Large-Scale Synthesis of the Anti-Cancer Marine Natural Product (+)-Discodermolide. Part 2: Synthesis of Fragments C1-6 and C 9-14

Article abstract of DOI:10.1021/op0341317

Kilogram-scale syntheses of fragments C_1-6 (6) and C _9-14 (4) of (+)-discodermolide from common precursor 3 are described. Improved procedures for each step of both fragments were developed by minimizing or eliminating the formation

Full text of DOI:10.1021/op0341317

Organic Process Research & Development 2004, 8, 101−106
Large-Scale Synthesis of the Anti-Cancer Marine Natural Product
(+)-Discodermolide. Part 2: Synthesis of Fragments C1-6 and C9-14
Stuart J. Mickel,* Gottfried H. Sedelmeier, Daniel Niederer, Friedrich Schuerch, Dominique Grimler, Guido Koch,
Robert Daeffler, Adnan Osmani, Alfred Hirni, Karl Schaer, and Remo Gamboni
Chemical and Analytical DeVelopment, NoVartis Pharma AG, CH 4002 Basel, Switzerland
Andrew Bach, Apurva Chaudhary, Stephen Chen, Weichun Chen, Bin Hu, Christopher T. Jagoe, Hong-Yong Kim,
Frederick R. Kinder, Jr., Yugang Liu, Yansong Lu, Joseph McKenna, Mahavir Prashad, Timothy M. Ramsey,
Oljan Repi cˇ , Larry Rogers, Wen-Chung Shieh, Run-Ming Wang, and Liladhar Waykole
NoVartis Institutes for Biomedical Research, One Health Plaza, East HanoVer, New Jersey 07936, U.S.A.
Abstract:
a strategy involving acetylene chemistry, followed by a
Negishi coupling, and introduction of the vinyl iodide at
the end (Scheme 3). Unfortunately neither of these elegant
routes was deemed suitable for scale-up primarily because
(1) the selenium chemistry utilized by Paterson is highly
toxic and (2) in the Panek approach, the use of large ex-
cesses of the Schwarz reagent combined with the uncertain
stability of the p-methoxybenzyl group in 4 (despite literature
reports that this group would survive the chemistry).5
Therefore, the original procedure starting with 3 described
Kilogram-scale syntheses of fragments C1-6 (6) and C9-14 (4)
of (+)-discodermolide from common precursor 3 are described.
Improved procedures for each step of both fragments were de-
veloped by minimizing or eliminating the formation of byprod-
ucts that were isolated and characterized in Smith’s synthesis.
Introduction
The marine natural product (+)-discodermolide1 (1)
2
contains a stereo triad that repeats itself three times (C2-4
,
by Smith was developed for our multikilogram production
C
10-12, C18-20).
of fragment 4.
Similarly, fragment C1-6 (6), required for the construction
of the lactone ring of (+)-discodermolide, can also be
synthesized from 3. As a result, there would be a synergy in
preparing both fragments 4, 5, and 6 from the same precursor
3
for our multigram synthesis of (+)-discodermolide. The
preparation of fragment 5 is discussed in part 3 of this series.
Results and Discussion
These fragments can, therefore, be made conveniently from
a common precursor 3, as described by Smith. In Part 2 of
this series, we discuss the large-scale preparation of inter-
mediates C9-14 (4) and C1-6 (6) from the common precursor
Synthesis of Fragment C9-14 (4). The four-step route
that we employed for the preparation of fragment 4 from
the common precursor 3 (obtained from 2, as described in
part 1 of this series) is shown in Scheme 4.
2
3
(Scheme 1).
Silylation of 3 with tert-butyldimethylsilyl triflate afforded
TBDMS ether 8 in excellent yield (90%) after chromatog-
raphy on silica gel. Smith’s procedure employed DIBAL-H
for the reduction of Weinreb amide 8 at -78 °C to produce
the desired aldehyde 9. However, it also generated an alcohol
byproduct due to the uncontrolled over-reduction of the
resulting aldehyde. We developed an alternative process for
the reduction employing Red-Al at -20 °C, a temperature
that is easier for pilot-plant operation. It was equally effective
and avoided tedious low-temperature operations in our plant.
The isolated yield of 9 as an oil was also high (68%) after
chromatography on silica gel.
Fragment C9-14 (4) contains a cis-trisubstituted double
bond at C13-14 and offers a synthetic challenge in controlling
the stereochemistry. Numerous approaches for the construc-
tion of this trisubstituted cis double bond have been
described, some of which were quite ingenious. For example,
Paterson described a route leading to a trisubstituted ole-
fin via a Claisen rearrangement (Scheme 2). Panek utilized
3
4
*
Corresponding author: E-mail: stuart_john.mickel@pharma.novartis.com.
(
1) (a) Gunasekera, S. P.; Gunasekera, M.; Longley, R. E.; Schulte, G. K. J.
Org. Chem. 1990, 55, 4912; correction J. Org. Chem. 1991, 56, 1346. (b)
Gunasekera, S. P.; Paul, G. K.; Longley, R. E.; Isbrucker, R. A.; Pomponi,
S. A. J. Nat. Prod. 2002, 65, 1643.
(2) Smith, A. B.; Beauchamp, T. J.; LaMarche, M. J.; Kaufman, M. D.; Qiu,
Y.; Arimoto, H.; Jones, D. R.; Kobayashi, K. J. Am. Chem. Soc. 2000, 122,
(4) (a) Panek, J. S.; Hu, T. J. Org. Chem. 1997, 62, 4912. (b) Arefolov, A.;
Langille, N. F.; Panek, J. S. Org. Lett. 2001, 3, 3281. (c) Arefolov, A.;
Panek, J. S. Org. Lett. 2002, 4, 2397.
8
654.
(
3) Paterson, I; Florence, G. J.; Gerlach, K.; Scott, J. P. Angew. Chem., Int.
Ed. 2000, 39, 377.
(5) Critcher, D. J.; Connolly, S.; Wills, M. J. Org. Chem. 1997, 62, 6638.
1
0.1021/op0341317 CCC: $27.50 © 2004 American Chemical Society
Vol. 8, No. 1, 2004 / Organic Process Research & Development
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101
Published on Web 12/04/2003

Scheme 1. Synthetic strategy leading to fragment C
1
6 9
- (6) and C -14 (4)
Scheme 2. Paterson’s approach to C13,14-cis-trisubstituted double bond
The success of converting amide 8 into aldehyde 9 was
very dependent on the quality of silyl ether 8. If 8 was not
pure, the yield of aldehyde would drop to below 60%. The
reaction time and temperature were also found to be critical.
When the reaction was held too long at 0 °C, a competing
de-silylation reaction occurred that led to the formation of
significant amounts of hydroxy aldehyde 10. If necessary,
however, aldehyde 10 can easily be isolated and subjected
to the standard silylation conditions to regenerate 9. By
maintaining the reaction temperature between -5 to 0 °C,
formation of 10 was also minimized. Another byproduct
(olefin 11) was isolated in small quantity, which was formed
by â-elimination either of silyl alcohol from 9 or of water
from 10. Attempts to convert all of 8 into 9 were unsuc-
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8
Scheme 3. Panek’s approach to C13,14-cis-trisubstituted
double bond
ketone 13 during the workup. This byproduct can be avoided
by using nonaqueous workup.
8
Smith reported that the reaction of 9a with 9 afforded
epoxide 14 in addition to the desired 4 in a 1:1 ratio.
Alternative approaches were investigated to minimize this
major byproduct; however, they were unsuccessful. For
9
example employing a method described by Shen, where the
initially formed betaine intermediate was deprotonated with
a second equivalent of base and then iodinated, produced
des-iodo olefin 12. Utilizing Hanessian’s phosphonates10 in
this process also resulted in only des-iodo olefin 12.
Scheme 4. Synthesis of fragment C
9
-
14
Synthesis of Fragment C1-6 (6). The five-step synthesis
of fragment 6 from common precursor 3 is outlined in
Scheme 5.
2
The published approach to aldehyde 16 from 3 was
followed. Hydrogenolysis of PMB ether 8 (same intermediate
as for fragment 4 synthesis) with palladium on carbon in
tert-butyl alcohol afforded alcohol 15. Due to its propensity
for lactonisation to 18, 15 was used as a tert-butyl alcohol
solution immediately for the next step without isolation or
purification. Oxidation of 15 with TEMPO (2,2,6,6-tetra-
methylpiperidine-1-oxy radical) and diacetoxy iodobenzene
furnished aldehyde 16 as an oil, which was again used for
the next step without purification. Further elaboration of 16
cessful. The final reaction conditions were a compromise to
minimize byproduct formation. Aldehyde 9 was stable if
stored at <-10 °C.
3
to the analogous Paterson fragment 6 needed for the final
aldol coupling (see Part 5 of this series) proceeded by
utilising a methyl Grignard reagent and produced secondary
alcohol 17 as a mixture of diastereoisomers. Since 17 also
lactonized readily to 19, it was oxidized immediately with
6
Utilizing the Zhao olefination procedure, also used by
2
7
Smith and Marshall, we obtained the desired cis-vinyl
iodide 4 in 31% yield after chromatography purification on
silica gel. Only small amounts of the undesired trans isomer
were detected (cis:trans ) 15:1). We did not observe any
des-iodo olefin 12, suggesting that the formation of 9a from
SO
fragment C1-6) after chromatography. By following these
continuous operations, the amounts of both lactones (18 and
9) were minimized. The overall yield for the five-step
3
/pydridine in DMSO to yield pure methyl ketone 6
(
1
9
b via ylide iodination (Scheme 4) had been completed
sequence was 66% on a routine scale of several kilograms.
before it was added to aldehyde 9.
This olefination step was one of the most difficult
reactions for scale-up. We consistently obtained 25-31%
yield on the maximum scale of 2.5 kg of aldehyde 9.
Complicated workup procedures and instability of 4 con-
tributed to low yield. Smith utilized iodine for the conversion
of ethyltriphenylphosphonium iodide (9b) into the iodo ylide
2
(
9a). We found that N-iodosuccinimide can be used to
replace iodine without detriment. While this makes the
reaction easier to handle, it did not contribute to an increase
in yield. Initially, we observed the formation of the methyl
Having prepared both fragments C9-14 (4) and C1-6 (6)
in large quantities from common precursor 3, synthesis of
(8) Arimoto, H.; Kaufmann, M. D.; Kobayashi, K.; Qiu, Y.; Smith, A. B. Synlett
(6) Chen, J.; Zhao, K. Tetrahedron Lett. 1994, 35, 2827.
1998, 765.
(7) Marshall, J. A.; Johns, B. A. J. Org. Chem. 1998, 63, 7885.
(9) Shen, Y.; Gao, S. J. Chem. Soc., Perkin Trans. 1 1995, 1331.
Vol. 8, No. 1, 2004 / Organic Process Research & Development
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103

Scheme 5. Synthesis of fragment C
1
6
- (6)
the third structural segment (Fragment C15-21) will be
undertaken next (Part 3).
and the cooling bath temperature adjusted to 0 °C. The
reaction mixture was quenched by the portionwise addition
of 10% aqueous solution of citric acid (initially 4 × 0.6 kg
portions followed by one portion of 139 kg, total 141.4 kg).
The mixture was allowed to warm to room temperature, and
the two-phase system was stirred for an additional 20 min.
The organic phase was separated and washed with 10% citric
acid solution (141 kg) and twice with diluted brine (111 kg
water plus 34 kg of saturated sodium chloride solution). The
Experimental Section
(2R,3S,4S)-3-(tert-Butyldimethylsilanyloxy)-5-(4-meth-
oxybenzyloxy)-2,4-dimethylpentanoic acid methoxymethyl
amide (8). To a cooled (0-5 °C) solution of amide 3 (25
kg, 76.8 mol) in toluene (84.0 kg), 2,6-lutidine (10.7 kg, 99.9
mol) was added tert-butyldimethylsilyl triflate (24.4 kg, 92.3
mol) dropwise over a period of 30 min, maintaining the
temperature between 0 and 5 °C. The reaction mixture was
stirred for 30-60 min at 0-5 °C and treated with 10%
aqueous solution of sodium hydrogen sulphate (120 kg). The
phases were separated, and the aqueous phase was re-
extracted with toluene (63 kg). The combined organic phases
were washed twice with water (2 × 120 kg) and concentrated
under vacuum at 40 °C to give crude silyl ether 8 (37 kg) as
an oil. This crude material was chromatographed in two
portions of 18 kg over silica gel (150 kg) eluting initially
with heptane/ethyl acetate 15/1 followed by ethyl acetate to
2 4
organic phase was dried over Na SO (3 kg), filtered, and
concentrated under vacuum to give crude 9 (11.76 kg) as an
oil. Chromatography on silica gel, eluting with heptane/ethyl
1
acetate, 9/1, delivered pure aldehyde 9 (8.30 kg, 68%): H
NMR (CDCl
3
) δ 9.70 (d, J ) 2 Hz, 1H), 7.25 (m, 2H), 6.85
(m, 2H), 4.40 (ABq, J ) 13 Hz, 2H), 4.20 (m, 1H), 3.81 (s,
3
1
H), 3.40 (m, 1H), 3.38 (m, 1H), 2.50 (m, 1H), 2.05 (m,
H), 1.13 (d, J ) 6 Hz, 3H), 0.95 (d, J ) 6 Hz, 3H), 0.85
(s, 9H), 0.05 (s, 3H), 0.00 (s, 3H).
Also isolated were the following two byproducts.
1
Desilylated aldehyde 10: H NMR (CDCl
3
) δ 9.69 (s,
1
1H), 7.19 (m, 2H), 6.83 (m, 2H), 4.40 (s, 2H), 4.03 (dt, J )
give the purified 8 (30.4 kg, 90%) as an oil: H NMR
9
3
1
6
2
.0, 2.0 Hz, exch D O, 1H), 3.75 (s, 3H), 3.58 (dd, J ) 9.13,
.2 Hz, 1H), 3.45 (pseudo t, J ) 8.41 Hz, 1H), 2.38 (m,
H), 1.94 (m, 1H), 1.08 (d, J ) 6.9 Hz, 3H), 0.79 (d, J )
(CDCl
3
) δ 7.18 (m, 2H), 6.80 (m, 2H), 4.32 (ABq, J ) 11.5
Hz, 2H), 3.86 (dd, J ) 8.17, 2.53 Hz, 1H), 3.74(s, 3H), 3.54-
3
1
.48 (m, 4H), 3.09 (dd, J ) 9.8, 8.2 Hz, 1H), 3.05 (m, 4H),
.84 (br m, 1H), 1.05 (d, J ) 7 Hz, 3H), 0.94 (d, J ) 6.6
.5 Hz, 3H).
1
r,â-Unsaturated aldehyde 11: H NMR (CDCl
3
) δ 9.31
Hz, 3H), 0.83 (s, 9H), 0.00 (s, 6H).
(s, 1H), 7.18 (m, 2H), 6.80 (m, 2H), 6.25 (d, J ) 15 Hz,
(2R,3S,4S)-3-(tert-Butyldimethylsilanyloxy)-5-(4-meth-
1
H), 4.35 (s, 2H), 3.75 (s, 3H), 3.31 (m, 2H), 2.95 (m, 1H),
oxybenzyloxy)-2,4-dimethylpentanal (9). A solution of
amide 8 (14.1 kg, 32.07 mol) in toluene (78 kg) was cooled
to an internal temperature of -20 °C. Red-Al (14.0 kg, 70%
solution in toluene, 48.48 mol) was added dropwise over 60
min, maintaining the temperature at -20 °C. After the
addition was completed, the reaction was stirred for 60 min
1
.73 (s, 3H), 1.05 (d, J ) 6 Hz, 3H).
tert-Butyl-{(Z)-(1R,2S)-4-iodo-1-[(S)-2-(4-methoxyben-
zyloxy)-1-methylethyl]-2-methylpent-3-enyloxy}-dimeth-
ylsilane (4). (A) Procedure Utilizing Iodine. A suspension
of ethyltriphenylphosphonium iodide (4.44 kg, 10.62 mol)
in dry THF (40 L) was treated with a 40% solution of sodium
hexamethyldisilazane in THF (4.87 kg, 10.6 mol) at room
temperature. The resulting red solution was added dropwise
within 30 min to a cold (-78 °C) solution of iodine (2.7 kg,
10.6 mol) in THF. The resulting dark red suspension was
(10) (a) Stowell, M. H. B.; Ueland, J. M.; McClard, R. W. Tetrahedron Lett.
1990, 31, 3261. (b) Patois, C.; Savignac, P. Tetrahedron Lett. 1991, 32,
1317. (c) Hanessian, S.; Bennani, Y. L.; Delorne, D. Tetrahedron Lett. 1990,
31, 6461. (d) Hanessian, S.; Bennani, Y. L. Tetrahedron Lett. 1990, 31,
6465.
104
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stirred for an additional 15 min at -78 °C, and a 40%
solution of sodium hexamethyldisilazane in THF (4.6 kg,
combined filtrates were evaporated under vacuum to give
the crude product. Chromatography, as described above,
yielded pure 4 (956 g, 27.5%).
9.56 mol) was added over 10 min. The slightly turbid red
solution was then treated with a solution of 9 (2.55 kg, 6.7
mol) in THF (10 L). The reaction mixture was warmed to
Des-iodo olefin 12 (Obtained by the Procedure De-
scribed by Shen ): H NMR (CDCl ) δ 7.21 (m, 2H), 6.83
3
9
1
-
20 °C and stirred for 20 min. A solution of ammonium
(m, 2H), 5.31 (m, 1H), 5.19 (m, 1H), 4.36 (s, 2H), 3.77 (s,
3H), 3.50 (dd, J ) 9.2, 4.9 Hz, 1H), 3.40 (dd, J ) 7.3, 3.9
Hz, 1H), 3.20 (dd, J ) 10.3, 8.5 Hz, 1H), 2.62 (m, 1H),
1.97 (m, 1H), 1.54 (dd, J ) 6.7 & 1.5 Hz, 3H), 0.93 (d, J )
7.1 Hz, 3H), 0.88 (d, J ) 6.7 Hz, 3H), 0.83 (s, 9H), 0.01 (s,
3H), 0.00 (s, 3H).
(2R,3S,4S)-3-(tert-Butyldimethylsilanyloxy)-5-hydroxy-
2,4-dimethylpentanoic Acid Methoxymethyl Amide (15).
A 51.3% water suspension of palladium on charcoal (1.11
kg, 20%) was diluted with tert-butyl alcohol (11.8 kg). This
suspension was added to a solution of 8 (2.78 kg, 6.32 mol)
in tert-butyl alcohol (10 kg). The suspension was hydroge-
chloride (12 kg) in water (70 L) was added. The organic
layer was separated and the aqueous layer re-extracted with
THF (20 L). The combined organic layers were washed with
brine (50 L), dried over MgSO
concentrated under vacuum at 30 °C to a volume of about
5 L. Heptane was added, followed by Cellflock filter aid
12 kg). The mixture was filtered and the solid rinsed with
4
and filtered. The filtrate was
3
(
heptane (70 L) in three portions. The combined filtrates were
concentrated under vacuum to give crude iodide 4 (22.3 kg).
This material was chromatographed over 50 kg of silica gel
eluting initially with heptane/TBME, 99/1 (37 L), followed
by heptane/TBME, 97/3 (14 L), to give pure 4 (1.08 kg, 31%)
2
nated under H (9 bar) for 35 min at room temperature. The
1
after evaporation of the solvents: H NMR (CDCl
3
) δ 7.25
reaction mixture was filtered and the catalyst rinsed with
tert-butyl alcohol (4 kg). The tert-butyl alcohol solution of
15 was used immediately in the next step.
(
m, 2H), 6.86 (m, 2H), 5.27 (dq, J ) 8.8, 1.5 Hz, 1H) [Note:
containing < 1.0% of trans CdCH signal at δ 6.0 as a dq],
.40 (ABq, J ) 11.7 Hz, 2H), 3.80 (s, 3H), 3.58 (pseudo t,
J ) 6 Hz, 1H), 3.50 (dd, J ) 9.0, 4.8 Hz, 1H), 3.22 (dd, J
9.25, 8 Hz, 1H), 2.50-2.40 (m, 4H, CHMe + Me), 1.95
m, 1H), 0.99 (d, J ) 6.85 Hz, 3H), 0.94 (d, J ) 6.86 Hz,
H), 0.88 (s, 9H), 0.03 (s, 3H), 0.00 (s, 3H). Further elution
4
(2R,3S,4R)-3-(tert-Butyl-dimethylsilanyloxy)-2,4-di-
methyl-5-oxo-pentanoic Acid Methoxymethyl Amide (16).
To the tert-butyl alcohol solution of 15 were added TEMPO
(2,2,6,6-tetramethylpiperidin-1-oxy radical, 146.6 g, 0.94
mol) and solid diacetoxy iodobenzene (4.13 kg, 12.8 mol)
at room temperature. The suspension was stirred for 75 min
at room temperature and diluted with toluene (13.7 L) and
10% aqueous solution of sodium thiosulfate (23 L). The two-
phase system was stirred for 10 min at room temperature,
and the phases were separated. The organic phase was
concentrated to about one-third of its original volume and
filtered. The solid was rinsed with toluene (1 L), and the
combined filtrates were concentrated under vacuum at 45
°C to give 2.27 kg of crude aldehyde 16 as an oil, which
was used without further purification.
(2R,3S,4S)-3-(tert-Butyl-dimethylsilanyloxy)-5-hydroxy-
2,4-dimethylhexananoic Acid Methoxymethyl Amide (17).
The crude aldehyde 16 (1.4 kg) was dissolved in dichloro-
methane (16 L) and cooled to -20 °C. A solution of meth-
ylmagnesium bromide (5.3 L, 1.4 M) was added dropwise
within 90-100 min, maintaining the temperature at -20 °C.
The reaction mixture was quenched with 10% aqueous
solution of ammonium chloride (44 L) and allowed to warm
to 5 °C. The dichloromethane phase was separated and
washed with water (2 × 10 L). The solvent was concentrated
under vacuum to give 1.61 kg of crude alcohol 17 as an oil,
which was used without further purification.
)
(
3
yielded both cis- and trans-epoxide 14 as well as small
amounts of ketone 13.
1
cis-Epoxide 14: H NMR (CDCl
3
) δ 7.21 (m, 2H), 6.81
(m, 2H), 4.37 (ABq, J ) 11.5 Hz, 2H), 3.75 (s, 3H), 3.72
(dd, J ) 6.5, 2.9 Hz, 1H), 3.51 (dd, J ) 9.0, 4.6 Hz, 1H),
3
1
.19 (dd, J ) 9.05, 7.85 Hz), 3.03 (dq, J ) 5.88, 1.33 Hz,
H), 2.72 (dd, J ) 9.41, 4.2 Hz, 1H), 1.96 (m, 1H), 1.43
(m, 1H), 1.20 (d, J ) 5.4 Hz, 3H), 0.89 (d, J ) 7 Hz, 3H),
0
3
.86 (d, J ) 7 Hz, 3H), 0.84 (s, 9H), 0.02 (s, 3H), 0.00 (s,
H).
1
trans-Epoxide 14: H NMR (CDCl
3
) δ 7.21 (m, 2H), 6.81
(m, 2H), 4.37 (ABq, J ) 11.6 Hz, 2H), 3.78 (s, 3H), 3.61
(dd, J ) 6.6, 2.8 Hz, 1H), 3.42 (dd, J ) 9.0, 5 Hz, 1H),
3
1
1
0
.23 (dd, J ) 9.3, 7.1 Hz, 1H), 3.02 (dq, J ) 5.7, 1.4 Hz,
H), 2.79 (dd, J ) 9.5, 4.0 Hz, 1H), 1.96 (m, 1H), 1.55 (m,
H), 1.23 (d, J ) 5.5 Hz, 3H), 1.07 (d, J ) 6.6 HZ, 3H),
.91 (d, J ) 6.9 Hz, 3H), 0.91 (s, 9H), 0.02 (s, 6H).
1
Ketone 13: H NMR (CDCl
3
) δ 7.27 (m, 2H), 6.85 (m,
2H), 4.39 (ABq, J ) 11.5 Hz, 2H), 3.78 (s, 3H), 3.50 (dd,
J ) 9.1, 4.5 Hz, 1H), 3.47 (dd, J ) 6.16, 3 Hz, 1H), 3.21
dd, J ) 9.1, 7.4 Hz, 1H), 2.48 (dd, J ) 16.3, 4.4 Hz, 1H),
(
2
1
.28 (dd, J ) 16.2, 8.0 Hz, 1H), 2.21 (m, 1H), 1.89 (m,
H), 0.96 (d, J ) 7 Hz, 3H), 0.86 (s, 9H), 0.86 (d, J ) 6.6
(2R,3S,4R)-3-(tert-Butyldimethylsilanyloxy)-2,4-dimethyl-
5-oxo-hexananoic acid methoxymethyl amide (6). The
crude alcohol 17 (1.35 kg) was dissolved in dichloromethane
(4 L) and cooled to 0 °C. Triethylamine (3.0 L) and DMSO
(1.6 L) were added. The mixture was cooled to -20 °C,
and a solution of the sulphur trioxide pyridine complex (2.73
kg) in DMSO (8 L) was added over 20 min. The mixture
was warmed to 0 °C and stirred for an additional 2 h. The
mixture was diluted with tert-butyl methyl ether (27.4 L)
and treated with a solution of sodium hydrogen sulfate (1.86
Hz, 3H), 0.01 (s, 3H), 0.00 (s, 3H).
(B) Procedure Utilizing N-Iodosuccinimide. This was
performed exactly the same as the above Procedure A, except
that N-iodosuccinimide was used to replace iodine. The
workup was simplified as follows: sodium sulfate decahy-
drate was added to the reaction mixture and the suspension
stirred for 10 min at -20 °C. The resulting light-yellow
suspension was treated with heptane and Cellflock (filter aid)
and filtered. The solid was washed with heptane, and the
Vol. 8, No. 1, 2004 / Organic Process Research & Development
•
105

kg) in water (17 L). The organic phase was separated and
washed sequentially with sodium bicarbonate (20 L) and
water (20 L). The solvent was concentrated under vacuum
to give crude 6 (1.26 kg) as an oil. Chromatography on silica
gel (25 kg) eluting with heptane/tert-butyl methyl ether 10/1
(3R,4S,5S)-4-(tert-Butyldimethylsilanyloxy)-3,5,6-tri-
methyltetrahydropyran-2-one (19) (1:1 mixture of dia-
1
stereoisomers): H NMR (CDCl
3
) δ 4.33 (dd, J ) 6.8, 2.7
Hz, 2H), 3.66 (dd, J ) 9.9, 4.1 Hz, 2H), 2.37 (qd, J ) 11.2,
7.0 Hz, 2H), 1.88 (m, 2H), 1.26 (d, J ) 6.6 Hz, 3H), 1.22
(d, J ) 6.9 Hz, 3H), 0.89 (d, J ) 7.4 Hz, 3H), 0.85-0.82
(m, 21H), 0.01 (m, 12H).
gave, after removal of solvents, 0.94 kg (73% overall yield
1
from 8) of pure compound 6: H NMR (CDCl
3
) δ 4.28 (dd,
J ) 7.8, 4.2 Hz, 1H), 3.67 (s, 3H), 3.10-2.93 (br m, 4H),
2.69 (s, 3H), 1.09 (d, J ) 6.8 Hz, 3H), 1.03 (d, J ) 6.9 Hz,
Acknowledgment
3
H), 0.86 (s, 9H), 0.06 (s, 6H). Also isolated were the
We thank Professor S. V. Ley from the University of
Cambridge, U.K., for many useful discussions and sugges-
tions.
following compounds:
3R,4S,5S)-4-(tert-Butyldimethylsilanyloxy)-3,5-dimeth-
yltetrahydropyran-2-one (18): H NMR (CDCl
(
1
3
) δ 4.19
(
dd, J ) 11.2, 9.9 Hz, 1H), 4.06 (ddd, J ) 10.9, 4.7, 0.8 Hz,
Received for review September 16, 2003.
OP0341317
1
1
0
H), 3.62 (m, 1H), 2.55 (qd, J ) 7.7, 3.9 Hz 1H), 2.13 (m,
H), 1.23 (d, J ) 7.5 Hz, 3H), 0.90 (d, J ) 7.4 Hz, 3H),
.83 (s, 9H), 0.01 (s, 3H), 0.00 (s, 3H).
106
•
Vol. 8, No. 1, 2004 / Organic Process Research & Development