ([R]D ) -62.2 (c ) 1.9, EtOH)) with ent-5 ([R]D
66 (c ) 1.9, EtOH; at 93% ee) as reported in ref 7 above.
)
S0022-3263(97)01564-8 CCC: $15.00 © 1998 American Chemical Society
Published on Web 01/09/1998

A Precursor of Halicolactone and Neohalicholactone
J . Org. Chem., Vol. 63, No. 3, 1998 643
Sch em e 2a
Sch em e 3a
a
(a ) (i) OsO4, NMO, acetone; (ii) NaIO4, NaHCO3, MeOH, H2O;
(b) HO2C(CH2)4PPh3Br, NaHMDS, THF; (c) 2,4,6-trichlorobenzoyl
chloride, Et3N, DMAP, toluene; (d ) TBAF, THF; (e) IBX, DMSO.
of 1, the minor isomer 10L was also converted to the
required isomer via a Mitsunobu inversion of the hydroxy
group (Scheme 2). Surprisingly, attempted ozonolysis of
the terminal alkene of 10U led to an intractable mixture
of products. This problem was however overcome by
following a two-step sequence via OsO4-catalyzed dihy-
droxylation of 10U followed by oxidation with NaIO4,
which resulted in the clean formation of the expected
hydroxy aldehyde 11 (Scheme 3). Cis-selective Wittig
reaction of this aldehyde with the reagent derived from
(4-carboxybutyl)triphenylphosphonium bromide in the
presence of NaHMDS at -78 °C10 yielded the lactone
precursor hydroxy acid 12. Lactonization of the acid 12
under Yamaguchi conditions11 cleanly afforded the ex-
pected nine-membered lactone 13 in 66% yield.
a
(a ) Ac2O, DMAP, CH2Cl2; (b) RuCl3‚H2O, NaIO4, CH3CN-
CCl4-H2O; (c) MeNH(OMe)‚HCl, 1,1′-carbonyldiimidazole, Et3N,
CH2Cl2; (d ) allylmagnesium bromide, Et2O-THF; (e) TBDMSCl,
imidazole, CH2Cl2; (f) K-Selectride, THF, -78 °C; (g) (i) Ph3P,
DEAD, glacial AcOH, THF; (ii) NaOMe, MeOH.
The smooth formation of the lactone ring has been
attributed to the presence of the cis-double bond, which
provides both an enthalpic and entropic assistance to the
above cyclization.10 Finally, deprotection of the TBDMS
linkage and oxidation of the resulting alcohol 14 culmi-
nated in the synthesis of the aldehyde 15, a known
precursor of halicholactone (1a ) and neohalicholactone
(1b),5 thereby representing a formal synthesis of the
above compounds.
Con clu sion
F igu r e 1. ∆δ ) (δS - δR) × 103 for (R)- and (S)-MTPA esters
of compound 10U.
In summary, our strategy of initial synthesis of an
enantiopure bifunctional cyclopropane ring with dif-
ferential substitution followed by construction of the rest
of the target molecule on this cyclopropane framework
represents an effective convergent approach for the title
compounds. Moreover, following the above approach and
starting from the versatile cyclopropane intermediate 2,
it should also be possible to synthesize the other members
of the described oxylipin family. Efforts in this direction
are currently underway.
of the ketone 9 using K-Selectride (potassium tri-sec-
butylborohydride) afforded a 9:1 ratio of diastereomeric
alcohols 10U (less polar) and 10L (more polar), which
were easily separated by column chromatography.
Stereochemical assignment of the newly created asym-
metric center was achieved by Mosher’s modified method.9
Thus, esterification of the major isomer 10U with both
(R)- and (S)-R-methoxy-R-(trifluoromethyl)phenylacetic
acid (MTPA) demonstrated positive chemical shift dif-
ferences (∆δ ) δS - δR ) for protons on C-1 through C-4
(Figure 1), while protons on C-6 through C-8 showed
negative differences, which is consistent with C-5 bearing
an S configuration.
Exp er im en ta l Section
Gen er a l. Reagents and solvents were obtained from com-
mercial suppliers and used as received, unless otherwise noted.
Moisture- or air-sensitive reactions were conducted under a
Having found the major diastereoisomer 10U to be of
appropriate stereochemistry for the proposed synthesis
(10) Crichter, D. J .; Connoly, S.; Mahon, M. F.; Wills, M. J . Chem.
Soc. Chem. Commun. 1995, 139-140 and references therein.
(11) Inaga, J .; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M.
Bull. Chem. Soc. J pn. 1979, 52, 1989-1993.
(9) (a) Ohtani, I.; Kusumi, J .; Kashman, Y.; Kakisawa, H. J . Am.
Chem. Soc. 1991, 113, 4092-4096. (b) Yoshida, W. Y.; Bryan P. J .;
Baker, B. J .; McClintock, J . B. J . Org. Chem. 1995, 60, 780-782.

644 J . Org. Chem., Vol. 63, No. 3, 1998
Mohapatra and Datta
nitrogen atmosphere in oven-dried (120 °C) glass apparatus.
Diethyl ether and THF were distilled from sodium benzophe-
none ketyl prior to use. Toluene was dried over sodium,
whereas dichloromethane and triethylamine were distilled
from CaH2 and stored over molecular sieves and anhydrous
KOH, respectively. All yields reported refer to isolated mate-
rial judged to be homogeneous by TLC and NMR spectroscopy.
Column chromatography was performed on silica gel 60 (60-
120 mesh), using ethyl acetate/hexane mixture as eluent,
unless specified otherwise. The NMR spectra were recorded
in CDCl3 on a 200 MHz spectrometer with TMS as the internal
standard. Elemental analyses were carried out at the Indian
Association for the Cultivation of Science, J adavpur, Calcutta,
India.
P r ep a r a tion of Dioxa bor ola n e 4. This reagent was
prepared according to the reported procedure,7 by reacting
(S,S)-(-)-N,N,N′,N′-tetramethyltartaric acid diamide with 1-
butaneboronic acid to yield a light yellow oil: 1H NMR δ 0.73-
0.88 (m, 5H), 1.18-1.42 (m, 4H), 2.94 (s, 6H), 3.18 (s, 6H), 5.45
(s, 2H); EIMS 272 (M+ + 2).
for 24 h. CH2Cl2 (50 mL) was then added to the mixture,
which was then filtered. The layers were separated, the
aqueous layer was extracted with CH2Cl2 (3 × 30 mL), and
the combined CH2Cl2 layers were dried over anhydrous Na2-
SO4. Removal of solvent and purification of the residue by
column chromatography afforded the cyclopropane carboxylic
acid 2 (1.2 g, 93%) as a colorless liquid: [R]D ) -18.6 (c ) 1,
EtOH); IR (neat) 3240, 1740, 1694 cm-1 1H NMR δ 0.9 (m,
;
1H), 1.25 (m, 1H), 1.55 (m, 1H), 1.77 (m, 1H), 2.12 (s, 3H), 3.8
(dd, J ) 4.2 and 10.5 Hz, 1H), 4.02 (dd, J ) 4.2 and 10.7 Hz,
1H), 9.85 (br s, 1H); CIMS 159 (MH+). Anal. Calcd for
C7H10O4 (158.16): C, 53.16; H, 6.33. Found: C, 52.94; H, 6.70.
(1R,2R)-tr a n s-2-(Acet oxym et h yl)cyclop r op a n e-1-(N-
m eth oxy-N-m eth yl)ca r boxa m id e (7). To a solution of the
carboxylic acid 2 (839 mg, 5.3 mmol) in CH2Cl2 (20 mL) was
added 1,1′-carbonyldiimidazole (1.11 g, 6.9 mmol); the mixture
was stirred for 30 min. The solution was then cooled to 0 °C
and a mixture of N,O-dimethylhydroxylamine hydrochloride
(671 mg, 6.9 mmol) in 0.9 mL (6.9 mmol) of Et3N was added.
The mixture was stirred at 0 °C for 1 h and at room
temperature for 14 h, after which CH2Cl2 (50 mL) was added;
the mixture was washed sequentially with 1 N HCl (2 × 50
mL), saturated aqueous NaHCO3, and brine. Drying (Na2SO4)
of the organic phase and removal of solvent followed by column
chromatography of the residue yielded the pure amide 7 (875
mg, 82%) as a colorless liquid: [R]D ) -20.8 (c ) 1, CHCl3);
P r ep a r a tion of th e Zn (CH2I)2‚DME Com p lex Solu tion
in CH2Cl2.7 To a solution of 3.8 mL (37.3 mmol) of Et2Zn in
37 mL of CH2Cl2 and 3.9 mL (37.3 mmol) of freshly distilled
DME at -15 °C was added 6 mL (75 mmol) of CH2I2 over a
period of 30 min, as the internal temperature was maintained
below -10 °C. The resulting colorless solution was used as
such in the cyclopropanation reaction.
1
IR (neat) 1738, 1655 cm-1 ; H NMR δ 0.79 (m, 1H), 1.21 (m,
(1R,2R)-tr a n s-1-(H yd r oxym et h yl)-2-p h en ylcyclop r o-
p a n e (5). To a mixture of dioxaborolane 4 (2.2 g, 8.2 mmol),
cinnamyl alcohol (1 g, 7.5 mmol), and 4 Å molecular sieves
(300 mg) in 40 mL of CH2Cl2 at -15 °C was added the Zn-
(CH2I)2‚DME complex solution as prepared above, over a
period of 30 min, as the internal temperature was kept below
-10 °C. After completion of addition, the mixture was stirred
for 2 h at -10 °C and kept in the refrigerator (-10 °C) for
another 20 h. The reaction was then quenched by addition of
saturated aqueous NH4Cl (25 mL), the organic layer separated,
the aqueous layer extracted with ether (3 × 50 mL) and the
combined organic layers stirred vigorously with aqueous KOH
(5M, 30 mL) for 16 h. The organic layer was separated,
washed sequentially with 10% aqueous HCl, saturated aque-
ous NaHCO3, water, and brine, dried (anhydrous Na2SO4), and
concentrated. Column chromatography of the crude residue
afforded the pure product 5 (1.04 g, 97%) as a colorless liquid:
[R]D ) -62.2 (c ) 1.9, EtOH), [for ent-5 [R]D ) +66 (c ) 1.9,
EtOH)];7 1H NMR δ 0.95 (m, 2H), 1.42 (m, 1H), 1.9 (m, 1H),
3.58 (d, J ) 6.66 Hz, 2H), 7.13 (m, 5H); 13C NMR δ 142.4, 128.1,
125.6, 125.3, 65.9, 24.9, 21.0, 13.6; EIMS 148 (M+). Anal.
Calcd for C10H12O (148.2): C, 81.04; H, 8.16. Found: C, 80.82;
H, 8.24.
1H), 1.67 (m, 1H), 2.01 (s, 3H), 2.08 (m, 1H), 3.15 (s, 3H), 3.71
(s, 3H), 3.87 (dd, J ) 7.1 and 11.55 Hz, 1H), 4.06 (dd, J ) 6.7
and 11.55 Hz, 1H); 13C NMR δ 172.9, 170.5, 66.4, 61.5, 32.6,
20.9, 20.2, 16.2, 12.6; HRMS (EI) calcd for C9H15NO4 201.1001,
found 201.1006. Anal. Calcd for C9H15NO4 (201.23): C, 53.72;
H, 7.51; N, 6.96. Found: C, 53.99; H, 7.30; N, 6.70.
(1R,2R)-tr a n s-2-(Hyd r oxym eth yl)-1-(1-oxo-bu t-3-en yl)-
cyclop r op a n e (8). To an ice-cooled solution of the amide 7
(1.6 g, 7.96 mmol) in THF (20 mL) was added dropwise an
ether solution of allylmagnesium bromide (1.2 M, 40 mL, 48
mmol); the mixture was stirred for 30 min at 0 °C and 6 h at
room temperature. The reaction was then quenched with
aqueous HCl (5%, 25 mL) and extracted with ethyl acetate (4
× 50 mL). The combined organic extracts were dried (Na2-
SO4), concentrated, and purified by column chromatography
to afford the allylcyclopropyl ketone 8 (970 mg, 87%) as a
colorless liquid: [R]D ) -59.4 (c ) 1, CHCl3); IR (neat) 3416,
1684 cm-1
;
1H NMR δ 0.87 (m, 1H), 1.29 (m, 1H), 1.65 (m,
1H), 1.89 (m, 1H), 2.48 (br s, 1H, exchangeable with D2O), 3.25
(d, J ) 7.6 Hz, 2H), 3.32 (dd, J ) 4.4 and 12.2 Hz, 1H), 3.62
(dd, J ) 4.4 and 12.2 Hz, 1H), 5.11 (m, 2H), 5.89 (m, 1H);
HRMS (EI) calcd for C8H12O2 141.0915 (MH+), found 141.0901.
Anal. Calcd for C8H12O2 (140.18): C, 68.55; H, 8.62. Found:
C, 68.73; H, 8.29.
(1R,2R)-tr a n s-1-(Acet oxym et h yl)-2-p h en ylcyclop r o-
p a n e (6). To an ice-cooled solution of the cyclopropyl methanol
1 (600 mg, 4.05 mmol) and a catalytic amount of 4-(dimethyl-
amino)pyridine (15 mg) in CH2Cl2 (15 mL) was added dropwise
freshly distilled acetic anhydride (1.98 mL, 21 mmol); the
mixture was stirred for 10 min at 0 °C followed by 45 min at
room temperature. The mixture was then diluted with CH2-
Cl2 (25 mL) and poured into water, and the organic layer was
separated and washed sequentially with saturated aqueous
NaHCO3, water and brine. After drying over Na2SO4 and
removal of solvent using a rotary evaporator, the residue was
chromatographed to afford the pure product 6 (613 mg, 96.5%)
as a colorless liquid: [R]D ) -64.8 (c ) 1.25, CHCl3); IR (neat)
(1R,2R)-tr a n s-2-[(ter t-Bu tylsilyloxy)m eth yl]-1-(1-oxo-
bu t-3-en yl)cyclop r op a n e (9). A solution of the cyclopropyl
methanol 8 (500 mg, 3.5 mmol) and imidazole (595 mg, 8.7
mmol) in CH2Cl2 (6 mL) at 0 °C was treated with tert-
butyldimethylsilyl chloride (580 mg, 3.8 mmol) and the solu-
tion was stirred at 0 °C for 30 min and 7 h at room
temperature. After quenching the reaction by addition of
water (3 mL), the resulting mixture was diluted with CH2Cl2
(10 mL), the organic layer was separated, dried over Na2SO4,
and concentrated, and the residue was purified by column
chromatography to yield the silyl ether derivative 9 (816 mg,
90%) as a colorless liquid: [R]D ) -62.4 (c ) 1, CHCl3); IR
1744, 1488 cm-1 ; H NMR δ 0.98 (m, 2H), 1.47 (m, 1H), 1.89
(neat) 1706 cm-1 1H NMR δ 0.02 (s, 6H), 0.85 (s, 9H), 0.89
;
1
(m, 1H), 2.08 (s, 3H), 4.06 (d, J ) 7.2 Hz, 2H), 7.15 (m, 5H);
13C NMR δ 171.0, 141.9, 128.2, 125.8, 125.7, 67.8, 21.7, 21.3,
20.9, 13.8; HRMS (EI) calcd for C12H14O2 190.0993, found
190.1001. Anal. Calcd for C12H14O2 (190.24): C, 75.76; H,
7.42. Found: C, 76.05; H, 7.35.
(1R ,2R )-t r a n s-2-(Ace t oxym e t h yl)cyclop r op a n e ca r -
boxylic Acid (2). To a stirred mixture of the acetoxycyclo-
propane 6 (1.56 g, 8.2 mmol) and NaIO4 (30.12 g, 147.7 mmol)
in acetonitrile (20 mL), carbon tetrachloride (20 mL), and
water (30 mL) at room temperature was added RuCl3‚H2O (38
mg, 0.18 mmol) portionwise; the mixture was stirred vigorously
(m, 1H), 1.19 (m, 1H), 1.59 (m, 1H), 1.9 (m, 1H), 3.27 (d, J )
7.2 Hz, 2H), 3.46 (dd, J ) 4.2 and 10.5 Hz, 1H), 3.71 (dd, J )
4.2 and 10 Hz, 1H), 5.13 (m, 2H), 5.94 (m, 1H); 13C NMR δ
199.2, 134.2, 118.4, 70.8, 45.6, 29.7, 25.9, 23.6, 18.2, 14.4, -5.2;
EIMS 255 (MH+). Anal. Calcd for C14H26SiO2 (254.44): C,
66.08; H, 10.30. Found: C, 66.15; H, 10.29.
(1R,2R)-tr a n s-2-[(ter t-Bu tylsilyloxy)m eth yl)]-1-[(1S)-1-
h yd r oxyb u t -3-en yl]cyclop r op a n e (10U) a n d (1R,2R)-
tr a n s-2-[(ter t-Bu tylsilyloxy)m eth yl]-1-[(1R)-1-h ydr oxybu t-
3-en yl]cyclop r op a n e (10L). To a stirred solution of the
cyclopropyl ketone 9 (127 mg, 0.5 mmol) in THF (8 mL) at

A Precursor of Halicolactone and Neohalicholactone
J . Org. Chem., Vol. 63, No. 3, 1998 645
-78 °C was added dropwise K-Selectride (1M solution in THF,
1 mL, 1 mmol) and stirring continued for 30 min. After
quenching the reaction by sequential addition of MeOH (1 mL)
and 10% aqueous NaOH solution (5 mL) at -78 °C, the
reaction mixture was allowed to warm to room temperature
and stirred for 1 h. The mixture was then extracted with ether
(3 × 30 mL), and the combined extracts were dried (Na2SO4),
concentrated, and purified by flash chromatography (ethyl
acetate:hexanes ) 1:15), affording the pure diastereoisomers
10U (Rf ) 0.4, 106 mg, 83%) and 10L (Rf ) 0.28, 12 mg, 9%)
as colorless liquids. 10U: [R]D ) -7.4 (c ) 1, CHCl3); 1H NMR
δ 0.02 (s, 6H), 0.42 (2d, J ) 8 and 10 Hz, 2H), 0.75 (m, 1H),
0.84 (s, 9H), 0.96 (m, 1H), 2.29 (m, 2H), 2.98 (m, 1H), 3.3 (dd,
J ) 4 and 10.5 Hz, 1H), 3.58 (dd, J ) 4.2 and 10 Hz, 1H), 5.08
(m, 2H), 5.82 (m, 1H); 13C NMR δ 134.8, 117.4, 74.4, 65.9, 41.4,
29.6, 25.9, 23.1, 19.1, 7.6, -5.2; CIMS 255 (M+ - 1). Anal.
Calcd for C14H28SiO2 (256.45): C, 65.57; H, 11.00. Found: C,
65.49; H, 10.63. 10L: [R]D ) -12.99 (c ) 1, CHCl3); 1H NMR
δ 0.01 (s, 6H), 0.44 (m, 2H), 0.74 (m, 1H), 0.84 (m, 1H), 0.90
(s, 9H), 1.4 (m, 1H), 2.3 (m, 2H), 2.98 (m, 1H), 3.35 (dd, J )
5.9 and 10.44 Hz, 1H), 3.55 (dd, J ) 5.2 and 11.4 Hz, 1H),
5.06 (m, 2H), 5.82 (m, 1H); 13C NMR δ 134.8, 117.5, 74.7, 65.6,
41.8, 29.5, 25.9, 22.8, 18.9, 7.9, -5.3; CIMS 255 (M+ - 1).
Con ver sion of th e Hyd r oxym eth ylen e Cyclop r op a n e
10L to th e Cor r esp on d in g â-OH Isom er 10U. To a solution
of 10L (75 mg, 0.2 mmol) in THF (3 mL) was added Ph3P (138
mg, 0.5 mmol) and glacial acetic acid (0.03 mL, 0.5 mmol) and
the mixture was cooled to 0 °C. To this stirred solution was
added dropwise diethyl azodicarboxylate (0.104 mL, 0.6 mmol)
dissolved in THF (1 mL). The reaction mixture was allowed
to warm to room temperature and was stirred overnight. After
removal of solvent under vacuum, the residue was dissolved
in CH2Cl2 (15 mL) and washed sequentially with dilute
aqueous NaHCO3, water, and brine. After drying over Na2-
SO4 and removal of solvent under vacuum, the crude residue
was dissolved in 2 mL of MeOH and treated with a solution of
NaOMe (0.05 M in MeOH, 5 mL). After stirring for 3 h at
room temperature, the reaction mixture was concentrated, and
the residue was taken up in CH2Cl2 (10 mL) and washed
successively with water and brine. Removal of solvent and
purification of the residue by column chromatography yielded
the pure product 10U (68 mg, 91%, two steps), similar in all
respects to the major isomer 10U, as obtained previously via
reduction of the ketone 9.
(S)- a n d (R)-Mosh er Ester s of Alcoh ol 10U. A solution
of the cyclopropyl alcohol 10U (13 mg, 0.05 mmol), (S)-(-)-R-
methoxy-R-(trifluoromethyl)phenylacetic acid (S-MTPA) (16
mg, 0.07 mmol), N,N-dicyclohexylcarbodiimide (18 mg, 0.09
mmol), and a catalytic amount of DMAP (4 mg) in CH2Cl2 (1
mL) was stirred at room temperature for 8 h. The precipitated
solid was filtered off, the filtrate was concentrated, and the
residue was purified by column chromatography to yield the
pure (S)-MTPA ester: 1H NMR δ 0.008 (s, 6H), 0.51 (m, 1H),
0.61 (m, 1H), 0.85 (s, 9H), 1.04 (m, 1H), 1.18 (m, 1H), 2.42 (m,
2H), 3.35 (dd, J ) 4.6 and 12.6 Hz, 1H), 3.56 (s, 3H), 3.63 (dd,
J ) 4.2 and 12.6 Hz, 1H), 4.59 (m, 1H), 4.95 (m, 2H), 5.63 (m,
1H), 7.38 (m, 5H).
The reaction of (R)-(+)-R-methoxy-R-(trifluoromethyl)phen-
ylacetic acid (R-MTPA) with the alcohol 10U similarly afforded
the (R)-MTPA ester: 1H NMR δ 0.011 (s, 6H), 0.45 (m, 1H),
0.58 (m, 1H), 0.85 (s, 9H), 0.96 (m, 1H), 1.12 (m, 1H), 2.52 (m,
2H), 3.22 (dd, J ) 6.6 and 12.3 Hz, 1H), 3.54 (s, 3H), 3.59 (dd,
J ) 4.8 and 12.3 Hz, 1H), 4.60 (m, 1H), 5.07 (m, 2H), 5.78 (m,
1H), 7.39 (m, 5H).
of methanol (4.5 mL) and water (3 mL), and solid NaHCO3
(340 mg, 0.66 mmol) was added. This stirred mixture was then
treated with NaIO4 (870 mg, 4 mmol). After 30 min the
reaction mixture was diluted by adding water (10 mL), the
methanol was removed under vacuum, and the residue was
extracted with ethyl acetate (3 × 25 mL). Drying (Na2SO4),
removal of solvent, and purification of the residue by column
chromatography afforded the pure hydroxy aldehyde 11 (133
mg, 86%, two steps) as a colorless liquid. This aldehyde was
however found to degrade on storage and was used im-
mediately in the next reaction: [R]D ) -25.4 (c ) 1, CHCl3);
1H NMR δ 0.05 (s, 6H), 0.46 (m, 2H), 0.8 (m, 1H), 0.9 (s, 9H),
1.01 (m, 1H), 1.58 (m, 1H), 1.9 (m, 1H), 3.34 (m, 1H), 3.52 (m,
1H), 4.8 (m, 1H), 9.84 (s, 1H).
(5Z,8S)-8-H yd r oxy-8-[(1R,2R)-tr a n s-2-[(ter t-b u t ylsil-
yloxy)m eth yl]cyclop r op yl]oct-5-en oic Acid (12). To an
ice-cooled solution of (4-carboxybutyl)triphenylphosphonium
bromide (474 mg, 1.07 mmol) in THF (10 mL) was added
dropwise sodium hexamethyldisilazide (1.3 M solution in THF,
2.2 mL, 2.86 mmol); the mixture was stirred for 30 min. The
reaction mixture was then cooled to -78 °C, and the hydroxy-
aldehyde 11 (185 mg, 0.71 mmol), dissolved in 5 mL of THF,
was added dropwise. After stirring for 2 h at -78 °C and 2 h
at room temperature, the reaction was quenched with satu-
rated aqueous NH4Cl and extracted with ethyl acetate (3 ×
50 mL), and the combined extracts were dried (Na2SO4) and
concentrated to afford the crude product, which on column
chromatography yielded the pure hydroxy acid 12 (220 mg,
90%) as a colorless liquid: [R]D ) -5.73 (c ) 1.5, CHCl3); IR
1
(neat) 3456, 1708 cm-1; H NMR δ 0.05 (s, 6H), 0.46 (m, 2H),
0.8 (m, 1H), 0.88 (s, 9H), 1.01 (m, 1H), 1.72 (m, 2H), 2.15 (m,
2H), 2.34 (m, 4H), 3.04 (m, 1H), 3.36 (dd, J ) 5.2 and 12.4 Hz,
1H), 3.65 (dd, J ) 4.8 and 12.4 Hz, 1H), 5.48 (m, 2H); 13C NMR
δ 178.1, 132.2, 126.6, 75.0, 66.0, 34.7, 33.3, 26.5, 25.9, 24.5,
23.2, 19.1, 18.3, 7.7, -5.1; CIMS 343 (MH+).
(1R,2R)-tr a n s-1-[(4Z,2S)-2,3,6,7,8,9-Hexa h yd r o-9-oxo-2-
oxon in yl]-2-[(ter t-bu tylsilyloxy)m eth yl]cyclopr opan e (13).
To a room-temperature solution of the hydroxy acid 12 (100
mg, 0.29 mmol) and triethylamine (0.05 mL, 0.31 mmol) in
THF (2 mL) was added dropwise 2,4,6-trichlorobenzoyl chlo-
ride (0.05 mL, 0.29 mmol); the mixture was stirred for 2 h.
The precipitated solids were then filtered, the filtrate was
diluted with toluene (200 mL) and added dropwise (7-8 h) to
a refluxing solution of 4-(dimethylamino)pyridine (141 mg, 1.16
mmol) in toluene (35 mL) followed by stirring at room
temperature for 10 h. Toluene was removed under reduced
pressure and the residue purified by column chromatography
to yield the cyclopropyl lactone 13 (62 mg, 66%) as a colorless
liquid: [R]D ) -54.66 (c ) 0.3, CHCl3); IR (neat) 1740 cm-1
;
1H NMR δ 0.05 (br s, 6H), 0.49 (m, 2H), 0.86 (br s, 9H), 0.93
(m, 1H), 1.06 (m, 1H), 1.75 (m, 1H), 2.02 (m, 2H), 2.17 (m,
2H), 2.21 (m, 2H), 2.46 (m, 2H), 3.50 (m, 2H), 4.18 (br t, J )
9.7 Hz, 1H), 5.44 (m, 2H); 13C NMR δ 174.4, 134.5, 124.9, 76.4,
65.4, 33.9, 33.6, 26.5, 25.9, 19.9, 19.5, 7.8, 1.0; HRMS (CI) calcd
t
for C14H23SiO3 267.4194 (M+ - Bu), found 267.4204.
(1R,2R)-tr a n s-1-[(4Z,2S)-2,3,6,7,8,9-Hexa h yd r o-9-oxo-2-
oxon in yl]-2-(h yd r oxym et h yl)cyclop r op a n e (14). To a
stirred solution of the cyclopropyl lactone 13 (80 mg, 0.24
mmol) in THF (4 mL) at 0 °C was added a solution of
tetrabutylammonium fluoride (1 M solution in THF, 0.085 mL,
0.29 mmol) and stirring was continued at 0 °C for 30 min and
6 h at room temperature. After removal of the solvent under
vacuum, the residue was purified by column chromatography
to afford the hydroxymethyl cyclopropane 14 (52 mg, 92%) as
a colorless liquid: [R]D ) -149.2 (c ) 1, CHCl3); IR (neat) 3408,
(3S )-3-H yd r oxy-3-[(1R ,2R )-t r a n s-2-[(t er t -b u t ylsilyl-
oxy)m et h yl]cyclop r op yl]p r op ion a ld eh yd e (11). To a
stirred solution of compound 10U (210 mg, 0.6 mmol) and
N-methylmorpholine N-oxide (325 mg, 2.4 mmol) in acetone
(3 mL) and water (3 mL) at room temperature was added a
catalytic amount of OsO4 solution in toluene (5% solution, 5
mol %). After 8 h a saturated aqueous Na2SO3 solution was
added to the reaction mixture, which was then extracted with
ethyl acetate (3 × 25 mL). The combined extracts were dried
over Na2SO4 and concentrated to afford the crude dihydroxy-
lated compound (195 mg), which was dissolved in a mixture
1732 cm-1 1H NMR δ 0.61 (m, 2H), 0.99 (m, 1H), 1.27 (m,
;
1H), 1.81 (m, 1H), 2.07 (m, 3H), 2.25 (m, 2H), 2.50 (m, 2H),
3.48 (m, 2H), 4.17 (m, 1H), 5.45 (m, 2H); CIMS 211 (MH+).
(1R,2R)-tr a n s-2-[(4Z,2S)-2,3,6,7,8,9-Hexa h yd r o-9-oxo-2-
oxon in yl]cyclop r op a n eca r boxa ld eh yd e (15). To a room-
temperature solution of 2-iodoxybenzoic acid (67 mg, 0.24
mmol) in DMSO (1 mL) was added a solution of the hy-
droxymethyl cyclopropane 14 (40 mg, 0.12 mmol) in THF (3
mL); the mixture was stirred for 2 h. Water (6 mL) was then
added to the reaction mixture, the precipitated solid was

646 J . Org. Chem., Vol. 63, No. 3, 1998
Mohapatra and Datta
filtered off, and the filtrate was extracted with ether (3 × 20
mL). The combined filtrate on drying (Na2SO4) and removal
of solvent afforded the crude product which was column
chromatographed to yield the pure cyclopropyl aldehyde 15
(35 mg, 89%) as a colorless liquid: [R]D ) -155.4 (c ) 0.7,
(MH+). Anal. Calcd for C12H16O3 (208.26): C, 69.21; H, 7.75.
Found: C, 69.59; H, 7.94.
Ack n ow led gm en t. We thank Dr. M. K. Gurjar for
his support and encouragement and Dr. B. V. Rao for
helpful discussions. D.K.M. also thanks UGC, New
Delhi, for a research fellowship.
1
CHCl3); IR (neat) 1744, 1696 cm-1; H NMR δ 1.11 (m, 1H),
1.39 (m, 1H), 1.77 (m, 2H), 2.07 (m, 3H), 2.16 (m, 2H), 2.25
(m, 2H), 2.47 (m, 2H), 4.33 (br t, J ) 9.4 Hz, 1H), 5.45 (m,
2H), 9.21 (d, J ) 5.6 Hz, 1H); 13C NMR δ 200.0, 173.8, 135.1,
124.0, 74.1, 33.8, 33.4, 27.8, 26.3, 25.5, 25.3, 12.7; CIMS 209
J O971564X