HELVETICA

CHIMICA
ACTA Vol. 67 (1984)
~ 1989

230. Approaches to the Synthesis of Cytochalasans

Part 7')

Synthesis of Some Building Blocks for the Construction of the Macrocyclic Moiety
by Daniel Wallach, Ivan G . Csendes, Peter E. Burckhardt, Tibur Schmidlin and Christoph Tamm*
Institut fur Organische Chemie der Universitat, St. Johanns-Ring 19, CH-4056 Base1

(7.VIII.84)

Summary
The synthesis of ethy1(2E,4E,8R)-8-methyl-lO-[(2H-tetrahydropyran-2-yl)oxy]-2,4-
decadienoate (II), methyl (2E,8R)-8-methyl-lO-[(2H-tetrahydropyran-2-yl)oxy]-2-de-
cenoate (16), synthons for the construction of the macrocyclic moieties of the cytocha-
lasins A, B and F, and of (3R)-[7-(1,3-dioxolan-2-yl)-3-methylheptyl]triphenyl-
phosphonium bromide (24), a C,-building block for deoxaphomin, proxiphomin and
protophornin is described. In all instances (+)-(R)-pulegone (5) served as starting mate-
rial.

The structural pattern of the macrocyclic moiety 1 or 2 of several cytochalasans2)

exhibits striking similarity due to the presence of the CH3-group at chiral C-atom C(16)
and due to the position of two double bonds between C(13),C(14) and C(21),C(22),
respectively3).In the macrolides of type 2, the location of the 0-bridge represents an
additional common feature. Dissection of the strategic bonds led to a synthetic scheme
[3] according to which building blocks of type 3 and 4, consisting of 8 or 10 C-atoms,
respectively, are required (Scheme I).
Scheme I

+ y-x

1 3

2 4
') Part 6: [l].
2, These comprise the cytochalasins A, B, and F, deoxaphomin, proxiphomin and protophomin.
3, For convenience, the numbering used in this communication corresponds to that used for the cytochala-
sans [2].
1990 HELVETICA
CHIMICA - Vol.67 (1984)
AC~A

Any attempt to prepare synthons such as 3 and 4 faces the problem of the stereo
control at C(16). In principal, the same is valid for an additional chiral centre to be
introduced into the target molecules bearing a OH-group at C(20). To solve this prob-
lem, we decided to use (+)-(R)-pulegone (5) as starting material because the secondary
CH,-group of this monoterpene possesses the same absolute configuration as in 3-
methylpimelic acid as shown by interrelation of both compounds. (3R)-3-methyl-
pimelic acid has been obtained by degradation of cytochalasin B in the course of its
structure elucidation. In the first part of this communication, we report attempts to
prepare a C,,-chain as required for the macrolide type. In the second part, the synthesis
of a C,-chain suitable for the construction of macro-carbocyclic proxiphomin and pro-
tophomin is described.

K
5 6 R=H 7 R = THP

T H P O ~ ~ THP 0

14 X=Br 15 X = I
. OC,H,
11 I

THPO THP 0
OCH, O C A
18 R = H 19 R = A c 13
 HELVETICA ACTA Vol. 67 (1984)
CHIMICA ~ 1991

For the synthesis of the C,,-building block, a C,-unit was joined with a C,-moiety.
Starting from (R)-pulegone (5), citronellol (6) was prepared according to Plesek [5].
Protection of the OH-group in 6 was achieved by acid-catalyzed addition of dihydro-
pyrane [6] to give compound 7 in good yield (Scheme 2). In the next step, the olefin 7
was degradated by ozonolysis. Depending on the workup conditions, either aldehyde 8
or alcohol 9 were obtained. Extension of the chain was achieved by the reaction of 8
with the ylide 10b [7], which was prepared from ethyl 4-bromocrotonate, leading to the
diene-carboxylate 11. For the introduction of an 0-function in the y-position, 11 was
treated with m -chloroperbenzoic acid. Selective oxidation of the C(y ),C(d)-double
bond took place. However, several attempts to convert the epoxide 12 into the desired
OH-derivative 13 have failed.
Starting from alcohol 9, two key building blocks, bromide 14 and iodide 15, were
prepared in high yield via tosylation or mesylation followed by exchange of halide.
Cross coupling [8] of the Grignard compound of 14 with methyl 4-bromocrotonate
gave the C,,-synthon 16 in ca. 60% yield. Although compound 16 still lacks the 0-
function at C(4) furnishing the final functionality at C(20) in structure Z4), it meets the
requirements needed for the transformation into a phosphorane. The latter could
operate as a building block like compound 4.
Introduction of an additional 0-function into a C,-synthon required for the syn-
thesis of deoxaphomin was achieved by starting from bromide 14. For this purpose the
Grignard compound of 14 was reacted with 1-(dimethoxyacety1)piperidine [9] to give
the a-ketoacetal 17 (yield 19%). The latter was easily reduced by NaBH, to the epimer-
ic cr-hydroxyacetals 18. For selective deprotection of the primary OH-group, the acetyl
derivative 19 was prepared.
Another goal of this investigation was the synthesis of the C,-unit of type 3 re-
quired for the construction of proxiphomin and protophomin. It has been achieved by
three different routes by the linking of a C,- with a C,-unit, whereby the overall yields
were gradually increased. The first sequence started from bromide 14, which by reac-
tion of its Grignard compound with ethylene oxide yielded about 40% of the extended
alcohol 20 (Scheme 3). Oxidation of 20 to the aldehyde 21 was accoinplished by pyri-
dinium dichromdte (PDC) in 65% yield. Treatment of 21 with EtOH and catalytic
amounts of pyridinium p-toluenesulfonate (PPTS) resulted in a transetherification.
Thus, the aldehyde group of 21 was protected as an aCetd1 by simultaneous deprotec-
tion of the primary OH-group. The resulting hydroxy-acetal 22 was obtained in 85%
yield. The primary OH-group of 22 was replaced by Br using the mesylate as inter-
mediate. After reacetalization, the ethylene acetal 23 was obtained in a total yield of
86 %. On heating 23 with Ph,P in benzene, the phosphonium bromide 24 was obtained
in 70% yield. The product was very hygroscopic and difficult to purify.
Bromide 14 did not react smoothly with Mg. The addition of the resulting Grignard
reagent to ethylene oxide was always accompanied by some reduction of 14 to the
corresponding alkane, thus decreasing the yield. Therefore the use of 2-(lithio-
methyl)-Cdihydro- 1,3-thioazole (25) [ 101 was investigated as an alternative route for

4, Since epimerization may easily occur at C(20), it is advisable to introduce chirality in a final reduction step.
A synthesis, yet by a different strategy, of the synthon 4 needed for the construction of the cytochalasins B
and F has been reported recently [I].
1992 HELVETICA ACTA- Vol. 67 (1984)
CHIMICA

Scheme 3

14 -
Mg T H P O b W 5 THP-0
R 20 21 H

C2H,0H
PPTS

1. MsCVTEA
2. LiBr/Acetone
3. [ CH,OH), /PPTS

CHIOH
H
S
O
-

26
N
S I ppis
(C,H, 1 P

1 H,O/ Ether

H
S
O-
H N S ___
27

the C,-extension. The alkylated thiazole 26, in which the 2H-tetrahydropyran-2-yl

group has been lost by the workup with acid, was hydrogenated by Al(Hg) in wet Et,O
to give thiazolidine 27 in 57% (calculated on the basis of the iodide 15). Desulfuriza-
tion by HgCl, led to the hydroxy aldehyde 28. It showed a high tendency to form
polymeric acetals. However, by treatment with MeOH and PPTS again a monomeric
species, i.e. compound 29, was obtained from the polymeric product. The phospho-
nium bromide 24 was prepared from 29 by the same sequence as outlined already for
the conversion of 22 to 24. Since iodide 15 is accessible in higher yield than bromide 14
and the yields of the remaining steps range from 60 to 80% each, an improvement had
 HELVETICA ACTA Vol.67 (1984)
CHIMICA ~ 1993

been achieved as compared to the ethylene-oxide procedure. Nevertheless, the use of

mercury may be regarded as a disadvantage. Therefore, a third route was studied.
(Z)-2-Ethoxyvinyllithium (30) is a useful equivalent of acetaldehyde for a chain
extension [ll]. If this reagent is alkylated by iodide 15, an enol ether is expected to be
formed, which should add EtOH to give compound 22. In fact, we converted 15 into
the enol ether 31 in good yield, but only in the presence of 5 equiv. of hexamethylphos-
phoric triamide. This observation is in contrast to the conditions quoted in [l 11. Acid-
catalyzed addition of EtOH to 31 yielded the acetal 22, whose conversion to the target
molecule 24 has already been carried out (see above). Taking advantage of the se-
quence using (Z)-2-ethoxyvinyllithium (30), the optically active phosphonium bromide
245) may now be easily obtained from (R)-citronellol (6)in seven steps.

The support of these investigations by the Schweizerischer Nationalfonds zur Forderung der wissenschaft-
lichen Forschung is gratefully acknowledged.

Experimental Part

General. See [13]. 90-MHz 'H-NMR spectra and IR spectra were recorded on a Varian EM 390 and a
Perkin-Elmer model 177 grating spectrometer, respectively. Air- and water-sensitive reactions were carried out
in a dry Ar atmosphere. All solvents were adequately dried before use.
Abbreviations. CC = column chromatography on silica gel, HMPT = hexamethylphosphoric triamide,
MCPBA = m -chloroperbenzoie acid, PDC = pyridinium dichromate, PPTS = pyridinium p-toluenesulfonate.
(3R)-3,7-Dimethyl-6-octen-l-ol (Citronellol) (6). Following the procedure described in [5], 74. I g (79%) of
6 were obtained, starting from 92.1 g (0.60 mol) of (+)-(R)-pulegone (5). The physical data of 6 were in
agreement with the reported values [5].
(6R)-2,6-Dimethyl-8-((2H-tetrahydropyran-2-yl)oxy]-2-octene (7). To a solution of 6 (27.4 ml, 0.15 mol)
and 3,4-dihydro-2H-pyran (27.2 ml, 0.30 mol) in benzene (50 ml) some drops of SOCI, were added. After some
min. the mixture began to warm up. It was stopped by cooling down to 10". The mixture was kept at r.t. for 15
h. Evaporation i.u. left a residue, which was diluted with Et2 0 (400 ml) and washed with 2~ KHCO, (1 x 75
and 2 x 25 ml) and H,O (2 x 50 mi). The org. layer yielded after evaporation of the solvents i.u. 38.41 g of crude
7, which was purified by destillation to give 32.30 g (90%) of 7, b.p. 109-112" (0.65 Torr). [a12 = 4" 0.5" *
(c = 2, CH2CI2).IR (film): 2950, 2880, 1130, 1080, 1040, 870, 815. 'H-NMR (60 MHz, CDCI,): 0.90 (d,J = 6,
CH3-C(6)); 1.1-2.1 (m,19H); 3.24.2 (m,2H-C(8), 2H-C(6')); 4.58 (br., H-C(2')); 5.12 (m,H-C(3)). MS:
240 ( M +), 156, 154, 123, 109, 95, 85.
(4R)-4-Methyl-6-( (2H-tetrahydropyran-2-yl)oxy]hexanal(8). An O,/O, mixture was bubbled through a
solution of 7 (12.0 g, 50 mmol) in MeOH (100 ml) at -50" until 50 mmol of 0, bad been absorbed. 4.5 ml of
(CH3),S were added and the mixture was stirred at -10" for 2 h. After evaporation of the solvents i.u. the
residue was diluted with Et20 (250 ml) and washed with H20. On evaporation i.v. the org. layer gave 9.50 g of
crude product. It was purified by CC (CH,CI,/EtOH gradient) to give 6.00 g (56%) of pure 8 as colourless oil.
[ a ] g = 4" f 1" (c = 2, CHCI,). IR (film): 2950, 2880, 1730, 1125, 1080, 1035. 'H-NMR (60 MHz, CDC13): 0.90
( d , J = 5, H3C-C(4)); 1.2-1.9 (m. 11H); 2.4 (br., 2H-C(2)); 3.2-3.8 (m, 2H-C(6), 2H-C(6')); 4.6 (br.,
H-C(2')); 9.8 (br., H-C(1)). MS: 213 ( M + - l), 185, 170, 129, 85.
(4R)-4-Methyl-6-[(2H-tetrahydropyran-2-yl)oxy]hexan-l-ol (9). A stirred solution of 7 (25.45 g, 106
mmol) in MeOH (260 ml) was cooled to -65" and treated with O3 (6.04 g, 126 mmol). The solution has to
remain colourless. To the still cold solution, NaBH, (14.0 g, 370 mmol) was added in small portions. After
having reached r.t. the mixture was kept stirring for an additional 2.5 h. The product was extracted by Et2O
(1 x 800 and 2 x 200 ml), which was washed with H,O (3 x 80 ml). Evaporation of the solvents i.v. gave 22.40
g (98%) of 9, pure according to TLC, as a colourless oil. [alg= 2" i 0.5" (c = 2.5, CH,CI,). IR (film): 3410 br.,
2940, 2870, 1140, 1125, 1075, 1030. 'H-NMR (60 MHz, CCI,): 0.95 ( d , J = 5, CH,-C(4)); 1.0-1.9 (m,13H); 2.8

5, This compound, but in its racemic form, has independently been synthesized by Kim et al. 1121.
1994 CHIMICA
HELVETICA ACTA- Vol. 67 (1984)

(br. s, HO-C(1)); 3.1-3.9 (m, 2H-C(1), 2H-C(6), 2H-C(6')); 4.5 (br., H-C(2')). MS: 216 ( M +), 143, 131,
115, 101, 97, 85.
Ethyl (2E.4E,8Rj-R-Metl1yl-l0-~(2H-tetrahydropyrun-2-yljo.wy]-2.4-decadienoute (11). A solution of 8
(1.30 g, 6.0 mmol) in 5 ml of THF was added to a solution of 0.48 g o f NaOEt and phosphonium bromide 10a
[7] (2.80 g, 6.1 mmol) in 10 ml of EtOH at r.t. After 12 h the mixture was filtered. The concentrated filtrate was
diluted with Et,O (500 ml) and washed with H,O. On evaporation of the solvents iu., 2.05 g of crude 11 were
obtained. Purification of the latter by CC (CH,CI,/MeOH gradient) yielded 0.95 g (51%) of pure 11 as a
colourless oil. IR (film): 2940, 1720, 1640, 1260, 1080, 1035. UV (EtOH): 206.5 (3.82), 213 (3.76), 261 (4.20).
'H-NMR (60 MHz, CDCI,): 0.95 (6J = 6, CH,-C(B)); 1.2-1.9 (m, 11H); 1.35 (1, J = 7, CH,CH,O); 2.3 (m,
2H-C(6)); 3.2-3.8 (m. 2H-C(10), 2H-C(6')); 4.25 (y, J = 7, CH,CH,O); 4.6 (br., H-C(2')); 5.7 (br., H-C(5));
5.95 (d, J = 15, H-C(2)); 6.2 (br., H-C(4)); 7.4 (hr., H-C(3)). MS: 310 ( M ' ) , 309, 265, 237, 195, 85.
Ethyl /2E,4RS,5RS,~Rj-4.5-Epoxy-8-methyl-l~-[(2H-tetra~~ydrop~~run-2-yl)osy~-2-decenoute (12). A
solution of 11 (650 mg, 2.0 mmol) in CHCI, (25 ml) was treated at r.t. with MCPBA (430 mg, 2.5 mmol) for 3 d.
Excess of peracid was destroyed by addition of 2N Na,SO, (5 ml). The mixture was washed consecutively with
2~ Na,CO, and H,O. Evaporation of the solvent i.u. left 550 mg of residue, which was purified by CC (CH,CI,/
MeOH gradient) to yield 360 mg ( 5 5 % ) of pure 12. [a12 = 5" + 1" (c = 1.85, CHCI,). IR (film): 2975, 1720,
1655, 1080, 1040, 875. U V (EtOH): 218 (4.10). 'H-NMR (60 MHz, CDCI,): 0.90 (d, J = 6, CH,-C(8)); 1.2-1.9
(m, 13H); 1.25 (/, J = 7, CH,CH,O); 3.2-3.8 ( m , H-C(4), H-C(5). 2H-C(10), 2H-C(6')); 4.18 (q, J = 7,
CH,CH,O); 4.6 (br., H-C(2')); 6.10 (d, J = 15, H-C(2)); 6.80 (dd, J = 15, J ' = 6, H-C(3)). MS: 325
( M - I), 281, 85.
+

~4Rj-l-Sromo-4-mathyI-6-[(2~-tetruh.vdropyrun-2-yljoxy~hesune (14). To a stirred solution of 9 (22.4 g,

103 mmol) in pyridine (270 ml), TsCl (37.0 g, 194 mniol) were added at 0". Aftcr 1 h a white precipitate was
formed. The mixture was kept for 1 d at o", then toluene (200 ml) was added and the suspension was filtered by
rinsing with toluene (4 x 50 ml). Evaporation of the filtrate i.u. gave 53.3 g of an oil, which was purified by CC
(CH,CI,/Et,O gradient) to yield 27.97 g (73%) of pure tosylate. The latter was dissolved in acetone (195 ml) and
LiBr (25.99 g, 299 mmol) were added. The mixture was stirred at r.t. for 1 d. The suspension obtained was
filtered using acetone/Et,O 1.3 (in total 440 ml), the filtrate was concentrated to 80 ml and taken up in Et,O
(650 and 2 x 215 ml). The org. layers were washed with H,O (4 x 60 ml), dried and evaporated i.u. to yield
20.14 g (96% based on tosylate) of 14 as a TLC-pure, colourless oil. [aJg= 4" i 0.5" (c = 3, CH,Cl,). IR (film):
2940, 2870, 1200, 1140, 1120, 1080, 1030. 'H-NMR (60 MHz, CCI,): 0.95 (d, J = 6, CH,-C(Q)); 1.1-2.1 (m,
13H); 3.2-3.9 (w,2H-C(1), 2H-C(6), 2H-C(6')); 4.48 (br., H-C(2')). MS: 279 ( M '), 277, 179, 177, 150, 97,
85.
(4Rj-l-Iodoo-4-methy1-6-[(2H-~etruh.vdropyran-2-yl~osy~~1exune (15). To a solution of 9 (6.75 g, 31.2
mmol) and Et,N (7.0 ml, 50 mmol) in 150 mi of CH,Cl,, MsCl (2.8 ml, 36 mmol) was added dropwise at 0".
After stirring for 15 min at o",the mixture was extracted with ice-cold H20, sat. NH,CI, sat. KHCO, and brine.
Evaporation of the solvents i.u. gave 8.68 g (95%) of mesylate, pure according to TLC, as a yellowish oil. To a
solution of the latter (8.6 g, 29.2 mmol) in 30 ml of acetone, Nal (6.0 g, 40 mmol) was added. The mixture was
stirred for 17 h at r-t., then taken up in Et,O and washed successively with NaZS,O, and brine. On evaporation
i.u., the org. phases gave a yellowish oil, which was further purified by CC (CH,CI,) to yield 8.9 g (93 %) of pure
15. 1R (film): 2930, 2865. 'H-NMR (60 MHz, CCl,): 0.95 (d, J = 6, CH,-C(4)); 1.05-2.15 ( m , 13H); 3.10 (t,
J = 7, 2H-C(1)); 2.95-3.95 ( m , 2H-C(6), 2H-C(6')); 4.374.55 (br., H-C(2')).
Methyl (2E,8 R-8-Methyl-lO-( (ZH-tetrahydropyrtrn-2-yl)oxy]-2-decenoate (16). To a suspension of Mg
(0.61 g, 25 mg-atom) in 5 ml of Et,O, bromoethane (0.4 ml) were added to start an auxilary Crignard reaction.
To the proceeding reaction mixture, a solution of 14 (2.79 g, 10.0 mmol) in THF (20 ml) was added within 1 h,
the mixture being kept at 75" for 2 h. The resulting Grignard compound was then added dropwise to a well-
stirred and chilled solution of methyl 4-bromocrotonate (2.77 ml, 20.0 mmol) in TH F (15 ml) within 1.5 h. The
mixture was kept at 15" for 14 h. Hydrolysis by 0 . 2 NH4C1
~ (150 ml) and evaporation of the solvent i.u. gave a
residue, which was taken up in EtzO (100 ml). The org. solution was washed with 0 . 1 NH,CI ~ (10 ml) and brine
(2 x 10 ml), the aq. layers being re-extracted by Et,O (3 x 40 ml). The combined org. phases yielded 3.0 g of
crude 16, which was purified by CC (CH,CI,/Et,O gradient) to give 1.74 g (58%) of 16 as a yellowish oil.
'H-NMR (60 MHz, CCI,): 0.93 (d, J = 6, CH,-C(S)); 1.1-2.5 ( m , 17H); 3.1-4.2 (m, 2H-C(10), 2H-C(6')); 3.6
(s, CH,O-C(l)); 4.4 (br., H-C(2')); 5.92 (d, J = 15, H-C(2)); 6.9 (dt, J = 15, J' = 7, H-C(3)).
(6 R j - 1 1-Dimethoxy-6-methyl-8-[(2 H-~etruh.vdropyrun-2-yl)
I osy]octan-2-one (17). To a suspension of Mg
(3.5 g, 144 nig-atom) in 100 ml of Et,O, hromoethane (2.1 g) was added dropwise to start a Grignard reaction.
To this mixture, a solution of 14 (5.00 g, 17.9 mmol) in Et,O (100 ml) was added slowly under reflux. Refluxing
was continued for 5 h. After addition of I-(dimethoxyacety1)piperidine [9] (10.00 g, 53.5 mmol), dissolved in
 HELVETICA
CIIIMICA
ACTA Vol.67 (1984)
- 1995

EtZO (75 ml), refluxing was continued for 4 h. The mixture was hydrolyzed by 50% of NH,CI (60 ml). The
Et20-layer was separated, the aq. phase extracted with Et2 0 (2 x 100 ml) and the combined org. phases were
washed with H20, dried and evaporated i.u. to give crude 17.Purification of the latter by CC (CH2C12/acetone
gradient) yielded 1.04 g (19Oh) of 17 as a colourless oil. IR (CH2C12):2975, 1725, 1120, 1070, 1030. 'H-NMR
(60 MHz, CDCI,): 0.90 (d, J = 6, CA3-C(6)); 1.2-1.9 (m, 13H); 2.55 ( I , J = 7, 2H-C(3)); 3.4 (3, 2
CH?O-C(I)); 3.6-3.9 (nz, 2H-C(8), 2H-C(6')); 4.45 (s,H-C(1)); 4.6 (br., H-C(2')). MS: 302 ( M +), 301, 271,
227, 85.
(2RS,6R)-l,l-Dirnethoxy-6-methyl-8-~(2H-tetrahydropyran-2-yl)o~y]octan-2-~l (18). A solution of 17
(1.70 g, 5.20 mmol) in 100 ml of MeOH was treated with NaBH, (2.00 g) at r.t. for 12 h. Workup as described
for the preparation of 17 from 14 yielded 1.62 g of crude product, which was purified by CC (benzene/MeOH
gradient) to give 1.48 (87%) of 18 as a colourless oil. IR (CH2CI,): 3560, 2940, 2880, 1120, 1075, 1030. 'H-
NMR (60 MHz, CDCI,): 0.90 (d, J = 6, CH,-C(6)); 1.2-1.9 (m, 15H); 2.1 (br., HO-C(2)); 3.4 (s, 2
CH30-C(I)); 3.6-3.9 (m, H-C(2), 2H-C(8), 2H-C(6')); 4.1 (d, J = 7, H-C(1)); 4.55 (br., H-C(2')). MS: 304
( M ' ) , 303, 272, 229, 75.
/2RS.6R/-I,1-Dimethoxy-6-meihy1-8-((2H-tetrahydropyran-2-yl)oxy]oct-2-y1 Acetate (19). A mixture of
18 (1.30 g, 4.27 mmol), pyridine (20 ml) and Ac20 (14 ml) was kept at r.t. for 24 h. Evaporation of the solvents
left a residue, which was diluted with Et2 0 (150 ml) and washed with 0 . 1 ~ HCI and H20. After removal of the
solvent i.u. 1.42 g of a yellowish oil were obtained. Purification of the latter by CC (CH2C12/MeOHgradient)
yielded 1.30 g (88%) of 19 as a colourless oil. IR (CH2CI,): 2950, 2880, 1735, 1230, 1130, 1075, 1030. 'H-NMR
(90 MHz, CDCI,): 0.90 (d, J = 6, CH3-C(6)); 1.2-1.9 (m, 15H); 2.05 (s, CH,COO-C(2)); 3.40 (s, 2
CH,O-C(1)); 3.63.9 (m, 2H-C(8), 2H-C(6')); 4.25 (d, J = 7, H-C(1)); 4.60 (br., H-C(2')); 5.05 (br.,
H-C(2)).
(6Rj-6-Methyl-8-[(2H-tetrahydropyran-2-y[/oxyl-l-uctunol(20).The Grignard reagent o f 14 (5.58 g, 20.0
mmol), which was prepared in the same way as described for 16 from 14, was added dropwise to a solution of
ethylene oxide (1.5 ml, 30.0 mmol) in 7.5 ml of Et2 0 at -5" within 1 h. The milky suspension obtained was
allowed to warm up and was refluxed for 1 h. Hydrolysis with 4~ NH,CI (50 ml) was followed by extraction
+
with Et2O (125 and 2 X 75 ml). The org. phases were washed with ice-water (3 x 25 g 25 ml), dried and
evaporated i.0. to yield 7.00 g of a yellow oil. Purification of the latter by CC (CH2C12/Et20gradient) gave 1.84
g (38 %) of pure 20 as a colourless oil. [a]g = 16" 0.5" (c = 2.3, CH2C12).IR (film): 3420, 2950, 2880. 'H-
NMR (60 MHz, CCI,): 0.90 (d, J = 6, CH3-C(6)); 1.1-2.0 (m, 17H); 2.5 (br. d, HO-C(1)); 3.14.0 (m.
2H-C(1), 2H-C(8), 2H-C(6')); 4.5 (br,, H-C(2')). MS: 244 ( M +), 171, 101, 85.
(6R)-6-i\.iethyl-8-~(2H-tetrahydropyran-2-yl)uxy]-l-octunal(21). To a solution of 20 (1.27 g, 5.2 mmol) in
20 ml of CH2C12, PDC (3.2 g, 8.5 mmol) was added. The suspension was stirred at r.t. for 1 d. After dilution
with Et2O (30 ml), the mixture was filtered through a short column of Florisil. Evaporation of the filtrate gave
a residue, which was purified by CC (Et,O) to yield 825 mg (65%) of pure 21.IR (film): 2940, 2870, 2720, 1725.
'H-NMR (90 MHz, CDCI,): 0.89 (4 J = 6, CH3-C(6)); 1.1-2.0 (m, 15H); 2.45 (id, J = 7, J' = 1.8, 2H-C(2));
3.27-4.10 (m, 2H-C(8). 2H-C(6')); 4.51-4.68 (br. s, H-C(2')); 9.76 ( t , J = 1.8, H-C(1)). MS: 241 ( M - l),
169, 101, 85.
(3R)-3-Methyl-8,8-diethoxy-I-octanol (22).a ) A solution of 21 (380 mg, 1.6 mmol) and PPTS (40 mg) in
15 ml of EtOH was stirred at 55" for 3 h. The mixture was taken up in Et 2 0 and washed with Na2C03 and
brine. The org. phase gave on evaporation of the solvent i.0. a colourless oil, which was purified by CC (Et20)
to yield 314 mg (85%) of pure 22.b) Analogous treatment of 31 (4.5 g. 16.6 mmol) gave 3.58 g (93%) of pure
22. IR (film): 3420, 2940, 2880, 1135, 1070. 'H-NMR (90 MHz, CDCI,): 0.89 (d,J = 6, CH3-C(3)); 1.12-1.74
(m, 12H); 1.20 ( l , J = 7, 2 CH,CH20); 3.39-3.82 (m, 2H-C(1)); 3.60 (ya,J = 7, 2 x CH,CH20); 4.48 ( t , J = 5 ,
H-C(8)). MS: 232 ( M +), 231, 187, 157, 141, 123, 103, 75.
2-/(5'R)-7'-bromo-5'-meihylheptyl]-1,3-dioxolane (23).a ) To a solution of 22 (3.5 g, 15.0mmol) and Et,N
(10 ml, 72 mmol) in 100 ml of CH2C12MsCI (2.3 ml, 30.0 mmol) was added dropwise at 0". After stirring for 15
min at o", the mixture was extracted with ice-water, sat. NH,CI, sat. KHCO,, and brine. On evaporation i.u. the
org. phase yielded 4.4 g (94%) of mesylate as a yellowish oil, which was pure according to TLC. To a solution
of this mesylate (4.4 g, 14.1 mmol) in 35 ml of acetone was added LiBr ( 5 g, 57 mmol) and the mixture was
stirred at r.t. for 13 h. After concentration i.u. it was diluted with Et20 and washed with brine. Evaporation of
the solvent i.0. left 3.7 g of residue, which was dissolved in 100 ml of benzene. After addition of ethylene glycol
(10 ml) and PPTS (370 my) the mixture was reflnxed for 3 h. The product was extracted with Et20. The org.
layers were washed with sat. KHCO, and brine, dried and evaporated to give crude 23. The latter was purified
by CC (CH2C12)followed by bulb-to-bulb destillation to yield 3.4 g (91 % based on the mesylate) of pure 23.b )
In the same manner as described above, 29 (400~ mg, 1.95 mmol) yielded 460 mg (88%) of 23.
1996 CHIMICA
HELVETICA ACTA Val. 67 (1984)
-

MI^ = -2.5" f 0.5" (c = 19.2, CHCl,). IR (film): 2920, 2860, 1360, 1180. 'H-NMR (YO MHz, CDCI,): 0.88 (d,
J = 6, CH,-C(5')); 1.00-2.05 (m, 11H); 3.43 (t, J = 7, 2H-C(7')); 3.884.10 (m, 2H-C(4), 2H-C(5)); 4.84 ( I ,
J = 4, H-C(2)). MS: 266, 264, 251, 249, 185, 73.
( 3R)-[7- (I',3'-dioxolun-2'-yl)-3-mrthylheptyl]tripheny~hosphoniuin Bromide (24). A solution of 23 (6.0 g,
22.6 mmol) and Ph3P (6.55 g, 25 mmol) in 10 ml of benzene was refluxed for 3 d. The solvent was evaporated to
give a brown oil, which was purified by CC (CH2C12/MeOH9:l) to yield 9 g (75%) of pure, hygroscopic salt
24. 1R (CH2Cl2): 3050, 2940, 2860, 1590, 1435, 1115, 730, 695. 'H-NMR (YO MHz, CDCI,): 0.99 (d, J = 6,
CH3-C(3)); 1.10-2.00 (m,IIH); 3.40-4.07 (m,2H-C(1), 2H-C(4'), 2H-C(5')); 4.81 ( f , J = 4, H-C(2')); 7.65-
8.05 (m, 15H). I3C-NMR (22.63 MHz, CDCI,): 19.1 (4, CH,-C(3)); 20.8 ( f d ,J(C,P) = 53, C(1)); 24.0 (t, C(6));
26.5 (t. C(5));29.2 (td,J(C,P) = 4, C(2)); 33.4 (dd, J(C,P) = 14, C(3)); 33.7 (I, C(4)); 36.0 (t, C(7)); 64.7 (t, C(4'),
C(5')); 104.3 (d, C(2')); 118.2 (sd, J(C,P) = 86, ipso-C arom.); 130.6 (dd, J(C,P) = 12, mela-C arom.); 133.6 (dd
J(C,P) = 9, ortho-C arom.); 135.1 (dd, J(C,P) = 3, p u n - C arom.). MS: 447 ( M - 79/81 (Br)). Anal. calc. for
+

C,,H,,BrO,P (527.50): C 66.03, H 6.87; found: C 65.28, H 6.90.

(3R)-3-Methyl-7-~4'-dihydro-1"-th~uzol-2'-yl)-l-h~p~anol (26). To a solution of 2-methyl-4-dihydro-1,3-
thiazol (6.3 ml, 66.6 mmol) in 80 ml of THF, BuLi (49 ml, 73.5 mmol) was added at -78" over a period of 20
min. The mixture was stirred at -78" for 3 h. Then, a solution of 15 (23.9 g, 73 mmol) in 15 ml of TH F was
added dropwise over a period of 10 min. The mixture was stirred for an additional 1.5 h at -78", before it was
allowed to warm slowly to r.t. over night. The reaction was quenched by addition of 150 g of ice-water, and the
pH was adjusted to 2 by adding 6N HCI. After stirring for 2 h at r.t., the org. layer was separated and the aq.
layer was extracted with pentane. The org. layer was washed with brine, dried and evaporated Z.O. to give a
residue, which was purified by CC (CH2C12);5.58 g of 15 were recovered. The aq. layer was adjusted to pH = 10
by addition of 8N KOH, saturated with NaCl and extracted with Et20. Removal of the solvent i.u. yielded crude
26. After purification by bulb-to-bulb destillation 8.89 g (62% based on 2-methyl-4-dihydro- 1,3-thiazole) of
pure 26 were obtained. IR (film): 3330, 2930, 2860, 1625. 'H-NMR (YO MHz, CDCI;): 0.89 (d, J = 6,
CH;-C(3)); 1.12-1.88 (m, 10H); 2.52 ( t , J = 8, 2H-C(7)); 3.27 (fd,J = 8, J ' = 1, 2H-C(5')); 3.66 (t, J = 6,
2H-C(1)); 4.21 (td,J = 8, J ' = 1, 2H-C(4)). MS: 215 ( M '), 200, 114, 101.
(3R)-3-Methyl-7-(I',3'-thiazolidin-2-yl)-l-heptanol (27).To Al(Hg) [lo] prepared starting from 11 g of Al,
a solution of 26 (8.89 g, 43.3 mmol) in 600 ml of Et2O (previously shaken with H 2 0 ) was added and the mixture
was refluxed for 2.5 h. After it had been kept for an additional 2.5 h at r.t., the mixture was filtered and the
filtrate evaporated i.u. to give 8.26 g (92%) of 27 as a colourless oil, pure according to TLC. IR (film): 3340,
3270, 2935, 2860. 'H-NMR (60 MHz, CDC1,): 0.90 (d, J = 6, CH,-C(3)); 1.07-2.00 (m, 11H); 2.15--2.45 (br.,
OH, NH); 2.70-2.80 (m, 2H-C(4'), 2H-C(5')); 3.60 ( t , J = 6, 2H-C(1)); 4.41 ( I , J = 6, H-C(2)).
(6R)-8-Hydroxy-6-methy/octunul (28). To a solution of HgCI, (21 g ) in YO ml of acetonitrile/H,O 4:1, a
solution of 27 (8.26 g, 38 mmol) in 10 ml of CH,CN was added dropwise within 15 min. The mixture was stirred
at r.t. for 2 h. 75 ml of H 2 0 were added prior to filtration of the mixture. The extraction of the filtrate by Et 2 0
gave 5.33 g (88%) of crude aldehyde 28, which immediately formed a polymeric product. The latter was used in
the next step without purification.
(3R)-8,8-Dimethoxy-3-methyl-I-octano1(29). A solution of 28 (5.33 g, 33 mmol) and PPTS (100 mg) in 50
ml of MeOH was refluxed for 1 h. The mixture was diluted with Et20, which was washed with Na2CO; and
brine. Evaporation of the solvent i.u. left a colourless oil, which was purified by CC (Et20) to yield 5.37 g (80%)
of pure 29. IR (film): 3400, 2940, 2880, 1130, 1055. 'H-NMR (90 MHz, CDCI,): 0.89 (d, J = 6, CH,-C(3));
1.20-1.70 (m, 12H); 3.31 (s, 2 CH,O-C(S)); 3.68 (I, J = 7, 2H-C(1)); 4.36 ( 1 . J = 5, H-C(8)). MS: 203
( M '- - I), 173, 123, 75.
(IZ,6R)-l-Ethoxy-6-met~1yl-8-[(ZH-tetrahydropyrun-~-yl)oxy~-l-octene (31). To a solution of ( 2 ) - 2 -
ethoxyvinyl bromide (7.1 g, 47 mmol) in 50 ml of THF t-BuLi (50 ml, 95 mmol) was added dropwise at -78".
After stirring for I h at -78", HMPT (19.25 ml, 110 mmol) followed by a solution of 15 (7.5 g, 22.9 mmol) in 20
ml of T HF was added. The mixture was kept at -78" for 12 h and at r.t. for 8 h before working up. The
reaction was quenched by addition of H2O and the product was extracted with Et,O. The crude product
obtained was purified by CC (CH,C12) to yield 4.58 g (74%) of 31. IR (film): 3030, 2930, 2865, 1665. 'H-NMR
(60 MHz, CCI,): 0.90 (d, J = 6, CH,-C(6)); 1.1&2.15 (m. 15H); 1.22 (t, J = 7, CH3CH20); 3.15-3.90 (m,
2H-C(8), 2H-C(6')); 3.70 (q, J = 7, CH3CH20);4.20 ( d f ,J = 6, J' = 6, H-C(2)); 4.40-4.58 (br., H-C(2'));
5.77 (dt, J = 6, J' = 1, H-C(1)). MS: 270 ( M t ), 241, 225, 123, 101, 85.
 CHIMICA ACTA VOl. 67 (1984)
HELVETICA ~ 1997

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