Applications of crotyldiisopinocampheylboranes in synthesis: A formal total synthesis of (+)-calyculin A

Article abstract of DOI:10.1139/v01-133

The formal total synthesis of the marine metabolite (+)-calyculin A is reported. The key steps involve (i) the use of Brown allylboration chemistry to control the relative and absolute stereochemistry of homoallylic alcohol arrays, thus setting eight of the desired stereocenters; (ii) Stille coupling methodology in the construction of the cyano tetraene unit of the natural product; and (iii) a modified Cornforth-Meyers approach to the synthesis of the oxazole fragment.

Full text of DOI:10.1139/v01-133

1562
Applications of crotyldiisopinocampheylboranes in
synthesis: a formal total synthesis of (+)-calyculin A
Oren P. Anderson, Anthony G.M. Barrett, Jeremy J. Edmunds,
Shun-Ichiro Hachiya, James A. Hendrix, Kiyoshi Horita, James W. Malecha,
Christopher J. Parkinson, and Andrew VanSickle
Abstract: The formal total synthesis of the marine metabolite (+)-calyculin A is reported. The key steps involve (i) the
use of Brown allylboration chemistry to control the relative and absolute stereochemistry of homoallylic alcohol arrays,
thus setting eight of the desired stereocenters; (ii) Stille coupling methodology in the construction of the cyano tetraene
unit of the natural product; and (iii) a modified Cornforth–Meyers approach to the synthesis of the oxazole fragment.
Key words: calyculin, marine natural product, phosphatase inhibitor, total synthesis, palladium catalyzed coupling reac-
tions, allylboration reactions, aldol reactions, spiroketal, Cornforth–Meyers oxazole reaction.
Résumé : Une synthèse total d’un métabolite d’origine marine, la (+)-calyculine A, été descrite. Les étapes clés de la
synthèse reposent sur l’utilisation: de la chimie d’allylboration de Brown afin de contrôler la stéréochemie relative et
absolue d’une série d’alcools homoallyliques ayant ainsi permis la création de 8 centres asymétriques; de la réaction de
couplage de Stille dans la construction du motif cyanotétraène du produit naturel; d’une approache modifiée de Corn-
forth–Meyers pour la préparation de la partie oxazole.
Mots clés : calyculine, produit naturel d’origine marine, inhibiteur de la phosphatase, synthèse totale, réactions de cou-
plage catalysées par la palladium, réactions d’allylborations, réactions d’aldolisations, spirocétal, réaction d’oxazole se-
lon Cornforth–Meyers.
[Traduit par la Rédaction] Anderson et al. 1592
Introduction
hibits protein phosphatases, an unexpected phenomenon, as the
presence of the phosphate group was believed to be key to the
calyculins’ biological activity (5). The relative stereochemistry
of 1 was determined by X-ray analysis (1) and the absolute
configuration later elucidated by Matsunaga and Fusetani (6),
through analysis of the C(37)–C(33) and C(32)–C(29) degra-
dation fragments and Shioiri and co-workers (7) through
asymmetric synthesis of the C(37)–C(33) fragment. Total
synthesis of (+)-calyculin 1, the antipode of the natural prod-
uct, by Evans et al. (8) later corroborated this absolute
stereochemical assignment.
Due to the structural complexity of these marine me-
tabolites and their associated biological profile, they
have attracted a great deal of synthetic attention (for other
synthetic efforts toward the synthesis of the calyculins, see
ref. 9). This has culminated in several total syntheses of the
calyculin family, the first reported by Evans et al. (8). Their
approach centered on the union of a “southern” C(1)–C(25)
spiroketal unit and “northern” C(26)–C(37) amide oxazole
fragment through Wittig chemistry, the former subunit also
The calyculins represent a group of marine natural
products isolated from the sponge Discodermia calyx (1).
These structurally remarkable compounds have shown po-
tent inhibitory activity toward phosphatase enzymes, nota-
bly the serine–threonine PP-1 and PP-2A protein
phosphatases. For example, (–)-calyculin A, the antipode of
1, is active against rabbit skeletal muscle type PP-2A
phosphatases at 0.5–1.0 nmol dm–3 concentrations and is
also 20–300 times more potent than okadaic acid against
various PP-1 enzymes. (–)-Calyculin A is a representative
member of a series of eight similar structures (calyculins
B–H) (2), the other calyculins differing by the presence of
an additional methyl unit at C-32 and (or) geometric differ-
ences at D2 and (or) D6. A further five related structures,
calyculin J, the caliculinamides A, B, and F, and des-N-
methylcalyculin A have recently been isolated (3). The
dephosphono derivative of calyculin A has been obtained
from the same marine organism (4). This compound also in-
Received January 30, 2001. Published on the NRC Research Press Web site at http://canjchem.nrc.ca on October 29, 2001.
Dedicated to Professor Victor Snieckus on the occasion of his 64th birthday. Happy Birthday Vic.
O.P. Anderson, J.A. Hendrix, K. Horita, and J.W. Malecha. Department of Chemistry, Colorado State University, Fort Collins,
CO 80523, U.S.A.
A.G.M. Barrett,1 S.-I. Hachiya, C.J. Parkinson, and A. VanSickle. Department of Chemistry, Imperial College of Science,
Technology and Medicine, South Kensington, London, SW7 2AZ, U.K.
J.J. Edmunds. Department of Chemistry, Northwestern University, Evanston, IL 60208, U.S.A.
1Corresponding author (telephone: (44)-207-594-5767; fax: (44)-207-594-5766; e-mail: agmb@ic.ac.uk).
Can. J. Chem. 79: 1562–1592 (2001)
© 2001 NRC Canada
DOI: 10.1139/cjc-79-11-1562

Anderson et al.
1563
Scheme 1.
of a tetrasubstituted allylborane in the synthesis of the gem-
dimethyl moiety present in this subunit. Retrosynthetically,
we considered that (+)-calyculin A 1 should be accessible
from the oxazole amide 2, the cyanostannane 3, and the
spiroketal fragment 4, the later being constructed using aldol
methodology between the methyl ketone 5 and aldehyde 6 to
establish the C(14)–C(15) bond (Scheme 1). Key to our
overall strategy, is the employment of the elegant masked
aldol chemistry developed by Brown and co-workers (14b–
d, g, h), employing the derivatives of diisopinocampheylborane
7–10 as versatile reagents for the construction of homoallylic
alcohols. Our synthetic plan also parallels other endeavors
(8, 11–13) in the synthesis of calyculin A 1, whereby the
coupling of oxazole 2 and spiroketal 4 fragments was based
upon Wittig chemistry (for our previous publications to-
wards the total synthesis of (+)-calyculin A, see ref. 15).
OH
O
Me
37
32
O
MeO
N
H
Me2N
OH
N
26
25
(+)-calyculin A 1
O
Me
Me
OH
Me
O
(HO)2PO
Me Me Me
1
CN
6
14
15
O
Me
Me
OH OH OMe
OR
O
Me
37
32
O
MeO
Me2N
N
H
Me
OR
N
Me
26
B
B
Me
)
)
2
Bu3P Br
2
2
Me
O
25
7
9
8
H
Me
Me
Me
Me
Me
SiMe2NiPr2
O
PMBO
Me Me Me
B
B
1
)
)
CN
OR1
2
2
6
14
OSEM
SnBu3
O
15
I
5
Me
OR1 OR1 OMe
10
Me
3
4
Results and discussion
OR1
25
Synthesis of the C(1)–C(5) cyanodiene fragment 3
Construction of the (Z,E)-cyano diene 3 was based upon
the use of Stille chemistry for the elaboration of the C(3)–
C(4) bond. This approach would also facilitate the elabora-
tion of the (E,E)-isomer, an appropriate building block for
the synthesis of other calyculins with this geometry at D2.
Therefore, conjugate addition of tributylstannyl cuprate (16)
to ethyl but-2-ynoate 11 and quenching with methanol gave
the (Z)-b-stannylcrotonate 12 (52%) and the corresponding
(E)-isomer 17 (7%). The trans-geometry of the major prod-
uct was established by measurement of the 117,119Sn–H cou-
Me
Me
OR1
Me
O
PMBO
Me Me Me
6
14
Me
H
O
15
I
Me
OR1
O
O
5
6
R = TES R1 = TBS
1
being constructed using this methodology at C(8)–C(9).
Enantioselective synthesis of these fragments was achieved
using auxiliary-based asymmetric aldol methodology, estab-
lishing ten of the fifteen stereocenters present in 1. The
approach to calyculin A 1 adopted by Masamune and co-
workers (10) employed Wadsworth–Emmons type coupling
to elaborate the C(8)–C(9) olefin with Stille coupling, was
also used in the synthesis of the C(5)–C(6) bond, paralleling
other synthetic endeavors in this area. Interestingly, they
constructed the C(25)–C(26) alkene by utilizing a Julia-
olefination approach to link up the “northern” and “south-
ern” hemispheres. Smith et al. (11) have also recently pub-
lished total syntheses of both ent-1 and (–)-calyculin B
utilizing an advanced intermediate to synthesize either com-
pound through Peterson olefination at C(2). Their approach
also elected to construct the C(25)–C(26) alkene through
phosphonium ylide chemistry, as does the formal synthesis
of calyculin A (1) by Shioiri and co-workers (12). Calyculin
C has also succumbed to total synthesis through the efforts
of Ogawa and Armstrong (13) using allylborane reagents in
the elaboration of the spiroketal unit, notably the novel use
pling constant (J = 97 Hz) in the H NMR spectrum (17).
Conversion of ester 12 to the corresponding amide 13 was
achieved using the methodology of Weinreb and co-workers
(18), and subsequent dehydration using trichloroacetyl chlo-
ride and triethylamine gave the nitrile 14. Iododestannylation
afforded solely the desired (Z)-iodide 15 and this was
smoothly coupled with the distannane 16 (19) using Stille
methodology to give the requisite C(1)–C(5) diene coupling
fragment 3 with complete geometric retention (Scheme 2).
For ease of synthesis upon scale up, in situ generation of the
vinyl iodide 15, using iodine in DMF and subsequent addition
of bis(triphenylphosphino)palladium dichloride and distannane
16 gave the cyanodiene 3 in moderate yield (50%) in a one-
pot procedure. This protocol also circumvented the need for
the isolation of the volatile iodide intermediate 15.
In parallel to the synthesis of stannane 3, the minor trans-
isomer 17 was converted by sequential reaction with tri-
methylaluminum and ammonium chloride (72%), trichloro-
acetyl chloride and triethylamine (95%), and iodine followed
by stannane 16 and palladium(0) catalysis (39%) into the
(E,E)-isomer 22. Comparisons of spectral data for each in-
© 2001 NRC Canada

1564
Can. J. Chem. Vol. 79, 2001
Scheme 2.
Scheme 3.
Me
O
SnBu3
Me
Bu3SnLi, PhSCua
MeAl(Cl)NH2
Y
7c
Cl3CCOCl
Et3Nc
R1
EtO2C
Me
RO
X
11
O
b
12: X = OEt
13: X = NH2
24: R = H, R1 = OMe
25: R = TES, R1 = OMe
26: R = TES, R1 = H
TES-Cl, DMFa
DIBAl-Hb
SnBu3
Bu3Sn
16
PdCl2(PPh3)2
NC
3
Me
e
Me Me
Me Me
OR1
14: Y = SnBu3
15: Y = I
NISd
Swerne
H
RO
O
OTBS
29
Reagents and Conditions: (a) Bu3SnSnBu3, n-BuLi, PhSCu, THF, -35°C then
MeOH, Et2O (52%); (b) AlMe3, NH4Cl, PhH, 50°C (76%); (c) Cl3CCOCl,
Et3N, CH2Cl2, 0°C (95%); (d) NIS, THF, Et2O (65%); (e) 16, PdCl2(PPh3)2
(cat ) THF 60°C (55%)
27: R = TES, R1 = H
28: R = H, R1 = TBS
TBSOTf,
then AcOHd
Me Me Me
Ph3P=C(Me)CO2Etf
AlMe3, Cp2ZrCl2
termediate 12, 13, 14, 15, and 3 with the data for the corre-
sponding (E)- and (E,E)-isomers 17, 18, 19, 20, and 22,
respectively, were fully consistent with assignment of stereo-
chemistry in each case. Finally, separate iododestannylation
of both 3 and 22 gave the corresponding (Z,E)- and (E,E)-
dienyl iodides 21 and 23 with retention of geometry. These
results unequivocally established the geometric integrity and
purity of the key intermediate 3.
k
then I2
R
13
OTBS
30: R = CO2Et
31: R = CH2OH
32: R = CHO
DIBAl-Hg
h
MnO2
i
PPh3,CBr4
n-BuLi, THFj
33: R = CH=CBr2
=
34: R = C=CH
Me Me Me
Me Me Me
OsO4,
then NaIO4
O
Me
SnBu3
Me
I
I
R
l
NC
Me
OTBS
Me
TBSO
X
Y
35
MeMgBrm
Swernn
17: X = OEt
18: X = NH2
19: Y = SnBu3
20: Y = I
36: R = CHO
37: R = CH(OH)CH3
5: R = C(O)Me
CN
I
X
NC
Reagents and Conditions: (a) TES-Cl, CH2Cl2, imidazole, DMAP (cat.)
(90%); (b) DIBAl-H, hexanes, -70°C (89%); (c) 7, THF, -78°C then
NaBO3 4H2O, H2O (76%); (d) THF, TBSOTf, 2,6-lutidine, -78°C then
AcOH, 25°C (84%); (e) (COCl)2, DMSO, Et3N, CH2Cl2 (78%); (f)
Ph3P=C(Me)CO2Et, THF, reflux (96%); (g) DIBAl-H, THF, 25°C (86%);
(h) MnO2, CH2Cl2 (81%); (i) PPh3, CBr4, CH2Cl2 (89%); (j) n-BuLi,
THF, -78°C (80%); (k) AlMe3, Cp2ZrCl2, CH2Cl2 then I2 (69-86%); (l)
OsO4 (cat.), NMO, acetone, H2O (<61%) then NaIO4, THF, MeOH,
H2O; (m) MeMgBr, THF, -78°C (80%, 2 steps); (n) (COCl)2, DMSO,
Et3N, CH2Cl2 (79%).
Me
21
Me
22: X = SnBu3
23: X = I
Synthesis of the C(6)–C(14) vinyl iodide subunit 5
We envisaged that construction of the vinyl iodide 5 would
arise from the methylzirconation–iodinolysis of alkyne 34
according to the procedure of Negishi et al. (20). Alkyne 34
would in turn come from the suitably elaborated aldehyde
29, the synthesis of which involves a key Brown homologation
to unambiguously set the C(11) and C(12) stereochemistry
(Scheme 3). Thus, synthesis of vinyl iodide 5 commenced
from aldehyde 26, prepared from commercially available methyl
(S)-(+)-3-hydroxy-2-methylpropanoate 24 via triethylsilyl
protection of the alcohol and DIBAl-H reduction. Brown
homologation (14) of aldehyde 26 using the borane reagent
7 derived from (–)-pinene gave the homoallylic alcohol 27,
which was formed in excellent diastereomeric excess (>96%)
duction with sodium borohydride gave alcohol 40 that was
desilylated and per-acetylated to furnish the triacetate 42.
1
Both the lack of optical rotation and the H and 13C NMR
spectra of 40 were fully consistent with the expected meso-
stereochemistry. Since the synthesis of alcohol 27 started
from methyl (2S)-2-methyl-3-triethylsilyloxypropanoate (24),
this correlation established both the relative and absolute
stereochemistry of the two CHMe stereocenters. The C(2)–
C(3) anti-stereochemistry followed from the known stereo-
chemical bias of the Brown crotylboration reaction (14) using
reagent 7. With the knowledge that the desired stereochemical
configuration was in place, the synthesis of ketone 5 pro-
ceeded with the selective tert-butyldimethylsilylation and
detriethylsilylation (21) of alcohol 27 to give ether 28. Oxi-
dation under Swern (22) conditions and homologation of the
resulting aldehyde 29 gave the a,b-unsaturated ester 30 with
excellent (E)-selectivity (>95%). Ester 30 was transformed
via aldehyde 32 and homologated under the protocol of
Corey and Fuchs (23) into the acetylene 34. Elimination of
1
as judged by H NMR analysis.
In parallel to the conversion of ester 24 into ether 27 in
Scheme 3, the early transformations were repeated in the
antipode series starting from methyl (2R)-2-methyl-3-
triethylsilyloxypropanoate. Whilst the intermediate 38 was
not transformed further towards calyculin, it was used to
confirm the stereochemistry of the key intermediate 28. Con-
version of the silyl ether 38 into the meso-triacetate 42 is
outlined in Scheme 4. This was accomplished through catalytic
osmium tetraoxide mediated dihydroxylation and periodate
cleavage of the olefin giving aldehyde 39. Subsequent re-
© 2001 NRC Canada

Anderson et al.
1565
Scheme 4.
Scheme 5.
CN
Me Me Me
Me Me
b
a
NaBH4
PdCl2(PPh3)2
R
H
TESO
3 + 36
Me
Me
43
TBSO
O
OTBS
a
38: R = CH2
39: R = O
OsO4, NaIO4
Reagents and Conditions: (a) PdCl2(PPh3)2 (cat.), THF, 60°C (75%).
Me Me
Me Me
p-TSA, MeOHc
Scheme 6.
OR
RO
OH
TESO
Me
22
O
8a
OR
41: R = H
42: R = Ac
OTBS
21
DMBO
40
DMBO
H
Ac2O, Et3Nd
OR
44
45: R = H
TBSOTf,
2,6-lutidineb
46: R = TBS
Reagents and Conditions: (a) OsO4 , N-methylmorpholine
-N-oxide, Me2CO, H2O; NaIO4, THF, MeOH; (b) NaBH4,
MeOH, 0°C (93%); (c) p-MeC6H4SO3H, MeOH (100%);
(d) Ac2O, Et3N, DMAP, CH2Cl2 (97%).
Me
H
c
OsO4, NaIO4
DMBO
TBSO
47
O
the intermediate dibromide 33 was carried out using either
lithium diisopropylamide (15) or n-butyllithium. However,
in either case, rapid purification of 33 was required to obtain
the acetylene 34 in acceptable yields. Syn-methylzirconation
(20) of acetylene 34 followed by in-situ iodinolysis of the
vinyl alane intermediate gave triene 35 exclusively as the
(E)-isomer. This reaction, however, proved highly dependent
upon the nature of the C(13) substituent. Attempted methyl-
zirconation of protected derivatives of the analogous C(13)
primary alcohol, C(13), C(14) diol, or the C(13) aldehyde
gave intractable product mixtures. Quite remarkably,
osmylation of triene 35 resulted in selective oxidation of the
terminal olefin (D13) thereby providing a route to the key
ketone 5. Subsequent periodate cleavage of the vicinal diol
(24) gave aldehyde 36, which was transformed through
methylmagnesium bromide addition and subsequent Swern
oxidation to the desired C(6)–C(14) calyculin A methyl
ketone 5 (Scheme 3). Whilst this sequence of transforma-
tions from triene 35 into the C(13) ketone 5 did indeed work
acceptably, it unfortunately proceeded in variable yields es-
pecially on scale up. However sufficient material was accu-
mulated to further progress the synthesis.
OR OR1
TBSO
O
9d
16
17
H
OSEM
48
49: R = TBS, R1 = H
50: R = TBS, R1 = PMB
51: R = H, R1 = PMB
KHMDS, MPMCle
TBAF, THFf
OH OPMB
MeMgBrh
O
OPMB
Swerng
H
OSEM
OSEM
52
53
O
OPMB
Swerni
OSEM
54
Reagents and Conditions: (a) 8, THF, Et2O, -78°C then
NaBO3 4H2O, H2O (72%); (b) TBSOTf, 2,6-lutidine, CH2Cl2,
(94%); (c) OsO4 (cat.), NMO, acetone, H2O then NaIO4, THF,
H2O (88%); (d) 9, THF, Et2O, -78°C then HOCH2CH2NH2,
NaH (cat.) (60%); (e) KHMDS, THF, DMF, p-MeOC6H4CH2Cl;
(f) TBAF, THF (98% over both steps); (g) (COCl)2, DMSO,
Our projected route toward calyculin A 1 is flexible in the
timing of the construction of the C(5)–C(6) bond. However,
we wished at this stage to explore this chemistry and hence
attempted the palladium(0) catalyzed reaction of the vinyl
iodide 36 with the vinyl stannane 3 (Scheme 5). Much to our
delight, this Stille coupling (25) afforded the tetraene nitrile
43 as a single geometric isomer in good yield (75%) and
thus indicated the viability of our disconnection strategy.
°
Et3N, CH2Cl2, -78 to 20 C, (89%); (h) MeMgBr, THF (95%);
(i) (COCl)2, DMSO, Et3N, CH2Cl2, -78 to 20°C, (85%).
excellent enantiomeric excess, vide infra. Protection of the
resultant alcohol as the tert-butyldimethylsilyl ether 46 and
conversion of the terminal olefin into the corresponding al-
dehyde 47 was carried out via osmylation and periodate
cleavage (Scheme 6). Addition of the (Z)-borane 9 to alde-
hyde 48 proceeded smoothly to yield the syn-diol derivative
49, again with excellent control of relative (>95%) and abso-
Synthesis of the C(15)–C(25) spiroketal subunit
Our first synthetic approach toward the spiroketal core of
the calyculins employed a convergent strategy, again using
Brown allylborane chemistry to control the relative and ab-
solute stereochemistry of the two fragments 47 and 54 prior
to aldol reaction. Thus, reaction of aldehyde 44 with (–)-(Z)-
crotonyldiisopinocampheylborane 8, derived from (+)-pinene,
furnished the corresponding homoallylic alcohol 45. This es-
tablished the desired syn-relative stereochemistry at C(21)
1
lute (>95%) stereochemistry, as estimated through H NMR
and Mosher ester 55 analysis (26). With the desired C(16)
and C(17) stereochemistry established, transformation of
alkene 49 into the methyl ketone 54 was accomplished using
1
and C(22) (>95% as determined by H NMR analysis) with
© 2001 NRC Canada

1566
Can. J. Chem. Vol. 79, 2001
Scheme 7.
standard methodology. Thus, protection of the newly formed
C(17) alcohol gave the p-methoxybenzyl ether 50. Deprotection
of the tert-butyldimethylsilyl ether using tetrabutylammonium
fluoride, oxidation under Swern conditions, methyl Grignard
addition, and reoxidation afforded the methyl ketone 54 in
excellent overall yield (52% over 6 steps).
ODMB
Swernb
LDA, 47
Me
Me
54
Me
PMBO
O
then TsOHa
21 OH
O
56a 21S (48%)
56b 21R (22%)
ODMB
K-selectridec
Me
Me
O
56a
Me
PMBO
O
O
57
Lithium diisopropylamide mediated aldol coupling between
ketone 54 and aldehyde 47 and subsequent acidification gave
the spiroketal core as a mixture of C(21)-epimeric alcohols
56a and 56b. Much to our delight, the initial aldol adduct
underwent clean cleavage of the robust SEM protecting
group (21), removal of the tert-butyldimethylsilyl ether, and
spiroketalization in a single operation under mild acidic con-
ditions. The epimeric alcohols 56 could be easily separated
and individually authenticated but on a larger scale the mix-
ture was oxidized under Swern conditions to produce the
ketone 57, which was stereoselectively reduced using K-
Selectride (27) yielding the desired axial diastereoisomer
56a (Scheme 7). The final spiroketal 56a was obtained free
from other diastereoisomers (TLC, NMR; after the correc-
tion at C(21)). Since the high enantiomeric purity of alcohol
Reagents and Conditions: (a) LDA, THF, -78°C; 47; TsOH,
MeOH, 25°C (70%); (b) (COCl)2, DMSO, Et3N, CH2Cl2 (95%
from 56a, 100% from 56b); (c) KBHsBu3, THF, -78°C to -10°C
then NaOH, H2O2 (93%).
Scheme 8.
Me
CO2Me
Me
BOMCl,
Ph3P=CHCO2Med
HO
BOMO
Hunigs basea
R
58
b
59: R = CO2Me
60: R = CH2OH
61: R = CHO
LiAlH4
Swernc
Sharplessf
Me
Me
O
BOMO
OH
BOMO
R
1
51 was established by H NMR spectral analysis of ester 55,
DIBAl-He
62: R = CO2Me
63: R = CH2OH
64
the initial allylboration reaction and chromatographic purifi-
cation must have given alcohol 45 with high absolute as well
as relative stereocontrol.
MeO OMe
PPTSh
A second approach towards the spiroketal unit was devel-
oped to provide additional material for the total synthesis.
Thus, the commercial ester 58, as employed in the construction
of 38 (vide supra), was protected as the benzyloxymethyl
ether 59 (21), reduced to the alcohol 60 using lithium alumi-
num hydride, and oxidized under Swern conditions to give
aldehyde 61 (Scheme 8). Wittig homologation and reduction
of the resultant a,b-unsaturated ester 62 with DIBAL-H fur-
nished the allylic alcohol 63. Sharpless asymmetric
epoxidation (28) was used to elaborate the epoxy alcohol 64,
thereby controlling the absolute stereochemistry of C(23).
Epoxide ring opening, through intramolecular hydride deliv-
ery upon treatment with Red-Al, gave diol 65, which was
smoothly converted to the corresponding acetonide 66 under
standard conditions. Deprotection of the benzyloxymethyl
ether using sodium in ammonia and Swern oxidation of the
resultant primary alcohol gave the aldol partner 68 in excel-
lent overall yield (77% over 10 steps, Scheme 8).
Me
Me
Red-Alg
BOMO
RO
OH
O
O
OH
65
i
66: R = BOM
67: R = H
Na, NH3
Swernj
Me
O
H
O
O
68
i
°
Reagents and Conditions: (a) PhCH2OCH2Cl, Pr2NEt, CH2Cl2, -78 to -10 C; (b)
LiAlH4, Et2O; (c) (COCl)2, DMSO, Et3N, CH2Cl2; (d) Ph3P=CHCO2Me,
ClCH2CH2Cl (95% over four steps); (e) DIBAl-H, CH2Cl2 (99%); (f) Ti(OiPr)4,
L-(+)-diethyl tartrate, 3Å molecular sieves, tBuOOH, CH2Cl2, -20°C (90%);
(g) NaAlH2(OCH2CH2OMe)2, THF; (h) PPTS, Me2C(OMe)2, PhH (100% over 2
°
steps); (i) Na, NH3, THF (100%); (j) (COCl)2, DMSO, Et3N, CH2Cl2, -78 to -20 C,
(93%).
Aldol reaction of ketone 54 and aldehyde 68 gave, after
acidification, the spiroketal system 69, again as an epimeric
mixture (Scheme 9). Oxidation gave the keto-aldehyde 70,
which upon reduction using K-Selectride gave diol 71 as a
single diastereoisomer. The constitution and relative stereo-
chemistry of spiroketal 71 was established by a single crys-
tal X-ray structure determination (Fig. 1). The structure of
BOM = PhCH2OCH2
the spiroketal core of 71 is similar to that found for calyculin
A (1), but some interesting differences exist. For example,
the intra-ring angles at C(19) in 71 are as follows: O(8)-
© 2001 NRC Canada

Anderson et al.
1567
Fig. 1. Thermal ellipsoid plot for spiroketal 71. Most hydrogen
Scheme 9.
atoms have been omitted for clarify.
OH
Me
Me
OH
Me
PMBO
O
LDA, 68
then TsOHa
Swernb
54
O
69
OR1
Me
O
H
K-Selectridec
Me
Me
Me
Me
PMBO
O
Me
O
OR2
PMBO
O
O
O
X
70
the C(13), C(15)-oxygen substituents and late palladium(0)
catalyzed coupling with the dienylstannane 3. Enolization of
the ketone 5 using lithium hexamethyldisilazide and subse-
quent reaction with the C(1)–C(25) aldehydes 6 and 74 gave
the b-hydroxy ketones 76 (76%) and 77 (43%), respectively.
In the second unoptimized aldol reaction quantities of the
starting ketone 5 (54%) and the aldehyde 74 (35%) were re-
covered unchanged. Both reactions proceeded with complete
71: R1 = R2 = H, X = CH2
72: R1 = TES, R2 = H, X = CH2
73: R1 = TES, R2 = TBS, X = CH2
74: R1 = TES, R2 = TBS, X = O
75: R1 = R2 = TBS, X = CH2
6: R1 = R2 = TBS, X = O
Silylated,e or f
g
O3
h
O3
1
Reagents and Conditions: (a) LDA, THF, -78°C, 68 (96%) then
diastereoselectivity as judged by H NMR spectroscopy of
the crude reaction mixture. In the case of b-hydroxy ketone
77 the stereochemistry at C(15) was established by partial
DDQ oxidation to produce the corresponding acetal 78 and
analysis of the 1H NMR spectrum. Thus, reaction of aldol 77
with DDQ in dichloromethane in the presence of molecular
sieves (3 Å) gave the p-methoxybenzylidene acetal 78 (29).
TsOH, MeOH, 25°C (85%); (b) (COCl)2, DMSO, Et3N, CH2Cl2,
s
°
-78 to -20 C; (c) KBH Bu3, THF, -78°C to -10°C then NaOH,
H2O2 (76% over both steps); (d) TESCl, Et3N, imidazole,
CH2Cl2, -40 C (78%); (e) TBSOTf, isoPr2NEt, CH2Cl2, -50 to -20
°
°C (100%); (f) TBSOTf, 2,6-lutidine, CH2Cl2, -5°C (90%); (g) O3,
CH2Cl2, -78 °C; Me2S, -78°C to 25 °C (76%); (h) O3, CH2Cl2, -78
°C; Me2S, -78°C to 25 °C (89%).
1
Analysis of its H NMR spectrum (inter alia d: 5.52 (s, 1H,
ArCH), 4.04 (dd, 1H, J = 9.0, 6.0 Hz, 16-CH), 3.74 (d, 1H,
J = 6.0 Hz, 17-CH), 2.83 (dd, 1H, J = 15.5, 3.0 Hz, 14-CH),
2.60 (dd, 1H, J = 15.5, 8.0 Hz, 14-CH)) was consistent with
a trans disposition of H(15) and H(16) (J = 9 Hz) and a cis
configuration of H(16) and H(17) (J = 6 Hz) corresponding
to the (15S)-stereochemistry, the opposite to that found in
(+)-calyculin A. It is not clear, without additional experi-
mentation, as to the exact origin of this high stereochemical
bias. Possibly it is the result of the aldol reaction proceeding
by a chelation controlled addition pathway (tetrahydrofuran
ether as the Lewis basic site) or via a Felkin-type addition
pathway. Significant efforts to alter the stereochemical out-
come of this key aldol reaction were unsuccessful.
Reduction of the b-hydroxy ketone 76 with lithium alumi-
num hydride, which presumably took place via ligand ex-
change at aluminum by the C(15) alcohol and intramolecular
hydride delivery, gave a 5:1 mixture of the diols 79 and 80.
The stereochemistries of the two isomers 79 and 80 were de-
termined by formation of the derived acetonides 81 and 82,
respectively, and Rychnovsky (30) analysis of the 13C NMR
spectra. The acetonide 81 derived from the major diol 79
showed inter alia 13C NMR d: 97.6, 30.2, and 19.9 (CMe2),
whereas the isomer 82 showed inter alia 13C NMR d: 99.9,
25.2, and 25.1 (CMe2) consistent with the syn-acetonide and
the anti-acetonide structures, respectively. Rychnovsky and
co-workers have reported that syn-acetonides show the three
isopropylidene resonances typically at d 98.5, 30, and 19,
C(19)-C(18) = 104.0(5)° (71), 108.2° (calyculin A); O(10)-
C(19)-C(20) = 110.2(5)° (71), 105.6° (calyculin A). The
inter-ring angles about C(19) differ less dramatically, if at all:
O(8)-C(19)-O(10) = 110.8(5)° (71), 109.5° (calyculin A);
C(18)-C(19)-C(20) = 116.6(5)° (71), 116.4° (calyculin A).
Since one would expect that different crystal packing forces
might exert maximum effect on the inter-ring angles, the ob-
served differences in the intra-ring angles presumably result
from the changes in the substituent pattern in the fused five-
and six-membered rings in 71. Since the spiroketal 71 was
derived ultimately from methyl (R)-2-methyl-3-hydroxy-
propanoate, the ORTEP clearly identifies all the stereo-
centers are of correct absolute stereochemistry. The diol 71
was converted into the three silyl ethers 72, 73, and 75 by
double triethylsilylation, selective C(25)-OH triethylsilylation
followed by C(21)-OH tert-butyldimethylsilylation and double
tert-butyldimethylsilylation respectively. Finally ozonolysis
of alkenes 73 and 75 gave the corresponding aldehydes 74
and 6, respectively, thereby completing the second calyculin
building block, the C(15)–C(25) spiroketal unit.
Synthesis of the C(1)–C(25) spiroketal tetraene nitrile
We sought to construct the C(15)–C(25) tetraene nitrile
entity of calyculin by aldol addition of the enolate derived
from ketone 5 with the spiroketal 6 followed by alteration of
© 2001 NRC Canada

1568
Can. J. Chem. Vol. 79, 2001
Scheme 10.
OTES
Me
OR
Me
Me
O
O
MeO
Me
Me
OTBS
OTBS
Me
PMBO
O
O
DDQb
LHMDS,
O
5
Me Me Me
Me
6 or 74
78
O
O
13
Me
15H
I
H
TBSO
Me
TBSO
O
OH
Me
Me
H
O
17O
76: (R = TBS)
77: (R = TES)
O
R
Me
H16
Me
c
LiAlH4
J15-16 = 9.0 Hz
J16-17 = 6.0 Hz
I
OTBS
Me
Me
Me Me
Me Me
OMe
Me
PMBO
O
, PPTSd
PMBO
PMBO
Me
Me Me Me
Me
OTBS
13
15
O
13
O
13
15
O
O
O
I
O
OH
O
Me
TBSO
OH
81
82
97.6 ppm
lit.35 98.5 ppm
99.9 ppm
lit.35100.5 ppm
79 (13R)
80 (13S)
19.9, 30.2 ppm
lit.3519, 30 ppm
25.1, 25.2 ppm
lit.3525, 25 ppm
Reagents and Conditions: (a) LiHMDS, THF, -78°C then 6 (76 76%; 77 34%); (b) (R = TES) DDQ, 3Å mol. sieves, CH2Cl2, -20°C to 0°C
(49%); (c) LiAlH4, THF, -78°C (79 73%; 80 15%); (d) CH3C(OMe)=CH2, PPTS, CH2Cl2, 0°C to 25°C (81 (13R) 65%; 82 (13S) 77%).
Scheme 11.
OTBS
Me
OTBS
Me
Me
Me
Me
PMBO
O
Me
PMBO
O
DIBAl-Hc
TBSOTf,
Dess-
Martinb
Me Me Me
Me Me Me
79
OTBS
OTBS
2,6-lutidinea
O
O
I
I
OH
O
Me
TBSO
OTBS
83
Me
TBSO OTBS
84
OTBS
OTBS
Me
Me
Me
Me
OTBS
Me
HO
O
Me
R2O
O
PdCl2(MeCN)2
CN
Me Me Me
Me Me Me
OTBS
3f
O
O
I
OR1
TBSO OTBS
OMe
OTBS
Me
Me
TBSO
Me
Evans intermediate 88
85: R1 = H, R2 = PMB
86: R1 = Me, R2 = PMB
87: R1 = Me, R2 = H
t-BuOK, MeId
DDQe
Reagents and Conditions: (a) TBSOTf, 2,6-lutidine, MeCN-CH2Cl2 (1:1), -78°C (74%); (b) Dess-Martin periodinane, CH2Cl2
(80%); (c) DIBAl-H, CH2Cl2, -78°C (97%); (d) t-BuOK, MeI, THF, -78°C (87%); (e) DDQ, CH2Cl2-pH 7 buffer-i-PrOH (5:2:2)
(100%); (f) PdCl2(MeCN)2, NMP, 3, -5°C to 5°C (91%).
whereas the corresponding signals for anti-acetonides are at
d 100.5, 25, and 25 (Scheme 10).
Selective monosilylation of the C(13) alcohol in diol 79
was carried out using tert-butyldimethylsilyl triflate in
acetonitrile and dichloromethane at –78°C to produce an al-
cohol most probably the C(15) alcohol 83 (Scheme 11).
Subsequent oxidation using the Dess-Martin periodinane
(31) gave a product that was assigned as the C(15) ketone
© 2001 NRC Canada

Anderson et al.
1569
Scheme 12.
Scheme 13.
OR
O
TsOHc
BnOLia
THF
10a
Me
O
O
H
N
O
NBoc
OR
NBoc
O
O
NaH,
MPMClb
90: R = H
91: R =PMB
89
96
Me
HCl, MeOHd
Me
NH2
Cl
OMe
OPMB
OPMB
X
OsO4,
R
RO
MeO
e
AlMe3, NH4Clb
Cl3CCOCl, Et3Nc
97: X = CO2Bn
98: X = CONH2
99: X = CN
NaIO4
BocN
OPMB
BocN
Me
OPMB
100
R
92: R = H
93: R = Me
f
94: R = CHO
95: R = CO2H
NaH, MeId
NaClO2, H2O2
Me
MeO2CCH2NH3Cle
N
CO2Me
OMe
Reagents and Conditions: (a) 10, THF, Et2O, -78°C then H2O2,
KF, KHCO3 (reference 30); (b) NaH, DMF, p-MeOC6H4CH2Cl,
(65%); (c) TsOH, MeOH (90%); (d) NaH, MeI, DMF (72%); (e)
OsO4 (cat.), NMO, t-BuOH, Me2CO then NaIO4, MeOH, H2O; (f)
NaClO2, H2O2, MeCN, NaH2PO4 (65% from 93).
101
Y
Me
Z
Me
1. t-BuOK, HCO2Mef
NaBH4,
MeOHi
O
O
g
2. BF3 OEt2
N
N
CO2Me
CO2Me
104: Z = OH
84. Since the NMR spectra of this compound and that of
ketone 76 showed myriad resonance differences notwith-
standing only the presence of an additional TBS group, the
compound was most likely the C(15) ketone 84. This assign-
ment was consistent with changes in the positions of key
MsCl, Et3Nj
102: Y = CH2
103: Y = O
h
OsO4, NaIO4
k
105: Z = OMs
106: Z = N3
NaN3
H2, Pd/Cl
107: Z = NH2
°
Reagents and Conditions: (a) n-BuLi, PhCH2OH,THF,-20 C
1
peaks in the H NMR spectra including the C(9) and (11)
(97%); (b) NH4Cl, AlMe3, PhMe, 60°C (81%); (c) Cl3CCOCl,
methyl peaks, the C(14) methylene and the C(16) and (17)
methine peaks [(76: 3.64 (d, 1H, J = 5.7 Hz, 17-H), 3.20 (d,
1H, J = 18 Hz, 14-H), 2.45 (dd, 1H, J = 18, 10.3 Hz, 14-H),
1.00 and 0.81 (2d, each 3H, J = 7 Hz, 10-Me, 12-Me); 84:
4.67 (d, 1H, J = 5.6 Hz, 16-H), 3.60 (d, 1H, J = 5.7 Hz, 17-
H), 3.56 (dd, 1H, J = 18.5, 8.7 Hz, 14-H), 2.57 (dd, 1H, J =
18.5, 2.0 Hz, 14-H), 1.16 and 0.97 (2d, each 3H, J = 7 Hz,
10-Me, 12-Me)). As expected on the basis of the stereo-
chemistry of the key aldol reaction to produce 76 and 77,
DIBAL-H reduction of ketone 84 proceeded to produce the
(15R)-alcohol 85 (Scheme 11). The inversion of C(15)
stereochemistry in the oxidation reduction sequence, which
may have been the result of a chelation controlled addition
pathway (tetrahydrofuran ether as the Lewis basic site) or via
a Felkin-type addition pathway, was clearly apparent from
Et3N , CH2Cl2 , 0°C (78%) ; (d) HCl , MeOH , - 5°C
(e) MeO CCH NH Cl, Et N, CH Cl , -10°C to 25°C
(96%);
(69%);
2
2
3
3
2
2
(f) t-BuOK, HCO Me,THF,-10°C to 25°C;
(g) BF3 OEt2, THF,
OsO4, NaIO4, H2O,
2
-78°C to 25°C (77% over both steps); (h)
Me CO (79%); (i) NaBH , MeOH, -12°C
(93%); (j) Et3N,
2
4
MeSO2Cl , Et O , -10°C (84%) ; (k) Me SO ,
NaN3 , 70°C
2
2
(l) H , Pd/C (cat.), MeOH (98%).
(87%);
2
linking the C(37)–C(33) ꢀ-amino acid with the C(32)–C(26)
aminoalkyl oxazole. Again an allylboration strategy was used
to elaborate the C(37)–C(33) ꢀ-amino acid unit 95. The diol
90 was prepared from the Garner aldehyde 89 (32) and the
allylborane derivative 10 (33) with oxidative cleavage of the
intermediate C–Si bond (for a review on the oxidation of the
carbon–silicon bond, see ref. 34). Dialkylation with 4-
methoxybenzyl bromide gave the diether 91 (Scheme 12).
Selective hydrolysis of the isopropylidene ketal using 4-
toluenesulfonic acid gave alcohol 92, which was doubly
methylated by reaction with methyl iodide and sodium hy-
dride to produce the O,N-dimethylated ether 93. Sequential
catalytic osmium tetraoxide mediated dihydroxylation and
periodate cleavage gave the corresponding aldehyde 94,
which was further oxidized using sodium chlorite and hy-
drogen peroxide (35) to produce the key carboxylic acid 95.
The synthesis of the oxazole unit was accomplished using
a modified Cornforth–Meyers approach (Scheme 13) (36).
Benzyl ester 97 was readily prepared using Evans alkylation
(37) and cleavage of the resultant oxazolidinone 96 using
lithium benzyloxide. Ester 97 was converted to the nitrile 99
via Weinreb amide (18) synthesis using trimethylaluminum
and ammonium chloride and subsequent dehydration using
1
comparisons of the H NMR and 13C NMR spectra.
Methylation of alcohol 85, using excess potassium tert-
butoxide and methyl iodide proceeded smoothly and gave
methyl ether 86 in good yield (76%). Subsequent deprotection
of the p-methoxybenzyl residue at C(17) using DDQ oxida-
tion proceeded in quantitative yield to give the alcohol 87.
Finally, Stille coupling (25) of the dienyl stannane 3 with the
dienyl iodide 87 using PdCl2(MeCN)2 as the catalyst at –5 to
5°C gave the (Z,E,E,E)-tetraene nitrile 88 (91%). Stille cou-
pling at higher temperatures resulted in partial isomerization
of the delicate tetraene entity. The product C(1)–C(25) (+)-
calyculin A intermediate 88 showed data in agreement with
that reported by the Evans group in their total synthesis of
(+)-calyculin A (1) (8).
Synthesis of C(26)–C(37) amide-oxazole unit
We sought to prepare the amide oxazole entity 2 using a
convergent strategy with late elaboration of the amide bond
© 2001 NRC Canada

1570
Can. J. Chem. Vol. 79, 2001
Scheme 14.
trichloroacetyl chloride and triethylamine (Scheme 13). The
addition of methanol and hydrogen chloride (36) to nitrile
99 gave the imidate 100 that was allowed to react with
glycine methyl ester to produce the trans-imidation product
101. C-Formylation, using the Cornforth–Meyers protocol
with methyl formate in the presence of potassium tert-
butoxide, and boron trifluoride diethyl etherate mediated
cyclization gave the oxazole 102. Lewis acid catalysis in this
step was found to be superior to the use of acetic acid (15).
The alkene 102 was converted into the corresponding alde-
hyde 103 by osmium tetraoxide mediated dihydroxylation
and periodate cleavage. Subsequent reduction with sodium
borohydride in methanol proceeded smoothly to produce the
alcohol 104. Gratifyingly, this whole sequence of transforma-
tions from oxazolidinone 96 to alcohol 104 proceeded with-
out any significant racemization. Thus, esterification of alcohol
104 with (R)-a-methoxy-a-(trifluoromethyl)phenylacetic
acid, 4-(N,N-dimethylamino)pyridine, and 1,3-dicyclohexyl
carbodiimide gave the Mosher ester 108. In parallel, racemic
benzyl 2-methyl-4-pentenoate was converted into the
racemic modification of the alcohol 104 using exactly the
same methods as in Scheme 13 and converted into the ester
R2O
O
Me
HOBt, EDCIa
O
MeO
R1
N
H
95
107
NMe OR2
N
CO2Me
110: R1 = Boc, R2 =PMB
111: R1 = H, R2 =H
112: R1 = Me, R2 = TES
HCl, EtOAcb
TES-Cl, DIPEA,
then MeIc
TESO
O
Me
d
LiAlH4
O
MeO
Me2N
N
H
N
OTES
HO
113
Reagents and Conditions: (a)EDCI,1-HOBt, 4Å mol. sieves; 107,
DMF (72%); (b) HCl, EtOAc; (c) MeCN, iPr2NEt, TES-Cl; MeI
(59% over both steps); (d) Et2O, LiAlH4, -78°C (62%).
1
mixture 109. Comparison of the H NMR spectra for esters
Conclusions
108 and 109 were fully consistent with the diastereoisomic
purity of 108 and the enantiomeric purity of alcohol 104, re-
spectively.
We have demonstrated the synthetic utility of the powerful
Brown allylboration methodology for the diastereoselective
construction of heavily functionalized homoallylic alcohols
and the use of this masked aldol methodology in the succinct
preparation of complex natural product arrays. Utilizing
this methodology, we have completed the synthesis of the
C(1)–C(25) tetraene nitrile 88 and C(26)–C(37) oxazole am-
ide 113 intermediates reported by Evans in his total synthe-
sis of synthesis of (+)-calyculin (1). This work therefore
constitutes a formal total synthesis of the (+)-antipode of
this remarkable natural product.
CF3 Ph
MeO
CF3 Ph
MeO
O
O
O
Me
O
Me
O
O
N
N
CO2Me
CO2Me
108
109
The alcohol 104 was converted into the corresponding
amine 107 via methanesulfonylation, azide displacement, and
hydrogenation over palladium on carbon. Initial attempts at
coupling the C(26)–C(32)amine 107 with the C(33)–C(37)
carboxylic acid 95 employed DCC and 1-hydroxybenzotriazole
(HOBT) hydrate as coupling agents, but yields of amide 110
(Scheme 14) were disappointingly low and removal of the
side product dicyclohexylurea proved troublesome. How-
ever, coupling of 95 with 107 using 1-ethyl-3-(3-dimethyl-
aminopropyl)carbodiimide hydrochloride (EDCI) and
dehydrated HOBT in the presence of powdered molecular
sieves (4 Å) in DMF proceeded in superior yields and gave
the amide 110 (72%). Conversion of ester 110 to the Evans
intermediate 112 (8) was achieved via cleavage of the Boc
and 4-methoxybenzyl protecting groups upon treatment with
a saturated solution of hydrogen chloride in ethyl acetate
and direct triethylsilylation and N-methylation. These three
transformations were most conveniently accomplished in a
one-pot procedure. The product C(26)–C(37) amide-oxazole
112 showed data in agreement with that reported by the Ev-
ans group in their total synthesis of (+)-calyculin A (1) (8).
Finally, lithium aluminum hydride reduction of the ester 112
gave the corresponding alcohol 113. The product alcohol
113 also showed data in agreement with that reported by the
Evans group in their total synthesis of (+)-calyculin A (1) (8).
Experimental
General procedures
All reactions were carried out under a dry argon or nitrogen
atmosphere at ambient temperature unless otherwise stated.
Low reaction temperatures were recorded as bath tempera-
tures. Chromatography refers to column chromatography us-
ing E. Merck or BDH silica gel 60, 230–400 mesh (eluants
are given in parenthesis). Analytical thin layer chromatogra-
phy (TLC) was performed on E. Merck precoated silica gel
60 F254 plates. Solvents were purified by distillation. Anhy-
drous THF, Et2O, PhH, and PhMe were distilled from so-
dium benzophenone ketyl. DMF was distilled at reduced
pressure from BaO or Al2O3 and stored over molecular
sieves (4 Å). CH2Cl2 was distilled from CaH2. Et3N and i-
Pr2EtN were distilled from CaH2 and stored over KOH. All
other chemicals were used without further purification un-
less otherwise stated. Optical rotations were measured in
CHCl3 solution.
Ethyl 3-(tributylstannyl)-(2Z)-propenoate (12)
Bu3SnSnBu3 (9.84 g, 17.0 mmol) was dissolved in THF
(125 mL), cooled to 0°C and n-BuLi in hexanes (1.6 M,
10.6 mL, 0.017 mol) was added to generate a faint yellow
solution. After stirring at 0°C for 5 min, the mixture was
© 2001 NRC Canada

Anderson et al.
1571
1
cooled to –20°C and PhSCu (2.99 g, 17.3 mmol) added to
generate a red-black mixture after stirring at –20°C for
15 min. The mixture was cooled to –78°C and treated with
ester 11 (1.46 g, 13.0 mmol) in THF (25 mL). The mixture
was stirred at –78°C for 10 min, then allowed to warm to
–35°C and stirred between –35°C and –50°C for a further
3.5 h. MeOH (10 mL) and Et2O (100 mL) were added se-
quentially and the mixture was allowed to warm to room
temperature. The resulting solution was filtered through sil-
ica eluting with Et2O. Chromatography (hexanes) afforded
stannane 12 (2.72 g, 52%) and the corresponding trans
stannyl ester 17 (0.409 g, 7%). The cis-isomer 12 was ob-
tained as a colorless oil. TLC Rf = 0.2 (hexanes). EI-MS
m/z: 401, 375, 347 ([M – Bu]+), 319, 233, 205, 137, 57. EI-
HRMS calcd. for C14H27O2Sn: 347.1033 ([M – Bu]+);
found: 347.1042 ([M – Bu]+). IR (film) (cm–1): 1702, 1601,
1656, 1596, 1458, 1399, 1315, 876. H NMR (400 MHz,
CDCl3) d: 5.93 (m, 1H, JSn,H = 64.8 Hz), 5.30 (br s, 2H,
NH2), 2.36 (m, 3H, JSn,H = 44.0 Hz), 1.50, 1.30, 0.90 (3m,
27H). 13C NMR (68 MHz, CDCl3) d: 167.9, 161.9, 130.7,
28.8, 27.2, 21.9, 13.5, 9.2. Anal. calcd. for C16H33NOSn:
C 51.36, H 8.89, N 3.74; found: C 51.28, H 8.86, N 3.59.
3-(Tributylstannyl)-(2Z)-butenonitrile (14)
Freshly distilled Cl3CCOCl (2.72 mL, 0.024 mol) in
CH2Cl2 (10 mL) was added dropwise over 5 min to 13
(7.00 g, 0.019 mol) and Et3N (5.2 mL, 0.037 mol) in ice
cold dry CH2Cl2 (60 mL). The resulting yellow suspension
was stirred at 0°C for 90 min, added to pH 7 buffer (50 mL),
extracted with CH2Cl2 (125 mL) and then the extract was
dried (Na2SO4) and chromatographed (hexanes–Et2O, 9:1) to
give nitrile 14 (6.7 g, 95%) as a faint green oil. TLC Rf =
0.75 (hexanes–Et2O, 9:1). EI-MS m/z: 356 (M0+), 300 ([M –
Bu]+), 244, 186, 159, 121. EI-HRMS calcd. for C12H22NSn:
300.0774 ([M – Bu]+); found: 300.0773 ([M – Bu]+). IR
(film) (cm–1): 2214, 1458, 1377, 1074, 813. 1H NMR
(400 MHz, CDCl3) d: 5.90 (m, 1H, JSn,H = 94.4 Hz), 2.12 (br
d, 3H, J = 1.8 Hz, JSn,H = 34.5 Hz), 1.52 (m, 6H), 1.32 (m,
6H), 1.12 (m, 6H), 0.9 (m, 9H). 13C NMR (68 MHz, CDCl3)
d: 176.3, 118.8, 109.2, 28.9, 28.4, 27.3, 13.7, 10.0. Anal.
calcd. for C16H31NSn: C 53.96, H 8.78, N 3.93; found:
C 53.57, H 8.75, N 3.69. A similar dehydration of amide 18
using Cl3CCOCl and Et3N gave nitrile 19 (95%) as a color-
less oil. TLC Rf = 0.9 (hexanes–Et2O, 9: 1). EI-MS m/z: 357
(M0+), 300 ([M – Bu]+), 244, 188, 159, 121. EI-HRMS
calcd. for C12H22NSn: 300.0774 ([M – Bu]+); found:
300.0783 ([M – Bu]+). IR (film) (cm–1): 2209, 1459, 1376,
1
1458, 1368, 1316, 1197, 1044, 863. H NMR (400 MHz,
CDCl3) d: 6.41 (br s, 1H, JSn,H = 106 Hz), 4.17 (q, 2H, J =
7.1 Hz), 2.13 (br d, 3H, J = 2 Hz, JSn,H = 41 Hz), 1.47–0.88
(m, 30H). 13C NMR (68 MHz, CDCl3) d: 171.4, 167.8,
129.3, 60.0, 29.2 (d, JSn,C = 18.6 Hz), 27.4 (d, JSn,C
=
29 Hz), 27.3, 14.3, 13.7, 10.9. Anal. calcd. for C18H36O2Sn:
C 53.62, H 9.00; found: C 53.54, H 9.22. Stannyl ester 17
was obtained as a colorless oil. TLC Rf = 0.2 (hexanes). EI-
MS m/z: 347 ([M – Bu]+), 291, 235, 179, 113. IR (neat)
1
(cm–1): 1715, 1176. H NMR (400 MHz, CDCl3) d: 5.96 (m,
1H, JSn,H = 64.4 Hz), 4.16 (q, 2H, J = 7.1 Hz), 2.40 (d, 3H,
J = 1.5 Hz), 1.50, 1.30, 0.90 (3m, 30H). 13C NMR (68 MHz,
CDCl3) d: 168.8, 164.3, 128.2, 59.4, 28.9, 27.3, 22.3, 14.3,
13.5, 9.4. Anal. calcd. for C18H36O2Sn: C 53.62, H 9.00;
found: C 53.38, H 9.19.
1
1074, 995, 875, 810, 669. H NMR (270 MHz, CDCl3) d:
5.43 (m, 1H, JSn,H = 47.7 Hz), 2.27 (m, 3H, JSn,H = 35.8 Hz),
1.50, 1.30, 0.94 (3m, 27H). 13C NMR (68 MHz, CDCl3) d:
175.4, 115.0, 106.9, 28.8, 27.2, 24.8, 13.5, 9.6. Anal. calcd.
for C16H31NSn: C 53.96, H 8.78, N 3.93; found: C 53.79,
H 8.77, N 3.77.
3-(Tributylstannyl)-(2Z)-butenamide (13)
AlMe3 in PhMe (2 M, 1.87 mL, 3.74 mmol) was added
dropwise with stirring to a suspension of NH4Cl (200 mg,
3.74 mmol) in PhH (20 mL) at 0°C. The colorless solution
was stirred at 0°C for 30 min and at room temperature for
1 h. This mixture was transferred to ester 12 (500 mg,
1.24 mmol) in dry PhH (5 mL) and heated at 50°C for 24 h.
The mixture was cooled, carefully quenched with H2O, di-
luted with Et2O, and stirred for 30 min. Buffer (pH 7) and
saturated aqueous Na2SO4 were added and the mixture was
filtered through Celite eluting with EtOAc (125 mL). The
filtrate was washed with brine, dried (MgSO4), and chromato-
graphed (hexanes–Et2O, 1 :1) to give stannane 13 (354 mg,
76%) as a crystalline solid: mp 35°C. TLC Rf = 0.25 (hex-
anes–Et2O, 1:1). EI-MS m/z: 318 ([M – Bu]+), 204, 184,
136, 57. EI-HRMS calcd. for C12H24NOSn: 318.0880 ([M –
Bu]+); found: 318.0848 ([M – Bu]+). IR (CCl4) (cm–1): 3495,
3334, 1670, 1593, 1275, 788, 669. 1H NMR (400 MHz,
CDCl3) d: 6.41 (m, 1H, JSn,H = 107 Hz), 5.50, 5.30 (2 br s,
2H, NH2), 2.14 (m, 3H, JSn,H = 40 Hz), 1.45, 1.30, 0.90 (m,
27H). 13C NMR (68 MHz, CDCl3) d: 169.4, 168.7, 129.3,
29.3 (d, JSn,C = 10 Hz), 27.4, 26.7, 13.7, 11.5. Anal. calcd.
for C16H33NOSn: C 51.36, H 8.89, N 3.74; found: C 51.42,
H 9.07, N 3.77. A similar reaction of ester 17 with AlMe3
and NH4Cl gave amide 18 (72%) as low melting solid: mp
38–40°C. TLC Rf = 0.23 (hexanes–Et2O, 1:1). EI-MS m/z:
318 ([M – Bu]+), 298, 262, 242, 204, 179, 121. EI-HRMS
calcd. for C12H24NOSn: 318.0880 ([M – Bu]+); found:
318.0861 ([M – Bu]+). IR (KBr disc) (cm–1): 3403, 3209,
3-Iodo-(2Z)-butenonitrile (15)
N-Iodosuccinimide (683 mg, 3.04 mmol) was added to
nitrile 14 (1.0 g, 2.81 mmol) in THF (10 mL). After 12 h,
more N-iodosuccinimide (340 mg, 1.51 mmol) (total 1.6
equiv.) was added and the stirring maintained a further 8 h.
Silica was added, the mixture was rotary evaporated, and
chromatographed (hexanes–Et2O, 4:1) to give nitrile 15
(353 mg, 65%) as low melting colorless hexagonal crystals.
TLC Rf = 0.20 (hexanes–Et2O, 9:1). EI-MS m/z: 193 (M0+),
165, 149, 129, 109, 95. EI-HRMS calcd. for C4H4IN:
192.9389 (M0+); found: 192.9395 (M0+). IR (film) (cm–1):
2224, 1613, 1376, 1272, 1101, 796 cm–1. 1H NMR
(400 MHz, CDCl3) d: 6.13 (m, 1H), 2.69 (d, 3H, J = 1.6 Hz).
13C NMR (101 MHz, CDCl3) d: 122.6, 118.1, 110.2, 34.6.
3-Methyl-5-(tributylstannyl)-(2Z,4E)-pentadienenitrile (3)
PdCl2(PPh3)2 (143 mg, 0.2 mmol) and stannane 16 (2.0 g,
3.3 mmol, 1.8 equiv.) in THF (4 mL) were added sequen-
tially to nitrile 15 (353 mg, 1.82 mmol) in THF (9 mL). The
resulting yellow mixture was stirred for 14 h producing a
dull red solution. After a further 2 h at reflux, silica was
added, the mixture rotary evaporated, and chromatographed
to give nitrile 3 (382 mg, 55%) as a colorless oil. TLC Rf =
© 2001 NRC Canada

1572
Can. J. Chem. Vol. 79, 2001
1
0.8 (hexanes–Et2O, 9:1). EI-MS m/z: 361, 326 ([M – Bu]+),
300, 270, 212, 177, 121, 94. EI-HRMS calcd. for
C14H24NSn: 326.0931 ([M – Bu]+); found: 326.0933 ([M –
Bu]+). IR (film) (cm–1): 2213, 1459, 1377, 1342, 1073, 984,
(cm–1): 1744, 1241, 1199, 1177, 1094. H NMR (270 MHz,
CDCl3) d: 3.77 (dd, 1H, J = 9.4, 6.9 Hz), 3.66 (s, 3H), 3.62
(dd, 1H, J = 9.9, 6.2 Hz), 2.63 (m, 1H), 1.12 (d, 3H, J =
7.0 Hz), 0.92 (m, 9H), 0.55 (m, 6H). 13C NMR (101 MHz,
CDCl3) d: 175.5, 64.9, 51.5, 42.5, 13.5, 6.6, 4.3. Anal. calcd.
for C11H24O3Si: C 56.85, H 10.41; found: C 56.97, H 10.57.
1
874, 809. H NMR (270 MHz, CDCl3) d: 7.14 (d, 1H, J =
19 Hz), 6.87 (d, 1H, J = 19 Hz), 5.18 (q, 1H, J = 0.7 Hz),
1.99 (d, 3H, J = 1.5 Hz), 1.50, 1.32, 0.90 (3m, 27H). 13C
NMR (68 MHz, CDCl3) d: 156.0, 142.8, 142.3, 109.1, 95.5,
29.0, 27.2, 13.6, 9.7. Stannane 3 was further authenticated
by conversion into the corresponding dienyl iodide 21. I2
(50 mg, 0.2 mmol) was added to stannane 3 (68 mg,
0.18 mmol) in Et2O (3 mL) at 0°C. After 17 h, KF (70 mg),
sodium thiosulfate (100 mg), MeOH (2 drops), H2O (2
drops), and Et2O (5 mL) were added and the mixture stirred
vigorously until colorless. The mixture was filtered through
Celite–MgSO4–sand, rotary evaporated, and chromatographed
(hexanes–Et2O, 4:1) to give iodide 21 (27mg, 70%) as a
colorless low melting crystalline solid. TLC Rf = 0.3 (hex-
anes–Et2O, 9:1). EI-MS m/z: 219 (M0+), 127, 92. EI-HRMS
calcd. for C6H6IN: 218.9545 (M0+); found: 218.9547 (M0+).
(2S)-2-Methyl-3-(triethylsilyl)oxypropanal (26)
DIBAl-H in hexanes (1.24 M, 50 mL, 0.062 mol) was
added to ester 25 (14.4 g, 0.062 mol) in hexane (100 mL) at
–70°C so as to maintain an internal temperature of –70°C.
After 2 h at –70°C, MeOH (6 mL) was added and the cold
mixture added to Na2SO4 (60 g) in H2O (300 mL) and Et2O
(500 mL). After 1 h standing, the mixture was filtered
through Celite and the organic phase was separated, washed
with brine, dried (MgSO4), and rotary evaporated. The re-
sulting oil was dried under vacuum (65°C at 4 mm Hg) to
afford aldehyde 26 (11.16 g, 89%) as a colorless oil: bp
145°C (20 mm Hg). TLC Rf = 0.43 (hexanes–Et2O, 9:1).
[a]2D3 = +31.4° (c = 9.65). IR (film) (cm–1): 2726. H NMR
1
1
IR (KBr disc) (cm–1): 2215, 1599, 1557, 946, 809, 724. H
(400 MHz, CDCl3) d: 9.74 (s, 1H), 3.83, (m, 2H), 2.55 (m,
1H), 1.09 (d, 3H, J = 7.0 Hz), 0.95 (m, 9H), 0.56 (m, 6H).
13C NMR (101 MHz, CDCl3) d: 204.6, 63.2, 48.8, 10.2, 6.6,
4.2. This crude product was used directly without further pu-
rification.
NMR (300 MHz, CDCl3) d: 7.67 (d, 1H, J = 14.7 Hz), 7.07
(d, 1H, J = 14.7 Hz), 5.15 (br s, 1H), 2.01 (br s, 3H). 13C
NMR (101 MHz, CDCl3) d: 155.2, 142.3, 116.2, 97.2, 88.7,
18.9. Anal. calcd. for C6H6IN: C 32.90, H 2.76, N 6.40;
found: C 32.85, H 2.83, N 6.01. A similar iododestannylation
of nitrile 19 (286 mg) and PdCl2(PPh3)2 catalyzed coupling
of the resultant iodide 20 with stannane 16 gave nitrile 22
(39% overall) as a colorless oil. TLC Rf = 0.8 (hexanes–
Et2O, 9:1). EI-MS m/z: 352, 326 ([M – Bu]+), 300, 270, 244,
214. EI-HRMS calcd. for C14H24NSn: 326.0931 ([M –
Bu]+); found: 326.0931 ([M – Bu]+). IR (film) (cm–1): 2211,
(2S,3R,4R)-2,4-Dimethyl-1-(triethylsilyl)oxy-5-hexen-3-ol
(27)
trans-2-Butene (5 mL) was added to t-BuOK in THF
(1 M, 7.3 mL, 7.3 mmol) at –78°C. n-BuLi in hexanes
(1.58 M, 4.62 mL, 7.3 mmol) was added dropwise at –78°C
and the deep yellow solution stirred at –50°C for 10 min.
The solution was recooled to –78°C and (+)-B-methoxydiiso-
pinocampheylborane (2.77 g, 8.77 mmol) in Et2O (8 mL)
was added dropwise. After 30 min, BF3·OEt2 (1.2 mL,
9.76 mmol) followed by aldehyde 26 (1.1 g, 5.44 mmol) in
Et2O (8 mL) were added dropwise. The mixture was stirred
for 3 h at –78°C, then saturated aqueous sodium perborate
(10 mL) was added and the mixture allowed to warm up to
room temperature. Additional saturated aqueous sodium
perborate (20 mL) was added, the mixture stirred for 12 h,
and subsequently extracted with Et2O (3 × 70 mL). The or-
ganic phase was washed with brine, dried (Na2SO4), and ro-
tary evaporated to give alcohol 27 (1.064 g, 76%) as a
colorless oil: bp 105°C (1 mm Hg). TLC Rf = 0.3 (hexanes–
Et2O, 9:1). [a]2D3 = +20.7° (c = 5.2). EI-MS m/z: 259 (M0+),
229 ([M – Et]+), 203, 187, 173. EI-HRMS calcd. for
C12H25O2Si: 229.1624 ([M – Et]+); found: 229.1622 ([M –
1
1458, 985, 600. H NMR (400 MHz, CDCl3) d: 6.80 (d, 1H,
J = 19.4 Hz), 6.58 (d, 1H, J = 19.4 Hz), 5.17 (br s, 1H), 2.13
(br s, 3H), 1.5, 1.3, 0.8 (3m, 27H). 13C NMR (101 MHz,
CDCl3) d: 157.3, 145.5, 141.4, 117.9, 97.3, 29.0, 27.2, 16.0,
13.7, 9.6. Stannane 22 was further authenticated by
iododestannylation giving nitrile 23 (65%) as a colorless
oil. TLC Rf = 0.3 (hexanes–Et2O, 9:1). EI-MS m/z: 219
(M0+), 127. EI-HRMS calcd. for C6H6IN: 218.9545 (M0+);
found: 218.9553 (M0+). IR (KBr disc) (cm–1): 2213, 1594,
1559, 1439, 947, 831, 763, 726. 1H NMR (400 MHz,
CDCl3) d: 7.15 (d, 1H, J = 14.8 Hz), 6.99 (d, 1H, J =
14.8 Hz), 5.23 (br s, 1H), 2.14 (br s, 3H). 13C NMR
(101 MHz, CDCl3) d: 155.7, 145.0, 116.7, 98.9, 86.9, 16.2.
Anal. calcd. for C6H6IN: C 32.90, H. 2.76, N 6.40; found:
C 32.65, H 2.75, N 6.34.
Et]+). IR (film) (cm–1): 3495, 1077, 1006, 788, 744, 730. H
1
Methyl (2S)-2-methyl-3-(triethylsilyl)oxypropanoate (25)
NMR (270 MHz, CDCl3) d: 5.90 (m, 1H), 5.05 (m, 2H),
3.98 (dd, 1H, J = 2.6, 0.7 Hz), 3.72 (m, 1H), 3.60 (m, 1H),
3.40 (m, 1H), 2.35 (m, 1H), 1.80 (m, 1H), 1.10 (d, 3H, J =
6.9 Hz), 0.96 (t, 9H, J = 7.6 Hz), 0.81 (d, 3H, J = 7.0 Hz),
0.61 (q, 6H, J = 7.6 Hz). 13C NMR (101 MHz, CDCl3) d:
139.6, 114.6, 80.3, 68.5, 41.5, 38.0, 17.9, 13.0, 6.9, 4.3.
Anal. calcd. for C14H30O2Si: C 65.05, H 11.70; found:
C 64.70, H 11.75.
Et3SiCl (40 mL, 0.238 mol) followed by 24 (24.0 g,
0.203 mol) and DMAP (10 mg) were added to ice cooled
imidazole (33.3 g, 0.489 mol) in CH2Cl2 (100 mL). After
3 h at 0°C and 1 h at room temperature, the mixture was
poured into pH 7 buffer and extracted with CH2Cl2, washed
with pH 7 buffer, and the aqueous phase re-extracted with
Et2O. The combined organic phases were dried (MgSO4)
and filtered through alumina. The filtrate was rotary evapor-
ated and the residue distilled (135°C) to afford ester 25
(49.5 g, 90%) as a colorless oil: bp 90°C (15–16 mm Hg).
TLC Rf = 0.9 (hexanes–Et2O, 9:1). [a]2D3 = +17.5° (c =
13.65). EI-MS m/z: 203 ([M – Et]+), 119, 117. IR (film)
(2S,3R,4R)-2,4-Dimethyl-3-((tert-butyldimethylsilyl)oxy)-
5-hexen-1-ol (28)
2,6-Lutidine (200 L, 1.74 mmol) followed by t-
© 2001 NRC Canada

Anderson et al.
1573
BuMe2SiOTf (295 L, 1.28 mmol) were added dropwise to
alcohol 27 (0.30 g, 1.16 mmol) in THF (5 mL) at –78°C. Af-
ter stirring for 10 min at –78°C, AcOH (5 mL) and H2O
(1 mL) were added and the mixture allowed to warm to
room temperature. After a further 3 h stirring, Et2O (40 mL)
and saturated aqueous NaHCO3 were added in sequence to
neutrality and the mixture was extracted with Et2O. The or-
ganic phase was dried (MgSO4), rotary evaporated, and
chromatographed (hexanes–Et2O, 9:1 to 4:1) to give ether 28
(252 mg, 84%) as a colorless oil. TLC Rf = 0.2 (hexanes–
Et2O, 4:1). [a]2D3 –5.30° (c = 6.3). EI-MS m/z: 204, 202, 201,
200, 199, 159. EI-HRMS calcd. for C10H21O2Si: 201.1337
([M – Bu]+); found: 201.1322 ([M – Bu]+). IR (film) (cm–1):
3338, 1473, 1256, 1036, 836, 774, 669. 1H NMR (400 MHz,
CDCl3) d: 5.80 (m, 1H), 5.02 (m, 2H), 3.60 (m, 2H), 2.48
(m, 1H), 2.42 (m, 1H), 1.82 (m, 1H), 1.06 (d, 3H, J =
7.0 Hz), 0.94 (d, 3H, J = 7.0 Hz), 0.91 (s, 9H), 0.10 (s, 3H),
0.00 (s, 3H). 13C NMR (101 MHz, CDCl3) d: 140.9, 114.6,
80.7, 66.0, 43.2, 37.5, 26.0, 25.7, 18.2, 18.0, 16.02, 15.96,
–3.6, –4.0. Anal. calcd. for C14H30O2Si: C 65.05, H 11.70;
found: C 65.04, H 11.76.
C18H31O3Si: 325.2110 ([M – Me]+); found: 325.2222 ([M –
Me]+). IR (neat) (cm–1): 1712, 1648, 1463, 1366, 1256,
1097, 1038, 862, 837, 774, 772. 1H NMR (300 MHz,
CDCl ) : 6.82 (br d, 1H, J = 10.2 Hz), 5.85 (m, 1H), 5.00
d
3
(m, 2H), 4.17 (m, 2H), 3.51 (t, 1H, J = 4.9 Hz), 2.65 (m,
1H), 2.35 (m, 1H), 1.81 (d, 3H, J = 1.5 Hz), 1.28 (t, 3H, J =
7.1 Hz), 0.98 (d, 3H, J = 6.9 Hz), 0.96 (d, 3H, J = 6.4 Hz),
0.89 (s, 9H), 0.05 (s, 3H), 0.03 (s, 3H). 13C NMR (75 Hz,
CDCl3) d: 168.4, 145.4, 140.9, 126.4, 114.4, 79.6, 60.3,
43.0, 37.2, 26.1, 18.3, 17.7, 16.5, 14.3, 12.5, –3.7, – 4.0.
Anal. calcd. for C19H36O3Si: C 67.00, H 10.66; found:
C 66.81, H 10.78.
(4S,5R,6R)-2,4,6-Trimethyl-5-(tert-butyldimethylsilyl)oxy-
(2E,7)-octadien-1-ol (31)
DIBAl-H in hexanes (1 M, 13.0 mL, 0.013 mol) was
added over 5 min to the ester 30 (2.0 g, 5.88 mmol) in
CH2Cl2 (100 mL) at –78°C. After 1 h, the mixture was al-
lowed to warm to –20°C over 1 h, recooled to –78°C and
MeOH (1 mL) and saturated aqueous Na2SO4 (30 mL) were
added sequentially. After allowing to warm to room temper-
ature, the CH2Cl2 layer was removed by decantation. The re-
maining crystalline residue was washed with CH2Cl2
(100 mL) and the combined CH2Cl2 extracts washed with
brine, dried (MgSO4), and rotary evaporated. Chromatogra-
phy (hexanes–Et2O, 4:1 to 1:1) gave alcohol 31 (1.553 g,
86%) as a colorless oil. TLC Rf = 0.25 (hexanes–Et2O, 4:1).
[a]2D3 = –7.57° (c = 2.8). EI-MS m/z: 243 ([M – C4H7]+),
225, 199, 159, 115. EI-HRMS calcd. for C13H27O2Si:
243.1780 ([M – C4H7]+), 225.1675 ([M – C4H9O]+); found:
243.1786 ([M – C4H7]+), 225.1671 ([M – C4H9O]+). IR
(film) (cm–1): 3309, 1254, 1039, 836, 773. 1H NMR
(400 MHz, CDCl3) d: 5.85 (m, 1H), 5.43 (d, 1H, J = 9.8 Hz),
4.99 (dd, 1H, J = 6.9, 1.0 Hz), 4.96 (s, 1H), 4.00 (br s, 2H),
3.43 (t, 1H, J = 4.4 Hz), 2.55 (m, 1H), 2.34 (m, 1H), 1.64 (s,
3H), 0.97 (d, 3H, J = 6.9 Hz), 0.91 (d, 3H, J = 7.0 Hz), 0.89
(s, 9H), 0.04 (s, 3H), 0.03 (s, 3H). 13C NMR (101 MHz,
CDCl3) d: 141.6, 133.2, 129.7, 113.9, 79.7, 69.3, 42.7, 36.2,
26.1, 18.5, 18.4, 17.2, 13.9, –3.76, –3.82. Anal. calcd. for
C17H34O2Si: C 68.39, H 11.48; found: C 68.48, H 11.61.
(2R,3R,4R)-2,4-Dimethyl-3-(tert-butyldimethylsilyl)oxy-5-
hexenal (29)
DMSO (0.413 mL, 5.8 mmol) in CH2Cl2 (2 mL) was
added dropwise with stirring over 10 min to (COCl)2
(0.413 mL, 4.34 mol) in CH2Cl2 (6 mL) at –78°C. After
25 min, alcohol 28 (0.9 g, 3.49 mmol) in CH2Cl2 (2 mL)
was added dropwise. The mixture was stirred at –78°C for
45 min, then Et3N (2.74 mL, 19.95 mmol) was added
dropwise and stirring continued at –78°C for 45 min. The
solution was allowed to warm to room temperature and pH 7
buffer (6 mL) and Et2O (25 mL) were added. The ethereal
layer was washed with brine and dried (MgSO4). Chroma-
tography (hexanes–Et2O, 4:1) afforded aldehyde 29
(695 mg, 78%) as a colorless oil. TLC Rf = 0.3 (hexanes–
Et2O, 9:1). [a]2D3 = – 49.8° (c = 7.6). EI-MS m/z: 257 ([M +
H]+), 199 ([M – Bu]+), 173, 143, 129. EI-HRMS calcd. for
C10H19O2Si: 199.1154 ([M – Bu]+); found: 199.1158 ([M –
Bu]+). IR (film) (cm–1): 1725, 1256, 1040, 1006, 915, 837,
1
775, 670. H NMR (400 MHz, CDCl3) d: 9.78 (d, 1H, J =
2.7 Hz), 5.80 (m, 1H), 5.02, (m, 2H), 3.80 (t, 1H, J =
4.4 Hz), 2.56 (m, 1H), 2.42 (m, 1H), 1.07 (d, 3H, J =
7.1 Hz), 1.05 (d, 3H, J = 7.0 Hz), 0.90 (s, 9H), 0.08 (s, 3H),
0.05 (s, 3H). 13C NMR (68 MHz, CDCl3) d: 204.7, 139.9,
115.3, 78.0, 49.9, 43.2, 25.9, 16.2, 16.1, 12.1, –4.1, – 4.4.
Anal. calcd. for C14H28O2Si: C 65.57, H 11.00; found:
C 65.31, H 10.99.
(4S,5R,6R)-2,4,6-Trimethyl-5-(tert-butyldimethylsilyl)oxy-
(2E,7)-octadienal (32)
Activated MnO2 (8.5 g, 97.8 mmol) was added to allylic
alcohol 31 (1.50 g, 5.03 mmol) in CH2Cl2 (50 mL), the
black mixture was stirred for 16 h and filtered through Celite
eluting with CH2Cl2. Rotary evaporation and chromatogra-
phy (hexanes–Et2O, 9:1) gave aldehyde 32 (1.255 g, 81%) as
a colorless oil. TLC Rf = 0.9 (hexanes–Et2O, 9:1). [a]D22
=
Ethyl (4S,5R,6R)-2,4,6-trimethyl-5-(tert-butyldimethyl-
silyl)oxy-(2E,7)-octadienoate (30)
–9.7° (c = 5.35). EI-MS m/z: 281 ([M – Me]+), 241, 199,
155, 115. EI-HRMS calcd. for C16H29O2Si: 281.1937 ([M –
Me]+); found: 281.1932 ([M – Me]+). IR (film) (cm–1):
1690, 1641, 1462, 1377, 1255, 1099, 1034, 837, 774, 679.
1H NMR (400 MHz, CDCl3) d: 9.40 (s, 1H), 6.63 (dd, 1H,
J = 10.0, 1.3 Hz), 5.81 (m, 1H), 5.03 (br s, 1H), 5.00 (br d, 1H,
J = 8.8 Hz), 3.60 (t, 1H, J = 4.1 Hz), 2.85 (m, 1H), 2.32 (m,
1H), 1.72 (d, 3H, J = 1.3 Hz), 1.03 (d, 3H, J = 7.0 Hz), 0.95
(d, 3H, J = 7.0 Hz), 0.91 (s, 9H), 0.08 (s, 3H), 0.05 (s, 3H).
13C NMR (101 MHz, CDCl3) d: 195.8, 157.8, 140.6, 137.6,
114.8, 79.2, 43.5, 36.9, 26.0, 18.3, 18.1, 15.7, 9.3, –3.7, –3.9.
Ph3P=C(Me)CO2Et (3.77 g, 10.40 mmol) in THF (10 mL)
was added to aldehyde 29 (1.325 g, 5.176 mmol) in THF
(10 mL). The resulting yellow mixture was heated 75°C for
3 days and cooled to room temperature, whereupon
unreacted ylide precipitated. This was dissolved in CHCl3
and then silica gel was added. Rotary evaporation and chro-
matography (hexanes–Et2O, 9:1) gave ester 30 (1.772 g,
96%) as a colorless oil. TLC Rf 0.3 (hexanes–Et2O, 9:1).
[a]2D3 = –35.4° (c = 2.75). EI-MS m/z: 325 ([M – Me]+), 285,
283 ([M – Bu]+), 199, 171, 143, 125. EI-HRMS calcd. for
© 2001 NRC Canada

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Can. J. Chem. Vol. 79, 2001
Bu]+). IR (film) (cm–1): 1253, 1111, 1048, 1034, 836, 772.
1H NMR (270 MHz, CDCl3) d: 6.26 (s, 1H), 5.80 (m, 2H),
5.00 (m, 2H), 3.49 (t, 1H, J = 4.4 Hz), 2.60 (m, 1H), 2.30
(m, 1H), 2.04 (d, 3H, J = 0.6 Hz), 1.77 (d, 3H, J = 1.0 Hz),
0.95 (d, 3H, J = 7.0 Hz), 0.91 (d, 3H, J = 7.0 Hz), 0.91 (s,
9H), 0.05 (s, 3H), 0.03 (s, 3H). 13C NMR (101 MHz,
CDCl3) d: 148.5, 141.5, 132.8, 132.4, 114.1, 79.6, 78.1,
43.3, 36.6, 26.1, 22.6, 18.9, 18.3, 16.3, 14.5, –3.7, –4.0. Re-
action on a smaller scale proceeded in superior yield to give
iodide 35 (191 mg, 86%).
(5S,6R,7R)-1,1-Dibromo-3,5,7-trimethyl-6-(tert-butyl-
dimethylsilyl)oxy-(1,3E,8)-nonatriene (33)
CBr4 (3.36 g, 0.01 mol) was added in one portion to PPh3
(5.30 g, 0.020 mol) in CH2Cl2 (20 mL) at 0°C. The mixture
was stirred 5 min, then aldehyde 32 (1.20 g, 4.05 mmol) in
CH2Cl2 (10 mL) was added. After stirring for 5 min, the
mixture was filtered through silica eluting with hexanes and
rotary evaporated at low temperature. Chromatography (hex-
anes) gave dibromide 33 (1.648 g, 89%) as an unstable color-
less oil. TLC Rf = 0.9 (hexanes). [a]2D2 = –7.1° (c = 2.85).
EI-MS m/z: 452 (M0+), 395, 253, 199, 172, 143, 115. EI-
HRMS calcd. for C18H32Br2OSi: 452.0569 (M0+), 394.9864
([M – Bu]+); found: 452.0548 (M0+), 394.9929 ([M – Bu]+).
(5S,6R,7S)-6-(tert-Butyldimethylsilyl)oxy-1-iodo-8-oxo-
2,3,5,7-tetramethylnonan-1E,3E-diene (5)
1
IR (CCl4) (cm–1): 1640, 1255, 1037, 837, 788. H NMR
OsO4 in THF (0.065 M, 3.5 mL, 0.244 mmol) and
pyridine (77 L) were added to diene 35 (88 mg,
0.203 mmol) in dry THF (4 mL) at room temperature. The
mixture was stirred for 1.7 h when Celite (500 mg) and satu-
rated aqueous sodium bisulfite (3 mL) were added. After
further stirring for 2.5 h, the mixture was filtered and diluted
with Et2O (20 mL). The organic phase was washed with
H2O, 1 M HCl, aqueous NaHCO3 (10%), and brine and
dried (Na2SO4). Rotary evaporation and chromatography
(hexanes–Et2O, 1:2.5) gave the crude diol (51 mg, 54%) as a
colorless oil. TLC Rf = 0.5 (Et2O). EI-HRMS calcd. for
C18H34IO2Si: 437.1373 ([M – CH2OH]+); found: 437.1388
([M – CH2OH]+). IR (CCl4) (cm–1): 3399, 1253, 1075, 1032,
837, 773, 600. 1H NMR (400 MHz, CDCl3) major
diastereoisomer d: 6.28 (s, 1H), 5.69 (d, 1H, J = 9.9 Hz),
3.72–3.35 (m, 5H), 2.72 (m, 1H), 2.02 (s, 3H), 1.80 (s, 3H),
1.79 (m, 1H), 1.00 (d, 3H, J = 6.9 Hz), 0.92 (s, 9H), 0.79 (d,
3H, J = 7.1 Hz), 0.11 (s, 3H), 0.10 (s, 3H). 13C NMR
(101 MHz, CDCl3) major diastereoisomer d: 148.2, 133.7,
131.3, 79.6, 78.6, 74.0, 64.7, 39.4, 37.4, 26.0, 22.6, 18.1,
17.9, 14.7, 14.3, –4.0, –4.4. N-Methylmorpholine-N-oxide
(10 mg, 87 mol) and OsO4 in H2O (0.3 M, ca 10 L) were
added to diene 35 (29 mg, 67 mol) in Me2CO and H2O
(1:1, 1 mL) at room temperature. The mixture was stirred for
7 h when sodium bisulfite was added and, after 20 min, the
mixture was filtered through Celite. Rotary evaporation and
chromatography (Et2O) gave the crude diol (19 mg, 61%)
and recovered triene 35 (6 mg, 21%). Both of these
osmylation processes proved to be capricious and proceeded
in variable yield on scale up. The crude diol from either
preparation was used directly in the next step. The crude
1,2-diol (147 mg, 0.314 mmol) was allowed to react with
NaIO4 (174 mg, 0.91 mmol) in THF (5 mL), MeOH
(0.8 mL), and H2O (2 mL) for 30 min at room temperature.
The resulting mixture was diluted with CH2Cl2 (50 mL) and
washed with H2O and brine. The organic layer was dried
(Na2SO4) and rotary evaporated to leave the crude aldehyde
36 as a pale yellow oil. TLC Rf = 0.4 (hexanes–Et2O, 9:1).
[a]2D2 = +0.41° (c = 3.15). EI-MS m/z: 379 ([M – Bu]+), 252,
201, 173, 145. IR (film) (cm–1): 1723, 1463, 1378, 1254,
(400 MHz, CDCl3) d: 6.93 (s, 1H), 5.82 (m, 1H), 5.72 (d,
1H, J = 9.9 Hz), 5.00 (d, 1H, J = 3.2 Hz), 4.97 (s, 1H), 3.46
(t, 1H, J = 4.1 Hz), 2.60 (m, 1H), 2.32 (m, 1H), 1.85 (s, 3H),
0.95 (d, 3H, J = 7.0 Hz), 0.94 (d, 3H, J = 7.0 Hz), 0.91 (s,
9H), 0.05 (s, 3H), 0.03 (s, 3H). 13C NMR (101 MHz,
CDCl3) d: 141.4, 141.2, 139.0, 130.0, 114.2, 85.3, 79.5,
43.1, 36.4, 26.1, 18.3, 18.2, 16.6, 15.4, –3.7, –3.8.
(5S,6R,7R)-3,5,7-trimethyl-6-(tert-butyldimethylsilyl)oxy-
(3E,8)-nonadien-1-yne (34)
n-BuLi in hexanes (2.28 M, 5.0 mL, 11.4 mmol) was
added dropwise to dibromide 33 (2.36 g, 5.22 mmol) in THF
(25 mL) at –78°C generating a yellow solution. After 1 h,
the mixture was allowed to warm to room temperature and
stirred for 1 h. Water (1 mL) was added, the mixture rotary
evaporated, and Et2O was added. The organic phase was
washed with brine, dried (MgSO4), and chromatographed
(hexanes–Et2O, 49:1) to give alkyne 34 (1.23 mg, 80%) as a
colorless oil. TLC Rf = 0.8 (hexanes). [a]2D2 = –48.4° (c =
3.7). EI-MS m/z: 292 (M0+), 277, 237, 199, 179, 161, 115.
EI-HRMS calcd. for C18H32OSi: 292.2222 (M0+); found:
292.2238 (M0+). IR (film) (cm–1): 3315, 2097, 1463, 1256,
1
1102, 1037, 1032, 880, 836, 774, 636, 609, 606. H NMR
(400 MHz, CDCl3) d: 5.95 (dd, 1H, J = 9.1, 1.2 Hz), 5.84
(m, 1H), 5.00 (m, 2H), 3.43 (t, 1H, J = 4.5 Hz), 2.76 (s, 1H),
2.61 (m, 1H), 2.35 (m, 1H), 1.78 (d, 3H, J = 1.4 Hz), 0.98
(d, 3H, J = 6.9 Hz), 0.92 (d, 3H, J = 6.9 Hz), 0.91 (s, 9H),
0.06 (s, 3H), 0.05 (s, 3H). 13C NMR (101 MHz, CDCl3) d:
143.1, 141.1, 115.5, 114.3, 87.2, 79.4, 73.5, 42.8, 37.0, 26.1,
18.3, 17.9, 17.2, 16.8, –3.78, –3.82.
(5S,6R,7R)-1-Iodo-2,3,5,7-tetramethyl-6-(tert-butyl-
dimethylsilyl)oxy-(1E,3E,8)-nonatriene (35)
AlMe3 in PhMe (2 M, 1.92 mL, 3.84 mmol) was added
dropwise to Cp2ZrCl2 (560 mg, 1.916 mmol) in CH2Cl2
(8 mL) and, after 10 min, alkyne 34 (510 mg, 1.75 mmol) in
CH2Cl2 (6 mL) was added. After 16 h, I2 (530 mg,
2.088 mmol) in THF (10 mL) was added and, after a further
30 min stirring, the solution was cooled to 0°C and carefully
treated with H2O (3 mL). The solution was filtered through
Celite eluting with Et2O and the organic phase was washed
with pH 7 buffer and brine and dried (MgSO4). Rotary evap-
oration and chromatography (hexanes) gave iodide 35
(520 mg, 69%) as an unstable oil that turned purple upon
prolonged standing. TLC Rf = 0.9 (hexanes). EI-MS m/z:
379, 377 ([M – Bu]+), 251, 199. EI-HRMS calcd. for
C15H26IOSi: 377.0798 ([M – Bu]+); found: 377.0795 ([M –
1
1075, 1034, 1006, 939, 838, 773, 673. H NMR (400 MHz,
CDCl3) d: 9.76 (d, 1H, J = 2.6 Hz), 6.31 (s, 1H), 5.68 (d,
1H, J = 9.5 Hz), 3.84 (t, 1H, J = 3.8 Hz), 2.65 (m, 1H), 2.48
(m, 1H), 2.03 (s, 3H), 1.79 (s, 3H), 1.06 (d, 3H, J = 7.0 Hz),
1.00 (d, 3H, J = 6.9 Hz), 0.90 (s, 9H), 0.08 (s, 3H), 0.06 (s,
3H). 13C NMR (101 MHz, CDCl3) d: 204.7, 148.1, 134.9,
130.2, 79.1, 77.7, 51.1, 37.9, 25.9, 22.6, 18.2, 17.8, 14.7,
11.8, –4.0, –4.1. The crude aldehyde 36 was used in the
© 2001 NRC Canada

Anderson et al.
1575
next reaction without further purification. Aldehyde 36
(134 mg, crude) in dry THF (3.0 mL) was added dropwise to
MeMgBr in PhMe and THF (3:1) (1.4 M, 722 L,
1.0 mmol) in dry THF (4 mL) at –78°C. After 30 min, the
mixture was poured into saturated aqueous NH4Cl and ice
and extracted with Et2O. The extracts were combined,
washed with brine, and dried (MgSO4). Rotary evaporation
and chromatography (Et2O–hexanes, 1:3) gave alcohol 37
(114 mg, 80% from the diol). Since the alcohol 37 was unsta-
ble, it was used directly in the next reaction. DMSO (86 L,
1.21 mmol) in dry CH2Cl2 (3 mL) was added dropwise to
oxalyl chloride (88 L, 1.01 mmol) in dry CH2Cl2 (4 mL) at
–78°C. After 8 min, alcohol 37 (114 mg, 0.252 mmol) in dry
CH2Cl2 (3 mL) was added and stirring was continued for
10 min at –78°C, when Et3N (296 L, 2.12 mmol) was
added dropwise. The mixture was allowed to warm up to
–30°C over 15 min and then diluted with Et2O (50 mL). The
organic phase was washed with H2O, 0.5 M HCl, H2O, satu-
rated aqueous NaHCO3, and brine and then dried (MgSO4).
Rotary evaporation and chromatography (hexanes–Et2O,
6:1) gave ketone 5 (90 mg, 79%) as a colorless oil. TLC
Rf = 0.43 (hexanes–Et2O, 5:1). [a]2D0 = +23° (c = 0.70). EI-
MS m/z: 435 ([M – Me]+), 393, 301, 251, 215. EI-HRMS
calcd. for C18H32IO2Si: 435.1216 ([M – Me]+); found:
435.1208 ([M – Me]+). IR (film) (cm–1): 1718, 1462, 1377,
ration and chromatography (hexanes–EtOAc, 5:1) gave the
crude alcohol 40 (75 mg, 93%). TsOH·H2O (3 mg,
0.017 mmol) was added to alcohol 40 (75 mg, 0.163 mmol)
in MeOH (1.6 mL) at room temperature. After 3 h, Et3N
(50 L) was added and the mixture rotary evaporated and
chromatographed (hexanes–EtOAc, 1:1 then MeOH:CH2Cl2,
1:9) to give the crude triol 41 (24 mg, 100%). Ac2O (60 L),
Et3N (80 L), and DMAP (5 mg) were added to triol 41
(24 mg, 0.16 mmol) in CH2Cl2 (1 mL). After 30 min, excess
Ac2O was quenched with MeOH (0.1 mL). Rotary evapora-
tion and chromatography (hexanes–EtOAc, 2:1) gave triester
42 (45 mg, 97%) as a colorless oil. [a]2D0 = 0° (c = 2.25). IR
(film) (cm–1): 2973, 1739, 1460, 1376, 1228, 1128. 1H NMR
(300 MHz, CDCl3) d: 4.90 (t, 1H, J = 6.5 Hz), 4.06 (dd, 2H,
J = 4.5, 11.0 Hz), 3.92 (dd, 2H, J = 11.0, 6.5 Hz), 2.22–2.13
(m, 2H), 2.05 (s, 3H), 2.04 (s, 6H), 1.00 (d, 6H, J = 7.0 Hz).
13C NMR (75 MHz, CDCl3) d: 171.1, 170.6, 76.5, 65.5,
34.3, 21.0, 20.8, 14.9.
(10S,11S,12S)-3,7,8,10,12-Pentamethyl-13-oxo-11-(tert-
butyldimethylsilyl)oxy-(2Z,4E,6E,8E)-tridecatetraenenitrile
(43)
PdCl2(PPh3)2 (3 mg) in THF (0.5 mL) was added to the
aldehyde 36 (75 mg, 0.172 mmol) and stannyl nitrile 3
(80 mg, 0.21 mmol) in THF (0.5 mL) and the yellow mix-
ture was heated with stirring at 60°C for 2 h. The resultant
black mixture was cooled and directly chromatographed
(hexanes–Et2O, 4:1) to afford the tetra-ene nitrile 43 (52 mg,
75%) as a yellow oil. TLC Rf = 0.25 (hexanes–Et2O, 9:1).
[a]2D2 = +70.6° (c = 2.3). EI-MS m/z: 401 (M0+), 344, 315,
286, 252, 201, 173, 145, 115. EI-HRMS calcd. for
C24H39NO2Si: 401.2750 (M0+); found: 401.2751 (M0+). IR
(film) (cm–1): 2208, 1723, 1592, 1583, 1462, 1379, 1254,
1
1253. H NMR (300 MHz, CDCl3) d: 6.28 (s, 1H), 5.80 (dq,
1H, J = 9.5, 1.0 Hz), 3.88 (dd, 1H, J = 7.5, 2.5 Hz), 2.64 (q,
1H, J = 7.5 Hz), 2.57 (ddt, 1H, J = 9.5, 7.5, 2.5 Hz), 2.14 (s,
3H), 2.03 (d, 3H, J = 1.0 Hz), 1.78 (d, 3H, J = 1.0 Hz), 0.97
(d, 3H, J = 7.5 Hz), 0.93 (d, 3H, J = 7.5 Hz), 0.87 (s, 9H),
0.06 (s, 3H), 0.02 (s, 3H). 13C NMR (85 MHz, CDCl3) d:
211.9, 148.3, 134.3, 130.3, 78.8, 77.6, 52.0, 36.6, 31.1, 26.2,
22.7, 18.5, 18.3, 14.7, 13.4, –3.9, –4.3.
1
1040, 1034, 962, 838, 775. H NMR (400 MHz, CDCl3) d:
9.76 (d, 1H, J = 2.7 Hz), 6.99 (dd, 1H, J = 14.2, 11.2 Hz),
6.85 (d, 1H, J = 14.8 Hz), 6.36 (d, 1H, J = 10.8 Hz), 5.82
(d, 1H, J = 9.5 Hz), 5.09 (br s, 1H), 3.86 (t, 1H, J = 4.7 Hz),
2.77 (m, 1H), 2.50 (m, 1H), 2.07 (d, 3H, J = 1.3 Hz), 2.00
(s, 3H), 1.86 (s, 3H), 1.07 (d, 3H, J = 7.0 Hz), 1.03 (d, 3H, J =
6.9 Hz), 0.90 (s, 9H), 0.09 (s, 3H), 0.06 (s, 3H). 13C NMR
(101 MHz, CDCl3) d: 204.6, 156.5, 143.4, 136.1, 133.5,
131.7, 129.1, 125.0, 117.4, 95.1, 77.8, 51.2, 38.3, 34.1, 25.9,
22.3, 19.4, 18.2, 17.8, 14.6, 14.3, 14.1, 11.8, –4.0, –4.2.
(2R,4S)-2,4-Dimethyl-1,3,5-pentanetriyl triacetate (42)
The silyl ether 38 was prepared from methyl (2R)-2-methyl-
3-triethylsilyloxypropanoate (ent-24) (17.5 g) and (–)-B-
methoxydiisopinocampheylborane following the methods as
for the (S)-antipode 27. Ether 38 was dissolved in Me2CO
(50 mL) and H2O (5 mL), then OsO4 in H2O (5%, 1 mL)
and N-methylmorpholine-N-oxide (9.5 g, 0.0698 mol) were
added. After stirring for 6 h at room temperature, saturated
aqueous sodium metabisulfite (20 mL) and Celite (20 g)
were added and, after 3 h, the mixture was filtered. The fil-
trate was rotary evaporated, the resultant solid extracted with
Et2O (300 mL), and the filtrate washed with H2O (2 ×
50 mL), 1 M HCl (50 mL), H2O (50 mL), 10% aqueous
NaHCO3 (50 mL), and brine and dried (Na2SO4). Rotary
evaporation and chromatography (hexanes–EtOAc, 8:1 to
3:2) gave the crude vicinal diol (14.2 g, 40% overall from
ester ent-24). NaIO4 (1.11 g, 6.21 mmol), MeOH (5 mL),
and H2O (2 mL) were added to an aliquot of the diol (2.1 g,
5.17 mmol) in THF (15 mL) and the mixture stirred for
20 min at room temperature. An insoluble solid was re-
moved by filtration and the filtrate was extracted with
CH2Cl2 (3 × 50 mL). The extracts were washed with H2O
and brine and dried (Na2SO4). Rotary evaporation and chro-
matography (hexanes–Et2O, 22:1) gave the crude aldehyde
39 (1.93 g, 100%). NaBH4 (6.6 mg, 0.175 mmol) was added
to an aliquot of the aldehyde 39 (80 mg, 0.175 mmol) in
MeOH (1 mL) with ice cooling. After 20 min, rotary evapo-
3-(3,4-Dimethoxybenzyl)oxypropan-1-ol
Camphorsulfonic acid (50 mg) and 3,4-dimethoxy-
benzaldehyde (20 g, 0.120 mol) were added to 1,3-
propanediol (22 g, 0.289 mol) in PhH (100 mL). The mix-
ture was heated to reflux (Dean-Stark) for 12 h, cooled to
room temperature, and treated with pH 7 buffer (50 mL).
The organic phase was separated,washed with brine (2 ×
100 mL), and dried (MgSO4). The mixture was heated to re-
flux (Dean-Stark) for a further 2 h and cooled to 0°C.
DIBAl-H in PhMe (1.46 M, 25 mL, 0.365 mmol) was added
dropwise at 0°C, stirred for 5 min at 0°C and then 1 h at
room temperature. A further aliquot of DIBAl-H in PhMe
(1.46 M, 8 mL) was added and the mixture stirred at room
temperature for 30 min. The solution was cooled to 0°C and
quenched with EtOAc (10 mL) and aqueous NaOH (3 M,
7 mL). The resulting solution was filtered through Celite
eluting with EtOAc and the organic fraction washed with
© 2001 NRC Canada

1576
Can. J. Chem. Vol. 79, 2001
H2O and brine and dried (MgSO4). Rotary evaporation and
chromatography (hexanes–EtOAc, 1:1, then EtOAc) gave 3-
(3,4-dimethoxybenzyl)oxy-1-propanol (10 g, 37%) as a vis-
cous oil: TLC Rf = 0.25 (Et2O). EI-MS m/z: 226 (M0+), 211,
195, 167, 151. EI-HRMS calcd. for C12H18O4: 226.1205
(M0+); found: 226.1197 (M0+). IR (film) (cm–1): 3466, 1593,
1515, 1465, 1420, 1365, 1360, 1265, 1238, 1157, 1090,
280.1675 (M0+); found: 280.1678 (M0+). IR (CCl4) (cm–1):
3469, 1612, 1593, 1465, 1420, 1364, 1265, 1239, 1168,
1139, 1088, 1030, 916, 767, 765. 1H NMR (400 MHz,
CDCl3) d: 6.87–6.82 (m, 3H), 5.78 (m, 1H), 5.05 (m, 2H),
4.46 (s, 2H), 3.89 (s, 3H), 3.88 (s, 3H), 3.65 (m, 3H), 2.85
(d, 1H, J = 3.4 Hz), 2.26 (m, 1H), 1.75 (m, 2H), 1.05 (d,
3H, J = 6.8 Hz). 13C NMR (75 MHz, CDCl3) d: 149.0,
148.5, 140.8, 130.5, 120.0, 114.4, 111.1, 73.8, 72.8, 68.6,
55.7, 55.6, 43.6, 33.4, 14.8. Anal. calcd. for C16H24O4:
C 68.54, H 8.63; found: C 68.45, H 8.84.
1
1028, 820, 811, 765. H NMR (400 MHz, CDCl3) d: 6.87–
6.83 (m, 3H), 4.45 (s, 2H), 3.88 (s, 3H), 3.87 (s, 3H), 3.79–
3.75 (m, 2H), 3.65–3.62 (m, 2H), 2.34 (m, 1H), 1.87–1.84
(m, 2H). 13C NMR (101 MHz, CDCl3) d: 149.0, 148.6,
130.6, 120.2, 110.9, 110.9, 73.2, 69.1, 61.9, 55.91, 55.88,
55.84, 55.80, 32.1. Anal. calcd. for C12H18O4: C 63.70,
H 8.02; found: C 63.48, H 8.17.
(3R,4R)-1-(3,4-Dimethoxybenzyl)oxy-4-methyl-3-(tert-
butyldimethyl)oxy-5-hexene (46)
2,6-Lutidine (1 mL, 8.59 mmol) followed by t-
BuMe2SiOTf (1.3 mL, 5.62 mmol) were added to alcohol 45
(1.43 g, 5.11 mmol) in CH2Cl2 (15 mL) at –78°C. The mix-
ture was allowed to warm to room temperature over 90 min
and quenched with pH 7 buffer (5 mL). The solution was di-
luted with Et2O (100 mL), washed with brine, dried
(MgSO4), and evaporated to dryness. Chromatography (hex-
anes–Et2O, 9:1) afforded the silyl alcohol 46 (1.89 g, 94%)
3-(3,4-Dimethoxybenzyl)oxypropanal (44)
DMSO (3 mL, 0.042 mmol) in CH2Cl2 (4 mL) was added
dropwise over 10 min to (COCl)2 (3 mL, 0.034 mol) in
CH2Cl2 (50 mL) at –78°C. After stirring at –78°C for 25 min,
3-(3,4-dimethoxybenzyl)oxypropan-1-ol (6.0 g, 0.0265 mol)
in CH2Cl2 (4 mL) was added dropwise. After 45 min, Et3N
(20 mL, 0.143 mol) was added dropwise at –78°C and stir-
ring was continued for a further 45 min; the solution was
then allowed to warm to room temperature. Buffer (pH 7,
50 mL) and Et2O (200 mL) were added and the ethereal
layer was washed with brine and dried (MgSO4). Chroma-
tography (hexanes–EtOAc, 1:1) gave aldehyde 44 (4.59 g,
77%) as a colorless oil. TLC Rf = 0.4 (hexanes–Et2O, 3:7).
EI-MS m/z: 224 (M0+), 209, 193, 167, 151, 139. EI-HRMS
calcd. for C12H16O4: 224.1049 (M0+); found: 224.1046
(M0+). IR (film) (cm–1): 1723, 1712, 1593, 1515, 1465,
1420, 1363, 1265, 1258, 1157, 1092, 1028, 856, 812, 766.
1H NMR (300 MHz, CDCl3) d: 9.80, (t, 1H, J = 1.8 Hz),
7.2–6.8 (m, 3H), 4.45 (s, 2H), 3.89 (s, 3H), 3.88 (s, 3H),
3.82 (t, 2H, J = 6.1 Hz), 2.70 (dt, 2H, J = 6.1, 1.8 Hz). 13C
NMR (75 MHz, CDCl3) d: 200.7, 149.1, 148.8, 130.4, 120.2,
111.2, 73.0, 63.5, 55.9, 43.8.
as a colorless oil. TLC Rf = 0.5 (hexanes–Et2O, 1:1). [a]D22
=
+28.1° (c = 7.2). EI-MS m/z: 394 (M0+), 339, 281, 251, 224,
199, 173, 167, 151. EI-HRMS calcd. for C22H38O4Si:
394.2539 (M0+); found: 394.2524 (M0+). IR (film) (cm–1):
1594, 1517, 1465, 1420, 1362, 1259, 1106, 1092, 1032, 912,
1
837, 774. H NMR (400 MHz, CDCl3) d: 6.85 (m, 3H), 5.88
(m, 1H), 5.00 (m, 2H), 4.44 (d, 1H, J = 11.3 Hz), 4.39 (d,
1H, J = 11.3 Hz), 3.88 (s, 3H), 3.87 (s, 3H), 3.71 (m, 1H),
3.50 (m, 2H), 2.30 (m, 1H), 1.8–1.6 (m, 2H), 0.96 (d, 3H,
J = 6.9 Hz), 0.88 (s, 9H), 0.04 (s, 6H). 13C NMR (101 MHz,
CDCl3) d: 148.9, 148.4, 140.8, 131.1, 120.2, 114.2, 110.9,
110.8, 72.9, 72.8, 66.8, 55.9, 55.7, 43.0, 33.4, 25.9, 18.1,
14.8, –4.4, –4.6. Anal. calcd. for C22H38O4Si: C 66.96,
H 9.71; found: C 67.10, H 9.96.
(2S,3R)-5-(3,4-Dimethoxybenzyl)oxy-2-methyl-3-(tert-
butyldimethylsilyl)oxypentanal (47)
(3R,4R)-1-(3,4-Dimethoxybenzyl)oxy-4-methyl-5-hexen-
3-ol (45)
Aqueous OsO4 (0.3 M, 10 drops) was added to alkene 46
(520 mg, 1.320 mmol) in THF and H2O (1:1, 5 mL) and N-
methylmorpholine-N-oxide (235 mg, 1.74 mmol) and the
brown solution was stirred at room temperature for 7 h.
NaIO4 (370 mg, 1.73 mmol) was added and the resulting
mixture was stirred for a further 2 h, filtered through Celite,
eluting with Et2O (100 mL), and the ethereal layer was
washed with pH 7 buffer and brine and dried (Na2SO4).
Chromatography (hexanes–Et2O, 9:1 to 1:1) gave aldehyde
47 (432 mg, 88%) as a tan oil. TLC Rf = 0.4 (hexanes–Et2O,
1:1). [a]2D1 = +44.1° (c = 3.2). EI-MS m/z: 396 (M0+), 339,
282, 264, 236, 224, 189. EI-HRMS calcd. for C21H36O5Si:
396.2332 (M0+); found: 396.2286 (M0+). IR (film) (cm–1):
1726, 1593, 1515, 1463, 1419, 1362, 1259, 1157, 1103,
Freshly condensed cis-2-butene (5 mL) was added to t-
BuOK (2.675 g, 0.0238 mol) in THF (50 mL) at –78°C. n-
BuLi in hexanes (1.6 M, 15 mL, 0.024 mol) was added
dropwise resulting in the formation of a yellow precipitate,
which was allowed to warm to –55°C and stirred for an ad-
ditional 20 min. Upon recooling to –78°C, (–)-B-methoxy-
diisopinocampheylborane (8.27 g, 0.0262 mol) in Et2O
(30 mL) was added dropwise over 10 min. The colorless
mixture was stirred at –78°C for 30 min, then BF3.OEt2
(4.19 mL, 0.034 mol) was added in one portion followed by
aldehyde 44 (4.45 g, 0.020 mol) in Et2O (25 mL) dropwise.
The mixture was stirred at –78°C for 4 h and H2O (20 mL)
was added when the mixture was allowed to warm to room
temperature. Sodium perborate (20 g) was added and the
mixture was stirred vigorously overnight. The mixture was
extracted with Et2O (200 mL) and the extracts were washed
with H2O and brine, dried (MgSO4), and rotary evaporated.
Chromatography (hexanes–Et2O, 1:1) gave alcohol 45
(4.00 g, 72%) as a colorless oil. TLC Rf = 0.4 (hexanes–
Et2O, 3:7). [a]2D3 = +9.5° (c = 9.95). EI-MS m/z: 280 (M0+),
224, 167, 151, 137, 107. EI-HRMS calcd. for C16H24O4:
1
1033, 939, 888, 777, 669. H NMR (400 MHz, CDCl3) d:
9.78 (s, 1H), 6.87–6.82 (m, 3H), 4.44 (d, 1H, J = 11.6 Hz),
4.38 (d, 1H, J = 11.5 Hz), 4.32 (m, 1H), 3.89 (s, 3H), 3.88
(s, 3H), 3.49 (m, 2H), 2.48 (m, 1H), 1.80 (m, 2H), 1.05 (d,
3H, J = 7.0 Hz), 0.86 (s, 9H), 0.07 (s, 3H), 0.04 (s, 3H). 13C
NMR (101 MHz, CDCl3) d: 205.1, 148.9, 148.5, 130.7,
120.2, 110.9, 110.8. 72.9, 69.3, 66.3, 55.9, 55.8, 55.7, 51.6,
34.5, 25.7, 18.0, 7.9, –4.5, –4.6.
© 2001 NRC Canada

Anderson et al.
1577
0.88 (m, 2H), 0.05 (s, 6H), 0.01 (s, 9H). 13C NMR
(101 MHz, CDCl3) d: 136.9, 118.2, 91.7, 79.1, 77.3,
72.5, 65.8, 39.0, 25.8, 21.9, 20.4, 18.2, 18.1, –1.5, –5.6.
Anal. calcd. for C20H44O4Si2: C 59.35, H 10.96; found:
C 59.15, H 11.11.
2,2-Dimethyl-3-(tert-butyldimethylsilyl)oxypropanal (48)
Imidazole (15 g, 0.220 mol) followed by t-BuMe2SiCl
(15 g, 0.1 mol) were added to 2,2-dimethyl-1,3-propanediol
(20 g, 0.192 mol) in DMF (10 mL). The resulting viscous
mixture was stirred at room temperature for 16 h, then Et2O
(200 mL) and H2O (200 mL) were added. The ethereal layer
was washed with pH 7 buffer (2 × 100 mL) and brine and
dried (MgSO4). After rotary evaporation, the residue was
distilled to leave 2,2-dimethyl-3-(tert-butyldimethylsilyl)oxy-
1-propanol (15.8 g, 63%) as a colorless oil. DMSO (1 mL,
0.014 mol) in CH2Cl2 (2 mL) was added to (COCl)2 (1 mL,
0.011 mol) in CH2Cl2 (25 mL) at –78°C such that the inter-
nal reaction temperature did not increase by more than 5°C.
This mixture was stirred at –78°C for 30 min and then the
alcohol (2 g, 7.87 mmol) in CH2Cl2 (5 mL) was added
dropwise. The mixture was stirred at –78°C for 35 min,
then Et3N (6 mL, 0.043 mmol) was added slowly and the
mixture allowed to warm to –10°C. Buffer (pH 7, 20 mL)
and Et2O (100 mL) were added and the ethereal fraction
washed with pH 7 buffer and brine and dried (Na2SO4).
Chromatography (hexanes–Et2O, 9:1) afforded aldehyde 48
(1.72 g, 86%) as a colorless oil. TLC Rf = 0.75 (hexanes–
Et2O, 9:1). IR (film) (cm–1): 1730, 1472, 1362, 1401, 1256,
(3S,4S)-3-(4-Methoxybenzyl)oxy-2,2-dimethyl-4-(2-
trimethylsilylethoxy)-methoxy-5-hexen-1-ol (51)
KN(SiMe3)2 (3.14 g, 0.0157 mol) in THF (20 mL) was
added to alcohol 49 (5.60 g, 0.0138 mol) in THF (30 mL) at
–78°C. After stirring for 10 min at –78°C, the mixture was
stirred at 0°C for 10 min and treated with 4-MeOC6H4CH2Cl
(2.2 mL, 0.0162 mol). After 1 h, the mixture was allowed to
warm up to room temperature and DMF (10 mL) added. Af-
ter 30 min, saturated aqueous NH4Cl (10 mL) was added
and the mixture was diluted with Et2O (400 mL), washed
with brine, and dried (MgSO4). Rotary evaporation gave
silyl ether 50 as a colorless oil. TLC Rf = 0.45 (hexanes–
Et2O, 1:1). EI-MS m/z: 524 (M0+), 409, 393, 289, 257. EI-
HRMS calcd. for C28H52O5Si2: 524.3353 (M0+); found:
524.3357 (M0+). IR (CCl4) (cm–1): 1613, 1514, 1472, 1389,
1
1361, 1259, 1250, 1173, 1094, 1036, 924, 837, 775, 668. H
NMR (400 MHz, CDCl3) d: 7.29 (d, 2H, J = 8.5 Hz), 6.85
(d, 2H, J = 8.5 Hz), 5.92 (m, 1H), 5.28 (m, 1H), 5.24 (m,
1H), 4.72 (d, 1H, J = 7.1 Hz), 4.68 (d, 1H, J = 6.9 Hz), 4.66
(d, 1H, J = 6.9 Hz), 4.51 (d, 1H, J = 10.8 Hz), 4.32 (dd, 1H,
J = 7.9, 3.1 Hz), 3.80 (s, 3H), 3.79 (m, 1H), 3.54 (m, 3H),
3.27 (d, 1H, J = 9.6 Hz), 0.99 (s, 3H), 0.98 (s, 3H), 0.91 (s,
9H), 0.90 (m, 2H), 0.05 (s, 3H), 0.04 (s, 3H), 0.00 (s, 9H).
13C NMR (101 MHz, CDCl3) d: 158.9, 137.7, 131.4, 129.4,
117.4, 113.6, 92.2, 84.4, 78.2, 75.6, 70.2, 65.7, 55.2, 40.8,
25.9, 21.8, 21.2, 18.3, 18.1, –1.5, –5.4, –5.5. Anal. calcd. for
C28H52O5Si2: C 64.07, H 9.99; found: C 63.89, H 10.19. The
silyl ether 50 was dissolved in Bu4NF in THF (1 M,
0.040 mL) and maintained at room temperature for 16 h.
Et2O (400 mL) and H2O (100 mL) were added, and the ethe-
real layer was washed with brine and dried (MgSO4). Chro-
matography (hexanes–Et2O, 3:2) gave alcohol 51 (5.65 g,
98%) as a colorless oil. TLC Rf = 0.45 (hexanes–Et2O, 1:1).
[a]2D1 = +39.6° (c = 5.8). EI-MS m/z: 410 (M0+), 308, 279,
252, 179. EI-HRMS calcd. for C22H38O5Si: 410.2489 (M0+);
found: 410.2477 (M0+). IR (film) (cm–1): 3465, 1613, 1586,
1514, 1465, 1302, 1249, 1174, 1100, 1036, 931, 859, 836,
1
1103, 1006, 897, 864, 842, 775, 669. H NMR (400 MHz,
CDCl3) d: 9.57 (s, 1H), 3.59 (s, 2H), 1.04 (s, 6H), 0.86 (s,
9H), 0.03 (s, 6H). 13C NMR (101 MHz, CDCl3) d: 206.2,
68.4, 48.1, 25.8, 18.6, 18.2, –5.6. The crude aldehyde 48
was used directly in the next step without any further puri-
fication.
(3S,4S)-2,2-Dimethyl-1-(tert-butyldimethylsilyl)oxy-4-(2-
(trimethylsilyl)ethoxy)methoxy-5-hexen-3-ol (49)
sec-BuLi in hexanes (1.4 M, 20 mL, 0.028 mol) was
added over 10 min to Me3SiCH2CH2OCHsOCH2CH=CH2
(5.30 g, 0.028 mol) in THF (75 mL) at –78°C. The resulting
yellow mixture was stirred at –78°C for a further 30 min,
then (+)-B-methoxydiisopinocampheylborane (9.74 g, 0.031
mol) in Et2O (30 mL) was added dropwise over 20 min to
yield a colorless solution. After a further 20 min at –78°C,
BF3·OEt2 (4.9 mL, 0.0389 mol) was added immediately fol-
lowed by the dropwise addition of aldehyde 48 (6.50 g,
0.026 mol) in Et2O (30 mL). This viscous mixture was stirred
for 4 h at –78°C and allowed to slowly warm to –40°C.
Ethanolamine (10 mL, 0.166 mol) was added and the mix-
ture allowed to warm up to room temperature and stirred for
1 h. Additional ethanolamine (10 mL) was added followed
by NaH dispersion in oil (50%, 50 mg). After stirring for
12 h, the mixture was extracted with EtOAc–Et2O (1:1,
500 mL), the extracts were washed with pH 7 buffer and
brine, and dried (MgSO4). Chromatography (hexanes–Et2O,
9:1) afforded alcohol 49 (6.28 g, 60%) as a colorless oil.
TLC Rf = 0.45 (hexanes–Et2O, 9:1). [a]2D2 = +74.1° (c =
2.35). EI-MS m/z: 405 ([M + H]+), 331, 289, 257, 217. EI-
HRMS calcd. for C17H35O4Si: 331.2305 ([M – SiMe3]+);
found: 331.2148 ([M – SiMe3]+). IR (film) (cm–1): 3500,
1
759, 694. H NMR (400 MHz, CDCl3) d: 7.27 (d, 2H, J =
9.3 Hz), 6.86 (d, 2H, J = 8.6 Hz), 5.95 (m, 1H), 5.30 (dm,
1H, J = 16.0 Hz), 5.26 (dm, 1H, J = 9.4 Hz), 4.73 (d, 1H,
J = 7.0 Hz), 4.69 (d, 1H, J = 11.0 Hz), 4.68 (d, 1H, J =
7.0 Hz), 4.50 (d, 1H, J = 11.0 Hz), 4.36 (dd, 1H, J = 7.4,
3.3 Hz), 3.79 (s, 3H), 3.78 (m, 1H), 3.50 (m, 3H), 3.35 (m,
3H), 2.82 (br t, 1H, J = 5 Hz), 1.02 (s, 3H), 0.97 (s, 3H), 0.9
(m, 2H), 0.00 (s, 9H). 13C NMR (101 MHz, CDCl3) d:
159.3, 137.0, 130.6, 129.3, 117.4, 113.8, 92.6, 87.4, 77.7,
75.3, 70.1, 65.9, 55.2, 40.4, 23.4, 22.4, 22.2, 18.1, –1.5.
Anal. calcd. for C22H38O5Si: C 64.35, H 9.33; found:
C 64.06, H 9.42. DCC (26 mg, 0.127 mmol) was added to
alcohol 51 (40 mg, 0.0976 mmol), (R)-(+)-a-methoxy-a-
(trifluoromethyl)phenylacetic acid (30 mg, 0.127 mmol), and
DMAP (3 mg) in dry CH2Cl2 (0.6 mL) at 0°C under Ar. Af-
ter stirring for 30 min at 0°C and 1.5 h at room temperature,
excess DCC was quenched with AcOH (0.1 mL). The mix-
ture was diluted with Et2O (30 mL), and the resulting insolu-
1
1473, 1389, 1251, 1099, 1025, 933, 837, 786. H NMR
(400 MHz, CDCl3) d: 5.94 (m, 1H), 5.25 (m, 2H), 4.73
(d, 1H, J = 7.0 Hz), 4.63 (d, 1H, J = 7.0 Hz), 4.22 (dd,
1H, J = 8.2, 2.4 Hz), 3.75 (m, 1H), 3.54 (d, 1H, J =
9.3 Hz), 3.52 (m, 1H), 3.48 (d, 1H, J = 2.7 Hz), 3.40 (d,
1H, J = 9.4 Hz), 1.02 (s, 3H), 0.93 (s, 3H), 0.89 (s, 9H),
© 2001 NRC Canada

1578
Can. J. Chem. Vol. 79, 2001
ble solid was removed by filtration. The filtrate was washed
with 10% aqueous NaHCO3 and brine, and the organic layer
was dried (MgSO4). Rotary evaporation and chromatography
(Et2O–hexanes, 1:2) gave (3S,4S)-3-(4-methoxybenzyl)oxy-
2,2-dimethyl-4-(2-trimethylsilylethoxy)-methoxy-5-hexen-1-yl-
(50 mL) at –78°C. After 20 min, alcohol 53 (4.90 g, 0.0116
mol) in CH2Cl2 (15 mL) was added dropwise over 10 min.
The mixture was stirred at –78°C for 40 min, then Et3N
(10 mL, 0.0717 mol) was added and the mixture allowed to
slowly warm up to room temperature. The solution was di-
luted with Et2O (200 mL), washed with pH 7 buffer and
brine, and dried (MgSO4). Chromatography (hexanes–Et2O,
4:1) gave ketone 54 (4.18 g, 85%) as a yellow oil. TLC Rf =
0.7 (hexanes–Et2O, 1:1). [a]2D3 = +23.9° (c = 5.5). FAB-MS
m/z: 445 ([M + Na]+), 437, 363, 303, 275, 252. EI-HRMS
calcd. for C23H38O5SiNa: 445.2386 ([M + Na]+); found:
445.2345 ([M + Na]+). IR (film) (cm–1): 1702, 1514, 1354,
1257, 1248, 1173, 1101, 1036, 934, 836. 1H NMR
(400 MHz, CDCl3) d: 7.25 (d, 2H, J = 8.7 Hz), 6.85 (d, 2H,
J = 8.7 Hz), 5.72 (m, 1H), 5.27 (m, 1H), 5.24 (m, 1H), 4.77
(d, 1H, J = 10.7 Hz), 4.64 (d, 1H, J = 6.9 Hz), 4.58 (d, 1H, J =
6.9 Hz), 4.51 (d, 1H, J = 10.7 Hz), 4.17 (dd, 1H, J = 8.2,
5.5 Hz), 3.80 (s, 3H), 3.75 (d, 1H, J = 5.6 Hz), 3.68 (m,
1H), 3.50 (m, 1H), 2.14 (s, 3H), 1.18 (s, 3H), 1.16 (s, 3H),
0.88 (apparent t, 2H), –0.02 (s, 9H). 13C NMR (101 MHz,
CDCl3) d: 212.7, 159.0, 136.1, 130.8, 129.2, 118.8, 113.6,
92.3, 85.9, 78.7, 75.6, 65.5, 55.2, 51.6, 27.1, 23.2, 21.1,
18.0, –1.5. Anal. calcd. for C23H38O5Si: C 65.36, H 9.06;
found: C 65.15, H 9.28.
(R)-(+)-a-methoxy-a-(trifluoromethyl)phenylacetate
(55)
(50 mg, 82%) as a colorless oil. 1H NMR (300 MHz,
CDCl3) d: 7.50–7.46 (m, 2H), 7.39–7.34 (m, 3H), 7.20 (d,
2H, J = 8.5 Hz), 6.83 (d, 2H, J = 8.5 Hz), 5.82 (ddd, 1H,
J = 17.5, 10.0, 7.5 Hz), 5.19–5.18 (m, 2H), 4.65 (d, 1H, J =
7.0 Hz), 4.64 (d, 1H, J = 10.5 Hz), 4.61 (d, 1H, J = 7.0 Hz),
4.32 (d, 1H, J = 10.5 Hz), 4.30 (d, 1H, J = 10.5 Hz), 4.24
(dd, 1H, J = 7.5, 3.5 Hz), 3.77 (s, 3H), 3.70 (dt, 1H, J = 9.5,
7.5 Hz), 3.50 (q, 3H, J = 1.0 Hz), 3.55–3.46 (m, 1H), 3.26
(d, 1H, J = 3.5 Hz), 1.02 (s, 3H), 1.00 (s, 3H), 0.97–0.83
(m, 2H), –0.04 (s, 3H). 13C NMR (101 MHz, CDCl3) d:
166.5, 159.3, 137.1, 132.5, 130.9, 129.8, 129.4, 128.6,
127.7, 118.1, 113.9, 92.4, 85.1, 77.8, 75.8, 73.0, 66.1, 55.5,
39.7, 22.1, 21.7, 18.3, –1.3.
(2R/S,4S,5S)-4-(4-Methoxybenzyl)oxy-3,3-dimethyl-5-((2-
trimethylsilyl)ethoxy)methoxy-6-hepten-2-ol (53)
DMSO (1.6 mL, 0.023 mol) in CH2Cl2 (3 mL) was added
dropwise to (COCl)2 (1.6 mL, 0.0183 mol) in CH2Cl2
(65 mL) at –78°C. After 30 min, alcohol 51 (5.65 g, 0.0138
mol) in CH2Cl2 (20 mL) was added over 10 min. Following
an additional 40 min at –78°C, Et3N (10 mL, 0.072 mol)
was added and the mixture allowed to warm to room temper-
ature. The solution was diluted with Et2O (300 mL) and
washed with pH 7 buffer (100 mL) and brine and dried
(MgSO4). Rotary evaporation gave aldehyde 52 (5.04 g,
89%) as a yellow oil, which was used directly in the next
step without any further purification. MeMgBr in Et2O
(3.0 M, 7.2 mL, 0.0216 mol) was added to aldehyde 52
(5.04 g, 0.0123 mol) in THF (20 mL) at –78°C. The mixture
was allowed to slowly warm to 0°C, then saturated aqueous
NH4Cl (10 mL) was cautiously added. The mixture was di-
luted with Et2O (200 mL), washed with H2O and brine, and
dried (MgSO4). Chromatography (hexanes–Et2O, 1:1) af-
forded alcohol 53 (4.96 g, 95%) as a colorless oil. TLC Rf =
0.5 (hexanes–Et2O, 1:1). FAB-MS m/z: 447 ([M + Na]+),
425 ([M + H]+), 293, 226, 199, 179. FAB-HRMS calcd. for
C23H40O5SiNa: 447.2543 ([M + Na]+); found: 447.2579 ([M +
Na]+). IR (film) (cm–1): 3467, 1613, 1609, 1515, 1466,
(2R,3R,4S,6R,8S,9S)-2-(2-(3,4-Dimethoxybenzyloxy)ethyl)-
8-ethenyl-9-(4-methoxybenzyl)oxy-3,10,10-trimethyl-1,7-
dioxaspiro[4.5]decan-4-ol (56a) and (2R,3R,4R,6R,8S,9S)-
2-(2-(3,4-dimethoxybenzyloxy)ethyl)-8-ethenyl-9-(4-
methoxybenzyl)oxy-3,10,10-trimethyl-1,7-
dioxaspiro[4.5]decan-4-ol (56b)
n-BuLi in hexanes (1.6 M, 4.0 mL, 6.39 mmol) was added
dropwise to i-Pr2NH (913 L, 6.51 mmol) in THF (8 mL) at
0°C. After 10 min, the mixture was cooled to –78°C and
ketone 54 (2.29 g, 5.43 mmol) in THF (11 mL) was added
dropwise. The mixture was stirred at –55 to –45°C for
15 min, cooled to –78°C, and then aldehyde 47 (1.66 g,
4.19 mmol) in THF (13 mL) was added. Following an addi-
tional 20 min at –78°C, the solution was allowed to warm
slowly to –25°C over 1 h. Saturated aqueous NH4Cl was
added and the mixture was allowed to warm to room temper-
ature. After dilution with Et2O (50 mL), the mixture was ex-
tracted with Et2O (2 × 100 mL), and the extracts were
washed with brine and dried (Na2SO4). Rotary evaporation
and chromatography (hexanes–EtOAc, 5:2) gave recovered
54 (440 mg) and the aldol product (3.39 g, 99%) as a color-
less oil. The aldol product was treated with TsOH·H2O
(960 mg) in MeOH (60 mL) for 1.5 h at 0°C and 4 h at room
temperature. After neutralization with Et3N (0.5 mL), rotary
evaporation and chromatography (hexanes–EtOAc, 1:1) gave
spiroketal 56a (1.10 g, 48%) and 56b (515 mg, 22%).
Spiroketal 56a was obtained as a colorless oil. TLC Rf = 0.40
(Et2O). [a]2D5 = +67.3° (c = 4.5). EI-MS m/z: 556 (M0+), 538,
435, 417, 405. EI-HRMS calcd. for C32H44O8: 556.3036
(M0+); found: 556.3033 (M0+). IR (film) (cm–1): 3519, 1611,
1515, 1465, 1420, 1414, 1302, 1248, 1119, 1111, 1071,
1
1390, 1255, 1249, 1173, 1101, 925, 836, 758, 702. H NMR
(400 MHz, CDCl3) d: 7.28 (d, 2H, J = 8.7 Hz), 6.87 (d, 2H,
J = 8.8 Hz), 5.98 (m, 1H), 5.29 (dm, 1H, J = 17.3 Hz), 5.24
(dm, 1H, J = 10.5 Hz), 4.74 (d, 1H, J = 6.9 Hz), 4.70 (d,
1H, J = 7.0 Hz), 4.48 (d, 1H, J = 10.8 Hz), 4.44 (m, 1H),
3.90 (m, 1H), 3.80 (s, 3H), 3.76 (m, 1H), 3.56 (m, 1H), 3.43
(d, 1H, J = 3.4 Hz), 3.41 (d, 1H, J = 3.5 Hz), 1.08 (d, 3H, J =
6.4 Hz), 0.96 (s, 3H), 0.92 (m, 2H), 0.89 (s, 3H), 0.01 (s,
9H). 13C NMR (75 MHz, CDCl3) d: 159.33, 159.25, 137.7,
137.0, 130.7, 130.4, 129.3, 117.6, 117.0, 113.9, 113.8, 92.9,
92.4, 90.3, 87.7, 77.5, 77.3, 75.9, 74.7, 71.6, 71.4, 66.0,
55.2, 43.5, 42.2, 23.0, 21.9, 19.8, 18.3, 18.2, 17.4, 17.3, –1.4.
1
1031, 887, 881, 788, 765. H NMR (300 MHz, CDCl3) d:
(4S,5S)-4-(4-Methoxybenzyl)oxy-3,3-dimethyl-5-((2-
trimethylsilyl)ethoxy)methoxy-6-hepten-2-one (54)
DMSO (1.3 mL, 0.0183 mol) in CH2Cl2 (3 mL) was
added dropwise to (COCl)2 (1.3 mL, 0.0149 mol) in CH2Cl2
7.27 (d, 2H, J = 8.6 Hz), 6.84 (d, 2H, J = 8.7 Hz), 6.80 (m,
3H), 6.02 (m, 1H), 5.23 (dm, 1H, J = 17.4 Hz), 5.10 (dm,
1H, J = 10 Hz), 4.63 (dd, 1H, J = 8.6, 6.4 Hz), 4.43 (d, 1H,
J = 11.0 Hz), 4.33 (d, 1H, J = 11.0 Hz), 4.30 (m, 1H), 4.14
© 2001 NRC Canada

Anderson et al.
1579
(d, 1H, J = 11.5 Hz), 4.02 (d, 1H, J = 11.4 Hz), 3.87 (s,
3H), 3.86 (s, 3H), 3.79 (br d, 1H), 3.72 (s, 3H), 3.50 (m,
3H), 1.8–1.5 (m, 4H), 1.13 (s, 3H), 0.94 (s, 3H), 0.82 (d, 3H,
J = 7.1 Hz). 13C NMR (75 MHz, CDCl3) d: 159.0, 149.0,
148.4, 136.7, 131.6, 130.8, 129.2, 119.9, 117.4, 113.5,
111.13, 111.07, 108.3, 88.1, 83.6, 73.9, 72.3, 71.1, 67.4,
63.2, 55.9, 55.8, 55.1, 50.6, 37.8, 33.0, 29.2, 23.7, 17.0,
10.8. Spiroketal 56b was obtained as a colorless oil. TLC
Rf = 0.25 (Et2O). [a]2D5 = +74.0° (c = 2.25). EI-MS m/z: 556
(M0+), 538, 435, 417, 405. EI-HRMS calcd. for C23H44O8:
556.3036 (M0+); found: 556.3066 (M0+). IR (film) (cm–1):
3438, 1611, 1515, 1466, 1450, 1363, 1248, 1139, 1104,
K-Selectride was quenched with MeOH (2 mL), and then
NaOH (3 M, 5 mL) and H2O2 (30%, 5 mL) were added. The
resulting aqueous mixture was stirred for 1.5 h at 0°C and
diluted with Et2O (100 mL). The ethereal layer was washed
with H2O (2 × 30 mL) and brine (50 mL) and dried
(Na2SO4). Rotary evaporation and chromatography (hex-
anes–EtOAc, 3:2) gave spiroketal 56a (1.12 g, 93%).
(2S)-3-(Benzyloxy)methoxy-2-methyl-1-propanol (60) (38)
PhCH2OCH2Cl (13.8 g, 0.088 mmol) was added to alco-
hol 58 (8.0 g, 0.067 mmol) and i-Pr2NEt (18.5 mL,
0.106 mmol) in CH2Cl2 (30 mL) at 0°C. The mixture was
subsequently stirred at room temperature for 12 h when
MeOH (15 mL) was added. The solution was diluted with
Et2O (200 mL), washed sequentially with 1 M HCl, H2O,
10% aqueous NaHCO3, and brine. The organic layer was
dried (MgSO4) and rotary evaporated to leave a colorless oil,
which was dissolved in Et2O (100 mL) and added to LiAlH4
(3.8 g, 1.0 mmol) in Et2O (150 mL) at 0°C. After stirring for
15 min at 0°C and 1 h at room temperature, excess LiAlH4
was quenched by the careful addition of MeOH. Following
further stirring for 30 min, H2O (15.2 mL) and aqueous
NaOH (15%, 4 mL) were added and, after 1 h, the insoluble
solid was removed by filtration. Rotary evaporation of the
filtrate and chromatography (hexanes–Et2O, 1:3) gave alco-
hol 60 (14.8 g, 100%).
1
1032, 992, 908, 788, 785. H NMR (300 MHz, CDCl3) d:
7.26, (d, 2H, J = 8.5 Hz), 6.84 (d, 2H, J = 8.5 Hz), 6.80 (m,
3H), 6.02 (m, 1H), 5.23 (dm, 1H, J = 17.2 Hz), 5.12 (dm,
1H, J = 10.0 Hz), 4.60 (dd, 1H, J = 8.6, 5.6 Hz), 4.43 (d,
1H, 10.9 Hz), 4.34 (d, 1H, J = 10.9 Hz), 4.19 (m, 1H), 4.17
(d, 1H, J = 11.5 Hz), 4.04 (d, 1H, J = 11.5 Hz), 4.00 (dm,
1H, J = 10.5 Hz), 3.87 (s, 3H), 3.85 (s, 3H), 3.73 (s, 3H),
3.55 (d, 1H, J = 5.6 Hz), 3.47 (m, 2H), 1.9–1.4 (m, 4H),
1.14 (s, 3H), 0.96 (s, 3H), 0.81 (d, 3H, J = 6.9 Hz). 13C
NMR (75 MHz, CDCl3) d: 159.1, 149.1, 148.5, 137.2, 131.6,
131.1, 129.2, 120.1, 117.1, 113.6, 111.3, 111.1, 108.3, 88.7,
83.1, 73.8, 72.5, 68.6, 67.6, 67.5, 56.0, 55.9, 55.2, 50.3,
38.4, 33.1, 32.2, 23.9, 17.0, 4.0.
(2R,3S,6R,8S,9S)-2-(2-(3,4-Dimethoxybenzyl)oxyethyl)-8-
ethenyl-9-(4-methoxybenzyl)oxy-3,10,10-trimethyl-1,7-
dioxaspiro[4.5]-decan-4-one (57)
Methyl (4S)-5-(benzyloxy)methoxy-4-methyl-2-pentenoate
(62)
From 56a: DMSO (243 L, 3.42 mmol) in CH2Cl2 (5 mL)
was added dropwise to (COCl)2 (230 L, 2.63 mmol) in
CH2Cl2 (5 mL) at –78°C. After 5 min, spiroketal 56a
(1.05 g, 1.88 mmol) in CH2Cl2 (12 mL) and, after 10 min,
Et3N (767 L, 5.5 mmol) were both slowly added. The mix-
ture was allowed to warm up to 0°C over 15 min and diluted
with Et2O (80 mL). The ethereal layer was washed with H2O
(2 × 30 mL) and brine and dried (Na2SO4). Rotary evapora-
tion and chromatography (hexanes–EtOAc, 3:2) gave ketone
57 (992 mg, 95%) as a colorless oil. TLC Rf = 0.6 (Et2O).
1H NMR (400 MHz, CDCl3) d: 7.27 (d, 2H, J = 9.5 Hz),
6.86 (d, 2H, J = 8.7 Hz), 6.79 (d, 2H, J = 8.0 Hz), 6.74 (m,
2H), 6.00 (m, 1H), 5.24 (dm, 1H, J = 16.2 Hz), 5.11 (dm,
1H, J = 10.0 Hz), 4.63 (dd, 1H, J = 8.6, 5.3 Hz), 4.44 (d,
1H, J = 10.9 Hz), 4.37 (d, 1H, J = 10.9 Hz), 4.32 (dm, 1H,
J = 10.6 Hz), 4.15 (d, 1H, J = 11.6 Hz), 4.02 (d, 1H, J =
11.3 Hz), 3.87 (s, 3H), 3.86 (s, 3H), 3.74 (s, 3H), 3.58 (d,
1H, J = 5.4 Hz), 3.50 (m, 2H), 2.57 (d, 1H, J = 14.2 Hz),
2.30 (m, 1H), 2.21 (d, 1H, J = 15.0 Hz), 1.85 (m, 1H), 1.24
(s, 3H), 1.08 (m, 1H), 1.07 (d, 3H, J = 7.2 Hz), 0.96 (s, 3H).
Alcohol 56b (515 mg, 0.926 mmol) was converted into 57
(510 mg, 100%) under identical Swern oxidation conditions.
The crude ketone from both experiments 57 was reduced di-
rectly without any further purification.
DMSO (9.5 g, 0.122 mol) in CH2Cl2 (80 mL) was added
dropwise to (COCl)2 (8.1 mL, 92.9 mmol) in CH2Cl2
(80 mL) at –78°C. After 10 min, alcohol 60 (14.0 g,
66.7 mmol) in CH2Cl2 (100 mL) was added, stirring was
continued for 15 min at –78°C and Et3N (33.7 mL, 0.241
mol) was slowly added. After stirring for 10 min, the result-
ing mixture was allowed to warm up to –10°C for 15 min,
diluted with CH2Cl2 (100 mL), and washed with H2O (3 ×
15 mL) and brine. The organic layer was dried (Na2SO4) and
rotary evaporated to leave the crude aldehyde 61, which was
used without further purification. Ph3P=CHCO2Me (29.0 g,
0.867 mmol) was added to the aldehyde in ClCH2CH2Cl
(200 mL) and the mixture was heated at 70°C for 16 h. After
rotary evaporation, the residue was diluted with Et2O
(200 mL). Filtration, rotary evaporation, and chromatogra-
phy (hexanes–EtOAc, 7:1) gave ester 62 (for the (R)-anti-
pode of 62, see ref. 39) (16.7 g, 95%) as a colorless oil.
[a]2D5 = –16° (c = 1.6). 1H NMR (300 MHz, CDCl3) d: 7.26–
7.25 (m, 5H), 6.95 (dd, 1H, J = 16.0, 7.0 Hz), 5.87 (dd, 1H,
J = 16.0, 1.5 Hz), 4.73 (s, 2H), 4.57 (s, 2H), 3.71 (s, 3H),
3.51 (d, 2H, J = 6.5 Hz), 2.66–2.57 (m, 1H), 1.08 (d, 3H,
J = 7.0 Hz). 13C NMR (75 MHz, CDCl3) d: 167.0, 151.3,
137.9, 128.5, 127.9, 127.8, 120.8, 94.8, 71.7, 69.5, 51.5,
36.8, 16.1.
(2R,3R,4S,6R,8S,9S)-2-[2-(3,4-Dimethoxybenzyloxy)ethyl]-
8-ethenyl-9-(4-methoxybenzyl)oxy-3,10,10-trimethyl-1,7-
dioxaspiro[4.5]decan-4-ol (56a)
Ketone 57 (1.25 g, 2.17 mmol) in THF (20 mL) was
added dropwise to K-Selectride in THF (0.5 M, 8.7 mL,
4.34 mmol) in THF (10 mL) at –78°C. After 2 h, the mix-
ture was allowed to warm up to –20°C over 20 min. Excess
(4S)-5-(Benzyloxy)methoxy-4-methyl-2-penten-1-ol (63)
Ester 62 (16.2 g, 61.4 mmol) in CH2Cl2 (100 mL) was
added dropwise to DIBAl-H in PhMe (1.5 M, 90 mL,
135 mmol) in CH2Cl2 (100 mL) at –78°C and, after 1 h, ex-
cess DIBAl-H was quenched with MeOH (30 mL). Stirring
was continued until H2 evolution ceased, then H2O (40 mL)
in THF (40 mL) was carefully added to the clear solution.
© 2001 NRC Canada

1580
Can. J. Chem. Vol. 79, 2001
This was allowed to warm up to 0°C over 15 min and the re-
sulting suspension stirred vigorously for 1.5 h. Filtration, ro-
tary evaporation, and chromatography (hexanes–EtOAc, 1:1)
gave alcohol 63 (for the (R)-antipode of 63, see ref. 40)
(14.3 g, 99%) as a colorless oil. 1H NMR (300 MHz,
CDCl3) d: 7.36–7.26 (m, 5H), 5.77–5.63 (m, 2H), 4.76 (s,
2H), 4.60 (s, 2H), 4.13–4.10 (m, 2H), 3.51 (dd, 1H, J = 9.5,
6.5 Hz), 3.46 (dd, 1H, J = 9.5, 6.5 Hz), 2.54–2.46 (m, 1H),
1.28 (t, 1H, J = 6.0 Hz), 1.06 (d, 3H, J = 7.0 Hz). The prod-
uct was used directly without further purification.
72.2, 70.2, 62.2, 39.0, 36.0, 11.7. The diol 65 was used di-
rectly in the next step. Diol 65 (15 g) was allowed to react
with (MeO)2CMe2 (20 mL) and pyridinium 4-toluene-
sulfonate (500 mg, 1.98 mmol) in PhH (100 mL) at room
temperature for 3 h. Et3N (ca. 1.0 mL) was added, and ro-
tary evaporation and chromatography (hexanes–Et2O, 1:1)
gave ether 66 (15.9 g, 100% from epoxide 64) as a colorless
oil. [a]2D5 = –11.7° (c = 13.8). EI-MS m/z: 294 (M0+), 279,
115, 91. EI-HRMS calcd. for C17H26O4: 294.1831 (M0+);
found: 294.1817 (M0+). IR (film) (cm–1): 3031, 1497, 1455.
1H NMR (300 MHz, CDCl3) d: 7.34–7.25 (m, 5H), 4.73 (s,
2H), 4.58 (s, 2H), 3.93 (dt, 1H, J = 11.5, 3.0 Hz), 3.89 (ddd,
1H, J = 8.5, 6.0, 2.5 Hz), 3.82 (ddd, 1H, J = 11.5, 5.5,
1.5 Hz), 3.58 (dd, 1H, J = 9.5, 6.0 Hz), 3.44 (dd, 1H, J =
9.5, 6.0 Hz), 1.79–1.63 (m, 2H), 1.41 (s, 3H), 1.34 (s, 3H),
1.37–1.30 (m, 1H), 0.96 (d, 3H, J = 7.0 Hz). 13C NMR
(75 MHz, CDCl3) d: 138.0, 128.5, 127.9, 127.7, 98.2, 94.9,
69.9, 69.5, 69.3, 60.1, 38.6, 30.0, 28.5, 19.3, 12.2. Anal.
calcd. for C17H26O4: C 69.36, H 8.90; found: C 69.24,
H 9.00.
(2S,3S)-2-[1-(Benzyloxy)methoxy-(2R)-propyl]-3-
(hydroxymethyl)oxirane (64)
L-(+)-Diethyl tartrate (1.9 g, 9.21 mmol) and alkene 63
(14.3 g, 60.6 mmol) in CH2Cl2 (50 mL) were added sequen-
tially to a suspension of powdered molecular sieves (3 Å,
8 g) in CH2Cl2 (50 mL). The mixture was cooled to –20°C
and Ti(O-i-Pr)4 (2.4 mL, 8.13 mmol) was added with stir-
ring. After 20 min at –20°C, t-BuOOH in 2,2,4-trimethyl-
pentane (3 M, 24 mL, 72.0 mmol) was added slowly and the
mixture stirred for 1.5 h at room temperature. The solution
was filtered through Celite, washing with CH2Cl2, and the
combined washings dried (Na2SO4). Rotary evaporation and
chromatography (hexanes–Et2O, 1:2) gave epoxide 64
(13.7 g, 90%) as a colorless oil. TLC Rf = 0.40 (hexanes–
EtOAc, 1:1). [a]2D5 = –26° (c = 4.35). EI-MS m/z: 221 ([M –
CH2OH]+), 191, 174, 91. EI-HRMS calcd. for C13H17O3:
(2R,3R)-3,5-Isopropylidenedioxy-2-methyl-propane-1-ol
(67)
Ether 66 (3.4 g, 11.5 mmol) in THF (10 mL) was added
dropwise to Na (630 mg, 27.3 mmol) in liquid NH3 (10 mL)
at –78°C. After 1 h, the mixture was allowed to warm to
room temperature, for the NH3 to vent, and then rotary evap-
orated. The residue was extracted with CH2Cl2, filtered, ro-
tary evaporated, and chromatographed (hexanes–Et2O, 1:1)
221.1178 ([M
–
CH2OH]+); found: 221.1182 ([M
–
CH2OH]+). IR (film) (cm–1): 3448, 1497, 1455. H NMR
(300 MHz, CDCl3) d: 7.37–7.29 (m, 5H), 4.75 (s, 2H), 4.60
(s, 2H), 3.89 (ddd, 1H, J = 12.5, 4.5, 2.5 Hz), 3.64 (ddd, 1H,
J = 12.5, 4.5, 2.5 Hz), 3.55–3.53 (m, 2H), 3.05 (dt, 1H, J =
4.5, 2.5 Hz), 2.90 (dd, 1H, J = 7.0, 2.5 Hz), 1.77 (sept, 1H,
J = 7.0 Hz), 1.67–1.64 (br m, 1H), 1.04 (d, 3H, J = 7.0 Hz).
13C NMR (75 MHz, CDCl3) d: 137.9, 128.6, 127.9, 127.8,
94.9, 70.4, 69.5, 62.0, 58.5, 58.0, 35.9, 13.6. Anal. calcd. for
C14H20O4: C 66.64, H 7.99; found: C 66.90, H 8.03.
1
to give alcohol 67 (2.09 g, 100%) as a colorless oil. [a]D25
=
–11° (c = 5.05). EI-MS m/z: 159 ([M – Me]+), 115. EI-
HRMS calcd. for C8H15O3: 159.1021 ([M – Me]+); found:
159.1025 ([M – Me]+). IR (film) (cm–1): 3425, 1461, 1382,
1
1271. H NMR (300 MHz, CDCl3) d: 4.05 (ddd, 1H, J =
12.0, 4.0, 2.5 Hz), 3.96 (dt, 1H, J = 11.5, 2.5 Hz), 3.86 (ddd,
1H, J = 11.5, 5.5, 2.5 Hz), 3.68 (ddd, 1H, J = 11.0, 7.5,
4.5 Hz), 3.55 (ddd, 1H, J = 11.0, 6.5, 4.0 Hz), 2.63 (dd, 1H,
J = 6.5, 4.5 Hz), 1.90–1.77 (m, 2H), 1.43 (s, 3H), 1.36 (s,
3H), 1.34–1.27 (m, 1H), 0.88 (d, 3H, J = 7.0 Hz). 13C NMR
(75 MHz, CDCl3) d: 98.4, 71.9, 65.2, 60.0, 39.3, 29.9, 26.9,
19.1, 11.6. Anal. calcd. for C9H18O3: C 62.04, H 10.41;
found: C 61.71, H 10.64.
(4R)-4-(1-(Benzyloxy)methoxy)-(2R)-propyl)-2,2-
dimethyl-1,3-dioxane (66)
Epoxide 64 (13.7 g, 0.0544 mmol) in THF (80 mL) was
added dropwise to Red-Al in PhMe (3.4 M, 22.6 mL,
76.8 mmol) in THF (80 mL) at –20°C. The solution was al-
lowed to warm to room temperature over 15 min and left at
this temperature for 3 h, after which excess Red-Al was
quenched with MeOH at 0°C. H2O (24 mL) and aqueous
NaOH (15%, 24 mL) were added, the mixture was stirred
for 1 h at room temperature, and the resulting insoluble solid
removed by filtration. The filtrate was evaporated under re-
duced pressure and the residue chromatographed (hexanes–
EtOAc, 1:5) to give the diol 65 (15.0 g) as a colorless oil.
TLC Rf = 0.38 (hexanes–EtOAc, 1:2). [a]2D5 = +3.3° (c =
6.85). EI-MS m/z: 255 ([M + H]+), 223 ([M – CH2OH]+),
205, 148. EI-HRMS calcd. for C13H19O3: 223.1334 ([M –
CH2OH]+); found: 223.1340 ([M – CH2OH]+). IR (film)
(2S)-(2,2-Dimethyl-1,3-dioxolan-(4R)-yl)propanal (68)
DMSO (1.8 mL, 25.4 mmol) in CH2Cl2 (15 mL) was
added to (COCl)2 (1.8 mL, 20.9 mmol) in CH2Cl2
(20 mL) at –78°C. After 5 min, alcohol 67 (2.8 g,
16.1 mmol) in CH2Cl2 (15 mL) was added and stirring
was continued for 10 min at –78°C, then Et3N (7.0 mL,
50.0 mmol) was added slowly. The solution was allowed to
warm to –20°C over 15 min and poured into H2O. The aque-
ous mixture was extracted with CH2Cl2 (2 × 100 mL) and the
extracts washed with H2O and brine. The organic layer was
dried (Na2SO4), rotary evaporated, and chromatographed
(hexanes–Et2O, 3:2) to give aldehyde 68 (2.65 g, 95%) as a
1
1
(cm–1): 3390, 1497, 1454. H NMR (300 MHz, CDCl3) d:
colorless oil. IR (film) (cm–1): 2993, 1725, 1458, 1382. H
7.32–7.23 (m, 5H), 4.71 (s, 2H), 4.56 (s, 2H), 3.98–3.92 (m,
1H), 3.83–3.77 (m, 2H), 3.61–3.54 (m, 2H), 2.92 (d, 1H, J =
4.0 Hz), 2.58 (br t, 1H, J = 4.5 Hz), 1.87–1.70 (m, 2H),
1.58–1.48 (m, 1H), 0.90 (d, 3H, J = 7.0 Hz). 13C NMR
(75 MHz, CDCl3) d: 138.5, 129.0, 128.4, 128.3, 95.4, 73.8,
NMR (300 MHz, CDCl3) d: 9.74 (d, 1H, J = 1.0 Hz), 4.24
(ddd, 1H, J = 12.0, 5.0, 2.5 Hz), 3.97 (dt, 1H, J = 12.0,
3.0 Hz), 3.84 (ddd, 1H, J = 12.0, 5.0, 1.5 Hz), 2.48–2.39 (m,
1H), 1.76–1.58 (m, 2H), 1.09 (d, 3H, J = 7.0 Hz). 13C NMR
(75 MHz, CDCl3) d: 204.1, 98.5, 68.8, 59.6, 50.7, 29.7, 28.0,
© 2001 NRC Canada

Anderson et al.
1581
19.0, 8.3. The unstable aldehyde 68 was used directly
without further purification.
anes–EtOAc, 3:1). [a]2D0 = +10° (c = 1.1). EI-MS m/z: 406
(M0+), 388, 270, 234, 229, 211, 163. EI-HRMS calcd. for
C23H34O6: 406.2350 (M0+); found: 406.2346 (M0+). IR (film)
(cm–1): 3536, 3449, 1611, 1586, 1510, 1452. 1H NMR
(300 MHz, CDCl3) d: 7.19 (d, 2H, J = 8.0 Hz), 6.82 (d, 2H,
J = 8.0 Hz), 6.05 (ddd, 1H, J = 17.5, 9.5, 8.0 Hz), 5.30 (dd,
1H, J = 17.5, 1.0 Hz), 5.26 (dd, 1H, J = 9.5, 1.0 Hz), 4.59
(dd, 1H, J = 8.0, 5.0 Hz), 4.55 (d, 1H, J = 12.5 Hz), 4.43 (br
d, 1H, J = 11.0 Hz), 4.29 (dd, 1H, J = 11.0, 2.0 Hz), 4.25
(d, 1H, J = 12.5 Hz), 3.82–3.73 (m, 4H), 3.78 (s, 3H), 3.48
(d, 1H, J = 5.0 Hz), 1.96–1.90 (m, 1H), 1.76 (br d, 1H, J =
14.0 Hz), 1.64–1.57 (m, 1H), 1.53 (br d, 1H, J = 14.0 Hz),
1.35–1.34 (m, 1H), 0.93 (s, 3H), 0.84 (d, 3H, J = 7.0 Hz),
0.81 (s, 3H). 13C NMR (75 MHz, CDCl3) d: 159.5, 135.7,
130.6, 129.6, 118.4, 113.7, 108.6, 86.1, 83.9, 73.3, 70.8,
69.6, 63.3, 55.3, 50.5, 38.4, 35.2, 29.0, 23.4, 17.4, 11.1.
Anal. calcd. for C23H34O6: C 67.95, H 8.43; found: C 67.60,
H 8.03. Diffraction data from a single crystal of 71 was ob-
tained on a Bruker P4 four-circle diffractometer operating in
the ꢁ–2ꢁ scan mode at –100°C. The unit cell constants were
obtained by refinement against the setting angles for 25 re-
flections widely distributed in reciprocal space. The diffrac-
tion pattern exhibited symmetry consistent with the space
group P212121 in the orthorhombic crystal system. The
structure was solved by direct methods and refined by full-
matrix least-squares.2 All non-hydrogen atoms were refined
with anisotropic thermal displacement parameters. Hydrogen
atoms were placed in idealized positions, with the exception
of H26 and H9, which were located in the difference Fourier
map and were refined independently with isotropic thermal
displacement parameters.
(2R,3R,4RS,6R,8S,9S)-8-Ethenyl-2-(2-hydroxyethyl)-9-(4-
methoxybenzyl)oxy-3,10,10-trimethyl-1,7-dioxaspiro[4.5]-
decan-4-ol (69)
n-BuLi in hexanes (1.6 M, 9.4 mL, 15.0 mmol) was added
dropwise to i-Pr2NH (2.1 mL, 15.0 mmol) in THF (15 mL)
at 0°C. The clear solution was stirred for 10 min at 0°C and
the cooled to –78°C, at which point ketone 54 (6.4 g,
15.2 mmol) in THF (30 mL) was slowly added over 10 min.
The mixture was stirred at –60 to –45°C for 20 min and
recooled to –78°C. Aldehyde 68 (2.6 g, 14.9 mmol) in THF
(15 mL) was added dropwise and the mixture stirred for
30 min at –78°C and then allowed to warm to –20°C. The
solution was poured into a mixture of saturated aqueous
NH4Cl and ice. The mixture was extracted with Et2O (3 ×
100 mL) and the organic phase washed with H2O and brine
and dried (Na2SO4). Rotary evaporation and chromatography
(hexanes–Et2O, 3:2) gave recovered ketone 54 (2.4 g, 38%)
and the aldol adduct (5.4 g, 61%; 96% allowing for recov-
ered 54). TsOH·H2O (100 mg, 0.526 mmol) was added to
this adduct (4.9 g, 8.25 mmol) in MeOH (100 mL) and the
mixture stirred for 3.5 h at room temperature. Et3N (3 mL)
was added, at which point rotary evaporation and chromatog-
raphy (hexanes–EtOAc, 1:2) gave spiroketal 69 (2.86 g, 85%)
as a mixture of diastereomeric alcohols, which were directly
oxidized to produce the corresponding ketone 70.
(2R,3R,4S,6R,8S,9S)-8-Ethenyl-2-(2-hydroxyethyl)-9-(4-
methoxybenzyl)oxy-3,10,10-trimethyl-1,7-dioxaspiro[4.5]-
decan-4-ol (71)
(2R,3R,4S,6R,8S,9S)-8-Ethenyl-9-(4-methoxybenzyl)oxy-
2-(triethylsilyl)oxyethyl-3,10,10-trimethyl-1,7-dioxaspiro-
[4.5]decan-4-ol (72)
DMSO (716 L, 10.1 mmol) in CH2Cl2 (7.5 mL) was
added to (COCl)2 (732 L, 8.39 mmol) in CH2Cl2 (10 mL)
at –78°C. After stirring for 5 min, the diastereomeric alco-
hols 69 (1.31 g, 3.23 mmol) in CH2Cl2 (10 mL) were added
and stirring was continued for 10 min at –78°C. Et3N
(2.8 mL, 20.1 mmol) was added slowly, the solution was al-
lowed to warm up to –20°C over 15 min and then poured
into H2O. The aqueous mixture was extracted with CH2Cl2
(2 × 100 mL) and the extracts washed with H2O and brine.
The organic layer was dried (Na2SO4) and rotary evaporated
to give the crude keto-aldehyde 70 (1.25 g). This compound
in THF (25 mL) was added dropwise to K-Selectride in THF
(0.5 M, 17 mL, 8.5 mmol) in THF (10 mL) at –78°C. The
mixture was stirred for 2 h at –78°C and excess K-Selectride
quenched with MeOH (10 mL). The solution was allowed to
warm up to –10°C and aqueous NaOH (15%, 8 mL) and aque-
ous H2O2 (30%, 10 mL) were added sequentially at –5°C. The
resulting alkaline mixture was vigorously stirred for 2 h at
0°C when it was extracted with CH2Cl2 (10 mL) and the ex-
tract washed with H2O and brine and dried (Na2SO4.). Ro-
tary evaporation and chromatography (hexanes–EtOAc, 1:2)
gave diol 71 (0.997 g, 76% from 69) as colorless crystals:
mp 96.5–98°C (from EtOAc–hexanes). TLC Rf = 0.41 (hex-
Et3SiCl (509 L, 3.03 mmol) was slowly added over 1.5 h
to diol 71 (1.1 g, 2.71 mmol), Et3N (0.7 mL), and imidazole
(454 mg, 6.67 mmol) in dry CH2Cl2 (30 mL) at –40°C (Ar).
After the mixture was stirred for 2 h at –20°C, excess re-
agent was quenched with MeOH (1.0 mL) and the resultant
mixture diluted with CH2Cl2 (50 mL). The solution was
washed with H2O and brine and dried (Na2SO4). Rotary
evaporation and chromatography (hexanes–EtOAc, 5:1) gave
72 (1.1 g, 78%) as a colorless oil. TLC Rf = 0.39 (hexanes–
Et2O, 1:1). [a]2D0 = +49.0° (c = 2.35). EI-MS m/z: 520 (M0+),
484, 429, 401, 317, 289, 241. EI-HRMS calcd. for
C29H48O6Si: 520.3220 (M0+); found: 520.3213 (M0+). IR
(film) (cm–1): 3535, 2953, 1613, 1587, 1514, 1466. 1H NMR
(300 MHz, CDCl3) d: 7.20 (d, 2H, J = 8.5 Hz), 6.82 (d, 2H,
J = 8.5 Hz), 6.11 (ddd, 1H, J = 17.5, 10.0, 9.0 Hz), 5.20
(dd, 1H, J = 17.5, 1.0 Hz), 5.17 (dd, 1H, J = 10.0, 1.0 Hz),
4.58 (dd, 1H, J = 9.0, 6.0 Hz), 4.45 (d, 1H, J = 12.0 Hz),
4.28 (d, 1H, J = 12.0 Hz), 4.29–4.24 (m, 1H), 3.80 (d, 1H,
J = 10.0 Hz), 3.80–3.64 (m, 3H), 3.78 (s, 3H), 3.47 (d, 1H,
J = 6.0 Hz), 1.78–1.41 (m, 5H), 1.03 (s, 3H), 0.91 (t, 9H,
2 Supplementary material may be purchased from the Depository of Unpublished Data, Document Delivery, CISTI, National Research Council
Canada, Ottawa, ON K1A 0S2, Canada. For information on obtaining material electronically go to http://www.nrc.ca/cisti/irm/unpub_e.shtml.
Crystallographic information has also been deposited with the Cambridge Crystallographic Data Centre. Copies of the data can be obtained,
free of charge, on application to the Director, CCDC, 12 Union Road, Cambridge CB2 1EZ, U.K. (fax: 44-1223-336033 or e-mail:
deposit@ccdc.cam.ac.uk).
© 2001 NRC Canada

1582
Can. J. Chem. Vol. 79, 2001
J = 8.0 Hz), 0.87 (s, 3H), 0.81 (d, 3H, J = 7.0 Hz), 0.53 (q,
6H, J = 8.0 Hz). 13C NMR (75 MHz, CDCl3) d: 159.2,
137.1, 131.0, 129.3, 117.6, 113.7, 108.5, 87.6, 83.9, 73.7,
71.3, 63.3, 60.4, 55.4, 50.6, 38.1, 36.5, 29.4, 24.1, 17.3,
11.1, 7.0, 4.7. Anal. calcd. for C29H48O6Si: C 66.88, H 9.29;
found: C 67.13, H 9.29.
(2R,3R,4S,6R,8S,9S)-4-(tert-Butyldimethylsilyl)oxy-2-
(tert-butyldimethylsilyl)oxyethyl-8-ethenyl-9-(4-
methoxybenzyl)oxy-3,10,10-trimethyl-1,7-
dioxaspiro[4.5]decane (75)
2,6-Lutidine (1.35 mL, 11.6 mmol) and t-BuMe2SiOTf
(739 L, 3.22 mmol) were added to diol 71 (328 mg,
0.808 mmol) in CH2Cl2 (5.0 mL) at –10°C. After 1 h at –5°C,
the mixture was quenched with MeOH (2 mL), diluted with
Et2O (10 mL), washed with H2O and brine, and dried
(Na2SO4). Rotary evaporation and chromatography (hex-
anes–PhMe, 1:2) gave spiroketal 75 (475 mg, 90%) as a col-
orless oil. [a]2D5 = +58.3° (c = 0.23). IR (film) (cm–1): 1614,
1513, 1471, 1252, 1115, 1086, 917, 899, 773. 1H NMR
(300 MHz, CDCl3) d: 7.24 (d, 2H, J = 8.5 Hz), 6.84 (d, 2H,
J = 8.5 Hz), 6.08 (m, 1H), 5.19 (dd, 1H, J = 17.3, 1.4 Hz),
5.09 (dd, 1H, J = 10.0, 1.9 Hz), 4.54 (m, 1H), 4.48 (d, 1H,
J = 11.5 Hz), 4.42 (m, 1H), 4.31 (d, 1H, J = 11.5 Hz), 3.81
(m, 1H), 3.79 (s, 3H), 3.81–3.64 (m, 2H), 3.46 (d, 1H, J =
5.9 Hz), 1.67 (m, 1H), 1.61 (dd, 1H, J = 14.0, 3.6 Hz), 1.48–
1.38 (m, 2H), 1.37 (dd, 1H, J = 14.0, 2.0 Hz), 1.04 (s, 3H),
0.88 (s, 18H), 0.85 (s, 3H), 0.81 (d, 3H, J = 7.1 Hz), 0.02 (s,
3H), 0.00 (s, 9H). 13C NMR (75 MHz, CDCl3) d: 158.8,
138.1, 131.4, 129.0, 115.7, 113.5, 106.8, 88.1, 82.5, 73.3,
71.0, 63.1, 61.0, 55.2, 50.8, 38.7, 36.4, 30.6, 26.0, 25.8,
24.1, 18.3, 18.1, 17.3, 10.6, –4.5, –4.8, –5.2, –5.3.
(2R,3R,4S,6R,8S,9S)-4-(tert-Butyldimethylsilyl)oxy-8-
ethenyl-9-(4-methoxybenzyl)oxy-2-(triethylsilyl)oxyethyl-
3,10,10-trimethyl-1,7-dioxaspiro[4.5]decane (73)
t-BuMe2SiOSO2CF3 (477 L, 2.08 mmol) was added to
72 (900 mg, 1.73 mmol) and i-Pr2NEt (906 L, 5.2 mmol) in
dry CH2Cl2 (10 mL) at –50°C (Ar). The reaction mixture
was allowed to warm to –20°C during 1.5 h. After excess re-
agent was quenched with MeOH (2.0 mL), the mixture was
rotary evaporated and then chromatographed (hexanes–
EtOAc, 11:1) to give 73 (1.11 g, 100%) as a colorless oil.
TLC Rf = 0.43 (hexanes–Et2O, 11:1). [a]2D0 = +55° (c =
1.35). EI-MS m/z: 634 (M0+), 577, 502, 484, 457, 441, 385.
EI-HRMS calcd. for C35H62O6Si2: 634.4085 (M0+); found:
634.4075 (M0+). IR (film) (cm–1): 2953, 1614, 1587, 1515,
1
1464, 1422. H NMR (300 MHz, CDCl3) d: 7.21 (d, 2H, J =
8.5 Hz), 6.82 (d, 2H, J = 8.5 Hz), 6.06 (ddd, 1H, J = 17.5,
10.0, 8.0 Hz), 5.16 (dd, 1H, J = 17.5, 1.0 Hz), 5.06 (dd, 1H,
J = 10.0, 1.0 Hz), 4.49 (dd, 1H, J = 8.0, 6.0 Hz), 4.46 (d,
1H, J = 12.0 Hz), 4.37 (dt, 1H, J = 9.0, 3.0 Hz), 4.29 (d,
1H, J = 12.0 Hz), 3.78 (s, 3H), 3.81–3.73 (m, 2H), 3.65–
3.57 (m, 1H), 3.44 (d, 1H, J = 6.0 Hz), 1.71–1.55 (m, 2H),
1.44–1.32 (m, 3H), 1.01 (s, 3H), 0.91 (t, 9H, J = 8.0 Hz),
0.85 (s, 9H), 0.79 (d, 3H, J = 7.0 Hz), 0.53 (q, 6H, J =
8.0 Hz), –0.01 (s, 3H), –0.02 (s, 3H). 13C NMR (75 MHz,
CDCl3) d: 159.0, 138.2, 131.5, 129.1, 115.7, 113.6, 106.9,
88.2, 82.6, 73.5, 71.2, 63.4, 61.0, 55.3, 50.9, 38.8, 36.6, 30.7,
25.9, 24.2, 18.2, 17.4, 10.7, 7.0, 4.7, –4.4, –4.7. Anal. calcd.
for C35H62O6Si2: C 66.20, H 9.84; found: C 66.48, H 9.95.
(2R,3R,4S,6R,8R,9S)-4-(tert-Butyldimethylsilyl)oxy-2-
(tert-butyldimethylsilyl)oxyethyl-9-(4-methoxybenzyl)oxy-
3,10,10-trimethyl-1,7-dioxaspiro[4.5]decane-8-
carboxaldehyde (6)
Ozone was bubbled through spiroketal 75 (83.5 mg,
0.128 mmol) in CH2Cl2 (4 mL) at –78°C for 1 min, then
Me2S (1 mL) was immediately added. The solution was
purged with N2 and allowed to warm to room temperature.
After 1 h, the mixture was filtered through Na2SO4, rotary
evaporated, and chromatographed (hexanes–Et2O, 9:1) to
give spiroketal 6 (72.5 mg, 89%) as a pale yellow oil.
[a]2D5 = +72.9° (c = 0.17). IR (film) (cm–1): 1726, 1614,
(2R,3R,4S,6R,8R,9S)-4-(tert-Butyldimethylsilyl)oxy-9-(4-
methoxybenzyl)oxy-2-(triethylsilyl)oxyethyl-3,10,10-
1
1516, 1466, 1386, 1252, 1128, 1113, 1083, 835, 775. H
trimethyl-1,7-dioxaspiro[4.5]decane-8-carboxaldehyde (74)
O3–O2 was bubbled through alkene 73 (43 mg,
0.0726 mmol) in CH2Cl2 (3 mL) at –78°C. The solution, sat-
urated with O3, was stirred for 10 min and purged with Ar
when Me2S (1 mL) was added and the mixture was allowed
to warm up to room temperature over 1 h. Rotary evapora-
tion and chromatography (hexanes–Et2O, 7:1) gave 74
(35 mg, 76%) as a colorless oil. TLC Rf = 0.50 (hexanes–
Et2O, 4:1). [a]20 = +97° (c = 1.64). EI-MS m/z: 636 (M0+),
608, 579, 441,D339, 163. EI-HRMS calcd. for C34H60O7Si2:
636.3878 (M0+); found: 636.3888 (M0+). IR (film) (cm–1):
NMR (300 MHz, CDCl3) d: 9.65 (d, 1H, J = 3.0 Hz), 7.15
(d, 2H, J = 8.5 Hz), 6.80 (d, 2H, J = 8.5 Hz), 4.66 (m, 1H),
4.38 (d, 1H, J = 11.0 Hz), 4.36 (dd, 1H, J = 6.5, 3.0 Hz),
4.28 (d, 1H, J = 11.0 Hz), 3.84 (m, 1H), 3.76 (s, 3H), 3.75
(d, 1H, J = 6.5 Hz), 3.59 (m, 1H), 3.49 (m, 1H), 1.66 (dd,
1H, J = 14.0, 3.5 Hz), 1.57 (m, 1H), 1.45 (dd, 1H, J = 14.0,
2.5 Hz), 1.48–1.34 (m, 2H), 1.04 (s, 3H), 0.85 (s, 9H), 0.83
(s, 9H), 0.80 (d, 3H, J = 7.1 Hz), 0.80 (s, 3H), 0.00 (s, 3H),
–0.01 (s, 3H), –0.03 (s, 3H), –0.05 (s, 3H). 13C NMR
(75 MHz, CDCl3) d: 206.0, 159.0, 130.4, 129.5, 113.5, 109.1,
88.8, 84.9, 74.0, 70.6, 62.9, 59.4, 55.2, 50.7, 38.5, 36.3, 30.3,
25.9, 25.7, 23.5, 18.2, 18.0, 16.8, 10.5, –4.6, –4.9, –5.4.
1
2953, 1723, 1613, 1514, 1464, 1385. H NMR (300 MHz,
CDCl3) d: 9.63 (d, 1H, J = 3.0 Hz), 7.16 (d, 2H, J = 8.5 Hz),
6.81 (d, 2H, J = 8.5 Hz), 4.63 (dt, 1H, J = 9.5, 2.5 Hz), 4.39
(d, 1H, J = 11.0 Hz), 4.35 (dd, 1H, J = 6.5, 3.0 Hz), 4.28 (d,
1H, J = 11.0 Hz), 3.83 (q, 1H, J = 3.0 Hz), 3.77 (s, 3H),
3.75 (d, 1H, J = 6.5 Hz), 3.59–3.54 (m, 2H), 1.69–1.54 (m,
1H), 1.47–1.41 (m, 2H), 1.03 (s, 3H), 0.89 (t, 9H, J =
8.0 Hz), 0.87 (s, 9H), 0.81 (d, 3H, J = 7.0 Hz), 0.79 (s, 3H),
0.50 (q, 6H, J = 8.0 Hz), 0.00 (s, 3H), –0.01 (s, 3H). 13C
NMR (75 MHz, CDCl3) d: 206.1, 159.2, 130.4, 129.6, 113.6,
109.2, 88.8, 85.0, 74.1, 70.7, 63.2, 59.5, 55.3, 50.9, 38.6,
36.4, 30.4, 25.8, 23.6, 18.1, 17.0, 10.6, 6.9, 4.6, –4.4, –4.8.
(2R,3R,4S,6R,8S,9S)-4-(tert-Butyldimethylsilyl)oxy-2-
(tert-butyldimethylsilyl)oxyethyl-((1S,4S,5S,6S)-5-(tert-
butyldimethylsilyl)oxy-1-hydroxy-10-iodo-3-oxo-4,6,8,9-
tetramethyldeca–7,9-dien-1-yl)-9-(4-methoxybenzyl)oxy-
3,10,10-trimethyl-1,7-dioxaspiro[4.5]decane (76)
n-BuLi in hexanes (2.5 M, 94.3 L, 0.236 mmol) was
added dropwise to (Me3Si)2NH (54.9 L, 0.260 mmol) in
THF (0.5 mL) at –30°C and the mixture stirred at –20°C for
20 min and then cooled to –78°C. Ketone 5 (106 mg,
© 2001 NRC Canada

Anderson et al.
1583
0.236 mmol) in THF (1.5 mL) was added over 7 min and the
mixture stirred for an additional 7 min at –78°C. Aldehyde 6
(140 mg, 0.219 mmol) in THF (1.25 mL) was added over
7 min and the mixture left for 7 min at –78°C. The mixture
was quenched with saturated aqueous NH4Cl (1.0 mL) and
allowed to warm up to room temperature over 2 h. The solu-
tion was diluted with Et2O (10 mL), washed with H2O
(1 mL) and brine (1 mL), and dried (Na2SO4). Rotary evapo-
ration and chromatography (hexanes–Et2O, 9:1) gave ketone
10.5 Hz), 2.03 (s, 3H), 1.78 (s, 3H), 1.77–1.67 (m, 1H),
1.41–1.21 (m, 4H), 0.97 (d, 3H, J = 7.0 Hz), 0.97 (s, 3H),
0.91–0.77 (m, 18H), 0.88 (s, 9H), 0.84 (s, 9H), 0.50 (q, 6H,
J = 8.0 Hz), 0.07 (s, 3H), 0.00 (s, 3H),–0.01 (s, 3H), –0.03
(s, 3H). 13C NMR (75 MHz, CDCl3) d: 214.9, 159.1, 148.2,
133.7, 131.5, 130.5, 129.5, 113.8, 107.0, 86.8, 82.2, 78.8,
76.1, 74.8, 71.0, 67.0, 64.2, 61.7, 55.4, 52.7, 51.1, 47.7,
38.8, 36.6, 36.0, 30.4, 26.4, 26.0, 23.8, 22.8, 18.8, 18.6,
18.1, 17.5, 14.6, 13.0, 10.7, 7.0, 4.5, -3.6, –4.1, –4.5, –5.0.
DDQ (3.4 mg, 16.6 mol) was added to spiroketal 77
(15.0 mg, 13.8 mol) and molecular sieves (3 Å, 10 mg) in
CH2Cl2 (1 mL) at –20°C. The mixture was allowed to warm
to 0°C and stirred for 10 min when it was diluted with Et2O
and quenched with saturated aqueous NaHCO3. The organic
phase was washed with H2O (1 mL) and brine (1 mL) and
dried (Na2SO4). Rotary evaporation and chromatography
(hexanes–Et2O, 6:1) gave acetal 78 (7.0 mg, 49%) as a col-
orless oil. TLC Rf = 0.44 (2 developments, hexanes–Et2O,
7:1). 1H NMR (300 MHz, CDCl3) d: 7.40 (d, 2H, J =
8.5 Hz), 6.83 (d, 2H, J = 8.5 Hz), 6.23 (s, 1H), 5.77 (d, 1H,
J = 9.0 Hz), 5.52 (s, 1H), 4.21–4.14 (m, 2H), 4.04 (dd, 1H,
J = 9.0, 6.0 Hz) 3.93 (dd, 1H, J = 6.5, 2.5 Hz), 3.77 (s, 3H),
3.74 (d, 1H, J = 6.0 Hz), 3.77–3.73 (m, 1H), 3.60–3.52 (m,
1H), 3.49–3.41 (m, 1H), 2.83 (dd, 1H, J = 15.5, 3.0 Hz),
2.68 (dq, 1H, J = 7.0, 6.5 Hz), 2.60 (dd, 1H, J = 15.5,
8.0 Hz), 2.47 (dq, 1H, J = 7.0, 2.5 Hz), 2.00 (s, 3H), 1.70 (s,
3H), 1.66–1.37 (m, 5H), 1.09 (s, 3H), 0.90–0.79 (m, 39H),
0.49 (q, 6H, J = 8.0 Hz), 0.03 (s, 3H), 0.01 (s, 3H), –0.02 (s,
3H), –0.05 (s, 3H).
76 (181 mg, 76% from 6) as a pale yellow oil. [a]D20
=
+22.4° (c = 0.17). FAB-HRMS (NaI added) calcd. for
C53H95IO9Si3Na: 1109.5226 ([M + Na]+); found: 1109.5277
([M + Na]+). IR (film) (cm–1): 3560, 1707, 1613, 1514,
1
1464, 1384, 1361, 1251, 1110, 1083, 1023, 836, 776. H
NMR (300 MHz, CDCl3) d: 7.29 (d, 2H, J = 8.6 Hz), 6.87
(d, 2H, J = 8.6 Hz), 6.32 (s, 1H), 5.92 (d, 1H, J = 9.5 Hz),
4.61 (d, 1H, J = 11.5 Hz), 4.54 (d, 1H, J = 11.5 Hz), 4.33
(m, 1H), 4.04 (m, 2H), 3.90 (dd, 1H, J = 9.6, 5.7 Hz), 3.84
(m, 1H), 3.80 (s, 3H), 3.77 (m, 1H), 3.64 (d, 1H, J =
5.7 Hz), 3.38 (m, 1H), 3.20 (d, 1H, J = 18.0 Hz), 3.17 (m,
1H), 2.65 (m, 1H), 2.62 (m, 1H), 2.45 (dd, 1H, J = 18.5,
10.3 Hz), 2.07 (s, 3H), 1.82 (s, 3H), 1.76 (m, 1H), 1.61 (dd,
1H, J = 14.0, 3.5 Hz), 1.46–1.36 (m, 2H), 1.28 (m, 1H), 1.02
(s, 3H), 1.00 (d, 3H, J = 6.9 Hz), 0.91 (s, 9H), 0.88 (s, 3H),
0.87 (s, 9H), 0.86 (s, 9H), 0.84 (s, 3H), 0.81 (d, 3H, J =
7.1 Hz), 0.10 (s, 3H), 0.03 (s, 3H), 0.01 (s, 3H), 0.00 (s,
3H), –0.03 (s, 6H). 13C NMR (75 MHz, CDCl3) d: 214.7,
159.0, 148.0, 133.6, 131.4, 130.3, 129.2, 113.7, 106.9, 86.8,
82.0, 78.7, 76.0, 74.7, 70.9, 66.8, 64.2, 62.0, 55.2, 52.5,
51.0, 47.6, 38.6, 36.3, 35.8, 30.2, 26.2, 26.0, 25.8, 23.6, 22.7,
18.7, 18.3, 17.9, 17.3, 14.4, 12.9, 10.6, –3.8, –4.3, –4.7, –5.2,
–5.3, –5.5.
(2R,3R,4S,6R,8S,9S)-4-(tert-Butyldimethylsilyl)oxy-2-(tert-
butyldimethylsilyl)oxyethyl-((1S,3R,4S,5S,6S)-5-(tert-
butyldimethylsilyl)oxy-1,3-dihydroxy-10-iodo-4,6,8,9-
tetramethyldeca-7,9-dien-1-yl)-9-(4-methoxybenzyl)oxy-
3,10,10-trimethyl-1,7-dioxaspiro[4.5]decane (79) and
(2R,3R,4S,6R,8S,9S)-4-(tert-butyldimethylsilyl)oxy-2-(tert-
butyldimethylsilyl)oxyethyl-((1S,3S,4S,5S,6S)-5-(tert-
butyldimethylsilyl)oxy-1,3-dihydroxy-10-iodo-4,6,8,9-
tetramethyldeca-7,9-dien-1-yl)-9-(4-methoxybenzyl)oxy-
3,10,10-trimethyl-1,7-dioxaspiro[4.5]decane (80)
LiAlH4 in THF (1 M, 76 L, 79 mol) was added
dropwise to ketone 76 (20.9 mg, 19.0 mol) in THF (1 mL)
at –78°C. After 1 h, the mixture was quenched with H2O
(100 L) and allowed to warm to room temperature. The so-
lution was diluted with CH2Cl2 and Celite and anhydrous
Na2SO4 were added with vigorous stirring. After 30 min, the
mixture was filtered through Celite with CH2Cl2. Rotary
evaporation and chromatography (hexanes–Et2O, 5:1) gave
diol 80 (3.1 mg, 15%) and diol 79 (15.0 mg, 73%) both as
pale yellow oils. Data for diol 80: TLC Rf = 0.46 (hexanes–
Et2O, 5:1). [a]2D4 = +29.7° (c = 0.28). FAB-HRMS (NaI
added) calcd. for C53H97IO9Si3Na: 1111.5383 ([M + Na]+);
found: 1111.5403 ([M + Na]+). IR (film) (cm–1): 3508, 1514,
1471, 1252, 1111, 1080, 835, 773. 1H NMR (300 MHz,
CDCl3) d: 7.27 (d, 2H, J = 8.5 Hz), 6.87 (d, 2H, J = 8.5 Hz),
6.27 (s, 1H), 5.81 (d, 1H, J = 10.0 Hz), 4.71 (d, 1H, J =
11.3 Hz), 4.35 (d, 1H, J = 11.3 Hz), 4.35–4.17 (m, 2H),
4.03–4.00 (m, 2H), 3.80 (s, 3H), 3.82–3.58 (m, 5H), 2.89–
2.84 (m, 2H), 2.76 (m, 1H), 2.03 (s, 3H), 1.96 (m, 1H), 1.81
(s, 3H), 1.69 (m, 1H), 1.60–1.22 (m, 6H), 0.97 (d, 3H, J =
7.0 Hz), 0.93 (s, 3H), 0.90 (s, 9H), 0.89 (s, 3H), 0.87 (s,
(2R,3R,4S,6R,8S,9S)-4-(tert-Butyldimethylsilyl)oxy-2-
(triethylsilyl)oxyethyl-((1S,4S,5S,6S)-5-(tert-
butyldimethylsilyl)oxy-1-hydroxy-10-iodo-3-oxo-4,6,8,9-
tetramethyldeca-7,9-dien-1-yl)-9-(4-methoxybenzyl)oxy-
3,10,10-trimethyl-1,7-dioxaspiro[4.5]decane (77)
Ketone 5 (78 mg, 0.173 mmol) in dry THF (1 mL) was
slowly added to LiN(SiMe3)2 in THF (0.26 M, 665 L,
0.173 mmol), freshly prepared from HN(SiMe3)2 and n-BuLi
at –78°C (Ar). After 7 min, aldehyde 74 (99 mg,
0.156 mmol) in dry THF (1 mL) was added at –78°C. After
stirring for 30 min at –78°C, the mixture was allowed to
warm to –50°C over 15 min, then solid NH4Cl (100 mg) was
added and the mixture was diluted with Et2O (50 mL). The
mixture was washed with H2O and brine and dried
(Na2SO4). Rotary evaporation and chromatography (hex-
anes–Et2O, 9:1) gave 77 (73.5 mg, 43%) along with recov-
ered starting ketone 5 (43 mg, 54%) and aldehyde 74
(35 mg, 35%). The aldol adduct 77 was obtained as a color-
less oil. TLC Rf = 0.23 (hexanes–Et2O, 6:1). [a]2D0 = +22°
(c = 0.60). IR (film) (cm–1): 3571, 1706, 1614, 1514, 1463,
1
1382, 1302. H NMR (300 MHz, CDCl3) d: 7.26 (d, 2H, J =
8.5 Hz), 6.84 (d, 2H, J = 8.5 Hz), 6.28 (s, 1H), 5.88 (d, 1H,
J = 9.5 Hz), 4.57 (d, 1H, J = 11.5 Hz), 4.52 (d, 1H, J =
11.5 Hz), 4.31–4.25 (m, 1H), 4.01 (dd, 1H, J = 7.5, 2.0 Hz),
3.99 (dt, 1H, J = 9.0, 2.5 Hz), 3.88–3.73 (m, 3H), 3.77 (s,
3H), 3.60 (d, 1H, J = 5.5 Hz), 3.36 (dt, 1H, J = 10.0,
5.5 Hz), 3.15 (d, 1H, J = 2.5 Hz), 3.11 (dd, 1H, J = 18.5,
1.5 Hz), 2.64–2.54 (m, 2H), 2.41 (dd, 1H, J = 18.5,
© 2001 NRC Canada

1584
Can. J. Chem. Vol. 79, 2001
9H), 0.86 (s, 9H), 0.86 (m, 3H), 0.82 (d, 3H, J = 7.1 Hz),
0.12 (s, 3H), 0.06 (s, 6H), 0.00 (s, 9H). Data for diol 79:
TLC Rf = 0.54 (hexanes–Et2O, 5:1). [a]2D4 = +25.2° (c =
0.27). IR (film) (cm–1): 3489, 1514, 1471, 1252, 1109, 1080,
18.3, 18.2, 18.0, 17.3, 14.5, 10.6, 10.2, 4.0, – 4.5, –4.8, –5.0,
–5.2.
(2R,3R,4S,6R,8S,9S)-4-(tert-Butyldimethylsilyl)oxy-2-
(tert-butyldimethylsilyl)oxyethyl-8-((4S,6S)-((2S,3S,4S)-3-
(tert-butyldimethylsilyl)oxy-8-iodo-4,6,7-trimethylocta-
5,7-dien-2-yl)-2,2-dimethyl-1,3-dioxan-6-yl)-9-(4-meth-
oxybenzyl)oxy-3,10,10-trimethyl-1,7-dioxaspiro[4.5]-
decane (82)
1
970, 939, 899, 835, 739. H NMR (300 MHz, CDCl3) d:
7.25 (d, 2H, J = 8.6 Hz), 6.87 (d, 2H, J = 8.6 Hz), 6.20 (s,
1H), 5.97 (d, 1H, J = 9.7 Hz), 4.71 (d, 1H, J = 11.3 Hz),
4.33 (d, 1H, J = 11.3 Hz), 4.23 (m, 1H), 4.08 (m, 1H), 4.02
(dd, 1H, J = 4.5, 2.1 Hz), 3.88 (dd, 1H, J = 8.8, 6.2 Hz),
3.80 (s, 3H), 3.77 (m, 2H), 3.72 (d, 1H, J = 6.2 Hz), 3.60
(m, 1H), 3.47 (m, 1H), 3.18 (m, 1H), 2.74 (m, 1H), 2.11 (br
d, 1H, J = 14.5 Hz), 2.02 (s, 3H), 1.79 (s, 3H), 1.72–1.23
(m, 8H), 1.14 (s, 3H), 0.99 (d, 3H, J = 6.9 Hz), 0.91 (s,
9H), 0.87 (s, 9H), 0.85 (s, 3H), 0.84 (s, 9H), 0.82 (d, 3H,
J = 7.1 Hz), 0.74 (d, 3H, J = 7.0 Hz), 0.08 (s, 6H), 0.00 (s,
6H), –0.01 (s, 6H). 13C NMR (75 MHz, CDCl3) d: 159.4,
148.3, 133.2, 130.0, 129.6, 114.2, 107.1, 87.6, 82.4, 77.7,
76.2, 75.0, 74.5, 72.3, 70.8, 64.2, 61.8, 55.2, 51.1, 46.0,
39.3, 38.4, 36.3, 34.8, 30.2, 26.0, 25.9, 24.0, 22.6, 19.8,
18.30, 18.29, 17.5, 14.5, 12.0, 10.7, –4.0, –4.6, –4.7, –5.0,
–5.2, –5.3.
Ketal 82 (18 mg, 77%), which was prepared in an identi-
cal manner to that reported for ketal 81, was obtained as
a colorless oil. TLC Rf = 0.46 (hexanes–PhMe, 1:3). [a]26
=
–2.8° (c = 0.56). FAB-HRMS (NaI added) calcd. Dfor
C56H101IO9Si3Na: 1151.5696 ([M + Na]+); found: 1151.5679
([M + Na]+). IR (film) (cm–1): 1614, 1514, 1463, 1380, 1250,
1083, 1029, 836, 774. 1H NMR (400 MHz, CDCl3) d: 7.26 (d,
2H, J = 8.6 Hz), 6.84 (d, 2H, J = 8.6 Hz), 6.20 (s, 1H), 6.03
(d, 1H, J = 9.4 Hz), 4.56 (d, 1H, J = 11.5 Hz), 4.43 (d, 1H,
J = 11.5 Hz), 4.16 (m, 1H), 4.12 (m, 1H), 4.04 (dd, 1H, J =
9.6, 5.6 Hz), 3.92 (dt, 1H, J = 15.0, 5.0 Hz), 3.78 (s, 3H),
3.82–3.75 (m, 2H), 3.67 (dd, 1H, J = 5.0, 1.0 Hz), 3.56 (m,
1H), 3.55 (d, 1H, J = 5.7 Hz), 2.77 (m, 1H), 2.03 (br s, 3H),
1.90 (m, 1H), 1.83 (m, 1H), 1.81 (m, 1H), 1.77 (d, 3H, J =
0.8 Hz), 1.60 (dd, 1H, J = 14.0, 3.5 Hz), 1.58 (m, 1H), 1.46
(m, 1H), 1.41 (m, 1H), 1.34 (dd, 1H, J = 14.0, 2.0 Hz), 1.31
(s, 3H), 1.13 (s, 3H), 0.96 (d, 3H, J = 7.0 Hz), 0.96 (s, 3H),
0.93 (s, 9H), 0.87 (s, 9H), 0.86 (s, 9H), 0.84 (d, 3H, J =
7.1 Hz), 0.83 (s, 3H), 0.82 (d, 3H, J = 7.0 Hz), 0.08 (s, 6H),
0.02 (s, 3H), 0.00 (s, 3H), –0.04 (s, 3H), –0.05 (s, 3H). 13C
NMR (100 MHz, CDCl3) d: 158.5, 148.6, 132.7, 131.6, 131.2,
128.3, 113.4, 106.6, 99.9, 86.1, 82.9, 78.6, 77.5, 74.4, 70.8,
67.4, 65.1, 63.7, 61.8, 55.2, 50.9, 44.9, 36.7, 35.3, 35.2, 30.2,
26.0, 25.8, 25.2, 25.1, 23.6, 22.5, 20.2, 18.3, 18.2, 18.0, 17.1,
14.3, 10.5, 8.6, –4.1, –4.3, –4.6, –5.0, –5.2, –5.3.
(2R,3R,4S,6R,8S,9S)-4-(tert-Butyldimethylsilyl)oxy-2-
(tert-butyldimethylsilyl)oxyethyl-8-((4R,6S)-((2S,3S,4S)-3-
(tert-butyldimethylsilyl)oxy-8-iodo-4,6,7-trimethylocta-
5,7-dien-2-yl)-2,2-dimethyl-1,3-dioxan-6-yl)-9-(4-methoxy-
benzyl)oxy-3,10,10-trimethyl-1,7-dioxaspiro[4.5]decane (81)
Pyridinium toluene-4-sulfonate (6.5 mg, 26 L) was
added to diol 79 (28.4 mg, 26 mol) and 2-methoxy-
propene (50 L, 521 mol) in CH2Cl2 (1.0 mL) at 0°C and
the mixture stirred for 1 h at room temperature. Et3N
(0.1 mL) was added at 0°C, and the mixture was rotary
evaporated to 30% by volume, diluted with Et2O (10 mL),
washed with H2O (1 mL) and brine (1 mL), and dried
(Na2SO4). Rotary evaporation and chromatography (hex-
anes–PhMe, 1:2 to 1:3) gave ketal 81 (19.2 mg, 65%) as a
(2R,3R,4S,6R,8S,9S)-4-(tert-Butyldimethylsilyl)oxy-2-
(tert-butyldimethylsilyl)oxyethyl-((1S,3R,4S,5S,6S)-3,5-
di(tert-butyldimethylsilyl)oxy-1-hydroxy-10-iodo-4,6,8,9-
tetramethyldeca-7,9-dien-1-yl)-9-(4-methoxybenzyl)oxy-
3,10,10-trimethyl-1,7-dioxaspiro[4.5]decane (83)
t-BuMe2SiOTf (2.37 L, 6.61 mol) in dry CH3CN
(23.7 L) was added to diol 79 (6 mg, 5.3 mol) and 2,6-
lutidine (20.0 L, 0.17 mmol) in CH2Cl2–CH3CN (1:1,
0.8 mL) at –50°C. After 10 min, the solution was cooled to
pale yellow oil. TLC Rf = 0.66 (hexanes–Et2O, 6:1). [a]26
=
–6.5° (c = 0.18). FAB-HRMS (NaI added) calcd. Dfor
C56H101IO9Si3Na: 1151.5696 ([M + Na]+); found: 1151.5779
([M + Na]+). IR (film) (cm–1): 1614, 1514, 1463, 1379,
1
1252, 969, 774, 732, 669. H NMR (400 MHz, CDCl3) d:
7.26 (d, 2H, J = 8.6 Hz), 6.85 (d, 2H, J = 8.6 Hz), 6.22 (s,
1H), 6.00 (d, 1H, J = 9.4 Hz), 4.57 (d, 1H, J = 11.5 Hz),
4.39 (d, 1H, J = 11.5 Hz), 4.15 (m, 2H), 3.93 (dd, 1H, J =
5.0, 2.5 Hz), 3.91 (dd, 1H, J = 9.5, 5.5 Hz), 3.89 (dt, 1H, J =
10.0, 5.3 Hz), 3.80 (s, 3H), 3.76 (m, 1H), 3.68 (ddd, 1H, J =
11.5, 9.0, 2.5 Hz), 3.53 (d, 1H, J = 5.5 Hz), 3.51 (dt, 1H, J =
10.0, 6.0 Hz), 2.61 (ddt, 1H, J = 9.4, 7.0, 2.0 Hz), 2.03 (s,
3H), 1.89 (dt, 1H, J = 12.5, 2.5 Hz), 1.78 (br s, 3H), 1.73
(m, 1H), 1.71 (m, 1H), 1.58 (dd, 1H, J = 14.2, 3.6 Hz),
1.46 (m, 1H), 1.39 (m, 1H), 1.35 (s, 3H), 1.32 (m, 1H),
1.30 (s, 3H), 1.20 (q, 1H, J = 12.5 Hz), 0.94 (d, 3H, J =
7.0 Hz), 0.93 (s, 3H), 0.92 (s, 9H), 0.87 (s, 9H), 0.86 (s,
9H), 0.81 (d, 3H, J = 6.9 Hz), 0.80 (s, 3H), 0.77 (d,
3H, J = 7.1 Hz), 0.08 (s, 3H), 0.05 (s, 3H), 0.01 (s,
3H), –0.01 (s, 6H), –0.04 (s, 3H). 13C NMR (100 MHz,
CDCl3) d: 158.7, 148.5, 132.9, 131.7, 131.4, 129.0,
113.4, 106.8, 97.6, 86.2, 83.7, 77.7, 75.0, 74.5, 70.9,
70.8, 67.6, 63.8, 61.8, 55.2, 50.4, 45.5, 38.5, 36.5, 34.5,
33.7, 30.5, 30.2, 26.0, 25.93, 25.86, 23.6, 22.5, 19.9,
–78°C when additional t-BuMe2SiOTf (2.37
L,
6.61 mol) in dry CH3CN (23.7 L) was added. After
10 min, further t-BuMe2SiOTf (2.37 L, 6.61 mol) in dry
CH3CN (23.7 L) was added and, after a further 15 min,
the reaction mixture was quenched with precooled MeOH
at –78°C. The mixture was diluted with Et2O (10 mL),
washed with H2O (1 mL) and brine (1 mL), and dried
(Na2SO4). Rotary evaporation and chromatography (hex-
anes–Et2O, 24:1 to 15:1) gave alcohol 83 (4.7 mg, 74%) as
a colorless oil. [a]2D6 = +30.6° (c = 0.29). FAB-HRMS (NaI
added) calcd. for C59H111IO9Si4Na: 1225.6248 ([M +
Na]+); found: 1225.6307 ([M + Na]+). IR (film) (cm–1):
1
3480, 1514, 1471, 1252, 1078, 1030, 836, 775. H NMR
(300 MHz, CDCl3) d: 7.25 (d, 2H, J = 8.6 Hz), 6.81 (d, 2H,
J = 8.6 Hz), 6.23 (s, 1H), 5.96 (d, 1H, J = 9.3 Hz), 4.57
(d, 1H, J = 11.4 Hz), 4.51 (d, 1H, J = 11.4 Hz), 4.19 (m,
2H), 3.99 (m, 1H), 3.81 (m, 1H), 3.77 (s, 3H), 3.76 (m,
© 2001 NRC Canada

Anderson et al.
1585
1H), 3.69 (m, 2H), 3.60 (m, 1H), 3.58 (m, 1H), 3.47 (m,
1H), 2.57 (m, 1H), 2.01 (s, 3H), 1.75 (s, 3H), 1.87–1.08
(m, 8H), 1.01 (s, 3H), 0.95 (d, 3H, J = 7.0 Hz), 0.91 (s,
9H), 0.87 (s, 3H), 0.86 (s, 9H), 0.84 (s, 9H), 0.83 (s, 9H),
0.79 (d, 3H, J = 7.1 Hz), 0.71 (d, 3H, J = 7.1 Hz), 0.09 (s,
3H), 0.06 (s, 3H), 0.05 (s, 3H), 0.04 (s, 3H), 0.00 (s, 3H),
–0.01 (s, 3H), –0.06 (s, 3H), –0.07 (s, 3H). 13C NMR
(75 MHz, CDCl3) d: 158.9, 148.3, 132.7, 131.5, 131.1,
129.0, 113.6, 107.0, 87.4, 84.1, 78.1, 76.6, 74.1, 73.0, 71.2,
69.5, 64.4, 61.2, 55.2, 50.5, 46.3, 38.0, 35.9, 35.4, 31.0,
26.4, 26.0, 23.7, 22.6, 19.1, 18.5, 18.2, 17.9, 17.6, 14.4,
10.9, 10.2, –4.0, –4.1, –4.5, –4.8, –5.2.
(1 mL) and dried (Na2SO4). Rotary evaporation and chro-
matography (hexanes–Et2O, 16:1) gave alcohol 85
(30.6 mg, 97%) as a pale yellow oil. [a]2D5 = +45.0° (c =
0.24).
FAB-HRMS
(NaI
added)
calcd.
for
C59H111IO9Si4Na: 1225.624 8 ([M
+
Na]+); found:
1225.6286 ([M + Na]+). IR (film) (cm–1): 3526, 1614,
1515, 1471, 1252, 1106, 1071, 836, 775. 1H NMR
(300 MHz, CDCl3) d: 7.21 (d, 2H, J = 8.6 Hz), 6.81 (d,
2H, J = 8.6 Hz), 6.23 (s, 1H), 5.96 (d, 1H, J = 9.3 Hz),
4.49 (d, 1H, J = 11.3 Hz), 4.42 (d, 1H, J = 11.3 Hz), 4.34
(m, 1H), 4.17 (m, 1H), 3.98 (m, 1H), 3.92 (m, 1H), 3.75
(m, 1H), 3.75 (s, 3H), 3.52 (d, 1H, J = 5.5 Hz), 3.63–
3.47 (m, 2H), 3.43 (m, 1H), 3.28 (s, 1H), 2.56 (m, 1H),
2.00 (s, 3H), 1.78 (s, 3H), 1.69–1.12 (m, 8H), 0.99 (s,
3H), 0.96 (d, 3H, J = 7.1 Hz), 0.89 (s, 9H), 0.86 (s, 3H),
0.85 (s, 9H), 0.81 (s, 9H), 0.80 (s, 9H), 0.78 (d, 3H, J =
7.1 Hz), 0.69 (d, 3H, J = 6.8 Hz), 0.21 (s, 3H), 0.04 (s,
3H), 0.00 (s, 6H), –0.01 (s, 3H), –0.03 (s, 3H), –0.09 (s,
6H). 13C NMR (75 MHz, CDCl3) d: 159.2, 148.4, 133.3,
131.0, 130.1, 129.4, 113.8, 106.6, 89.3, 83.6, 78.0, 76.9,
74.8, 71.0, 68.7, 67.2, 64.5, 61.2, 55.2, 50.8, 45.4, 37.9,
36.6, 36.3, 35.8, 30.7, 26.6, 26.0, 23.8, 22.6, 18.7, 18.4,
18.1, 17.3, 14.4, 10.9, 9.9, –2.9, –3.7, –4.2, –4.4, –4.6, –4.8,
–5.3.
(2R,3R,4S,6R,8S,9S)-4-(tert-Butyldimethylsilyl)oxy-2-
(tert-butyldimethylsilyl)oxyethyl-((3R,4S,5S,6S)-3,5-
di(tert-butyldimethylsilyl)oxy-10-iodo-1-oxo-4,6,8,9-
tetramethyldeca-7,9-dien-1-yl)-9-(4-methoxybenzyl)oxy-
3,10,10-trimethyl-1,7-dioxaspiro[4.5]decane (84)
Dess-Martin periodinane (31) (28.4 mg, 6.7 mol) was
added to alcohol 83 (16.1 mg, 13.3 mol) in CH2Cl2 (1 mL).
After 40 min, the mixture was diluted with Et2O and quenched
with saturated aqueous NaHCO3 and saturated aqueous
Na2SO3 at 0°C. After vigorous stirring for 30 min, the or-
ganic phase was washed with H2O (1 mL) and brine (1 mL)
and dried (Na2SO4). Rotary evaporation and chromatography
(hexanes–PhMe, 2:5) gave ketone 84 (12.8 mg, 80%) as a
pale yellow oil. [a]2D6 = +50.7° (c = 0.15). FAB-HRMS (NaI
added) calcd. for C59H109IO9Si4Na: 1223.6091 ([M + Na]+);
found: 1223.6146 ([M + Na]+). IR (film) (cm–1): 1718,
(2R,3R,4S,6R,8S,9S)-4-(tert-Butyldimethylsilyl)oxy-2-
(tert-butyldimethylsilyl)oxyethyl-((1R,3R,4S,5S,6S)-3,5-
di(tert-butyldimethylsilyl)oxy-10-iodo-1-methoxy-4,6,8,9-
tetramethyldeca-7,9-dien-1-yl)-9-(4-methoxybenzyl)oxy-
3,10,10-trimethyl-1,7-dioxaspiro[4.5]decane (86)
1
1514, 1471, 1252, 1106, 1079, 1035, 836, 775. H NMR
(300 MHz, C6D6) d: 7.24 (d, 2H, J = 8.7 Hz), 6.84 (d, 2H,
J = 8.7 Hz), 6.28 (s, 1H), 6.23 (d, 1H, J = 9.1 Hz), 4.78 (m,
2H), 4.67 (d, 1H, J = 5.6 Hz), 4.53 (d, 1H, J = 11.5 Hz),
4.25 (d, 1H, J = 11.5 Hz), 3.95 (m, 1H), 3.84 (m, 1H), 3.79
(m, 2H), 3.60 (d, 1H, J = 5.7 Hz), 3.56 (dd, 1H, J = 18.5,
8.7 Hz), 3.37 (s, 3H), 2.81 (m, 1H), 2.57 (dd, 1H, J = 18.5,
2.0 Hz), 2.15 (s, 3H), 2.00 (m, 1H), 1.83 (m, 1H), 1.69 (s,
3H), 1.45 (dd, 1H, J = 14.5, 3.5 Hz), 1.38 (dd, 1H, J =
14.5, 2.5 Hz), 1.33 (m, 2H), 1.16 (d, 3H, J = 7.0 Hz), 1.11
(s, 9H), 1.07 (s, 3H), 1.06 (s, 9H), 1.05 (s, 9H), 1.02 (2s,
12H), 0.97 (d, 3H, J = 7.0 Hz), 0.91 (d, 3H, J = 7.1 Hz),
0.35 (s, 3H), 0.33 (s, 3H), 0.23 (s, 3H), 0.14 (s, 3H), 0.13
(2s, 6H), 0.12 (s, 3H), 0.09 (s, 3H). 13C NMR (75 MHz,
CDCl3) d: 211.1, 158.8, 148.4, 132.5, 131.2, 130.9, 128.5,
113.5, 109.1, 88.4, 87.2, 78.0, 76.5, 74.1, 70.5, 67.7, 66.1, 60.9,
55.3, 50.7, 45.9, 43.5, 37.6, 35.6, 35.1, 31.0, 26.2, 26.0, 25.94,
25.89, 23.2, 22.5, 19.5, 18.4, 18.2, 18.1, 17.1, 14.3, 10.5, 10.2,
–3.4, –4.1, –4.3, – 4.60, –4.64, –5.0, –5.3.
t-BuOK in THF (1 M, 200 L, 200 mol) and MeI
(36 L, 589 mol) were added dropwise in sequence to
alcohol 85 (28.4 mg, 23.6 mol) in THF (3.0 mL) at –
78°C. Three further additions of MeI (20 L, 330 mol)
were made at 10 min intervals. The mixture was poured
onto ice cooled saturated aqueous NaHCO3, extracted
with Et2O, and the organic phase washed with H2O
(1 mL) and brine (1 mL) and dried (Na2SO4). Rotary
evaporation and chromatography (hexanes–Et2O, 40:1 to
24:1) gave ether 86 (25.1 mg, 87%) as a pale yellow oil.
[a]2D6 = +47.7° (c = 0.14). FAB-MS (NaI added) m/z:
1239 ([M + Na]+), 782, 629. IR (film) (cm–1): 1615,
1515, 1471, 1250, 1106, 1080, 835, 774. 1H NMR
(300 MHz, CDCl3) d: 7.29 (d, 2H, J = 8.7 Hz), 6.81 (d,
2H, J = 8.7 Hz), 6.28 (s, 1H), 5.90 (d, 1H, J = 8.9 Hz),
4.47 (d, 1H, J = 11.3 Hz), 4.46 (m, 1H), 4.42 (d, 1H, J =
11.3 Hz), 4.27 (m, 1H), 4.02 (dd, 1H, J = 8.8, 5.0 Hz),
3.82 (m, 1H), 3.79 (s, 3H), 3.64 (s, 3H), 3.70–3.58 (m,
3H), 3.45 (dd, 1H, J = 5.0, 2.5 Hz), 3.38 (d, 1H, J =
5.0 Hz), 2.63 (m, 1H), 2.05 (s, 3H), 1.81 (s, 3H), 1.80
(m, 1H), 1.69 (dd, 1H, J = 14.1, 3.8 Hz), 1.60–1.51 (m,
4H), 1.44 (m, 1H), 1.26 (m, 1H), 1.09 (s, 3H), 1.00 (d,
3H, J = 7.0 Hz), 0.94 (s, 9H), 0.92 (s, 3H), 0.89 (s, 9H),
0.87 (s, 9H), 0.84 (d, 3H, J = 7.1 Hz), 0.71 (m, 3H), 0.70
(s, 9H), 0.18 (s, 3H), 0.06 (s, 3H), 0.02 (s, 3H), 0.00 (s,
9H), –0.01 (s, 6H). 13C NMR (75 MHz, CDCl3) d: 158.6,
148.4, 133.3, 131.6, 131.3, 128.1, 113.4, 107.1, 87.5,
86.9, 78.03, 77.95, 77.6, 73.9, 71.5, 67.9, 64.3, 60.9,
60.2, 55.2, 50.7, 44.8, 37.8, 37.2, 35.9, 33.9, 31.0, 26.4,
26.1, 26.0, 23.4, 22.5, 18.6, 18.3, 18.1, 18.0, 17.3, 14.5,
10.5, 10.4, –3.5, –3.7, –4.0, –4.6, –5.0, –5.1, –5.2.
(2R,3R,4S,6R,8S,9S)-4-(tert-Butyldimethylsilyl)oxy-2-
(tert-butyldimethylsilyl)oxyethyl-((1R,3R,4S,5S,6S)-3,5-
di(tert-butyldimethylsilyl)oxy-1-hydroxy-10-iodo-4,6,8,9-
tetramethyldeca-7,9-dien-1-yl)-9-(4-methoxybenzyl)oxy-
3,10,10-trimethyl-1,7-dioxaspiro[4.5]decane (85)
Ketone 84 (31.5 mg, 26.2 mol) in CH2Cl2 (2 mL) was
added to DIBAl-H in hexanes (1 M, 300 L, 300 mol)
in CH2Cl2 (1 mL) at –78°C. After 30 min, the mixture
was quenched with precooled MeOH at –78°C, diluted
with Et2O (10 mL), and saturated aqueous potassium so-
dium tartrate was added with vigorous stirring. After 2 h,
the mixture was washed with H2O (1 mL) and brine
© 2001 NRC Canada

1586
Can. J. Chem. Vol. 79, 2001
3H), 1.87 (s, 3H), 1.83 (m, 1H), 1.75 (dd, 1H, J = 14.3,
3.9 Hz), 1.69–1.58 (m, 4H), 1.49 (m, 1H), 1.29 (m, 1H),
1.09 (s, 3H), 1.02 (d, 3H, J = 7.0 Hz), 0.94 (s, 9H), 0.88 (s,
18H), 0.87 (s, 12H), 0.83 (d, 3H, J = 7.1 Hz), 0.77 (d, 3H,
J = 7.1 Hz), 0.17 (s, 3H), 0.09 (s, 3H), 0.08 (s, 3H), 0.05
(2s, 6H), 0.03 (s, 6H), 0.02 (s, 3H). 13C NMR (100 MHz,
CDCl3) d: 156.7, 144.3, 134.4, 133.9, 133.4, 128.5, 124.0,
117.5, 108.5, 94.6, 87.9, 80.2, 78.9, 77.6, 70.6, 68.4, 65.3,
60.1, 60.0, 49.3, 45.1, 37.3, 35.5, 34.1, 30.3, 26.4, 26.00,
25.96, 25.9, 22.1, 19.4, 18.6, 16.6, 14.5, 14.0, 10.3, 10.1,
(2R,3R,4S,6R,8S,9S)-4-(tert-Butyldimethylsilyl)oxy-2-
(tert-butyldimethylsilyl)oxyethyl-((1R,3R,4S,5S,6S)-3,5-
di(tert-butyldimethylsilyl)oxy-10-iodo-1-methoxy-4,6,8,9-
tetramethyldeca-7,9-dien-1-yl)-9-hydroxy-3,10,10-
trimethyl-1,7-dioxaspiro[4.5]decane (87)
DDQ (7.5 mg, 33.4 mol) was added to ether 86
(7.4 mg, 6.07 mol) in CH2Cl2 (0.5 mL), pH 7 buffer
(0.2 mL), and isopropanol (0.2 mL). After 1 h, further
DDQ (7.5 mg, 33.4 mol) was added. After 1.5 h stir-
ring, the mixture was diluted with Et2O and the reaction
mixture quenched with saturated aqueous NaHCO3. The
organic phase was washed with H2O (1 mL) and brine
(1 mL) and dried (Na2SO4). Rotary evaporation and chro-
matography (hexanes–Et2O, 24:1) gave alcohol 87
(6.7 mg, 100%) as a pale yellow oil. [a]2D5 = +43.2° (c =
1
–3.5, –3.76, –3.83, –4.2, –4.7, –5.0, –5.4. The H and 13C
NMR spectra of 88 were in agreement with spectra of au-
thentic material kindly provided by Professor David A. Ev-
ans. The corresponding data reported by Evans et al. (8)
25
577
were as follows: [a]
= +76.6° (CH2Cl2, c = 0.59). FAB-
HRMS (NaI added) calcd. for C58H111NO8Si4Na:
1084.7284 ([M + Na]+); found: 1084.7275 ([M + Na]+). IR
(film) (cm–1): 3498, 2953, 2927, 2856, 2210, 1591, 1471,
1380, 1360, 1253, 1101, 1072, 1030, 1006, 960, 876, 835,
0.13).
FAB-HRMS
(NaI
added)
calcd.
for
C52H105IO8Si4Na: 1119.5829 ([M
+
Na]+); found:
1119.5850 ([M + Na]+). IR (film) (cm–1): 3496, 1471,
1
1388, 1254, 1101, 1073, 836, 774. H NMR (300 MHz,
1
774. H NMR (500 MHz, CDCl3) d: 7.02 (dd, 1H, J = 14.9,
CDCl3) d: 6.24 (s, 1H), 5.89 (d, 1H, J = 9.1 Hz), 4.55 (m,
1H), 4.20 (m, 1H), 3.93 (dd, 1H, J = 8.8, 4.0 Hz), 3.91
(m, 1H), 3.60 (s, 3H), 3.60–3.56 (m, 2H), 3.51–3.41 (m,
3H), 3.37 (d, 1H, J = 12.0 Hz), 2.61 (m, 1H), 2.01 (s,
3H), 1.78 (s, 3H), 1.81–1.51 (m, 6H), 1.46 (m, 1H), 1.24
(m, 1H), 1.07 (s, 3H), 0.96 (d, 3H, J = 7.0 Hz), 0.90 (s,
9H), 0.85 (s, 18H), 0.84 (s, 12H), 0.80 (d, 3H, J =
7.1 Hz), 0.72 (d, 3H, J = 7.1 Hz), 0.14 (s, 3H), 0.06 (s,
3H), 0.04 (s, 3H), 0.03 (s, 3H), 0.02 (s, 3H), 0.00 (s,
6H), –0.01 (s, 3H). 13C NMR (75 MHz, CDCl3) d: 133.2,
131.7, 108.6, 88.0, 80.3, 79.0, 78.0, 77.4, 70.6, 68.4,
65.4, 60.1, 60.0, 49.3, 45.0, 37.4, 37.0, 35.6, 34.2, 30.4,
26.4, 26.0, 25.9, 22.6, 22.1, 18.6, 18.4, 18.1, 16.6, 14.5,
10.4, 10.2, –3.5, –3.7, –4.1, –4.7, –5.0, –5.3.
11.2 Hz), 6.83 (d, 1H, J = 15.0 Hz), 6.35 (d, 1H, J =
11.1 Hz), 6.08 (d, 1H, J = 9.1 Hz), 5.06 (s, 1H), 4.58 (m,
1H), 4.25 (m, 1H), 3.96 (dd, 1H, J = 8.8, 4.1 Hz), 3.82 (m,
1H), 3.63 (s, 3H), 3.61 (m, 2H), 3.53–3.46 (m, 3H), 3.38
(d, 1H, J = 12.0 Hz), 2.75 (m, 1H), 2.07 (s, 3H), 2.01 (s,
3H), 1.87 (s, 3H), 1.83 (m, 1H), 1.75 (dd, 1H, J = 14.3,
3.8 Hz), 1.69–1.58 (m, 4H), 1.49 (m, 1H), 1.29 (m, 1H),
1.10 (s, 3H), 1.02 (d, 3H, J = 7.0 Hz), 0.94 (s, 9H), 0.88 (s,
18H), 0.87 (s, 12H), 0.83 (d, 3H, J = 7.1 Hz), 0.77 (d, 3H,
J = 7.1 Hz), 0.18 (s, 3H), 0.09 (s, 3H), 0.08 (s, 3H), 0.06
(s, 3H), 0.05 (s, 3H), 0.03 (s, 6H), 0.02 (s, 3H). 13C NMR
(100 MHz, CDCl3) d: 156.7, 144.2, 134.4, 133.9, 133.4,
128.5, 124.0, 117.5, 108.5, 94.6, 87.9, 80.2, 78.9, 77.6,
70.5, 68.4, 65.3, 60.1, 60.0, 49.3, 45.1, 37.3, 37.3, 35.5,
34.1, 30.3, 26.4, 26.0, 26.0, 25.9, 22.1, 19.4, 18.6, 16.6,
14.5, 14.0, 10.3, 10.1, –3.5, –3.8, –3.8, –4.2, –4.7, –5.0,
–5.4.
(10S,11S,12R,13R)-11,13-Di(tert-butyldimethylsilyl)oxy-
((2R,3R,4S,6R,8S,9S)-4-(tert-butyldimethylsilyl)oxy-2-(tert-
butyldimethylsilyl)oxyethyl-9-hydroxy-3,10,10-trimethyl-
1,7-dioxaspiro[4.5]decane-8-yl)-15-methoxy-3,7,8,10,12-
pentamethyl-pentadeca-2,4,6,8-tetraenenitrile (88) (8)
Stannyl diene 3 (41.2 mg, 107 mol) in N-methylpyr-
rolidinone (2.0 mL) was added dropwise to iodide 87
(14.8 mg, 13.5 mol) and Pd(MeCN)2Cl2 (2.0 mg,
7.71 mol) in N-methylpyrrolidinone (2.0 mL) at –5°C. Af-
ter 30 min, further Pd(MeCN)2Cl2 (2.0 mg, 7.71 mol) was
added and the solution was allowed to warm up to 5°C over
20 min. After 1 h, the mixture was poured into ice cooled
saturated aqueous NaHCO3, extracted with Et2O (3 ×
5 mL), and the combined extracts washed with H2O
(1 mL) and brine (1 mL) and dried (Na2SO4). Rotary
evaporation and chromatography (hexanes–Et2O, 7:1)
tert-Butyl-(4R)-4-((1R,2S)-1,2-di(4-methoxybenzyl)oxy-3-
buten-1-yl)-2,2-dimethyl-3-oxazolidinecarboxylate (91)
NaH (60% dispersion in oil, 0.57 g, 14.00 mmol) was
added in 2 portions with stirring over 15 min to diol 90 (33)
(1.31 g, 4.56 mmol) and 4-MeOC6H4CH2Cl (2.17 g,
13.9 mmol) in DMF (9 mL) at 0°C. The mixture was al-
lowed to warm to room temperature and stirred for 16 h. Ex-
cess NaH was quenched with pH 7 buffer and the mixture
partitioned between H2O and Et2O. The ethereal layer was
washed with brine and dried (Na2SO4). Rotary evaporation
and chromatography (PhMe–EtOAc, 1:49 to 1:19) gave
carbamate 91 (1.57 g, 65%) as an oil. [a]2D5 = 77.5° (c =
1.02). CI-MS m/z: 528 ([M + H]+). IR (film) (cm–1): 1695,
1514, 1391, 1366, 1249, 1173, 1068, 1036. 1H NMR
(250 MHz, DMSO-d6, 350 K) d: 7.20 (m, 4H), 6.88 (m, 4H),
5.85 (m, 1H), 5.30 (m, 2H), 4.54 (d, 1H, J = 11.1 Hz), 4.48
(d, 1H, J = 11.8 Hz), 4.43 (d, 1H, J = 11.2 Hz), 4.28 (d, 1H,
J = 11.7 Hz), 4.01 (m, 4H), 3.77 (m, 1H), 3.75 (s, 3H), 3.74
(s, 3H), 1.41 (br s, 15H). 13C NMR (62.5 MHz, DMSO-d6,
350 K) d: 158.5, 151.2, 135.5, 130.1, 130.0, 128.6, 128.5,
117.4, 113.4, 113.3, 92.6, 79.8, 78.9, 78.7, 72.2, 69.5, 62.7,
56.9, 54.7, 27.7, 25.5, 24.2. Anal. calcd. for C30H41NO7:
C 68.29, H 7.83, N 2.65; found: C 68.10, H 7.88, N 2.75.
gave 88 (8) (13.0 mg, 91%) as a white foam. [a]D22
+73.9° (c = 0.18). FAB-HRMS (NaI added) calcd. for
=
C58H111NO8Si4Na: 1084.7285 ([M
+
Na]+); found:
1084.7249 ([M + Na]+). IR (film) (cm–1): 3492, 2210, 1592,
1471, 1380, 1361, 1254, 1102, 1073, 1031, 1006, 961, 877,
1
836, 775. H NMR (400 MHz, CDCl3) d: 7.01 (dd, 1H, J =
15.0, 11.1 Hz), 6.83 (d, 1H, J = 15.0 Hz), 6.35 (d, 1H, J =
11.1 Hz), 6.07 (d, 1H, J = 9.1 Hz), 5.06 (s, 1H), 4.58 (m,
1H), 4.24 (m, 1H), 3.96 (dd, 1H, J = 8.8, 4.0 Hz), 3.82 (m,
1H), 3.62 (s, 3H), 3.61 (m, 2H), 3.53–3.46 (m, 3H), 3.39
(d, 1H, J = 12.0 Hz), 2.75 (m, 1H), 2.07 (s, 3H), 2.00 (s,
© 2001 NRC Canada

Anderson et al.
1587
dehyde 94, which was dissolved in CH3CN (25 mL) and
mixed with NaH2PO4·H2O (0.69 g, 5.0 mmol) in 27% aque-
ous H2O2 (6.1 mL, 50 mmol). NaClO2 (1.09 g, 12.0 mmol)
was added in small portions over 1 h to this vigorously
stirred mixture and stirring was maintained for 12 h. The
mixture was diluted with PhMe (50 mL) and washed succes-
sively with brine (2 × 50 mL) and 20% aqueous Na2S2O3
(50 mL). The product was extracted with aqueous KOH
(0.21 M, 100 mL) and the aqueous layer back extracted with
hexanes. The aqueous fraction was acidified with aqueous
H3PO4 (0.49 M, 10 mL) and extracted with CH2Cl2 (2 ×
50 mL). The extracts were dried (Na2SO4) and rotary evapo-
rated to give acid 95 (4.26 g, 65%) as a foam. Rf = 0.40
(MeOH–CHCl3, 1:9). [a]D25 = +63.6° (c = 0.98). IR (film)
(2R,3R,4S)-2-(tert-Butyloxycarbonyl)amino-3,4-di(4-
methoxybenzyl)oxy-5-hexen-1-ol (92)
TsOH·H2O (97 mg, 0.51 mmol) was added to acetonide
91 (1.34 g, 2.54 mmol) in MeOH (40 mL) and, after 9 h at
room temperature, Et3N (0.11 mL, 0.77 mmol) was added.
Rotary evaporation and chromatography (hexanes–EtOAc,
2:1) gave alcohol 92 (1.11 g, 90%) as an oil. [a]2D5 = 78.4°
(c = 1.14). CI-MS m/z: 488 ([M + H]+), 432, 241, 154, 137,
121. IR (film) (cm–1): 3426, 1713, 1694, 1514, 1249, 1173,
1037. 1H NMR (270 MHz, CDCl3) d: 7.22 (m, 4H), 6.85 (m,
4H), 5.88 (m, 1H), 5.39 (m, 2H), 5.09 (br d, 1H), 4.61 (d,
1H, J = 7.3 Hz), 4.57 (d, 1H, J = 7.8 Hz), 4.41 (d, 1H, J =
11.0 Hz), 4.28 (d, 1H, J = 11.5 Hz), 3.94 (m, 1H), 3.82 (m,
2H), 3.78 (s, 6H), 3.69 (m, 1H), 3.51 (m, 1H), 2.6 (br s, 1H),
1.40 (s, 9H). 13C NMR (62.5 MHz, CDCl3) d: 159.2, 159.0,
155.3, 134.9, 129.8, 129.54, 129.51, 129.2, 119.8, 113.7,
113.6, 81.9, 79.7, 79.0, 73.3, 69.8, 62.3, 55.0, 54.9, 51.6,
28.1. Anal. calcd. for C27H37NO7: C 66.51, H 7.65, N 2.87;
found: C 66.87, H 7.82, N 2.98.
1
(cm–1): 3400, 1749, 1691, 1613, 1513, 1250, 1172. H NMR
(250 MHz, DMSO-d6, 350 K) d: 7.28 (m, 2H), 7.21 (m, 2H),
6.89 (m, 2H), 6.86 (m, 2H), 4.67 (d, 1H, J = 5.6 Hz), 4.62
(d, 1H, J = 5.0 Hz), 4.38 (d, 1H, J = 5.3 Hz), 4.34 (d, 1H,
J = 5.8 Hz), 4.39 (br m, 1H), 4.06 (br m, 1H), 3.98 (m, 1H),
3.75 (s, 3H), 3.74 (s, 3H), 3.55 (m, 2H), 3.19 (s, 3H), 2.70
(s, 3H), 1.36 (s, 9H). 13C NMR (62.5 MHz, DMSO-d6, 350
K) d: 171.1, 158.6, 154.6, 130.0, 129.8, 129.0, 128.7, 113.4,
79.6, 78.5, 78.2, 71.7, 71.0, 69.5, 57.5, 56.0, 54.8, 31.6,
27.7. Anal. calcd. for C28H39NO9: C 63.02, H 7.37, N 2.63;
found: C 62.78, H 7.08, N 2.45.
(3S,4R,5R)-5-(N-tert-Butyloxycarbonyl)-N-methylamino-
6-methoxy-3,4-di(4-methoxybenzyl)oxy-1-hexene (93)
NaH (60% dispersion in oil, 0.71 g, 18 mmol) was added
portionwise over 1.5 h to amine 92 (2.90 g, 5.95 mmol) and
MeI (6.77 g, 47.7 mmol) in DMF (24 mL) and stirred for
28 h at room temperature. The mixture was poured into H2O
(100 mL), extracted into Et2O (3 × 50 mL), and the com-
bined organics washed with brine and dried (Na2SO4). Ro-
tary evaporation and chromatography (gradient Et2O–
CH2Cl2, 1:9 to 1:4) gave carbamate 93 (2.20 g, 72%) as a
colorless oil. [a]2D5 = +69.7° (c = 0.98). CI-MS m/z: 516
([M + H]+), 460. 416, 241, 137, 121. IR (film) (cm–1): 1693,
1682, 1614, 1514, 1249, 1156, 1036, 826. 1H NMR
(250 MHz, DMSO-d6, 350 K) d: 7.23 (m, 4H), 6.89 (m, 4H),
5.89 (m, 1H), 5.30 (m, 2H), 4.67 (d, 1H, J = 11.0 Hz), 4.51
(d, 1H, J = 11.8 Hz), 4.42 (d, 1H, J = 11.0 Hz), 4.33 (d, 1H,
J = 11.8 Hz), 4.03 (m, 1H), 3.87 (m, 1H), 3.78 (m, 1H), 3.75
(s, 6H), 3.57 (m, 1H), 3.46 (m, 1H), 3.19 (s, 3H), 2.65 (s,
3H), 1.36 (s, 9H). 13C NMR (62.5 MHz, DMSO-d6, 350 K)
d: 158.5, 154.5, 134.3, 130.2, 130.1, 128.8, 128.5, 118.1,
113.4, 113.3, 80.2, 79.8, 78.2, 72.2, 69.4, 69.3, 57.5, 55.0,
54.7, 30.3, 27.6. Anal. calcd. for C29H41NO7: C 67.55,
H 8.01, N 2.72; found: C 67.77, H 8.32, N 2.71.
(2R)-Benzyl-2-methyl-4-pentenoate (97)
n-BuLi in hexanes (1.6 M, 125 mL, 200 mmol) was
added to PhCH2OH (27.6 mL, 266 mmol) in THF
(150 mL) at –23°C. After 1 h, the 1,3-oxazolidinone 96 (37)
(30.0 g, 133 mmol) in THF (125 mL) was added and the so-
lution was kept at –20°C for 2.5 h. Half-saturated NH4Cl
(250 mL) was added, the mixture rotary evaporated and the
aqueous residue extracted with CH2Cl2 (3 × 350 mL). The
combined extracts were washed with pH 7 buffer (300 mL)
and brine (200 mL), dried, rotary evaporated, and
chromatographed (hexanes–EtOAc, 9:1) to give ester 96
(26.5 g, 97%) as a colorless oil. Rf = 0.52 (hexanes–EtOAc,
9:1).[a]2D5 = –2.7° (c = 2.5). EI-MS m/z: 204 (M0+), 130, 91,
69, 41. EI-HRMS calcd for C13H16O2: 204.1150 (M0+);
found: 204.1156 (M0+). IR (film) (cm–1): 2977, 1736, 1642,
1456, 1382, 1275, 1173, 917. 1H NMR (400 MHz, CDCl3) d:
7.34 (m, 5H), 5.72 (m, 1H), 5.11 (s, 2H), 5.06 (m, 2H), 2.58
(m, 1H), 2.43 (m, 1H), 2.19 (m, 1H), 1.17 (d, 3H, J =
6.8 Hz). 13C NMR (101 MHz, CDCl3) d: 175.8, 136.1,
135.3, 128.5, 128.1, 116.9, 66.1, 39.2, 37.7, 16.5.
(3R,4R,5R)-4-(N-tert-Butyloxycarbonyl)-N-methylamino-5-
methoxy-2,3-di(4-methoxybenzyl)oxyhexanoic acid (95)
OsO4 (57 mg, 0.22 mmol) and N-methylmorpholine-N-ox-
ide (1.72 g, 14.7 mmol) followed by H2O (6 mL) were
added to alkene 93 (6.31 g, 12.2 mmol) in t-BuOH (24 mL)
and Me2CO (12 mL). After stirring for 16 h, the solution
was diluted with Et2O (75 mL) and washed successively
with 10% aqueous Na2S2O3 (20 mL) and brine (20 mL). The
organic phase was dried (Na2SO4) and rotary evaporated.
The resulting oil was dissolved in MeOH (102 mL) and
treated with NaIO4 (3.12 g, 14.6 mmol) in H2O (25 mL). Af-
ter 20 min, solid material was removed via filtration through
Celite and the filtrate rotary evaporated. The residue was
partitioned between brine (20 mL) and Et2O (60 mL) and
the organic phase washed with 10% aqueous Na2S2O3
(20 mL) and brine (20 mL) and then dried (Na2SO4). Rotary
evaporation gave an oil, presumably containing the crude al-
(2R)-2-Methyl-4-pentenamide (98)
AlMe3 in PhMe (2 M, 55 mL, 110 mmol) was added
slowly to a suspension of NH4Cl (5.9 g, 110 mmol) in PhMe
(200 mL) at 0°C. After 1 h at 0°C and 1.5 h at room temper-
ature, gas evolution had ceased and the solution was trans-
ferred to ester 97 (7.5 g, 36.7 mmol) in PhMe (50 mL). The
mixture was heated at 60°C for 36 h and allowed to cool to
room temperature. HCl (5%) was added as a quench and the
resulting precipitate removed by filtration, washing with
EtOAc. The combined organic extracts were dried (Na2SO4),
rotary evaporated, and chromatographed (hexanes–EtOAc,
1:1) to give amide 98 (3.40 g, 81%) as a colorless solid. Rf =
0.39 (EtOAc); mp 79 to 80°C. [a]2D5 = –22.9° (c = 1.3). EI-
MS m/z: 113 (M0+). EI-HRMS calcd. for C6H11NO:
© 2001 NRC Canada

1588
Can. J. Chem. Vol. 79, 2001
113.0840 (M0+); found: 113.0844 (M0+). IR (CHCl3) 3354,
3186, 2974, 1659. 1H NMR (400 MHz, CDCl3) d: 6.44 (br s,
1H), 5.91 (br s, 1H), 5.87 (m, 1H), 5.77 (m, 2H), 2.38 (m,
2H), 2.16 (m, 1H), 1.16 (d, 3H, J = 6.8 Hz). 13C NMR
(100 MHz, CDCl3) d: 178.9, 135.6, 116.8, 40.3, 38.1, 17.1.
Anal. calcd. for C6H11NO: C 63.69, H 9.80; N. 12.37;
found: C 63.49, H 9.73; N. 12.39.
for C10H17NO3: C 60.28, H 8.59, N 7.02; found: C 60.42,
H 8.75, N 6.83.
Methyl 2-(4-penten-(2R)-yl)-4-oxazolecarboxylate (102)
Imidate 101 (1.64 g, 8.24 mmol) and HCO2Me (0.6 mL,
9.9 mmol) in THF (12 mL) were added dropwise over 0.5 h
to t-BuOK in THF (1 M, 8.2 mL, 8.2 mmol) at –10°C. The
mixture was stirred for 3 h at –10°C and for 14 h at room
temperature and then rotary evaporated. The residue was
suspended in THF (40 mL), cooled to –78°C whereupon
BF3·OEt2 (2.2 mL, 18.0 mmol) was added over 5 min. The
mixture was allowed to warm to room temperature over 1 h
and stirred for a further 45 h. The resulting orange solution
was poured into 10% aqueous NaHCO3 (200 mL), extracted
with Et2O (2 × 100 mL), and the combined organic phases
were washed with brine and dried (Na2SO4). Rotary evapo-
ration and chromatography (hexanes–EtOAc, 4:1) gave
oxazole 102 (1.23 g, 77%) as a colorless oil. Rf = 0.63
(hexanes–EtOAc, 3:1). [a]2D5 = –4.5° (c = 1.0). EI-MS m/z:
195 (M0+). EI-HRMS calcd. for C10H13NO: 195.0895 (M0+);
found: 195.0901 (M0+). IR (film) (cm–1): 2979, 1748, 1584.
1H NMR (300 MHz, CDCl3) d: 8.21 (s, 1H), 5.77 (m, 1H),
5.03 (m, 2H), 3.91 (s, 3H), 3.13 (m, 1H), 2.58 (m, 1H), 2.41
(m, 1H), 1.37 (d, 3H, J = 7.0 Hz). 13C NMR (75 MHz,
CDCl3) d: 168.3, 161.3, 143.3, 134.5, 132.6, 116.9, 51.5,
38.6, 33.3, 17.2. Anal. calcd. for C10H13NO: C 61.52,
H 6.71, N 7.17; found: C 61.15, H 6.69, N 7.08.
(2R)-2-Methyl-4-pentenenitrile (99)
Et3N (12.3 mL, 88.4 mmol) and Cl3CCOCl (9.9 mL,
88.4 mmol) in CH2Cl2 (20 mL) were added to amide 98
(5.0 g, 44.2 mmol) in CH2Cl2 (140 mL) at 0°C. The mixture
was stirred at 0°C for 3 h, diluted with pH 7 buffer (75 mL),
and extracted with CH2Cl2 (3 × 100 mL). The combined ex-
tracts were dried (MgSO4) and rotary evaporated. The resi-
due was distilled under reduced pressure to give nitrile 99
(3.3 g, 78%) as a colorless oil; bp 68°C (151 mm Hg).
[a]2D5 = –17.4° (c = 1.1). EI-MS m/z: 95 (M0+). EI-HRMS
calcd. for C6H9N: 95.0891 (M0+); found: 95.0753 (M0+). IR
(film) (cm–1): 2985, 2241, 1644. 1H NMR (300 MHz,
CDCl3) d: 5.80 (m, 1H), 5.21 (m, 2H), 2.66 (m, 1H), 2.33
(m, 2H), 1.31 (d, 3H, J = 6.9 Hz). 13C NMR (75 MHz,
CDCl3) d: 132.8, 122.2, 118.5, 37.6, 25.0, 17.1.
(2R)-Methyl 2-methyl-4-pentenimidate hydrochloride (100)
Anhydrous HCl was bubbled through nitrile 99 (2.64 g,
29.9 mmol) in MeOH (1.3 mL, 32.0 mmol) at –10°C until
the solution was saturated. On standing at –5°C for 24 h, the
mixture solidified and the solid was dried in vacuo, triturated
with Et2O, and the solid isolated by filtration to give hydro-
chloride 100 (4.66 g, 96%) as a colorless powder; mp 106 to
107°C. [a]2D5 = +35.8° (c = 1.0). EI-MS m/z: 126 ([M –
H2Cl]+). EI-HRMS calcd. for C7H12NO: 126.0918 ([M –
H2Cl]+); found: 126.0913 ([M – H2Cl]+). IR (CHCl3) (cm–1):
Methyl 2-(4-oxo-(2R)-butyl)-4-oxazolecarboxylate (103)
NaIO4 (5.90 g, 27.6 mmol) in H2O (50 mL) was added
dropwise to oxazole 102 (2.57 g, 13.14 mmol) and OsO4 in
H2O (2.5%, 16 drops) in Me2CO (25 mL) and H2O (25 mL).
The mixture was stirred for 5 h, poured into H2O (200 mL),
and extracted with CHCl3 (5 × 50 mL). After drying (Na2SO4)
of the extracts, rotary evaporation, and chromatography
(hexanes–EtOAc, 2:1 to 1:1) gave aldehyde 103 (2.05 g,
79%) as a colorless liquid. Rf = 0.34 (hexanes–EtOAc, 1:1).
EI-MS m/z: 197 (M0+). EI-HRMS calcd. for C9H11NO4:
197.0688 (M0+); found: 197.0681 (M0+). IR (film) (cm–1):
3161, 2955, 1732, 1584. 1H NMR (300 MHz, CDCl3) d: 9.76
(s, 1H), 8.12 (s, 1H), 3.86 (s, 3H), 3.55 (m, 1H), 3.14 (dd,
1H, J = 18.2, 7.0 Hz), 2.76 (dd, 1H, J = 18.2, 6.7 Hz), 1.36
(d, 3H, J = 7.1 Hz). 13C NMR (100 MHz, CDCl3) d: 199.1,
167.5, 161.3, 143.6, 132.9, 51.7, 47.6, 27.7, 18.2.
1
2886, 1654. H NMR (400 MHz, CDCl3) d: 5.76 (m, 1H),
5.12 (m, 2H), 4.29 (s, 3H), 3.27 (m, 1H), 2.48–2.32 (m, 2H),
1.30 (d, 3H, J = 6.8 Hz). 13C NMR (100 MHz, CDCl3) d:
182.5, 133.3, 118.5, 60.6, 38.2, 37.7, 16.7.
(5R)-Methyl 3-aza-4-methoxy-5-methyl-3,7-octadienoate
(101)
Glycine methyl ester hydrochloride (3.86 g, 30.7 mmol)
was added to hydrochloride 100 (4.79 g, 29.3 mmol) and
glass chips in CH2Cl2 cooled to –10°C. This was followed
by dropwise addition of Et3N (4.16 mL, 29.9 mmol) over
2 h (syringe pump). After stirring for 1 h, the mixture was
allowed to warm to room temperature and stirred for an
additional 43 h. The solution was cooled to 0°C and
quenched with cold pH 7 buffer (1.5 M, 100 mL), ex-
tracted with Et2O (2 × 50 mL), and the combined ethereal
extracts dried (Na2SO4). Rotary evaporation and distillation
(Kugelrohr) gave imidate 101 (4.03 g, 69%) as a colorless
liquid; bp 70°C (0.35 mm Hg). [a]2D5 = +22.6° (c = 1.7). EI-
MS m/z: 199 (M0+). EI-HRMS calcd. for C10H17NO3:
199.1208 (M0+); found: 199.1208 (M0+). IR (film) (cm–1):
Methyl 2-(4-hydroxy-(2R)-butyl)-4-oxazolecarboxylate (104)
NaBH4 (0.39 g, 10.3 mmol) was added in small portions
over 5 min to aldehyde 103 (2.03 g, 10.28 mmol) in MeOH
(100 mL) at –12°C. After 1 h, chilled (5°C) aqueous KHSO4
(1 M, 50 mL) was added, the mixture was extracted with
CHCl3 (5 × 50 mL), and the extracts dried (Na2SO4). Rotary
evaporation and chromatography (hexanes–EtOAc, 1:1, then
EtOAc) gave alcohol 104 (1.90 g, 93%) as a colorless oil.
Rf = 0.42 (EtOAc). [a]2D5 = –25.0° (c = 1.0). CI-MS m/z: 200
([M + H]+). CI-HRMS calcd. for C9H13NO4: 199.0844
(M0+); found: 199.0829 (M0+). IR (film) (cm–1): 3413, 2953,
1
1
2947, 1752, 1674. H NMR (300 MHz, CDCl3) d: 5.66 (m,
1736, 1585. H NMR (300 MHz, CDCl3) d: 8.03 (s, 1H),
1H), 5.00 (m, 2H), 4.09 (s, 2H), 3.72 (s, 3H), 3.66 (s, 3H),
2.66 (m, 1H), 2.30 (m, 1H), 2.12 (m, 1H), 1.10 (d, 3H, J =
6.8 Hz). 13C NMR (100 MHz, CDCl3) d: 171.1, 169.1,
135.7, 116.7, 52.6, 51.9, 49.9, 38.1, 33.2, 17.1. Anal. calcd.
3.72 (s, 3H), 3.49 (m, 3H), 3.08 (m, 1H), 1.89 (m, 1H), 1.72
(m, 1H), 1.20 (d, 3H, J = 6.9 Hz). 13C NMR (75 MHz,
CDCl3) d: 168.9, 161.4, 143.4, 132.3, 59.2, 51.6, 37.0, 30.1,
17.9. (R)-a-methoxy-a-(trifluoromethyl)phenylacetic acid
© 2001 NRC Canada

Anderson et al.
1589
(26 mg, 0.11 mmol) in CH2Cl2 (0.25 mL), 1,3-dicyclohexyl
carbodiimide (22 mg, 0.11 mmol), and DMAP (2 mg) were
added sequentially with stirring to alcohol 104 (20 mg,
0.10 mmol). After 2 h, the mixture was diluted with Et2O
(10 mL) and filtered. The organic solution was evaporated
and the residue chromatographed (hexanes–EtOAc, 1:1) to
furnish ester 108 (38 mg, 91%) as a colorless oil. Rf = 0.50
(hexanes–EtOAc, 1:1). EI-MS m/z: 415 (M0+), 189, 150,
105. EI-HRMS calcd for C19H20F3NO6: 415.1217 (M0+);
found: 415.1222 (M0+). IR (film) (cm–1): 1756, 1274, 1166,
maintained under a H2 atmosphere for 2 h. The catalyst
was removed by filtration and the filtrate rotary evaporated
to leave amine 107 (83 mg, 98%) as a colorless oil.
[a]2D5 = –29.6° (c = 1.1). EI-MS m/z: 198 (M0+). EI-HRMS
calcd. for C9H14N2O3: 198.1004 (M0+); found: 198.0997
1
(M0+). IR (film) (cm–1): 2927, 2877, 1742, 1671, 1622. H
NMR (300 MHz, CDCl3) d: 8.06 (s, 1H), 3.78 (s, 3H), 3.05
(m, 1H), 2.57 (t, 2H, J = 7.1 Hz), 1.85 (m, 1H), 1.66 (m,
1H), 1.24 (d, 3H, J = 7.9 Hz), 1.19 (br s, 2H). 13C NMR
(75 MHz, CDCl3) d: 168.9, 161.2, 143.4, 132.7, 51.8, 39.5,
38.5, 31.2, 18.2.
1
1114. H NMR (300 MHz, CDCl3) d: 8.09 (s, 1H), 7.46–
7.34 (m, 5H), 4.35 (m, 2H), 3.90 (s, 3H), 3.52 (s, 3H), 3.08
(m, 1H), 2.26 (m, 1H), 2.02 (m, 1H), 1.33 (d, 3H, J =
7.0 Hz). The mixture of diastereoisomeric Mosher esters 109
prepared in the same way from the corresponding racemic
alcohol (±)-104 showed: 1H NMR (400 MHz, CDCl3) d:
8.11 (s, 1H), 7.48–7.36 (m, 5H), 4.35 (m, 2H), 3.91 (s, 3H),
3.53 (s, 3H), 3.09 (m, 1H), 2.26 (m, 1H), 2.02 (m, 1H), 1.36
(d, 1.5H, J = 7.0 Hz), 1.35 (d, 1.5H, J = 7.0 Hz).
(2R,3R,4R)-4-(N-(tert-Butyloxy)carbonyl-N-methyl)amino-
2,3-di(4-methoxybenzyl)oxy-5-methoxy-N-(3R-((4-
methoxycarbonyl)-2-oxazolyl)-1-butyl)pentamide (110)
1-Hydroxybenzotriazole (1.21 g, 8.96 mmol), powdered
molecular sieves (4 Å, 3.0 g), and 1-ethyl-3-(3-dimethyl-
aminopropyl)carbodiimide hydrochloride (0.855 g, 4.46 mmol)
were added sequentially to acid 95 (2.49 g, 4.67 mmol) in
DMF (10 mL) at 0°C. After 1 h, amine 107 (0.88 g,
4.5 mmol) in DMF (10 mL) was added and the mixture al-
lowed to warm to room temperature and stirred for 10 h. The
mixture was filtered and the filtrate rotary evaporated. The
residue was partitioned between Et2O (75 mL) and 10%
aqueous NaHCO3 (25 mL), the organic phase washed with
aqueous citric acid (0.1 M, 25 mL) and brine (2 × 25 mL)
and dried (Na2SO4). Chromatography (EtOAc–PhMe, 2:1)
gave amide 110 (2.28 g, 72%) as a yellow oil. Rf = 0.55
(MeOH–CHCl3, 1:9). [a]2D5 = +21.4° (c = 1.02). FAB-MS
m/z: 714 (M0+). IR (neat) (cm–1): 3420, 1745, 1688, 1612,
1584, 1513, 1455, 1246, 821, 775. 1H NMR (250 MHz,
DMSO-d6, 350 K) d: 8.61 (s, 1H), 7.60 (br s, 1H), 7.29 (m,
2H), 7.20 (m, 2H), 6.88 (m, 4H), 4.56 (m, 2H), 4.45 (d, 1H,
J = 11.7 Hz), 4.36 (d, 1H, J = 10.9 Hz), 4.20 (br m, 1H),
3.96 (m, 2H), 3.80 (s, 3H), 3.75 (s, 3H), 3.74 (s, 3H), 3.61
(br m, 1H), 3.50 (m, 1H), 3.19 (s, 3H), 3.13 (m, 2H), 3.03
(m, 1H), 2.67 (s, 3H), 1.95 (m, 1H), 1.72 (m, 1H), 1.35 (s,
9H), 1.27 (d, 3H, J = 7.0 Hz). Anal. calcd. for C37H51N3O11:
C 62.26, H 7.20, N 5.89; found: C 61.93, H 7.27, N 5.81.
Methyl 2-(4-(methanesulfonyl)oxy-(2R)-butyl)-4-
oxazolecarboxylate (105)
Et3N (2.3 mL, 16.0 mmol) and MeSO2Cl (0.9 mL,
10 mmol) were added to alcohol 104 (1.61 g, 8.09 mmol) in
Et2O (40 mL) at –10°C. The mixture was stirred at –10°C
for 45 min, diluted with H2O (25 mL), and extracted with
CHCl3 (3 × 25 mL). The combined extracts were dried
(Na2SO4), rotary evaporated, and chromatographed (EtOAc–
CH2Cl2, 1:9) to give mesylate 105 (1.89 g, 84%) as a color-
less solid; mp 61–63°C. Rf = 0.69 (EtOAc). [a]2D5 = –34.0°
(c = 1.0). EI-MS m/z: 277 (M0+). EI-HRMS calcd. for
C10H15NO4S: 277.0620 (M0+); found: 277.0619 (M0+). IR
1
(CHCl3) (cm–1): 3098, 1726. H NMR (300 MHz, CDCl3) d:
8.07 (s, 1H), 4.15 (m, 2H), 3.76 (s, 3H), 3.13 (m, 1H), 2.88
(s, 3H), 2.17 (m, 1H), 1.97 (m, 1H), 1.27 (d, 3H, J =
7.1 Hz). 13C NMR (75 MHz, CDCl3) d: 167.4, 161.2, 143.6,
132.6, 67.1, 51.7, 36.9, 33.5, 29.8, 17.9. Anal. calcd. for
C10H15NO6S: C 43.31, H 5.45, N 5.05; found: C 43.29,
H 5.48, N 4.91.
Methyl 2-(4-azido-(2R)-butyl)-4-oxazolecarboxylate (106)
NaN3 (1.11 g, 17.1 mmol) was added to mesylate 105
(1.89 g, 6.82 mmol) in DMSO (45 mL), the mixture was
heated to 70°C for 7 h, cooled to room temperature, and di-
luted with cold H2O (200 mL). The mixture was extracted with
EtOAc (3 × 50 mL) and the combined extracts dried (Na2SO4).
Rotary evaporation and chromatography (hexanes–EtOAc, 1:1 to
1:2) gave azide 106 (1.33 g, 87%) as a colorless liquid. Rf =
0.56 (hexanes–EtOAc, 1:1). [a]2D5 = –39.0° (c = 2.3). EI-MS
m/z: 225 ([M + H]+). CI-HRMS calcd. for C9H12N4O3:
224.0909 (M0+); found: 224.0922 (M0+). IR (film) (cm–1):
(2R,3R,4R)-4-Dimethylamino-5-methoxy-N-(3R-((4-
methoxycarbonyl)-2-oxazolyl)-1-butyl)-2,3-
di((triethylsilyl)oxy)pentamide (112)
Oxazole-amide 110 (586 mg, 0.821 mmol) was dissolved
in EtOAc saturated with aqueous HCl (2.8M, 12 mL) and
stirred at room temperature for 4 h. After rotary evaporation,
the residue was washed with Et2O and dissolved in CH3CN
(8.0 mL). Et3SiCl (0.34 mL, 2.05 mmol) and i-Pr2NEt
(1.4 mL, 8.20 mmol) were added. After stirring for 2 h, MeI
(0.26 mL, 4.10 mmol) was added. Following 10 h stirring at
room temperature, the mixture was diluted with Et2O and
quenched with saturated aqueous NaHCO3. The organic
phase was washed with H2O (1.0 mL) and brine (1.0 mL)
and then dried (Na2SO4). Rotary evaporation and chroma-
tography (hexanes–EtOAc, 1:2 to 1:4) gave oxazole 112 (8)
(300 mg, 59%) as a yellow oil. [a]2D5 = +4.4° (c = 0.89).
FAB-HRMS calcd. for C29H58N3O7Si2: 616.3813 ([M +
H]+); found: 616.3734 ([M + H]+). IR (film) (cm–1): 3438,
2958, 2877, 1750, 1676, 1584, 1519, 1459, 1323, 1237,
1197, 1142, 1110, 1076, 1007, 857, 839, 740. 1H NMR
(400 MHz, CDCl3) d: 8.14 (s, 1H), 6.54 (m, 1H), 4.26 (s,
1
2953, 2099, 1747, 1584. H NMR (300 MHz, CDCl3) d: 8.10
(s, 1H), 3.81 (s, 3H), 3.26 (t, 2H, J = 6.8 Hz), 3.09 (m, 1H),
2.05 (m, 1H), 1.81 (m, 1H), 1.29 (d, 3H, J = 7.1 Hz). 13C
NMR (75 MHz, CDCl3) d: 167.8, 161.4, 143.6, 132.8, 51.8,
48.7, 33.5, 30.9, 18.1. Anal. calcd. for C9H12N4O3: C 48.21,
H 5.39, N 24.98; found: C 47.90, H 5.28, N 24.76.
Methyl 2-(4-amino-(2R)-butyl)-4-oxazolecarboxylate (107)
A suspension of 10% Pd(C) (8 mg) and azide 106 (96 mg,
0.43 mmol) in MeOH (1.5 mL) was purged with Ar and then
© 2001 NRC Canada

1590
Can. J. Chem. Vol. 79, 2001
1H), 4.03 (d, 1H, J = 9.8 Hz), 3.89 (s, 3H), 3.51 (d, 2H, J =
5.6 Hz), 3.27 (s, 3H), 3.23 (m, 1H), 3.14 (m, 1H), 3.10–3.04
(m, 2H), 2.23 (s, 6H), 2.03 (m, 1H), 1.80 (m, 1H), 1.37 (d,
3H, J = 7.0 Hz), 0.95 (m, 18H), 0.64 (m, 12H). 13C NMR
(100 MHz, CDCl3) d: 171.9, 168.5, 161.8, 143.7, 133.0,
77.3, 73.7, 70.5, 61.5, 58.4, 52.1, 41.7, 36.8, 34.7, 31.6,
18.3, 6.9, 6.8, 4.9, 4.7. The corresponding data reported by
Evans (8) were as follows: [a]2D5 = +4.3° (CH2Cl2, c = 0.70).
FAB-HRMS+ calcd. for C29H57N3O7Si2Na: 638.3633 ([M +
Na]+); found: 638.3651 ([M + Na]+). IR (film) (cm–1): 3435,
2960, 2882, 1756, 1680, 1587, 1518, 1460, 1321, 1236,
1196, 1141, 1110, 1073, 1005, 857, 838, 740. 1H NMR
(500 MHz, CDCl3) d: 8.16 (s, 1H), 6.56 (t, 1H, J = 5.8 Hz),
4.28 (s, 1H), 4.05 (d, 1H, J = 10.1 Hz), 3.91 (s, 3H), 3.53 (d,
2H, J = 6.2 Hz), 3.29 (s, 3H), 3.27 (m, 1H), 3.15 (m, 1H),
3.11–3.05 (m, 2H), 2.24 (s, 6H), 2.04 (m, 1H), 1.82 (m, 1H),
1.39 (d, 3H, J = 7.1 Hz), 0.97 (m, 18H), 0.67 (m, 12H). 13C
NMR (100 MHz, CDCl3) d: 171.9, 168.5, 161.7, 143.7,
133.0, 77.3, 73.8, 70.5, 61.5, 58.3, 52.1, 41.7, 36.8, 34.7,
31.6, 18.3, 6.9, 6.8, 4.9, 4.7.
Acknowledgments
We thank the National Institutes of Health for support of
this program (AI-20644), G. D. Searle & Company (now
Pharmacia) for unrestricted support and microanalyses, Glaxo
Wellcome for the endowment (to A.G.M.B.), the Uehara
Memorial Life Science Fund for a fellowship (to K. H.), and
the Wolfson Foundation for establishing the Wolfson Centre
for Organic Chemistry in Medical Science at Imperial Col-
lege. We additionally thank Professor David A. Evans for
sending us copies of the H and 13C NMR spectra of 88 and
113 and Dr. Nick S. Stock for assistance with drafting the
manuscript.
1
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7. (a) Y. Hamada, Y. Tanada, F. Yokokawa. and T. Shioiri. Tetra-
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bridge. 1993. p. 117.
(2R,3R,4R)-4-Dimethylamino-5-methoxy-N-(3R-((4-
hydroxymethyl)-2-oxazolyl)-1-butyl)-2,3-di((triethylsilyl)-
oxy)pentamide (113)
LiAlH4 in Et2O (1.0 M, 1.5 mL, 1.50 mmol) was added
dropwise to ester 112 (300 mg, 0.487 mmol) in Et2O
(5 mL) at –78°C and the mixture stirred for 1.5 h. EtOAc
was added to quench excess LiAlH4 and the solution al-
lowed to warm to room temperature. H2O (3.0 mL) and,
after 10 min, anhydrous Na2SO4 were added and the mix-
ture stirred vigorously for 30 min. Filtration, rotary evap-
oration, and chromatography (hexanes–EtOAc, 1:2 to 1:9)
gave oxazole 113 (8) (177 mg, 62%) as a pale yellow oil.
[a]2D5
= +5.8° (c = 1.2). FAB-HRMS calcd. for
C28H58N3O6Si2: 588.3864 ([M + H]+); found: 588.3810
([M + H]+). IR (film) (cm–1): 3430, 2955, 2878, 1665,
1525, 1459, 1239, 1129, 1070, 1008, 741. 1H NMR
(300 MHz, CDCl3) d: 7.48 (s, 1H), 6.58 (m, 1H), 4.55 (s,
2H), 4.26 (s, 1H), 4.05 (d, 1H, J = 9.8 Hz), 3.52 (d, 2H,
J = 5.8 Hz), 3.27 (s, 3H), 3.27–3.14 (m, 2H), 3.10–2.98
(m, 2H), 2.38 (m, 1H), 2.23 (s, 6H), 1.96 (s, 1H), 1.78 (m,
1H), 1.37 (d, 3H, J = 7.0 Hz), 0.96 (m, 18H), 0.64 (m,
12H). 13C NMR (75 MHz, CDCl3) d: 171.9, 168.0, 140.0,
134.6, 77.4, 73.7, 70.5, 61.6, 58.4, 56.7, 41.7, 36.8, 34.9,
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1
31.6, 18.4, 7.0, 6.8, 4.9, 4.7. The H and 13C NMR spectra
of 113 were in agreement with spectra of authentic mate-
rial kindly provided by Professor David A. Evans. The
corresponding data reported by Evans (8) were as follows:
[a]2D5 = +4.8° (CH2Cl2, c = 1.12). FAB-HRMS calcd. for
C28H57N3O6Si2: 588.3864 ([M + H]+); found: 588.3846
([M + H]+). IR (film) (cm–1): 3400, 2960, 2870, 1660,
1
1530, 1455, 1070, 1010. H NMR (400 MHz, CDCl3) d:
7.48 (s, 1H), 6.58 (br s, 1H), 4.55 (s, 2H), 4.26 (s, 1H),
4.04 (d, 1H, J = 9.7 Hz), 3.52 (d, 2H, J = 5.8 Hz), 3.28
(s, 3H), 3.20 (m, 2H), 3.02 (m, 2H), 2.23 (s, 6H), 1.96
(m, 1H), 1.78 (m, 1H), 1.34 (d, 3H, J = 7.0 Hz), 0.96
(m, 18H), 0.63 (m, 12H). 13C NMR (100 MHz, CDCl3)
d: 171.9, 168.0, 139.9, 134.6, 77.4, 73.7, 70.5, 61.5,
58.4, 56.8, 41.7, 36.8, 34.9, 31.5, 18.4, 6.9, 6.8, 4.9,
4.7.
© 2001 NRC Canada

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