Total synthesis of pteridic acids A and B

Article abstract of DOI:10.1016/j.tet.2008.01.132

A convergent synthesis of pteridic acids A and B, epimeric spiroacetal polyketides with potent plant growth promoter properties, is described. The use of boron aldol methodology efficiently achieved the stereocontrolled construction of advanced C1-C11 and

Full text of DOI:10.1016/j.tet.2008.01.132

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 4768e4777
www.elsevier.com/locate/tet
Total synthesis of pteridic acids A and B
*
Ian Paterson , Edward A. Anderson , Alison D. Findlay, Christopher S. Knappy
*
University Chemical Laboratory, Lensfield Road, Cambridge CB2 1EW, UK
Received 25 September 2007; received in revised form 29 October 2007; accepted 2 November 2007
Available online 6 February 2008
Abstract
A convergent synthesis of pteridic acids A and B, epimeric spiroacetal polyketides with potent plant growth promoter properties, is described.
The use of boron aldol methodology efficiently achieved the stereocontrolled construction of advanced C1eC11 and C12eC16 subunits, which
were coupled to generate a linear (Z)-enone precursor that underwent spiroacetalization with HF$pyridine, providing pteridic acids A and B after
saponification.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Spiroacetal; Natural products; Aldol reaction; Plant growth promoter
1. Introduction
the formation of adventitious roots in kidney beans at excep-
tionally low concentrations.
The spiroacetal motif is a feature common to a vast array of
naturally occurring substances, including those of marine,
plant and bacterial origin, which often display impressive
biological profiles.1 Spiroacetal-containing natural products
therefore provide an attractive target for total synthesis, both
in terms of the inherent complexity associated with efficient
construction of the spiroacetal moiety, and also in terms of
the wide-ranging and potent biological activities often associ-
ated with this important scaffold. Within this laboratory, syn-
thetic endeavours directed towards accessing such molecular
frameworks have recently encompassed a range of challenging
polyketide targets, including spongistatin 1/altohyrtin A (1),2
siphonarin B (2),3 spirangien A (3)4 and spirastrellolide A
(4)5 (Fig. 1).
Structurally, the pteridic acids differ only in being epimeric
at the C11-acetal centre. They comprise a highly substituted
[6,6]-spiroacetal scaffold featuring seven stereocentres, and
an unsaturated side chain appended at C7, which incorporates
a further stereocentre and a carboxylic acid terminus. The spi-
roacetal unit of pteridic acid A benefits from stabilization by
a double anomeric effect, offset by pseudo-axial ethyl and
methyl groups at C14 and C15, respectively, while pteridic
acid B, which exhibits only a single anomeric effect, profits
energetically from pseudo-equatorial alkyl substituents at
C14 and C15. Molecular modelling (MacroModel, MM2) re-
veals the global minima of the epimeric spiroacetals to be of
similar energy, possibly accounting for their natural coexis-
tence as microbial secondary metabolites.
Pteridic acids A and B (5 and 6, Fig. 2) are also spiroacetal-
containing polyketides, isolated by Igarashi et al.6 from a fer-
mentation broth of Streptomyces hygroscopicus TP-A0451
(obtained from the stems of the bracken Pteridium aquili-
nium). Preliminary biological testing indicated that the pteridic
acids have potent plant growth promoter properties, inducing
In 2005, Nakahata and Kuwahara reported the first total
synthesis of (þ)-pteridic acid A, accompanied by the reassign-
ment of the configuration of the methyl-bearing C10 stereo-
centre relative to that indicated previously.7a Subsequent
work also allowed completion of a total synthesis of (ꢀ)-pteri-
dic acid B using a late-stage MgBr2-mediated spiroacetal iso-
merization.7b Herein, we report an expedient total synthesis of
these interesting microbial polyketide metabolites, which uti-
lizes our versatile boron aldol methodology to install much
of the required stereochemistry, and employs a late-stage
* Corresponding authors. Tel.: þ44 1223 336407; fax: þ44 1223 336362.
E-mail addresses: ip100@cam.ac.uk (I. Paterson), edward.anderson@
chem.ox.ac.uk (E.A. Anderson).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.01.132

I. Paterson et al. / Tetrahedron 64 (2008) 4768e4777
4769
O
O
HO
OMe
AcO
O
O
O
HO
O
O
O
O
O
O
HO
O
AcO
OH
O
O
O
HO
OH
2: Siphonarin B
OH
OH
OH
Cl
1: Spongistatin 1 (Altohyrtin A)
O
O
OMe
Cl
O
H
HO2C
O
O
MeO
OH
CO2H
O
HO
H
OH
H
HO
H
O
H
O O
OH
OMe
O
HO
MeO
OH
3: Spirangien A
Figure 1. Structures of spiroacetal-containing polyketide natural products.
HO
4: Spirastrellolide A
1
HO
HO
HO
7
7
CO2H
CO2H
CO2H
O
O
O
O
O
11
11
11 O
spiroacetalization
15
15
15
5 and 6
6: Pteridic Acid B
5: Pteridic Acid A
TBSO
15
1
11
CO2Et
O
O
O
7
vinyl lithium
addition
7
7
11
11
15
aldol
HWE
15
TBSO
1
11
O
H
12
CO2Et
15
Br
O
O
8
9
Figure 2. Structures of pteridic acids A and B with calculated minimum energy
conformations.
aldol
Scheme 1. Retrosynthetic analysis of the pteridic acids leading to key building
blocks 8 and 9.
spiroacetalization to obtain both pteridic acids A and B from
a fully elaborated linear precursor.
As shown in Scheme 2, formation of the C1eC11 aldehyde
8 began with a boron-mediated anti aldol reaction to rapidly
establish the required C6eC10 stereopentad.8 Formation of
the (E)-enolate of the Roche ester derived ethyl ketone (S)-
10,9 upon treatment with c-Hex2BCl/Et3N, was followed by
addition of the a-chiral aldehyde (R)-11.10 The expected anti,-
anti aldol adduct 12 was generated in 87% yield with excellent
selectivity (>99:1 dr) in this matched situation.11 The high
level of enolate p-facial selectivity is governed by the forma-
tion of a stabilizing formyl hydrogen bond with the oxygen of
2. Results and discussion
In our synthetic plan (Scheme 1), the (Z)-enone 7 was
envisaged to function as a suitable acyclic precursor to the pteri-
dic acids and might arise, in turn, from coupling of the C1eC11
aldehyde 8 with the C12eC16 vinyl bromide 9. These two
subunits should be accessible with a high level of stereocontrol
using aldol methodology developed in our laboratory.

4770
I. Paterson et al. / Tetrahedron 64 (2008) 4768e4777
PMB
O
Me
H
L
a
H
H
O
R
S
+
B
(87%, >99:1 dr)
L
TBSO
OH
12
O
OPMB
TBSO
O
O
OPMB
Me
O
H
11
10
H
TBSO
Me
aldol TS
(86%, 95:5 dr)
b
1
f
e
6
H
10
6
R
CO2Et
(90%)
(96%)
O
O
TBSO
O
O
O
TBSO
OR1 OR1 OR2
13: R1 = H, R2 = PMB
17: R = CH2OTBS
18: R = CH2OH
8: R = CHO
(92%) g
(95%) h
(99%) c
(83%) d
16
14: R1–R1 = CMe2, R2 = PMB
15: R1–R1 = CMe2, R2 = H
Scheme 2. (a) c-Hex2BCl, Et3N, Et2O, ꢀ78/0 ꢁC; (b) Me4NBH(OAc)3, AcOH, MeCN, ꢀ30 ꢁC; (c) 2,2,-dimethoxypropane, PPTS, rt; (d) H2, Pd(OH)2, EtOAc,
rt; (e) DMP, NaHCO3, CH2Cl2, rt; (f) (EtO)2P(O)CH2(CH)2CO2Et, LiHMDS, THF, ꢀ78 ꢁC; (g) TBAF, THF, 0 ꢁC/rt; (h) DMP, NaHCO3, CH2Cl2, rt.
the PMB ether in the bicyclic aldol transition state shown, act-
ing in unison with the minimization of allylic strain between the
a-stereocentre of the enolate and the methyl substituent.12 This
stereoinduction from the boron enolate is further enhanced by
the conformational preference of the aldehyde a-stereocentre,
which in the case of (E)-boron enolate aldol reactions is
matched/reinforced for the formal FelkineAnh adduct, which
avoids syn-pentane interactions between the aldehyde substitu-
ents and the enolate methyl group.13 Installation of the remain-
ing C7 stereocentre was achieved using an EvanseSaksena
hydroxyl-directed reduction.14 Thus, treatment of 12 with
Me4NBH(OAc)3 in MeCN/AcOH (3:1) provided the corre-
sponding 1,3-anti diol 13 in 87% yield and 95:5 dr, which
was then converted into the acetonide 14 by (MeO)2CMe2 in
the presence of catalytic acid (PPTS). Hydrogenolysis of the
PMB ether (H2, Pd(OH)2), followed by oxidation of the result-
ing alcohol 15 using DesseMartin periodinane (DMP),15 led
smoothly to the corresponding aldehyde 16. With the correctly
configured aldehyde 16 in hand, elaboration of the diene side
chain of the pteridic acids was undertaken via a HornereWad-
swortheEmmons olefination. A high degree of selectivity for
the desired (E,E)-diene 17 (>95:5) was achieved using tri-
ethyl-4-phosphonocrotonate with LiHMDS as base. Finally,
TBAF-mediated cleavage of the TBS ether, followed by
DesseMartin oxidation of the resulting alcohol 18 to give the
aldehyde 8 (79%, 3 steps), completed the efficient stereocon-
trolled construction of the C1eC11 subunit.
Synthesis of the C12eC16 vinyl bromide coupling partner 9
commenced with preparation of the ketone 19 via a second anti-
selective boron aldol reaction, this time using our lactate-based
methodology (Scheme 3).16 Based on our standard procedure,
the Weinreb amide 2016a derived from ethyl (S)-lactate was
treated with n-PrMgCl followed by benzoylation to give
the propyl ketone (S)-21. Enolization of 21 with c-Hex2BCl/
Me2NEt, followed by addition of acetaldehyde at ꢀ85 ꢁC,
generated the desired anti adduct 22 (90:10 dr).17 Again the
enolate p-facial selectivity is presumably governed by the for-
mation of a stabilizing formyl hydrogen bond, now involving
the carbonyl oxygen of the benzoate, in the bicyclic aldol
transition state shown, along with minimization of allylic strain
between the a-stereocentre of the enolate and the ethyl substi-
tuent.12,16a From here, TBS ether formation to give the b-siloxy
Ph
O
O
RO
O
O
O
Me
a
b
S
OBz
L
OBz
MeO
OH
H
N
O
H
Et
(90:10 dr)
(91%, 2 steps) c
(64%)
B
L
Me
O
21
20
22: R = H
19: R = TBS
Me
H
aldol TS
(92%) d, e
TBSO
16
TBSO
TBSO
O
g
f
12
Br
H
(97%)
(82%)
Br
Br
9
24
23
Scheme 3. (a) n-PrMgCl, THF, 0 ꢁC/rt, (PhCO)2O, DMAP, i-Pr2NEt, THF; (b) c-Hex2BCl, Me2NEt, Et2O, ꢀ78/0 ꢁC; (c) TBSCl, imidazole, DMAP, CH2Cl2,
rt; (d) NaBH4, MeOH, K2CO3, rt; (e) NaIO4, MeOH, pH 7 buffer, rt; (f) CBr4, PPh3, Et3N, CH2Cl2, ꢀ55 ꢁC; (g) Pd(PPh3)4, Bu3SnH, C6H6, rt.

I. Paterson et al. / Tetrahedron 64 (2008) 4768e4777
4771
ketone 19 was followed by a one-pot NaBH4 reduction/ester
solvolysis, then cleavage of the resulting glycol with NaIO4,
to generate aldehyde 23 in 92% overall yield. Treatment of
23 with CBr4 and PPh3 converted the aldehyde into the corre-
sponding vinyl dibromide 24,18 the less hindered bromide of
which was selectively reduced (Pd(PPh3)4, Bu3SnH)19 to pro-
vide the necessary (Z)-alkenyl bromide 9 and complete the
efficient preparation of the C12eC16 subunit.
acetonide was also observed, followed by in situ cyclization
to give both spiroacetal epimers 25 and 26 (ca. 1:1 mixture).
Unfortunately, the yield for this reaction was unacceptably
1
low (20%) and proved unreliable upon scale-up. Detailed H
NMR analysis of the by-products revealed that significant
dehydration had occurred and, as such, water was added as
a co-solvent in the reaction. Pleasingly, treatment of 7 with
HF$pyridine in THF/H2O (10:1) again generated 25 and 26
as a roughly equimolar mixture, but in an improved yield
(57%). These compounds were readily separable by chroma-
tography and could be assigned by comparison of the 1H
NMR spectra with those of the natural acids. Specifically,
the double anomeric effect stabilization experienced by pteri-
dic acid A ethyl ester 25, which places the C14 ethyl and C15
methyl substituents in pseudo-axial positions (cf. Fig. 2), is
At this point, the development of suitable reaction condi-
tions for the coupling of 8 and 9 was investigated (Scheme
4). Gratifyingly, generation of the corresponding (Z)-alkenyl
lithium species, via treatment of the bromide 9 with tert-butyl
lithium in Et2O at ꢀ78 ꢁC, followed by addition of the alde-
hyde 8, generated two epimeric alcohol adducts, which were
subjected directly to DesseMartin oxidation to give the (Z)-
enone 7 in 53% overall yield. With the desired linear precursor
7 in hand, our envisaged endgame required a suitable acid
treatment to cleave the TBS ether and acetonide groups,
thereby inducing spiroacetalization of the resulting triol with
the C11 ketone. However, our concerns over the intervention
of competing undesired reaction pathways proved to be justi-
fied, as exposure of 7 to a range of acidic conditions (e.g.,
CSA, HCl, PPTS, TFA, H2SiF6, etc.) led to intractable com-
plex mixtures of products. We reasoned that possible side-re-
actions, including hetero-Michael additions to the enone or
dienoate, or acid-mediated eliminations, might be avoided
by a selective cleavage of the TBS ether of 7 to generate a mix-
ture of hemiacetal products that could subsequently be con-
verted into the desired spiroacetals via acetonide cleavage.
In the event, treatment of 7 with HF$pyridine in THF induced
deprotection of the TBS ether. Fortuitously, cleavage of the
evidenced by a small H14eH15 coupling constant (J14e15
ꢂ
1 Hz). In contrast, pteridic acid B ethyl ester 26, with the
epimeric C11 configuration, benefits from a bis-equatorial ar-
rangement of these substituents, resulting in a correspondingly
large coupling constant (J14e15¼9.9 Hz) between the two
(axial) protons.
At this stage, all that remained was saponification of the es-
ters to produce the corresponding acids, avoiding any potential
equilibration at the C11-acetal centre. Separate treatment of
the epimeric ethyl esters with KOH in EtOH generated pteridic
acids A (25/5, 76%) and B (26/6, 73%). The spectro-
scopic data obtained (1H, 13C NMR, MS, IR) and the specific
rotation, [a]2D0 þ20.7 (c 0.07, CHCl3) cf. þ22.3 (c 1.0, CHCl3)
for 5 and [a]2D0 ꢀ21.8 (c 0.22, CHCl3) cf. ꢀ20.8 (c 0.68,
CHCl3) for 6, correlated fully with that reported previously
for pteridic acids A and B.6,7
TBSO
3. Conclusions
H
CO2Et
Br
9
O
O
O
In conclusion, we have developed an expedient synthetic
route to pteridic acids A and B that proceeds in a combined
10.6% yield over 12 steps from ketone 10. Key features are
the use of our versatile boron aldol methodology to configure
the majority of the stereocentres, with both C11-epimers being
generated via a late-stage spiroacetalization reaction.
8
(53%) a, b
TBSO
11
O
CO2Et
O
O
7
4. Experimental
c
(57%)
4.1. Molecular modelling
Molecular modelling was performed using Macromodel
(Version 8.0). To thoroughly probe the conformational poten-
tial surface, a 10,000 step Monte Carlo Multiple Minimum
search was performed using the MM2 force field in conjunc-
tion with the generalized Born/surface area (GB/SA) chloro-
form solvent model.
HO
HO
CO2R
+
CO2R
11 O
O
14
11 O
O
15
15
14
25: R = Et
5: R = H
Pteridic acid A
26: R = Et
6: R = H
Pteridic acid B
d (76%)
d (73%)
4.2. Compound numbering
t
Scheme 4. (a) BuLi, Et2O, ꢀ78 ꢁC, 8, ꢀ78 ꢁC; (b) DMP, NaHCO3, CH2Cl2,
The numbering system introduced by Igarashi has been
adopted.6
rt; (c) HF$pyridine, THF/H2O (10:1), 0 ꢁC/rt; (d) KOH (aq), EtOH, rt.

4772
I. Paterson et al. / Tetrahedron 64 (2008) 4768e4777
18
8
17
6
18
8
17
dried (Na2SO4) and concentrated in vacuo. Flash chromatogra-
phy (1:3 Et2O/pet. ether) afforded diol 13 (26 mg, 87%, 95:5
dr) as a colourless oil. Rf 0.13 (1:2 Et2O/pet. ether); [a]D20
þ17.2 (c 1.47, CHCl3); IR (neat) 3446, 2958, 2930, 2858,
HO
HO
19
6
CO2H
1
CO2H
1
3
3
10
10
O
O
O
19
11
15
11 O
1613 cmꢀ1 1H NMR (500 MHz, CDCl3) d 7.24 (2H, d,
;
15
13
13
16
16
J¼8.5 Hz, PhHa), 6.87 (2H, d, J¼8.6 Hz, PhHb), 4.48 (1H, d,
J¼11.4 Hz, CH2aPh), 4.43 (1H, d, J¼11.4 Hz, CH2bPh), 3.93
(1H, d, J¼9.5 Hz, H7), 3.84e3.80 (2H, m, H9 and 7-OH),
3.80 (3H, s, OMe), 3.79 (1H, obs. dd, J¼9.7, 3.6 Hz, H11a),
3.70 (1H, dd, J¼9.7, 3.8 Hz, H11b), 3.57 (1H, dd, J¼9,
4.4 Hz, H5a), 3.52 (1H, t, J¼8.8 Hz, H5b), 3.52e3.50 (1H,
obs. s, 9-OH), 2.04e1.93 (1H, m, H6), 1.80e1.73 (1H, m,
H10), 1.69 (1H, quint, J¼6.9, 3.7 Hz, H8), 0.99 (3H, d,
J¼7.0 Hz, Me19), 0.89 (9H, s, SitBu), 0.84 (3H, d, J¼
6.9 Hz, Me18), 0.79 (3H, d, J¼6.9 Hz, Me17), 0.06 (6H, s,
SiMe); 13C NMR (125 MHz, CDCl3) d 159.3, 129.8, 129.4,
113.9, 75.8, 75.4, 73.2, 69.0, 55.3, 37.3, 36.4, 36.0, 25.9,
18.2, 13.1, 9.9, 9.2, ꢀ5.5, ꢀ5.6; HRMS (ESþ) calcd for
C24H45O5Si ([MþH]þ): 441.3031, found: 441.3032.
20
20
21
21
5: Pteridic Acid A
6: Pteridic Acid B
4.3. Experimental section
4.3.1. Ketone 12
To a stirred solution of dicyclohexylboron chloride (278 mL,
1.31 mmol) in dry Et2O (2 mL) at ꢀ78 ꢁC was added Et3N
(226 mL, 1.62 mmol). Ketone 109 (297 mg, 1.25 mmol) in
Et2O (2 mL) was added via cannula and the reaction mixture
allowed to warm to 0 ꢁC over 1 h before recooling to
ꢀ78 ꢁC. A solution of aldehyde 1110 (278 mg, 1.37 mmol) in
Et2O (3 mL) was added via cannula and the resulting solution
was stirred for a further 3 h before placing in the freezer over-
night (ꢀ20 ꢁC). MeOH (2 mL) and pH 7 buffer (2 mL) were
then added dropwise, followed by H2O2 (1 mL, 30%). The
mixture was stirred vigorously at rt for 1 h and the phases sep-
arated. The aqueous phase was extracted with Et2O (3ꢃ10 mL)
and the combined organic phases were dried (MgSO4) and con-
centrated in vacuo. Flash chromatography (1:6 Et2O/pet. ether)
afforded ketone 12 (525 mg, 87%, >99:1 dr) as a colourless oil.
Rf 0.29 (1:2 Et2O/pet. ether); [a]2D0 þ15.5 (c 1.55, CHCl3); IR
(neat) 3483, 2956, 2934, 2882, 2858, 1712, 1613,
4.3.3. Acetonide 14
To a stirred solution of diol 13 (73 mg, 0.17 mmol) in 2,2-
dimethoxypropane (2 mL) at rt was added PPTS (30 mg,
0.12 mmol). The resulting solution was stirred at rt for 16 h be-
fore quenching by the addition of satd aqueous NaHCO3
(2 mL). The phases were separated and the aqueous phase ex-
tracted with CH2Cl2 (3ꢃ2 mL). The combined organics were
dried (Na2SO4), concentrated in vacuo, and flash chromatogra-
phy (1:1 Et2O/pet. ether) afforded acetonide 14 (80 mg, 99%)
as a colourless oil. Rf 0.71 (1:1 Et2O/pet. ether); [a]2D0 ꢀ8.5
(c 2.27, CHCl3); IR (neat) 2956, 2932, 2857, 1614,
1587 cmꢀ1 1H NMR (500 MHz, CDCl3) d 7.21 (2H, d,
;
J¼8.6 Hz, PhHa), 6.86 (2H, d, J¼8.6 Hz, PhHb), 4.44 (1H, d,
J¼11.7 Hz, CH2aPh), 4.39 (1H, d, J¼11.7 Hz, CH2bPh), 4.01
(1H, dt, J¼9.4, 2.3 Hz, H9), 3.80 (3H, s, OMe), 3.71 (1H,
dd, J¼9.8, 4.3 Hz, H11a), 3.67 (1H, dd, J¼9.8, 5.3 Hz,
H11b), 3.64 (1H, dd, J¼8.7, 8 Hz, H5a), 3.43 (1H, dd, J¼9,
5.1 Hz, H5b), 3.12 (1H, d, J¼2.5 Hz, 9-OH), 3.09e3.04 (1H,
m, H6), 2.84 (1H, dq, J¼9.4, 7.1 Hz, H8), 1.75e1.69 (1H, m,
H10), 1.06 (3H, d, J¼7.0 Hz, Me17), 0.93 (3H, d, J¼7.0 Hz,
Me18), 0.91 (3H, d, J¼7.0 Hz, Me19), 0.89 (9H, s, SitBu),
0.06 (3H, s, SiMe), 0.05 (3H, s, SiMe); 13C NMR (125 MHz,
CDCl3) d 217.5, 159.2, 130.1, 129.2, 113.8, 75.1, 73.0, 72.2,
68.0, 55.3, 49.5, 46.2, 36.0, 25.9, 18.3, 13.5, 13.0, 9.2, ꢀ5.5,
ꢀ5.5; HRMS (ESþ) calcd for C24H43O5Si ([MþH]þ):
439.2874, found: 439.2877.
1587 cmꢀ1 1H NMR (500 MHz, CDCl3) d 7.26 (2H, d,
;
J¼8.5 Hz, PhHa), 6.88 (2H, d, J¼8.6 Hz, PhHb), 4.41 (2H,
app. s, CH2Ph), 3.80 (3H, s, OMe), 3.57 (1H, dd, J¼11.0,
4.2 Hz, H9), 3.55 (1H, dd, J¼8.5, 3.0 Hz, H11a), 3.51 (1H,
dd, J¼9.4, 7.8 Hz, H5a), 3.45e3.41 (2H, m, H5b and H7),
3.38 (1H, dd, J¼8.7, 6.5 Hz, H11b), 1.84 (2H, m, H8 and
H10), 1.70e1.62 (1H, m, H6), 1.29 (3H, s, Me), 1.25 (3H, s,
Me), 0.95 (3H, d, J¼6.7 Hz, Me18), 0.89 (9H, s, SitBu), 0.87
(3H, d, J¼6.9 Hz, Me17), 0.85 (3H, d, J¼6.7 Hz, Me19),
0.04 (3H, s, SiMe), 0.04 (3H, s, SiMe); 13C NMR (125 MHz,
CDCl3) d 159.0, 131.1, 129.1, 113.7, 100.4, 73.9, 72.8, 72.4,
70.4, 65.0, 55.3, 39.3, 35.0, 33.8, 25.9, 25.0, 23.6, 18.2, 13.5,
11.6, 10.8, ꢀ5.4, ꢀ5.4; HRMS (ESþ) calcd for C27H49O5Si
([MþH]þ): 481.3344, found: 481.3350.
4.3.2. Diol 13
A solution of tetramethylammonium triacetoxyborohydride
(90 mg, 0.34 mmol) in MeCN (6.5 mL) and AcOH (2.5 mL)
was stirred at rt for 1 h. The mixture was cooled to ꢀ40 ꢁC
and a solution of ketone 12 (30 mg, 0.07 mmol) in MeCN
(10 mL) added via cannula. The resulting solution was stirred
at ꢀ40 ꢁC for 1 h and then stirred at ꢀ30 ꢁC overnight. The re-
action was quenched by the addition of satd aqueous NaHCO3
(10 mL) and CH2Cl2 (10 mL). Satd aqueous sodium potassium
tartrate (10 mL) was added and the mixture stirred vigorously
for 1 h. The phases were separated and the aqueous phase ex-
tracted with CH2Cl2 (3ꢃ5 mL). The combined organics were
4.3.4. Alcohol 15
To a solution of acetonide 14 (53 mg, 0.11 mmol) in EtOAc
(2 mL) at rt was added Pd(OH)2 (20 wt % on carbon, 15 mg,
0.11 mmol). The resulting suspension was stirred for 5 min be-
fore being evacuated/filled with H2 gas five times and then left
under a positive pressure of H2 for 2.5 h. The mixture was
filtered through a thin layer of Celite, eluting with Et2O
(3ꢃ10 mL) and the filtrate then concentrated in vacuo. Flash
chromatography (1:9 Et2O/pet. ether/100% Et2O) afforded
alcohol 15 (33 mg, 83%) as a colourless oil. Rf 0.19 (1:9
Et2O/pet. ether); [a]D20 þ10.4 (c 1.64, CHCl3); IR (neat)

I. Paterson et al. / Tetrahedron 64 (2008) 4768e4777
4773
1
2957, 2929, 2858, 1463 cmꢀ1; H NMR (500 MHz, CDCl3)
5.79 (1H, d, J¼15.4 Hz, H2), 4.20 (2H, q, J¼7.1 Hz,
CO2CH2Me), 3.50 (1H, dd, J¼9.5, 7.9 Hz, H11a), 3.47e3.41
(3H, m, H7, H9 and H11b), 2.44e2.36 (1H, m, H6), 1.92e
1.84 (1H, m, H8), 1.70e1.62 (1H, m, H10), 1.29 (3H, t,
J¼7.1 Hz, CO2CH2Me), 1.28 (3H, s, Me), 1.23 (3H, s, Me),
0.98 (3H, d, J¼6.7 Hz, Me17), 0.89 (9H, s, SitBu), 0.87 (3H,
d, J¼7.1 Hz, Me19), 0.86 (3H, d, J¼6.8 Hz, Me18), 0.04 (3H,
s, SiMe), 0.03 (3H, s, SiMe); 13C NMR (125 MHz, CDCl3)
d 167.4, 147.9, 145.3, 127.5, 119.3, 100.6, 73.7, 73.2, 64.9,
60.1, 39.3, 36.8, 35.2, 25.9, 24.9, 23.6, 18.2, 15.8, 14.3, 11.7,
10.7, ꢀ5.4, ꢀ5.4; HRMS (EI) calcd for C25H46O5Si ([M]þ):
454.3109, found: 454.3107.
d 3.61 (1H, dd, J¼10.4, 4.1 Hz, H7), 3.58 (1H, dd, J¼9.6,
8.4 Hz, H5a), 3.52 (1H, td, J¼9.9, 3.1 Hz, H5b), 3.47 (1H,
dd, J¼9.7, 2.7 Hz, H11a), 3.46 (1H, dd, J¼7.8, 2.8 Hz, H9),
3.43 (1H, dd, J¼9.6, 5.6 Hz, H11b), 3.27 (1H, d, J¼9.2 Hz,
5-OH), 1.95e1.87 (1H, m, H6), 1.87e1.81 (1H, m, H8),
1.70e1.63 (1H, m, H10), 1.35 (3H, s, Me), 1.30 (3H, s,
Me), 0.89 (9H, s, SitBu), 0.87 (3H, d, J¼6.8 Hz, Me18),
0.87 (3H, d, J¼6.8 Hz, Me19), 0.77 (3H, d, J¼6.8 Hz,
Me17), 0.03 (3H, s, SiMe), 0.03 (3H, s, SiMe); 13C NMR
(125 MHz, CDCl3) d 100.6, 76.3, 73.5, 69.2, 64.8, 39.2,
35.2, 35.0, 25.9, 25.2, 23.6, 18.2, 12.7, 11.7, 10.6, ꢀ5.4,
ꢀ5.4; HRMS (ESþ) calcd for C19H41O4Si ([MþH]þ):
361.2769, found: 361.2764.
4.3.7. Alcohol 18
To a stirred solution of dienoate 17 (630 mg, 1.39 mmol) in
THF (15 mL) at 0 ꢁC was added tetrabutylammonium flouride
(1.66 mL, 1 M in THF, 1.66 mmol) dropwise. The resulting so-
lution was stirred at rt for 3 h before quenching by the addition
of satd aqueous NH4Cl (15 mL). The resultant biphasic mixture
was stirred vigorously before concentration in vacuo. The re-
maining aqueous phase was extracted with Et2O (4ꢃ15 mL)
and the combined organic phases dried (MgSO4) and concen-
trated in vacuo. Flash chromatography (1:2 Et2O/pet. ether) af-
forded alcohol 18 (435 mg, 92%) as a colourless oil. Rf 0.17
(1:2 Et2O/pet. ether); [a]2D0 þ14.1 (c 1.21, CHCl3); IR (neat)
4.3.5. Aldehyde 16
To a stirred solution of alcohol 15 (137 mg, 0.38 mmol) in
CH2Cl2 (6 mL) at 0 ꢁC was added NaHCO3 (48 mg,
0.57 mmol) followed by DesseMartin periodinane (242 mg,
0.57 mmol). The resultant mixture was stirred at rt for 1 h, be-
fore being quenched with satd aqueous NaHCO3 (6 mL) and
sodium thiosulfate (6 mL). The organic phase was separated
and the aqueous phase extracted with CH2Cl2 (3ꢃ10 mL).
The combined organic phases were then dried (MgSO4) and
concentrated in vacuo. Flash chromatography (1:49/1:19
Et2O/pet. ether) afforded aldehyde 16 (146 mg, 96%) as a col-
ourless oil. Rf 0.41 (1:9 Et2O/hexane); [a]2D0 ꢀ28.9 (c 1.49,
1
3467, 2982, 2936, 2878, 1713, 1642, 1618 cmꢀ1; H NMR
(500 MHz, CDCl3) d 7.26 (1H, obs. dd, J¼15.3, 10.5 Hz,
H3), 6.21 (1H, dd, J¼15.4, 10.6 Hz, H4), 6.13 (1H, dd,
J¼15.4, 7 Hz, H5), 5.80 (1H, d, J¼15.4 Hz, H2), 4.20 (2H,
q, J¼7.1 Hz, CO2CH2Me), 3.68e3.62 (2H, m, H11), 3.51
(1H, dd, J¼7.3, 2.8 Hz, H9), 3.47 (1H, dd, J¼10.3, 4.1 Hz,
H7), 2.44e2.36 (1H, m, J¼10.6, 6.8 Hz, H6), 2.34e2.30
(1H, m, 11-OH), 1.98e1.90 (1H, m, H8), 1.88e1.80 (1H, m,
H10), 1.32 (3H, s, Me), 1.29 (2H, t, J¼7.1 Hz, CO2CH2Me),
1.26 (3H, s, Me), 0.99 (3H, d, J¼6.8 Hz, Me17), 0.97 (3H, d,
J¼7.1 Hz, Me19), 0.90 (3H, d, J¼6.7 Hz, Me18); 13C NMR
(125 MHz, CDCl3) d 167.3, 147.3, 145.1, 127.7, 119.5,
100.8, 77.4, 73.2, 66.9, 60.2, 37.8, 36.7, 34.4, 25.0, 23.5,
15.7, 14.3, 12.2, 10.7; HRMS (ESþ) calcd for C19H33O5
([MþH]þ): 341.2323, found: 341.2321.
CHCl3); IR (neat) 2957, 2933, 2859, 1733, 1463 cmꢀ1; H
1
NMR (500 MHz, CDCl3) d 9.69 (1H, d, J¼3.0 Hz, H5), 3.90
(1H, dd, J¼10.9, 4.4 Hz, H7), 3.53e3.48 (2H, m, H9 and
H11a), 3.45 (1H, dd, J¼9.8, 5.5 Hz, H11b), 2.53e2.45 (1H,
m, H6), 1.93e1.86 (1H, m, H8), 1.72e1.64 (1H, m, H10),
1.29 (3H, s, Me), 1.27 (3H, s, Me), 0.98 (3H, d, J¼6.9 Hz,
Me17), 0.89 (9H, s, SitBu), 0.88 (3H, d, J¼6.1 Hz, Me19),
0.88 (3H, d, J¼7.0 Hz, Me18), 0.04 (3H, s, SiMe), 0.03
(3H, s, SiMe); 13C NMR (125 MHz, CDCl3) d 204.8, 100.7,
73.5, 70.5, 64.8, 46.0, 39.2, 34.7, 25.9, 25.0, 23.4, 18.2,
11.7, 10.7, 10.1, ꢀ5.4, ꢀ5.5; HRMS (ESþ) calcd for
C19H39O4Si ([MþH]þ): 359.2612, found: 359.2614.
4.3.6. Dienoate 17
To a solution of triethyl-4-phosphonocrotonate (254 mg,
1.01 mmol) in THF (4 mL) at ꢀ78 ꢁC was added LiHMDS
(0.97 mL, 1 M in THF, 0.97 mmol) and the resultant solution
stirred for 10 min. A solution of aldehyde 14 (146 mg,
0.41 mmol) in THF (2 mL) was then added slowly via cannula
and the reaction mixture allowed to warm to ꢀ25 ꢁC and stirred
for 1.5 h. The reaction was then allowed to warm to rt and
quenched by the addition of satd aqueous NH4Cl (6 mL). The
aqueous phase was extracted with Et2O (3ꢃ7 mL) and the com-
bined organic phases dried (MgSO4) and concentrated in vacuo.
Flash chromatography (1:19 Et2O/pet. ether) afforded dienoate
17 (167 mg, 90%) as a colourless oil. Rf 0.28 (1:19 Et2O/pet.
ether); [a]2D0 ꢀ5.2 (c 1.70, CHCl3); IR (neat) 2959, 2935,
4.3.8. Aldehyde 8
To a stirred solution of alcohol 18 (68 mg, 0.20 mmol)
in CH2Cl2 (3 mL) at 0 ꢁC was added NaHCO3 (22 mg,
0.26 mmol) followed by DesseMartin periodinane (106 mg,
0.25 mmol). The resultant mixture was stirred at rt for 1 h, be-
fore being quenched with satd aqueous NaHCO3 (3 mL) and
sodium thiosulfate (3 mL). The organic phase was separated
and the aqueous phase extracted with CH2Cl2 (3ꢃ7 mL). The
combined organic phases were dried (MgSO4) and concen-
trated in vacuo. Flash chromatography (1:6/1:1 Et2O/pet.
ether) afforded aldehyde 8 (64 mg, 95%) as a yellow oil. Rf
0.38 (1:1 Et2O/pet. ether); [a]2D0 þ37.6 (c 2.03, CHCl3); IR
(neat) 2983, 2938, 2878, 1712, 1642, 1618 cmꢀ1; H NMR
1
1
2858, 1717, 1643, 1618 cmꢀ1; H NMR (500 MHz, CDCl3)
(500 MHz, CDCl3) d 9.70 (1H, d, J¼0.9 Hz, H11), 7.25 (1H,
dd, J¼15.3, 10.6 Hz, H3), 6.21 (1H, dd, J¼15.4, 10.6 Hz,
H4), 6.12 (1H, dd, J¼15.4, 7.1 Hz, H5), 5.80 (1H, d,
d 7.26 (1H, obs. dd, J¼15.3, 10.3 Hz, H3), 6.21 (1H, dd,
J¼15.4, 10.3 Hz, H4), 6.14 (1H, dd, J¼15.4, 6.8 Hz, H5),

4774
I. Paterson et al. / Tetrahedron 64 (2008) 4768e4777
J¼15.4 Hz, H2), 4.19 (2H, q, J¼7.1 Hz, CO2CH2Me), 3.76
(1H, dd, J¼7.4, 3.4 Hz, H9), 3.48 (1H, dd, J¼10.3, 4.3 Hz,
H7), 2.44e2.40 (2H, m, H6 and H10), 1.95 (1H, qnd, J¼7,
2.6 Hz, H8), 1.30 (3H, s, Me), 1.29 (3H, t, J¼7.1 Hz,
CO2CH2Me), 1.24 (3H, s, Me), 1.15 (3H, d, J¼7.0 Hz,
Me19), 0.98 (3H, d, J¼6.8 Hz, Me17), 0.93 (3H, d,
J¼6.7 Hz, Me18); 13C NMR (100 MHz, CDCl3) d 204.0,
167.3, 147.1, 145.1, 127.8, 119.6, 101.1, 73.9, 72.9, 60.2,
49.0, 36.7, 34.8, 24.6, 23.4, 15.7, 14.3, 12.0, 8.0; HRMS (EI)
calcd for C19H30O5 ([M]þ): 339.2166, found: 339.2167.
o-PhH), 7.58 (1H, t, J¼7.4 Hz, p-PhH), 7.46 (2H, t,
J¼7.7 Hz, m-PhH), 5.48 (1H, q, J¼7.1 Hz, CHMeOBz), 4.02
(1H, dq, J¼6.5, 6.3 Hz, H15), 2.84 (1H, dd, J¼12.9, 6.5 Hz,
H14), 2.45 (1H, d, J¼6.9 Hz, 15-OH), 1.83e1.71 (2H, m,
H20), 1.57 (3H, d, J¼7.1 Hz, CHMeOBz), 1.23 (3H, d,
J¼6.4 Hz, Me16), 1.00 (3H, t, J¼7.5 Hz, Me21); 13C NMR
(125 MHz, CDCl3) d 211.7, 165.8, 133.3, 129.8, 129.5,
128.5, 75.3, 67.9, 55.9, 22.4, 21.6, 15.8, 11.5; HRMS (ESþ)
calcd for C15H21O4 ([MþH]þ): 265.1434, found: 265.1436.
4.3.11. Silyl ether 19
4.3.9. Ketone 21
To a stirred solution of ketone 22 in DMF (15 mL) at
0 ꢁC was added tert-butyldimethylchlorosilane (7.22 g,
47.9 mmol), followed by imidazole (6.28 g, 88.3 mmol) and
DMAP (373 mg, 3.05 mmol). The reaction mixture was al-
lowed to warm to rt and stirred for 3 h before the addition of
water (30 mL). The phases were then separated and the aque-
ous phase extracted with CH2Cl2 (4ꢃ50 mL). The combined
organic phases were dried (MgSO4) and concentrated in vacuo.
Flash chromatography (1:9 Et2O/pet. ether) afforded silyl ether
19 (4.57 g, 91%) as a colourless oil. Rf 0.23 (1:19 Et2O/pet.
ether); [a]2D0 ꢀ7.6 (c 1.69, CHCl3); IR (neat) 2959, 2932,
To a stirred solution of Weinreb amide 2016a (1.27 g,
9.52 mmol) in THF (20 mL) at 0 ꢁC was added n-PrMgCl
(14.3 mL, 2 M in Et2O, 28.6 mmol) dropwise. The resulting
solution was stirred at 0 ꢁC for 2 h, allowed to warm to rt
and stirred for a further 1.5 h. The reaction was quenched by
the addition of satd aqueous NH4Cl (20 mL) and the phases
separated. The aqueous phase was extracted with CH2Cl2
(3ꢃ15 mL) and the combined organic phases dried (MgSO4)
were concentrated in vacuo to afford a colourless oil, which
was then taken up in THF (20 mL). Benzoic anhydride
(3.23 g, 14.3 mmol) and 4-dimethylaminopyridine (47 mg,
0.38 mmol) were added at rt, followed by the dropwise addi-
tion of diisopropylethylamine (2.15 mL, 15.3 mmol). The
mixture was stirred at rt for 16 h before the dropwise addition
of dimethylethylenediamine (1.15 mL, 10.5 mmol). Stirring
was continued for a further 1.5 h before the addition of water
(15 mL). The phases were separated and the aqueous phase ex-
tracted with Et2O (3ꢃ15 mL). The combined organic phases
were dried (MgSO4) and concentrated in vacuo. Flash chroma-
tography (1:9 Et2O/hexane) afforded ketone 21 (1.34 g, 64%)
as a colourless oil. Rf 0.19 (1:9 Et2O/hexane); spectroscopic
data identical to that reported for ent-21.16b
1
2885, 2858, 1721, 1603 cmꢀ1; H NMR (500 MHz, CDCl3)
d 8.09 (2H, d, J¼7.1 Hz, o-PhH), 7.58 (1H, t, J¼7.4 Hz,
p-PhH), 7.46 (2H, t, J¼7.8 Hz, m-PhH), 5.47 (1H, q,
J¼6.9 Hz, CHMeOBz), 4.02 (1H, app. dq, J¼8.1, 6.1 Hz,
H15), 2.84 (1H, td, J¼8.8, 3.8 Hz, H14), 1.70e1.61 (1H, m,
H20a), 1.61e1.52 (1H, m, H20b), 1.51 (3H, d, J¼6.9 Hz,
CHMeOBz), 1.16 (3H, d, J¼6.1 Hz, Me16), 0.93 (3H, t,
J¼7.5 Hz, Me21), 0.84 (9H, s, SitBu), 0.03 (3H, s, SiMe),
ꢀ0.03 (3H, s, SiMe); 13C NMR (125 MHz, CDCl3) d 209.4,
165.6, 133.1, 129.9, 129.8, 128.4, 75.9, 69.9, 57.1, 25.8,
22.0, 21.7, 17.9, 15.2, 11.6, ꢀ4.7, ꢀ4.8; HRMS (ESþ) calcd
for C21H35O4Si ([MþH]þ): 379.2299, found: 379.2303.
4.3.10. Ketone 22
4.3.12. Aldehyde 23
To a solution of dicyclohexylboron chloride (4.2 mL,
19.8 mmol) in Et2O (50 mL) at ꢀ78 ꢁC was added dimethyl-
ethylamine (2.57 mL, 23.7 mmol). The resulting solution was
stirred for 15 min and a solution of ketone 20 (2.91 g,
13.2 mmol) in Et2O (10 mL) then added dropwise via cannula.
After allowing to warm to 0 ꢁC and stirring for 1.25 h, the
reaction mixture was cooled to ꢀ85 ꢁC and freshly distilled ac-
etaldehyde (2.22 mL, 39.4 mmol) was added. The resultant
slurry was stirred for 1 h at ꢀ85 ꢁC, 1.7 h at ꢀ78 ꢁC, and
then placed in the freezer (ꢀ20 ꢁC) overnight. After warming
to 0 ꢁC, MeOH (15 mL) and pH 7 buffer (15 mL) were added,
followed by the dropwise addition of H2O2 (15 mL, 30%). The
resultant biphasic mixture was stirred vigorously at rt for 1 h
before the phases were separated and the aqueous phase was
extracted with CH2Cl2 (3ꢃ15 mL). The combined organic
phases were washed with satd aqueous NaHCO3 (20 mL) and
brine (20 mL), dried (MgSO4) and concentrated in vacuo. Flash
chromatography (1:2 Et2O/pet. ether) afforded 22 as a white
solid. Rf 0.13 (1:2 Et2O/pet. ether); [a]2D0 þ48.4 (c 1.74,
To a stirred solution of silyl ether 19 (2.74 g, 7.23 mmol) in
MeOH (23 mL) at rt was added sodium borohydride (549 mg,
14.5 mmol) and the resulting mixture was stirred for 30 min.
After cooling to 0 ꢁC, potassium carbonate (4.00 g, 28.9
mmol) was added and the mixture was allowed to warm to rt
and stirred for a further 6 h. Water (15 mL) and pH 7 buffer
(15 mL) were added and the biphasic mixture extracted with
CH2Cl2 (3ꢃ30 mL). The combined organic phases were dried
(MgSO4) and concentrated in vacuo. Residual methyl benzoate
was removed by flash chromatography (1:4/100% Et2O/pet.
ether) to give a colourless oil, which was dissolved in MeOH
(84 mL) and pH 7 buffer (15 mL). Sodium periodate (5.19 g,
24.2 mmol) was added and the resultant slurry stirred at rt
for 3 h before water (60 mL) was added. The resultant biphasic
mixture was extracted with CH2Cl2 (3ꢃ50 mL) and the com-
bined organic phases were then dried (MgSO4) and concen-
trated in vacuo. Flash chromatography (1:4 Et2O/pet. ether)
afforded aldehyde 23 (1.53 g, 92%) as a yellow oil. Rf 0.66
(1:2 Et2O/pet. ether); [a]2D0 ꢀ17.7 (c 2.05, CHCl3); IR (neat)
CHCl3); IR (neat) 3311, 2968, 2939, 1730, 1717, 1602 cmꢀ1
;
2959, 2932, 2883, 2859, 1727 cmꢀ1
;
1H NMR (500 MHz,
1H NMR (500 MHz, CDCl3) d 8.09 (2H, d, J¼7.5 Hz,
CDCl3) d 9.69 (1H, d, J¼3.8 Hz, H13), 4.07 (1H, qd, J¼6.1,

I. Paterson et al. / Tetrahedron 64 (2008) 4768e4777
4775
t
5.1 Hz, H15), 2.12e2.06 (1H, m, H14), 1.78e1.68 (1H, m,
H20a), 1.57e1.50 (1H, m, H20b), 1.21 (3H, d, J¼6.3 Hz,
Me16), 0.91 (3H, t, J¼7.5 Hz, Me21), 0.87 (9H, s, SitBu),
0.06 (3H, s, SiMe), 0.06 (3H, s, SiMe); 13C NMR (125 MHz,
CDCl3) d 205.5, 68.9, 61.1, 25.7, 22.3, 19.5, 17.9, 11.8,
ꢀ4.2, ꢀ5.0; HRMS (ESþ) calcd for C12H27O2Si ([MþH]þ):
231.1775, found: 231.1774.
Et2O (5 mL) and cooled to ꢀ78 ꢁC. BuLi (0.81 mL, 1.7 M in
pentane) was added dropwise and the resulting solution stirred
for 10 min before addition of the ethereal solution of aldehyde
8 via cannula. The reaction mixture was stirred at ꢀ78 ꢁC for
50 min, allowed to warm to 0 ꢁC and quenched by the addition
of satd aqueous NH4Cl (10 mL). The phases were separated and
the aqueous phase extracted with Et2O (3ꢃ10 mL). The com-
bined organic phases were then dried (MgSO4) and concen-
trated in vacuo to give an oil, which was dissolved in CH2Cl2
(10 mL) and cooled to 0 ꢁC. NaHCO3 (62 mg, 0.74 mmol)
and DesseMartin periodinane (306 mg, 0.72 mmol) were
added and the resulting suspension stirred at rt for 2.5 h. Satd
aqueous NaHCO3 (8 mL) and sodium thiosulfate (8 mL) were
added and the mixture was stirred for a further 30 min. The
phases were separated and the aqueous phase extracted with
CH2Cl2 (3ꢃ15 mL). The combined organic phases were then
dried (MgSO4) and concentrated in vacuo. Flash chromatogra-
phy (1:30/1:19/1:1 Et2O/pet. ether) yielded enone 7
(171 mg, 53%) as a yellow oil. Rf 0.54 (1:2 Et2O/pet. ether);
[a]2D0 þ71.0 (c 1.72, CHCl3); IR (neat) 2960, 2933, 2878,
4.3.13. Vinyl dibromide 24
To a solution of CBr4 (493 mg, 1.48 mmol) [dried by stirring
under vacuum (1 mmHg) at rt for 1.5 h] in CH2Cl2 (2 mL) at
0 ꢁC was added a solution of triphenylphosphine (771 mg,
2.94 mmol) in CH2Cl2 (2.3 mL). The resultant solution was
stirred for 5 min and triethylamine (100 mL, 0.74 mmol) was
added dropwise. After cooling to ꢀ55 ꢁC, a solution of aldehyde
23 (171 mg, 0.74 mmol) in CH2Cl2 (1.7 mL) was added via can-
nula. The reaction mixture was stirred for 2.5 h, before being
warmed to 0 ꢁC and quenched with satd aqueous NaHCO3
(6 mL). The phases were separated and the aqueous phase ex-
tracted with CH2Cl2 (3ꢃ5 mL). The combined organic phases
were dried (MgSO4) and concentrated in vacuo. Flash chroma-
tography (pet. ether) afforded vinyl dibromide 24 (279 mg,
97%) as a colourless oil. Rf 0.50 (pet. ether); [a]2D0 þ25.0 (c
2858, 1716, 1689, 1643, 1617 cmꢀ1 1H NMR (500 MHz,
;
CDCl3) d 7.28 (1H, dd, J¼15.3, 10.6 Hz, H3), 6.38 (1H, d,
J¼11.8 Hz, H12), 6.20 (1H, dd, J¼15.5, 10.6 Hz, H4), 6.12
(1H, dd, J¼15.8, 6.7 Hz, H5), 6.11 (1H, dd, J¼11.7, 10.3 Hz,
H13), 5.79 (1H, d, J¼15.4 Hz, H2), 4.20 (2H, q, J¼7.1 Hz,
CO2CH2Me), 3.90 (1H, qd, J¼6.3, 2.7 Hz, H15), 3.59 (1H,
dd, J¼6.6, 4.9 Hz, H9), 3.45 (1H, dd, J¼10.4, 4 Hz, H7), 3.35
(1H, dddd, J¼10.6, 7.6, 5.4, 2.5 Hz, H14), 2.67 (1H, qd,
J¼6.9, 4.9 Hz, H10), 2.41e2.32 (1H, m, H6), 1.93e1.86 (1H,
qnd, J¼6.7, 4.1 Hz, H8), 1.56e1.51 (1H, m, H20a), 1.36e
1.30 (1H, m, H20b), 1.29 (3H, t, J¼7.1 Hz, CO2CH2Me), 1.28
(3H, s, Me), 1.24 (3H, s, Me), 1.13 (3H, d, J¼6.9 Hz, Me19),
1.05 (3H, d, J¼6.3 Hz, Me16), 0.95 (3H, d, J¼6.8 Hz, Me17),
0.91 (3H, d, J¼6.7 Hz, Me18), 0.88 (9H, s, SitBu), 0.83 (3H,
t, J¼7.5 Hz, Me21), 0.05 (3H, s, SiMe), 0.04 (3H, s, SiMe);
13C NMR (125 MHz, CDCl3) d 202.6, 167.4, 150.4, 147.6,
145.2, 127.6, 127.4, 119.4, 100.8, 75.5, 72.8, 69.9, 60.2, 50.8,
46.7, 36.7, 35.5, 25.8, 25.0, 24.8, 23.5, 22.3, 18.0, 15.6, 14.3,
12.1, 11.9, 11.3, ꢀ4.2, ꢀ4.9; HRMS (ESþ) calcd for
C32H57O6Si ([MþH]þ): 565.3919, found: 565.3921.
1
2.75, CHCl3); IR (neat) 2959, 2930, 2858, 1618 cmꢀ1; H
NMR (500 MHz, CDCl3) d 6.30 (1H, d, J¼10 Hz, H13), 3.84
(1H, qd, J¼6.2, 3.4 Hz, H15), 2.25 (1H, tdd, J¼9.3, 5.0,
3.5 Hz, H14), 1.56e1.48 (1H, m, H20a), 1.44e1.34 (1H, m,
H20b), 1.10 (3H, d, J¼6.2 Hz, Me16), 0.90 (3H, t, J¼7.5 Hz,
Me21), 0.89 (9H, s, SitBu), 0.05 (6H, s, SiMe); 13C NMR
(125 MHz, CDCl3) d 140.1, 88.7, 69.6, 53.3, 25.8, 23.9, 21.9,
18.0, 11.8, ꢀ4.2, ꢀ4.9; HRMS (ESꢀ) calcd for C13H26Br3OSi
([MþBr]ꢀ): 462.9309, found: 462.9293.
4.3.14. Vinyl bromide 9
Vinyl dibromide 24 (300 mg, 0.78 mmol) was azeotroped
from benzene before being dissolved in benzene (4 mL). Tri-
butyltin hydride (0.31 mL, 0.14 mmol) was added dropwise
and the solution degassed, before freshly prepared Pd(PPh3)4
(135 mg, 0.15 mol) was added, and stirred for 3.7 h. The re-
action mixture was concentrated cautiously in vacuo and flash
chromatography (pet. ether) afforded vinyl bromide 9 (196 mg,
82%) as a colourless oil. Rf 0.44 (pet. ether); [a]2D0 þ22.8 (c
4.3.16. Esters 25 and 26
1.40, CHCl3); IR (neat) 2959, 2930, 2858, 1646, 1622 cmꢀ1
;
To a solution of TBS ether 7 (12 mg, 21.2 mmol) in THF/
H2O (10:1, 1.65 mL) in a polypropylene vessel at 0 ꢁC was
added HF$pyridine (300 mL). After 16 h at rt, the reaction mix-
ture was partitioned between satd aqueous NaHCO3 (10 mL)
and CH2Cl2 (7 mL). The phases were separated and the aque-
ous phase washed with CH2Cl2 (3ꢃ7 mL). The combined or-
ganic phases were then dried (Na2SO4) and concentrated in
vacuo. Flash chromatography (1:4/1:3 EtOAc/pet. ether)
afforded esters 25 (2.5 mg, 30%) and 26 (2.3 mg, 27%) as col-
ourless oils. 25 had Rf 0.35 (30% EtOAc/40e60 pet. ether);
[a]2D0 þ21.3 (c 0.15, MeOH); IR (neat) 3438, 2972, 1715,
1H NMR (500 MHz, CDCl3) d 6.28 (1H, d, J¼7.0 Hz, H12),
6.01 (1H, dd, J¼9.7, 7.1 Hz, H13), 3.89 (1H, qd, J¼6.3,
2.9 Hz, H15), 2.49 (1H, tdd, J¼9.3, 5.0, 2.9 Hz, H14), 1.59e
1.50 (1H, m, H20a), 1.44e1.34 (1H, m, H20b), 1.08 (3H, d,
J¼6.3 Hz, Me16), 0.89 (3H, t, J¼7.5 Hz, Me21), 0.88 (9H, s,
SitBu), 0.05 (3H, s, SiMe), 0.05 (3H, s, SiMe); 13C NMR
(125 MHz, CDCl3) d 135.8, 108.8, 69.8, 49.3, 25.8, 24.0,
21.7, 18.0, 11.8, ꢀ4.2, ꢀ4.9.
4.3.15. Enone 7
Prior to reaction, aldehyde 8 (177 mg, 0.52 mmol) was azeo-
troped from benzene, dissolved in dry Et2O (2.4 mL) and further
dried over CaH2 for 1 h. Vinyl bromide 9 (233 mg, 0.76 mmol)
was also azeotroped from benzene and then dissolved in dry
1638, 1140, 1032, 996 cmꢀ1 1H NMR (500 MHz, C6D6)
;
d 7.53 (1H, dd, J¼15.4, 7.5 Hz, H3), 6.06 (1H, dd, J¼15.3,
7.5 Hz, H5), 5.97 (1H, dd, J¼15.3, 10.9 Hz, H4), 5.91 (1H,
d, J¼15.3 Hz, H2), 5.65 (1H, ddd, J¼10.0, 5.5, 1.1 Hz, H13),

4776
I. Paterson et al. / Tetrahedron 64 (2008) 4768e4777
Table 1
Comparison of 1H NMR data for synthetic and natural pteridic acids A and B
Position
Natural pteridic
acid A6 (CDCl3, 400 MHz)
Synthetic pteridic
acid A (CDCl3, 500 MHz)
Natural pteridic
acid B6 (CDCl3, 400 MHz)
Synthetic pteridic
acid B (CDCl3, 500 MHz)
2
5.77 (1H, d, 15.4)
5.77 (1H, d, 15.4)
5.76 (1H, d, 15.4)
5.76 (1H, d, 15.3)
7.26 (1H, obscured)
6.23 (1H, dd, 10.6, 15.2)
6.13 (1H, dd, 7.2, 15.3)
2.53 (1H, m)
3
7.25 (1H, dd, 10.0, 15.4)
6.18 (1H, dd, 9.8, 15.4)
6.25 (1H, dd, 6.8, 15.4)
2.48 (1H, ddq, 9.8, 6.8, 6.8)
3.75 (1H, dd, 2.2, 10.0)
2.06 (1H, ddq, 2.2, 4.6, 6.8)
3.85 (1H, dd, 2.2, 10.0)
1.62 (1H, quint, 6.9)
5.51 (1H, dd, 1.2, 10.2)
5.96 (1H, ddd, 1.0, 5.8, 10.2)
1.61 (1H, dq, 11.0, 6.8)
3.91 (1H, q, 6.8)
7.25 (1H, dd, 10.2, 15.4)
6.18 (1H, dd, 9.9, 15.4)
6.25 (1H, dd, 6.9, 15.4)
2.48 (1H, ddq, 9.8, 6.9, 6.9)
3.75 (1H, dd, 2.2, 10.0)
2.06 (1H, m)
7.26 (1H, dd, 10.5, 15.4)
6.24 (1H, dd, 10.5, 15.4)
6.14 (1H, dd, 7.5, 15.4)
2.53 (1H, ddq, 10.0, 6.8, 6.8)
3.26 (1H, dd, 2.0, 9.8)
2.07 (1H, ddq, 1.7, 4.9, 6.8)
3.70 (1H, dd, 4.6, 11.2)
1.78 (1H, dq, 11.4, 6.8)
5.92 (1H, dd, 1.9, 10.7)
5.89 (1H, d, 10.7)
4
5
6
7
3.26 (1H, dd, 1.8, 9.9)
2.07 (1H, m)
8
9
3.85 (1H, dd, 4.7, 10.9)
1.63 (1H, q, 7.0)
3.69 (1H, dd, 4.9, 11.4)
1.78 (1H, dq, 11.4, 6.7)
5.92 (1H, dd, 1.8, 10.5)
5.89 (1H, br d, 10.9)
1.85 (1H, m)
10
12
13
14
15
16
17
18
19
20
21
5.51 (1H, dd, 1.1, 10.2)
5.96 (1H, dd, 5.9, 10.3)
1.60 (1H, dq, 11.0, 6.7)
3.91 (1H, q, 6.9)
1.86 (1H, m)
3.89 (1H, dq, 9.8, 6.1)
1.22 (3H, d, 6.1)
0.97 (3H, d, 6.8)
3.89 (1H, dq, 9.9, 6.0)
1.22 (3H, d, 6.2)
0.97 (3H, d, 6.7)
1.24 (3H, d, 6.8)
1.00 (3H, d, 6.8)
1.24 (3H, d, 7.0)
1.00 (3H, d, 6.9)
0.91 (3H, d, 7.0)
0.90 (3H, d, 6.8)
0.92 (3H, d, 6.9)
0.90 (3H, d, 7.0)
0.97 (3H, d, 6.8)
0.91 (3H, d, 6.8)
0.97 (2H, d, 6.9)
0.91 (3H, d, 6.7)
1.45 (2H, quint, 7.3)
0.93 (3H, t, 7.3)
1.45 (2H, quint, 7.3)
0.92 (3H, t, 7.3)
1.20 (1H, m), 1.49 (1H, m)
0.87 (3H, t, 7.6)
1.20 (1H, m), 1.49 (1H, m)
0.87 (3H, t, 7.5)
5.42 (1H, dd J¼9.9, 0.7 Hz, H12), 4.06 (2H, q, J¼7.1 Hz,
CO2CH2Me), 3.84 (1H, br q, J¼7.0 Hz, H15), 3.78 (1H, dt,
J¼10.8, 4.9 Hz, H9), 3.66 (1H, dd, J¼9.8, 2.3 Hz, H7),
2.37e2.29 (1H, m, H6), 1.79e1.73 (1H, m, H8), 1.60e1.57
(1H, dq, J¼11.1, 6.6 Hz, H10), 1.40e1.26 (3H, m, H14, and
H20), 1.21 (3H, d, J¼7.0 Hz, Me16), 1.00 (3H, d, J¼6.7 Hz,
Me19), 0.99 (3H, t, J¼7.0 Hz, CO2CH2Me), 0.92 (3H, d,
J¼7.0 Hz, Me18), 0.77 (3H, t, J¼7.1 Hz, Me21), 0.71 (3H,
J¼6.7 Hz, Me17); 13C NMR (125 MHz, C6D6) d 166.9,
148.8, 145.3, 129.6, 128.7, 127.4, 120.0, 97.0, 74.6, 72.2,
71.6, 60.0, 41.0, 40.7, 38.8, 36.8, 26.7, 23.1, 15.0, 14.3, 12.9,
12.0, 4.8; HRMS (ESþ) calcd for C23H36O5 ([MþNa]þ):
415.2455, found: 415.2450. 26 had Rf 0.23 (30% EtOAc/40e
60 pet. ether); [a]2D0 e19.3 (c 0.11, MeOH); IR (neat) 2967,
dropwise. After 16 h at rt, the reaction mixture was partitioned
between pH 4 buffer (1 mL) and CH2Cl2 (2 mL). The phases
were separated and the aqueous phase washed with CH2Cl2
(5ꢃ2 mL). The combined organic phases were then dried
(Na2SO4) and concentrated in vacuo. Flash chromatography
(1:2/1:3 pet. ether/EtOAc) afforded pteridic acid A (1.7 mg,
76%) as a white solid. Rf 0.52 (8% MeOH/CH2Cl2); [a]D20
þ20.7 (c 0.07, CHCl3); IR (neat) 3718, 2964, 2927, 1692,
1
1640, 1261 cmꢀ1; H NMR (500 MHz, CDCl3), see Table 1;
13C NMR (125 MHz, CDCl3), see Table 2; HRMS (ESþ) calcd
for C21H32NaO5 ([MþNa]þ): 387.2147, found: 387.2163.
Table 2
Comparison of 13C NMR data for synthetic and natural pteridic acids A and B
1714, 1639, 1456, 1262, 1005 cmꢀ1 1H NMR (500 MHz,
;
Position
Natural
Synthetic
Natural
Synthetic
C6D6) d 7.54 (1H, dd, J¼15.0, 10.5 Hz, H3), 6.05 (1H, dd,
J¼15.5, 11.0 Hz, H4), 5.96 (1H, d, J¼14.9 Hz, H2), 5.91
(1H, dd, J¼14.6, 6.7 Hz, H5), 5.65 (2H, m, H12 and H13),
4.12 (1H, dd, J¼9.9, 6.1 Hz, H15), 4.07 (2H, q, J¼7.3 Hz,
CO2CH2Me), 3.29 (1H, dt, J¼11.3, 5.3 Hz, H9), 2.97 (1H,
dd, J¼9.8, 2.3 Hz, H7), 2.35e2.26 (1H, m, H6), 1.79e1.73
(1H, dq, J¼11.3, 6.7, H10), 1.75 (1H, ddd, J¼9.9, 8.2,
3.9 Hz, H14), 1.70e1.64 (1H, m, H8), 1.30e1.23 (1H, m,
H20a), 1.16e1.10 (1H, obs., H20b), 1.14 (3H, d, J¼6.4 Hz,
Me16), 1.05 (3H, t, J¼6.9 Hz, Me19), 1.00 (3H, t, J¼7.1 Hz,
CO2CH2Me), 0.92 (3H, d, J¼7.0 Hz, Me18), 0.82 (3H, t,
J¼7.5 Hz, Me21), 0.76 (3H, J¼6.9 Hz, Me17); 13C NMR
(125 MHz, C6D6) d 166.8, 148.2, 145.5, 133.7, 128.5, 124.6,
119.9, 98.0, 75.7, 73.9, 68.0, 60.0, 42.6, 41.0, 38.7, 36.7,
23.6, 19.6, 15.3, 14.3, 11.8, 10.1, 4.9; HRMS (ESþ) calcd for
C23H36NaO5 ([MþNa]þ): 415.2455, found: 415.2447.
pteridic acid
A6 (CDCl3,
100 MHz)
pteridic acid
A (CDCl3,
125 MHz)
pteridic acid
B6 (CDCl3,
100 MHz)
pteridic acid
B (CDCl3,
125 MHz)
1
171.97
118.37
147.47
126.84
150.11
38.49
74.48
36.24
72.48
40.86
96.86
127.52
130.25
40.35
71.60
22.87
15.17
4.51
171.55
118.20
147.47
126.83
150.13
38.50
74.48
36.23
72.46
40.86
96.84
127.50
130.25
40.36
71.58
22.88
15.17
4.51
171.85
118.28
147.57
127.44
149.33
38.37
75.57
36.24
74.25
40.74
96.87
134.00
123.43
42.26
68.13
19.51
15.29
4.85
171.21
118.17
147.52
127.45
149.28
38.38
75.57
36.23
74.25
40.79
97.86
134.00
123.44
42.27
68.13
19.54
15.31
4.87
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
28
19
20
21
12.48
26.20
11.88
12.49
26.20
11.90
11.48
23.34
9.92
11.51
23.36
9.95
4.3.17. Pteridic acid A 5
To a solution of ester 25 (2.5 mg, 6.3 mmol) in EtOH/H2O
(2:1, 300 mL) at rt was added aqueous KOH (10%, 25 mL)

I. Paterson et al. / Tetrahedron 64 (2008) 4768e4777
4777
Chem. Commun. 2007, 1852; (c) Paterson, I.; Anderson, E. A.; Dalby,
S. M.; Lim, J. H.; Maltas, P.; Moessner, C. Chem. Commun. 2006,
4186; (d) Paterson, I.; Anderson, E. A.; Dalby, S. M.; Loiseleur, O.
Org. Lett. 2005, 7, 4121; (e) Paterson, I.; Anderson, E. A.; Dalby,
S. M.; Loiseleur, O. Org. Lett. 2005, 7, 4125.
6. Igarashi, Y.; Iida, T.; Yoshida, R.; Furumi, T. J. Antibiot. 2002, 55, 764.
7. (a) Nakahata, T.; Kuwahara, S. Chem. Commun. 2005, 1028; (b) Naka-
hata, T.; Fujimura, S.; Kuwahara, S. Chem.dEur. J. 2006, 12, 4584.
8. (a) Paterson, I.; Channon, J. A. Tetrahedron Lett. 1992, 33, 797; (b) Pater-
son, I.; Goodman, J. M.; Isaka, M. Tetrahedron Lett. 1989, 30, 7121.
9. (a) Paterson, I.; Arnott, E. A. Tetrahedron Lett. 1998, 39, 7185; (b)
Paterson, I.; Florence, G. J.; Gerlach, K.; Scott, J. P.; Sereinig, N.
J. Am. Chem. Soc. 2001, 123, 9535.
4.3.18. Pteridic acid B 6
An identical procedure was used on ester 26 (2.3 mg,
5.8 mmol) to that reported above. Flash chromatography
(1:2/1:3 pet. ether/EtOAc) gave pteridic acid B (1.5 mg,
73%) as a white solid. Rf 0.50 (8% MeOH/CH2Cl2); [a]D20
ꢀ21.8 (c 0.22, CHCl3); IR (neat) 3726, 2968, 2929, 1689,
1
1639, 1265 cmꢀ1; H NMR (500 MHz, CDCl3), see Table 1;
13C NMR (125 MHz, CDCl3), see Table 2; HRMS (ESþ) calcd
for C21H32NaO5 ([MþNa]þ): 387.2147, found: 387.2136.
Acknowledgements
10. Aldehyde 11 was prepared from methyl (R)-3-hydroxy-2-methylpropio-
nate: (i) TBSCl, imidazole, DMF; (ii) DIBALH, CH2Cl2; (iii) (COCl)2,
DMSO, CH2Cl2, Et3N.
We thank the EPSRC (EP/C541677/1), Homerton College,
Cambridge (Research Fellowship to E.A.A.), and Merck
Research Laboratories for support, and Robert Paton (Cam-
bridge) for molecular modelling assistance.
11. For a review on asymmetric aldol reactions using boron enolates, see:
Paterson, I.; Cowden, C. J. Org. React. 1997, 51, 1.
12. For DFT calculations on related aldol transition states, see: Paton, R. S.;
Goodman, J. M. Org. Lett. 2006, 8, 4299.
13. (a) Roush, W. R. J. Org. Chem. 1991, 56, 4151; (b) Gennari, C.; Vieth, S.;
Comotti, A.; Vulpetti, A.; Goodman, J. M.; Paterson, I. Tetrahedron 1992,
48, 4439.
References and notes
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2. (a) Paterson, I.; Chen, D. Y.-K.; Coster, M. J.; Acena, J. L.; Bach, J.;
Gibson, K. R.; Keown, L. E.; Oballa, R. M.; Trieselmann, T.; Wallace,
D. J.; Hodgson, A.; Norcross, R. D. Angew. Chem., Int. Ed. 2001, 40,
4055; (b) Paterson, I.; Coster, M. J.; Chen, D. Y.-K.; Oballa, R. M.;
Wallace, D. J.; Norcross, R. D. Org. Biomol. Chem. 2005, 3, 2399; (c)
Paterson, I.; Coster, M.; Chen, D. Y.-K.; Gibson, K. R.; Wallace, D. J.
Org. Biomol. Chem. 2005, 3, 2410; (d) Paterson, I.; Coster, M. J.; Chen,
D. Y.-K.; Acena, J. L.; Bach, J.; Keown, L.; Trieselmann, T. Org. Biomol.
Chem. 2005, 3, 2420; (e) Paterson, I.; Chen, D. Y.-K.; Coster, M. J.;
Acena, J. L.; Bach, J.; Wallace, D. J. Org. Biomol. Chem. 2005, 3, 2431.
3. Paterson, I.; Chen, D. Y.-K.; Franklin, A. S. Org. Lett. 2002, 4, 391.
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15. Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
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´
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17. The configuration was established by the advanced Mosher method, see:
Ohtani, I.; Kusumi, Y.; Kashman, H.; Kakisawa, H. J. Am. Chem. Soc.
1991, 113, 4092. A reduced level of diastereoselectivity (90:10 dr) is
observed for propyl ketone 21 relative to the analogous aldol reactions
of the corresponding ethyl ketone (ꢄ97:3 dr).
18. (a) Ramirez, F.; Desai, N. B.; McKelvie, N. J. Am. Chem. Soc. 1962, 84,
1745; (b) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 13, 3769.
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