Synthetic studies toward potent cytostatic macrolide bryostatin: An expedient synthesis of C1-C10 fragment

Article abstract of DOI:10.1016/j.tetlet.2012.07.043

The stereoselective synthesis of C1-C10 fragment of cytostatic macrolide bryostatin is described. Two of the three chiral centers have been established via the Sharpless kinetic resolution of racemic allylic alcohol 15 followed by regioselective reduction

Full text of DOI:10.1016/j.tetlet.2012.07.043

Tetrahedron Letters 53 (2012) 6163–6166
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthetic studies toward potent cytostatic macrolide bryostatin: an
expedient synthesis of C1–C10 fragment
⇑
J. S. Yadav , S. Aravind, G. Mahesh Kumar, B. V. Subba Reddy
Natural Products Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 20 April 2012
Revised 9 July 2012
Accepted 11 July 2012
Available online 15 July 2012
The stereoselective synthesis of C1–C10 fragment of cytostatic macrolide bryostatin is described. Two of
the three chiral centers have been established via the Sharpless kinetic resolution of racemic allylic alco-
hol 15 followed by regioselective reduction of epoxy alcohol 8 with Red-Al. Diastereoselective Aldol reac-
tion of an aldehyde 7 with methyl isobutyrate affords the corresponding b-hydroxyester 23 which is then
transformed into tetrahydropyran ring system 3 via an intramolecular hemi-ketalization.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Bryostatins
Bugula neritina
Antineoplastic activity
Aldol reaction
Lactonization
Macrolide
The bryostatins are important class of 20 antitumor macro-
lides1–3 which have shown considerable clinical application for
the treatment of various human cancers.4 Bryostatins are bioactive
marine natural products which were isolated from the bryozoans
Bugula neritina, Linnaeus, and Amathia convolute. The discovery
and structural determination of bryostatins (1) were first reported
by Pettit in 1982.5 Bryostatins (1) are found to exhibit a significant
in vivo antineoplastic activity against lymphocytic leukemia, B-cell
lymphoma, reticulum cell sarcoma, ovarian carcinoma, and mela-
noma. They also display a diverse range of other biological effects
such as the stimulation of T-cells and the immune system,3 and the
inhibition of tumor promoting phorbols related to protein kinase
C.6 As a result, many attempts have been made for the formal syn-
thesis of brayostatins.7,8 until now only six approaches have been
reported for the total synthesis of bryostatins.9–12 A similar frag-
ment of bryostatins has been reported earlier by our group.8c In-
spired by their potential application as drug candidates, we
attempted the total synthesis of these natural products.
As a part of our interest on the total synthesis of biologically ac-
tive molecules, we herein report the synthesis of C1–C10 fragment
of bryostatin. Out of three stereogenic centers, two were con-
structed by means of Sharpless kinetic resolution of allylic alcohol
and regioselective reduction of epoxy alcohol and the third one
was obtained through the diastereoselective Aldol reaction15 The
following reagents such as homopropargyl alcohol, 1,3-propane-
diol, and methyl isobutyrate were used as starting materials.
The synthesis of C1–C10 fragment was proposed to be obtained
by means of Aldol reaction between methyl isobutyrate and C1–C7
aldehyde. Our next plan was to synthesize the C1–C7 aldehyde,
which could be prepared from (E)-allylic alcohol via the Sharpless
kinetic resolution and regioselective reduction of epoxy alcohol
with Red-Al.
Mono-protection of 1,3-propanediol (11) with benzyl bromide
followed by oxidation with PCC on Celite gave the aldehyde 13 in
75% overall yield. Alkynylation of 13 with homopropargyl ether
(14) in THF16 gave the propargyl alcohol (9) which was then re-
duced with LAH17 to give the desired (E)-allylic alcohol (15). The
Sharpless kinetic resolution of alcohol (15) with (+)-DET gave the
Our retrosynthetic analysis of bryostatin (1) is outlined in
Scheme 1. The construction of C1–C10 fragment, a common unit
in all bryostatins, was achieved via the Sharpless kinetic resolu-
tion13 of 15 followed by regioselective reduction of epoxy alcohol.14
Our group has made a significant effort to explore the synthetic
utility of Sharpless kinetic resolution for the synthesis of various
intermediates in total synthesis of some natural products.
epoxy alcohol (8) ½a D25
ꢁ8.9 (c = 1.0, CHCl3) in 38% yield with
ꢀ
>98% ee. Regioselective reduction of epoxy alcohol (8) with Red-
Al (5.0 equiv) in THF (ca. 0.68 M) between ꢁ30 and ꢁ10 °C afforded
the diol which was then subjected to THP deprotection to yield the
triol 19 ½a 2D5
ꢀ
+7.6 (c = 1.0, CHCl3) in quantitative yield. Selective
protection of primary hydroxyl group of the triol 19 with Ac2O in
the presence of TEA in DCM gave the acetate 20 in 75% yield. After
protection of primary alcohol of the triol as acetate, the resulting
⇑
Corresponding author. Fax: +91 40 27160512.
E-mail address: yadavpub@iict.res.in (J.S. Yadav).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.07.043

6164
J. S. Yadav et al. / Tetrahedron Letters 53 (2012) 6163–6166
HO
MeO
O
MeO
13
OAc
MeO
OR2
9
B
A
B
A
2
O
O
O
O
O
15
5
O
OH
1
OR1
OH
H
23
OH
O
C
O
OH
O
19
26
RO
OH
OMe
MeO
1
OMOM
O
A
O
Bryostatin 11: R = H
3
Bryostatin 1:
R =
O
OH OBn
MeO
O
O
O
O
OBn
O
O
O
O
OBn
5
O
4
O
H
MeO
O
+
O
O
O
OBn
OTHP
OH OBn
O
6
7
8
HO
+
HO
OH
OTHP
10
11
9
OH OBn
Scheme 1. Retrosynthetic analysis of bryostatin.
THPO
a,b
c
OBn
BnO
OH
HO
OH
O
THPO
11
13
14
9
OH
THPO
THPO
OBn
e
d
THPO
OBn
O
8
OH
+
15
OBn
16
OH
f,g
h,i
8
OAc
O
O
OBn
OH OH OH OBn
19
21
H
k
j
OH
O
O
OBn
O
OBn
O
O
7
22
MeO
MeO
l
+
7
O
OH
24
O
O
O
OBn
OBn
O
O
OH
23
O
O
O
OBn
OBn
MeO
H
m
n,o
23
O
O
O
O
O
O
O
5
30
MeO
O
OMOM
A
p,q
r
30
O
O
O
O
OBn
O
3
4
OH OBn
Scheme 2. Reagents and conditions: (a) NaH, BnBr, TBAI, THF, 4 h, 66%; (b) PCC, Celite, DCM, 3 h, 84%; (c) EtMgBr generation followed by 14, then 13, THF, 83%; (d) LAH, THF,
96%; (e) (+)-DIPT, Ti(OiPr)4, TBHP, ꢁ20 °C, DCM, (8/16 = 38:41); (f) Red-Al, THF, 93%; (g) p-TsOH, MeOH, 90%; (h) Et3N, Ac2O, DCM, 75%; (i) 2,2-DMP, p-TsOH, DCM, 93%; (j)
K2CO3, MeOH, quantitative yield; (k) Dess–Martin periodinane, NaHCO3, DCM, 87%; (l) LDA, ꢁ78 °C, Methyl isobutyrate, THF, (23/24 = 59:35); (m) MOMCl, iPr2NEt, DCM, 89%;
(n) DIBAL-H, DCM, 0 °C, 91%; (o) DMP, NaHCO3, DCM, 0 °C, 94%; (p) CH2@CHMgBr, THF, 0 °C, 86%; (q) DMP, NaHCO3, DCM, 0 °C, 89%; (r) PPTS, CH(OCH3)3, MeOH, 73%.

J. S. Yadav et al. / Tetrahedron Letters 53 (2012) 6163–6166
6165
The diastereomeric mixture of b-hydroxyesters (23,24)15 was
separated by column chromatography 23 as a major isomer and
24 as a minor isomer. In order to confirm the exact stereochemistry
of the newly generated hydroxyl center at C7, the following series
of reactions were performed as shown in Scheme 4.
The major isomer 23 was treated with a catalytic amount of p-
TsOH in MeOH to afford the triol (25) in 90% yield. The compound
25 was then subjected to acetonide protection employing the stan-
dard conditions with 2,2-DMP to yield the two possible regioisom-
ers 26 and 23 in 1:1 ratio, which were easily separated through
column chromatography. As we already have the authentic com-
pound 23, the newly obtained isomer 26 was easily distinguished
by TLC and isolated in 46% yield by column chromatography. 13C
NMR spectrum of compound 26 showed the gem-dimethyl carbon
of dioxolane ring at 23.99 ppm, which confirms the anti-stereo-
chemistry between the two hydroxyl groups.15 Thus the stereo-
chemistry at C7 and C5 was found to be anti, in major
diastereomer 23.
Similarly, the minor isomer 24 was treated with p-TsOH in
MeOH to afford the triol (27) in 89% yield. Compound 27 was then
protected as its acetonide employing the standard conditions with
2,2-DMP. The syn isomer 28 was obtained exclusively in 88% yield.
The 13C NMR of compound 28 showed the gem-dimethyl carbon of
dioxolane ring at 30.07 ppm, which confirms the syn-stereochem-
istry between two hydroxyl groups.13 Thus, the stereochemistry at
C7 and C5 was found to be syn, in minor diastereomer 24.
In summary, we have accomplished a stereoselective synthesis
of C1–C10 fragment 3 of bryostatin from a commercially available
homopropargyl alcohol, 1,3-propanediol and methyl isobutyrate.21
The present synthesis demonstrates an efficient route to the syn-
thesis of fragment 3 using Sharpless kinetic resolution/Red-Al
reduction to produce the C3 and C5 chiral centers. Aldol reaction
between anion 6 and aldehyde 7 was successfully utilized to estab-
lish the C7 chiral center.
THPO
OBn
a
THPO
OBn
Ph
O
O
OH
O
8
OMe
CF3
17
Scheme 3. Reagents and conditions: EDCI, MTPA, DMAP, DCM, 77%.
O
MTPA-derivative
1,3-diol 20 was then protected as its isopropylideneacetal 21.
Deacetylation of 21 with K2CO3 in MeOH gave the primary alcohol
22 in quantitative yield. Oxidation of primary alcohol 22 gave the
aldehyde 7. Aldol reaction of an aldehyde 7 with the lithium eno-
late derived from methyl isobutyrate (6) (7.4 equiv) and LDA15
(7.0 equiv) in THF at ꢁ78 °C afforded the b-hydroxyester 23 ½a D25
ꢀ
+1.9 (c = 1, CHCl3) as a major isomer in 59% yield. Protection of
alcohol (23) with MOMCl in the presence of EtNiPr2 in DCM gave
the MOM ether. Reduction of ester functionality 5 with DIBAL-H
(2.2 equiv) furnished the primary alcohol in 91% yield, which was
then subjected to oxidation with Dess–Martin periodinane18
(DMP) to yield the aldehyde 30. Grignard reaction16 of aldehyde
30 with vinylmagnesium bromide in THF gave the allylic alcohol
which was then oxidized with DMP in DCM to afford the enone 4
in 88% overall yield. Deprotection of acetonide from compound 4
with trimethylorthoformate in the presence of PTSA19 (Scheme 2)
in methanol at room temperature gave the target fragment 3.
The above conditions affect not only the cleavage of acetonide
but also induce the ring-closure via hemi-ketalization.
The enantiomeric excess of epoxy alcohol 8 was measured by
converting into its MTPA derivative,20 using EDCI, methoxy trifluo-
romethylphenylacetic acid (MTPA) and a catalytic amount of
DMAP in dry DCM. The MTPA derivative 17 was obtained in 77%
yield. 1H NMR spectrum of compound 17 showed predominantly
one singlet (integration 22:0.2) at 3.53 ppm corresponds to
methoxy protons in MTPA group, which confirms the presence of
Acknowledgement
one enantiomer predominantly (>98% ee) in compound
(Scheme 3).
8
S.A. thanks CSIR, New Delhi for the award of Fellowship.
MeO
MeO
a
O
OH OH OH OBn
90%
O
OH
O
O
OBn
23
25
b
MeO
MeO
+
O
O
O
OH OBn
O
OH
O
O
OBn
23 (44%)
26 (46%)
MeO
a
MeO
89%
O
OH
24
O
O
OBn
O
OH OH OH OBn
27
b
MeO
O
O
O
OH OBn
28 (88%)
Scheme 4. Reagents and conditions: (a) p-TsOH, MeOH; (b) 2,2-DMP, p-TsOH, DCM.

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J. S. Yadav et al. / Tetrahedron Letters 53 (2012) 6163–6166
14. Ma, P.; Martin, V. E.; Masamune, S.; Sharpless, K. B.; Viti, S. M. J. Org. Chem.
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Experimental section
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All the reactions were carried out under inert atmosphere, unless mentioned,
following standard syringe septa techniques. Solvents were dried and purified
by conventional methods prior to use. The progress of all the reactions were
monitored by thin-layer chromatography (TLC) using glass plates precoated
with silica gel-60 F254 to
a thickness of 0.5 mm (Merck). Column
chromatography was performed on silica gel (60–120 mesh) and neutral
alumina using diethyl ether, ethyl acetate, and hexane as eluents. Optical
rotation values were measured with a Perkin–Elmer P241 polarimeter and
JASCO DIP-360 digital polarimeter at 25 °C and IR spectra were recorded on
Perkin–Elmer FT-IR spectrophotometer. 1H and 13C NMR spectra were recorded
on Varian Gemini 200 MHz, Bruker Avance 300 MHz, Varian Unity 400 MHz, or
Varian Inova 500 MHz spectrometer using trimethylsilane as an internal
standard in CDCl3. Mass spectra were recorded on Micro mass VG-7070H for
ESI–MS and HRMS, VG Autospec M for FABMS.
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Compound 8: Colorless liquid; Rf = 0.4 (SiO2, 40% EtOAc in hexane); ½a D25
ꢁ8.9
ꢀ
(c = 1.0, CHCl3); 1H NMR (400 MHz, CDCl3): d 7.29–7.14 (m, 5H), 4.53–4.45 (m,
1H) 4.42 (s, 2H), 3.84–3.51 (m, 5H), 3.49–3.34 (m, 2H), 3.18–3.06 (brs, 1H),
3.06–2.95 (m, 1H), 2.75–2.67 (m, 1H), 1.92–1.56 (m, 6H), 1.55–1.33 (m, 4H);
13C NMR (75 MHz, CDCl3): d 137.8, 128.2, 127.4, 98.8, 72.9, 68.5, 68.3, 67.4,
64.0, 63.8, 62.3, 62.1, 60.4, 53.9, 53.6, 33.3, 33.2, 31.9, 30.4, 25.2, 19.4; IR (neat):
t
max 3447, 2925, 2858, 1451, 1360, 1118, 1075, 1029, 977, 740, 698 cmꢁ1; ESI–
MS: m/z 359 [M+Na]; HRMS (ESI) calcd for C19H28O5Na: 359.1834. Found:
359.1820. Compound 23 Major isomer: Colorless viscous liquid; Rf = 0.4 (SiO2,
50% EtOAc in hexane); ½a D25
ꢀ
+1.9 (c = 1.0, CHCl3); 1H NMR (200 MHz, CDCl3): d
7.35–7.19 (m, 5H), 4.46 (s, 2H), 4.17–4.04 (m, 1H), 4.04–3.90 (m, 1H), 3.85 (dd,
1H, J = 6.8, 4.5 Hz), 3.69 (s, 3H), 3.56–3.44 (m, 2H), 2.92–2.66 (brs, –OH), 1.79–
1.63 (m, 3H), 1.62–1.38 (m, 3H), 1.32 (s, 3H), 1.29 (s, 3H), 1.17 (s, 3H), 1.16 (s,
3H); 13C NMR (75 MHz, CDCl3): d 177.87, 138.42, 128.24, 127.57, 100.37, 72.99,
72.49, 66.53, 64.01, 63.83, 51.73, 46.81, 37.82, 37.01, 35.90 26.91, 24.70 (2C),
21.88, 20.28; IR (neat): t
max 3056, 1729 cmꢁ1; ESI–MS: m/z 417 [M+Na]; HRMS
(ESI) calcd for C22H34O6Na: 417.2253. Found: 417.2242. Compound 4: Colorless
liquid; Rf = 0.4 (SiO2, 10% EtOAc in hexane). ½a D25
ꢀ
ꢁ4.8 (c = 1.0, CHCl3); 1H NMR
(200 MHz, CDCl3): d 7.34–7.22 (m, 5H), 6.86–6.75 (m, 1H), 6.29 (dd, 1H,
J = 16.6, 2.2 Hz), 5.60 (dd, 1H, J = 9.8, 2.2 Hz), 4.61 (d, 1H, J = 6.7 Hz), 4.56 (d, 1H,
J = 6.7 Hz), 4.46 (s, 2H), 4.01–3.87 (m, 2H), 3.85–3.78 (m, 1H), 3.57–3.43 (m,
2H), 3.30 (s, 3H), 1.72 (dd, 2H, J = 12.8, 6.0 Hz), 1.63–1.36 (m, 4H), 1.32 (s, 3H),
1.27 (s, 3H), 1.14 (s, 3H), 1.09 (s, 3H); 13C NMR (75 MHz, CDCl3): d 202.8, 138.4,
131.9, 128.2, 127.7, 127.5, 127.4, 100.2, 98.4, 80.7, 73.0, 66.5, 64.9, 63.5, 63.0,
55.6, 38.7, 38.6, 35.9, 25.0, 24.9, 20.3, 20.5; IR (neat): tmax 2924, 2854, 1735,
1694, 1459, 1377, 1223, 1101, 1032, 748, 699 cmꢁ1; ESI–MS: m/z 457 [M+Na];
HRMS (ESI) calcd for C25H38O6Na: 457.2720. Found: 457.2722. Compound 3:
Colorless viscous liquid; Rf = 0.6 (SiO2, 30% EtOAc in hexane). ½ ꢀ +16.5
a 2D5
(c = 0.5, CHCl3); 1H NMR (200 MHz, CDCl3): d 7.42-7.16 (m, 5H), 5.69–5.55 (m,
1H), 5.37–5.23 (m, 2H), 4.65 (d, 1H, J = 6.7 Hz), 4.57 (d, 1H, J = 6.7 Hz), 4.50 (s,
2H), 4.15–3.97 (m, 1H), 3.97–3.79 (m, 2H), 3.72–3.54 (m, 2H), 3.32 (s, 3H), 3.08
(s, 3H), 1.79–1.67 (m, 3H), 1.66–1.38 (m, 3H), 0.99 (s, 3H), 0.80 (s, 3H); 13C
NMR (75 MHz, CDCl3): d 134.3, 129.6, 128.2, 127.5, 127.4, 118.5, 95.8, 95.7,
76.7, 73.0, 68.5, 67.3, 65.1, 48.8, 42.9, 42.7, 41.4, 37.1, 33.8, 29.6.,20.7, 16.9; IR
(neat): tmax 3446, 2925, 2855, 1097, 1040 cmꢁ1; ESI–MS: m/z 456 [M+Na];
HRMS (ESI) calcd for C24H39O6Na: 456.2725. Found: 456.2727.