Studies toward an asymmetric synthesis of CP-263,114 and CP-225,917

Article abstract of DOI:10.1135/cccc20000490

An enantioselective approach to construction of the complex framework of the CP compounds is presented. The synthesis relies on initial elaboration of the two sidechains. The "upper" appendage was asymmetrically dihydroxylated with both AD-mix reagents in order to lend flexibility to the scheme and provide the necessary handle for evolving the additional stereogenic centers. These fragments were linked to benzoic acid via Birch reduction-alkylation and subsequent cuprate addition. A series of functionalization reactions including dissolving metal reduction, Claisen rearrangement, iodolactonization, regioselective epoxide cleavage-oxidation, and intramolecular Wadsworth-Emmons cyclization took advantage of highly efficient stereocontrol. However, this flexibility was thwarted when deprotonation of a penultimate intermediate failed to be regioselective in the proper direction.

Full text of DOI:10.1135/cccc20000490

490
Devaux, O’Neil, Guillo, Paquette:
STUDIES TOWARD AN ASYMMETRIC SYNTHESIS OF CP-263,114 AND
CP-225,917
1
2
3
Jean-François DEVAUX , Steven V. O’NEIL , Nathalie GUILLO
4,
and Leo A. PAQUETTE *
Evans Chemical Laboratories, The Ohio State University, Columbus, OH 43210, U.S.A;
1
2
e-mail: jean-francois.devaux@lacq.elf-atochem.fr, steven.oneil@bms.com,
3
4
nathalie.guillo@sanofi-synthelabo.com, paquette.1@osu.edu
Received Decem ber 23, 1999
Accepted February 25, 1999
Dedicated to Professor Otakar Červinka on the occasion of his 75th birthday in recognition of his
outstanding contributions to the area of organic stereochemistry.
An en an tioselective approach to con struction of th e com plex fram ework of th e CP com -
poun ds is presen ted. Th e syn th esis relies on in itial elaboration of th e two sidech ain s. Th e
“upper” appen dage was asym m etrically dih ydroxylated with both AD-m ix reagen ts in order
to len d flexibility to th e sch em e an d provide th e n ecessary h an dle for evolvin g th e addition al
stereogen ic cen ters. Th ese fragm en ts were lin ked to ben zoic acid via Birch reduction -alkylation
an d subsequen t cuprate addition . A series of fun ction alization reaction s in cludin g dissolvin g
m etal reduction , Claisen rearran gem en t, iodolacton ization , regioselective epoxide cleav-
age-oxidation , an d in tram olecular Wadsworth –Em m on s cyclization took advan tage of h igh ly ef-
ficien t stereocon trol. However, th is flexibility was th warted wh en deproton ation of
pen ultim ate in term ediate failed to be regioselective in th e proper direction .
a
Key w ord s: Dih ydroxylation ; Birch reduction ; Allylic oxidation ; Iodolacton ization ; Claisen
rearran gem en t; CP com poun ds; Total syn th esis.
Two fun gal m etabolites, kn own by th e un glam orous n am es CP-263,114 (1)
an d CP-225,917 (2), h ave captured th e atten tion of th e syn th etic organ ic
com m un ity as a result of th eir im pressive biological properties an d un prec-
eden ted structural features1. Th ese com plex n on adrides h ave been iden ti-
fied as in h ibitors of Ras farn esyltran sferase2 an d squalen e syn th ase3, wh ose
biological effects are of con siderable curren t in terest. Wh ile a n um ber of
strategies h ave recen tly been reported for accessin g th e cen tral fram ework
of 1 an d 2 (ref.4), on ly in m id-1999 h as on e group succeeded in accom -
plish in g a racem ic total syn th esis5. Wh ile th e relative con figuration of C7
was n ot establish ed at th e tim e of origin al disclosure6, its relative con figura-
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

Asymmetric Synthesis
491
tion is n ow recogn ized to be as sh own . Th e absolute stereoch em istry of 1
an d 2 rem ain s elusive, alth ough th eir ch em ical in tercon version h as been
realized.
Th e syn th etic plan for elaboratin g th e n in e-m em bered rin g an d pen dan t
side ch ain s of th e title com poun ds was en vision ed to be possible by oxida-
tive couplin g7 of ester en olate an ion s position ed at C11 an d C12. Furth er
discon n ection of 3 led us back to th e keto lacton e 4 wh ere th e four con tigu-
ous stereogen ic cen ters about th e cycloh exan on e rin g were expected to be
set in an absolute sen se by referen ce back to th e con figuration of C6 an d
C7 with in th e dioxolan e substructure (Sch em e 1). Th e workability of th e
n um erous bon d con n ection s dem an ded by th is blueprin t are detailed
h erein .
O
O
6
HO
OH
7
Me
Me
O
O
O
O
O
11
O
Me
Me
O
O
O
12
2
O
O
1
HO2C
HO2C
O
Me
O
O
O
Me
H
O
O
t-BuO2C
Me
O
O
Me
t-BuO2C
O
3
4
t-BuO2C
SCHEME 1
RESULTS AND DISCUSSION
Synthesis of the C1–C7 Lateral Chain
Th e syn th esis of octa-2,6-diyn -1-ol (9) h as previously been reported8. In
lin e with th e earlier observation s, pen t-3-yn -1-ol (5) un derwen t sm ooth
tosylation an d subsequen t displacem en t with th e lith ium acetylide 7 in
refluxin g dioxan e (Sch em e 2). Th e success of th is step appears to be lin ked
to th e use of eth ereal m eth yllith ium with evaporation of low-boilin g sol-
ven t prior to th e h igh tem perature reaction . Subsequen t rem oval of th e
THP group proceeded to deliver 9 in 58% overall yield.
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

492
Devaux, O’Neil, Guillo, Paquette:
Regiocon trolled reduction of on e of th e triple bon ds in 9, accom plish ed
with Red-Al (ref.9), afforded 10 an d set th e stage for h igh -efficien cy con ver-
sion to brom ide 11 in th e presen ce of DIPHOS dibrom ide10. Th e in troduc-
1.
OTHP ,
7
TsCl
HO
TsO
RO
CH3Li
py
(90%)
Me
HO
Me
dioxane, ∆
Me
5
8, R = THP
9, R = H
6
2. TsOH, MeOH
(58% for 2 steps)
PPh2
.
2 Br2
PPh2
Red-Al
Br
ether
(87%)
Me
CH2Cl2
(95%)
Me
10
11
OMe
MeO
AD-mix α
MeSO2NH2
OH
O
O
Br
Br
(TsOH),
acetone
(74% from 11)
NaHCO3
t-BuOH/H2O
HO
Me
Me
12
13
0 °C
SCHEME 2
tion of ch irality was realized by Sh arpless asym m etric dih ydroxylation
followin g th e classical procedure11, but with proper atten tion to th e sen si-
tivity of product brom o diol to base. Th e acquisition of acetal 13 fin alized
th e syn th esis of th is buildin g block12
.
Th e en an tiom eric excess residen t in 13 was determ in ed by th e Mosh er es-
ter m eth od13. Treatm en t of th e un purified AD-m ix α reaction m ixture with
KOH afforded levorotatory 14, [α] 2D0 –6.0 (c 1.91, CHCl3). Th e de of its
(R)-MTPA ester was foun d to be 83%. Th e absolute con figuration s were as-
sign ed in accordan ce with establish ed face selection criteria an d proved by
1
com parison of th e H NMR ch em ical sh ifts of th e (S)-MTPA an d (R)-MTPA
esters of (–)-14 (Sch em e 3).
Our in itial efforts in th is area were com pleted prior to th e tim e wh en th e
relative con figuration at C7 was recogn ized. Th e arbitrary ch oice was m ade
by us to pursue th e use of AD-m ix α. Alth ough th is ch oice turn ed out to be
in correct, th e route was too advan ced to m ake a late-stage adjustm en t wh en
th e fin din gs in ref.1 becam e kn own to us6b.
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

Asymmetric Synthesis
493
OMe
Cl
F3C
Ph
O
OH
1. AD-mix α
OMTPA
83% de
OMTPA
NaHCO3
2. KOH, THF
(75%)
O
O
O
Et3N, DMAP
CDCl3
Me
Me
Me
(-)-14
11
OMe
F3C
O
OH
1. AD-mix β
Ph
NaHCO3
Cl
2. KOH, THF
Et3N, DMAP
CDCl3
O
Me
(+)-14
89% de
SCHEME 3
Elaboration of the Second Lateral Chain
Th e triple bon d in com m ercially available oct-2-yn -1-ol (15) was isom erized
to th e free term in us of th e ch ain with potassium h ydride in 1,3-diam in o-
propan e14, an d th e resultin g carbin ol 16 was “m on o-un zipped” by exposure
to a catalytic quan tity of potassium tert-butoxide in DMSO (Sch em e 4). Th e
furth er con version of alkyn ol 17 to brom ide 18a an d iodide 18b followed
preceden t15
.
Li, KOt-Bu
(KOt-Bu)
HO
Me
HO
H2N(CH2)3NH2
(83%)
DMSO, 80 °C
(96%)
16
15
1. Li, NH3
(97%)
Me
X
Me
PPh2
PPh2
CH2Cl2 (98%)
HO
2a.
.
2 Br2
18a, X = Br
18b, X = I
17
or
2b. Ph3P, I2
imidazole, CH2Cl2 (58%)
SCHEME 4
Assembly of the 4,5-Disubstituted Cyclohex-2-en-1-one
As foresh adowed by our retrosyn th etic strategy, proper attach m en t of 13
an d 18 to a fun ction alized six-m em bered rin g h ad n ow to be addressed. To
th is en d, ben zoic acid was subjected to Birch reduction an d th e resultin g
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

494
Devaux, O’Neil, Guillo, Paquette:
dian ion 16 was alkylated with brom ide 13 (Sch em e 5). Esterification of th e
resultin g carboxylic acid with diazom eth an e furn ish ed 19 in 83% overall
yield. Th e bis-allylic position could th en be oxidized17, th ereby leadin g to
th e crystallin e cycloh exadien on e 20. Con jugate addition of various
cuprates derived from 18a to 20 in itially proved to be problem atical. How-
ever, th e discovery was ultim ately m ade th at th e desired con version to 21
could be effected with th e cyan o cuprate in th e presen ce of boron trifluor-
Me
CO2Me
1. Li, NH3,
COOH
PDC, t-BuOOH
13
O
O
Celite, C6H6
(79%)
2. CH2N2
(83% for 2 steps)
19
Me
Me
CO2Me
O
Me
CuLiCN
O
CO2Me
O
.
BF3 OEt2, THF
-78 °C to -40 °C
(91%)
O
O
O
5
Me
20
21
Me
Me
1. KOt-Bu,
O
+
O
ether, H2O
O
O
Me
Me
O
2. 100-110 °C
(67%)
O
22
23
Me
Na2CO3,
24
Me
MeOH, ∆
O
O
O
SCHEME 5
ide eth erate. Th e use of eth er as th e reaction m edium for con version of io-
1
dide 18b in to th e organ olith ium reagen t is particularly critical18. H NMR
an alysis in dicated th at 21 con sisted of a m ixture of four isom ers in th e ratio
60 : 12 : 16 : 12. Recourse to m edium pressure liquid ch rom atograph y on
silica gel resulted in th e separation of 21a an d 21b from th e oth er pair
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

Asymmetric Synthesis
495
(21c/21d ). Alth ough th e absolute con figuration at C5 in th ese m olecules
was n ot establish ed, it was subsequen tly m ade clear th at 21a an d 21d sh are
th e iden tical stereoch em istry at th at position .
A study of th e sapon ification -decarboxylation of 21 was n ext un dertaken .
Wh ereas exposure to KOH or LiOH in duced gradual decom position an d th e
con dition s developed by Krapch o19 (NaCl, DMSO) an d by Liotta20 (Ph SeH,
NaH, HMPA) led to in tractable tars, h ydrolysis could be realized with potas-
sium tert-butoxide in m oist THF (ref.21). Decarboxylation occurred sim ulta-
n eously, alth ough h eatin g of th e n eat product at 100 °C for several m in utes
was usually carried out to com plete th e process.
Th e discovery th at β,γ-un saturated keton es 22 an d 23 (form ed in a ratio
of 3.2 : 1) could be con ven ien tly separated by m edium pressure liquid ch ro-
m atograph ic m eth ods precluded th e n eed to effect th e partial separation of
esters 21, alth ough th ese experim en ts were perform ed to validate con figu-
ration al in terrelation sh ips. An un qualified distin ction between 22 an d 23
was n ot un covered, an d th e m ajor con stituen t 22 was th erefore utilized in
th e studies defin ed below. As a con sequen ce, th e absolute stereoch em istry
about th e cycloh exan e rin g is n ot kn own with certain ty an d h as been arbi-
trarily assign ed.
Isom erization of 22 to its α,β-un saturated isom er 24 was accom plish ed
with catalytic quan tities of sodium carbon ate in refluxin g degassed m eth a-
n ol for several h ours22. As a result of com petin g degradation , con siderable
effort was expen ded in th e optim ization of th is process. Th e m ost favorable
con dition s in volved arrestin g th e h eatin g process at th e poin t wh ere it was
possible to isolate 46% of 24 alon gside 22% of recovered 22.
Incorporation of all the Carbon Centers
Reduction of 24 un der Luch e con dition s23 gave alcoh ol 25 with a selectiv-
ity in excess of 95% (Sch em e 6). At th is poin t, advan tage was taken of th e
lim ited level of fun ction alization to reduce th e alkyn e lin kage un der dis-
solvin g m etal con dition s. Th e resultin g alcoh ol 26 was subsequen tly tran s-
form ed in to vin yl eth er 27 (ref.24) in advan ce of Claisen rearran gem en t to
provide aldeh yde 28. Followin g oxidation to carboxylic acid 29,
iodolacton ization m ade possible th e stereoselective in troduction of two ad-
dition al stereogen ic cen ters aroun d th e cycloh exan e rin g periph ery.
To advan ce lacton e 30, it was n ecessary to effect its reduction to th e
lactol stage in advan ce of con version to epoxy aldeh yde 31 by addition of
silver(I) oxide. Hydride reduction an d p-m eth oxyben zyl protection of th e
acetaldeh yde side ch ain set th e stage for regiocon trolled oxidative cleavage
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

496
Devaux, O’Neil, Guillo, Paquette:
Me
Me
NaBH4,
.
Li
CeCl3 7 H2O
O
24
O
NH3
(89%)
MeOH
(91%)
O
O
Me
Me
HO
HO
26
25
Me
Me
,
O
OHC
xylene
Hg(OCOCF3)2
O
O
Et3N
(95%)
170 °C
(95%)
O
O
Me
Me
O
27
28
Me
Me
NaClO2, NaH2PO4
, t-BuOH
O
O
HO2C
NIS
O
O
CH2Cl2
(79%)
O
O
(99%)
Me
Me
I
30
29
Me
Me
1. NaBH4
(94%)
OHC
O
RO
O
1. (i-Bu)2AlH
30
O
O
2. Ag2O, CH3I,
CH2Cl2
2. NaH,
PMBCl,
DMF
O
O
Me
Me
(69%)
32, R = H
31
(83%)
33, R = PMB
Me
O
O
P(OEt)2
1.
Cl
PMBO
CSA, DMSO
CO2t-Bu ,
O
HO
35
py (81%)
Et3N, CH2Cl2
(53%)
O
Me
O
2. LHMDS, THF
(83%)
34
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

Asymmetric Synthesis
497
Me
KHMDS
BrCH2CO2t-Bu
PMBO
O
O
O
O
DMF
(69%)
Me
CO2t-Bu
36
Me
Me
PMBO
O
O
PMBO
O
O
+
O
O
O
Me
O
Me
t-BuO2C
CO2t-Bu
CO2t-Bu
37
38
t-BuO2C
SCHEME 6
of th e oxiran e rin g25. Esterification of 34 with th e acid ch loride 35 (ref.26)
in tan dem with subsequen t in tram olecular Wadsworth –Em m on s cycli-
zation provided lacton e 36 in excellen t yield. Th is advan ced in term ediate
was deproton ated with lith ium h exam eth yldisilazide (an d oth er bases) in
th e expectation th at en olization would take place distal from th e oxygen
cen ter because of th e usual in ductive con tribution s27. Despite n um erous at-
tem pts to override h igh ly regioselective deproton ation from with in th e
buten olide rin g, n o eviden ce was foun d for th e gen eration of th e targeted
product 39. Exam ples of such kin etic con trol are kn own but few in n um-
ber28–32. Sin ce th e rin g system apparen tly plays an im portan t role in th is
outcom e, we were clearly at an im passe. It is im portan t to recogn ize th at
en olization of 36 toward th e oxygen cen ter destroys a key stereogen ic cen -
ter th at causes 37 an d 38 to be form ed in n ear equal am oun ts (ratio 2 : 1).
Th is com plication would n ot arise wh en progressin g to 39 wh ere electro-
philic capture from the less sterically congested enolate π-surface is anticipated.
Based on these experiments, alternative methods for properly setting the projected
bridgeh ead double bon d h ave been explored an d will be described elsewh ere.
Me
PMBO
O
O
O
O
Me
CO2t-Bu
t-BuO2C
39
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

498
Devaux, O’Neil, Guillo, Paquette:
EXPERIMENTAL
Meltin g poin ts are un corrected. Th e colum n ch rom atograph ic separation s were perform ed
with Woelm silica gel (230–400 m esh ). Solven ts were reagen t grade an d in m ost cases dried
prior to use. Th e purity of all com poun ds was sh own to be >95% by TLC an d h igh -field
1H NMR. IR spectra (waven um bers in cm –1) were recorded on a Perkin –Elm er Model 1320
spectrom eter. 1H, 13C an d 19F NMR spectra were taken on a Bruker AC 300 in strum en t.
Ch em ical sh ifts are given in ppm (δ scale), couplin g con stan ts (J) in Hz. Th e h igh -resolution
an d fast atom -bom bardm en t spectra were recorded at Th e Oh io State Un iversity Cam pus
Ch em ical In strum en tation Cen ter. Elem en tal an alyses were perform ed at Atlan tic Microlab,
In c., Norcross, GA, U.S.A. Specific rotation s are given in deg cm 3 g–1 dm –1
.
Pen t-3-yn -1-yl Tosylate (6)
A solution of pen t-3-yn -1-ol (39.00 g, 0.46 m ol) in an h ydrous pyridin e (310 m l) was treated
at 5 °C durin g 30 m in with TsCl (101.65 g, 1.22 equivalen ts – previously dissolved in eth er
an d wash ed with 10% NaOH solution un til th e organ ic ph ase was colorless, dried, an d
recrystallized at –40 °C). Th e reaction m ixture was stirred at 20 °C for 3 h , poured in to wa-
ter, an d extracted with eth er (3 × 200 m l). Th e com bin ed organ ic ph ases were wash ed with
6
M HCl (4 × 100 m l), water, saturated NaHCO3 solution (15 m l), an d brin e (50 m l). Th e
acidic aqueous layers were reextracted with eth er an d th ese extracts were processed in th e
predescribed m an n er prior to bein g com bin ed. Th e eth ereal solu tion s were dried an d
con cen trated to leave
a dark brown solid. Trituration of th is m aterial with petro-
leum eth er–eth er (4 : 1) furn ish ed 99.10 g (90%) of 6 as a tan solid, wh ich was used with out
furth er purification . 1H NMR (200 MHz, CDCl3): 7.74 (dt, J = 8.6, 1.8, 2 H); 7.30 (d, J = 8.6,
2 H); 4.00 (JAB = 7.2, 2 H); 2.42 (m , 2 H); 2.40 (s, 3 H); 1.65 (t, J = 2.5, 3 H). 13C NMR
(50 MHz, CDCl3): 144.8, 132.8, 129.8 (2 C); 127.8 (2 C); 78.1, 73.0, 68.2, 21.5, 19.5, 3.3.
Octa-2,6-diyn -1-ol8 (9)
A solution of fresh ly distilled 7 (16.82 g, 1.30 equivalen ts) in dioxan e (200 m l, distilled from
sodium ben zoph en on e ketyl) was treated at 0 °C un der N2 with 1.4 M m eth yllith ium in
eth er (84.2 m l, 1.18 m ol) durin g 30 m in . Th e eth er was rem oved at 20 °C an d 70 Torr. At 0 °C,
23.83 g (0.12 m ol) of 6 dissolved in dioxan e (100 m l) was in troduced over 5 m in , an d th e
reaction m ixture was refluxed wh ile m ech an ically stirred for 15 h , poured in to ice water
(200 m l) an d eth er (300 m l), an d extracted with eth er (3 × 100 m l). Th e com bin ed organ ic
ph ases were wash ed with brin e, dried, an d con cen trated to leave 8 as a dark brown oil.
The unpurified 8 was taken up in m ethanol (300 m l), treated with 1.14 g (6 m ole %) of TsOH,
refluxed for 12 h , cooled, adm ixed with 1 g of NaHCO3, an d freed of m eth an ol un der
reduced pressure. Water (100 ml) was added and the product was extracted into ether (4 × 110 ml).
Th e com bin ed organ ic layers were wash ed with brin e, dried, an d con cen trated. Flash ch ro-
m atograph y of th e residue on silica gel (elution with 30% eth er in petroleum eth er) afforded
8.44 g (58%) of 9 as a ligh t tan solid. 1H NMR (200 MHz, CDCl3): 4.12 (m , 2 H); 3.25 (br s,
1 H); 2.35–2.20 (m , 4 H); 1.60 (t, J = 2.4, 3 H). 13C NMR (50 MHz, CDCl3): 83.8, 78.9, 76.1,
76.0, 50.2, 18.7, 18.3, 2.8.
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

Asymmetric Synthesis
499
(E)-Oct-2-en -6-yn -1-ol8 (10)
A 3.3 M solution of Red-Al in toluen e (49.6 m l, 2.5 equivalen ts) was diluted with an h ydrous
eth er (65 m l) an d treated dropwise with a solution of 9 (8.00 g, 65.6 m m ol) in dry eth er
(60 m l) such th at th e tem perature was m ain tain ed at 0–5 °C. Th e reaction m ixture was
stirred at 20 °C for 2 h , return ed to 0 °C, carefully quen ch ed with 3.6 M sulfuric acid
(350 m l). Th e com bin ed organ ic ph ases were wash ed with water (100 m l) an d brin e (60 m l),
dried, an d con cen trated. Flash ch rom atograph y of th e residue on silica gel (elution with
30% eth er in petroleum eth er) gave 7.09 g (87%) of 10 as a colorless oil. 1H NMR (200 MHz,
CDCl3): 5.65–5.59 (m , 2 H); 4.00 (d, J = 4.4, 2 H); 2.14–2.10 (m , 4 H); 1.68 (t, J = 2.5, 3 H).
13C NMR (50 MHz, CDCl3): 130.8, 130.1, 78.4, 75.9, 63.2, 31.7, 18.7, 3.3.
(E)-1-Brom ooct-2-en -6-yn e (11)
A m agn etically stirred solution of 1,2-bis(diph en ylph osph in o)eth an e (13.01 g, 0.6 equivalen ts)
in CH2Cl2 (340 ml) was treated dropwise at 0–5 °C with a solution of bromine (10.44 g, 1.2 equiva-
lents) in CH2Cl2 (50 m l). A solution of 10 (6.76 g, 54.4 m m ol) in CH2Cl2 (68 m l) was n ext
in troduced at th e sam e tem perature. Th e reaction m ixture was stirred at 20 °C for 3 h , di-
luted with eth er (200 m l) an d pen tan e (1 l), an d filtered th rough a sh ort pad of silica gel.
After th e solids h ad been rin sed with 2 : 1 pen tan e–eth er, th e com bin ed filtrates were evapo-
rated an d th e residue was purified by flash ch rom atograph y on silica gel (elution with 1.5%
ether in petroleum ether) to provide 9.68 g (95%) of 11 as a colorless oil. IR (CHCl3): 1 662, 1 436.
1H NMR (300 MHz, CDCl3): 5.83–5.69 (m , 2 H); 3.95 (d, J = 6.7, 2 H); 2.24–2.19 (m , 4 H); 1.77
(t, J = 2.4, 3 H). 13C NMR (75 MHz, CDCl3): 134.4, 127.3, 77.9, 76.2, 32.9, 31.5, 18.4, 3.3.
HR MS (EI), m/z: (M+) calculated: 186.0044; foun d: 186.0042. For C8H11Br (187.1) calculated:
51.36% C, 5.93% H; foun d: 51.12% C, 5.84% H.
(4R,5S)-4-(Brom om eth yl)-2,2-dim eth yl-5-(pen t-3-yn yl)-1,3-dioxolan e (13)
A solution of AD-m ix
α (35.0 g), sodium bicarbon ate (6.30 g, 3 equivalen ts), an d
m eth an esulfon am ide (2.38 g, 1 equivalen ts) in water (125 m l) an d tert-butyl alcoh ol
(125 m l) was cooled to 0 °C, treated with 11 (4.68 g, 25.0 m m ol), an d vigorously stirred at
0 °C for 26 h . Sodium m etabisulfite (25 g) was n ext cautiously in troduced durin g 20 m in .
After an addition al 40 m in of stirrin g, eth yl acetate (100 m l) an d water (70 m l) were added,
an d th e separated organ ic layer was wash ed with water (80 m l) an d brin e (80 m l). Th e aque-
ous ph ase was extracted with eth yl acetate (5 × 100 m l), an d th e com bin ed organ ic extracts
were wash ed with water an d brin e prior to dryin g an d solven t rem oval. Flash ch rom atogra-
ph y on silica gel (elution with 50% eth yl acetate in petroleum eth er) furn ish ed 5.14 g of a
m ixture of 12 an d (–)-14 as a crystallin e solid.
Th e above m aterial was directly dissolved in aceton e (70 m l) con tain in g 2,2-di-
m eth oxypropan e (6.1 m l, >2 equivalen ts) an d pyridin ium tosylate (380 m g, >6 m ole %),
stirred at 20 °C for 35 h , an d evaporated. Flash ch rom atograph y on silica gel (elution with
5% eth yl acetate in petroleum eth er) afforded 4.83 g (74%) of 13 in addition to 0.60 g (17%)
of (–)-14.
Compound 13. IR (CHCl3): 1 483, 1 382, 1 379, 1 236. 1H NMR (300 MHz, CDCl3): 3.96
(m , 1 H); 3.93 (m , 1 H); 3.46 (d, J = 5.2, 2 H); 2.33–2.24 (m , 2 H); 1.85–1.75 (m , 2 H); 1.77
(t, J = 2.4, 3 H); 1.41 (s, 3 H); 1.40 (s, 3 H). 13C NMR (75 MHz, CDCl3): 109.4, 79.7, 78.0,
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Devaux, O’Neil, Guillo, Paquette:
77.9, 76.3, 33.1, 32.3, 27.4, 27.2, 15.4, 3.4. HR MS (EI), m/z: (M+) calculated: 261.0490;
foun d: 261.0499. [α]2D0 –19.7 (c 1.54, CHCl3).
Compound (–)-14. IR (CHCl3): 3 599, 1 436, 1 385, 1 232. 1H NMR (200 MHz, CDCl3): 3.53
(br q, J ≈ 6, 1 H); 2.95 (ddd, J = 5.2, 4.1, 2.8, 1 H); 2.77 (dd, J = 4.9, 4.2, 1 H); 2.70 (br s, 1 H);
2.69 (dd, J = 4.9, 2.8, 1 H); 2.30–2.20 (m , 2 H); 1.75–1.65 (m , 5 H). 13C NMR (50 MHz,
CDCl3): 78.0, 76.1, 70.5, 55.1, 44.8, 33.1, 14.8, 3.2. HR MS (EI), m/z: (M+) calculated:
140.0837; foun d: 140.0844. [α]2D0 –6.0 (c 1.91, CHCl3).
(2S,3S)-1,2-Epoxyoct-6-yn -3-ol (–)-(14), (2R,3R)-1,2-Epoxyoct-6-yn -3-ol (+)-(14), an d
Mosh er Ester An alysis
Alcoh ol (–)-(14), likewise directly obtain ed from th e crude product of dih ydroxylation of 11
(187 m g, 1.0 m m ol) with AD-m ix α, was treated with 200 m g of KOH in THF (5 m l) at 25 °C
for 1 h . Water was added, th e product was extracted in to eth er, an d th e com bin ed organ ic
layers were wash ed with saturated NaCl solution , con cen trated an d ch rom atograph ed (elu-
tion with 50% eth yl acetate in petroleum eth er). Th ere were isolated 105 m g of (–)-14.
A parallel dih ydroxylation was con ducted on 11 (187 m g, 1.0 m m ol) with 1.4 g of
AD-m ix β, 252 m g of solid NaHCO3, 95 m g of m eth an esulfon am ide in water (5 m l) an d
tert-butyl alcoh ol (5 m l) at 0 °C for 24 h . Th e resultin g product was treated directly with
200 m g of KOH in THF (5 m l) at 0–25 °C for 1 h . Water was added, th e product was ex-
tracted in to eth er, an d th e com bin ed organ ic layers were wash ed with saturated NH4Cl solu-
tion , dried, con cen trated, an d ch rom atograph ed in th e predescribed m an n er. Th ere were
isolated 105 m g (75%) of (+)-14, [α]2D0 +6.2 (c 0.83, CHCl3), spectroscopically iden tical to th e
(–)-isom er.
Preparation of th e respective Mosh er esters accordin g to stan dard protocol afforded prod-
ucts wh ich were directly an alyzed33 by 1H an d 19F NMR (Table I).
TABLE I
1H an d 19F NMR data – diastereom eric purity of MTPA esters of alcoh ols 14
Param eter
(R)-MTPA ester of (–)-14
(R)-MTPA ester of (+)-14
–CHOH
–OCH3
5.10 (dt, J = 7.8, 6.2 Hz)
5.57 (d, J = 1.1 Hz)
2.80 (t, J = 4.4 Hz)
2.64 (dd, J = 4.9, 2.6 Hz)
–72.77
5.04 (dt, J = 5.0, 3.9 Hz)
5.60 (d, J = 1.1 Hz)
2.88 (t, J = 4.4 Hz)
2.75 (dd, J = 4.8, 2.5 Hz)
–72.70
H2C
O
19F
via 1H NMR
via 19F NMR
10.8 : 1 (83% de)
11 : 1 (83% de)
16.9 : 1 (89% de)
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Asymmetric Synthesis
501
Meth yl 1-{[(4S,5S)-2,2-Dim eth yl-5-(pen t-3-yn yl)-1,3-dioxolan -4-yl]m eth yl}-
cycloh exa-2,5-dien e-1-carboxylate (19)
To a stirred solution of ben zoic acid (2.70 g, 22.1 m m ol) in liquid NH3 (150 m l, distilled
from sodium ) cooled to –49 °C un der N2 was added lith ium m etal (0.43 g, 3.4 equivalen ts)
un til a blue color persisted. After 10 m in , a solution of 13 (4.80 g, 18.4 m m ol) in an h ydrous
eth er (15 m l) was slowly in troduced, an d stirrin g was m ain tain ed for 45 m in . After th e addi-
tion of solid NH4Cl (2.9 g) an d evaporation of th e NH3, th e residue was taken up in water
(60 m l) an d eth er (150 m l), an d th e separated aqueous ph ase was n eutralized with 2 M HCl
prior to eth er extraction (5 × 60 m l). Th e com bin ed organ ic ph ases were wash ed with brin e
(50 m l) an d con cen trated in vacuo to give 6.18 g of crude acid, wh ich was dissolved in eth er
(50 m l) at 0 °C an d treated with diazom eth an e. After solven t evaporation , th e residue was
subjected to flash ch rom atograph y on silica gel (elution with 10% eth yl acetate in petro-
leum eth er) to provide 4.90 g (83%) of 19 as a colorless oil. IR (n eat): 1 717, 1 434, 1 378,
1 279. 1H NMR (200 MHz, CDCl3): 5.81 (m , 4 H); 3.61 (s, 3 H); 3.60 (m , 2 H); 2.60 (m , 2 H);
2.22–2.15 (m , 2 H); 2.15–2.00 (m , 1 H); 1.79 (d, J = 14.2, 1 H); 1.72 (t, J = 2.4, 3 H);
1.65–1.50 (m , 2 H); 1.27 (s, 3 H); 1.24 (s, 3 H). 13C NMR (50 MHz, CDCl3): 174.5, 127.5,
126.7, 125.5, 125.2, 108.3, 79.8, 78.1, 76.9, 75.7, 52.0, 46.5, 43.2, 31.8, 27.1 (2 C); 25.8,
15.4, 3.3. FAB MS, m/z: (M+) calculated: 319.19; foun d: 319.19. [α]D20 –3.9 (c 0.81, CHCl3).
Meth yl 1-{[(4S,5S)-2,2-Dim eth yl-5-(pen t-3-yn yl)-1,3-dioxolan -4-yl]m eth yl}-
4-oxo-cycloh exa-2,5-dien e-1-carboxylate (20)
To a stirred solution of 19 (4.34 g, 13.6 m m ol) in ben zen e (160 m l) were added successively
at 5 °C 16.4 g of Celite, 20.51 g (4 equivalen ts) of pyridin ium dich rom ate, an d 7.47 m l of
tert-butylh ydroperoxide (70% in water, 4 equivalen ts). Th e m ixture was stirred for 8.5 h , di-
luted with water (350 m l), an d filtered th rough a pad of silica gel. Th e solids were rin sed
with eth er (5 × 100 m l) an d th e filtrates were con cen trated to leave a residue, purification of
wh ich by flash ch rom atograph y (elution with 30% eth yl acetate in petroleum eth er) af-
forded 3.59 g (79%) of 20 as a colorless solid, m .p. 90.5–91 °C (from petroleum eth er). IR
(CHCl3): 1 736, 1 668, 1 629, 1 220, 1 211. 1H NMR (300 MHz, CDCl3): 7.15–7.05 (m , 2 H);
6.33 (m , 2 H); 3.73 (s, 3 H); 3.71 (ddd, J = 11.8, 8.0, 6.0, 1 H); 3.59 (ddd, J = 9.3, 8.0, 2.2,
1 H); 2.29–2.19 (m , 2 H); 2.19 (dd, J = 14.0, 9.3, 1 H); 2.09 (dd, J = 14.0, 2.2, 1 H); 1.75 (t, J = 2.5,
3 H); 1.68–1.62 (m , 2 H); 1.33 (s, 3 H); 1.30 (s, 3 H). 13C NMR (75 MHz, CDCl3): 184.9,
170.3, 147.7, 147.6, 129.7, 129.6, 109.0, 79.6, 77.8, 76.8, 76.2, 53.6, 51.0, 41.8, 31.7, 27.1,
27.0, 15.3, 3.4. HR MS (EI), m/z: (M+) calculated: 332.1624; foun d: 332.1624. [α]2D0 –39.4 (c 0.78,
CHCl3). For C19H24O5 (332.4) calculated: 68.66% C, 7.28% H; foun d: 68.36% C, 7.35% H.
Meth yl (6S)-1-{[(4S,5S)-2,2-Dim eth yl-5-(pen t-3-yn -1-yl)-1,3-dioxolan -4-yl]m eth yl}-
6-[(E)-oct-6-en -1-yl]-4-oxocycloh ex-2-en e-1-carboxylate (21)
A solution of 18b (ref.15) (2.22 g, 9.32 m m ol) in dry eth er (20 m l) was blan keted with argon ,
cooled to –78 °C, an d treated with 1.7 M tert-butyllith ium in pen tan e (11.3 m l). Th e wh ite
suspen sion was stirred for 1 h at –78 °C an d for 1 h at –10 °C. A secon d th ree-n ecked flask
was ch arged with copper(I) cyan ide (774 m g, 8.64 m m ol, previously dried for 2 days at
55–60 °C un der h igh vacuum ) an d blan keted with argon . Dry THF (20 m l) was in troduced
an d th e suspen sion was cooled to –78 °C prior to th e addition of th e organ olith ium solution
via can n ula. After 1 h each at –78 an d –50 °C, th e reaction m ixture was treated with boron
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

502
Devaux, O’Neil, Guillo, Paquette:
trifluoride eth erate (1.63 m l, 12.9 m m ol) followed by 20 (1.23 g, 3.70 m m ol) dissolved in
THF (20 m l). Th e latter addition was perform ed very slowly (45 m in ) in order to m ain tain a
tem perature at –78 °C, th en allowed to warm to –40 °C durin g 2 h , at wh ich poin t it was
recooled to –78 °C before bein g quen ch ed with a 4 : 1 m ixture of saturated NH4Cl solution
an d aqueous am m on ia (25 m l). Th e products were extracted in to eth er (4 × 25 m l) an d th e
com bin ed organ ic ph ases were wash ed with brin e, dried, an d con cen trated. Flash ch rom a-
tograph y of th e residue on silica gel (elution with 15% eth yl acetate in petroleum eth er) fur-
n ish ed 1.49 g (91%) of 21 as a m ixture of four isom ers in a ratio of 60 : 12 : 16 : 12
(1H NMR an alysis). An aliquot fraction of th ese isom ers (675 m g) was partially separated un -
der m edium -pressure con dition s to yield 382 m g of 21a an d 21b, alon gside 120 m g of 21c
an d 21d , an d 173 m g of a m ixed fraction .
Th e m ajor isom er of th e 21a/21b colorless oil m ixture. 1H NMR (300 MHz, CDCl3): 7.14 (dd,
J = 10.4, 1.1, 1 H); 5.97 (d, J = 10.4, 1 H); 5.32 (m , 2 H); 3.65 (s, 3 H); 3.62 (m , 2 H); 2.60
(dd, J = 17.4, 4.8, 1 H); 2.41 (dd, J = 17.4, 5.0, 1 H); 2.20 (m , 4 H); 2.04 (dd, J = 14.4, 2.0, 1 H);
1.85 (br s, 2 H); 1.68 (t, J = 2.5, 3 H); 1.66–1.55 (m , 5 H); 1.27 (s, 3 H); 1.26 (s, 3 H);
2.25–1.10 (series of m , 8 H). 13C NMR (75 MHz, CDCl3): 197.8, 173.2, 149.7, 131.1, 128.8,
124.6, 108.7, 80.0, 77.8, 76.7, 76.0, 51.9, 50.4, 41.3, 40.9, 37.8, 32.3, 31.8, 29.6, 29.2, 28.7,
27.0, 26.9, 26.8, 17.8, 15.2, 3.3. HR MS (EI), m/z: (M+) calculated: 444.2876; foun d:
444.2878.
(5R)-4-{[(4S,5S)-2,2-Dim eth yl-5-(3-pen tyn yl)-1,3-dioxolan -4-yl]m eth yl}-
5-[(E)-oct-6-en -1-yl]cycloh ex-3-en -1-on e (22)
Potassium tert-butoxide (19.26 g, 12 equivalen ts) was dissolved in an h ydrous THF (200 m l),
cooled to 0 °C un der argon , treated with water (0.50 m l, 2 equivalen ts), an d stirred for
10 m in . Th e 21 isom er m ixture (6.36 g, 14.3 m m ol) dissolved in dry THF (170 m l) was in -
troduced over 15 m in , followed by 20 m in of stirrin g at 0 °C an d 4.5 h at room tem perature.
After bein g recooled to 0 °C, th e reaction m ixture was quen ch ed with ice, n eutralized with
10% HCl, an d extracted with eth er (5 × 90 m l). Th e com bin ed organ ic layers were wash ed
with brin e (80 m l), dried, an d con cen trated. Th e residue was h eated at 105 °C for 5–10 m in
an d subjected to flash ch rom atograph y on silica gel. Elution with 15% eth yl acetate in pe-
troleum eth er led to th e isolation of 2.82 g (51%) of 22 an d 0.92 g (16%) of 23.
Colorless oil 22. IR (CHCl3): 1 711, 1 380, 1 237. 1H NMR (300 MHz, CDCl3): 5.56 (dd, J = 3.6,
3.6, 1 H); 5.39 (m , 2 H); 3.85–3.70 (m , 2 H); 2.91 (br dd, J = 12.8, 3.9, 1 H); 2.80 (br d, J = 12.8,
1 H); 2.60 (dd, J = 13.5, 5.6, 1 H); 2.55 (m , 1 H); 2.47 (dd, J = 13.5, 1.9, 1 H); 2.40–2.25 (m ,
4 H); 1.95 (m , 2 H); 1.76 (t, J = 2.5, 3 H); 1.75–1.70 (m , 2 H); 1.65 (m , 3 H); 1.39 (s, 3 H);
1.37 (s, 3 H); 1.35–1.20 (m , 8 H). 13C NMR (75 MHz, CDCl3): 210.8, 139.3, 131.4, 124.8,
120.4, 108.4, 79.0, 78.9, 78.3, 76.0, 43.6, 39.7, 39.6, 38.0, 33.4, 32.5, 32.4, 29.4, 29.1, 27.4,
27.2, 26.8, 17.9, 15.6, 3.5. HR MS (EI), m/z: (M+) calculated: 386.2821; foun d: 386.2815. [α]2D0
+48.1 (c 1.10, CHCl3). For C25H39O3 (387.6) calculated: 77.47% C, 10.14% H; foun d: 77.42% C,
9.97% H.
(4S,5R)-4-{[(4S,5S)-2,2-Dim eth yl-5-(pen t-3-yn -1-yl)-1,3-dioxolan -4-yl]m eth yl}-
5-[(E)-oct-6-en -1-yl]cycloh ex-2-en -1-on e (24)
A solution of 22 (3.27 g, 8.46 m m ol) was diluted un der argon with 300 m l of m eth an ol
fresh ly distilled from m agn esium m eth an olate. Sodium carbon ate (30.5 m g, 3.4% equiva-
len ts) was in troduced an d th e m ixture was h eated at 75 °C for 13.5 h , cooled, an d treated
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

Asymmetric Synthesis
503
with cold eth an olic NH4Cl solution . After evaporation of th e m eth an ol, th e residue was pu-
rified by flash ch rom atograph y (elution with 15% eth yl acetate in petroleum eth er) an d sub-
sequen t MPLC to give 1.51 g (46%) of 24 an d 0.73 g (22%) of un reacted 22.
Colorless oil 24. IR (CHCl3): 1 673, 1 227. 1H NMR (300 MHz, CDCl3): 6.93 (dd, J = 10.2, 3.5,
1 H); 5.97 (dd, J = 10.2, 1.9, 1 H); 5.39 (m , 2 H); 3.82–3.68 (m , 2 H); 2.58 (dd, J = 16.4, 4.3,
1 H); 2.48 (m , 1 H); 2.37–2.20 (m , 3 H); 2.20 (dd, J = 16.4, 9.9, 1 H); 1.94 (m , 3 H); 1.76 (t, J =
2.5, 3 H); 1.87–1.65 (m , 3 H); 1.62 (m , 3 H); 1.39 (s, 3 H); 1.32 (s, 3 H); 1.35–1.17 (m , 8 H).
13C NMR (75 MHz, CDCl3): 199.4, 152.5, 131.2, 128.4, 124.6, 108.4, 79.8, 78.0, 77.7, 75.9,
41.2, 39.1, 37.7, 35.5, 32.8, 32.3, 32.0, 29.3, 29.0, 27.2, 27.1, 26.1, 17.7, 15.3, 3.3. HR MS (EI),
m/z: (M+) calculated: 386.2821; foun d: 386.2806. [α]D20 –1.6 (c 0.26, CHCl3).
(1S,4S,5R)-4-{[(4S,5S)-2,2-Dim eth yl-5-(pen t-3-yn -1-yl)-1,3-dioxolan -4-yl]m eth yl}-
5-[(E)-oct-6-en -1-yl]cycloh ex-2-en -1-ol (25)
A m ixture of 24 (550 m g, 1.42 m m ol) an d cerium trich loride h eptah ydrate (583 m g, 1.1
equivalen ts) in m eth an ol (8 m l) was cooled to 0 °C, treated with sodium boroh ydride
(70 m g, 1.3 equivalen ts), stirred for 10 m in , diluted with water (1 m l), an d freed of m eth an ol.
Furth er dilution with water (12 m l) was followed by eth er extraction (4 × 15 m l). Th e com -
bin ed organ ic ph ases were wash ed with brin e, dried, an d con cen trated. Flash ch rom atogra-
ph y of th e residue on silica gel (elution with 25% eth yl acetate in petroleum eth er) gave 503
m g (91%) of colorless oil 25. IR (CHCl3): 3 364, 1 440, 1 378, 1 241. 1H NMR (300 MHz,
CDCl3): 5.75 (ddd J = 10.2, 1.9, 1.9, 1 H); 5.67 (br d, J = 10.2, 1 H); 5.39 (m , 2 H); 4.20 (m , 1 H);
3.80 (ddd, J = 9.9, 8.0, 2.3, 1 H); 3.67 (dt, J = 8.0, 6.0, 1 H); 2.35–2.17 (m , 2 H); 2.16–2.00 (m ,
2 H); 2.00–1.96 (m , 2 H); 1.76 (t, J = 2.4, 3 H); 1.78–1.50 (m , 8 H); 1.37 (s, 3 H); 1.36 (s, 3 H);
1.35–1.15 (m , 9 H) (OH n ot observed). 13C NMR (75 MHz, CDCl3): 131.7, 131.5, 130.9,
124.6, 108.3, 80.0, 78.3, 77.9, 75.9, 67.6, 38.4, 37.9, 37.3, 36.9, 33.0, 32.5, 32.2, 29.5, 29.4,
27.4, 27.3, 26.5, 17.9, 15.5, 3.5. HR MS (EI), m/z: (M+) calculated: 388.2978; foun d:
388.2979. [α]2D0 –1.4 (c 0.29, CHCl3).
(1S,4S,5R)-4-{[(4S,5S)-2,2-Dim eth yl-5-[(E)-pen t-3-en -1-yl]-1,3-dioxolan -4-yl]m eth yl}-
5-[(E)-oct-6-en -1-yl]cycloh ex-2-en -1-ol (26)
To a solution of lith ium (180 m g, 5 equivalen ts) in liquid am m on ia (125 m l) was added a
solution of 25 (1.98 g, 5.15 m m ol) in THF (30 m l) via can n ula durin g 15 m in . After 30 m in
of stirrin g, th e am m on ia was evaporated in a flow of N2. Th e residue was taken up in eth er
(80 m l), an d water (40 m l) was added slowly. Th e organ ic ph ase was wash ed with saturated
NH4Cl solution an d brin e, th e aqueous ph ases were back-extracted with eth er (5 × 40 m l),
an d th e com bin ed organ ic solution s were dried an d con cen trated. Th e residue was purified
by flash ch rom atograph y on silica gel (elution with 20% eth yl acetate in petroleum eth er) to
afford 26 (1.80 g, 89%) as a colorless oil. IR (CHCl3): 3 600, 1 379, 1 371, 1 239. 1H NMR
(300 MHz, CDCl3): 5.76 (dt, J = 10.2, 1.9, 1 H); 5.69 (br d, J = 10.2, 1 H); 5.44–5.38 (m , 4 H);
4.21 (m , 1 H); 3.74 (ddd, J = 9.7, 8.1, 2.1, 1 H); 3.57 (dt, J = 7.5, 4.9, 1 H); 2.20–2.00 (m ,
4 H); 2.00–1.95 (br s, 2 H); 1.75 (ddd, J = 13.8, 9.9, 3.0, 1 H); 1.64 (m , 6 H); 1.62–1.50 (m ,
5 H); 1.38 (s, 6 H); 1.38–1.20 (m , 8 H) (OH n ot observed). 13C NMR (75 MHz, CDCl3): 131.8,
131.5, 130.9, 130.4, 125.4, 124.6, 108.1, 80.7, 78.1, 67.6, 38.4, 37.9, 37.4, 36.9, 33.0, 32.6,
32.5, 29.5, 29.4, 29.0, 27.3 (2 C); 26.5, 17.9. HR MS (EI), m/z: (M+) calculated: 390.3134;
foun d: 390.3139. [α]2D0 –102.7 (c 1.405, CHCl3). For C25H42O3 (390.6) calculated: 76.87% C,
10.84% H; foun d: 77.00% C, 10.91% H.
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

504
Devaux, O’Neil, Guillo, Paquette:
(4S,5S)-2,2-Dim eth yl-4-{[(1S,4S,6R)-6-[(E)-oct-6-en -1-yl]-4-(vin yloxy)cycloh ex-2-en -1-yl]-
m eth yl}-5-[(E)-pen t-3-en -1-yl]-1,3-dioxolan e (27)
To a solution of 26 (1.80 g, 4.61 m m ol) in eth yl vin yl eth er (100 m l fresh ly distilled from
sodium ) cooled to 0 °C un der argon was added trieth ylam in e (0.71 m l, 1.1 equivalen ts) an d
m ercuric trifluoroacetate (0.59 g, 0.3 equivalen ts). After on e day of stirrin g at room tem pera-
ture, addition al Hg(OCOCF3)2 (0.59 g) was in troduced, an d th is process was repeated a th ird
tim e. Th e solven t was evaporated un der reduced pressure, an d th e residue was taken up in 1 : 4
eth er–petroleum eth er (80 m l) an d wash ed with 10% NaOH solution (40 m l) an d brin e
(30 m l). Th e aqueous ph ases were extracted twice with th e m ixed solven t system , an d th e
com bin ed organ ic solution s were dried, con cen trated, an d purified by flash ch rom atograph y
on silica gel (elution with 5% eth yl acetate in petroleum eth er). Th ere were isolated 1.82 g
(95%) of colorless oil 27. IR (n eat): 1 633, 1 609, 1 453, 1 369. 1H NMR (300 MHz, CDCl3):
6.37 (dd, J = 14.2, 6.6, 1 H); 5.83 (ddd, J = 10.3, 2.1, 2.0, 1 H); 5.73 (br d, J = 10.3, 1 H);
5.47–5.39 (m , 5 H); 4.38 (m , 1 H); 4.29 (dd, J = 14.2, 1.6, 1 H); 4.02 (dd, J = 6.6, 1.6, 1 H);
3.74 (m , 1 H); 3.57 (m , 1 H); 2.18–1.97 (m , 5 H); 1.80–1.20 (m , 14 H); 1.63 (br s, 6 H); 1.37
(s, 6 H). 13C NMR (75 MHz, CDCl3): 150.2, 144.1, 131.5, 130.4, 127.0, 125.4, 124.6, 108.1,
88.4, 80.7, 78.1, 74.4, 38.1, 37.5, 37.0, 33.7, 33.0, 32.6, 32.5, 29.5, 29.4, 29.0, 27.3 (2 C);
26.5, 17.9 (2 C). HR MS (EI), m/ z: (M+) calcu lated: 416.3290; fou n d: 416.3294. [α ]D20 –91
(c 0.025, CHCl3). For C27H44O3 (416.6) calculated: 77.84% C, 10.64% H; foun d: 77.98% C,
10.68% H.
(1S,5R,6S)-6-{[(4S,5S)-2,2-Dim eth yl-5-[(E)-pen t-3-en -1-yl]-1,3-dioxolan -4-yl]m eth yl}-
5-[(E)-oct-6-en -1-yl]cycloh ex-2-en -1-acetaldeyde (28)
A sam ple of vin yl eth er 27 (1.66 g, 4.00 m m ol) was dissolved in fresh ly distilled xylen es,
blan keted with argon , an d h eated for 5 h at 170 °C in a sealed glass vessel. Th e xylen es were
evaporated un der h igh vacuum an d th e residue was ch rom atograph ed on silica gel (elution
with 5% eth yl acetate in petroleum eth er) to afford 1.58 g (95%) of 28 as a colorless oil. IR
(CHCl3): 1 720, 1 380, 1 240. 1H NMR (300 MHz, CDCl3): 9.75 (m , 1 H); 5.67 (br d, J = 9.8,
1 H); 5.50 (br d, J = 9.9, 1 H); 5.45–5.37 (m , 4 H); 3.69 (dt, J = 8.3, 2.8, 1 H); 3.54 (dt, J = 8.1,
5.0, 1 H); 2.75 (m , 1 H); 2.66 (ddd, J = 16.2, 4.9, 1.3, 1 H); 2.38 (ddd, J = 16.2, 7.8, 3.0, 1 H);
2.22–2.01 (m , 3 H); 1.95 (m , 2 H); 1.72 (m , 1 H); 1.64 (m , 6 H); 1.60–1.40 (m , 6 H); 1.34 (s,
6 H); 1.35–120 (m , 8 H). 13C NMR (75 MHz, CDCl3): 203.2, 134.5, 130.5, 129.1, 126.3,
125.4, 124.7, 108.1, 80.8, 77.9, 48.7, 40.0, 36.1, 34.2, 33.8, 33.7, 32.6, 32.4, 29.6, 29.5, 29.1,
28.9, 27.3 (2 C); 26.7, 17.9 (2 C). HR MS (EI), m/z: (M+) calculated: 416.3291; foun d:
416.3285. [α]2D4 –30.0 (c 1.03, CHCl3). For C27H44O3 (416.6) calculated: 77.84% C, 10.64% H;
foun d: 77.95% C, 10.57% H.
(1S,5R,6S)-6-{[(4S,5S)-2,2-Dim eth yl-5-[(E)-pen t-3-en -1-yl]-1,3-dioxolan -4-yl]m eth yl}-
5-[(E)-oct-6-en -1-yl]cycloh ex-2-en e-1-acetic acid (29)
To a well stirred m ixture of 28 (1.02 g, 2.45 m m ol) in tert-butyl alcoh ol (24 m l) an d
2-m eth yl-2-buten e (8 m l) was added dropwise a solution of sodium ch lorite (0.83 g, 3 equiv-
alen ts) an d sodium dih ydrogen ph osph ate (0.90 g) in distilled water (10 m l). After 5 h at
room tem perature, brin e (15 m l) was in troduced, th e solution was acidified with 1 M HCl
(10 m l) prior to eth er extraction (5 × 25 m l), an d th e com bin ed organ ic ph ases were wash ed
with brin e (15 m l), dried, an d con cen trated. Purification of th e residue by flash ch rom atog-
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

Asymmetric Synthesis
505
raph y on silica gel (elution with 15% eth yl acetate in petroleum eth er) furn ish ed 1.06 g
(99%) of 29 as a colorless oil. IR (CHCl3): 3 600–2 500, 1 707, 1 380. 1H NMR (300 MHz,
CDCl3): 5.66 (br ddt, J = 10.2, 3.7, 2.0, 1 H); 5.56 (br d, J = 10.2, 1 H); 5.47–5.37 (m , 4 H);
3.72 (dt, J = 7.8, 4.7, 1 H); 3.54 (dt, J = 8.2, 5.4, 1 H); 2.66 (dd, J = 14.8, 5.4, 1 H); 2.56 (m ,
1 H); 2.31 (dd, J = 14.8, 8.1, 1 H); 2.22–2.01 (m , 3 H); 1.95 (m , 2 H); 1.74 (br d, J = 18, 1 H);
1.64 (m , 6 H); 1.63–1.47 (m , 6 H); 1.36 (2 s, 6 H); 1.40–1.11 (m , 8 H). 13C NMR (75 MHz,
CDCl3): 178.4, 131.5, 130.5, 128.6, 126.0, 125.4, 124.7, 108.1, 80.8, 78.2, 39.4, 39.2, 36.4,
36.1, 35.0, 33.9, 32.6, 32.4, 29.6, 29.5, 29.0, 28.2, 27.3, 27.2, 27.1, 17.9 (2 C). HR MS (EI),
m/z: (M+) calculated: 432.3240; foun d: 432.3251. [α]D25 –16.1 (c 1.45, CHCl3).
(3aR,4S,5R,7R,6aR)-4-{[(4S,5S)-2,2-Dim eth yl-5-[(E)-pen t-3-en -1-yl]-1,3-dioxolan -4-yl]m eth yl}-
7-iodo-5-[(E)-oct-6-en -1-yl]-3a,4,5,6,7,7a-h exah ydro-1-ben zofuran -2(3H)-on e (30)
A cold (–70 °C), m agn etically stirred solution of 29 (42 m g, 0.10 m m ol) in CH2Cl2 (0.5 m l)
was added to N-iodosuccin im ide (32 m g, 1.5 equivalen ts) dissolved in CH2Cl2 (1 m l). After 1 h
at –70 °C an d 2 h at room tem perature, th e solven t was evaporated an d th e residue was pu-
rified ch rom atograph ically on silica gel (elution with 10% eth yl acetate in petroleum eth er).
Th ere were isolated 45 m g (79%) of 30 as a colorless oil. 1H NMR (300 MHz, CDCl3):
5.47–5.39 (m , 4 H); 4.79 (m , 1 H); 4.71 (m , 1 H); 3.67 (dt, J = 8.2, 3.3, 1 H); 3.54 (dt, J = 8.2,
6.0, 1 H); 3.00 (m , 1 H); 2.68 (dd, J = 17.1, 6.5, 1 H); 2.56 (d, J = 17.1, 1 H); 2.25–2.01 (m , 3 H);
1.97 (m , 2 H); 1.85 (m , 1 H); 1.64 (m , 6 H); 1.64–1.46 (m , 7 H); 1.38 (s, 3 H); 1.36 (s, 3 H);
1.40–1.15 (m , 8 H); for ch aracteristic J values see Fig. 1. 13C NMR (75 MHz, CDCl3): 176.5,
131.3, 130.3, 125.5, 124.8, 108.2, 83.1, 80.9, 77.1, 39.0, 37.8, 36.7, 34.2, 33.4, 32.5, 32.4,
32.0, 29.4, 29.2, 29.0, 27.3, 27.2, 27.1, 25.7, 17.9 (2 C). HR MS (EI), m/z: (M+) calculated:
558.2284; foun d: 558.2305. [α]2D0 –0.84 (c 0.275, CHCl3).
O
10.6 Hz
O
O
Z
3
O
Y
X
4
2
2.8 Hz
4 Hz
O
O
I
1
5
6
2.9 and
2.9 Hz
J
J
J
H1-H2 = 2.9 Hz (confirmed by irradiation of H3)
H2-H3 = 4.0 Hz (confirmed by irradiation of H1)
H3-H4 = 10.6Hz (confirmed by irradiation of H2)
JH1-H6a = 2.9 Hz (confirmed by irradiation of H3)
H1-H6b = 2.9 Hz (confirmed by irradiation of H3)
JH1-H3 ~ 1 Hz
J
FIG. 1
Ch aracteristic in teraction con stan ts (J) in 1H NMR spectrum of lacton e 30
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

506
Devaux, O’Neil, Guillo, Paquette:
(1R,2S,3R,5S,6R)-2-{[(4S,5S)-2,2-Dim eth yl-5-[(E)-pen t-3-en -1-yl]-1,3-dioxolan -4-yl]-
m eth yl}-5,6-epoxy-3-[(E)-oct-6-en -1-yl]cycloh exan e-1-acetaldeh yde (31)
A solution of 30 (50 m g, 0.09 m m ol) in CH2Cl2 (5 m l) was cooled to –78 °C, treated with
1.0 M DIBAL-H (135 µl, 0.135 m m ol), stirred for 90 m in , an d quen ch ed with 3 : 1 water–acetic
acid (1 m l). After 30 m in of vigorous stirrin g, th e reaction m ixture was diluted with eth er,
wash ed with saturated NaHCO3 solution an d brin e, dried, an d evaporated. Flash ch rom atog-
raph y of th e residue on silica gel (elution with 10% eth yl acetate in h exan es) gave 45 m g
(89%) of pure lactol as a clear oil. IR (n eat): 3 415, 1 729, 1 453, 1 371. 1H NMR (300 MHz,
CDCl3): 5.60 (m , 1 H); 5.48–5.39 (m , 4 H); 4.56 (m , 1 H); 4.50 (dd, J = 4.5, 4.5, 1 H); 3.68
(m , 1 H); 3.55 (m , 1 H); 2.85 (d, J = 3.7, 1 H); 2.60 (m , 1 H); 2.25–1.1 5 (series of m , 22 H);
1.65 (br s, 6 H); 1.37 (s, 6 H). 13C NMR (75 MHz, CDCl3): 131.4, 130.4, 125.5, 124.7, 108.1,
98.4, 81.7, 81.1, 77.9, 40.5, 40.3, 39.1, 36.4, 35.0, 34.5, 32.6, 32.5 (2 C); 29.9, 29.3, 29.1,
27.3, 27.2, 26.1, 17.9 (2 C) (on e C n ot observed). HR MS (EI), m/z: (M+) calculated:
560.2363; foun d: 560.2332.
A solution of th e above lactol (9.0 m g, 0.016 m m ol) in CH2Cl2 (1 m l) was treated with
m eth yl iodide (100 µl, 1.6 m m ol) an d silver(I) oxide (18.5 m g, 0.080 m m ol), stirred for 2 h ,
filtered th rough a cotton plug, an d con cen trated un der reduced pressure. Flash ch rom atogra-
ph y of th e residue (silica gel, elution with 10% eth yl acetate in h exan es) gave 5.4 m g (78%)
of 31 as a colorless oil. IR (n eat): 1 724, 1 453, 1 378, 1 238. 1H NMR (300 MHz, CDCl3):
9.88 (s, 1 H); 5.47–5.38 (m , 4 H); 3.59–3.52 (m , 2 H); 3.24 (dd, J = 4.8, 4.3, 1 H); 3.20 (dd, J = 4.3,
1.5, 1 H); 2.82 (dd, J = 13.5, 1.3, 1 H); 2.72 (dd, 8.4, 2.3, 1 H); 2.64 (m , 1 H); 2.17–2.06 (m ,
3 H); 1.95 (m , 2 H); 1.64 (br s, 6 H); 1.60–1.05 (series of m , 15 H); 1.34 (s, 3 H); 1.32 (s,
3 H). 13C NMR (75 MHz, CDCl3): 202.5, 131.3, 130.3, 125.5, 124.8, 108.2, 80.8, 77.3, 56.0,
53.3, 46.0, 35.8, 34.6, 34.0, 32.5, 32.3, 30.5, 29.5, 29.4, 29.0, 28.7, 27.3, 27.2, 25.7, 17.9
(2 C). HR MS (EI), m/z: (M+) calculated: 432.3240; foun d: 432.3218.
(1R,2S,3R,5S,6R)-2-{[(4S,5S)-2,2-Dim eth yl-5-[(E)-pen t-3-en -1-yl]-1,3-dioxolan -4-yl]-
m eth yl}-5,6-epoxy-3-[(E)-oct-6-en -1-yl]cycloh exan e-1-eth an ol (32)
Excess sodium boroh ydride was added to a solution of 31 (300 m g, 0.69 m m ol) in m eth an ol
(10 m l) at 0 °C. Th e reaction m ixture was stirred for 10 m in in th e cold, diluted with eth er,
an d wash ed with water. Th e resultin g aqueous ph ase was extracted twice with eth er, an d th e
com bin ed organ ic layers were wash ed with brin e, dried, an d con cen trated. Flash ch rom atog-
raph y of th e residue (silica gel, elution with 20% eth yl acetate in h exan es) gave 282 m g
(94%) of pure 32 as a clear oil. IR (n eat): 3 452, 1 540, 1 378, 1 240. 1H NMR (300 MHz,
CDCl3): 5.47–5.38 (m , 4 H); 3.79 (m , 2 H); 3.62–3.54 (m , 2 H); 3.27 (dd, J = 4.9, 4.3, 1 H);
3.21 (m , 1 H); 2.48 (m , 1 H); 2.19–1.83 (m , 9 H); 1.64 (br s, 6 H); 1.68–1.05 (series of m ,
14 H); 1.37 (s, 3 H); 1.36 (s, 3 H). 13C NMR (75 MHz, CDCl3): 131.3, 130.3, 125.5, 124.7,
108.3, 80.8, 77.4, 60.3, 55.7, 53.7, 35.7, 34.8, 34.5, 33.4, 33.0, 32.5, 32.0, 30.0, 29.5, 29.4,
28.9, 28.8, 27.3, 27.1, 25.6, 17.9 (2 C). HR MS (EI), m/z: (M+) calculated: 434.3396; foun d:
434.3401. [α]2D0 +23.9 (c 1.8, CHCl3). For C27H46O4 (434.7) calculated: 74.61% C, 10.67% H;
foun d: 74.48% C, 10.59% H.
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Asymmetric Synthesis
507
(4S,5S)-4-{[(1S,2R,3R,4S,6R)-3,4-Epoxy-2-{2-[(4-m eth oxyben zyl)oxy]eth yl}-6-[(E)-oct-
6-en -1-yl]cycloh exyl]m eth yl}-2,2-dim eth yl-5-[(E)-pen t-3-en -1-yl]-1,3-dioxolan e (33)
To a solution of 32 (125 m g, 0.288 m m ol) in DMF (1 m l) was added 80% sodium h ydride in
oil (14 m g, 0.43 m m ol) an d 4-m eth oxyben zyl ch loride (0.058 m l, 0.43 m m ol). Th e reaction
m ixture was stirred for 36 h , diluted with eth er, wash ed with water an d brin e, dried, an d
evaporated. Purification of th e residue by flash ch rom atograph y on silica gel (elution with
4% eth yl acetate in CH2Cl2) provided 132 m g (83%) of 33 as a clear oil. IR (n eat): 1 613,
1 513, 1 454, 1 368, 1 248. 1H NMR (300 MHz, CDCl3): 7.27 (d, J = 8.7, 2 H); 6.87 (d, J =
8.7, 2 H); 5.52–5.36 (m , 4 H); 4.49 (d, J = 11.5, 1 H); 4.43 (d, J = 11.5, 1 H); 3.80 (s, 3 H);
3.71–3.50 (m , 4 H); 3.19 (dd, J= 4.4, 4.4, 1 H); 3.14 (m , 1 H); 2.24–1.77 (series of m , 8 H);
1.64 (br s, 6 H); 1.69–1.10 (series of m , 15 H); 1.33 (s, 3 H); 1.32 (s, 3 H). 13C NMR (75 MHz,
CDCl3): 159.1, 131.4, 130.8, 130.4, 129.1 (2 C); 125.4, 124.7, 113.7 (2 C); 107.9, 80.9, 78.1,
72.4, 68.1, 55.4, 55.2, 52.9, 36.2, 35.9, 35.3, 33.4, 32.6, 32.5, 32.4, 31.2, 29.5, 29.4, 29.1,
28.5, 27.3, 27.2, 26.2, 17.0 (2 C). HR MS (EI), m/z: (M+) calculated: 554.3971; foun d:
554.3976. [α]2D0 –12.0 (c 3.0, CHCl3). For C35H54O5 (554.8) calculated: 75.77% C, 9.81% H;
foun d: 75.77% C, 9.86% H.
(2R,3R,4S,5R)-4-{[(4S,5S)-2,2-Dim eth yl-5-[(E)-pen t-3-en -1-yl]-1,3-dioxolan -4-yl]m eth yl}-
2-h ydroxy-3-{2-[(4-m eth oxyben zyl)oxy]eth yl}-5-[(E)-oct-6-en -1-yl]cycloh exan -1-on e (34)
Cam ph orsulfon ic acid (51 m g, 0.22 m m ol) was added to a solution of 33 (120 m g, 0.22
m m ol) in 5 m l of 4 : 1 CH2Cl2–DMSO. Th e solution was stirred for 1.5 h , treated with
trieth ylam in e (0.5 m l), an d 10 m in later diluted with eth er. Th e organ ic ph ase was wash ed
with water an d brin e, dried, an d con cen trated. Purification of th e residue by flash ch rom a-
tograph y (elution with 10% eth yl acetate in h exan es) yielded 65 m g (53%) of pure 34 as a
clear oil. IR (n eat): 3 486, 1 719, 1 514, 1 248. 1H NMR (300 MHz, CDCl3): 7.24 (d, J = 8.6,
2 H); 6.85 (d, J = 8.6, 2 H); 5.47–5.40 (m , 4 H); 4.41 (s, 2 H); 4.38 (m , 1 H); 3.79 (s, 3 H);
3.71 (ddd, J = 9.5, 7.7, 1.7, 1 H); 3.63 (d, J = 3.6, 1 H); 3.62–3.47 (m , 3 H); 2.61 (br d, J = 18.0,
1 H); 2.17–1.07 (series of m, 22 H); 1.65 (br s, 6 H); 1.37 (s, 3 H); 1.35 (s, 3 H). 13C NMR (75 MHz,
CDCl3): 212.2, 159.1, 131.3, 130.4, 129.2 (2 C); 125.5, 124.8, 113.7 (2 C); 108.1, 80.7, 78.0,
74.2, 72.4, 67.9, 55.2, 40.7, 40.0, 39.6, 37.8, 36.9, 34.8, 32.5, 30.5, 29.4, 29.3, 29.1, 29.0,
27.4, 27.3, 26.8, 17.9 (2 C). FAB MS, m/z: (M+) calculated: 570.39; foun d: 570.35.
tert-Butyl (5R,6S,7R,7aR)-6-{[(4S,5S)-2,2-Dim eth yl-5-[(E)-pen t-3-en -1-yl]-1,3-dioxolan -4-yl]-
m eth yl}-7-{2-[(4-m eth oxyben zyl)oxy]eth yl}-5-[(E)-oct-6-en -1-yl]-2-oxo-4,5,6,7-tetrah ydro-
2H-1-ben zofuran -3-propan oate (36)
A 0.5 M solution of 35 was prepared by addin g oxalyl ch loride (0.1 m l, 1.2 m m ol) to th e
carboxylic acid (125 m g, 0.38 m m ol) dissolved in dry ben zen e (10 m l). Th e solution was
stirred for 9 h an d con cen trated. Th e acid ch loride was taken up in CH2Cl2 (7.7 m l) an d
4 m l of th is solution (2.0 m m ol) were added to a solution of 34 (60 m g, 0.10 m m ol) an d
pyridin e (0.025 m l, 3.0 m m ol) in CH2Cl2 (10 m l) at 0 °C. Th e reaction m ixture was warm ed
to room tem perature, stirred for 12 h , diluted with eth er, an d wash ed with saturated
NaHCO3 solution an d brin e. Th e com bin ed aqueous wash in gs were extracted with eth yl ace-
tate an d th e organ ic layers were dried an d con cen trated. Flash ch rom atograph y of th e resi-
due on silica gel (elution with 50% eth yl acetate in h exan es) gave th e keto ph osph on ate
(71 m g, 81%).
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

508
Devaux, O’Neil, Guillo, Paquette:
Th e above in term ediate (80 m g, 0.080 m m ol) was dissolved in dry THF (10 m l), cooled to
–78 °C, an d treated with 0.10 m l of 1.0 M lith ium h exam eth ydisilazide (1.0 m m ol). Th e
coolin g bath was rem oved an d th e reaction m ixture was stirred for 8 h , diluted with eth er,
wash ed with 1 M HCl an d brin e, dried, an d con cen trated. Purification of th e residue by flash
ch rom atograph y on silica gel (elution with 20% eth yl acetate in h exan es) yielded 36 (48 m g,
83%) as a colorless oil. IR (n eat): 1 748, 1 732, 1 682, 1 614, 1 514, 1 454, 1 367. 1H NMR
(300 MHz, CDCl3): 7.22 (d, J = 8.6, 2 H); 6.84 (d, J = 8.6, 2 H); 5.50–5.37 (m, 4 H); 4.92 (d, J = 6.6,
1 H); 4.38 (s, 2 H); 3.78 (s, 3 H); 3.69 (ddd, J = 7.8, 7.8, 3.1, 1 H); 3.56 (m , 1 H); 3.44 (m ,
2 H); 2.68 (dd, J = 17.0, 5.1, 1 H); 2.52–2.36 (m , 5 H); 2.17–1.93 (m , 4 H); 1.83–1.09 (series
of m , 17 H); 1.65 (s, 3 H); 1.64 (s, 3 H); 1.36 (s, 3 H); 1.35 (s, 3 H). 13C NMR (75 MHz,
CDCl3): 174.2, 171.8, 161.5, 159.0, 131.3, 130.5, 130.3, 129.1, 125.5, 124.7, 124.6, 113.7,
108.1, 80.6, 80.4, 79.4, 78.7, 72.4, 68.7, 55.2, 40.6, 38.3, 38.1, 34.9, 32.9, 32.5, 32.4, 29.4
(2 C); 29.1, 29.0, 28.7, 28.0 (3 C); 27.7, 27.4, 27.3, 27.2, 18.9, 17.9 (2 C). FAB MS, m/z: (M+)
calculated: 722.48; foun d: 722.45.
tert-Butyl (3S,5R,6S,7R)-3-[(tert-Butyloxycarboyl)m eth yl]-6-{[(4S,5S)-2,2-dim eth yl-
5-[(E)-pen t-3-en -1-yl]-1,3-dioxolan -4-yl]m eth yl}-7-[2-(4-m eth oxyben zyloxy)eth yl]-
5-[(E)-oct-6-en -1-yl]-2-oxo-2,3,4,5,6,7-h exah ydro-1-ben zofuran -3-propan oate (37) an d
tert-Butyl (3R,5R,6S,7R)-3-[(tert-Butyloxycarboyl)m eth yl]-6-{[(4S,5S)-2,2-dim eth yl-
5-[(E)-pen t-3-en -1-yl]-1,3-dioxolan -4-yl]m eth yl}-7-[2-(4-m eth oxyben zyloxy)eth yl]-
5-[(E)-oct-6-en -1-yl]-2-oxo-2,3,4,5,6,7-h exah ydro-1-ben zofuran -3-propan oate (38)
A solution of 0.5 M potassium h exam eth yldisilazide in toluen e (0.04 m l, 0.2 m m ol) was
added to a solution of 36 (10 m g, 0.014 m m ol) in DMF (1 m l) at –40 °C. Th e reaction
mixture was stirred at this temperature for 20 min, treated with tert-butyl bromoacetate (0.007 ml,
0.047 m m ol), warm ed slowly to 20 °C durin g 1.5 h , quen ch ed with water, an d extracted
with eth er. Th e com bin ed organ ic layers were wash ed with brin e, dried, an d evaporated.
Th e residue was ch rom atograph ed on silica gel (elution with 10% eth yl acetate in h exan es)
to give 37 an d 38 as a 2 : 1 m ixture of diastereom ers (8 m g, 69%). IR (n eat): 1 798, 1 732,
1 614, 1 514, 1 455. 1H NMR (300 MHz, CDCl3): 7.25 (d, J = 8.6, 2 H); 6.86 (d, J = 8.6, 2 H);
5.40 (m , 4 H); 4.43 (s, 2 H); 3.80 (s, 3 H); 3.64–3.46 (m , 4 H); 2.77 (d, J = 15.4, 0.66 H); 2.76
(d, J = 15.7, 0.33 H); 2.53 (m , 1 H); 2.46 (d, J = 15.7, 0.33 H); 2.43 (d, J = 15.4, 0.66 H);
2.15–1.16 (series of m , 28 H); 1.63 (br s, 6 H); 1.41 (s, 5.9 H); 1.40 (s, 3.1 H); 1.39 (s, 3.1 H);
1.37 (s, 5.9 H); 1.33 (s, 3 H); 1.31 (s, 3 H). 13C NMR (75 MHz, CDCl3): 180.2, 171.6, 168.4,
159.1, 151.6, 131.4, 130.6, 130.4, 129.2 (2 C); 125.3, 124.8, 113.7 (2 C); 112.2, 108.1, 81.4,
80.8, 80.7, 78.2, 77.2, 68.2, 55.2, 50.1, 41.4, 39.7, 37.1, 35.6, 34.1, 33.9, 32.6, 32.3, 31.4,
30.6, 29.9, 29.5, 29.4, 29.3, 29.2, 28.0 (3 C); 27.9 (3 C); 27.5, 27.4, 27.3, 27.2, 22.0, 17.9 (2 C).
FAB MS, m/z: (M+) calculated: 836.54; foun d: 836.69.
Financial support has been provided by the Eli Lilly Company. We thank Dr K. Loening for assis-
tance with nomenclature. Fellowship support from the National Institutes of Health (S. V. O.), French
Ministere des Affaires Etrangeres/Bourse Lavoisier (J.-F. D.), and the Glaxo Wellcome Fund (N. G.) is
also gratefully appreciated.
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509
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