Towards the total synthesis of Calyculin C: preparation of the C13-C25 spirocyclic core

Article abstract of DOI:10.1016/j.tet.2009.07.070

A stereoselective synthesis of the C₁₃-C₂₅ of Calyculin C is described. Key steps involve the coupling of a terminal acetylene with a thiol ester and subsequent spirocyclisation using a double intramolecular hetero-Michael addition.

Full text of DOI:10.1016/j.tet.2009.07.070

Tetrahedron 65 (2009) 7927–7934
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Towards the total synthesis of Calyculin C: preparation
of the C13–C25 spirocyclic core
*
Damien Habrant, Alan J.W. Stewart, Ari M.P. Koskinen
Laboratory of Organic Chemistry, Helsinki University of Technology, PO Box 6100, FIN-02015 HUT, Espoo, Finland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 14 May 2009
Received in revised form 3 July 2009
Accepted 23 July 2009
Available online 29 July 2009
A stereoselective synthesis of the C13–C25 of Calyculin C is described. Key steps involve the coupling of
a terminal acetylene with a thiol ester and subsequent spirocyclisation using a double intramolecular
hetero-Michael addition.
Ó 2009 Elsevier Ltd. All rights reserved.
12
13
1. Introduction
resulted in the preparation of the C1–C8,11 C26–C32
,
C33–C38
fragments of Calyculin C. Herein we describe our latest results to-
wards the construction of the C13–C25 spirocyclic fragment.
As shown in Scheme 1, our retrosynthetic strategy for the C13–C25
fragment was based on a convergent approach. We have previously
shown that the C21 carbonyl group of structures such as 2 can be
selectively reduced using L-Selectride to deliver the axial di-
astereomer as found in the Calyculin family.14 Furthermore, struc-
turally and biologically related natural products such as Clavosines
A–C15 and Geometricin16 differ from the Calyculins in the stereo-
chemistry at this centre. It was assumed that the requisite equatorial
isomer of these molecules could be accessed via K-Selectride-me-
diated reduction. With the synthesis of not only Calyculin C, but also
the Clavosines and Geometricin in mind, we focused our efforts on
the synthesis of common intermediate spiroketal 2.
The DIHMA (double intramolecular hetero-Michael addition)
process for the construction of spiroketal moieties was initially in-
troduced by Crimmins17 and further adapted by Forsyth in the total
syntheses of natural products.18 We proposed that utilisation of such
DIHMA methodology would allow the formation of the key spi-
roketal 2 from the ynone 3. Ynone 3 could, in principle, be obtained
by coupling the terminal acetylene 4 with a carbonyl partner 5. Fi-
nally, we proposed alkyne 4 to arise from the known lactone 6.19
Originally isolated by Fusetani et al., from the marine sponge
Discodermia calyx, the Calyculins comprise a family of structurally
novel secondary metabolites that posses a remarkable range of
biological properties.1–3 The family is composed of 8 different
members, which vary by substitution at C32 and the olefin geom-
etry of the tetraene moiety (Calyculins A–H, see Fig. 1: Calyculin C).
Of particular significance is the observation that most members of
the family are potent inhibitors of protein phosphatases 1 and 2A4,5
whilst calyculins A–D also display potent cytotoxicity against L1210
leukamia cells.2
This interesting biological profile combined with their complex
structures made the Calyculins attractive from a synthetic point of
view. Several synthetic approaches have been described,6 leading
amongst others to the total syntheses of (þ)-Calyculin A by Evans7
and Barrett,6 (ꢀ)-Calyculin A by Masamune,8 (ꢀ)-Calyculin B by
Smith9 and Calyculin C by Armstrong.10 Efforts in our group have
OH
O
37
O
MeO
N
H
32
N
OH
N
26
25
O
2. Results and discussion
O
1
(HO)2PO
CN
OH
13
We have recently studied and validated the mechanism of the
spirocyclisation on a simplified model compound (Scheme 2).14,20
Asymmetric dihydroxylation of enoate 7 followed by protection
and reduction furnished lactol 8, which was converted to alkyne 9
using Ohira-Bestmann reagent 10 and silyl protection.21,22 This
represented the first example of the use of a hindered lactol in
a Seyferth–Gilbert-type homologation. Weinreb amide 12 was
obtained from oxazolidinone 11 via an Evans aldol reaction.23
O
8
9
OH
OH
OMe
Figure 1. Structure of Calyculin C.
* Corresponding author. Tel.: þ358 9 451 2526; fax: þ358 9 451 2538;
E-mail address: ari.koskinen@tkk.fi (A.M.P. Koskinen).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.07.070

7928
D. Habrant et al. / Tetrahedron 65 (2009) 7927–7934
OTBDPS
O
Weinreb–Nahm coupling24 of alkyne 9 and amide 12 furnished
alkynone 13, which, upon successive treatment by CSA and p-TsOH
underwent the spirocyclisation via the DIHMA pathway to yield
spirocylcle 14 as a single enantiomer.
RO
With this proof of concept in hand, we turned our attention
towards the actual spirocyclic core of Calyculin C (Scheme 3). Our
starting point was lactone 6, the synthesis of which has previously
been described by our group.19 15 was obtained in good yield and
selectivity (>7:1 by 1H NMR), by stereoselective reduction of ke-
tone 6 using potassium superhydride.8 MEM-protection of the re-
sultant alcohol required a large excess of reagents and a prolonged
reaction time but ultimately proceeded in 66% yield. DIBAL-H re-
duction of 15 efficiently furnished lactol 16. Unfortunately, Ohira–
Bestmann homologation of 16 gave only a low yield of alkyne 17.
Given that aldehydes adjacent to tertiary centres are well known to
undergo homologation it was assumed that the issue lay in the
position of the lactol–aldehyde equilibrium rather than steric fac-
tors. Attempts to force the equilibrium to favour the open-chain
form (by performing the reaction at higher temperatures or in
a microwave) only resulted in poorer yields.
OH
O
BnO
1
OMe
OTBDPS
O
RO
O
O
BnO
OMe
2
OTES
BnO
OTBDPS
OMe OR
O
MEMO
O
OTES
a, b
3
O
O
BnO
BnO
O
O
OMe
OMe
OTES
6
15
X
OTBDPS
BnO
c
O
OTES
OMe OR
4
5
MEMO
OH
d
OH
BnO
BnO
O
OMe OMEM
OMe
O
17
16
O
BnO
O
OMe
6
Scheme 3. Reagents and conditions: (a) KHBEt3, THF, ꢀ78 ꢁC, 76%; (b) MEMCl, iPr2NEt,
CH2Cl2, reflux, 66%; (c) DIBAL-H, THF, ꢀ78 ꢁC, 80%; (d) 10, K2CO3, MeOH, 36 ꢁC, 22%.
These disappointing results prompted us to devise an alterna-
tive strategy to access the key alkyne, which avoided reliance on the
lactol–aldehyde equilibrium (Scheme 4). Reduction of lactone 15
with LAH cleanly furnished diol 18, which was then subjected to
classical TES-protection (TESOTf, 2,6-lutidine in CH2Cl2). Un-
fortunately, no bis-protected 19 was formed but instead dioxolane
20 was obtained. Such dioxolane formation has previously been
reported by Boynton et al. upon treatment of a MEM-protected diol
with MgBr2 in EtOAc.25 Attempts to obtain 19 using the weaker
Lewis-acid TESCl were unsuccessful as, even when using a large
excess of reagents and elevated temperatures, only mono-pro-
tected products were obtained.
Scheme 1. Retrosynthetic analysis of spiroketal 1.
O
BnO
d, e
a, b, c
TBSO
OH
OMe
OBn
9
O
8
7
O
O
O
OTBS
O
O
f, g, h
N
N
OBn
P(OMe)2
O
MEMO
OH
OMe
a
Bn
N2
10
BnO
OH
12
O
BnO
11
O
OMe OMEM
OMe
15
i
18
OBn
j
BnO
b
TBSO
O
b
OBn
OBn
O
O
OTBS
TESO
TESO
O
14
BnO
13
BnO
OTES
Scheme 2. Reagents and conditions: (a) OsO4, (DHQ)2PYR, K3FeCN6, K2CO3, H2O/
t-BuOH (1:1), 0 ꢁC, 82%; (b) Cl3CNHOBn, CF3SO3H, CH2Cl2/c-C6H12 (1:3), 35 ꢁC, 91%; (c)
DIBAL-H, PhMe, ꢀ78 ꢁC, 90%; (d) 10, K2CO3, MeOH, 36 ꢁC, 61%; (e) TBSOTf, 2,6-lutidine,
CH2Cl2, 0 ꢁC, 89%; (f) Bu2BOTf, Et3N, CH2Cl2, 0 ꢁC then BnOCH2CH2CHO, ꢀ78 ꢁC, 80%;
(g) MeO(Me)NH$HCl, AlMe3, THF, 0 ꢁC, 89%; (h) TBSOTf, 2,6-lutidine, CH2Cl2, 0 ꢁC, 89%;
(i) 9, n-BuLi, THF, ꢀ78 ꢁC, 62%; (j) CSA, MeOH then p-TsOH, PhMe, rt, 86%.
OMe O
O
OMe OMEM
20
19
Scheme 4. Reagents and conditions: (a) LAH, THF, 0 ꢁC to rt; (b) TESOTf, 2,6-lutidine,
CH2Cl2, 0 ꢁC to rt, 60% over 2 steps.

D. Habrant et al. / Tetrahedron 65 (2009) 7927–7934
7929
With the MEM ether proving problematic both in terms of its
a ,b
O
HO
OH
OTBDPS
introduction and undesired reactivity, we were prompted to in-
vestigate an alternative protecting group for the C21 alcohol. An
allyl group was selected for this purpose (Scheme 5). Lactone 6 was
therefore protected, after reduction, to the corresponding allyl
ether using classical conditions in an 86% yield. As observed pre-
viously, reduction of the lactone ring using LAH in THF proceeded
cleanly to furnish diol 22, which was used in the next step without
purification. TES-protection of 22 yielded fully protected 23, with
a satisfactory yield of 88% for these two steps. The following step
involved the selective deprotection of the primary TES in the
presence of the secondary, in order to reach targeted aldehyde 24.26
Preliminary attempts to selectively deprotect the primary ether,
either in the presence of TBAF or different acid sources were not
satisfactory, leading to mixtures of starting material 23, fully
deprotected diol 22 and mono-deprotected compound. Pleasingly,
using slightly modified conditions described by Spur et al.,27 we
found out that direct oxidation of the primary silyl ether could be
achieved under Swern conditions. Indeed, after addition of 23 on
a DMSO/oxalyl chloride solution in CH2Cl2 at ꢀ78 ꢁC, we observed
that stirring the reaction mixture for 1 h at ꢀ25 ꢁC before addition
of Et3N at ꢀ78 ꢁC cleanly cleaved and oxidized the primary TES to
yield aldehyde 24 in a good isolated yield of 83%. Finally, Ohira–
Bestmann homologation of 24 proceeded successfully, and the key
alkyne 25 was obtained in excellent yield. This route proved to be of
sufficient efficiency and reproducibility to consistently deliver
acetylene 25 on gram scale.
26
27
c
O
OH
O
O
OTES
d, e
N
OTBDPS
O
R
f
OTBDPS
Bn
28
29 R = N(Me)OMe
30 R = H
Scheme 6. Reagents and conditions: (a) TBDPSCl, Et3N, CH2Cl2, rt; (b) SO3$Py, Et3N,
DMSO, CH2Cl2, rt, 88% over 2 steps; (c) 11, Bu2BOTf, Et3N, CH2Cl2, 0 ꢁC then 27, ꢀ78 ꢁC,
83%; (d) MeO(Me)NH$HCl, AlMe3, THF, 0 ꢁC, 71%; (e) TESOTf, 2,6-lutidine, CH2Cl2, 0 ꢁ
to rt, 97%; (f) DIBAL-H, THF, ꢀ78 ꢁC, 71%.
C
could be recovered. We then turned our attention to the synthesis
of more reactive aldehyde coupling partner 30, which was obtained
by simple reduction of amide 29 (Scheme 6). It is well known that
addition of lithium acetylides to readily enolizable aldehydes can
be performed in the presence of anhydrous lithium bromide, as
described by Carreira for the synthesis of (þ)-Zaragozic acid C.29
Unfortunately, in our case, application of these conditions led to the
recovery of alkyne 25 and formation of elimination product 32,30 no
trace of propargylic alcohol 31 being observed (Scheme 7).
Changing the reaction conditions by varying the amount of re-
actants, the temperature or the solvent did not lead to any im-
provement for the reaction of acetylide anion of 25 with 29 or 30.
Quenching the acetylide anion of 25 with D2O, however, resulted in
quantitative insertion of deuterium and thus it was apparent that
the lack of reactivity was not a matter of the acidity of 25 but in-
stead its poor nucleophilicity.
AllO
O
a, b
O
O
BnO
BnO
O
O
OMe
21
OMe
6
c
TESO
a
BnO
TESO
OH
+
25
30
d
OTBDPS
BnO
OTES
BnO
OH
OMe OAll
OH OTES
OMe OAll
23
OMe OAll
a
31
22
e
O
H
OTBDPS
TESO
TESO
f
32
O
BnO
BnO
Scheme 7. Reagents and conditions: n-BuLi, LiBr, THF, ꢀ78 ꢁC.
OMe OAll
OMe OAll
24
25
A range of alternative metallic species have been used for the
Scheme 5. Reagents and conditions: (a) KHBEt3, THF, ꢀ78 ꢁC, 76%; (b) allyl bromide,
t-BuOK, THF, rt, 86%; (c) LAH, THF, 0 ꢁC to rt; (d) TESOTf, 2,6-lutidine, CH2Cl2, 0 ꢁC to rt,
88% over 2 steps; (e) (COCl)2, DMSO, ꢀ25 ꢁC then Et3N, ꢀ78 ꢁC, 83%; (f) 10, K2CO3,
MeOH, rt, 92%.
construction of propargylic alcohols from the corresponding ter-
minal acetylenes and aldehydes. Unfortunately, neither Carreira’s
(Zn(OTf)2, Et3N, (þ)-N-methyl-ephedrine, toluene),31 Cozzi’s
(Me2Zn, toluene),32 Pu’s (Et2Zn, Ti(O-iPr)4, BINOL, toluene, ether),33
Shibasaki’s (InBr3, BINOL, Cy2NMe, CH2Cl2)34 or Konakahara’s
(InBr3, Et3N, Et2O)35 conditions proved to be efficient in our case
and only starting materials were recovered in all attempts
performed.
With key alkyne 25 in hand, we turned our attention to the
synthesis of its coupling partner (Scheme 6). 1,3-Propanediol 26
was selectively mono-protected as its TBDPS ether and the result-
ing alcohol oxidized to aldehyde 27 using the Parikh–Doering
protocol.28 Evans aldol reaction with 11 gave 28, which was reacted
with N,O-dimethylhydroxylamine followed by TES-protection to
furnish the Weinreb amide 29.
With each coupling partner in hand the key-coupling reaction
between alkyne 25 and Weinreb amide 29 was investigated. Un-
fortunately, under the conditions described for our model com-
pound 9 (Scheme 2; n-BuLi, THF, ꢀ78 ꢁC), only starting materials
Among the numerous methodologies reported for the con-
struction of
a,b-acetylenic ketones, the palladium and/or copper
coupling of terminal acetylenic derivatives with acid chlorides
appeared to be the method of choice.36 However, all attempts to
form the acid chloride derivative of 29 failed. We then turned our
attention to the method of Fukuyama in which dodecanethiol es-
ters are reacted with terminal acetylenes in the presence of

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D. Habrant et al. / Tetrahedron 65 (2009) 7927–7934
PdCl2(dppf)2 and CuI.37 To this end, thiol ester 34 was prepared in
two steps from alcohol 28 by silyl ether formation followed by
displacement of the oxazolidinone moiety with lithium dodeca-
nethiolate (Scheme 8).38
coupling step between alkyne 25 and thiol ester 34 furnished
alkynone 35, which upon acidic treatment underwent the pivotal
spirocyclisation. This represents the first example of the use of the
DIHMA process for the construction of this fragment. Application of
the described methodology towards the total synthesis of Calyculin
C and Geometricin are in progress and will be reported in due
course.
O
OTES
O
O
OTES
a
b
28
N
OTBDPS
S
OTBDPS
O
11
Bn
34
33
4. Experimental section
4.1. General
Scheme 8. Reagents and conditions: (a) TESOTf, 2,6-lutidine, CH2Cl2, 0 ꢁC to rt, 88%;
(b) dodecanethiol, n-BuLi, THF, 0 ꢁC, then 33, ꢀ78 ꢁC, 92%.
Pleasingly, using the above-described conditions, cross-cou-
pling of terminal acetylene 25 and thiol ester 34 produced the
desired ynone 35 in a moderate 55% yield (Scheme 9). The
unreacted thiol ester 34 could be recovered almost quantitatively
but alkyne 25 was completely consumed via its oxidative homo-
coupling to yield the corresponding Glaser-type diyne product 36.
Those observations are in close agreement with those reported by
Kuwahara et al. in their synthesis of Pteridic acids A and B.39 Finally,
upon exposure to p-TsOH in toluene, ynone 35 underwent TES-
deprotection followed by DIHMA to furnish the target spiroketal 37
as a single enantiomer in 57% yield.
All moisture sensitive reactions were carried out under an argon
atmosphere in flame-dried glassware. THF, CH2Cl2 and toluene
used were obtained by passing deoxygenated solvents through
activated alumina columns (MBraun SPS-800 Series solvent puri-
fication system). MeOH was obtained by distillation over magne-
sium methoxide, DMF by distillation over 4Å molecular sieves and
ninhydrin, Et3N and DMSO by distillation over CaH2 and storage
over 4Å molecular sieves. Oxalyl chloride was freshly distilled prior
to use. Allyl bromide was washed with a aqueous saturated solution
of NaHCO3 then water, dried over MgSO4 and distilled prior to use.
CuI was purified using standard method.40 Other solvents and re-
agents were used as obtained from supplier. Analytical TLC was
TESO
O
OTES
performed using Merck silica gel F254 (10–12 mm) plates and an-
BnO
alyzed by UV light (254 or 366 nm) and by staining upon heating
with standard permanganate or phosphomolybdic acid solutions.
For silica gel chromatography, the flash chromatography technique
was used, with Merck silica gel 60 (230–400 mesh) and p.a. grade
solvents. The 1H NMR and 13C NMR spectra were recorded in CDCl3
on a Bruker Avance 400 (1H 399.98 MHz; 13C 100.59 MHz) spec-
trometer. The chemical shifts are reported in ppm relative to CHCl3
S
OTBDPS
11
OMe OAll
25
34
a
(d d
7.26) for 1H NMR and ( 77.16) for 13C NMR. IR spectra were
TESO
BnO
recorded on a Perkin–Elmer Spectrum One spectrometer. Optical
rotations were obtained with a Perkin–Elmer 343 polarimeter. High
resolution mass spectrometric data were measured using Micro-
Mass LCT Premier Spectrometer.
OTBDPS
OMe OAll
O
OTES
35
4.2. (4R,5R)-5-((S)-3-(Benzyloxy)-1-methoxypropyl)-4-
((2-methoxyethoxy)methoxy)-3,3-dimethyltetrahydrofuran-
2-ol 16
b
OTBDPS
AllO
To a solution of lactone 15 (1.775 g, 4.48 mmol, 1 equiv) in tol-
uene (45 mL) was added DIBAL-H (1 M in toluene, 7.61 mL,
7.71 mmol, 1.7 equiv) at ꢀ78 ꢁC. The mixture was stirred for 40 min
at ꢀ78 ꢁC, then quenched by addition of MeOH (20 mL) and
allowed to warm to rt. 1 M HCl (50 mL) and EtOAc (50 mL) were
then added and stirring was continued for 1 h. After separation, the
aqueous phase was extracted with EtOAc (3ꢂ50 mL). The combined
organic extracts were washed with a saturated aqueous solution of
NaHCO3 (40 mL), brine (40 mL), dried over MgSO4 and concen-
trated in vacuo. Purification by flash chromatography (50% EtOAc/
hexane) afforded lactol 16 (1.428 g, 80%), as a yellow oil,1/1 mixture
of diastereomers. Rf (50% EtOAc/hexane:) 0.11; 1H NMR (CDCl3, 2
O
BnO
O
OMe
O
37
TESO
BnO
OAll OMe
OTES
OMe OAll
diastereomers) d: 1.03 (s, 3H), 1.06 (s, 3H), 1.08 (s, 3H), 1.12 (s, 3H),
OBn
1.66–1.75 (m, 2H), 1.88–1.95 (m, 2H), 3.34 (s, 3H), 3.35 (s, 3H), 3.38–
3.52 (m, 9H), 3.55–3.68 (m, 9H), 3.75–3.82 (m, 3H), 3.85 (d,
J¼4.7 Hz, 1H), 4.17 (dd, J¼4.6, 6.9 Hz, 1H), 4.24 (dd, J¼4.7, 7.5 Hz,
1H), 4.59 (s, 1H), 4.72–4.78 (m, 5H), 5.11 (d, J¼5.5 Hz, 1H), 7.27–7.33
36
Scheme 9. Reagents and conditions: (a) PdCl2(dppf), P(2-furyl)3, CuI, Et3N, DMF, 50 ꢁC,
55%; (b) p-TsOH, PhMe, rt, 57%.
(m, 10H); 13C NMR (CDCl3, 2 diastereomers)
d: 14.1, 18.3, 20.2, 22.6,
3. Conclusion
24.7, 29.3, 29.6, 31.0, 31.4, 31.9, 46.5, 47.1, 59.0, 59.2, 66.2, 66.3, 68.1,
68.4, 71.7, 73.0, 73.1, 77.6, 81.8, 84.2, 85.4, 86.3, 96.8, 97.0, 103.9,
105.1, 127.5, 127.6, 127.7, 128.2, 128.3, 138.4, 138.5; IR (ymax, thin
film) 3401, 2925, 2854, 1726, 1098 cmꢀ1; HRMS: calculated for
C21H34O7Na [MþNa]þ: 421.2226, found: 421.2219.
In conclusion, we have achieved the synthesis of an orthogo-
nally protected C13–C25 spirocyclic unit, which should prove ame-
nable to the convergent total synthesis of Calyculin C. The key-

D. Habrant et al. / Tetrahedron 65 (2009) 7927–7934
7931
4.3. (8R,9R,10S)-10-Methoxy-8-(2-methylbut-3-yn-2-yl)-14-
7.34 (m, 5H); 13C NMR (CDCl3)
d: 4.5, 6.9, 20.0, 20.6, 31.6, 38.5, 59.4,
phenyl-2,5,7,13-tetraoxatetradecan-9-ol 17
66.9, 69.4, 73.2, 78.1, 78.9, 80.7, 95.9, 127.7, 127.8, 128.4, 138.4; IR
(
ymax, thin film) 2955, 2876, 1456, 1363, 1239, 1099 cmꢀ1; HRMS:
A solution of lactol 16 (0.155 g, 0.39 mmol, 1 equiv) in MeOH
(8 mL) was treated with Ohira–Bestmann’s reagent 10 (0.108 g,
0.78 mmol, 2 equiv) and K2CO3 (0.149 g, 0.78 mmol, 2 equiv). The
mixture was heated to 35 ꢁC and stirred for 24 h. More 10 and
K2CO3 (1 equiv each) were added every 24 h during 6 days, after
which the reaction was stopped. The reaction mixture was cooled
to rt and MeOH was removed in vacuo. The residue was partitioned
between EtOAc (20 mL) and H2O (10 mL). The aqueous phase was
further extracted with EtOAc (3ꢂ15 mL). The combined organic
extracts were washed with brine (20 mL), dried over MgSO4 and
concentrated in vacuo. Purification by flash chromatography (30–
50% EtOAc/hexane) afforded expected alkyne 17 (0.034 g, 22%, 41%
calculated for C24H42O5NaSi [MþNa]þ: 461.2699, found: 461.2760.
4.6. (4R,5R)-4-(Allyloxy)-5-((S)-3-(benzyloxy)-1-methoxy
propyl)-3,3-dimethyldihydrofuran-2(3H)-one 21
Lactone 6 (0.257 g, 0.83 mmol, 1 equiv) was dissolved in THF
(5 mL). Potassium tert-butoxide (1 M in THF, 1.25 mL, 1.25 mmol,
1.5 equiv) was then added at 0 ꢁC and the reaction mixture was
stirred 30 min at 0 ꢁC, after which allyl bromide (0.10 mL,
1.25 mmol, 1.5 equiv) was added. The solution was stirred at rt
overnight, then quenched by addition of a saturated aqueous so-
lution of NH4Cl (5 mL). After separation, the aqueous phase was
further extracted with EtOAc (2ꢂ10 mL). Combined organic extracts
were dried over MgSO4 and concentrated in vacuo. Purification by
flash chromatography (20–30% EtOAc/hexane) afforded protected
based on recovery of 16) as a colourless oil and unreacted lactol 16
20
(0.071 g, 46%) as a yellow oil. Rf (50% EtOAc/hexane) 0.22; [
a
]
þ2.2
D
(c 1, CHCl3); 1H NMR (CDCl3)
d: 1.24 (s, 3H), 1.29 (s, 3H), 1.86–2.07
(m, 2H), 2.07 (s, 1H), 2.86 (d, J¼6.4 Hz, 1H), 3.36 (s, 3H), 3.39–3.42
(m, 1H), 3.38 (s, 3H), 3.46 (d, J¼2.3 Hz, 1H), 3.43 (s, 2H), 3.60–3.65
(m, 3H), 3.76–3.80 (m, 1H), 3.89–3.93 (m, 1H), 4.82 (s, 2H), 4.88 (d,
J¼6.6 Hz, 1H), 4.94 (d, J¼6.6 Hz, 1H), 7.25–7.34 (m, 5H); 13C NMR
compound 21 (0.248 g, 86%) as a colourless oil. Rf (50% EtOAc/
20
hexane) 0.64; [
a]
ꢀ7.1 (c 1, CHCl3); 1H NMR (CDCl3)
d: 1.11 (s, 3H),
D
1.26 (s, 3H), 1.64–1.72 (m, 1H), 1.84–1.92 (m, 1H), 3.46 (s, 3H), 3.58–
3.63 (m, 1H), 3.67–3.77 (m, 3H), 3.92 (ddt, J¼1.4, 5.5, 12.2 Hz, 1H),
4.09 (ddt, J¼1.4, 5.5,12.2 Hz,1H), 4.46–4.49 (m, 3H), 5.13 (ddt, J¼1.4,
1.4, 10.4 Hz, 1H), 5.24 (ddt, J¼1.6, 1.6, 17.2 Hz, 1H), 5.85 (ddt J¼5.3,
(CDCl3) d: 23.7, 26.8, 29.9, 36.2, 58.2, 59.0, 66.9, 68.4, 69.9, 71.3, 71.7,
73.0, 80.8, 82.8, 89.9, 97.8, 127.4, 127.7, 138.4; IR (ymax, thin film)
3522, 3291, 2927, 1455, 1100, 1024 cmꢀ1; HRMS: calculated for
C22H34O6Na [MþNa]þ: 417.2253, found: 417.2265.
10.6, 17.2 Hz, 1H), 7.25–7.33 (m, 5H); 13C NMR (CDCl3)
d: 18.4, 23.1,
30.4, 45.8, 59.4, 65.8, 73.2, 73.6, 77.3, 83.5, 84.2, 117.4, 127.7, 127.8,
128.2, 133.6, 138.4, 180.5; IR (ymax, thin film) 2973, 2934, 2869, 1771,
1455,1139,1096 cmꢀ1; HRMS: calculated for C20H28O5Na [MþNa]þ:
371.1834, found: 371.1836.
4.4. (3R,4R,5S)-7-(Benzyloxy)-5-methoxy-3-((2-methoxy
ethoxy)methoxy)-2,2-dimethylheptane-1,4-diol 18
Lithium aluminium hydride (0.44 g, 1.15 mmol, 2 equiv) was
suspended in THF (2 mL). Compound 15 (0.228 g, 0.57 mmol,
1 equiv) in THF (1 mL) was then added dropwise at 0 ꢁC; gas evo-
lution was observed. The mixture was allowed to warm to rt and
stirred for 2 h. The reaction was then quenched by successive ad-
dition of H2O (0.05 mL), 15% NaOH (0.05 mL) and H2O (0.15 mL).
After 30 min, the precipitate formed was filtered and washed with
EtOAc (20 mL). The organic extracts were washed with brine
(10 mL), dried over MgSO4 and concentrated in vacuo to afford diol
18 as a yellow oil, which was used in the next step without further
4.7. (3R,4R,5S)-3-(Allyloxy)-7-(benzyloxy)-5-methoxy-2,2-
dimethylheptane-1,4-diol 22
Lithium aluminium hydride (0.100 g, 2.59 mmol, 2 equiv) was
suspended in THF (7 mL). Compound 21 (0.452 g, 1.29 mmol,
1 equiv) in THF (3 mL) was then added dropwise at 0 ꢁC, gas evo-
lution was observed. The mixture was stirred for 1 h at 0 ꢁC and
then quenched by successive addition of H2O (0.1 mL), 15% NaOH
(0.1 mL) and H2O (0.3 mL). After 30 min, the precipitate formed was
filtered and washed with EtOAc (20 mL). The organic extracts were
washed with brine (10 mL), dried over MgSO4 and concentrated in
vacuo to afford diol 22 as a yellow oil, which was used in the next
step without further purification. Rf (50% EtOAc/hexane) 0.45; 1H
purification. Rf (5% MeOH/CH2Cl2) 0.67; 1H NMR (CDCl3)
d: 0.83 (s,
3H), 0.87 (s, 3H), 1.79–1.84 (m, 1H), 1.93–1.98 (m, 1H), 3.26–3.32 (m,
2H), 3.33 (s, 3H), 3.38 (s, 2H), 3.47–3.52 (m, 3H), 3.54–3.58 (m, 3H),
3.75–3.80 (m, 1H), 4.46 (s, 2H), 4.75 (d, J¼6.9 Hz, 2H), 4.84 (d,
J¼6.9 Hz, 2H), 7.21–7.31 (m, 5H); 13C NMR (CDCl3): 20.2, 23.2, 30.0,
40.2, 57.4, 58.3, 59.0, 66.6, 68.3, 70.2, 71.7, 73.2, 80.9, 82.8, 98.0,
127.7, 127.8, 128.4, 138.2; IR (ymax, thin film) 3460, 2931, 2876, 1455,
NMR (CDCl3) d: 0.89 (s, 3H), 0.91 (s, 3H), 1.76–1.83 (m, 1H), 1.92–
1.99 (m, 1H), 3.15 (br s, 1H), 3.20–3.24 (m, 2H), 3.41 (s, 3H), 3.58–
3.63 (m, 1H), 3.55–3.61 (m, 3H), 3.74–3.76 (m, 2H), 4.08 (ddt, J¼1.4,
5.5, 12.3 Hz, 1H), 4.19 (ddt, J¼1.4, 5.5, 12.3 Hz, 1H), 4.49 (dd, J¼0.7,
12.1 Hz, 2H), 5.13 (ddt, J¼1.4, 1.4, 10.4 Hz, 1H), 5.25 (ddt, J¼1.6, 1.6,
17.2 Hz, 1H), 5.90 (ddt, J¼5.4, 10.6, 17.2 Hz, 1H), 7.25–7.33 (m, 5H);
1365, 1099, 1035 cmꢀ1
; HRMS: calculated for C21H36O7Na
[MþNa]þ: 423.2359, found: 423.2375.
13C NMR (CDCl3)
d: 21.3, 23.4, 30.3, 40.5, 58.4, 66.7, 68.1, 70.0, 73.2,
4.5. ((1R,2S)-4-(Benzyloxy)-1-((R)-5,5-dimethyl-1,3-dioxan-4-
yl)-2-methoxybutoxy)triethylsilane 20
74.6, 80.9, 84.0, 116.7, 127.7, 127.8, 128.4, 134.6, 138.3; IR (ymax, thin
film) 3459, 2959, 2930, 2872,1455,1093 cmꢀ1 HRMS: calculated for
C20H32O5Na [MþNa]þ: 375.2147, found: 375.2149.
Crude diol 18 was dissolved in CH2Cl2 (5 mL). 2,6-Lutidine
(0.53 mL, 4.56 mmol, 8 equiv) and TESOTf (0.51 mL, 5.28 mmol,
4 equiv) were successively added at 0 ꢁC. The mixture was stirred
overnight and then quenched by addition of H2O (5 mL). After
separation, the aqueous phase was further extracted with CH2Cl2
(10 mL). Combined organic extracts were dried over MgSO4 and
concentrated in vacuo. Purification by flash chromatography (5%
4.8. (5R,6R)-6-(Allyloxy)-5-((S)-3-(benzyloxy)-1-methoxy
propyl)-3,3,10,10-tetraethyl-7,7-dimethyl-4,9-dioxa-3,10-
disiladodecane 23
Crude diol 22 was dissolved in CH2Cl2 (15 mL). 2,6-Lutidine
(1.23 mL, 10.57 mmol, 8 equiv) and TESOTf (1.19 mL, 5.28 mmol,
4 equiv) were successively added at 0 ꢁC. After 2 h at 0 ꢁC, a satu-
rated aqueous solution of NH4Cl (20 mL) was added to the mixture.
After separation, the aqueous phase was extracted with CH2Cl2
(20 mL). Combined organic extracts were dried over MgSO4 and
concentrated in vacuo. Purification by flash chromatography (0–2%
EtOAc/hexane) afforded di-protected compound 23 (0.665 g, 88%
EtOAc/hexane) furnished acetonide 20 (0.150 g, 60% over the 2
20
steps) as a colourless oil. Rf (10% EtOAc/hexane) 0.59; [
a]
ꢀ0.8 (c 1,
D
CHCl3); 1H NMR (CDCl3)
d
: 0.59 (q, J¼7.4 Hz, 6H), 0.85 (s, 3H), 0.90
(s, 3H), 0.96 (t, J¼7.4 Hz, 9H), 1.92–1.96 (m, 2H), 3.33–3.39 (m, 2H),
3.42 (s, 3H), 3.45 (d, J¼9.5 Hz, 1H), 3.61–3.64 (m, 2H), 3.86–4.00 (m,
2H), 4.51 (s, 2H), 4.96 (d, J¼11.1 Hz, 1H), 5.01 (d, J¼9.5 Hz, 1H), 7.28–

7932
D. Habrant et al. / Tetrahedron 65 (2009) 7927–7934
20
over 2 steps) as a yellow oil. Rf (5% EtOAc/hexane) 0.70; [
1, CHCl3); 1H NMR (CDCl3)
a]
ꢀ2.9 (c
58.8, 67.4, 70.0, 73.0, 73.5, 73.6, 80.5, 82.5, 91.3, 116.0, 127.6, 127.7,
D
d
: 0.58 (q, J¼8.2 Hz, 6H), 0.65 (q,
128.4, 135.5, 138.8; IR (ymax, thin film) 3306, 2953, 2875, 1458,
J¼8.1 Hz, 6H), 0.90 (s, 3H), 0.92 (s, 3H), 0.96 (t, J¼8.1 Hz, 9H), 0.97 (t,
J¼8.2 Hz, 9H), 1.74–1.81 (m, 1H), 2.02–2.10 (m, 1H), 3.18 (d,
J¼9.4 Hz, 1H), 3.34–3.38 (m, 1H), 3.39 (s, 3H), 3.45 (d, J¼4.3 Hz, 1H),
3.53 (d, J¼9.4 Hz, 1H), 3.57–3.61 (m, 2H), 3.88 (dd, J¼4.3, 5.3 Hz,
1H), 3.98 (ddt, J¼1.6, 5.3, 13.1 Hz, 1H), 4.22 (ddt, J¼1.6, 5.3, 13.1 Hz,
1H), 4.49 (d, J¼12.0 Hz, 1H), 4.53 (d, J¼12.0 Hz, 1H), 5.07 (ddt, J¼1.7,
1.7, 10.5 Hz, 1H), 5.25 (ddt, J¼1.9, 1.9, 17.2 Hz, 1H); 5.90 (ddt J¼5.2,
1097 cmꢀ1
483.2907, found: 483.2917.
;
HRMS: calculated for C27H44O4NaSi [MþNa]þ:
4.11. (R)-4-Benzyl-3-((2R,3S)-5-(tert-butyldiphenyl silyloxy)-
3-hydroxy-2-methylpentanoyl)oxazolidin-2-one 28
Bu2BOTf (1 M in CH2Cl2, 17.29 mL, 17.29 mmol, 1.2 equiv) was
added to a solution of 11 (3.679 g, 15.85 mmol, 1.1 equiv) in CH2Cl2
(40 mL) at 0 ꢁC. After 15 min, Et3N (2.63 mL, 18.73 mmol, 1.3 equiv)
was added. After 30 min at 0 ꢁC, the mixture was cooled to ꢀ78 ꢁC
and a solution of aldehyde 27 (4.503 g,14.41 mmol,1 equiv) in CH2Cl2
(10 mL) was added. The reaction mixture was stirred for 2 h at ꢀ78 ꢁC
then allowed to warm to 0 ꢁC and stirred for 2 h. Phosphate buffer
(pH 7, 15 mL) and MeOH (15 mL) were then added, the mixture was
stirred for 15 min and then a H2O2/MeOH solution (3/1, 20 mL) was
added. The reaction was allowed to warm to rt and stirred for 1 h.
Solvent was then evaporated and the residue was taken up by EtOAc
(40 mL) and H2O (30 mL). After separation, the organic extracts were
dried over MgSO4 and concentrated in vacuo. Purification by flash
10.5,17.2 Hz,1H); 7.27–7.35 (m, 5H); 13C NMR (CDCl3)
d: 4.5, 5.6, 7.0,
7.3, 20.1, 22.2, 40.7, 59.1, 67.3, 70.1, 73.0, 73.2, 73.3, 80.0, 80.6, 115.1,
127.5, 127.7, 128.4, 136.1, 138.8; IR (ymax, thin film) 2956, 2933, 1732,
1456, 1097 cmꢀ1; HRMS: calculated for C32H60O5NaSi2 [MþNa]þ:
603.3877, found: 603.3882.
4.9. (3R,4R,5S)-3-(Allyloxy)-7-(benzyloxy)-5-methoxy-2,2-
dimethyl-4-(triethylsilyloxy)heptanal 24
A solution of DMSO (1.49 mL, 20.94 mmol, 8.8 equiv) in CH2Cl2
(12 mL) was cooled to ꢀ78 ꢁC. Oxalyl chloride (0.90 mL, 10.47 mmol,
4.4 equiv) was added to the solution (gas evolution was observed).
TES-protected compound 23 (1.381 g, 2.38 mmol, 1 equiv) in CH2Cl2
(12 mL) was added. The solution was stirred for 20 min at ꢀ78 ꢁC
(solution turned pink) and thenwarmed to ꢀ25 ꢁC and stirred for 1 h
at this temperature (solution turned pale yellow). The solution was
then cooled down to ꢀ78 ꢁC and Et3N (4.97 mL, 35.70 mmol,
15 equiv) was added. The mixture was allowed to warm to rt and
after 45 min, the precipitate that had formed was filtered. H2O
(15 mL) was added to the filtrate. After separation, the aqueous
phase was further extracted with EtOAc (2ꢂ15 mL). Combined or-
ganic extracts were dried over MgSO4 and concentrated in vacuo.
Purification by flash chromatography (5–10% EtOAc/hexane) affor-
chromatography (20–40% EtOAc/hexane) afforded alcohol 28 (6.52 g,
20
83%) as a waxy solid. Rf (20% EtOAc/hexane) 0.34; [
a
]
ꢀ3.3 (c 1,
D
CHCl3); 1H NMR (CDCl3)
d
: 1.05 (s, 9H), 1.28 (d, J¼7.0 Hz, 3H), 1.62–
1.72 (m, 1H), 1.77–1.87 (m, 1H), 2.78–2.82 (m, 1H), 3.23–3.33 (m, 1H),
3.40 (br s, 1H), 3.80–3.91 (m, 2H), 4.15–4.27 (m, 3H), 4.65–4.72 (m,
1H), 7.20–7.45 (m, 11H), 7.65–7.69 (m, 4H); 13C NMR (CDCl3)
d: 11.3,
19.1, 26.9, 36.0, 37.8, 42.8, 55.2, 62.4, 66.2, 70.6, 127.3, 127.7, 128.9,
129.4, 129.8, 133.3, 135.2, 135.6, 153.1, 176.5; IR (ymax, thin film) 3500,
2960, 2935,1785,1690,1110 cmꢀ1; HRMS: calculated for C32H40NO5Si
[MþH]þ: 546.2676, found 546.2701.
ded aldehyde 24 (0.921 g, 83%) as a colourless oil. Rf (5% EtOAc/
4.12. (2R,3S)-5-(tert-Butyldiphenylsilyloxy)-3-hydroxy-N-
methoxy-N,2-dimethylpentanamide
20
hexane) 0.28; [
a
]
ꢀ0.9 (c 1, CHCl3); 1H NMR (CDCl3)
d: 0.61 (q,
D
J¼8.0 Hz, 6H), 0.94 (t, J¼8.2 Hz, 9H), 1.06 (s, 3H), 1.09 (s, 3H), 1.68–
1.77 (m, 1H), 2.06–2.12 (m, 1H), 3.30 (s, 3H), 3.36–3.41 (m, 1H), 3.50
(d, J¼3.8 Hz, 1H), 3.53–3.57 (m, 2H), 3.92 (dd, J¼3.8, 6.1 Hz, 1H), 4.01
(ddt, J¼1.5, 5.3 Hz, 12.8 Hz, 1H), 4.21 (ddt, J¼1.6, 4.9, 12.8 Hz, 1H),
4.48 (d, J¼12.0 Hz, 1H), 4.51 (d, J¼12.0 Hz, 1H), 5.13 (ddt, J¼1, 1.6,
10.5 Hz, 1H), 5.27 (ddt, J¼1.8, 1.6, 17.2 Hz, 1H), 5.87 (ddt, J¼5.2, 10.5,
N,O-dimethylhydroxylamine hydrochloride (2.50 g, 25.61 mmol,
2.2 equiv) was suspended in THF (20 mL) and cooled to 0 ꢁC. Tri-
methylaluminium (2 M in hexanes, 12.8 mL, 25.61 mmol, 2.2 equiv)
was added and the mixture was stirred for 15 min at 0 ꢁC and 1 h at
rt, where the solution became homogeneous. After cooling down to
0 ꢁC, a solution of 28 (6.35 g, 11.64 mmol, 1 equiv) in THF (20 mL)
and CH2Cl2 (15 mL) was added. The mixture was stirred for 3 h at
0 ꢁC and 30 min at rt. The reaction mixture was then added at 0 ꢁC to
a CH2Cl2/HCl 0.5 M mixture (1/1, 150 mL). Gas evolution was ob-
served and stirring was maintained for 2 h at 0 ꢁC. After separation,
the aqueous phase was further extracted with EtOAc (2ꢂ20 mL).
Combined organic extracts were dried over MgSO4 and concen-
trated in vacuo. Purification by flash chromatography (20–50%
17.2 Hz, 1H), 7.27–7.34 (m, 5H), 9.64 (s, 1H). 13C NMR (CDCl3)
d: 5.3,
7.2, 20.0, 20.3, 29.8, 50.5, 28.1, 67.0, 72.6, 73.1, 74.0, 79.9, 83.7, 116.1,
127.6, 127.8, 128.4, 134.9, 138.6, 205.0; IR (ymax, thin film) 2954, 2926,
1722, 1458, 1096 cmꢀ1
; HRMS: calculated for C26H44O5NaSi
[MþNa]þ: 487.2856, found: 487.2860.
4.10. ((3S,4R,5R)-5-(Allyloxy)-1-(benzyloxy)-3-methoxy-6,6-
dimethyloct-7-yn-4-yloxy)triethylsilane 25
EtOAc/hexane) afforded the Weinreb amide (3.54 g, 71%) as a yellow
20
Aldehyde 24 (0.940 g, 2.02 mmol, 1 equiv) was dissolved in
MeOH (20 mL). Ohira–Bestmann reagent 10 (0.972 g, 5.06 mmol,
2.5 equiv) and K2CO3 (0.700 g, 5.06 mmol, 2.5 equiv) were then
successively added and the mixture was stirred at rt overnight.
MeOH was then evaporated and the residue taken up in Et2O
(20 mL) and H2O (15 mL). After separation, the aqueous phase was
further extracted with EtOAc (2ꢂ20 mL). Combined organic ex-
tracts were dried over MgSO4 and concentrated in vacuo. Purifi-
oil. Rf (50% EtOAc/hexane) 0.60; [
(CDCl3)
a
]
D
ꢀ0.6 (c 1, CHCl3); 1H NMR
d
: 1.05 (s, 9H),1.21 (d, J¼6.8 Hz, 3H),1.64–1.67 (m,1H),1.76–
1.80 (m, 1H), 2.98 (br s, 1H), 3.19 (s, 3H), 3,67 (s, 3H), 3.83–3.86 (m,
2H), 3.98 (br s, 1H), 4.10–4.15 (m, 1H), 7.36–7.45 (m, 6H), 7.65–7.68
(m, 4H); 13C NMR (CDCl3)
d
: 11.6, 19.2, 26.9, 32.0, 36.3, 39.7, 61.6,
62.4, 71.0, 127.8, 129.8, 133.4, 135.6, 177.7; IR (ymax, thin film) 3436,
2931, 2857, 1638, 1427, 1111 cmꢀ1
; HRMS: calculated for
C24H35NO4NaSi [MþNa]þ: 452.2233; found: 452.2245.
cation by flash chromatography (5% EtOAc/hexane) afforded alkyne
20
25 (0.856 g, 92%) as a colourless oil. Rf (5% EtOAc/hexane) 0.35; [
a
]
4.13. (2R,3S)-5-(tert-Butyldiphenylsilyloxy)-N-methoxy-N,2-
dimethyl-3-triethylsilyloxypentanamide 29
D
ꢀ8.3 (c 1, CHCl3); 1H NMR (CDCl3)
d
: 0.66 (q, J¼7.6 Hz, 6H), 0.97 (t,
J¼7.6 Hz, 9H), 1.27 (s, 3H), 1.31 (s, 3H), 1.77–1.84 (m, 1H), 2.04–2.12
(m, 2H), 3.30 (d, J¼4.2 Hz,1H), 3.40 (s, 3H), 3.53–3.61 (m, 3H), 4.03–
4.08 (m, 2H), 4.26 (ddt, J¼1.6, 4.9, 13.0 Hz, 1H), 4.49 (d, J¼11.8 Hz,
1H), 4.53 (d, J¼11.8 Hz, 1H), 5.11 (ddt, J¼1.7, 1.7, 10.5 Hz, 1H), 5.27
(ddt, J¼1.8, 1.8, 17.2 Hz, 1H), 5.90 (dddd, J¼17.2, 10.5, 5.6, 5.0 Hz),
Weinreb amide (3.44 g, 8.00 mmol, 1 equiv) from the previous
step was dissolved in CH2Cl2 (40 mL). 2,6-Lutidine (3.73 mL,
32.00 mmol, 4 equiv) and TESOTf (3.73 mL, 16.00 mmol, 2 equiv)
were successively added at 0 ꢁC. After 2 h at 0 ꢁC, a saturated aqueous
solution of NH4Cl (20 mL) was added to the mixture. After separation,
7.27–7.34 (m, 5H); 13C NMR (CDCl3)
d: 5.6, 7.3, 25.2, 28.1, 30.9, 36.0,

D. Habrant et al. / Tetrahedron 65 (2009) 7927–7934
7933
the aqueous phase was extracted with CH2Cl2 (20 mL). Combined
organic extracts were dried over MgSO4 and concentrated in vacuo.
Purification by flash chromatography (10–30% EtOAc/hexane) affor-
added. The mixture was stirred for 1 h at ꢀ78 ꢁC, allowed to warm to
0 ꢁC and stirred 1 h at 0 ꢁC. The reaction was quenched by addition of
saturated aqueous solution of NH4Cl (10 mL). After extraction with
EtOAc (15 mL) and separation, organic extracts were washed with
brine (10 mL), dried over MgSO4 and concentrated in vacuo. Purifi-
cation by flash chromatography (2–5% EtOAc/hexane) furnished
ded protected compound 29 (4.24 g, 97%) as a colourless oil. Rf (20%
20
EtOAc/hexane) 0.57; [
a
]
þ0.3 (c 1, CHCl3); 1H NMR (CDCl3)
d: 0.58
D
(q, J¼8.0 Hz, 6H), 0.94 (t, J¼8.0 Hz, 9H), 1.04 (s, 9H), 1.13 (d, J¼6.9 Hz,
3H), 1.68–1.85 (m, 2H), 2.90–2.93 (m, 1H), 3.13 (s, 3H), 3.55 (s, 3H),
3.70–3.79 (m, 2H), 4.06–4.10 (m,1H), 7.34–7.44 (m, 6H), 7.65–7.67 (m,
thio-ester 34 (0.339 g, 92%) as a colourless oil. Rf (5% EtOAc/hexane)
20
0.82; [
a
]
ꢀ14.7 (c 1, CHCl3); 1H NMR (CDCl3)
: 0.60 (t, J¼8.0 Hz,
d
D
4H); 13C NMR (CDCl3)
d
: 5.1, 6.9, 13.9, 19.1, 26.8, 32.1, 38.8, 41.4, 60.7,
6H), 0.91 (t, J¼6.7 Hz, 3H), 0.95 (t, J¼8.0 Hz, 9H), 1.09 (s, 9H), 1.18 (d,
J¼7.0 Hz, 3H), 1.29–1.42 (m, 18H), 1.56–1.63 (m, 2H), 1.70–1.84 (m,
2H), 2.75–2.80 (m, 1H), 2.88 (t, J¼7.2 Hz, 2H), 3.71–3.75 (m, 2H), 4.31
(q, J¼6.2 Hz, 1H), 7.37–7.45 (m, 6H), 7.68–7.72 (m, 4H); 13C NMR
61.2, 71.2, 127.6, 129.5, 134.0, 135.6, 176.1; IR (ymax, thin film) 3468,
2932, 2857, 1664, 1427, 1112 cmꢀ1
;
HRMS: calculated for
C30H49NO4NaSi2 [MþNa]þ: 566.3098; found: 566.3110.
(CDCl3) d: 5.2, 7.1,12.1,14.2,19.2, 22.8, 26.9, 28.9, 29.1, 29.3, 29.5, 29.6,
4.14. (2R,3S)-5-(tert-Butyldiphenylsilyloxy)-2-methyl-3-
29.7, 29.8, 32.0, 38.1, 54.0, 60.6, 71.0, 127.7, 129.7, 133.9, 135.7, 202.1
(triethylsilyloxy)pentanal 30
some C are overlapping; IR (ymax, thin film) 2955, 2927, 2855, 1684,
1462, 1427, 1112 cmꢀ1
; HRMS: calculated for C40H68O3NaSSi2
A solution of Weinreb amide 29 (0.909 g, 1.67 mmol, 1 equiv) in
THF (10 mL) was cooled to ꢀ78 ꢁC and treated with DIBAL-H (1 M in
THF, 3.84 mL, 3.84 mmol, 2.3 equiv). After 3 h at ꢀ78 ꢁC, a saturated
aqueous solution of Rochelle’s salt (10 mL) was added and the
mixture was allowed to warm to rt. After separation, the aqueous
phase was further extracted with EtOAc (10 mL). Combined organic
extracts were dried over MgSO4 and concentrated in vacuo. Puri-
fication by flash chromatography (5% EtOAc/hexane) afforded al-
[MþNa]þ: 707.4328, found: 707.4318.
4.17. (7S,8R)-13-(Allyloxy)-14-(3-(benzyloxy)-1-methoxy
propyl)-16,16-diethyl-2,2,8,12,12-pentamethyl-3,3-diphenyl-7-
(triethylsilyloxy)-4,15-dioxa-3,16-disila octadec-10-yn-9-
one 35
To a solution of thio-ester 34 (63 mg, 0.092 mmol,1 equiv) in DMF
(0.2 mL) and Et3N (0.06 mL) were successively added PdCl2 (dppf)
(7 mg, 0.009 mmol, 0.1 equiv), CuI (34 mg, 0.18 mmol,1.9 equiv), P(2-
furyl)3 (5 mg, 0.023 mmol, 0.25 equiv) and a solution of alkyne 25
(85 mg, 0.18 mmol, 2.4 equiv) in DMF (0.2 mL). The mixture was
heated at 50 ꢁC for 3 h and then cooled to rt. Celite (0.1 g), Et2O (5 mL)
and H2O (2 mL) were added. After 10 min, the mixture was filtered
through a pad of Celite and washed with EtOAc (10 mL). After sepa-
ration, organic extracts were washed with H2O (5 mL), dried over
MgSO4 and concentrated in vacuo. Purification by flash chromatog-
raphy (2–20% EtOAc/hexane) furnished unreacted 34 (27 mg, 43%),
dehyde 30 (0.578 g, 71%) as a yellow oil. Rf (10% EtOAc/hexane)
20
0.75; [
a
]
D
þ0.3 (c 1, CHCl3); 1H NMR (CDCl3)
: 0.57 (q, J¼8.0 Hz,
d
6H), 0.92 (t, J¼8.0 Hz, 9H), 1.02 (d, J¼7.0 Hz, 3H), 1.06 (s, 9H), 1.70–
1.76 (m, 2H), 2.42–2.45 (m, 1H), 3.64–3.77 (m, 2H), 4.39–4.43 (m,
1H), 7.35–7.44 (m, 6H), 7.64–7.67 (m, 4H), 9.75 (s, 1H); 13C NMR
(CDCl3) d: 5.3, 6.9, 7.7, 19.2, 26.9, 37.3, 51.5, 60.6, 69.2, 127.7, 129.8,
133.7, 135.7, 205.2; IR (ymax, thin film) 3429, 2956, 2858, 1727, 1428,
1112 cmꢀ1
507.2727, found: 507.2724.
;
HRMS: calculated for C28H44NO3NaSi2 [MþNa]þ:
4.15. (R)-4-Benzyl-3-((2R,3S)-5-(tert-butyldiphenyl silyloxy)-
2-methyl-3-(triethylsilyloxy)pentanoyl) oxazolidin-2-one 33
dimer 36 (29 mg, 36%) as a brownish oil and expected product 35
20
(48 mg, 55%) as a yellow oil. 35: Rf (5% EtOAc/hexane) 0.35; [
a
]
ꢀ2.1
D
(c 1, CHCl3); 1H NMR (CDCl3)
d: 0.55 (q, J¼8.0 Hz, 6H), 0.64 (q,
Alcohol 28 (1.014 g, 1.76 mmol, 1 equiv) was dissolved in CH2Cl2
(20 mL). 2,6-Lutidine (0.82 mL, 7.05 mmol, 4 equiv) and TESOTf
(0.80 mL, 3.52 mmol, 2 equiv) were successively added at 0 ꢁC. Af-
ter 2 h at 0 ꢁC, a saturated aqueous solution of NH4Cl (10 mL) was
added to the mixture. After separation, the aqueous phase was
extracted with CH2Cl2 (20 mL). Combined organic extracts were
dried over MgSO4 and concentrated in vacuo. Purification by flash
chromatography (5–10% EtOAc/hexane) afforded TES-protected
J¼8.0 Hz, 6H), 0.90(t, J¼8 Hz, 9H), 0.96(t, J¼8 Hz, 9H),1.05 (s, 9H),1.11
(d, J¼7.0 Hz, 3H),1.29 (s, 3H),1.32 (s, 3H),1.70–1.79 (m, 3H), 2.02–2.11
(m, 1H), 2.55 (qd, J¼3.7, 7.0 Hz, 1H), 3.35 (s, 3H), 3.36–3.38 (m, 1H),
3.42–3.46 (m,1H), 3.55–3.59 (m, 2H), 3.67 (t, J¼7.0 Hz, 2H), 4.01–4.09
(m, 2H), 4.20–4.26 (m, 1H), 4.44–4.53 (m, 3H), 5.09–5.12 (m, 1H),
5.24–5.30 (m, 1H), 5.83–5.92 (m, 1H), 7.27–7.43 (m, 11H), 7.64–7.68
(m, 4H); 13C NMR (CDCl3)
d: 5.3, 5.6, 7.1, 7.3, 9.8, 19.3, 24.7, 26.8, 27.0,
30.5, 36.8, 38.6, 53.6, 58.6, 60.8, 67.4, 69.8, 73.1, 73.2, 73.6, 80.4, 81.9,
82.2, 100.4, 116.0, 127.5, 127.7, 127.8, 128.4, 129.7, 133.8, 135.2, 135.7,
138.8, 190.1; IR (ymax, thin film) 2654, 2876, 2205, 1673, 1457,
compound 33 (1.02 g, 88%) as a colourless oil. Rf (20% EtOAc/hex-
20
ane) 0.65; [
a]
ꢀ38.6 (c 1, CHCl3); 1H NMR (CDCl3)
d: 0.58 (q,
D
J¼7.9 Hz, 6H), 0.94 (t, J¼7.9 Hz, 9H), 1.08 (s, 9H), 1.23 (d, J¼6.8 Hz,
3H), 1.75–1.83 (m, 1H), 1.86–1.94 (m, 1H), 2.79 (dd, J¼9.6, 13.3 Hz,
2H), 3.30 (dd, J¼3.1, 13.3 Hz, 2H), 3.76 (t, J¼6.8 Hz, 2H), 3.91–3.98
(m, 1H), 4.08 (m, 1H), 4.16 (dd, J¼2.1, 9.1 Hz, 1H), 4.19–4.23 (m, 1H),
4.56–4.61 (m, 1H), 7.23–7.43 (m, 11H), 7.67–7.71 (m, 4H); 13C NMR
1095 cmꢀ1
;
HRMS: calculated for C55H86O7NaSi3 [MþNa]þ:
965.5579, found: 965.5603. 36: Rf (5% EtOAc/hexane) 0.23; NMR 1H
(CDCl3)
d
: 0.66 (q, J¼8.0 Hz, 12H), 0.97 (t, J¼8.0 Hz, 18H), 1.25 (s, 6H),
1.27 (s, 6H), 1.74–1.80 (m, 2H), 2.05–2.10 (m, 2H), 3.28 (d, J¼4.1 Hz,
2H), 3.37 (s, 3H), 3.41–3.45 (m, 2H), 3.59 (t, J¼6.7 Hz, 4H), 4.02–4.07
(m, 4H), 4.20–4.25 (m, 2H), 4.50 (d, J¼12.0 Hz, 2H), 4.53 (d, J¼12.0 Hz,
2H), 5.08–5.11 (m, 2H), 5.23–5.28 (m, 2H), 5.83–5.92 (m, 2H), 7.27–
(CDCl3) d: 5.1, 7.0, 12.5, 19.2, 27.0, 37.8, 38.3, 43.5, 55.9, 60.7, 66.0,
70.8, 127.4, 127.7, 129.0, 129.6, 129.7, 134.0, 135.5, 135.7, 153.1, 175.3;
IR (ymax, thin film) 2956, 2876, 1784, 1704, 1384, 1236, 1208,
7.34 (m, 10H); 13C NMR (CDCl3)
d: 5.5, 7.3, 25.3, 27.7, 29.8, 30.4, 36.9,
1111 cmꢀ1
682.3360, found: 682.3339.
;
HRMS: calculated for C38H53NO5NaSi2 [MþNa]þ:
58.5, 67.2, 67.5, 73.1, 73.3, 73.5, 80.6, 82.6, 84.6, 116.0, 127.5, 127.8,
128.4, 132.2, 132.3, 135.5, 138.8; IR (ymax, thin film) 3065, 2953, 2932,
2878, 1766, 1728, 1456, 1098 cmꢀ1
; HRMS: calculated for
4.16. (2R,3S)-S-Dodecyl 5-(tert-butyldiphenylsilyloxy)-2-
methyl-3-(triethylsilyloxy)pentanethioate 34
C54H86O8NaSi2 [MþNa]þ: 918.5861, found: 918.5841.
4.18. (2R,3R,5S,7S,8R)-3-(Allyloxy)-2-((S)-3-(benzyloxy)-1-
methoxypropyl)-7-(2-(tert-butyldiphenylsilyloxy) ethyl)-
4,4,8-trimethyl-1,6-dioxaspiro[4.5]decan-9-one 37
To a solution of dodecanethiol (0.52 mL, 2.16 mmol, 4 equiv) in
THF (7 mL) was added n-BuLi (2 M in hexanes, 0.81 mL, 1.62 mmol,
3 equiv) at 0 ꢁC. A precipitate formed and the mixture was stirred
30 min at 0 ꢁC, before being cooled down to ꢀ78 ꢁC. A solution of
compound 33 (0.356 g, 0.54 mmol, 1 equiv) in THF (3 mL) was
To a solution of ynone 35 (22 mg, 0.023 mmol, 1 equiv) in toluene
(1 mL) was added p-TsOH (5 mg, 0.025 mmol, 1.2 equiv) and the

7934
D. Habrant et al. / Tetrahedron 65 (2009) 7927–7934
6. Anderson, O. P.; Barrett, A. G. M.; Edmunds, J. J.; Hachiya, S. I.; Hendrix, J. A.;
Horita, K.; Malecha, J. W.; Parkinson, C. J.; VanSickle, A. Can. J. Chem. 2001, 79,
1562 and references cited therein.
7. Evans, D. A.; Gage, J. R.; Leighton, J. L. J. Am. Chem. Soc. 1992, 114, 9434.
8. Tanimoto, N.; Gerritz, S. W.; Sawabe, A.; Noda, T.; Filla, S. A.; Masanume, S.
Angew. Chem., Int. Ed. Engl. 1994, 33, 673.
9. Smith, A. B.; Friestad, G. K.; Barbosa, J.; Bertounesque, E.; Hull, K. G.; Iwashima,
M.; Qiu, Y.; Salvatore, B. A.; Spoors, P. G.; Duan, J. J. W. J. Am. Chem. Soc. 1999, 121,
10468.
10. Ogawa, A. K.; Armstrong, R. W. J. Am. Chem. Soc. 1998, 120, 12435.
11. Pihko, P. M.; Koskinen, A. M. P. Synlett 1999, 1966.
mixture was stirred 24 h at rt. The reaction was quenched by addi-
tion of a saturated aqueous solution of NaHCO3 (0.5 mL) and H2O
(0.5 mL). The mixture was diluted with EtOAc (5 mL) and the
aqueous phase was separated. Organic extracts were dried over
MgSO4 and concentrated in vacuo. Purification by flash chromatog-
raphy (5–20% EtOAc/hexane) afforded spiroketal 37 (9.5 mg, 57%) as
20
a colourless oil. Rf (20% EtOAc/hexane) 0.32; [
a
]
ꢀ3.7 (c 1, CHCl3);
D
NMR 1H (CDCl3)
d
: 0.94 (s, 3H), 0.97 (d, J¼6.6 Hz, 3H), 1.03 (s, 3H),
1.05 (s, 9H), 1.58–1.65 (m, 2H), 1.72–1.79 (m, 2H), 1.91–1.99 (m, 1H),
2.39 (d, J¼13.9 Hz, 1H), 2.52 (d, J¼13.9 Hz, 1H), 3.34 (s, 3H), 3.42 (dt,
J¼2.9, 6.0 Hz, 1H), 3.50–3.60 (m, 2H), 3.68 (d, J¼7.3 Hz, 1H), 3.70–
3.86 (m, 4H), 3.86 (ddt, J¼1.4, 5.4, 12.4 Hz, 1H), 4.01 (ddt, J¼1.4, 5.4,
12.4 Hz, 1H), 4.43 (d, J¼12.0 Hz, 1H), 4.48 (d, J¼12.0 Hz,1H), 5.11 (ddt,
J¼1.4, 1.4, 10.4 Hz, 1H), 5.23 (ddt, J¼1.6, 1.6, 17.2 Hz, 1H), 5.86 (ddt,
J¼5.4, 10.6, 17.2 Hz, 1H), 7.27–7.40 (m, 11H), 7.63–7.67 (m, 4H); 13C
12. Pihko, P. M.; Koskinen, A. M. P. J. Org. Chem. 1998, 63, 92.
13. Koskinen, A. M. P.; Chen, J. Tetrahedron Lett. 1991, 32, 6977.
14. Rauhala, V.; Na¨ttinen, K.; Rissanen, K.; Koskinen, A. M. P. Eur. J. Org. Chem. 2005,
4119.
15. Fu, X.; Schmitz, F. J.; Kelly-Borges, M.; McCready, T. L.; Holmes, C. F. B. J. Org.
Chem. 1998, 63, 7957.
16. Kehraus, S.; Knig, G. M.; Wright, A. D. J. Nat. Prod. 2002, 65, 1056.
17. Crimmins, M. T.; O’Mahony, R. J. Org. Chem. 1990, 55, 5894.
18. Trygstad, T. M.; Pang, Y.; Forsyth, C. J. J. Org. Chem. 2009, 74, 910.
19. Karisalmi, K.; Koskinen, A. M. P. Synthesis 2004, 1331.
20. Rauhala, V.; Nevalainen, M.; Koskinen, A. M. P. Tetrahedron 2004, 60, 9199.
21. Ohira, S. Synth. Commun. 1989, 19, 561.
22. Mu¨ller, S.; Liepold, B.; Roth, G. J.; Bestmann, H. J. Synlett 1996, 521.
23. Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103, 2127.
24. Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.
25. Boynton, J. A.; Hanson, J. R. J. Chem. Res., Synop. 1992, 378.
26. Crouch, R. D. Tetrahedron 2004, 60, 5833.
NMR (CDCl3) d: 10.9, 18.0, 19.3, 27.0, 29.8, 33.1, 33.6, 41.4, 48.4, 59.5,
61.2, 67.1, 67.5, 72.9, 73.4, 77.3, 80.3, 86.8, 108.5, 116.8, 127.5, 127.7,
127.8,128.4,129.8,133.9,134.7,135.6,135.7,138.9, 210.1; IR (ymax, thin
film) 2926, 2855, 1721, 1463, 1428, 1112 cmꢀ1; HRMS: calculated for
C43H58O7NaSi [MþNa]þ: 737.3850, found: 737.3862.
Acknowledgements
27. Rodriguez, A.; Nomen, M.; Spur, B. W.; Godfroid, J. J. Tetrahedron Lett. 1999, 40,
5161.
28. Nacro, K.; Baltas, M.; Gorrichon, L. Tetrahedron 1999, 55, 14013.
29. Carreira, E. M.; Du Bois, J. J. Am. Chem. Soc. 1995, 117, 8106.
30. Wang, J.; Hsung, R. P.; Ghosh, S. K. Org. Lett. 2004, 6, 1939.
31. Boyall, D.; Frantz, D.; Carreira, E. M. Org. Lett. 2002, 4, 2605.
32. Cozzi, P. G.; Rudolph, J.; Bolm, C.; Norrby, P. O.; Tomasini, C. J. Org. Chem. 2005,
70, 5733.
This research was supported by the Finnish Academy grant No.
123485.
References and notes
33. Gao, G.; Moore, D.; Xie, R. G.; Pu, L. Org. Lett. 2002, 4, 4143.
34. Takita, R.; Yakura, K.; Ohshima, T.; Shibasaki, M. J. Am. Chem. Soc. 2005, 127,
13760.
1. Kato, Y.; Fusetani, N.; Matsunaga, S.; Hashimoto, K.; Fujita, S.; Furuya, T. J. Am.
Chem. Soc. 1986, 108, 2780.
35. Sakai, N.; Kanada, R.; Hirasawa, M.; Konakahara, T. Tetrahedron 2005, 61, 9298.
36. Alonso, D. A.; Na´jera, C.; Pacheco, M. A. J. Org. Chem. 2003, 69, 1615.
37. Miyazaki, T.; Han-Ya, Y.; Tokuyama, H.; Fukuyama, T. Synlett 2004, 477.
38. Narasaka, K.; Saitou, M.; Iwasawa, N. Tetrahedron: Asymmetry 1991, 2, 1305.
39. Nakahata, T.; Fujimora, S.; Kuwahara, S. Chem.dEur. J. 2006, 12, 4584.
40. Dieter, R. K.; Silks, L. A.; Fishpaugh, J. R.; Kastner, M. E. J. Am. Chem. Soc. 1985,
107, 4679.
2. Kato, Y.; Fusetani, N.; Matsunaga, S.; Hashimoto, K.; Koseki, K. J. Org. Chem.
1988, 53, 3930.
3. Matsunaga, S.; Fujiki, H.; Sakata, D.; Fusetani, N. Tetrahedron 1991, 47, 2999.
4. Ishibara, H.; Martin, B. L.; Brautigan, D. L.; Haraki, H.; Ozaki, H.; Kato, N.;
Fusetani, N.; Watabe, K.; Hashimoto, K.; Uemura, D.; Hartshorne, D. J. Biochem.
Biophys. Res. Commun. 1989, 19, 871.
5. Lindvall, M. K.; Pihko, P. M.; Koskinen, A. M. P. J. Biol. Chem. 1997, 272, 23312.