Synthesis of a C1-C12 Fragment of Gulmirecin B

Article abstract of DOI:10.1055/s-0037-1611559

The synthesis of a C1-C14 fragment of the macrolide antibiotic gulmirecin B through formation of the C7-C8 bond by addition of a vinyllithium intermediate to a C1-C7 aldehyde was investigated. This crucial coupling was successful with a vinyllithium reagent corresponding to a C8-C12 fragment. The C8-C12 vinyl bromide was prepared from l -malic acid. The C1-C7 aldehyde building block was synthesized from hex-5-enoic acid by using an Evans alkylation, a cross-metathesis, and an asymmetric dihydroxylation as key steps.

Full text of DOI:10.1055/s-0037-1611559

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2019, 30, A–E
letter
A
en
R. Rengarasu, M. E. Maier
Letter
Synlett
Synthesis of a C1–C12 Fragment of Gulmirecin B
Rathikrishnan Rengarasu
cross-metathesis
CO2H
HO2C
Martin E. Maier*
0
0
0
0-
0
0
0
2-3
5
7
0-4
9
4
3
HO
OH
MeO2C
Evans alkylation
L-(–)-malic acid
10 steps
HO
Institut für Organische Chemie, Eberhard Karls
Universität Tübingen, Auf der Morgenstelle 18,
72076 Tübingen, Germany
4 steps
12
OPMB
O
11
HO
OTr
7
O
H
martin.e.maier@uni-tuebingen.de
OTr
H
7
O
O
O
X
OTIPS
12
8
5
11
6
9
THF, –78 °C
5
6
+
O
HO
OTIPS
1
O
O
Li
8
O
O
OPMB
37
OPMB
1
gulmirecin B (1b)
39 X = H, OH
40 X = O
DMP, CH2Cl2
r.t. (71%)
Received: 14.02.2019
HO
HO
D-arabinose
Accepted after revision: 03.05.2019
Published online: 22.05.2019
HO
HO
13
DOI: 10.1055/s-0037-1611559; Art ID: st-2019-r0247-l
O
O
11
HO
HO
H
H
O
8
Abstract The synthesis of a C1–C14 fragment of the macrolide antibi-
otic gulmirecin B through formation of the C7–C8 bond by addition of a
vinyllithium intermediate to a C1–C7 aldehyde was investigated. This
crucial coupling was successful with a vinyllithium reagent correspond-
ing to a C8–C12 fragment. The C8–C12 vinyl bromide was prepared
from L-malic acid. The C1–C7 aldehyde building block was synthesized
from hex-5-enoic acid by using an Evans alkylation, a cross-metathesis,
and an asymmetric dihydroxylation as key steps.
O
O
O
O
O
O
1
7
3
5
HO
O
O
O
OH
gulmirecin A (1a)
gulmirecin B (1b)
HO
HO
HO
HO
13
Key words gulmirecin B, disciformycin, hydrozirconation, asymmetric
O
dihydroxylation, cross-metathesis, Evans alkylation
11
O
HO
HO
H
O
8
H
O
O
O
O
O
O
O
O
In 2014, the groups of Nett1 and Müller2 independently
described the isolation, structure elucidation, and biosyn-
thesis of similar 12-membered glycosylated macrolides
(Figure 1). These polyketides, which were named gulmire-
cins A and B (1a and 1b, respectively) by the Nett group,
and disciformycins A and B (2a and 2b, respectively) by the
Müller group, displayed promising activities against gram-
positive bacteria. Both groups isolated these natural prod-
ucts from Pyxidicoccus fallax strains, which are predatory
bacteria of the Myxococcaceae type. All the macrolides
share a D-arabinose residue at the 7-OH group. Differences
can be identified in the region C2–C4. Due to their novel
structures and biological activity, these macrolides repre-
sent valuable targets for total synthesis. In particular, the
selective glycosylation poses a certain challenge. In addi-
tion, the creation of the stereocenters and the construction
of the two trisubstituted double bonds have to be ad-
dressed.
7
1
3
5
O
O
O
disciformycin A (2a)
disciformycin B (2b)
Figure 1 Structures of the macrolides gulmirecin A and B and discifor-
mycin A and B
The 4-trimethylsilyl group was expected to keep the C3–C4
double bond in place. A subsequent trans-selective hydro-
stannylation permitted the introduction of the methyl
group at C8.
Recent publications by Kirschning and co-workers de-
scribe a synthesis of the aglycon of disciformycin B (2b).4 A
key feature of their synthesis is an Evans aldol reaction of a
glycolate derivative to form the C6–C7 bond of compound 6.
The required C7–C12 aldehyde was constructed from D-lac-
tate. Chain extension reactions on 6 delivered a seco acid
that was converted into the macrolactone 7. The C12–C13
double bond was installed at the end of the macrolactone
by a Wittig reaction to give compound 8.
The first synthesis of the disciformycins was published
by the Fürstner group in 2018.3 They used a ring-closing
alkyne metathesis (rcam) on ester 3 to forge the macrolac-
tone ring of 4 (formation of the C8–C9 bond; Scheme 1).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E

B
R. Rengarasu, M. E. Maier
Letter
Synlett
Fürstner
13
11
9
Noyori reduction
rcam
11
8
8
11
OTBS
10
O
OTBS
TBSO
O
O
4 steps
metal
8
X
HO
PO
O
O
11
O
O
1b
+
7
1
5
O
O
X
1
PO
O
X
RC(O)O
3
5
7
7
5
OP
10
1
6
O
8
Grignard addition to
C5 aldehyde
OP
PO
TBSO
O
9
OPMB
4 (X = SiMe3, R = i-Bu)
3
OP
12a X = H
X = SiMe3
from D-glyceraldehyde
OPMB
12b X = N(OMe)Me
11
9
Scheme 2 Retrosynthetic considerations for the synthesis of an acyclic
aglycon of gulmirecin B (1b)
8
HO
Et3N
glycosylation
O
O
O
2b
2a
7
1
5
O
5
ditions furnished aldehyde 16 in high yield.6 For the next
three steps, we adapted a known sequence published for a
related compound.7 Thus, aldehyde 16 was converted into
the 1,1-dibromoalkene 17 by using CBr4 and Ph3P. Treat-
ment of 17 with BuLi in THF generated the corresponding
terminal acetylide, which was alkylated with MeI to give
the internal alkyne 18 in 74% yield. A subsequent hydrozir-
conation followed by quenching of the vinylzirconocene in-
termediate with N-bromosuccinimide (NBS) gave the vinyl
bromide 19. Here, the Schwartz reagent, zirconocene hy-
drochloride, was generated in situ from Cp2ZrCl2 and
DIBAL-H.8 The hydrozirconation produced a mixture of re-
gioisomers (~4:1) that was carried on the next step. Hydro-
lysis of the acetal with aqueous acetic acid allowed us to
isolate the pure vinyl bromide 20 with a terminal vicinal
diol moiety. Differentiation of the two hydroxy groups was
possible by tritylation of the primary alcohol to give the
ether 21, followed by silylation of the secondary hydroxy
group by using TIPSOTf with 2,6-lutidine as the base. This
led to the completely protected vinyl bromide 22. This com-
pound presented itself for coupling with an aldehyde.
To introduce the C12–C13 double bond, the trityl ether
of 22 was selectively cleaved under reductive conditions by
using Et3SiH and BF3·OEt2.9 Oxidation of the resulting alco-
hol 23 with 2-iodoxybenzoic acid (IBX) in DMSO furnished
aldehyde 24 in 76% yield. Chain extension of 24 with meth-
ylmagnesium bromide led to alcohol 25 as a mixture of di-
astereomers. Alcohol 25 was converted into the ketone 26
by treatment with the Dess–Martin periodinane reagent in
CH2Cl2. A final Wittig reaction of ketone 26 with the phos-
phonium salt derived from ethyl bromide, with potassium
hexamethyldisilazide [KN(SiMe3)2]10 as base, in THF provid-
ed the C8–C14 fragment 27 as a single diastereomer. The
configuration of the double bond was inferred from the
strong cross peaks in its NOESY spectrum between 11-
H/14-H and 10-H/14-H (gulmirecin numbering).
O
from D-lactate
OPMB
Kirschning
OPMB
Evans aldol
8
HO
OTBS
SEMO
BnO
O
O
chain extension
7
macrolactonization
O
6
BnO
Bn
4:1
N
6
OSEM
7
O
O
HO
O
O
4 steps
BnO
OH
8
Scheme 1 Key intermediates in the synthesis of disciformycins by the
Fürstner group and of the disciformycin aglycon by the Kirschning
group
For the disconnection of the acyclic C1–C14 precursor,
the region around C5–C8 seems the most suitable (Scheme
2). A key issue, however, is the differentiation of the three
oxygen functionalities at C5–C7. In an initial study, we envi-
sioned the formation of the C7–C8 bond through attack of a
vinylmetal intermediate 11 at aldehyde 12a. Depending on
the stereoselectivity of this reaction, the resulting C7 sec-
ondary alcohol might be used for attachment of the sugar.
Alternatively, we considered an oxidation/reduction se-
quence to create a single configuration at C7. The enone 10
might also be available from addition of a vinylmetal
species to Weinreb amide 12b. Alternatively, a Horner–
Wadsworth–Emmons reaction might be used to form
enone 10 (C8–C9 bond) but this would require different
building blocks.
We began our synthesis of the C8–C14 fragment 27
from L-(–)-malic acid (13) (Scheme 3), because the L-com-
pound is cheaper than its enantiomer. This required a
Mitsunobu macrolactonization of the seco acid. Reduction
of the carboxylic acid groups furnished the butanetriol 14,
which was converted into the dioxolane 15 by reaction with
cyclohexanone.5 Oxidation of alcohol 15 under Swern con-
For the synthesis of a C1–C7 fragment with a protected
5,6-diol subunit, one might start with L-tartrate. However,
we opted instead for an asymmetric dihydroxylation ap-
proach. Thus, hex-5-enoic acid11 (28) was conjugated with
the Evans auxiliary, derived from L-phenylalanine through a
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E

C
R. Rengarasu, M. E. Maier
Letter
Synlett
alcohol 36 and Swern oxidation of 36 gave aldehyde 37, cor-
responding to the C1–C7 fragment of gulmirecin B.
CO2H
cyclohexanone
OH
BH3•SMe2
HO2C
O
O
OH
OH
OH OH
TsOH, r.t.
THF, 0 °C
(58%, 2 steps)
L-(–)-malic acid (13)
14
15
NaHMDS
O
O
1. PivCl, Et3N, THF
THF, –78 °C
CO2H
H
N
O
2. 1,3-oxazolidin-2-one, BuLi
THF, –78 °C to r.t.
(54%)
CH3I (83%)
O
CBr4, PPh3
O
DMSO, (COCl)2
O
O
O
28
29
Bn
OR
CH2Cl2, Et3N
–78 °C (81%)
CH2Cl2, 0 °C
(65%)
Br
Br
17
16
O
O
N
CO2Me
LiBH4, MeOH
O
a) Cp2ZrCl2, DIBAL-H
THF, 0 °C to 55 °C
a) BuLi, THF
–78 °C
O
Grubbs II, toluene
85 °C, 12 h (95%)
THF, 0 °C (62%)
O
Bn
31 R = H
b) MeI, –78 °C to r.t.
(74%)
b) NBS, THF, 0 °C
(93%)
30
NaH, PMBCl, TBAI
18
THF, 0 °C to r.t. (75%)
32 R = PMB
OR
O
OPMB
OH
OPMB
OPMB
AcOH–H2O (1:1)
r.t. (42%, major isomer)
O
OH
ADmix-α
MeO2C
MeO2C
Br
Br
t-BuOH–H2O
19
20 R = H
21 R = Tr
OH
O
33
34
TrCl, py, DMAP
0 °C to r.t. (64%)
CH2Cl2, r.t. (59%)
O
OPMB
O
12
11
TIPSOTf, 2,6-lutidine
CH2Cl2, 0 °C (86%)
LiAlH4, THF
IBX, DMSO
Me2C(OMe)2
O
H
OR
O
8
0 °C to r.t.
(76%)
TsOH, r.t (71%)
OTIPS
OTIPS
0 °C to r.t. (96%)
CO2Me
Br
Br
22 R = Tr
24
35
HO
36
Et3SiH, BF3•OEt2
CH2Cl2, 0 °C (75%)
7
O
H
OPMB
23 R = H
DMSO, (COCl)2
1
OH
O
CH2Cl2, Et3N
–78 °C (95%)
3
5
DMP, CH2Cl2
O
MeMgBr, THF
O
37
NaHCO3, r.t.
(75%)
OTIPS
OTIPS
0 °C (76%)
Br
Br
26
25
Scheme 4 Synthesis of the C1–C7 fragment 37 of gulmirecin B
Ph3P(Et)Br, THF
11
With fragments 22, 27, and 37 in hand, we investigated
the formation of the C7–C8 bond (Scheme 5). To our disap-
pointment, halogen–metal exchange on vinyl bromide 27
(~0.025M in THF) by using t-BuLi (2.2 equiv) in THF at
–78 °C, followed by addition of aldehyde 37, did not give the
desired alcohol 38. Instead, substantial amounts of the de-
brominated derivative of 27 were isolated. Other conditions
[s-BuLi (1.5 equiv), THF, –78 °C; i-PrMgCl·LiCl (1.25 equiv),
THF, –78 °C; CrCl2 (5 equiv), NiCl2 (1 equiv), DMF/THF (1:1),
r.t.] proved no better. In contrast, the addition of the vinyl-
lithium derivative of 22, generated in the same way from s-
BuLi, proceeded smoothly with aldehyde 37 to give alcohol
39 as a mixture of C7 diastereomers.17 At this moment, we
cannot explain these differences. Oxidation of alcohol 39
with the Dess–Martin reagent provided enone 40, which
corresponds to a C1–C12 fragment of gulmirecin B. An in-
ternal redox isomerization of the dihydroxy ketone subunit
should set the correct functionality at C5–C7. Installation of
the C12–C13 double bond would have to be done after cou-
pling the two key fragments if this strategy was to be used.
Possibly, other coupling strategies might be preferable.18
In summary, we have developed routes to key building
blocks for the synthesis of the macrolide antibiotic gulmire-
cin B. The plan in this study was to find out whether forma-
tion of the C7–C8 bond through attack of a vinylmetal inter-
mediate on a C1–C7 fragment with an aldehyde or carbox-
KN(SiMe3)2, –78 °C
(66%)
8
OTIPS
Br
27
Scheme 3 Synthesis of the vinyl bromides 22 (C8–12 fragment) and
27 (C8–C14 fragment)
mixed anhydride, to give the oxazolidinone derivative12 29
(Scheme 4). Alkylation of the sodium enolate of hexenoic
acid derivative 29 with methyl iodide provided the corre-
sponding 2-methylhex-5-enoic acid derivative 30.12a,b Re-
ductive removal of the chiral auxiliary by treatment with
lithium borohydride in methanol led to alkenol 31.12a,b,13
The hydroxy group of 31 was subsequently protected as a
p-methoxybenzyl ether14 32 by treatment with NaH and p-
methoxybenzyl chloride. Chain extension of the alkene ter-
minus was accomplished by a cross-metathesis reaction15
with methyl acrylate in the presence of the Grubbs II cata-
lyst in hot toluene to give enoate 33 in 95% yield. Sharpless
asymmetric dihydroxylation16 of enoate 33 with ADmix-
in tert-BuOH–H2O gave the dihydroxy ester 34 in reason-
able yield; the fact that we observed only one set of signals
in the 13C NMR spectrum of 34 indicated a high diastereose-
lectivity in this reaction. Treatment of diol 34 with dime-
thoxypropane in the presence of a catalytic amount of TsOH
delivered the 1,3-dioxolane 35. A final redox sequence con-
sisting of reduction of the ester group with LiAlH4 to give
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E

D
R. Rengarasu, M. E. Maier
Letter
Synlett
References and Notes
14
11
(1) Schieferdecker, S.; König, S.; Weigel, C.; Dahse, H.-M.; Werz, O.;
Nett, M. Chem. Eur. J. 2014, 20, 15933.
(2) Surup, F.; Viehrig, K.; Mohr, K. I.; Herrmann, J.; Jansen, R.;
Müller, R. Angew. Chem. Int. Ed. 2014, 53, 13588.
7
HO
OTIPS
a) s-BuLi, THF, –78 °C
8
5
6
OTIPS
b) addition of aldehyde 37
Br
(3) Kwon, Y.; Schulthoff, S.; Dao, Q. M.; Wirtz, C.; Fürstner, A. Chem.
Eur. J. 2018, 24, 109.
(4) (a) Wolling, M.; Kirschning, A. Eur. J. Org. Chem. 2018, 648.
(b) Surup, F.; Steinmetz, H.; Mohr, K.; Viehrig, K.; Müller, R.;
Nett, M.; Schieferdecker, S.; Dahse, H.-M.; Wolling, M.;
Kirschning, A. WO 2016005049, 2016.
(5) Hanessian, S.; Ugolini, A.; Dubé, D.; Glamyan, A. Can. J. Chem.
1984, 62, 2146.
(6) Yadav, J. S.; Gopala Rao, Y.; Ravindar, K.; Subba Reddy, B. V.;
Narsaiah, A. V. Synthesis 2009, 3157.
(7) Smith, A. B. III.; Chen, S. S.-Y.; Nelson, F. C.; Reichert, J. M.;
Salvatore, B. A. J. Am. Chem. Soc. 1997, 119, 10935.
(8) (a) Wipf, P.; Jahn, H. Tetrahedron 1996, 52, 12853. (b) Huang, Z.;
Negishi, E.-i. Org. Lett. 2006, 8, 3675. (c) Zhao, Y.; Snieckus, V.
Org. Lett. 2014, 16, 390.
O
O
OPMB
27
1
38
12
11
OTr
OTr
7
HO
OTIPS
a) s-BuLi, THF, –78 °C
8
5
6
OTIPS
b) addition of aldehyde 37
Br
O
O
OPMB
22
1
39
12
11
OTr
O
OTIPS
7
DMP, CH2Cl2
r.t. (71%)
8
5
6
O
O
OPMB
(9) For a related procedure, see: Imagawa, H.; Tsuchihashi, T.; Singh,
R. K.; Yamamoto, H.; Sugihara, T.; Nishizawa, M. Org. Lett. 2003,
5, 153.
(10) For a related Wittig reaction on an -(trialkylsilyloxy)methyl
ketone, see: Jung, M. E.; van den Heuvel, A.; Leach, A. G.; Houk,
K. N. Org. Lett. 2003, 5, 3375.
1
40
Scheme 5 Attempts to couple vinyl bromides 27 and 22 with aldehyde
37. Only the vinyllithium derivative of bromide 22 reacted with alde-
hyde 37.
(11) (a) Sánchez, L. G.; Castillo, E. N.; Maldonado, H.; Chávez, D.;
Somanathan, R.; Aguirre, G. Synth. Commun. 2007, 38, 54.
(b) Ogibin, Y. N.; Starostin, E. K.; Aleksandrov, A. V.; Pivnitsky, K.
K.; Nikishin, G. I. Synthesis 1994, 901.
(12) (a) Ghosh, A. K.; Gong, G. J. Org. Chem. 2006, 71, 1085.
(b) Kaliappan, K. P.; Ravikumar, V. J. Org. Chem. 2007, 72, 6116.
(c) Taaning, R. H.; Thim, L.; Karaffa, J.; Campaña, A. G.; Hansen,
A.-M.; Skrydstrup, T. Tetrahedron 2008, 64, 11884.
(13) (a) Schmidt, T.; Kirschning, A. Angew. Chem. Int. Ed. 2012, 51,
1063. (b) Bluhm, N.; Kalesse, M. Synlett 2015, 26, 797.
(14) (a) Hiebel, M.-A.; Pelotier, B.; Piva, O. Tetrahedron Lett. 2010, 51,
5091. (b) Tomas, L.; Boije af Gennäs, G.; Hiebel, M. A.; Hampson,
P.; Gueyrard, D.; Pelotier, B.; Yli-Kauhaluoma, J.; Piva, O.; Lord, J.
M.; Goekjian, P. G. Chem. Eur. J. 2012, 18, 7452.
ylic acid function to construct an acyclic precursor of
gulmirecin B would be possible. A C1–C7 aldehyde 37 was
prepared through an Evans alkylation to set the C2 stereo-
genic center and an ADH reaction on the derived enoate 33
to generate the dihydroxy carbonyl unit at the C5–C7 termi-
nus. The vinyl bromides 22 (C8–C12 fragment) and 27 (C8–
C14 fragment) were prepared by routine steps from malic
acid. Initial investigations showed that neither the vinyllith-
ium derivative of 27 nor that of 22 added to the Weinreb
amide of 35. Whereas the vinyllithium derivative of 27 did
not add to aldehyde 37, the vinyllithium species of the C8–
C12 fragment 22 did react with aldehyde 37.
(15) Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am.
Chem. Soc. 2003, 125, 11360.
(16) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev.
1994, 94, 2483.
(17) C1–C12 fragment 39
Funding Information
Vinyl bromide 22 (0.15 g, 0.25 mmol) was dried by dissolving it
in a 1:1 mixture of benzene and toluene (3 mL), followed by
evaporation of the solvents using a Rotavapor and placing the
residue under a high vacuum for 1 h. THF (1.5 mL) was then
added under argon and the flask was cooled to –78 °C. A 1.4 M
solution of s-BuLi in cyclohexane (0.21 mL, 0.30 mmol) was
added dropwise and the mixture was stirred for 30 min at –78
°C before a solution of aldehyde 37 (0.14 g, 0.43 mmol) in THF
(1.5 mL) was added dropwise. After completion of the addition,
the mixture was stirred at –78 °C for 2 h and then at r.t. for 1 h.
Finally, the mixture was treated with sat. aq NH4Cl solution (5
mL). The layers were separated, and the aqueous layer was
extracted with EtOAc (2 × 8 mL). The combined organic layers
were washed with sat. aq NaCl (5 mL), dried (Na2SO4), filtered,
and concentrated under reduced pressure. The crude allylic
alcohol 39 (yield: 86 mg; dr = 10:4) was used in the next reac-
tion without chromatographic purification. HRMS (ESI-TOF):
Financial support by the state of Baden-Württemberg is gratefully ac-
knowledged.()
Acknowledgment
We thank the student Fotis Fotiakis (University of Tübingen) for help
with the scale-up of some steps.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1611559.
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E

E
R. Rengarasu, M. E. Maier
Letter
Synlett
m/z [M
873.5094.
Enone 40
+
Na]+ calcd for C53H74NaO7Si: 873.5094; found:
(s, 3 H, 8-CH3), 2.70–2.73 (m, 2 H, 10-H), 2.97 (t, J = 8.3 Hz, 1 H,
12-H), 3.10–3.20 (m, 2 H, 12-H, 1-H), 3.26 (dd, J = 9.0, 5.8 Hz, 1
H, 1-H), 3.77 (s, 3 H, OCH3), 4.10–4.18 (m, 1 H, 11-H), 4.22–4.26
(m, 1 H, 5-H), 4.34 (d, J = 7.4 Hz, 1 H, 6-H), 4.48 (d, J = 1.8 Hz, 2
H, CH2Ar), 6.86 (d, J = 8.6 Hz, 2 H, ArH), 6.97 (t, J = 6.4 Hz, 1 H, 9-
H), 7.17–7.27 (m, 12 H, ArH), 7.38–7.41 (m, 5 H, ArH). 13C NMR
(100 MHz, CDCl3):  = 11.8 (8-CH3), 12.3 {Si[CH(CH3)2]3}, 16.9
(2-CH3), 18.0 {Si[CH(CH3)2]3}, 26.2 [C(CH3)2], 27.2 [C(CH3)2], 29.7
(C-3), 30.6 (C-4), 33.4 (C-2), 34.8 (C-1), 55.2 (OCH3), 66.3 (C-12),
70.3 (C-11), 72.6 (CH2Ar), 75.5 (C-1), 78.0 (C-5 or C-6), 80.3 (C-6
or C-5), 86.6 (CPh3), 109.8 [C(CH3)2], 113.7, 127.0, 127.7, 128.6,
129.0, 130.8 (6 × Ar), 137.7 (C-8), 142.5 (C-9), 143.9 (Ar C), 159.0
(Ar C), 197.5 (C-7). HRMS (ESI-TOF): m/z [M + Na]+ calcd for
DMP (70 mg, 0.16 mmol) and NaHCO3 (20 mg, 0.24 mmol) were
added to a solution of alcohol 39 (70 mg, 0.08 mmol) in CH2Cl2
(5 mL) at 0 °C. The cooling bath was then removed and the
mixture was stirred for 2 h at r.t. The mixture was diluted with
sat. aq NaHCO3 (5 mL), the layers were separated, and the
aqueous layer was extracted with CH2Cl2 (2 × 5 mL). The com-
bined organic layers were washed with sat. aq NaCl (8 mL),
dried (Na2SO4), filtered, and concentrated under reduced pres-
sure. The crude product was purified by flash chromatography
[silica gel, PE–EtOAc (85:15)] to give a colorless oil; yield: 50 mg
(71%); Rf = 0.48 (PE–EtOAc, 9:1); []D19 –6.85 (c = 0.52, CH2Cl2).
1H NMR (400 MHz, CDCl3):  = 0.90 (d, J = 6.7 Hz, 3 H, 2-CH3),
0.94–0.96 {m, 21 H, Si[CH(CH3)2]3}, 1.25–1.30 (m, 1 H, 3-H), 1.30
[s, 3 H, C(CH3)2], 1.37–1.44 [m, 4 H, C(CH3)2, 3-H], 1.50–1.53 (m,
1 H, 4-H), 1.56–1.60 (m, 1 H, 4-H), 1.68–1.73 (m, 1 H, 2-H), 1.80
C
53H72NaO7Si: 871.4929; found: 871.4929.
(18) Edwards, J. T.; Merchant, R. R.; McClymont, K. S.; Knouse, K. W.;
Qin, T.; Malins, L. R.; Vokits, B.; Shaw, S. A.; Bao, D.-H.; Wei, F.-L.;
Zhou, T.; Eastgate, M. D.; Baran, P. S. Nature 2017, 545, 213.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E