Formal synthesis of the bryostatin Northern Hemisphere: Asymmetric synthesis of the B ring and C1-C9 fragment

Article abstract of DOI:10.1055/s-0030-1260586

A formal synthesis of the top half fragment of bryostatin 11 has been developed. Stereoselective construction of the B ring was achieved by using a ring-closing metathesis reaction in conjunction with asymmetric glycolate alkylation. Furthermore, the C1-C9 fragment was synthesized by Brown allylation, chelation-controlled aldol condensation, and Saksena-Evans reduction to construct all stereogenic centers. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1260586

LETTER
1413
Formal Synthesis of the Bryostatin Northern Hemisphere: Asymmetric
Synthesis of the B Ring and C1–C9 Fragment
Formal Synthesis
o
y
f
the
B
ryost
o
atin
N
orthern
k
Hemisphereo Nakagawa-Goto,*1 Michael T. Crimmins
Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
E-mail: goto@email.unc.edu
Received 7 December 2010
been completed until 2010,7–11 although many related
preparations of analogues4b,5e,12 and fragments5,13 have
been reported. The interesting biological activity as well
as unique structure of bryostatins led us to focus on the ef-
Abstract: A formal synthesis of the top half fragment of bryostatin
11 has been developed. Stereoselective construction of the B ring
was achieved by using a ring-closing metathesis reaction in con-
junction with asymmetric glycolate alkylation. Furthermore, the
C1–C9 fragment was synthesized by Brown allylation, chelation- fective total synthesis of bryostatin 11 (2).
controlled aldol condensation, and Saksena–Evans reduction to
construct all stereogenic centers.
In our synthetic strategy toward 2, we planned to connect
the top C1–C16 and bottom C17–C27 half fragments by
employing Yamaguchi coupling to form the ester linkage
and ring-closing olefin metathesis (RCM) or Julia
olefination4b,5a–e,7–13 to construct the C16–C17 double
bond. We first planned a RCM approach, although Tho-
mas and Trost have recently reported a lack of success in
their synthesis.14 As shown in Scheme 2, our retrosynthet-
ic analysis of the top half fragment began with opening of
the A ring (3 → 4) followed by disconnection of the B ring
and C1–C9 fragment (4 → 5 + 815). We could obtain the
B ring stereoselectively by using our established 2,6-di-
substituted tetrahydropyranone synthetic methodology.2
The C1–C9 linear subunit would be prepared by con-
Key words: bryostatin 11, asymmetric glycolate alkylation, ring-
closing metathesis
We previously reported a unified approach to the enantio-
selective synthesis of 2,6-cis- and 2,6-trans-disubstituted
tetrahydropyranones using asymmetric glycolate alkyla-
tion–ring closing metathesis reaction.2 To expand the util-
ity of our strategy for the total synthesis of natural
products, we describe herein the asymmetric synthesis of
the B ring and C1–C9 fragment of bryostatin 11, a marine
macrolide.
Bryostatins were originally isolated from the marine bry- structing all stereocenters, starting from 2,2-dimethyl pro-
ozoan Bugula neritina by Pettit and co-workers3 and 20 panediol 10. Finally, we would couple the B ring
kinds of bryostatins have been isolated to date.4,5c Bryo- precursor 5 with thioketal 8 according to Yamamura’s9 or
statins exhibit potent biological activities through a Hoffman’s15 method.
unique mode of action against protein kinase C.5 Especial-
ly, bryostatin 1 (1, Scheme 1) is currently under investiga-
Compound 11 was derived in two steps from (S)-(+)-ben-
zyl glycidyl ether (7) in 66% overall yield (Scheme 3).16
tion in human clinical trials as a single agent or in
It was converted into the desired oxazolidinone glycolate
combination with other chemotherapies.6 The limited sup-
1317 via a one-pot reaction from an intermediate alkoxy-
ply of bryostatins from natural sources demands that it be
provided by total synthesis for biological activity studies.
Nevertheless, only four total syntheses of bryostatins have
glycolic acid through the in situ formation of a mixed piv-
alic anhydride. Exposure of 13 to iodide 142 and
NaH(SiMe3)2 produced syn-diene 618 in 74% yield with
HO
OAc
11
MeO2C
9
7
13
A
H
B
O
O
Y
HO
O
OH
H
1
O
OAc
O
OH
OH
16
MeO2C
A
+
OH
B
C
OH
O
O
O
X
C
O
R
OH
CO2Me
21
OH
OH
CO2Me
3
bryostatin 1 (1) R = OC(O)CH=CH-CH=CH-C3H7
bryostatin 11 (2) R = H
X = CH2, Y = CH2=CH2 for RCM
Y = O, Y = CH2SO2Ph for Julia coupling
Scheme 1
SYNLETT 2011, No. 10, pp 1413–1418
x
x
.x
x
.2
0
1
1
Advanced online publication: 26.05.2011
DOI: 10.1055/s-0030-1260586; Art ID: S09310ST
© Georg Thieme Verlag Stuttgart · New York

1414
K. Nakagawa-Goto, M. T. Crimmins
LETTER
oxidized under Swern conditions, and a methylene Wittig
reaction with the resulting aldehyde gave olefin 1922 in
good yield. The desired B ring precursor 5 was obtained
by reductive removal of the benzyl ether under Birch con-
ditions, followed by standard two-step iodination (1.
TsCl, 2. NaI, acetone). The terminal olefin could be po-
tentially transformed to an aldehyde for Julia coupling, if
RCM failed.
O
9
1
3
B
S
S
OP OP OP
OP
MeO
OMe
4
8
O
B
S
I
11
1
15
9
+
With the stereoselective synthesis of B ring completed
successfully, assembly of the C1–C9 linear unit was per-
formed. Protection of 2,2-dimethyl-1,3-propanediol (10)
with benzyl chloride (1 mol equiv) in the presence of KOt-
Bu gave the monobenzyl ether in 74% yield (Scheme 4).
The remaining alcohol was oxidized under Swern condi-
tions to the aldehyde 20, which was exposed to Brown’s
asymmetric alkylation23 to construct the C7 stereogenic
center. The resulting mixture of the inseparable desired al-
lylic alcohol and 4-isocaranol was treated with PMBCl in
the presence of KH in THF to furnish PMB ether 2124 in
66% overall yield. The terminal olefin was oxidatively
cleaved to the aldehyde, which was condensed with ke-
tone 23 according to Vandewall’s procedure25 to afford
anti-hydroxy ketone 24.26 After various attempts, the 3,5-
anti-diol was constructed in good yield and selectivity
(anti/syn = 7.6:1) by using Evans–Saksena reduction
[Me4NHB(OAc)3, MeCN, AcOH].27 At this point, the use
of Li(Ot-Bu)3AlH as a reduction reagent gave lower selec-
tivity, although Vandewall reported a satisfactory result
with a similar compound with OBn at C7 and OPMB at
C9. Because Evans–Saksena reduction of the related hy-
droxy ketone with OPMB at C7 and OMOM at C9 also
provided better selectivity28 than Vandewall’s procedure,
a methoxy group on PMB might affect the selectivity of
Li(Ot-Bu)3AlH reduction. The resulting diol was protect-
ed as the acetonide, and then anti-acetonide 2529 was sep-
arated from syn-acetonide by column chromatography on
silica gel. Both the PMB group and the acetonide were
S
OP
OP OP
OP
MeO
OMe
5
O
O
1
Xc
OBn
O
OP
OP OP
OP
9
OMOM
6
O
OBn
OH OH
10
7
(P = protecting groups)
Scheme 2 Retrosynthetic analysis of top fragment
excellent diastereoselectivity. Ring-closing metathesis of
diene 6 with 10 mol% of Grubbs second-generation ruthe-
nium carbine 1519 as a catalyst led to 1620 in 89% yield,
along with 6% of recovered starting material. The MOM
enol ether was converted directly into methyl ketal 1721 in
82% yield by treatment with methyl orthoformate in the
presence of catalytic acid (PPTS–PTSA = 1:1) in THF–
MeOH (3:1, v/v) solution.
The oxazolidinone was reductively cleaved to give alco-
hol 18, plus inseparable oxazolidinone. The mixture was
O
O
OH
a, b
O
c, d
O
O
e
OBn
Xc
OBn
Xc
OBn
OBn
O
OMOM
7
11
I
13
O
NLi
i-Pr
14
OMOM
6
12
O
O
O
B
O
B
O
O
g
i, j
h
f
R
HO
OBn
Xc
OBn
Xc
z
Mes
Mes
Ph
MeO
OMe
MeO
OMe
MeO
OMe
OMOM
16
Cl
Cl
Ru
19, R = OBn
5, R = I
17
18
k–m
PCy3
15
Scheme 3 Reagents and conditions: (a) NaH, DMSO, 70 °C, 70 min then 7, DMSO, r.t., 30 min; (b) CaCO3, 1,2-dichlorobenzene, heat, over-
night (66% from 7); (c) NaH, THF, r.t., 10 min, then 11, r.t., overnight; (d) PivCl, Et3N, Et2O, 0 °C, 1 h, then 12, THF, –78 °C to 0 °C, 3 h (45%
from 11); (e) NaN(SiMe3)2, THF, –78 °C, 30 min, then 14, –78 °C to –45 °C, 1 h (74%); (f) 15 (10 mol%), CH2Cl2, reflux, overnight (89%);
(g) PTSA–PPTS (1:1), CH(OMe)3, THF–MeOH (3:1), reflux, 1 h (82%); (h) LiBH4, Et2O, MeOH, 0 °C, 1 h (80%); (i) (COCl)2, DMSO,
CH2Cl2, –78 °C, then Et3N (80%); (j) PPh3CH3Br, toluene, KOt-Bu, THF, r.t., overnight, (92%); (k) Na, NH3 (l), THF, –78 °C, 4 h (74%);
(l) TsCl, pyridine, 0 °C to r.t., overnight, (91%); (m) NaI, acetone, reflux, overnight (85%).
Synlett 2011, No. 10, 1413–1418 © Thieme Stuttgart · New York

LETTER
Formal Synthesis of the Bryostatin Northern Hemisphere
1415
O
a, b
c, d
e
f
g, h
7
9
O
OTBDPS
O
OH OH
10
OBn
20
OBn
i, j
OBn
OBn
OPMB
21
OPMB
22
OH
O
OTBDPS
PMBO
23
24
S
k, l
m
1
9
OBn
OR OR OTBDPS
OR
26
OBn
PMBO
O
O
O
OTBDPS
S
OR OR OR OTBDPS
RO
27
28
25
R = TBS
Scheme 4 Reagents and conditions: (a) BnCl, KOt-Bu, dioxane, reflux, overnight (74%); (b) (COCl)2, DMSO, –78 °C then Et3N (92%); (c)
4-ICr2B-allyl, Et2O, –78 °C, 3 h, warmed to r.t. over 2 h; 30% H2O2, NaOH, reflux, overnight; (d) PMBCl, KH, THF, r.t., overnight (81% from
20); (e) OsO4, NMO, THF, r.t., overnight, then NaIO4, THF, H2O (85%); (f) 23, LDA, THF, –78 °C, 2 h then 22, THF, –78 °C, 15 min (70%);
(g) Me4NHB(OAc)3, MeCN–AcOH, –30 °C, 22 h (98%, anti/syn = 7.6:1); (h) Me2C(OMe)2, PPTS, THF, r.t., overnight (96%) then separation;
(i) DDQ, CH2Cl2–H2O, then 70% AcOH, r.t., 1.5 h (78%); (j) TBSOTf, 2,6-lutidine, CH2Cl2, –15 °C to 0 °C, 2.5 h (92%); (k) Pd(OH)2/C, H2,
EtOAc, r.t., 24 h (69%); (l) (COCl)2, DMSO, –78 °C then Et3N (89%); (m) HS(CH2)3SH, MgBr2·OEt2, Et2O, r.t., 4 h (76%).
5
7
DDQ
4 Å MS
OBn
BnO
PMBO
O
O
OTBDPS
O
OH
O
OTBDPS
24
MP
29
Scheme 5
removed in a one-pot reaction to supply the trialcohol, With the B ring and C1–C9 linear unit in hand, the
which was then reprotected as the TBS triether 26. Subse- coupling31 of iodide 5 with thioketal 28 as well as further
quently, reductive cleavage of the benzyl ether and oxida- progress on the completion of the total synthesis of
tion of the resulting alcohol afforded aldehyde 27. bryostatin 11 will be reported in due course.
Treatment of 27 with 1,3-propanedithiol in the presence
of MgBr2·OEt2 provided thioketal 28 in 75% yield. Mean-
while, hydrogenation of 25 with Raney nickel accom-
Acknowledgment
K. Nakagawa-Goto acknowledges support from a research fel-
lowship from Uehara Memorial Foundation in Japan.
plished the selective removal of the benzyl ether to
provide the primary alcohol, which was converted into the
aldehyde under Swern conditions. Unfortunately, the
thioketalization of the resulting aldehyde yielded un-
known products without the desired compound.
References and Notes
(1) Current address: K. Nakagawa-Goto, Eshelman School of
Pharmacy, University of North Carolina at Chapel Hill,
Chapel Hill, NC 27599, USA.
(2) Crimmins, M. T.; Diaz, C. J.; Emmite, K. A. Heterocycles
2004, 62, 179.
The relative stereochemistry of C5 and C7 was confirmed
from the NOESY spectrum of the corresponding p-meth-
oxybenzylidene acetal 29 derived from b-hydroxy ketone
24 (Scheme 5). An NOE effect was observed between the
C5 equatorial proton and C6 protons, as well as between
the C7 axial proton and the benzyl protons (Figure 1).
Further support for the relative stereochemical assign-
ment of C5 and C7 was obtained by inspection of the 13C
NMR spectrum of acetonide 25 with regards to Rych-
novsky and Evans theory.30 In the 13C NMR spectrum of
anti-isomer 25 the gem-dimethyl groups on the acetonide
carbon were present at d = 25.98 and 25.71 ppm, due to a
twist-boat conformation. In comparison, the dimethyl car-
bons on the corresponding syn-isomer were observed at
d = 30.83 and 20.52 ppm, due to a chair conformation.
(3) Pettit, G. R.; Herald, C. L.; Doubek, D. L.; Herald, D. L.;
Arnold, E.; Clardy, J. J. Am. Chem. Soc. 1982, 104, 6846.
(4) (a) Pettit, G. R. J. Nat. Prod. 1996, 59, 812; and references
cited therein. (b) Lopanik, N.; Gustafson, K. R.; Lindquist,
N. J. Nat. Prod. 2004, 67, 1412.
(5) For recent reviews on bryostatin chemistry and biology, see:
(a) Mutter, R.; Wills, M. Bioorg. Med. Chem. 2000, 8, 1841.
(b) Hale, K. J.; Hummersone, M. G.; Manaviazar, S.;
Frigerio, M. Nat. Prod. Rep. 2002, 19, 413. (c) Sun, M. K.;
Alkon, D. L. CNS Drug Rev. 2006, 12, 1. (d) Abadi, G.;
Palen, W.; Geddings, J.; Irwin, T.; Kasali, N.; Colyer, J.;
Goodson, F.; Smith, J.; Jone, K.; Hester, J.; Noble, L.;
Groundwater, P. W.; Phillips, D.; Manning, T. J. Recent
Prog. Med. Plants 2006, 15, 363. (e) Hale, K. J.;
Manaviazar, S. Chem. Asian J. 2010, 5, 704.
R
H 5
H
(6) For current information, see: http://clinicaltrials.gov.
(7) Kageyama, M.; Tamura, T.; Nantz, M. H.; Roberts, J. C.;
Somfrai, P.; Whritenour, D. C.; Masamune, S. J. Am. Chem.
Soc. 1990, 112, 7407.
H
O
MP
Heq
7
O
R'
Hax
Figure 1 NOE observation of 29
Synlett 2011, No. 10, 1413–1418 © Thieme Stuttgart · New York

1416
K. Nakagawa-Goto, M. T. Crimmins
LETTER
in THF (20 mL) and cooled to –78 °C. n-BuLi (1.3 M in
(8) (a) Evans, D. A.; Carter, P. H.; Carreira, E. M.; Prunet, J. A.;
Charette, A. B.; Lautens, M. Angew. Chem. Int. Ed. 1998,
37, 2354. (b) Evans, D. A.; Carter, P. H.; Carreira, E. M.;
Charette, A. B.; Prunet, J. A.; Lautens, M. J. Am. Chem. Soc.
1999, 121, 7540.
(9) Ohmori, K.; Ogawa, Y.; Obitsu, T.; Ishikawa, Y.;
Nishiyama, S.; Yamamura, S. Angew. Chem. Int. Ed. 2000,
39, 2290.
(10) (a) Trost, B. M.; Dong, G. Nature (London) 2008, 456, 485.
(b) Trost, B. M.; Dong, G. J. Am. Chem. Soc. 2010, 132,
16403.
(11) Keck, G. E.; Poudel, Y. B.; Cummins, T. J.; Rudra, A.;
Covel, J. A. J. Am. Chem. Soc. 2011, 133, 744.
(12) (a) Keck, G. E.; Poudel, Y. B.; Rudra, A.; Stephens, J. C.;
Kedei, N.; Lewin, N. E.; Peach, M. L.; Blumberg, P. M.
Angew. Chem. Int. Ed. 2010, 49, 4580. (b) Nakagawa, Y.;
Yanagita, R. C.; Hamada, N.; Murakami, A.; Takahashi, H.;
Saito, N.; Nagai, H.; Irie, K. J. Am. Chem. Soc. 2009, 131,
7573.
hexanes, 11.5 mL, 14.9 mmol) was added dropwise via
syringe, and the mixture was stirred for 10 min. The lithiated
oxazolidinone 12 was added via cannula to the mixed
anhydride, and the reaction was stirred for an additional 10
min before being warmed to 0 °C, where stirring continued
for 3 h. The reaction was quenched by the addition of H2O
and extracted twice with EtOAc. The combined organic
layers were washed with brine and dried over Na2SO4.
Concentration in vacuo and purification by flash chroma-
tography gave acyl oxazolidinone 13 (1.98 g, 45% from 11)
as a colorless oil: 1H NMR (400 MHz, CDCl3): d = 7.39–
7.30 (m, 3 H), 7.30–7.24 (m, 2 H), 5.85–5.74 (m, 1 H), 5.39–
5.26 (m, 2 H), 4.78 (AB, J = 17.9 Hz, 2 H), 4.73 (AB,
J = 11.5 Hz, 2 H), 4.59 (s, 2 H), 4.40–4.33 (m, 1 H), 4.24–
4.18 (m, 2 H), 4.18–4.10 (m, 1 H), 3.67 (dd, J = 10.2, 6.6 Hz,
1 H), 3.58 (dd, J = 10.2, 4.2 Hz, 1 H), 2.48–2.37 (m, 1 H),
0.90 (d, J = 7.0 Hz, 3 H) 0.85 (d, J = 7.0 Hz, 3 H). HRMS:
m/z calcd for C19H25NO5Na [M+ + Na]: 370.1625; found:
370.1607.
(13) (a) Green, A. P.; Hardy, S.; Thomas, E. J. Synlett 2008,
2103. (b) Manaviazar, S.; Frigerio, M.; Bhatia, G. S.;
Hummersone, M. G.; Aliev, A. E.; Hale, K. J. Org. Lett.
2006, 8, 4477. (c) Keck, G. E.; Yu, T.; McLaw, M. D.
J. Org. Chem. 2005, 70, 2543. (d) Ball, M.; Baron, A.;
Bradshaw, B.; Omori, H.; MacCormick, S.; Thomas, E. J.
Tetrahedron Lett. 2004, 45, 8437. (e) Voight, E. A.; Seradi,
H.; Roethle, P. A.; Burke, S. D. Org. Lett. 2004, 6, 4045.
(f) Voight, E. A.; Roethle, P. A.; Burke, S. D. J. Org. Chem.
2004, 69, 4534. (g) Seidel, M. C.; Smits, R.; Stark, C. B. W.;
Frackenpohl, J.; Gaertzen, O.; Hoffman, H. M. R. Synthesis
2004, 1391. (h) Ohmari, K. Bull. Chem. Soc. Jpn. 2004, 77,
875. (i) O’Brien, M.; Taylor, N. H.; Thomas, E. J.
Tetrahedron Lett. 2002, 43, 5491. (j) Schmalz, H. G.;
Wirth, T. Organic Synthesis Highlights V; Wiley-VCH:
Weinheim, 2003, 307; and references cited therein.
(14) (a) Ball, M.; Bradshaw, B. J.; Dumeunier, R.; Gregson, T. J.;
MacCormick, S.; Omori, H.; Thomas, E. J. Tetrahedron
Lett. 2006, 2223. (b) Trost, B. M.; Yang, H.; Thiel, O. R.;
Frontier, A. J.; Brindle, C. S. J. Am. Chem. Soc. 2007, 129,
2206.
(18) Diene 6
Into a flask equipped with an addition funnel was added
sodium bis(trimethylsilyl)amide (0.75 M in toluene, 15 mL,
11.3 mmol). THF (30 mL) was added, and the solution was
cooled to –78 °C. Acyl oxazolidinone 13 (2.42 g, 7.0 mmol)
in THF (10 mL) was added dropwise via an addition funnel.
After stirring for 30 min at –78 °C, allyl iodide 14 (5.05 g,
22.1 mmol) in THF (10 mL) was added via syringe. After 10
min, the reaction was warmed to –45 °C and stirred at that
temperature for 1 h. The reaction was quenched by the
addition of sat. NH4Cl and warmed to r.t. The aqueous
layer was extracted twice with 50% EtOAc–hexanes. The
combined organic layers were washed with brine and dried
over Na2SO4. Concentration in vacuo and purification by
flash chromatography provided diene 6 (2.29 g, 74%) as a
colorless oil. 1H NMR (400MHz, CDCl3): d = 7.40–7.22 (m,
5 H), 5.83–5.71 (m, 1 H), 5.57–5.50 (m, 1 H), 5.37 (d,
J = 17.2 Hz, 1 H), 5.22 (d, J = 10.5 Hz, 1 H), 4.96–4.90 (m,
2 H), 4.54–4.43 (m, 2 H), 4.28–4.07 (m, 3 H), 3.97 (dd,
J = 9.0, 3.1 Hz, 1 H), 3.64–3.50 (m, 3 H), 3.41 (s, 3 H), 2.66
(dd, J = 14.2, 3.8 Hz, 1 H), 2.46 (dd, J = 14.2, 8.5 Hz, 1 H),
2.34–2.21 (m, 1 H), 0.83 (d, J = 6.9 Hz, 3 H), 0.80 (d, J = 6.9
Hz, 3 H). 13C NMR (400 MHz, CDCl3): d = 172.8, 156.5,
153.7, 138.7, 128.6, 128.5, 127.7, 127.6, 127.0, 118.0, 93.9,
87.7, 81.2, 75.8, 74.5, 72.9, 63.6, 58.3, 56.3, 39.2, 28.3, 18.0,
14.8. [a]D23 +68.9 (c 3.14, CH2Cl2). HRMS: m/z calcd for
C24H33NO7Na [M+ + Na]: 470.2155; found: 470.2192.
(19) Morgan, J. P.; Grubbs, R. H. Org. Lett. 2000, 2, 3153.
(20) Pyrane 16
(15) Vakalopoulos, A.; Lampe, T. F. J.; Hofmman, H. M. R. Org.
Lett. 2001, 3, 929.
(16) Takano, S.; Tomita, S.; Iwabushi, Y.; Ogasawara, K.
Synthesis 1988, 610.
(17) N-Acyloxazolidinone 13
A round-bottom flask was charged with NaH (60% on
mineral oil, 1.52 g, 39.3 mmol) and washed with hexanes to
remove the mineral oil. The NaH was then dissolved in THF
(15 mL) and cooled to 0 °C. Allylic alcohol 11 (2.27 g, 12.6
mmol) in THF (10 mL) was added and stirred at r.t. for 10
min. The mixture was cooled to 0 °C, and bromoacetic acid
(1.84 g, 13.5 mmol) in THF (5 mL) was added dropwise via
an addition funnel over 10 min with evolution of hydrogen
gas. The reaction mixture was warmed to r.t. and stirred
overnight. The cloudy reaction mixture was quenched
slowly with H2O at 0 °C. The organic layer was separated.
The aqueous layer was adjusted to pH 4 with 1 N HCl aq
solution and extracted with EtOAc. The combined organic
layers were washed with brine, dried over Na2SO4, and
concentrated to obtain the crude glycolic acid (2.8 g) as an
orange oil, which was dissolved in dry Et2O (40 mL). Et3N
(2.0 mL, 14.4 mmol) was added slowly, and the mixture was
cooled to –78 °C. Pivaloyl chloride (1.6 mL, 13.0 mmol)
was added dropwisee. After 5 min, the mixture was warmed
to 0 °C, where it was stirred for 1 h and subsequently
recooled to –78 °C. In a separate flask, (S)-(+)-4-iso-
propyloxazolidin-2-one (1.70 g, 13.1 mmol) was dissolved
Into a flask equipped with a reflux condenser was added
diene 6 (2.09 g, 4.68 mmol) in CH2Cl2 (1 L). Argon was
bubbled through the stirring solution for 1 h. The solution
was heated to reflux and Grubbs second-generation catalyst
(0.411 g, 0.49 mmol) was added in one portion. The reaction
was refluxed for 24 h and cooled to r.t. The air was bubbled
into the reaction mixture and stirred for 3 h at r.t.
Concentration in vacuo and purification by flash chroma-
tography provided pyrane 16 (1.72 g, 88%) as a colorless oil:
1H NMR (400 MHz, CDCl3): d = 7.36–7.34 (m, 3 H), 7.30–
7.26 (m, 2 H), 5.30 (dd, J = 10.7, 3.9 Hz, 1 H), 4.98 (d,
J = 6.2 Hz, 1 H), 4.91 (d, J = 6.2 Hz, 1 H), 4.90–4.88 (m, 1
H), 4.62 (d, J = 12.1 Hz, 1 H), 4.57 (d, J = 12.1 Hz, 1 H),
4.56–4.50 (m, 1 H), 4.50–4.44 (m, 1 H), 4.32 (t, J = 9.2 Hz,
1 H), 4.23 (dd, J = 9.2, 2.9 Hz, 1 H), 3.60 (dd, J = 10.2, 6.5
Hz, 1 H), 3.48 (dd, J = 10.2, 4.8 Hz, 1 H), 3.42 (s, 3 H), 2.57–
2.47 (m, 1 H), 2.45–2.32 (m, 2 H), 0.92 (d, J = 7.0 Hz, 3 H),
Synlett 2011, No. 10, 1413–1418 © Thieme Stuttgart · New York

LETTER
Formal Synthesis of the Bryostatin Northern Hemisphere
1417
0.88 (d, J = 7.0 Hz, 3 H). HRMS: m/z calcd for
C22H29NO7Na [M+ + Na]: 442.1842; found: 442.1860.
(21) Acetal 17
2828, 2361, 2339, 1458, 1358, 1314, 1075, 1049, 924, 737,
698 cm–1. 1H NMR (400 MHz, CDCl3): d = 7.36–7.31 (4 H,
m, ArH), 7.30–7.25 (1 H, m, ArH), 5.88 (1 H, ddd, J = 5.7,
10.5, 16.8 Hz, CH2=CH), 5.27 (1 H, d, J = 16.8 Hz,
Pyrane 16 (61.2 mg, 0.15 mmol) was dissolved in THF (1.2
mL) and MeOH (0.4 mL). Methylorthoformate (0.25 mL,
2.29 mmol), PPTS (2.1 mg, 0.01 mmol), and PTSA (1.9 mg,
0.01 mmol) were added to the mixture, which was then
refluxed for 1 h. The reaction mixture was quenched with
sat. NaHCO3 and extracted with EtOAc. The organic layer
was washed with brine and dried over Na2SO4.
CHH=CH), 5.12 (1 H, d, J = 10.5 Hz, CHH=CH), 4.56 (2 H,
s, CH2Ph), 4.06–4.00 (1 H, m, 6-H), 3.82–3.74 (1 H, m, 2-
H), 3.56 (1 H, dd, J = 5.6, 10.2 Hz, CH2OBn), 3.48 (1 H, dd,
J = 4.6, 10.2 Hz, CH2OBn), 3.22 (3 H, s, OCH3), 3.19 (3 H,
s, OCH3), 2.06–1.96 (2 H, m, 3- and 5-Heq), 1.38 (2 H, dd,
J = 11.9, 12.3 Hz, 3- and 5-Hax). 13C NMR (400 MHz,
CDCl3): d = 138.5, 128.6, 127.9, 127.8, 115.6, 99.0, 75.2,
73.7, 73.6, 73.1, 47.9, 47.6, 38.7, 35.4. HRMS: m/z calcd for
C17H24O4Na [M+ + Na]: 315.1572; found: 315.1580.
(23) Brown, H. C.; Randa, R. S.; Bhat, K. S.; Zaidlewicz, M.;
Rachela, U. S. J. Am. Chem. Soc. 1990, 112, 2389..
Concentration in vacuo and purification by flash
chromatography provided acetal 17 (51.5 mg, 82%) as a
colorless oil: 1H NMR (400 MHz, CDCl3): d = 7.38–7.30 (m,
3 H), 7.30–7.26 (m, 2 H), 5.22 (dd, J = 11.7, 2.2 Hz, 1 H),
4.60 (d, J = 10.2 Hz, 1 H), 4.56 (d, J = 10.2 Hz, 1 H), 4.50–
4.44 (m, 1 H), 4.31 (t, J = 8.7 Hz, 1 H), 4.23 (dd, J = 9.2, 3.1
Hz, 1 H), 3.92–3.85 (m 1 H), 3.60 (dd, J = 10.3, 5.9 Hz, 1 H),
3.50 (dd, J = 10.3, 4.5 Hz, 1 H), 3.29 (s, 3 H), 3.23 (s, 3 H),
2.40–2.30 (m, 2 H), 2.60–1.98 (m, 1 H), 1.62–1.54 (m, 1 H),
1.45 (t, J = 12.5 Hz, 1 H), 0.91 (d, J = 7.0 Hz, 3 H), 0.87 (d,
J = 7.0 Hz, 3 H). HRMS: m/z calcd for C22H31NO7Na [M+ +
Na]: 444.1998; found: 444.2040.
(24) PMB Ether 21
To a solution of 4-ICr2B-allyl in Et2O (ca. 270 mmol),
aldehyde 20 (8.25 g, 43.0 mmol), in Et2O (15.0 mL) was
added slowly via additional funnel at –78 °C. After stirring
for 2 h, the mixture was allowed to warm to r.t. Then aq
NaOH (3 M, 60 mL) was added carefully, followed by H2O2
(30% aq, 30 mL). The biphasic mixture was refluxed without
condenser to evaporate Et2O, and THF (60 mL) was added.
The mixture was refluxed overnight, then diluted with H2O
and the phases separated. The aqueous layer was back
extracted with Et2O. The combined organic layers were
washed with brine and dried over Na2SO4. Concentration in
vacuo and purification by flash chromatography provided
allylic alcohol (9.0 g) including a small amount of 4-ICr-OH.
The resulting alcohol (9.0 g) in THF (10.0 mL) was added to
a suspension of KH (30% in mineral oil, 7.96 g, 59.7 mmol)
in THF (50.0 mL) at 0 °C. After stirring at r.t. for 15 min, the
mixture was cooled to 0 °C. PMBCl (11.0 mL, 80.9 mmol)
was added, and the mixture was stirred at r.t. overnight. The
mixture was quenched with H2O and extracted with EtOAc
(3×). The combined organic layers were washed with brine
and dried over Na2SO4. Concentration in vacuo and
(22) Olefin 19
To a solution of 17 (1.23 g, 2.92 mmol) in Et2O (15 mL) and
MeOH (1.0 mL), lithium borohydride (2 M solution in THF,
7.0 mL, 14.0 mmol) was added at 0 °C. The reaction mixture
was stirred for 1 h and then quenched with 3 N NaOH aq.
The reaction mixture was allowed to warm to r.t. The
organic layer was separated, and the organic layer was
washed with 3 N NaOH aq. The combined aqueous layers
were re-extracted with Et2O. The combined organic layers
were washed with brine and dried over Na2SO4.
Concentration in vacuo and purification by flash chroma-
tography provided 891.2 mg of alcohol 18 including the
removed oxazolidinone (the ratio was 3:2 calcd from 1H
NMR). It was found that the alcohol could be carried on
without further purification. Into a flask equipped with a
low-temperature thermometer was added CH2Cl2 (3.0 mL)
and oxalyl chloride (2.0 M in CH2Cl2, 3.0 mL, 6.0 mmol).
After cooling to –78 °C, DMSO (0.85 mL, 12.0 mmol) in
CH2Cl2 (1.0 mL) was added dropwise via syringe. After
stirring for 10 min, the resulting primary alcohol in CH2Cl2
(3.0 mL) was added dropwise via syringe. After stirring for
15 min, Et3N (2.1 mL, 15.1 mmol) was added slowly via
syringe. The cooling bath was removed after 20 min, and the
reaction was allowed to warm to 0 °C. The reaction mixture
was quenched with H2O. The organic layer was separated
and washed with H2O. The combined aqueous layers were
re-extracted with CH2Cl2. The combined organic layers were
washed with brine, and dried over Na2SO4. Concentration in
vacuo and purification by flash chromatography provided
660.1 mg of aldehyde as colorless oil, which was a mixture
with the cleaved oxazolidinone (the ratio was 21:10 calcd
from 1H NMR) and used in the next reaction without further
purification.
To a solution of Ph3PCH3Br (2.49 g, 7.0 mmol) in toluene
(15.0 mL), KOt-Bu (520.0 mg, 4.6 mmol) in THF (3.0 mL)
was added, and the mixture was stirred at r.t. for 1.5 h. To the
resulting yellow suspension, aldehyde (660.1 mg) in toluene
(7.0 mL) was added, and the mixture was stirred at r.t.
overnight. The reaction was quenched by the addition of sat.
NH4Cl and warmed to r.t. The aqueous layer was extracted
with EtOAc. The organic layer was washed with brine and
dried over Na2SO4. Concentration in vacuo and purification
by flash chromatography provided 498.9 mg (60%, 3 steps
yields from 17) of olefin 19 as colorless oil: Colorless oil.
[a]D23 +1.09 (c 1.83, CH2Cl2). IR (film): nmax = 2938, 2861,
purification by flash chromatography provided PMB ether
21 (10.07 g, 70%, 2 steps yield from 20) as a colorless oil.
1H NMR (400 MHz, CDCl3): d = 7.36–7.30 (m, 4 H), 7.30–
7.25 (m, 1 H), 7.22 (d, J = 8.5 Hz, 2 H), 6.84 (d, J = 8.5 Hz,
2 H), 6.02–5.89 (m, 1 H), 5.14–5.06 (m, 1 H), 5.05–5.00 (m,
1 H), 4.55 (d, J = 10.7 Hz, 1 H), 4.49 (d, J = 12.3 Hz, 1 H),
4.45 (d, J = 12.3 Hz, 1 H), 4.39 (d, J = 10.7 Hz, 1 H), 3.79
(s, 3 H), 3.47 (dd, J = 8.6, 3.5 Hz, 1 H), 3.39 (d, J = 8.6 Hz,
1 H), 3.14 (d, J = 8.6 Hz, 1 H), 2.38–2.20 (m, 2 H), 0.95 (s,
3 H), 0.94 (s, 3 H). 13C NMR (400 MHz, CDCl3): d = 159.2,
139.1, 137.6, 131.7, 129.3, 128.5, 127.7, 127.6, 116.2,
113.8, 83.1, 77.61, 74.0, 73.3, 55.4, 40.2, 35.7, 22.3, 20.8.
[a]D23 +15.57 (c 4.74, CH2Cl2). HRMS: m/z calcd for
C23H30O3Na [M+ + Na]: 377.2087; found: 377.2081.
(25) Brabader, J. D.; Vandewalle, M. Synthesis 1994, 855.
(26) Hydroxy Ketone 24
To a solution of (i-Pr)2NH (1.5 mL, 10.7 mmol) in THF (3.0
mL), n-BuLi (1.4 M in hexane, 7.4 mL, 10.7 mmol) was
added dropwise at –30 °C. After stirring for 10 min, the
mixture was cooled to –78 °C, and a solution of 23 (3.54 g,
10.9 mmol) in THF (5.0 mL) was added slowly. The mixture
was stirred for 2 h, and a solution of aldehyde 22 (1.74 g, 4.9
mmol) in THF (5.0 mL) was added slowly. After stirring for
15 min, the mixture was treated according to Vandewalle’s
procedure to provide hydroxy ketone 24 (2.33 g, 70%) as a
colorless oil. 1H NMR (400 MHz, CDCl3): d = 7.68–7.60 (m,
4 H), 7.30–7.25 (m, 11 H), 7.23 (d, J = 8.6 Hz, 2 H), 6.83 (d,
J = 8.6 Hz, 2 H), 4.62 (d, J = 10.9 Hz, 1 H), 4.56 (d, J = 10.9
Hz, 1 H), 4.51 (d, J = 12.1 Hz, 1 H), 4.46 (d, J = 12.1 Hz, 1
H), 4.29–4.20 (m, 1 H), 3.92 (t, J = 6.1 Hz, 2 H), 3.81–3.75
Synlett 2011, No. 10, 1413–1418 © Thieme Stuttgart · New York

1418
K. Nakagawa-Goto, M. T. Crimmins
LETTER
(m, 1 H), 3.77 (s, 3 H), 3.40 (d, J = 8.7 Hz, 1 H), 3.16 (d,
J = 8.7 Hz, 1 H), 2.63–2.56 (m, 4 H), 1.66–1.56 (m, 1 H),
1.52–1.40 (m, 1 H), 1.03 (s, 9 H), 0.95 (s, 3 H), 0.94 (s, 3 H).
13C NMR (400 MHz, CDCl3): d = 211.2, 159.2, 138.9, 135.7,
133.5, 131.6, 130.0, 129.5, 128.5, 127.9, 127.7, 127.6,
113.9, 79.4, 74.8, 73.3, 64.9, 59.6, 55.5, 50.9, 46.3, 40.0,
37.6, 31.1, 27.0, 22.4, 20.8, 19.3. [a]D23 –3.63 (c 3.55,
CH2Cl2). HRMS: m/z calcd for C42H54O6SiNa [M+ + Na]:
705.3587; found: 705.3588.
overnight, the mixture was quenched with sat. NaHCO3. The
whole was extracted with EtOAc (3×). The combined
organic layers were washed with brine and dried over
Na2SO4. Concentration in vacuo and purification by flash
chromatography provided acetonide 25 (626.4 mg, 96%) as
a colorless oil. Further purification by flash chromatography
(CH2Cl2–hexane–Et2O = 4:1:0.2 then 35% EtOAc–hexane)
afforded anti-acetonide (553.6 mg) and syn-acetonide (72.8
mg) as a colorless oil. 1H NMR (400 MHz, CDCl3): d =
7.69–7.63 (m, 4 H), 7.44–7.30 (m, 10 H), 7.30–7.24 (m, 1
H), 7.21 (d, J = 8.6 Hz, 2 H), 6.84 (d, J = 8.6 Hz, 2 H), 4.60–
4.43 (m, 4 H), 4.15–4.02 (m, 2 H), 3.84–3.75 (m, 1 H), 3.79
(s, 3 H), 3.63–3.64 (m, 2 H), 3.38 (d, J = 8.6 Hz, 1 H), 3.16
(d, J = 8.6 Hz, 1 H), 1.79–1.50 (m, 4 H), 1.45–1.30 (m, 2 H),
(27) (a) Saksena, A. K.; Mangiaraeina, P. Tetrahedron Lett. 1983,
24, 273. (b) Evans, D. A.; Dimare, M. J. Am. Chem. Soc.
1986, 108, 2476.
(28) Nakagawa-Goto, K.; Crimmins, M. T. Synth. Commun.
2011, in press.
(29) Acetonide 25
1.38 (s, 3 H), 1.37 (s, 3 H), 1.04 (s, 9 H), 0.95 (s, 6 H). 13
C
A suspension of Me2NHB(OAc)3 (1.68 g, 6.39 mmol) in
MeCN (5.0 mL) and AcOH (5.0 mL) was stirred at r.t. for 30
min under argon. The mixture was cooled to –45 °C, and
hydroxy ketone 24 (773.7 mg, 1.14 mmol) in MeCN (5.0
mL) solution was then added. After stirring at –45 °C for 24
h, the mixture was quenched with 10% Rochelle’s salts and
extracted with CH2Cl2 (3×). The combined organic layers
were washed with brine and dried over Na2SO4.
Concentration in vacuo and purification by flash chroma-
tography afforded diol (760.8 mg, 98%, anti/syn = 7.6:1
mixture). To a solution of diol (614.0 mg, 0.9 mmol) in THF
(5.0 mL), 2,2-dimethoxypropane (5.0 mL, excess) and PPTS
(25.9 mg, 0.1 mmol) were added. After stirring at r.t.
NMR (400 MHz, CDCl3): d = 159.2, 139.1, 135.8, 135.8,
134.2, 134.1, 131.8, 131.1, 129.8, 129.0, 128.5, 127.8,
127.8, 127.7, 127.6, 113.9, 100.36, 79.6, 77.6, 74.5, 73.3,
63.9, 63.5, 60.3, 55.5, 40.1, 39.3, 39.1, 38.9, 38.4, 30.6, 29.9,
29.1, 27.1, 25.8, 25.5, 23.9, 23.2, 22.3, 21.0, 19.4, 14.3, 11.2.
[a]D23 –3.82 (c 2.49, CH2Cl2). HRMS: m/z calcd for
C45H60O6SiNa [M+ + Na]: 747.4051; found: 747.4016.
(30) (a) Rychnovsky, S. D.; Skalitzky, D. J. Tetrahedron Lett.
1990, 31, 945. (b) Evans, D. A.; Rieger, D. L.; Gage, J. R.
Tetrahedron Lett. 1990, 31, 7099.
(31) Similar coupling was successfully performed by Hale, see
ref. 12b.
Synlett 2011, No. 10, 1413–1418 © Thieme Stuttgart · New York