Synthesis of pederic acid and related model studies

Article abstract of DOI:10.1002/hlca.200490110

{[2-(Trimethylsilyl)ethoxy]methyl} (SEM)-protected pederic acid 16 was prepared by deriving the stereogenic center at C(7) from mannitol and those at C(2) and C(3) (mycalamide numbering) from trans-2,3-dimethyloxirane. Routes to pederamides involving a la

Full text of DOI:10.1002/hlca.200490110

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Helvetica Chimica Acta Vol. 87 (2004)
Synthesis of Pederic Acid and Related Model Studies
by Steffen Breitfelder, Anne C. Schuemacher, Thomas Rˆlle, Makoto Kikuchi, and Reinhard W. Hoffmann*
Fachbereich Chemie der Philipps Universit‰t Marburg, D-35032 Marburg
(fax: ‡4964212825677; e-mail: rwho@chemie.uni-marburg.de)
{[2-(Trimethylsilyl)ethoxy]methyl} (SEM)-protected pederic acid 16 was prepared by deriving the
stereogenic center at C(7) from mannitol and those at C(2) and C(3) (mycalamide numbering) from trans-
2,3-dimethyloxirane. Routes to pederamides involving a late oxygenation at C(7) were explored.
Introduction.
The pederins [1], theopederins [2], mycalamides [3], and
onnamides [4] are all amides of type 1 of pederic acid (ˆ(aS,2R,5R,6R)-tetrahydro-
a-hydroxy-2-methoxy-5,6-dimethyl-4-methylene-2H-pyran-2-acetic acid; 2). In previ-
ous syntheses (mycalamides [5][6], pederin [7 10]) of members of these classes of
compounds, the two parts of the target molecules were joined by formation of the
amide bond b (cf. Eqn. 1 in Scheme 1). We were interested in a different approach [11],
in which bond a is formed, requiring the right-hand building block to carry an
isocyanate function. The polarity of this functional group was to be reversed by
transformation to a lithiated carbamate, which should then be coupled with a nor-
pederic acid derivative (cf. Eqn. 2). While this approach worked fine with model
isocyanates [11], it failed when applied to a more elaborate isocyanate [12] that would
have led to a fully functionalized mycalamide. In continuing our efforts, we wanted
nevertheless to retain the approach via an isocyanate and considered forming bond b by
a decarboxylative coupling of a protected pederic acid to isocyanates (cf. Eqn. 3) [13].
To apply this reaction to a synthesis of pederin or the mycalamides, we needed a
reliable route to suitable protected pederic acid derivatives.
Several syntheses of pederic acid and derivatives have been reported over the last
25 years [7][14 19]. Except for two syntheses [18][19], establishment of the stereo-
genic center at C(7) (mycalamide numbering) required extra steps, such as oxidation to
a ketone and reduction with variable stereoselectivity. Therefore, we opted to derive
this stereogenic center from a chiral building block. Second, the previously used [15
17] import of the stereogenic centers at C(2) and C(3) (mycalamide numbering) from
enantiomerically pure trans-2,3-dimethyloxirane appeared highly advantageous. This
led us to the synthons trans-2,3-dimethyloxirane, 3, and 4 (Scheme 2).
We describe in the following a synthesis of the SEM-protected pederic acid 16 along
these lines (SEM ˆ [2-(trimethylsilyl)ethoxy]methyl).
Synthesis of Pederic Acid from Chiral Precursors. The glyceraldehyde building
block 3 was prepared from 1,3:4,6-di-O-benzylidene-d-mannitol (5) [20] (Scheme 3).
SEM Protection led to 6 in 92 99% yield, hydrogenation of which gave the tetrol 7
(98%). The primary-alcohol functions were protected as (tert-butyl)dimethylsilyl

Helvetica Chimica Acta Vol. 87 (2004)
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Scheme 1
PG ˆ protecting group
Scheme 2

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Helvetica Chimica Acta Vol. 87 (2004)
(TBDMS) ethers to give 8 (99%). Diol 8 was then cleaved by lead tetraacetate to give
aldehyde 9. In view of its tendency to racemize, the aldehyde was not purified but used
as obtained.
Scheme 3
The other building block, 10 (Scheme 4), was prepared [11] from trans-2,3-
dimethyloxirane and 4 according to the Kocienski protocol [17]. In our hands, the
SnCl4-mediated reaction of 10 with aldehyde 9 turned out to be capricious in that
variable amounts of a by-product arose, probably the product of an ene reaction [21].
The reaction became well-behaved when conditions were chosen that initiated the
transmetallation of the allylsilane to an allyltrichlorostannane (i.e., premixing of the
allylsilane with SnCl4) [22]. This way, the adduct 11 was obtained in 61 84% yield. One
diastereoisomer at the new stereogenic center predominated by 10 :1, but this was
irrelevant because this stereogenic centre was given up in the next step by DessÀMartin
oxidation [23] to ketone 12. With ketone 12 in hand, the tetrahydro-2H-pyran ring was
closed by pyridinium toluenesulfonate (PPTS) catalyzed acetalization to give 13. This
reaction had a bonus effect: Frequently, the starting ketone 12 was contaminated by
small amounts of the 7-epimer due to partial racemization of 9. This epimeric ketone
did not form an acetal under these conditions and could be removed at this stage. Thus,
the diastereoisomerically pure product 13 was obtained. To elaborate C(8) to a
carboxylic acid, the TBDMS group was cleaved by the action of Bu4NF. Ley oxidation
[24] of the resulting primary alcohol 14 led to aldehyde 15. To avoid epimerization of
15, the latter was subjected as obtained to Pinnick oxidation in the Smith variant [25].
The resulting acid 16 is −acid labile× [17][18] and not stable on storage, but it could be
characterized as the methyl ester 17.
The protected pederic acid 16 could, as expected, readily be coupled [13] with the
model isocyanate 18 [11] ( ! 19), but similar coupling with an isocyanate 20 [12]
corresponding to the right half of mycalamide B failed (Scheme 5).
Difficulties in forming an amide bond in this series (bond b, Scheme 1) had been
noted by others [6][10] and ascribed to the highly crowded situation around the
reaction center. In the past, this has forced previous workers to adopt approaches in

Helvetica Chimica Acta Vol. 87 (2004)
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Scheme 4
Scheme 5

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Helvetica Chimica Acta Vol. 87 (2004)
which C(8) and C(7) were attached first to the right-hand part via an amide bond,
followed by subsequent elaboration of the pederic acid moiety [6][8].
Other Approaches to Pederic Acid. While the above described synthesis of the
protected pederic acid 16 is high yielding and viable, it is rather pedestrian given the
many protective-group interconversions involved. For this reason, we started to
evaluate other approaches to pederic acid, e.g., those that would introduce the
oxygenation at C(7) late in the synthesis sequence. This would also reduce the steric
congestion around the amide bond if we were to attach a slimmed-down pederic acid
core to the isocyanate prior to complete elaboration of the pederic acid part. This led us
to explore the retro-synthesis given in Scheme 6. This plan was inspired by a sequence of
steps in the synthesis of rapamycin by Smith and co-workers [26] (see Scheme 7). To
evaluate this route, we focussed on the generation of the enolate 21. Obviously it cannot
be generated from the methyl ketone by deprotonation, as this would lead to the
conjugated enolate.
Scheme 6
Scheme 7

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We, therefore, envisaged a Cl-atom (cf. 26) as the locator for the enolate double
bond to be generated. The viability of this approach was tested in the following model
series (see Scheme 8). The dichlorocyclobutenone 22 and, in turn, the cyclobutenone 23
were generated by standard procedures [27][28]. The ring opening to the carboxylic
acid 24 could be performed in a noncatalyzed fashion [29] by simply heating 23 to reflux
in aqueous dioxane. The acid 24 was converted to the methyl ester 25. Reaction of the
latter with chloromethyllithium [30] led to the desired 26 (we did not probe whether
this a-chloro ketone could also be obtained [31] by addition of chloromethyllithium to
the cyclobutenone 23). The a-chloro ketone 26 was then subjected to SmI2-mediated
enolate formation [32], followed by in situ coupling to phenyl isocyanate to give 27.
Scheme 8
Encouraged by these results, we turned to alkyne 28 (Scheme 9). Though it was
readily prepared, we were unable to effect the addition of dichloroketene to this
alkyne. This is the more disturbing as a successful addition of dichloroketene to the
probably more hindered (tert-butyl)acetylene has been reported [33].
Scheme 9
We then used another option to access the desired a-chloro ketone 30 (Scheme 10).
To this end, the allylsilane 10 was allowed to react with freshly generated [34]
chloroacetaldehyde. The resulting chlorohydrin 29 could be oxidized to a-chloro
ketone 30 without isomerization of the CˆC bond. As before, SmI2-mediated enolate

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Helvetica Chimica Acta Vol. 87 (2004)
Scheme 10
formation coupled with in situ trapping by isocyanates gave the ketoamides 31 in
acceptable yields.
We then focussed on the oxygenation at C(7) of 31 (Scheme 11). We were
disappointed that the Dess-Martin oxidation of 31b did not provide the expected [26]
vicinal tricarbonyl compound 32 despite varied attempts. We then embarked on a slight
detour by generating the phenylhydrazone 33 from 31b by coupling with phenyl-
diazonium chloride. Attempts of oxidative cleavage [35] of 33, be it with sodium
periodate, hydroxyl-tosyloxy-iodobenzene (Kosers reagent), or dimethyldioxirane, did,
however, not lead to the desired vicinal tricarbonyl compound 32.
Scheme 11

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Thus, what was planned as a quick foray to reach pederic acid turned out to develop
into a siege, for which we no longer had the time nor resources. We, thus, concluded our
efforts having secured the above described route to the protected pederic acid 16 from
d-mannitol and trans-2,3-dimethyloxirane.
We would like to thank the Deutsche Forschungsgemeinschaft for support of this study. We are grateful to
¬
the Fonds der Chemischen Industrie for granting a Kekule Fellowship to A. C. S. Finally, special thanks go to the
Alexander v. Humboldt Foundation for a fellowship to M. K.
Experimental Part
General. Boiling range of petroleum ether 40 608. pH 7 Buffer: NaH2PO4 ¥ 2 H2O (56.2 g) and Na2HPO4 ¥
4 H2O (213.6 g) filled up to 1 l with H2O. All quoted temp. are uncorrected. Flash chromatography (FC): silica
gel SI 60 (40 63 mm), E. Merck KGaA, Darmstadt. NMR Spectra: Bruker ARX-200, AC-300, WH-400, AMX-
500; d in ppm rel. to Me4Si, J in Hz.
i
1. 1,3:4,6-Di-O-benzylidene-2,5-bis-O-{[2-(trimethylsilyl)ethoxy]methyl}-d-mannitol (6). Pr2NEt (2.35 ml,
13.2 mol) was added to a suspension of 1,3 :4,6-di-O-benzylidene-d-mannitol (5) [20] (790 mg, 2.20 mmol) in
CH2Cl2 (26 ml). A soln. of [2-(chloromethoxy)ethyl]trimethylsilane (2.20 g, 13.2 mmol) in CH2Cl2 (5 ml) was
added dropwise at 08 with stirring. After stirring for 3 d at room temp., the soln. was evaporated and the residue
20
purified by FC (petroleum ether/tBuOMe 5 :1): 6 (1.25 g, 92%). Colorless solid. M.p. 458. ‰aŠ ˆ ‡29.7 (c ˆ 1.33,
D
CHCl3). 1H-NMR (200 MHz, CDCl3): 7.51 7.47 (m, 5 H); 7.37 7.32 (m, 5 H); 5.49 (s, 2 H); 4.79 (d, J ˆ 9.9,
2 H); 4.66 (d, J ˆ 9.9, 2 H); 4.49 4.44 (m, 2 H); 4.10 4.00 (m, 2 H); 3.69 3.44 (m, 8 H); 0.98 0.88 (m, 4 H);
0.01 (s, 18 H). 13C-NMR (50 MHz, CDCl3): 137.7 (2 C); 128.8 (2 C); 128.2 (4 C); 125.9 (4 C); 101.0 (2 C); 95.3
(2 C); 77.1 (2 C); 70.4 (2 C); 66.6 (2 C); 65.6 (2 C); 18.0 (2 C); À 1.3 (6 C). Anal. calc. for C32H50O8Si2 (618.92):
C 62.10, H 8.15; found: C 61.83, H 8.25.
2. 2,5-Bis-O-{[2-(trimethylsilyl)ethoxy]methyl}-d-mannitol (7). A mixture of 20% Pd(OH)2/C (ca. 10 mg)
and 6 (640 mg, 1.03 mmol) in EtOH (34 ml) was degassed and subsequently stirred for 12 h under 1 bar of H2.
The suspension was filtered over a pad of −Kielselgur×, the filtrate evaporated, and the residue subjected to FC
20
(AcOEt): 7 (450 mg, 98%). Colorless solid. M.p. 71 728. ‰aŠ ˆ ‡18.9 (c ˆ 1.19, CHCl3). 1H-NMR (300 MHz,
D
CDCl3): 4.81 (d, J ˆ 6.8, 2 H); 4.74 (d, J ˆ 6.8, 2 H); 3.85 3.82 (m, 4 H); 3.72 3.68 (m, 4 H); 3.60 (t, J ˆ 8.3,
4 H); 0.94 (t, J ˆ 8.3, 4 H); À 0.57 (s, 18 H); signals of OH not detected. 13C-NMR (75 MHz, CDCl3): 95.9 (2 C);
81.2 (2 C); 69.6 (2 C); 66.3 (2 C); 63.3 (2 C); 18.1 (2 C); À 1.4 (6 C). Anal. calc. for C18H42O8Si2 (442.70): C
48.84, H 9.56; found: C 48.60, H 9.62.
3. 1,6-Bis-O-[(tert-butyl)dimethylsilyl]-2,5-bis-O-{[2-(trimethylsilyl)ethoxy]methyl}-d-mannitol (8). At 08,
1H-imidazole (449 mg, 6.60 mmol) was added to a soln. of 7 (730 mg, 1.65 mmol) in CH2Cl2 (60 ml). After the
1H-imidazole had dissolved, (tert-butyl)chlorodimethylsilane (50% in hexane; 1.99 g, 6.60 mmol) was added
dropwise. The mixture was stirred for 12 h at r.t. MeOH (2 ml) was added, the mixture evaporated, and the
residue submitted to FC (petroleum ether/tBuOMe 5 :1 containing 1% of Et3N): 8 (1.10 g, 99%). Colorless oil.
20
‰aŠ ˆ À18.5 (c ˆ 1.62, CHCl3). 1H-NMR (300 MHz, CDCl3): 4.81 (d, J ˆ 6.6, 2 H); 4.76 (d, J ˆ 6.6, 2 H); 3.93
D
(dd, J ˆ 10.1, J ˆ 4.0, 2 H); 3.84 (dd, J ˆ 6.9, J ˆ 5.1, 2 H); 3.78 3.71 (m, 2 H); 3.70 3.46 (m, 8 H); 0.90 0.87
(m, 4 H); 0.88 (s, 18 H); 0.06 (s, 12 H); 0.01 (s, 18 H). 13C-NMR (75 MHz, CDCl3): 95.8 (2 C); 78.8 (2 C); 69.6
(2 C); 65.7 (2 C); 64.4 (2 C); 25.7 (6 C); 18.3 (2 C); 18.1 (2 C); À 1.5 (6 C); À 5.5 (4 C). Anal. calc. for
C30H70O8Si4 (671.22): C 53.68, H 10.51; found: C 53.44, H 10.67.
4. (2R)-3-{[(tert-Butyl)dimethylsilyl]oxy}-2-{[2-(trimethylsilyl)ethoxy]methoxy}propanal (9). NaHCO3
(227 mg, 2.70 mmol) and Pb(OAc)4 (460 mg, 1.04 mmol) were added at À 788 immediately after each other
to a soln. of 8 (606 mg, 0.90 mmol) in CH2Cl2 (55 ml). The mixture was stirred for 20 min at À 788 and filtered
over a pad of −Kieselgur×. The −Kieselgur× was washed with CH2Cl2 (30 ml) and the combined filtrate dried
(K2CO3) and evaporated. Hexane (20 ml) was added and the mixture evaporated (removal of residual AcOH).
20
This process was repeated once: crude 9 (587 mg, 97%) which was used immediately. ‰aŠ ˆ ‡6.1 (c ˆ 3.45,
D
1
CHCl3). H-NMR (300 MHz, CDCl3): 9.69 (d, J ˆ 1.3, 1 H); 4.80 (s, 2 H); 4.02 (td, Jt ˆ 4.9, Jd ˆ 1.3, 1 H); 3.91
(d, J ˆ 4.9, 2 H); 3.76 3.58 (m, 2 H); 0.88 0.86 (m, 2 H); 0.86 (s, 9 H); 0.05 (s, 6 H); 0.01 (s, 9 H). 13C-NMR
(75 MHz, CDCl3): 202.2; 95.0; 82.5; 78.8; 69.6; 25.8 (3 C); 18.2; 18.0; À 1.5 (3 C); À 5.5 (2 C).
5. (2R,3RS,6R,7R)-1-{[(tert-Butyl)dimethylsilyl]oxy}-6-methyl-5-methylidene-2-{[2-(trimethylsilyl)ethoxy]-
methoxy}-7-[(trimethylsilyl)oxy]octan-3-ol (11). Three solns. were prepared separately and were stirred
individually over 4-ä molecular sieves at À 788: aldehyde 9 (560 mg, 1.67 mmol) in CH2Cl2 (12 ml), SnCl4

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Helvetica Chimica Acta Vol. 87 (2004)
(0.249 ml, 2.12 mmol) in CH2Cl2 (6 ml), and allylsilane 10 [11] (550 mg, 2.12 mmol) in CH2Cl2 (15 ml). The
SnCl4 soln. was transferred via canula into that of 10 and stirring was continued for 15 min at À 788. Then the
soln. of 9 was transferred via canula into the mixture. Et3N (1.63 ml, 11.7 mmol) was added dropwise, and
stirring was continued for 2 min at À 788. Aq. sat. NaHCO3 soln. (12 ml) was added, the mixture allowed to
reach r.t., the aq. layer extracted with CH2Cl2 (3 Â 20 ml), the combined org. layer washed with brine (10 ml),
dried (Na2SO4), and evaporated, and the residue subjected to FC (petroleum ether/tBuOMe 10 :1 containing
1% of Et3N): 11 (diastereoisomer mixture; 530 mg, 61%). Yellowish oil. 1H-NMR (300 MHz, CDCl3): 4.92 (br.
s, 1 H); 4.86 (br. s, 1 H); 4.81 (d, J ˆ 6.9, 1 H); 4.73 (d, J ˆ 6.9, 1 H); 3.82 3.61 (m, 1 H); 3.74 3.68 (m, 4 H);
3.56 3.54 (m, 1 H); 2.59 (d, J ˆ 5.4, 1 H); 2.32 2.07 (m, 4 H); 1.10 (d, J ˆ 6.0, 3 H); 1.03 (d, J ˆ 6.8, 3 H); 0.95
0.88 (m, 2 H); 0.88 (s, 9 H); 0.09 (s, 9 H); 0.05 (s, 6 H); 0.00 (s, 9 H). 13C-NMR (75 MHz, CDCl3): 149.3; 112.1;
95.3; 79.5; 71.6; 69.4; 65.6; 63.2; 47.6; 40.1; 25.8 (3 C); 22.0; 18.2; 18.1; 16.9; 0.3 (3 C); À 1.4 (3 C); À 5.5 (2 C).
Anal. calc. for C25H56O5Si3 (508.96): C 56.64, H 11.09; found: C 56.84, H 10.97.
6. (2R,6R,7R)-1-{[(tert-Butyl)dimethylsilyl]oxy}-6-methyl-5-methylidene-2-{[2-(trimethylsilyl)ethoxy]me-
thoxy}-7-[(trimethylsilyl)oxy]octan-3-one (12). DessÀMartin periodinane [36] (234 mg, 0.55 mmol) was added
to a soln. of 11 (125 mg, 0.240 mmol) in CH2Cl2 (10 ml). After stirring for 1 h, the mixture was filtered over a
column with −Kieselgur×, which was eluted with CH2Cl2 (120 ml). The eluates were evaporated: 12 (120 mg,
20
96%). Slightly yellowish oil. ‰aŠ ˆ ‡11.5 (c ˆ 1.04, CHCl3). 1H-NMR (400 MHz, CDCl3): 4.86 (d, J ˆ 6.9, 1 H);
D
4.70 (d, J ˆ 6.9, 1 H); 4.79 (br. s, 1 H); 4.76 (br. s, 1 H); 3.92 3.84 (m, 1 H); 3.73 3.59 (m, 4 H); 3.45 3.26
(m, 1 H); 2.11 2.02 (m, 3 H); 1.09 (d, J ˆ 6.1, 3 H); 1.02 (d, J ˆ 7.1, 3 H); 0.93 0.90 (m, 2 H); 0.87 (s, 9 H); 0.08
(s, 6 H); 0.06 (s, 9 H); 0.00 (s, 9 H). 13C-NMR (75 MHz, CDCl3): 199.1; 147.0; 114.5; 94.8; 83.8; 70.9; 65.7; 65.0;
47.6; 26.0 (3 C); 22.8; 18.5; 18.1; 17.8; 15.4; 0.3 (6 C); À 1.3 (2 C).
7. (2R,5R,6R)-2-{(1R)-2-{[(tert-Butyl)dimethylsilyl]oxy}-1-{[(2-trimethylsilyl)ethoxy]methoxy}ethyl}tetra-
hydro-2-methoxy-5,6-dimethyl-4-methylidene-2H-pyran (13). Pyridinium p-toluenesulfonate (ca. 5 mg) was
added to a soln. of 12 (124 mg, 0.239 mmol) in MeOH (10 ml). After stirring for 45 min, sat. aq. NaHCO3 soln.
t
(5 ml) was added, the aq. layer extracted with BuOMe (3 Â 10 ml), the combined org. layer washed with brine
(10 ml), dried (Na2SO4), and evaporated, and the residue subjected to FC (petroleum ether/tBuOMe 3 :1
20
D
1
containing 1% of Et3N): 13 (79 mg, 71%). Colorless oil. ‰aŠ ˆ ‡30.3 (c ˆ 1.42, CHCl3). H-NMR (300 MHz,
CDCl3): 4.89 (d, J ˆ 6.8, 1 H); 4.81 4.76 (m, 2 H); 4.67 (dd, J ˆ 9.0, 1.8, 1 H); 3.97 (dd, J ˆ 10.6, 2.4, 1 H); 3.87
3.56 (m, 5 H); 3.19 (s, 3 H); 2.37 (d, J ˆ 14.5, 1 H); 2.22 (d, J ˆ 14.5, 1 H); 2.17 (dd, J ˆ 7.0, 2.4, 1 H); 1.09 (d, J ˆ
6.5, 3 H); 0.96 (d, J ˆ 7.0, 3 H); 0.93 0.87 (m, 2 H); 0.89 (s, 9 H); 0.05 (s, 6 H); 0.01 (s, 9 H). 13C-NMR
(75 MHz, CDCl3): 147.5; 109.2; 100.2; 94.8; 76.4; 68.3; 65.2; 64.5; 47.8; 41.5; 33.8; 27.0 (3 C); 18.2; 17.8; 17.6; 12.0;
À 1.4 (3 C); À 5.4 (2 C). Anal. calc. for C23H48O5Si2 (460.80): C 59.95, H 10.50; found: C 59.60, H 10.31.
8. (aS,2R,5R,6R)-Tetrahydro-2-methoxy-5,6-dimethyl-4-methylidene-N-(tetrahydro-2H-pyran-2-yl)-a-{[2-
(trimethylsilyl)ethoxy]methoxy}-2H-pyran-2-acetamide (19). A soln. of 1m Bu4NF in THF (0.66 ml, 0.66 mmol)
was added at 08 to a soln. of 13 (160 mg, 0.347 mmol) in THF (7 ml). After stirring for 4 h, the soln. was
evaporated and the residue subjected to FC (petroleum ether/tBuOMe 2 :1 containing 1% of Et3N):
(aR,2R,5R,6R)-tetrahydro-2-methoxy-5,6-dimethyl-4-methylene-a-{[2-(trimethylsilyl)ethoxy]methoxy}-2H-
20
pyran-2-ethanol (14; 100 mg, 82%). Yellowish oil. ‰aŠ ˆ ‡40.1 (c ˆ 2.58, CHCl3). 1H-NMR (300 MHz, CDCl3):
D
4.82 (dd, J ˆ 4.6, 2.4, 2 H); 4.7 (dd, J ˆ 7.1, 2.4, 2 H); 3.89 3.80 (m, 3 H); 3.74 (dd, J ˆ 8.9, 7.6, 1 H); 3.65 3.57
(m, 2 H); 3.41 3.30 (m, 2 H); 3.19 (s, 3 H); 2.38 2.33 (m, 1 H); 2.21 2.17 (m, 1 H); 1.10 (d, J ˆ 6.5, 3 H); 0.97
(d, J ˆ 7.1, 3 H); 0.94 0.84 (m, 2 H); 0.01 (s, 9 H). 13C-NMR (75 MHz, CDCl3): 146.6; 109.8; 101.0; 95.3; 78.4;
68.8; 65.8; 62.9; 47.8; 41.4; 33.0; 18.1; 17.7; 11.9; À 1.4 (3 C).
Tetrapropylammonium perruthenate (7 mg, 0.018 mmol) was added to a soln. of 14 (51 mg, 0.15 mmol) and
N-methylmorpholine N-oxide (34 mg, 0.29 mmol) in CH2Cl2 (6 ml) containing 4-A molecular sieves (ca. 5 mg).
After stirring for 50 min, the mixture was filtered over −Kieselgur× followed by washing with CH2Cl2 (30 ml).
t
The soln. was evaporated and the resulting aldehyde 15 (50 mg, 94%) taken up in BuOH (3.5 ml) and 2-
methylbut-2-ene (0.9 ml). A soln. of sodium chlorite (1.38 mg, 1.90 mmol) and of sodium dihydrogen phosphate
dihydrate (187 mg, 1.20 mmol) in H2O (2 ml) was added. After stirring vigorously for 20 min, the aq. layer was
t
extracted with BuOMe (3 Â 15 ml), the combined org. layer dried (Na2SO4) and evaporated, hexane (10 ml)
added, and the mixture evaporated (removal of residual tBuOH). This process was repeated once. The resulting
crude acid 16 (50 mg, 95%) was used immediately.
Acid 16 (40 mg, 0.11 mmol) and isocyanate 18 [11] (14 mg, 0.10 mmol) were dissolved at 08 in CH2Cl2
( 3 ml). N,N-Dimethylpyridin-4-amine (ca. 5 mg) was added. After stirring 30 min at 08 and 3 h at r.t., the
mixture was evaporated and the residue subjected to FC (petroleum ether/tBuOMe 1:3 containing 1% of Et3N):
diastereoisomerically pure 19 (18 mg) followed by a mixture of diastereoisomeric amides (18 mg, total 80%). 19
(unassigned rel. configuration at the aminal C-atom): 1H-NMR (200 MHz, CDCl3): 5.08 (d, J ˆ 3.4, 1 H); 4.80

Helvetica Chimica Acta Vol. 87 (2004)
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(d, J ˆ 2.0, 1 H); 4.76 (br. s, 1 H); 4.69 (d, J ˆ 10.6, 1 H); 4.72 (d, J ˆ 10.6, 1 H); 4.36 4.09 (m, 2 H); 3.85 3.40
(m, 5 H); 3.21 (s, 3 H); 2.90 2.80 (m, 1 H); 2.30 2.10 (m, 2 H); 1.33 0.80 (m, 8 H); 1.08 (d, J ˆ 6.4, 3 H); 0.90
(d, J ˆ 7.2, 3 H); 0.06 (s, 9 H). 13C-NMR (50 MHz, CDCl3): 170.5; 146.9; 109.5; 100.2; 94.4; 77.7; 74.4; 69.0; 65.9;
‡
60.8; 48.1; 41.6; 32.7; 29.7; 25.4; 22.8; 18.0; 17.6; 11.6; À 1.4 (3 C). HR-FAB-MS: 443.2669 (C 22H41NO6Si ; calc.
443.2703).
9. (aS,2R,5R,6R)-Tetrahydro-2-methoxy-5,6-dimethyl-4-methylidene-a-{[2-(trimethylsilyl)ethoxy]meth-
oxy}-2H-pyran-2-acetic Acid Methyl Ester (17). In another experiment, acid 16 was generated as above from
aldehyde 15 (35 mg, 0.10 mmol) and dissolved in Et2O. A soln. of diazomethane (ca. 5 mmol) in Et2O (ca. 5 ml)
was added at 08. After stirring for 30 min at 08, sat. aq. NH4Cl soln. (ca. 1 ml) was added. After the yellow color
had disappeared, the aq. layer was extracted with Et2O ( 2Â 5 ml), the combined org. layer washed with brine
(5 ml), dried (Na2SO4), and evaporated, and the residue subjected to FC (petroleum ether/tBuOMe): 17
(36 mg, 96%). Colorless oil. 1H-NMR (400 MHz, CDCl3): 0.01 (s, 9 H); 0.85 0.90 (m, 5 H; including a d, J ˆ
6.99, at 0.89, 3 H); 1.07 (d, J ˆ 6.84, 3 H); 2.15 (dq, J ˆ 6.97 , 2.48, 1 H); 2.26 (d, J ˆ 14.73, 1 H); 2.87 (ddd, J ˆ
14.74, 2.18, 2.18, 1 H); 3.21 (s, 3 H); 3.56 3.64 (m, 2 H); 3.73 (s, 3 H); 3.81 (dq, J ˆ 6.53, 2.58, 1 H); 4.37
(s, 1 H); 4.64 4.72 (m, 3 H; including a dd, J ˆ 2.11, 2.11, at 4.70, 1 H, and an AB system, JA ˆ 4.67, JB ˆ 4.72,
JAB ˆ 7.04, 2 H); 4.79 (dd; J ˆ 2.04, 2.04, 1 H). 13C-NMR (100 MHz, CDCl3): À 1.48; 11.51; 17.65; 18.02; 32.68;
41.54; 48.06; 51.81; 65.87; 69.01; 74.75; 94.51; 100.06; 109.45; 146.76; 170.93.
10. 3-Methylideneheptanoic Acid (24). Cyclobutenone 23 [28] (158 mg, 1.20 mmol) was dissolved in H2O
(1.5 ml) to which had been added a few drops of 1,4-dioxane. The soln. was heated to reflux for 12 h. The pH was
adjusted to 3 by addition of a few drops of 1m HCl. The mixture was extracted with CH2Cl2 (3 Â 6 ml) and the
combined org. layer dried (Na2SO4) and evaporated: 24 (166 mg, 96%). Yellowish liquid. 1H-NMR (300 MHz,
CDCl3; see [37]): 10.71 (br. s, 1 H); 4.72 (2d, J ˆ 1.2, 2 H); 3.06 (s, 2 H); 2.17 2.09 (m, 2 H); 1.50 1.24
(m, 4 H); 0.89 (t, J ˆ 7.2, 3 H). 13C-NMR (75 MHz, CDCl3): 178.3; 142.0; 113.9; 41.7; 35.5; 29.5; 22.2; 13.9.
11. Methyl 3-Methylideneheptanoate (25). A soln. of 24 (644 mg, 4.22 mmol) in SOCl2 (ca. 3 ml) was stirred
for 15 h at r.t. Evaporation of the excess of SOCl2 gave the crude acyl chloride as a colorless oil (617 mg). The
latter was added at À 208 to a soln. of pyridine (3 ml) in MeOH (5 ml). After stirring for 3 h at r.t., H 2O and
Et2O (4 ml) were added. The aq. layer was extracted with Et2O ( 3Â 10 ml), the combined org. layer washed
with brine (10 ml), dried (Na2SO4), and evaporated: 25 (510 mg, 77%). Colorless oil which was purified by
distillation (758/1 Torr) before the next step. 1H-NMR (200 MHz, CDCl3): 4.92 (d, J ˆ 1.3, 1 H); 4.88 (d, J ˆ 0.8,
1 H); 3.69 (s, 3 H); 3.05 (br. d, J ˆ 0.8, 2 H); 2.09 (br. t, J ˆ 7.3, 2 H); 1.37 (m, 4 H); 0.9 (br. t, J ˆ 7.3, 3 H).
12. 1-Chloro-4-methylidenoctan-2-one (26). To a soln. of chloroiodomethane (0.33 ml, 4.48 mmol) in THF/
Et2O 1:1 (40 ml), at À 1008, 1.6m BuLi in hexane (1.4 ml, 2.24 mmol) was added. After stirring for 1 h at À 1008,
25 (100 mg, 0.640 mmol) was added at À 1008, and the mixture was allowed to reach À 788 during 1 h. The
mixture was poured into sat. aq. NH4Cl soln. (100 ml), the aq. layer extracted with Et2O ( 3Â 10 ml), the
combined org. layer washed with brine (10 ml), dried (MgSO4), and evaporated, and the residue subjected to
FC (pentane/tBuOMe 30 :1): 26 (60 mg, 54%). Colorless oil. 1H-NMR (200 MHz, CDCl3): 4.98 (d, J ˆ 1.5, 1 H);
4.89 (d, J ˆ 1.0, 1 H); 4.15 (s, 2 H); 3.29 (s, 2 H); 2.04 (t, J ˆ 7.6, 2 H); 1.36 (m, 4 H); 0.90 (t, J ˆ 6.9, 3 H).
13. 5-Methyliden-3-oxo-N-phenylnonanamide (27). At 08, 0.1m SmI2 in THF (4.6 ml, 0.46 mmol) was added
to a soln. of 26 (20 mg, 0.115 mmol) and phenyl isocyanate (15 ml, 0.137 mmol) in dry THF (2 ml). After stirring
for 3 h at 08, aq. NaHCO3 soln. (15 ml) was added, the aq. layer extracted with Et2O ( 3Â 3 ml), the combined
org. layer washed with brine (10 ml), dried (MgSO4), and evaporated, and the residue subjected to FC
(pentane/tBuOMe 4 :1 ! pentane/AcOEt 4 :1): 27 (16 mg, 53%). Colorless oil. 1H-NMR (200 MHz, CDCl3):
9.13 (br. s, 1 H); 7.55 (d, J ˆ 9.0, 2 H); 7.33 (t, J ˆ 7.8, 2 H); 7.18 7.08 (m, 1 H); 5.04 (d, J ˆ 1.3, 1 H); 4.92 (d, J ˆ
0.8, 1 H); 3.62 (s, 2 H); 3.26 (s, 2 H); 2.05 (t, J ˆ 7.4, 2 H); 1.50 1.20 (m, 4 H); 0.90 (t, J ˆ 7.4, 3 H). 13C-NMR
(50 MHz, CDCl3): 206.0; 163.3; 141.9; 137.5; 129.0 (2 C); 124.6; 120.1 (2 C); 115.2; 51.8; 47.8; 35.9; 29.6; 22.3;
13.9.
14. rel-(tert-Butyl){[(1R,2R)-1,2-dimethylbut-3-ynyl]oxy}dimethylsilane (28). At À 788, 1.6m BuLi in
hexane (12.8 ml, 20.8 mmol) was added to a soln. of ethynyltrimethylsilane (2.04 g, 20.8 mmol) in THF (60 ml).
After stirring for 10 min, BF3 ¥ OEt2 (2.95 g, 20.8 mmol) and racemic trans-2,3-dimethyloxirane (1.24 ml,
13.9 mmol) was added at À 788. After stirring for 1.5 h at À 788, sat. aq. NH4Cl soln. (50 ml) was added, the aq.
layer extracted with Et2O ( 3Â 40 ml), and the combined org. layer washed with brine (50 ml), dried (MgSO4),
and evaporated (removal of residual Et2O). The remaining crude THF soln. was used for the next step.
At 08, 1.0m Bu4NF in THF (14 ml, 14 mmol) was added to the above THF soln. After stirring for 30 min at
r.t., the reaction was quenched by addition of H2O (3 drops). The mixture was filtered with Et2O through a pad
of SiO2, the filtrate carefully evaporated, the residual liquid taken up in DMF (20 ml), and 1H-imidazole (2.43 g,
35.8 mmol) added at 08. After dissolution of the 1H-imidazole, tBuMe2SiCl (50 wt-% in toluene; 5.4 g, 18 mmol)

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Helvetica Chimica Acta Vol. 87 (2004)
was added dropwise. The mixture was stirred for 1 h at 758. H2O (10 ml) was added, the aq. layer extracted with
Et2O ( 4Â 40 ml), the combined org. layer dried (MgSO4) and evaporated, and the residue distilled at 40 508/
1 Torr): 28 (1.08 g, 37% over 3 steps). Colorless oil. 1H-NMR (200 MHz, CDCl3): 3.61 (dq, J ˆ 6.7, 6.3, 1 H); 2.32
(ddq, J ˆ 7.0, 7.0, 2.3, 1 H); 2.06 (d, J ˆ 2.3, 1 H); 1.25 (d, J ˆ 6.0, 3 H); 1.17 (d, J ˆ 6.8, 3 H); 0.89 (s, 9 H); 0.06
(s, 6 H).
15. rel-(5R,6R)-6-{[(tert-Butyl)dimethylsilyl]oxy}-1-chloro-5-methyl-4-methylideneheptan-2-one (30).
BF3 ¥ OEt2 (1.7 ml, 13 mmol) was added at 08 to a soln. of freshly distilled chloroacetaldehyde [34] (0.76 ml,
13 mmol) and the allylsilane 10 (2.0 g, 6.7 mmol) in CH2Cl2 (100 ml). After stirring for 3 h at 08, aq. NaHCO3
soln. (20 ml) was added, the aq. layer extracted with CH2Cl2 (3 Â 20 ml), the combined org. layer dried (MgSO4)
and evaporated, and the residue filtered with pentane/Et2O 9 :1 over a SiO2 column: alcohol 29 as a colorless oil
(1.03 g, 50%).
DessÀMartin periodinane [23] (400 mg, 1.21 mmol) was added at r.t. to a soln. of alcohol 29 (140 mg,
0.453 mmol) in wet CH2Cl2 (20 ml). After stirring for 1 h, the mixture was filtered over a pad of Celite and
washed with CH2Cl2. The eluents were washed with aq. NaHCO3 soln. (2 Â 20 ml), dried (MgSO4), and
evaporated, and the residue was subjected to FC (pentane/Et2O 10 :1): 30 (130 mg, 94%). Colorless oil.
1H-NMR (200 MHz, CDCl3): 5.00 (br. s, 1 H); 4.95 (br. d, J ˆ 1.0, 1 H); 4.14 (s, 2 H); 3.72 (dq, J ˆ 6.0, 5.9, 1 H);
3.43 (dd, J ˆ 15.5, 1.0, 1 H); 3.33 (dd, J ˆ 15.5, 0.4, 1 H); 2.18 (dq, J ˆ 6.5, 6.0, 1 H); 1.06 (d, J ˆ 6.0, 3 H); 1.03
(d, J ˆ 6.5, 3 H); 0.87 (s, 9 H); 0.04 (s, 3 H); 0.03 (s, 3 H). 13C-NMR (50 MHz, CDCl3): 199.8; 144.5; 115.2; 71.1;
47.2; 46.7; 33.5; 25.8; 20.9; 18.0; 15.5; À 4.5; À 4.9.
16. rel-(6R,7R)-7-{[(tert-Butyl)dimethylsilyl]oxy}-6-methyl-5-methyliden-3-oxo-N-(tetrahydro-2H-pyran-
2-yl)octanamide (31a). At 08, 0.1m SmI2 in THF (39 ml, 3.9 mmol) was added to a mixture of 30 (400 mg,
1.30 mmol), tetrahydro-2-isocyanato-2H-pyran (133 mg, 1.04 mmol) and 4-ä molecular sieves (500 mg) in dry
THF (5 ml). After stirring at r.t. for 3 h, sat. aq. NH4Cl soln. (ca. 50 ml) was added, the aq. layer extracted with
AcOEt (3 Â 20 ml), the combined org. layer was dried (MgSO4) and evaporated, and the residue subjected to
1
FC (pentane/AcOEt 3 :2): 31a (240 mg, 58%). Colorless oil. H-NMR (200 MHz, CDCl3): 7.65 (br. d, J ˆ 5.0,
1 H); 5.11 (br. t, J ˆ 9.1, 2.1, 1 H); 4.99 (br. s, 1 H); 4.92 (br. s, 1 H); 3.97 3.91 (br. d, 1 H); 3.68 (dq, J ˆ 6.1, 6.0,
1 H); 3.64 3.50 (m, 1 H); 3.44 (br. s, 2 H); 3.28 (br. d, J ˆ 5.0, 2 H); 2.12 (dq, J ˆ 6.7, 6.1, 1 H); 1.91 1.74
(m, 2 H); 1.58 1.40 (m, 4 H); 1.03 (d, J ˆ 5.8, 3 H); 1.00 (d, J ˆ 7.0, 3 H); 0.85 (s, 9 H); 0.02 (s, 3 H); 0.00
(s, 3 H). 13C-NMR (50 MHz, CDCl3): 205.6; 165.6; 144.6; 116.1; 77.8; 71.6; 67.5; 52.0; 48.0; 47.2; 31.6; 26.3; 25.4;
23.0; 21.4; 18.5; 16.1; À 4.0; À 4.4.
17. rel-(6R,7R)-7-{[(tert-Butyl)dimethylsilyl]oxy}-6-methyl-5-methyliden-3-oxo-N-phenyloctanamide
(31b). As described for 31a, with 0.1m SmI2 in THF (49 ml, 4.9 mmol), 30 (500 mg, 1.63 mmol), phenyl
isocyanate (291 mg, 2.44 mmol), 4-ä molecular sieves (500 mg), and THF (5 ml) for 5 h. FC (pentane/Et 2O
4 :1 ! 2 :1) furnished 31b (418 mg, 66%). Colorless oil. 1H-NMR (300 MHz, CDCl3): 9.19 (br. s, 1 H); 7.54
(d, J ˆ 7.8, 2 H); 7.31 (t, J ˆ 7.9, 2 H); 7.11 (t, J ˆ 7.3, 1 H); 5.04 (s, 1 H); 4.98 (s, 1 H); 3.71 (dq, J ˆ 5.9, 5.9, 1 H);
3.60 (s, 2 H); 3.41 (d, J ˆ 15.0, 1 H); 3.31 (d, J ˆ 15.0, 1 H); 2.16 (dq, J ˆ 6.6, 6.6, 1 H); 1.02 (d, J ˆ 6.3, 3 H); 1.00
(d, J ˆ 7.3, 3 H); 0.88 (s, 9 H); 0.05 (s, 3 H); 0.03 (s, 3 H). 13C-NMR (75 MHz, CDCl3): 206.2; 163.5; 144.2; 137.6;
129.0 (2 C); 124.6; 120.2 (2 C); 115.9; 71.4; 65.9; 51.8; 48.1; 46.8; 25.9; 20.9; 15.7; À 4.3; À 4.7.
18. rel-(6R,7R)-7-{[(tert-Butyl)dimethylsilyl]oxy}-6-methyl-5-methyliden-3-oxo-N-phenyl-2-(phenylhydra-
zono)octanamide (33). At 08, 3-methyl-1-(nitrosooxy)butane was added dropwise to a suspension of aniline
hydrochloride (20 mg) in AcOH (0.1 ml) until a clear soln. resulted. After stirring for 30 min, Et2O (2 ml) was
added, and the resulting white solid was washed with additional Et2O ( 3Â 2 ml). The salt was suspended in
EtOH (1 ml) and a soln. of 31b (17 mg, 0.048 mmol) in EtOH (0.3 ml) was added at 08, followed by 0.5m
AcONa in H2O (0.1 ml, 0.048 mmol) at 08. After stirring for 1 h, H2O (2 ml) was added, the aq. layer extracted
with Et2O ( 4Â 2 ml), dried (MgSO4), and evaporated, and the residue subjected to FC (pentane/Et2O 8 :1 !
2 :1): 33 (14 mg, 24%), besides recovered 31b (8 mg, 47%). 33: Colorless oil. 1H-NMR (300 MHz, CDCl3): 14.83
(br. s, 1 H); 11.52 (br. s, 1 H); 7.65 7.62 (m, 2 H); 7.42 7.34 (m, 6 H); 7.22 7.13 (m, 2 H); 5.02 (br. s, 1 H); 4.98
(br. s, 1 H); 3.86 3.78 (m, 3 H); 2.28 (dq, J ˆ 6.6, 6.6, 1 H); 1.13 (d, J ˆ 5.6, 3 H); 1.11 (d, J ˆ 6.6, 3 H); 0.87
(s, 9 H); 0.05 (s, 3 H); 0.04 (s, 3 H). 13C-NMR (75 MHz, CDCl3): 199.5; 163.0; 146.4; 141.5; 136.9; 129.4; 128.8;
125.5; 125.2; 124.6; 120.7; 115.8; 115.5; 114.1; 71.1; 47.2; 44.2; 25.6; 21.2; 17.9; 15.7; À 4.5; À 5.0.
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Received November 26, 2003