Short and Efficient Synthesis of (±)-A-Factor

Article abstract of DOI:10.1081/SCC-120027278

An efficient synthesis of (±)-A-factor via ring opening of electrophilic cyclopropane 2 with KOAc/AcOH, DMSO, as a key step is described.

Full text of DOI:10.1081/SCC-120027278

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Short and Efficient Synthesis of (±)‐A‐Factor
Subhash P. Chavan a , K. Pasupathy a & K. Shivasankar a
a Division of Organic Chemistry: Technology , National Chemical Laboratory , Pune,
411008, India
Published online: 16 Aug 2006.
To cite this article: Subhash P. Chavan , K. Pasupathy & K. Shivasankar (2004) Short and Efficient Synthesis of (±)‐A‐Factor,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 34:3,
397-404, DOI: 10.1081/SCC-120027278
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 3, pp. 397–404, 2004
Short and Efficient Synthesis of
(+)-A-Factor
*
Subhash P. Chavan, K. Pasupathy, and K. Shivasankar
Division of Organic Chemistry: Technology, National Chemical
Laboratory, Pune, India
ABSTRACT
An efficient synthesis of (+)-A-factor via ring opening of electrophilic
cyclopropane 2 with KOAc/AcOH, DMSO, as a key step is described.
Key Words: A-factor; Cyclopropane; Ring opening.
A-factor is a pleiotropic regulator which triggers the production of
streptomycin and sporulation in S. griseus.[1] It was first isolated, synthesized
and characterized by Khoklov and co-workers. They proposed the structure of
A-factor as (2S)-(60-methylheptanoyl)-(3S)-hydroxymethylbutyrolactone.[2,3]
Later in 1983 Mori et al.[4] revised the stereochemistry of A-factor as (2R)-
(60-methylheptanoyl)-(3R)-hydroxymethyl-butyrolactone. The chiral centre at
*
Correspondence: Subhash P. Chavan, Division of Organic Chemistry: Technology,
National Chemical Laboratory, Pune 411008, India.
397
DOI: 10.1081/SCC-120027278
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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Chavan, Pasupathy, and Shivasankar
C-2 was shown to rapidly epimerize by enolization. They reported the
synthesis of (2)-A-factor starting from (S)-(2)-paraconic acid[5,6] and also
developed a synthetic route for the same by an enzymatic approach.[7]
In 1994 Yadav et al.[8] accomplished the total synthesis of (+)-A-factor via
regioselective oxidation of an acetoxy furan derivative using MnO2-HCl. (R)-
(2)-A-factor has also been synthesized previously using the Johnson–
Claisen–Ireland rearrangement of a ketene acetal as a key step.[9] In 1998
Rawlings et al.[10] reported the asymmetric synthesis from pure (S)-paraconic
acid based upon the diastereoselective benzyloxymethylation of (4R)-3-(3-
phenylpropanoyl)-4-isopropyloxazolidin-2-one.
Herein we report a novel and efficient synthesis of (+)-A-factor in a
minimum number of steps, which allows the use of commercially available,
inexpensive, chemical reagents.
The retro synthesis delineated in Sch. 1 revealed that the target molecule
could be achieved from ring opening of electrophilic cyclopropane, which can
be prepared very easily from known literature procedures.[11–13]
When the cyclopropane 2 was subjected to crucial ring opening with
KOAc/AcOH[14] in dry DMSO at 1108C (Sch. 2), it gave rise to ring opened
as well as decarboxylated acetoxy lactone 3 in 66% yield. As per the literature
protocol,[15] activated cyclopropane 2 when treated with acetic acid and
H2SO4 failed to furnish the desired ring opened product (starting material
remained intact). Deacetylation of lactone 3 with K2CO3/aq. MeOH furnished
alcohol 4 in poor yield (27%). Improved yields during deacetylation was
obtained using NaOMe (cat)/MeOH. Later the hydroxylactone 5 was
efficiently converted to the tert-butyldimethylsilyl ether 5 in 77% overall yield
starting from acetoxy lactone 3.
Scheme 1.

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Short and Efficient Synthesis of (+)-A-Factor
399
Scheme 2. Reagents and conditions: (i), a) KOAc/AcOH, DMSO, 6 h, 1108C;
(ii) NaOMe (cat)/MeOH, 1 h, r.t.; and (iii) TBDMSCI, imidazole, CH2Cl2, 3 h, r.t.
The 4 steps preparation of the acid chloride 9 reported in the literature
produces an overall yield of 32% only.[10] In this paper we describe a successful
preparation of 6-methylheptanoyl chloride (9) in 40% overall yield. As shown
in the Sch. 3, 1-bromo-3-methylbutane was condensed with propargyl alcohol
using LiNH2/liqNH3 to furnish 6-methyl-2-heptyne-1-ol (6) in 61% yield. The
acetylenic alcohol was subjected to hydrogenation using 10% Pd/C (40 psi) as
well as with Raney nickel under normal pressure. It was observed that
hydrogenation under Raney nickel gave consistent and higher yields (81%) of
completely saturated alcohol as compared to Pd/C catalyzed hydrogenation
(61% yield). The saturated alcohol 7 was subjected to Jones oxidation to give
6-methylheptanoic acid (8) in 96% yield. The acid thus obtained was converted
to 6-methylheptanoyl chloride using SOCl2 in 85% yield.
Gratifyingly, condensation of silylether 5 and 6-methylheptanoyl chloride
with lithium hexamethyldisilazane (LHMDS) provided the silyl protected A-
factor in 85% yield (Scheme 3), whose conversion to (+)-A-factor can be
obtained from the established protocol.[9,10] It is pertinent to mention that
similar acylation reaction reported in literature[10,17] either using lithium
diisopropylamide or LHMDS furnished the corresponding acylated products
in poor yields.
In conclusion a new synthetic route to (+)-A-factor has been demon-
strated by use of a homoconjugate addition of KOAc/AcOH to doubly
Scheme 3. Reagents and conditions: (i) propargyl alcohol, LiNH2/liq NH3,
overnight, 2338C; (ii) Raney nickel, H2, MeOH, overnight, r.t.; (iii) Jones reagent,
8 h, 08C to r.t.; (iv) SOCl2, DMF (cat), 24 h, r.t.; and (v) 5, LHMDS, THF, 1 h, 2788C.

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Chavan, Pasupathy, and Shivasankar
activated cyclopropane 2. The notable feature of this synthetic route is that
(+)-A-factor is synthesized from simple and readily available starting
materials. Extension of this strategy to the synthesis of biologically active (S)-
(2)-A-factor is currently underway in our laboratory.
EXPERIMENTAL
Materials and General Methods
All solvents were distilled before use. DCM and DMSO were dried over
calcium hydride. Methanol was dried over magnesium methoxide cake and
THF was dried over sodium metal. Petroleum ether refers to boiling range of
60–808C.
TLC analysis was carried out on glass plates using silica gel GF-254 and
the plates were analyzed by keeping in iodine. In case were chromatographic
purification was done silica gel (60–120 mesh) was used as the stationary
phase.
Infra red spectra were recorded on a Perkin–Elmer 68B or 1615 FT as
solution in the specified solvent, neat as films between salt disks and IR
absorbance is expressed in cm21. The following abbreviations were used:
s ¼ strong, m ¼ medium, w ¼ weak and br ¼ broad. 1H NMR and 13C NMR
spectra were recorded on Bruker AC-200 (50 MHz). Figures in parenthesis
refer to 13C frequencies. Mass spectra were recorded at an ionization energy
70 eV on Finnigan MAT-1020; automated GC/MS instrument and mass
values are expressed as m/z.
2-Oxo-3-oxa-bicyclo[3.1.0]hexane-1-carboxylic acid methyl ester
(2). Sodium (1.8 g, 75 mmol), was dissolved in dry MeOH (80 mL), and to
it was added diethyl malonate (14.5 g, 90 mmol). To this solution epichloro-
hydrin (7.8 g, 84 mmol) in MeOH (10 mL) was added dropwise at room
temperature over 1 h, and the mixture was stirred at 758C for 20 h. The mixture
was filtered, and the filtrate was concentrated in vacuo. The residue was
dissolved in CH2Cl2 (100 mL) and washed with water. The organic layer was
dried over Na2SO4 and concentrated in vacuo, and chromatography on silica
gel (eluting with Pet. ether-EtOAc ¼ 6 : 4) afforded 1 as a colourless oil (5.5 g,
50%).
IR (CHCl3, cm21): 1778 s, 1730 s. 1H NMR (CDCl3, 200 MHz): 1.39 (m,
1H), 2.07(m, 1H), 2.75 (m, 1H), 3.79 (s, 3H), 4.2(m, 1H), 4.36 (dd,
J ¼ 9.37 Hz and 4.9 Hz) Mass: m/z (%): 156 (Mþ, 17), 126 (100), 100 (45),
97 (45), 83 (76), 69 (79), 59 (41), 53 (69).
Acetic acid 5-oxo-tetrahydro-furan-3-ylmethyl ester (3). A mixture of
2 (2 g, 15.625 mmol), potassium acetate (6.3 g, 64 mmol), and acetic acid

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Short and Efficient Synthesis of (+)-A-Factor
401
(4.62 g, 76 mmol) in dry DMSO (20 mL) was heated at 1108C for 6 h. After
cooling, the reaction mixture was diluted with EtOAc, and the organic phase
was washed with water brine and dried over anhydrous Na2SO4, and
concentrated in vacuo. Chromatography on silica gel (eluting with Pet. ether-
EtOAc ¼ 6 : 4) afforded 3 (1.33 g, 66%) as a colourless oil.
IR (neat, cm21): 1780 s, 1737 s. 1H NMR (CDCl3, 200 MHz): 4.38 (1H,
dd, J ¼ 7.32 Hz, 9.32 Hz), 4.07 (3H, m), 2.87 (1H, m), 2.62 (1H, dd,
J ¼ 9.04 Hz, 17.58), 2.33 (1H, dd, J ¼ 6.34 Hz, 17.58), 2.1 (3H, s). Mass: m/z
(%): 159 (M þ 1þ, 2), 128 (10), 98 (100), 85 (60), 70 (20).
4-(tert-Butyl-dimethyl-silanyloxymethyl)-dihydro-furan-2-one (5).
To a solution of acetoxy lactone 3 (1 g, 6.32 mmol) in dry MeOH under
argon atmosphere at 08C was added catalytic amount of NaOMe. After stirring
for 1 h at 08C, the solution was quenched with 2N HCl. After concentration in
vacuo the residue was dissolved in CH2Cl2 and washed with water. The water
layer was saturated with NaCl and extracetd with CH2Cl2 (3 ꢀ 25 mL). The
combined organic layers were dried over anhydrous Na2SO4 and concentrated
in vacuo to afford the hydroxy lactone 4.
IR (neat, cm21): 3409 br s, 1774 s. 1H NMR (CDCl3, 200 MHz): 4.38 (1H,
dd, J ¼ 7.33 Hz, 9.28 Hz), 4.19 (1H, dd, J ¼ 4.88 Hz, 9.2 Hz), 3.63 (2H, m),
2.73 (1H, m), 2.58 (1H, dd, J ¼ 8.79 Hz, 17.09 Hz), 2.35 (1H, dd, J ¼ 5.61 Hz,
17.09 Hz). Mass: m/z (%): 117 (M þ 1þ, 20), 98 (20), 85 (30), 74 (45), 69
(20), 57 (100). IR (neat, cm21): 1781 s.
To a solution of alcohol 4 (0.595 mg, 5.12 mmol) in dry dichloromethane
(5 mL) under argon atmosphere was added imidazole (0.768 g, 11 mmol)
followed, after a 10 min delay, by TBDMSCl (0.92 g, 6.15 mmol) and the
reaction was stirred at room temperature overnight. The reaction mixture
was washed with water and brine, dried over anhydrous Na2SO4, and concen-
trated in vacuo. Chromatography on silica gel (eluting with Pet. ether-
EtOAc ¼ 9 : 1) afforded the title compound (1.12 g, 77%) as a colourless oil
starting from 3. 1H NMR (CDCl3, 200 MHz): 4.3 (1H, dd, J ¼ 4 Hz and 6 Hz),
4.11 (1H, dd, J ¼ 4 Hz and 6 Hz), 3.57 (2H, m), 2.66 (1H, m), 2.49 (1H, dd,
J ¼ 6 Hz and 12 Hz), 2.29 (1H, dd, J ¼ 4 Hz, 12 Hz), 0.83 (9H, s), 0.00 (6H,s).
Mass: m/z (%): 215 (2), 174 (47), 173 (45) 155(47), 145 (30), 115 (13), 99
(13), 75 (100), 73 (37).
6-Methyl-hept-2-yn-1-ol (6). To a stirred flask charged with 700 mL of
liquid ammonia, was added 400 mg of Fe (NO3)2 with stirring. After a few
seconds a small portion of the lithium (from 3.9 g, 0.561 mol) was added. As
soon as the blue color of the dissolved metal has disappeared and a white
greyish suspension has formed, the remaining lithium was introduced in
similar manner. The entire amount of lithium was consumed in 30 min.
Freshly distilled propargyl alcohol (15 g, 0.267 mol) was then added dropwise
over 30 min. Ten minutes after the addition of propargyl alcohol, isoamyl

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Chavan, Pasupathy, and Shivasankar
bromide (48.5 g, 0.32 mol), was added dropwise over 30 min. Stirring was
continued for additional 6 h. The ammonia was then allowed to evaporate. The
resulting solid was hydrolysed by stirring with a saturated ammonium hydro-
chloride solution (200 mL). The solution was subjected to continuous extrac-
tion with ethyl acetate (3 ꢀ 100 mL). The combined organic phases were
dried over anhydrous Na2SO4 and concentrated in vacuo, and chromatography
on silica gel (eluting with Pet. ether-EtOAc ¼ 8.5 : 1.5) afforded the
compound as a colourless oil (20.56 g, 61%). IR (neat, cm21): 3344 br s,
2289 w, 2223 w.
1H NMR (CDCl3, 200 MHz): 4.19 (2H, s), 2.59 (1H, br, s), 2.18 (2H, m),
1.65 (1H, m), 1.38 (2H, dd, J ¼ 6 Hz, 14 Hz), 0.87(2H, d, J ¼ 6.35 Hz). 13C
NMR (CDCl3, 50 MHz): 85.9 (s), 78.34 (s), 50.7 (t), 37.5 (t), 27.1 (d), 22
(2C, q), 16.6 (t). Mass: m/z (%): 111 (32), 107 (7), 95 (56), 93 (100), 83 (30),
77 (20), 70 (40), 55 (43).
6-Methyl-heptan-1-ol (7). To a solution of alcohol 6 (10 g, 79.3 mmol)
in 100 mL of methanol was added 6 g of Raney nickel (washed with
3 ꢀ 10 mL methanol). Hydrogen was then admitted to the system under
normal pressure and the reaction mixture was stirred at room temperature
overnight. After hydrogenation was complete, the catalyst was removed by
filtration of the reaction mixture through a Celite pad. Filtrate was concen-
trated in vacuo. Chromatography on silica gel (eluting with Pet. ether-
EtOAc ¼ 8:2) afforded 2 (8.25 g, 81%) as an oil. IR (CHCl3, cm21): 3350 br s.
1H NMR (CDCl3, 200 MHz): 3.58 (2H, t, J ¼ 6.35 Hz), 2.72 (1H, br, s), 1.52
(3H, m), 1.32 (4H, m), 1.17 (2H, m), 0.84 (6H, d, J ¼ 6.34 Hz). Mass: m/z
(%): 97 (34), 84 (24), 83 (12), 70 (31), 69(80), 56 (100), 55 (73).
6-Methyl-heptanoic acid (8). The Jones reagent was prepared by
dissolving 70 g (0.70 mole) of chromium trioxide in 100 mL. of water. After it
was immersed in an ice bath, 112 g (61 mL, 1.10 moles) of concentrated
(18 M) sulfuric acid followed by 200 mL of water was added cautiously with
manual stirring. The solution was cooled to 08C–58C. A solution of 10 g
(1.00 mole) of alcohol 7 in 200 mL of acetone was cooled to 08C–58C. The
cooled Jones reagent prepared above was added dropwise with vigorous
stirring, at a rate to maintain the temperature of the reaction mixture at about
208C till the solution retains the brown colour. The stirring was continued for
3 h after the addition was complete. After removing the acetone in vacuo the
solution was subjected to continuous extraction with dichloromethane
(3 ꢀ 100 mL). The combined organic phases were dried over anhydrous
Na2SO4 and concentrated in vacuo to afford the crude acid 10.63 g (96%).
1
IR (CHCl3, cm21): 3425 br s, 1707 s. H NMR (CDCl3, 200 MHz): 2.35
(2H, t, J ¼ 8 Hz), 1.63 (3H, m), 1.25–1.33 (4H, m), 0.88 (6H, d, J ¼ 6.34 Hz).
Mass: m/z (%): 145 (M þ 1þ, 2), 129 (3), 101 (48), 85 (70), 82 (100), 72 (50),
59 (20).

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Short and Efficient Synthesis of (+)-A-Factor
403
6-Methylheptanoyl chloride (9). Thionyl chloride (18.17 g, 0.15 mol),
acid 11 (10 g, 0.069 mol) and a catalytic amount of dry DMF were combined
and stirred at room temperature for 24 h, and the excess thionyl chloride was
removed by distillation. Kughelrohr distillation furnished the title acid
chloride 9 (bp1108C at 5 mmHg) as a colourless liquid (9.54 g, 85%).
IR (neat, cm21): 1806 s. 1H NMR (CDCl3, 200 MHz): 2.88 (2H, t,
J ¼ 6.83 Hz), 1.7 (2H, m), 1.55 (1H, m), 1.36 (2H, m), 1.2 (2H, m), 0.88 (6H,
d, J ¼ 6.35 Hz).
4-tert-Butylsilanyloxymethyl-3-(6-methyl-heptanoyl)-dihydro-furan-
2-one (10). To a solution of protected alcohol 5 (0.5 g, 2.17 mmol) in dry
THF (20 mL) under argon atmosphere at 2788C was added freshly prepared
lithium bis(trimethylsilyl)amide (5.43 mmol) in THF (5 mL) dropwise. After
a 20 min delay, acid chloride 9 (0.493 g, 3.03 mmol) in THF (5 mL) was
added drop wise during 10 min at 2788C. After stirring for 1 h at 2788C, the
reaction mixture was allowed to warm to room temperature. The mixture was
poured into ice-AcOH-H2O and extracted with ether. The ether solution was
washed with saturated NaHCO3 solution (20 mL) and brine, dried over
anhydrous Na2SO4, and concentrated in vacuo. Chromatography on silica gel
(eluting with pet. ether-EtOAc ¼ 32 : 1) afforded the title compound 10 as a
1
colourless oil (0.66 g, 85%). IR (CHCl3, cm21): 1774 s, 1717 s. H NMR
(CDCl3, 200 MHz): 4.36 (1H, dd, J ¼ 7.9 Hz, 9.16 Hz), 4.15 (1H, dd,
J ¼ 5.49, 9.16 Hz), 3.59 (3H, m), 3.15 (1H, m), 2.91 (1H, m), 2.53 (1H, m),
1.21-1.55 (8H, m), 0.81 (15H, m), 0.0 (6H, s). 13C NMR (CDCl3, 50 MHz):
202.33 (s), 172.16 (s), 69.23 (t), 62.43 (t), 42.62 (d), 39.53 (d), 38.98 (t),
27.07 (t), 26.08(3C, q), 23.84 (t), 22.92 (2C, q), 18.10(s), 25.24 (2C, q).
Mass: m/z (%): 299 (11), 145 (21), 131 (25), 109 (42), 83 (28), 69 (21), 57
(79), 56 (100).
ACKNOWLEDGMENTS
Authors K.P and K.S thank CSIR, New Delhi for financialsupport.
Funding from CSIR, New Delhi under YSA (SPC) scheme is gratefully
acknowledged.
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Received in India July 31, 2003

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