Total synthesis of ( - )-spirangien A, an antimitotic polyketide isolated from the myxobacterium Sorangium Cellulosum

Article abstract of DOI:10.1002/asia.200800445

An expedient first total synthesis of (-)-spirangien A, a potent cytotoxic and antifungal polyketide of myxobacterial origin, is described. By using a common 1,3-diol intermediate obtained by an efficient aldol-reduction sequence for installation of the C

Full text of DOI:10.1002/asia.200800445

FULL PAPERS
DOI: 10.1002/asia.200800445
Total Synthesis of (ꢀ)-Spirangien A, an Antimitotic Polyketide Isolated from
the Myxobacterium Sorangium Cellulosum
Ian Paterson,* Alison D. Findlay, and Christian Noti[a]
Abstract: An expedient first total syn-
thesis of (ꢀ)-spirangien A, a potent cy-
totoxic and antifungal polyketide of
myxobacterial origin, is described. By
using a common 1,3-diol intermediate
obtained by an efficient aldol-reduction
sequence for installation of the C15–
C18 and C25–C28 stereotetrads and a
reagent-controlled boron aldol cou-
pling followed by spiroacetalization, a
highly convergent strategy was devel-
oped for construction of the elaborate
spiroacetal core. Conversion of this ad-
vanced spiroacetal intermediate into
(+)-spirangien diene, obtained previ-
ously by controlled degradation of spi-
rangien A, was then achieved by instal-
lation of the truncated side-chain using
an allylboration–Peterson sequence.
The total synthesis of (ꢀ)-spirangien A
was then achieved by the controlled at-
tachment of the unsaturated C1–C12
side-chain, avoiding exposure to light.
A Stork–Wittig olefination and double
Stille cross-coupling sequence was ex-
ploited to install the delicate conjugat-
ed pentaene chromophore featuring al-
ternating (Z)- and (E)-olefins, leading
initially to the methyl ester of spiran-
gien A, which proved significantly
more stable than the corresponding
free acid. Subsequent careful hydrolysis
afforded (ꢀ)-spirangien A, validating
the relative and absolute configuration.
Keywords:
cytotoxicity
aldol
reaction
·
·
· natural products
polyketides · spiro compounds
Introduction
of biological activity, spirangien A (1, Figure 1) has been
shown to possess both potent antifungal and cytotoxic activi-
ty, with an IC50 value of 0.7 ngmLꢀ1 against an L929 mouse
fibroblast cell line. To date, the mechanism of action associ-
ated with this promising anticancer activity has not been de-
termined. The spirangiens have a unique structural motif,
featuring a densely substituted spiroacetal core appended
with a side-chain bearing a delicate pentaene chromophore,
having alternating (Z)- and (E)-olefins, and a terminal car-
boxyl group. Spirangiens A and B (2) both possess 14 ste-
reocenters and differ only in the presence of a methyl or an
ethyl substituent at C31. The spiroacetal motif is a feature
common to a large array of natural product structures, in-
cluding those of marine, plant, and bacterial origin, which
often display impressive biological profiles.[8,9] Within our
Exploiting the wealth of novel natural products as both lead
structures and scaffolds for further elaboration has proven
highly successful in the quest for the discovery of efficacious
therapeutic agents.[1] As such, there is considerable interest
focused upon the identification of alternative sources of sec-
ondary metabolites.[2] Over the past two decades, myxobac-
teria have emerged as a prolific source of novel secondary
metabolites with pronounced biological activities and thera-
peutic potential.[3] Within the class of myxobacteria, the
genus Sorangium is the source of approximately half of all
metabolites isolated thus far, the most important being the
epothilone anticancer agents.[4,5]
Another interesting class of polyketide natural products
produced by Sorangium cellulosum (strain Soce90) is that of
the spirangiens, isolated initially by Hçfle and co-workers in
1993,[6] and reported by Niggemann et al. in 2005.[7] In terms
[a] Prof. Dr. I. Paterson, Dr. A. D. Findlay, Dr. C. Noti
University Chemical Laboratory
Lensfield Road, Cambridge, CB2 1EW (UK)
Fax : (+44)1223-336362
E-mail: ip100@cam.ac.uk
Homepage: http://www-paterson.ch.cam.ac.uk
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.200800445.
Figure 1. Structures of the spirangiens.
594
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Chem. Asian J. 2009, 4, 594 – 611

laboratory, synthetic endeavors directed towards accessing
such spiroacetal-containing molecular frameworks have en-
compassed a number of challenging targets, as exemplified
by spirastrellolide A[10] and spongistatin 1/altohyrtin A.[11]
Recently, we[12] and the Kalesse group,[13] among others,
have been attracted to the spirangiens as challenging bioac-
tive polyketide[14] targets for chemical synthesis, particularly
as the full stereostructure required rigorous assignment.
As an aid to stereochemical elucidation, Niggemann et al.
first performed a series of chemical degradation experiments
on spirangien A (Scheme 1).[7] The S configuration at the
thetic route to spirangien diene (3). This preliminary work
then provided us with a secure platform from which to prog-
ress to the first total synthesis of (ꢀ)-spirangien A by the
challenging introduction of the sensitive pentaene-contain-
ing side-chain.
Results and Discussion
At the outset, concerns over the instability of the spiran-
giens, associated with facile isomerization of the pentaene
chromophore, dictated a late-
stage incorporation of the unsa-
turated side-chain onto a fully
elaborated spiroacetal inter-
mediate to initially produce spi-
rangien A methyl ester (4). As
outlined retrosynthetically in
Scheme 2, we envisaged achiev-
ing this transformation by use
of a mild metal-mediated cou-
pling protocol, highly tolerant
Scheme 1. Chemical degradation of spirangien A as an aid to structural elucidation.
of other functional groups, such
that a complex Stille cross-cou-
pling[15] between vinyl iodide 5
isolated C3 stereocenter was thus determined by GC analy-
sis of an ozonolysis product. Moreover, a cross-metathesis
reaction of the pentaene moiety with ethene generated the
spiroacetal fragment 3 with a truncated side-chain, which
enabled X-ray crystal structure analysis. Whilst this led to a
secure determination of the relative stereochemistry, the ab-
solute configuration of 3, and
and stannane 6 was proposed. In turn, it was envisaged that
vinyl stannane 6 would be accessed by a Stille coupling of
(Z)-vinyl iodide 7 and the bis-stannylated (1E, 3Z, 5E)-
triene linker 8. Following unravelling of the spiroacetal core
in 5, careful inspection of the proposed open-chain precur-
sor 9 revealed a repeating pattern of four contiguous stereo-
correspondingly the C14–C28
spiroacetal-containing region of
the spirangiens, remained unre-
solved. Notably, the resulting
spirangien diene (3) also
showed
potent
cytoxicity
(IC50 =7 ngmLꢀ1 in the L929
mouse fibroblast line), retaining
around one tenth of the activity
of spirangien A itself, thus high-
lighting the importance of the
C10–C32 spiroacetal core to the
pharmacophore.
As part of a program direct-
ed towards the synthesis of an-
timitotic polyketides, we recent-
ly embarked on a total synthe-
sis of the spirangiens. Herein,
we provide a full account of the
development of an expedient
aldol-based strategy for the
controlled assembly of the spi-
rangiens and relevant back-
ground material on the evolu-
tion of a highly convergent syn- Scheme 2. Retrosynthetic analysis of spirangien A leading to common precursor 12.
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595

I. Paterson et al.
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centers at C15–C18 and C25–C28 that could potentially be
exploited to develop a modular and step-economic strategy.
Anticipating that this acyclic ketone 9 might arise from an
aldol coupling of aldehyde 10 and ketone 11, a parallel se-
quence of reactions could thus be developed to access both
10 and 11 from a common stereotetrad building block 12.
This plan was viewed as particularly attractive owing to the
ready availability of 12 by a robust aldol-reduction se-
quence.
(Scheme 4) retaining a PMB
ether at C29, with a view to in-
troducing the required trisubsti-
tuted alkene after spirocycliza-
tion. Thus, elaboration of the
common precursor 12 would re-
quire a controlled installation
of the C24 stereocenter.
Focussing on the preparation
of the C23–C29 aldehyde 10,
previous work[22] suggested that
hydroboration of the 1,1-disub-
stituted olefin of 1,3-diol 12
using borane in THF should
result in installation of the re-
quired R-configured stereocen-
ter at C24. Pleasingly, when al-
lylic alcohol 12 was treated with
BH3·SMe2 complex followed by
oxidative workup, the corre-
sponding C24,C25-syn triol 16
was obtained in high yield
(94%) and with a good level of
diastereoselectivity (6:1 d.r. by
1H NMR analysis of the crude
reaction mixture; Scheme 4).[23]
These epimeric triol products
proved readily separable by
Synthetic endeavors towards spirangien A began with the
preparation of the planned common intermediate 12, which
we had first prepared in the context of our discodermolide
total synthesis.[16] Starting from the ethyl ketone (S)-13,[17]
a
1,4-syn-selective aldol reaction mediated by dicyclohexylbor-
on chloride with methacrolein afforded the corresponding
3,4-anti adduct 14 in good yield (84%) and with the usual
excellent diastereoselectivity (Scheme 3). This boron aldol
Scheme 4. Synthesis of C23–
C29
aldehyde
10.
a) 1. BH3·SMe2, THF,
0!
208C, 3 h; 2. MeOH, NaOH,
H2O2; b) TBSCl, imidazole,
CH2Cl2, 208C, 2 h; c) 2,2-dime-
thoxypropane, PPTS, CH2Cl2,
column chromatography. Differ- 208C, 16 h; d) TBAF, THF,
0!208C, 1 h; e) Dess–Martin
periodinane, NaHCO3,
CH2Cl2, 208C, 1 h. 9-BBN=9-
borobicyclo[3.3.1]nonane;
TBSCl=tert-butyldimethylsilyl
chloride; TBAF=tetrabutyl
entiation of the hydroxyl
groups of 16 was then achieved
by selective silylation of the pri-
mary hydroxyl (TBSCl, imida-
zole). An appropriate choice of
protecting group for the re-
maining two hydroxyls (C25
and C27) was deemed crucial,
as it would be destined for re-
AHCTUNGTRENNUNG
ammonium fluoride; PMB=
para-methoxybenzyl.
Scheme 3. Preparation of common precursor 12. a) 1. c-Hex2BCl, Et3N,
Et2O, 0 8C, 1 h; H2C=C(Me)CHO, ꢀ78!ꢀ278C, 16 h; 2. MeOH, pH 7
buffer, H2O2; b) Me4NBH
c) EtCHO, SmI2, THF, ꢀ20!ꢀ108C, 2 h; d) K2CO3, MeOH/H2O (10:1),
208C, 5 h.
G
moval under mild acidic conditions designed to induce con-
current spiroacetalization. As such, an acetonide was select-
ed and treatment of the diol with 2,2-dimethoxypropane and
catalytic PPTS in CH2Cl2 gave 17 (89%, two steps). Cleav-
age of the TBS ether in 17 and Dess–Martin oxidation[24] of
the resulting alcohol completed the efficient preparation of
the C23–C29 aldehyde 10 (five steps from 12, 67% overall).
We then turned our attention to preparation of the requi-
site C13–C22 aldol coupling partner 11 (Scheme 5). With a
view towards the planned spiroacetalization step, and the re-
quired facile liberation of the C17 alcohol, an acetonide
seemed a natural choice as the 1,3-diol protecting group, in
accordance with that present in aldehyde 10. Thus, treat-
ment of 12 with 2,2-dimethoxypropane and catalytic PPTS
was performed and was followed by cleavage of the PMB
ether and conversion of the resulting alcohol into the iodide
18 (93%, three steps). A Myers asymmetric alkylation[25]
was selected for chain extension and concomitant introduc-
tion of the C20 oxygen-bearing stereocenter, where the aux-
reaction[18] proceeds through the (E)-enolate 15 and the fa-
vored bicyclic transition state (TS) shown, which is stabi-
lized by a formyl hydrogen bond involving the PMB ether
oxygen.[19] Next, an Evans–Saksena[20] hydroxyl-directed re-
duction protocol was employed, as it provided direct access
to the required diol 12. However, it was found to be more
scaleable to perform a two-step procedure, involving an
Evans–Tischenko[21] 1,3-anti reduction of 14 followed by
K2CO3-mediated hydrolysis of the resultant crude ester. This
generated the required diol 12 in 99% yield with essentially
complete stereocontrol (99:1 d.r.).
With expedient access to multigram quantities of the
common building block 12, our attention turned to prepara-
tion of the two key fragments required for the complex
aldol coupling to assemble the spiroacetal core of spiran-
gien. In our initial work, we targeted the aldehyde 10
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Chem. Asian J. 2009, 4, 594 – 611

Total Synthesis of (ꢀ)-Spirangien A
Scheme 5. Synthesis of C13–C22 ketone 11. a) 2,2-dimethoxypropane,
PPTS, CH2Cl2, 208C, 16 h; b) DDQ, CH2Cl2/pH 7 buffer (10:1), 0!208C,
2 h; c) I2, PPh3, Et3N, imidazole, PhMe, 0!208C, 3 h; d) 19, LDA, THF,
ꢀ78!208C, 1 h; 18, 0!208C, 16 h; e) MeLi, THF, ꢀ78!08C, 1 h; f)
TESOTf, 2,6-lutidine, CH2Cl2, ꢀ788C, 1 h. DDQ=2,3-dichloro-5,6-dicya-
no-1,4-benzoquinone; LDA=lithium diisopropylamide; TESOTf=trie-
thylsilyl trifluoromethanesulfonate.
Scheme 6. Aldol coupling and spiroacetalization. a) LDA, THF, ꢀ788C,
1 h; 10, ꢀ788C, 1 h; b) 1. (ꢀ)-Ipc2BCl, Et3N, Et2O, 0 8C, 1 h; 10, ꢀ78!
ꢀ308C, 16 h; 2. MeOH, pH 7 buffer, H2O2; c) Me3O·BF4, Proton Sponge,
CH2Cl2, 0!208C, 2 h; d) CSA, MeOH, 208C, 16 h. CSA=camphorsul-
fonic acid.
iliary might subsequently be cleaved directly to generate the
required methyl ketone. However, it is recognized[25b] that
use of hydroxyacetamide 19 (prepared from (ꢀ)-pseudoe-
phedrine and methyl glycolate) tends to result in lower dia-
stereoselectivities in alkylation reactions, possibly as a con-
sequence of the trianion that is generated upon enolization.
Furthermore, reactions with b-branched electrophiles are
usually slow, leading to diminished yields. In spite of these
concerns, we were gratified to find that, after suitable opti-
mization studies, alkylation of the lithium enolate derived
from 19 with iodide 18, followed by treatment with MeLi,
generated the desired methyl ketone 20 in high yield and se-
lectivity (80%, 25:1 d.r.). That the alkylation had proceeded
with the desired sense of stereoinduction at C20 was con-
firmed by preparation of the corresponding (R)- and (S)-
MTPA ester derivatives and application of the advanced
Mosher method.[26] TES ether formation then completed the
efficient preparation of the C13–C22 ketone 11 (six steps
from 12, 74% overall).
1
of diastereoisomers). Careful H NMR analysis of these de-
rivatives, again using the advanced Mosher method,[26] re-
vealed the major isomer of the aldol reaction to be 21, bear-
ing the undesired S configuration at the newly installed C23
stereocenter. The use of the dicyclohexylboron enolate (c-
Hex2BCl/Et3N) enhanced selectivity for the undesired prod-
uct (5:1 d.r.). Pleasingly, this inherent diastereoselectivity in
the undesired Felkin–Anh direction could be overturned by
reagent control, employing the appropriate Ipc ligand on
the boron enolate.[16,27] Thus, enolization of ketone 11 with
(ꢀ)-Ipc2BCl/Et3N, followed by addition of aldehyde 10, gen-
erated the two aldol adducts in 65% combined yield and
2.5:1 d.r. in favor of the desired diastereomer 9. The so
formed epimeric mixture of b-hydroxy ketones was pro-
gressed to the corresponding methyl ethers using mild (non-
anionic) conditions to prevent retro-aldol cleavage. Treat-
ment of 9 and 21 with Meerweinꢁs salt and Proton Sponge[28]
generated the corresponding methyl ethers 22 and 23 in a
combined yield of 83%.
With aldehyde 10 and methyl ketone 11 in hand, our at-
tention turned to their proposed union by aldol coupling
(Scheme 6). Preliminary studies using the lithium enolate of
11 (LDA) generated
a
2.8:1 mixture (ascertained by
The stage was now set to investigate the pivotal spiroace-
talization reaction, where we anticipated that the configura-
tion of the C21 acetal center would be controlled under
equilibrating conditions, as a result of double anomeric sta-
bilization. A range of acidic conditions, designed to induce
removal of the two acetonide protecting groups and concur-
rent formation of the requisite spiroacetal core of the spi-
1H NMR analysis of the crude reaction mixture) of epimeric
adducts 9 and 21, which proved inseparable by flash chro-
matography. To assign the stereochemistry, Mosher ester
analysis was performed on this mixture. Treatment of aldol
adducts 9 and 21, in turn, with (R)- and (S)-MTPA chlorides
and pyridine generated the MTPA esters (each as a mixture
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I. Paterson et al.
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rangiens, were evaluated. In the event, optimal results were
achieved using CSA in MeOH at ambient temperature. This
led to clean conversion of the C23-epimeric bis-acetonides
22 and 23 into the two spiroacetals 24 and 25 in 64% yield
in a ca. 2.5:1 ratio, in accordance with the aldol diastereose-
lectivity. Following chromatographic separation, unequivocal
assignment of their stereochemistry, including the configura-
tion of the C21 acetal carbon atom, was made by nOe analy-
the primary alcohol 26, which was then smoothly trans-
formed into iodide 27 (74%, three steps). Attempted dis-
placement of this leaving group with the organolithium spe-
cies generated from (2E)-2-bromobutene (tBuLi, THF) was
next performed. Disappointingly, the sole product of this re-
action was identified as 28, whereby unanticipated migration
of the ethereal C27 TES group to the C29 carbon atom had
occurred.
While related examples of such oxygen to carbon silyl mi-
grations (retro-Brook-type rearrangements) have been re-
ported previously,[29] which may sometimes be circumvented
by a solvent switch from THF to diethyl ether,[30] this and
other modifications to the experimental conditions proved
unproductive and the desired transformation of 27 into 29
could not be achieved satisfactorily. At the time, the unanti-
cipated difficulties encountered prompted a refinement of
our proposed synthetic strategy towards spirangien A, as
outlined in Scheme 8. We reasoned that a more streamlined
1
sis and comparison with the H NMR data reported for the
corresponding region of the spirangiens.[7] Both 24 and 25
were found to benefit from double anomeric stabilization,
with the observed coupling constants for H17 and H25 (in
both 24 and 25) showing close agreement with the values re-
ported. Assignment of the C23 configuration was made on
the basis of the diagnostic nOe enhancements indicated for
both epimers, with the anticipated major isomer 24 bearing
the correct configuration. The measured 1H–1H coupling
constants were also in agreement, with H23 (dt, J=12.0,
4.5 Hz) in 24 showing close agreement to the corresponding
spirangien value (dt, J=12.0, 4.7 Hz). In contrast, H23 in
the epimeric spiroacetal 25 appeared as a multiplet. By in-
ference, the previously performed Mosher ester analysis of
the aldol reaction outcome was also corroborated, as the
ratio of spiroacetal products favored 24.
With the full spiroacetal core in place, together with 12 of
the 14 stereocenters now introduced, suitable elaboration of
the C13 and C29 termini was necessary. For the introduction
of the C30–C31 trisubstituted double bond, it was envisaged
that displacement of a suitable leaving group at C29 with a
vinylic organometallic species would constitute a viable
strategy. To this end (Scheme 7), protection of the hydroxyl
groups of 24 as the corresponding TES ethers was followed
by cleavage of the PMB ether at C29 with DDQ to reveal
Scheme 8. Revised retrosynthetic analysis involving acyclic precursor 30.
approach would be to introduce the C30–C31 trisubstituted
alkene moiety prior to spiroacetalization, leading to the re-
vised acyclic precursor 30.
With this strategy evolution in mind, an efficient prepara-
tion of the new C23–C32 aldehyde fragment 31 for the aldol
coupling with ketone 11 was required. As shown in
Scheme 9, this started with oxidative cleavage of the PMB
ether of 17 with DDQ and conversion of the ensuing alcohol
into the corresponding primary iodide 32. Displacement of
ꢀ
Scheme 7. Attempted introduction of C30 C31 trisubstituted double
bond. a) TESOTf, 2,6-lutidine, CH2Cl2, ꢀ788C, 1 h; b) DDQ, CH2Cl2/
pH 7 buffer (10:1), 0!208C, 1 h; c) I2, PPh3, Et3N, imidazole, PhMe, 0!
208C, 3 h; d) (2E)-2-bromobutene, tBuLi, ꢀ788C; 27, THF, ꢀ78!08C,
1 h; DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoquinone
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Total Synthesis of (ꢀ)-Spirangien A
plexity of this aldol coupling, it
was gratifying to have formed
the desired product; however,
both the yield and selectivity
proved consistently moderate.
It therefore seemed appropriate
to investigate alternative reac-
tion conditons. Replacement of
the C20 TES ether of the
ketone coupling partner with a
more robust TBS ether was
evaluated, as were alternative
chiral boron enolates and Mu-
kaiyama-type
aldol
unions
(using a range of Lewis acids).
Unfortunately, in all cases ex-
amined poor yields or inferior
selectivities were obtained.
At this stage, with several op-
ꢀ
tions for C22 C23 bond forma-
tion having been investigated, it
was decided that the result of-
fered by the (ꢀ)-Ipc2BCl-medi-
ated aldol coupling presented
the most workable solution.
Consequently, the epimeric
mixture obtained by (ꢀ)-
Scheme 9. Revised C23–C29 aldehyde preparation, aldol coupling, and spiroacetalization. a) DDQ, CH2Cl2/
pH 7 buffer (10:1), 0!208C, 2 h; b) I2, PPh3, Et3N, imidazole, PhMe, 0!208C, 3 h; c) (2E)-2-bromobutene,
tBuLi, ꢀ1008C, 15 min; CuCN, Et2O, ꢀ78!ꢀ508C, 20 min; 32, Et2O, ꢀ50!208C, 6 h; d) TBAF, THF, 0!
208C, 1 h; e) Dess–Martin periodinane, NaHCO3, CH2Cl2, 208C, 1 h; f) (ꢀ)-Ipc2BCl, Et3N, Et2O, 0 8C, 1 h; 31,
ꢀ78!ꢀ308C, 2 h; 2. MeOH, pH 7 buffer, H2O2; g) Me3O·BF4, Proton Sponge, CH2Cl2, 0!208C, 2 h; h) CSA,
MeOH, 208C, 16 h.
this leaving group with the organolithium species generated
from (2E)-2-bromobutene (tBuLi, THF) was next per-
formed to afford the required alkene 33. In the absence of a
neighboring silyl ether, any competition from a retro-Brook-
type pathway was now negated, and the displacement reac-
tion proceeded as planned. While a small amount (ca. 20%)
of olefin side-product 34 corresponding to E2 elimination of
the iodide was observed in this reaction, this was conven-
iently removed by selective hydroboration of the product
mixture using 9-BBN, enabling the isolation of pure coupled
product 33. Whilst this two-step procedure proved conven-
ient and reliable on a small scale, an alternative procedure
that avoided any competing E2 elimination was clearly de-
sirable. In the event, the use of a CuCN-mediated displace-
ment reaction,[31] involving treatment of a solution of (2E)-
2-bromobutene with tert-butyllithium followed by transme-
talation to copper, was found to be superior. The desired
coupled product 33 was now formed exclusively, in a greatly
improved 98% yield, even when performed on a gram scale.
Cleavage of the TBS ether in 33 and Dess–Martin[24] period-
inane-mediated oxidation then completed the efficient prep-
aration of the C23–C32 aldehyde 31 (eight steps from 12,
47% overall, representing an improvement over our initial
report[12a]).
Ipc2BCl-mediated aldol coupling was transformed to the
corresponding methyl ethers 36 and 37 by treatment with
Meerweinꢁs salt and Proton Sponge[28] (87%). From here,
exposure of this mixture to CSA in MeOH at room temper-
ature generated the fully functionalized spiroacetals 38 and
39 in good yield (72%). Following chromatographic separa-
tion, strong evidence for the assigned stereochemistry was
provided by comparison with the NMR data for the previ-
ously synthesized spiroacetal core 24 of the spirangiens, and
with the natural product itself.[7]
Now, with the highly advanced spiroacetal 38 in hand,
completion of the diene degradation fragment 3 required in-
stallation of the C14 stereocenter and the truncated spiran-
gien side-chain (Scheme 10). Silylation of the hydroxyl
groups of 38 (TESOTf, 93%), followed by selective hydro-
boration of the disubstituted over the trisubstituted alkene
using 9-BBN, then generated the expected C14,C15-anti al-
cohol 40 cleanly (70%, >20:1 d.r.).[22,32] Subsequent Dess–
Martin periodinane-mediated oxidation gave aldehyde 41, in
readiness for installation of the (Z)-dienyl side-chain. Previ-
ous work on discodermolide[33] prompted initial examination
of a Nozaki–Hiyama/Peterson sequence using allyl silane 42.
However, complications pertaining to steric factors owing to
the conformational rigidity of 41 led to a low yield (25%) of
the targeted diene 43 and isolation of the undesired regioi-
someric side-product 44 (53%). An alternative procedure
was therefore sought and accordingly allyl boronate 45 was
employed,[34] which was obtained by modification of a
Roush protocol.[35] Treatment of aldehyde 41 with 45 (3m,
PhMe), followed by in situ KOH-mediated Peterson elimi-
Attention now turned to the union of fragments 31 and 11
by aldol coupling. Building upon previous experience,[27]
enolization of 11 with (ꢀ)-Ipc2BCl/Et3N in Et2O at 08C, fol-
lowed by addition of aldehyde 31, successfully generated the
corresponding epimeric aldol adducts 30 and 35, isolated as
an inseparable mixture (53%, ca. 2.5:1 d.r.). Given the com-
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599

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tive. As mentioned previously, concerns over the instability
and facile isomerization of the pentaene chromophore of
the spirangiens dictated the late-stage incorporation of the
side-chain onto a fully elaborated spiroacetal core.
As outlined in Scheme 11, we envisaged the rapid and ef-
ficient construction of the requisite pentaene moiety by se-
quential Stille[15] cross-coupling reactions at C11 C12 and
ꢀ
ꢀ
C5 C6, thus requiring the preparation of spiroacetal-con-
taining intermediate 5, bearing a truncated (Z)-vinyl iodide
side-chain, and a suitable stannyl tetraene partner 6. Further
disconnection of this tetraene revealed (Z)-vinyl iodide 7
and the bis-stannylated (1E, 3Z, 5E)-triene linker 8. Strate-
gically, it was recognized that the use of such a linker species
would offer welcome flexibility with regards to the order of
assembly of the full (4Z, 6E, 8Z, 10E, 12Z)-pentaene. A
Stille cross-coupling reaction between 7 and 8 to form tet-
raene 6 appeared to be the more straightforward and con-
vergent option, followed by a second Stille coupling to
attach the spiroacetal core of spirangien A. However, initial
formation of the spiroacetal-containing tetraene 46, fol-
lowed by attachment of the remaining C1–C5 unit 7 was rec-
ognized as a potentially viable alternative scenario. Owing
to the advanced nature of the spiroacetal-containing frag-
ment 5, we considered it prudent to prepare and employ a
suitable model system to gauge the relative merits of the
two proposed reaction sequences and enable the optimiza-
tion of the coupling conditions.
Scheme 10. Elaboration to spirangien diene (3). a) TESOTf, 2,6-lutidine,
CH2Cl2, ꢀ78!08C, 2 h; b) 1. 9-BBN, THF, 0!208C, 3 h; 2. MeOH,
NaOH, H2O2; c) Dess–Martin periodinane, NaHCO3, CH2Cl2, 208C, 1 h;
d) 1. 42, CrCl2, THF, 0!208C, 1 h; 2. KOH, MeOH, 0!208C, 16 h;
e) 1. 45, 4 ꢂ mol. sieves; 2. KOH, MeOH, 0!208C, 16 h; f) TBAF, THF,
0!208C, 3 h. TMS=trimethylsilyl.
In the degradation studies performed by Niggemann et al.
on spirangien A, the isolated C3 methoxy-bearing stereocen-
ter was assigned as having an S configuration.[7] Hence, it
nation of the ensuing anti-b-hydroxy silanes, now produced
only 43 (50%). Finally, global
deprotection of 43 with TBAF
completed the preparation of
the target C10–C32 diene deg-
radation fragment
3 (71%).
Gratifyingly, the spectroscopic
data (1H, 13C NMR and MS)
obtained for 1,3-diene 3 were in
complete accordance with that
reported for the corresponding
spirangien diene degradation
fragment.[7] Moreover, the mea-
20
sured specific rotation, ½aꢁD
=
+34 (c=0.04, MeOH), com-
pared to +33.1 (c=1.0,
MeOH), was also in agreement,
both in terms of magnitude and
sign, thereby leading to the
confident assignment of the ab-
solute configuration of the spi-
rangiens, as shown in structures
1 and 2 in Figure 1.
With the unambiguous as-
signment of the full configura-
tion now achieved, completion
of the total synthesis of spiran-
gien A became our next objec- Scheme 11. Retrosynthetic analysis of pentaene side-chain of spirangien A.
600
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ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2009, 4, 594 – 611

Total Synthesis of (ꢀ)-Spirangien A
was decided that the (Z)-vinyl iodide 7 required for con-
struction of the side chain should originate from dimethyl
(S)-malate (47), as shown in Scheme 12. Following a chemo-
Scheme 12. Preparation of (Z)-vinyl iodide 7 from dimethyl (S)-malate.
a) BH3·SMe2, THF, 0!208C; NaBH4, 0!208C, 1 h; b) TBSCl, imid., 0!
208C, 12 h; c) Me3O·BF4, Proton Sponge, CH2Cl2, 0!208C, 1 h;
d) TBAF, AcOH, THF, 0!208C; 16 h; e) (COCl)2, DMSO, Et3N,
CH2Cl2, ꢀ78!208C, 1 h; f) (Ph3PCH2I)+Iꢀ NaHMDS, HMPA, THF,
,
ꢀ100!208C, 1 h.
selective reduction of 47 (BH3·SMe2, cat. NaBH4),[36] the 1,2-
diol product was sequentially selectively silylated (TBSCl,
imidazole) and methylated with Meerweinꢁs reagent to
afford 48. Cleavage of the TBS ether provided alcohol 49
(88% from 47), where Swern oxidation led to the corre-
sponding aldehyde which was subjected to a Stork–Wittig[37]
olefination to generate the required (Z)-vinyl iodide 7 selec-
tively (53%, Z/E 19:1).
With the targeted iodide 7 now in hand, access to the bis-
stannylated triene linker 8 was required. This was obtained
in high geometric purity (>20:1, 68%) as the (1E, 3Z, 5E)-
isomer, according to the procedure of Brꢃckner and co-
workers[38] by a Z-selective, modified Julia olefination[39] be-
tween the benzothiazolylsulfone 50 and (E)-Bu3SnCH=
CHCHO (Scheme 13).
Scheme 13. Preparation of tetraene 6, model tetraene 52, and model pen-
taene 53. a) (E)-Bu3SnCH=CHCHO, KHMDS, THF, ꢀ78!208C, 16 h;
b) [Pd2ACHTNUGTRNEUNG(dba)3], Ph3As, DMF/THF (4:1), 208C, 16 h.
Encouraged by the positive results obtained thus far, we
returned our attention to the real system (Scheme 14). It
was clear that aldehyde 41, which had previously been effi-
ciently converted into degradation fragment 3, could equally
well serve as a precursor for the preparation of the required
coupling partner 5 for the assembly of spirangien A itself.
Hence, a Stork–Wittig[37] olefination of 41 using iodomethy-
lenetriphenyl phosphorane (generated using NaHMDS) in
THF/HMPA, followed by cleavage of the TES ethers using
CSA/MeOH, enabled the isolation of configurationally pure
iodide 5, in readiness for attachment of the C1–C11 side-
chain. Under analogous Pd-catalysis conditions to those em-
ployed previously, with strict exclusion of light and employ-
ing base-washed amberized glassware, bis-stannyl triene 8
was coupled with 5 to afford the desired tetraene 46 in 60%
yield. We were now poised to incorporate the remainder of
the side-chain, thus generating the corresponding methyl
ester 4 of spirangien A. Crucially, the Pd-catalyzed Stille re-
action of stannyl tetraene 6 with the corresponding (Z)-
vinyl iodide 5 afforded the desired product 4 in 65% yield.
The alternative coupling sequence between iodide 7 and
stannane 46 performed less well, leading to the formation of
4 in 42% yield. At this stage, spirangien A methyl ester was
isolated and submitted to careful HPLC purification. De-
With triene 8 in hand, it was now time to address the
preparation of the requisite tetraenes. Thus, a Stille cross-
coupling coupling between (Z)-vinyl iodide 7 and triene 8,
using catalytic [Pd2ACHTUNGTRENNUNG(dba)3] (5 mol%) and Ph3As (13 mol%)
in DMF/THF,[40] afforded the desired product 6 in 59%
yield. At this point, we elected to make use of (Z)-vinyl
iodide 51[41] as an appropriate model for the spiroacetal-con-
taining coupling fragment. Tetraene 52 was thus prepared in
60% yield under the same Pd-catalysis conditions, using 51
in combination with triene 8. With the targeted tetraenes 6
and 52 now in hand, the stage was set for the second Stille
reaction to afford the characteristic (4Z, 6E, 8Z, 10E, 12Z)-
pentaene moiety of the spirangiens. Under the same reac-
1
tion conditions ([Pd
N
tailed H and 13C NMR analysis of the so-obtained product
and (Z)-vinyl iodide 51 generated the desired pentaene 53
in 64% yield. In comparison, coupling between tetraene 52
and vinyl iodide 7 gave a 61% yield of 53. Necessarily, all of
these Stille coupling reactions were performed with the
strict exclusion of light to avoid undesired isomerization. In
this way, only minor traces (ꢂ10%) of geometric isomers
were evident by 1H and 13C NMR analysis.
and comparison with available literature data[7] for spiran-
gien A itself were then possible. Gratifyingly, other than
having the additional methyl signal, the NMR data for the
synthetic spirangien A methyl ester[42] was in good agree-
ment (see the Supporting Information for details), providing
a tantalizing glimpse of an eventual successful completion of
the total synthesis.
Chem. Asian J. 2009, 4, 594 – 611
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
601

I. Paterson et al.
FULL PAPERS
methyl ester. It is envisaged
that this completed total syn-
thesis will serve as an excellent
point from which to progress
SAR studies of the spirangiens,
and enable the determination
of the mechanism of action.
Notably, by suitable editing of
the pendant side-chain, poten-
tially more stable analogues
may be designed that retain the
associated potent antimitotic
activity.
Experimental Section
Scheme 14. Completion of the total synthesis of spirangien A (1). a) (Ph3PCH2I)+Iꢀ NaHMDS, HMPA, THF,
,
ꢀ78!208C, 1 h; b) CSA, MeOH, 208C, 16 h; c) [Pd
2ACHTUNGERTN(NUNG dba)3], Ph3As, DMF/THF (4:1), 208C, 16 h; d) KOH,
General procedures: See the Support-
ing Information for details of instru-
EtOH/H2O (2:1), 208C, 16 h.
mentation, purification of reagents
and solvents, and chromatography. All
Having secured the synthesis of spirangien A methyl
ester, the task still remained to identify suitable conditions
to hydrolyze to the corresponding acid, mindful of the need
to avoid isomerization of the delicate pentaene moiety.
After extensive experimentation,[43] optimal results were
achieved by treatment of ester 4 with KOH in aqueous
EtOH, which delivered the unstable[44] carboxylic acid 1
(85%). Notably, the spectroscopic data obtained for synthet-
ic 1 were in complete accordance with that reported for nat-
ural spirangien A.[7] Moreover, the measured specific rota-
tion, ½aꢁ2D0 =ꢀ17.5 (c=0.04, MeOH), compared to ꢀ19.4 (c=
1.0, MeOH), was also in agreement, both in terms of magni-
tude and sign, thereby validating the full configurational as-
signment of the spirangiens. Importantly, the methyl ester 4
was found to display much improved stability compared to
the natural product itself.
non-aqueous reactions were performed under an atmosphere of argon
using oven-dried apparatus and employing standard techniques for han-
dling air-sensitive materials.
Aldol adduct 14: To a solution of dicyclohexylboron chloride (20.0 mL,
91.4 mmol) in dry Et2O (80 mL) at 08C was added triethylamine
(14.4 mL, 104 mmol). Ketone (S)-13 (14.4 g, 60.9 mmol) in Et2O (40 mL)
was added by cannula and the reaction mixture was stirred at 08C for 1 h
before cooling to ꢀ788C. A solution of freshly distilled methacrolein
(10.1 mL, 122 mmol) in Et2O (40 mL) was added by cannula and stirring
was continued for 1 h before placing in the freezer overnight. The reac-
tion mixture was partitioned between Et2O (3ꢄ100 mL) and pH 7 buffer
(200 mL) and the organic extracts were concentrated in vacuo to give an
oil, which was then taken up in methanol (300 mL) and pH 7 buffer
(300 mL) and stirred at 08C. H2O2 (30% aqueous, 90 mL) was added
dropwise, and after stirring at room temperature for 2 h the mixture was
diluted with water and extracted with CH2Cl2 (3ꢄ200 mL). The com-
bined organics were washed with saturated aqueous Na2S2O3 (300 mL),
dried (MgSO4), and concentrated in vacuo. The resulting crude aldol
product was subjected to high-vacuum distillation (0.1 mm Hg/408C) to
remove excess cyclohexanol. Flash column chromatography (10!20%
EtOAc/hexanes) yielded aldol adduct 14 (15.7 g, 84%) as a colorless oil.
The characterization data for this compound was in agreement with that
reported.[16a]
Conclusions
Anti-diol 12: To a solution of aldol adduct 14 (9.40 g, 30.7 mmol) and
propionaldehyde (8.84 mL, 123 mmol) in THF (75 mL) at ꢀ108C was
added a solution of freshly prepared SmI2 (0.1m in THF, 61.4 mL,
6.14 mmol) dropwise. A color change of the SmI2 from deep blue to pale
yellow was observed. After 1.5 h at ꢀ108C the reaction was partitioned
between NaHCO3 (75 mL) and Et2O (3ꢄ100 mL). The combined organ-
ics were dried (MgSO4) and evaporated in vacuo to give crude ester. To a
solution of crude ester (11.2 g, 30.7 mmol) in MeOH (132 mL) and H2O
(13 mL) at room temperature was added K2CO3 (9.68 g, 61.4 mmol).
After stirring at room temperature for 5 h, the reaction was diluted with
H2O (100 mL) and extracted with CH2Cl2 (3ꢄ100 mL). The combined or-
ganics were dried (Na2SO4) and concentrated in vacuo to give diol 12
(9.46 g, quantitative). The characterization data for this compound was in
agreement with that reported.[16a]
In conclusion, we have completed the first total synthesis of
(ꢀ)-spirangien A, which proceeds in 18 steps and 2.0%
overall yield (via 6) from the readily available 1,3-diol 12.
This convergent and expedient strategy relies upon the use
of our boron aldol methodology and a common stereotetrad
building block, to rapidly assemble the spiroacetal core of
the spirangiens. Initially, efforts focussed on the preparation
of the advanced C10–C32 diene degradation fragement 3,
thereby enabling the assignment of the full configuration of
the spirangiens. With a confident assignment of stereochem-
istry achieved, the developed synthetic route served as a
secure platform from which to advance to the total synthesis
of spirangien A itself. Attachment of the delicate pentaene
side-chain was achieved by making use of Stork–Wittig ole-
fination and sequential Stille cross-coupling reactions with
the bis-stannyltriene linking unit 8, and subsequent hydroly-
sis of the initially formed (and more stable) spirangien
Triol 16: To a solution of diol 12 (750 mg, 2.43 mmol) in THF (25 mL) at
08C was added BH3·SMe2 (2m in THF, 3.65 mL, 7.30 mmol). The result-
ing solution was allowed to warm to room temperature and stirred at this
temperature for 3 h, before recooling to 08C. The reaction was quenched
by the addition of EtOH (19 mL), NaOH (10% aqueous, 21 mL), and
H2O2 (30% aqueous, 17 mL) and then stirred for 1 h. The phases were
separated and the aqueous phase was extracted with EtOAc (3ꢄ40 mL).
602
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ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2009, 4, 594 – 611

Total Synthesis of (ꢀ)-Spirangien A
The combined organics were dried (Na2SO4), concentrated in vacuo, and
purified by flash column chromatography (1!2% MeOH/CH2Cl2) to
yield desired syn-triol 16 (635 mg, 80%) and undesired anti-triol 16a
(111 mg, 14%) as colorless oils. Syn-triol 16: Rf 0.26 (100% EtOAc);
½aꢁ2D0 =+22.3 (c=5.47, CHCl3); IR (neat): n˜ =3361, 2965, 2934, 1613,
34.1, 33.7, 25.0, 23.7, 13.4, 12.2, 10.7 ppm; HRMS (ES+) calculated for
C21H34O5Na [M+Na+]: 389.2298, found: 389.2301.
Aldehyde 10: To a solution of alcohol 17a (25 mg, 68.2 mmol) in CH2Cl2
(1 mL) at room temperature was added NaHCO3 (46 mg, 0.54 mmol) fol-
lowed by Dess–Martin periodinane (116 mg, 0.27 mmol). The resulting
solution was stirred at room temperature for 1 h and then quenched by
the addition of hexanes (1.5 mL). The resulting suspension was filtered
through a silica plug (20% EtOAc/hexanes) to provide aldehyde 10
(24 mg, 96%), which was used directly. Rf 0.61 (20% EtOAc/hexanes);
½aꢁ2D0 =+15.7 (c=2.67, CHCl3); IR (neat): n˜ =1726, 1613, 1513, 1380,
1513, 1248 cmꢀ1 1H NMR (500 MHz, CDCl3): dH =7.23 (2H, d, J=
;
8.5 Hz, ArH), 6.87 (2H, d, J=8.6 Hz, ArH), 4.45 (2H, AB quartet, J=
2.5 Hz, OCH2Ar), 4.15 (1H, brs, OH27), 3.87 (1H, d, J=9.4 Hz, H27),
3.79 (3H, s, ArOCH3), 3.79–3.76 (1H, obs, H25), 3.72–3.63 (2H, m, H23a
and H23b), 3.41 (1H, dd, J=9.1, 4.0 Hz, H29a), 3.48 (1H, dd, J=9.1,
9.1 Hz, H29b), 3.33 (1H, brs, OH25), 2.66 (1H, brs, OH23), 2.03–1.96
(1H, m, H28), 1.86–1.79 (1H, m, H24), 1.76–1.69 (1H, m, H26), 0.97
(3H, d, J=7.2 Hz, Me24), 0.85 (3H, d, J=7.0 Hz, Me26), 0.77 ppm (3H,
d, J=6.8 Hz, Me28); 13C NMR (100 MHz, CDCl3): dC =159.4, 129.6,
129.4, 113.9, 76.7, 76.2, 75.8, 73.2, 67.7, 55.3, 35.7, 36.8, 35.7, 13.1, 9.8,
9.7 ppm; HRMS (ES+) calculated for C18H31O5 [M+H+]: 327.2166,
found: 327.2163. Anti-triol 16a: Rf 0.38 (100% EtOAc); ½aꢁ2D0 =+38.2
1223 cmꢀ1 1H NMR (400 MHz, CDCl3): dH =9.70 (1H, d, J=1.1 Hz,
;
CHO), 7.25 (2H, d, J=8.7 Hz, ArH), 6.87 (2H, d, J=8.7 Hz, ArH), 4.41
(2H, s, OCH2Ar), 3.80 (3H, s, ArOCH3), 3.75 (1H, dd, J=7.5, 3.3 Hz,
H25), 3.61 (1H, dd, J=10.8, 4.2 Hz, H27), 3.52 (1H, dd, J=8.7, 3.0 Hz,
H29a), 3.40 (1H, dd, J=8.7, 6.1 Hz, H29b), 2.41 (1H, qdd, J=7.5, 3.5,
1.2 Hz, H24), 1.96–1.88 (1H, m, H26), 1.88–1.78 (1H, m, H28), 1.31 (3H,
s, OCCATHGNUTREN(UNGN CH3)aACHTUGNTERNNUG(CH3)b), 1.25 (3H, s, OCAHCUTNGETRG(NNUN CH3)aCATHNUGTREN(NUGN CH3)b), 1.15 (3H, d, J=
(c=3.13, CHCl3); IR (neat): n˜ =3364, 2964, 2933, 1612, 1513, 1246 cmꢀ1
;
7.0 Hz, Me24), 0.94 (3H, d, J=6.8 Hz, Me28), 0.91 ppm (3H, d, J=
6.8 Hz, Me26); 13C NMR (100 MHz, CDCl3): dC =204.3, 159.0, 130.9,
129.1, 113.7, 100.9, 74.1, 72.9 72.0, 70.1, 55.2, 49.0, 34.5, 33.7, 24.6, 23.5,
13.4, 11.9, 7.9 ppm; HRMS (ES+) calculated for C21H32O5Na [M+Na+]:
387.2142, found: 387.2136.
1H NMR (500 MHz, CDCl3): dH =7.24 (2H, d, J=8.4 Hz, ArH), 6.90
(2H, d, J=8.6 Hz, ArH), 4.52 (1H, s, OH25), 4.45 (2H, AB quartet, J=
8.3 Hz, OCH2Ar), 4.46 (1H, s, OH27), 3.99–3.94 (1H, m, OH23), 3.91
(1H, d, J=9.0 Hz, H27), 3.81 (3H, s, ArOCH3), 3.70–3.66 (2H, m, H23a
and H23b), 3.59 (1H, dd, J=9.3, 4.0 Hz, H29a), 3.48–3.42 (2H, m, H29b
and H25), 2.09–1.97 (2H, m, H24 and H28), 1.84–1.76 (1H, m, H26), 1.08
(3H, d, J=7.1 Hz, Me26), 0.85 (3H, d, J=6.8 Hz, Me24 or Me28),
0.74 ppm (3H, d, J=6.9 Hz, Me24 or Me28); 13C NMR (100 MHz,
CDCl3): dC =159.5, 129.5, 129.3, 114.0, 84.1, 76.7, 76.6, 73.4, 69.6, 55.3,
38.0, 35.5, 34.5, 13.7, 12.7, 10.5 ppm; HRMS (ES+) calculated for
C18H31O5 [M+H+]: 327.2166, found: 327.2168.
Acetonide 12a: To a solution of diol 12 (2.00 g, 6.49 mmol) in CH2Cl2
(16 mL) at room temperature was added dimethoxypropane (14.1 mL,
115 mmol) followed by PPTS (163 mg, 0.06 mmol). The resulting solution
was stirred at room temperature overnight before quenching by addition
of saturated aqueous NaHCO3 (20 mL). The phases were separated and
the aqueous phase was extracted with CH2Cl2 (3ꢄ15 mL). The combined
organics were dried (Na2SO4), concentrated in vacuo, and purified by
flash column chromatography (10% EtOAc/40-60 petroleum ether) to
yield acetonide 12a (2.24 g, 99%) as a colorless oil. Rf 0.76 (30%
EtOAc/40-60 petroleum ether); ½aꢁ2D0 =+24.0 (c=1.67, CHCl3); IR (neat):
TBS ether 16b: To a solution of triol 16 (881 mg, 2.70 mmol) in CH2Cl2
(17 mL) at room temperature was added imidazole (239 mg, 3.51 mmol),
followed by tert-butyldimethylsilyl chloride (448 mg, 2.97 mmol). The re-
sulting solution was stirred at room temperature for 1 h and then
quenched by the addition of saturated aqueous NaHCO3 (20 mL). The
phases were separated and the aqueous phase was extracted with CH2Cl2
(3ꢄ10 mL). The combined organics were dried (Na2SO4), concentrated in
vacuo, and purified by flash column chromatography (10% EtOAc/hex-
anes) to yield TBS ether 16b (1.11 g, 93%) as a colorless oil. The data
for this compound was in agreement with that reported.[45]
n˜ =1614, 1512, 1378, 1246 cmꢀ1 1H NMR (500 MHz, CDCl3): dH =7.26
;
(2H, d, J=8.7 Hz, ArH), 6.88 (2H, d, J=8.8 Hz, ArH), 4.94 (1H, s,
H13a), 4.84 (1H, s, H13b), 4.42 (2H, s, OCH2Ar), 3.81 (3H, s, ArOCH3),
3.72–3.67 (2H, m, H17 and H15), 3.55 (1H, dd, J=8.5, 3.2 Hz, H19a),
3.41 (1H, dd, J=8.4, 5.8 Hz, H19b), 1.92–1.82 (2H, m, H16 and H18),
1.77 (3H, s, Me14), 1.36 (3H, s, OC
(CH3)aA
C
aACHTUNGTREN(NUNG CH3)b), 1.31 (3H, s, OC-
A
CHTUNGTRENNUNG
Acetonide 17: To a solution of diol 16b (741 mg, 1.68 mmol) in CH2Cl2
(12 mL) at room temperature was added dimethoxypropane (4.14 mL,
33.7 mmol) followed by PPTS (42 mg, 0.17 mmol). The resulting solution
was stirred at room temperature overnight before quenching by the addi-
tion of saturated aqueous NaHCO3 (15 mL). The phases were separated
and the aqueous phase was extracted with CH2Cl2 (3ꢄ10 mL). The com-
bined organics were dried (Na2SO4), concentrated in vacuo, and purified
by flash column chromatography (10% EtOAc/hexanes) to yield aceto-
nide 17 (771 mg, 96%) as a colorless oil. The data for this compound was
in agreement with that reported.[45]
Alcohol 12b: To a solution of PMB ether 12a (670 mg, 1.92 mmol) in
CH2Cl2 (60 mL) and pH 7 buffer (8 mL) at 08C was added DDQ
(524 mg, 2.31 mmol). The resulting solution was allowed to warm to
room temperature and stirred for 30 min before being quenched by the
addition of saturated aqueous NaHCO3 (80 mL). The phases were sepa-
rated and the aqueous phase was extracted with CH2Cl2 (3ꢄ50 mL). The
combined organics were washed (H2O), dried (Na2SO4), concentrated in
vacuo, and purified by flash column chromatography (10% EtOAc/tolu-
ene) to yield alcohol 12b (437 mg, 99%) as a colorless oil. Rf 0.28 (30%
EtOAc/40-60 petroleum ether); ½aꢁ2D0 =+58.8 (c=1.20, CHCl3); IR (neat):
Alcohol 17a: To a solution of TBS ether 17 (674 mg, 1.40 mmol) in THF
(20 mL) at 08C was added TBAF (1m in THF, 2.81 mL, 2.81 mmol). The
resulting solution was allowed to warm to room temperature, stirred for
2 h, and then quenched by the addition of saturated aqueous NH4Cl
(20 mL). The phases were separated and the aqueous phase was extract-
ed with CH2Cl2 (3ꢄ15 mL). The combined organics were dried (Na2SO4),
concentrated in vacuo, and purified by flash column chromatography
(30!40% EtOAc/hexanes) to yield alcohol 17a (500 mg, 98%) as a pale
yellow oil. Rf 0.29 (20% EtOAc/hexanes); ½aꢁ2D0 =+1.2 (c=1.40, CHCl3);
n˜ =3486, 1381, 1216, 1018 cmꢀ1 1H NMR (500 MHz, CDCl3): dH =4.94
;
(1H, s, H13a), 4.84 (1H, s, H13b), 3.73 (1H, d, J=6.8 Hz, H15), 3.71
(1H, dd, J=9.4, 4.2 Hz, H17), 3.62–3.57 (1H, m, H19a), 3.56–3.50 (1H,
m, H19b), 3.14 (1H, dd, J=9.8, 1.6 Hz, OH), 1.96–1.86 (2H, m, H16 and
H18), 1.77 (3H, s, Me14), 1.41 (3H, s, OC
ACHTUNTGRNENGU(CH3)aAHCTUNGTREN(NUGN CH3)b), 1.37 (3H, s,
IR (neat): n˜ =3419, 1613, 1514, 1379, 1267 cmꢀ1 1H NMR (400 MHz,
;
OC(CH3)aAHCTNUTGREG(NUNN CH3)b), 0.92 (3H, d, J=6.8 Hz, Me18), 0.78 ppm (3H, d, J=
N
6.9 Hz, Me16); 13C NMR (100 MHz, CDCl3): dC =144.0, 112.1, 100.9,
79.0, 75.8, 68.9, 36.0, 35.2, 25.1, 23.8, 17.9, 12.7, 11.8 ppm; HRMS (ES+)
calculated for C13H25O3 [M+H+]: 229.1798, found: 229.1796.
CDCl3): dH =7.27 (2H, d, J=8.9 Hz, ArH), 6.89 (2H, d, J=8.7 Hz,
ArH), 4.43 (2H, s, OCH2Ar), 3.82 (3H, s, ArOCH3), 3.72–3.62 (2H, m,
H29a and H29b), 3.62 (1H, dd, J=11.0, 4.2 Hz, H27), 3.55 (1H, dd, J=
8.7, 3.0 Hz, H23a), 3.51 (1H, dd, J=7.3, 3.0 Hz, H25), 3.41 (1H, dd, J=
8.7, 6.3 Hz, H23b), 2.46 (1H, brs, OH), 1.96–1.89 (1H, m, H26), 1.88–
Iodide 18: To a solution of alcohol 12b (983 mg, 4.31 mmol) in toluene
(25 mL) at room temperature was added triphenylphosphine (1.36 g,
5.17 mmol), followed by triethylamine (0.72 mL, 5.17 mmol). The result-
ing solution was cooled to 08C and a solution of iodine (1.31 g,
5.17 mmol) in toluene (25 mL) was added slowly by cannula. After
5 min, imidazole (ca. 20 mg, catalytic) was added and the solution was al-
1.80 (2H, m, H24 and H28), 1.35 (3H, s, OC
aA
Me24), 0.89 ppm (3H, d, J=6.6 Hz, Me26); 13C NMR (100 MHz, CDCl3):
dC =159.0, 131.0, 129.1, 113.4, 100.7, 77.9, 72.9, 72.1 70.3, 67.1, 55.3, 37.7,
ACHTUNTGRNENGU(CH3)aAHCTUNGTREN(NUGN CH3)b), 1.29 (3H, s,
(CH3)b), 0.99 (3H, d, J=7.0 Hz, Me28), 0.97 (3H, d, J=7.0 Hz,
OC
(CH3)
G
Chem. Asian J. 2009, 4, 594 – 611
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
603

I. Paterson et al.
FULL PAPERS
lowed to warm to room temperature. After stirring at this temperature
for 2 h the reaction was quenched by partitioning between Et2O and
H2O. The phases were separated and the aqueous phase was extracted
with Et2O (3ꢄ80 mL). The combined organics were dried (Na2SO4), con-
centrated in vacuo, and purified by flash column chromatography (10%
EtOAc/40-60 petroleum ether) to yield iodide 18 (1.33 g, 95%) as a col-
orless oil. Rf 0.68 (30% EtOAc/40-60 petroleum ether); ½aꢁ2D0 =+15.8 (c=
4.92 (1H, s H13a), 4.83 (1H, s, H13b), 4.10 (1H, dd, J=9.5, 4.0 Hz, H20),
3.68 (1H, d, J=7.2 Hz, H15), 3.36 (1H, dd, J=10.6, 4.4 Hz, H17), 2.16
(3H, s, Me22), 2.07 (1H, ddd, J=12.9, 9.4, 2.8 Hz, H19a), 1.92–1.85 (1H,
m, H16), 1.79–1.72 (1H, obs, H18), 1.76 (3H, s, Me14), 1.34 (3H, s, OC-
A
aACHTUNGTNERNU(GN CH3)b), 1.29 (1H, s, OCACHUTNRTEG(NNU CH3)aACUTNGHTR(NEUNNG CH3)b), 1.10 (1H, ddd, J=13.6,
AHCTUNGTRENNUNG
3.50, CHCl3); IR (neat): n˜ =2984, 1456, 1377, 1223 cmꢀ1
;
1H NMR
ACHTUNGTRENNUNG
(500 MHz, CDCl3): dH =4.94 (1H, s, H13a), 4.85 (1H, s, H13b), 3.70 (1H,
d, J=7.3 Hz, H15), 3.49 (1H, dd, J=10.3, 4.3 Hz, H17), 3.43 (1H, dd, J=
9.5, 3.2 Hz, H19a), 3.38 (1H, dd, J=9.6, 5.4 Hz, H19b), 1.93–1.86 (1H, m,
H16), 1.78 (3H, s, Me14), 1.47–1.43 (1H, m, H18), 1.42 (3H, s, OC-
100.7, 79.1, 73.2, 37.9, 36.1, 28.9, 24.9, 24.7, 23.8, 18.0, 15.4, 11.7, 6.7, 4.9,
4.8 ppm; HRMS (ES+) calculated for C22H46O4SiN [M+NH4]+: 416.3191,
found: 416.3189.
Aldol adducts
9
and 21: To
a
solution of (ꢀ)-Ipc2BCl (202 mg,
ACHTUNGTRENNUNG(CH3)aACHTUNGTRENNUNG(CH3)b), 1.36 (3H, s, OCACHTUNGETRNN(GNU CH3)aACHTNGURTEN(NUGN CH3)b), 0.94 (3H, d, J=4.3 Hz,
0.63 mmol) [dried by stirring under vacuum (1 mm Hg) at room tempera-
ture for 1.5 h] in Et2O (3 mL) at 08C was added triethylamine (110 mL,
0.79 mmol), followed by ketone 11 (157 mg, 0.39 mmol) in Et2O (3 mL)
by cannula. The reaction mixture was stirred for 1 h, cooled to ꢀ788C,
and a solution of aldehyde 10 (110 mg, 0.30 mmol) in Et2O (3 mL) was
then added by cannula. After 1 h at ꢀ788C and 16 h at ꢀ278C, the reac-
tion mixture was quenched by the addition of pH 7 buffer (4 mL),
MeOH (4 mL), and H2O2 (30% aqueous, 2 mL). After allowing to warm
to room temperature and stirring for 1 h, the phases were separated and
the aqueous phase was extracted with CH2Cl2 (3ꢄ5 mL). The combined
organics were washed with brine (10 mL), dried (Na2SO4), concentrated
in vacuo, and purified by flash column chromatography (20% EtOAc/
hexanes) to yield aldol adducts 9 and 21 (148 mg 65%, ca. 2.5:1 d.r. by
1H NMR analysis) as an inseparable mixture. Major diastereomer 9: Rf
0.16 (10% EtOAc/40-60 petroleum ether); IR (neat): n˜ =3504, 1713,
Me16 or Me18), 0.92 ppm (3H, d, J=4.6 Hz, Me16 or Me18); 13C NMR
(100 MHz, CDCl3): dC =144.0, 112.1, 100.9, 79.0, 75.8, 68.9, 36.0, 35.2,
25.1, 23.8, 17.9, 12.7, 11.8 ppm; HRMS (ES+) calculated for C13H24IO2
[M+H+]: 339.0815, found: 339.0817.
Ketone 20: To a suspension of LiCl (1.97 g, 46.5 mmol, weighed in glove
box and flame dried prior to use) in THF (30 mL) at room temperature
was added diisopropylamine (6.95 mL, 49.6 mmol). The resulting suspen-
sion was cooled to ꢀ788C and n-butyllithium (1.6m in hexanes, 29.1 mL,
46.5 mmol) was added. The solution was allowed to warm to 08C briefly
and then recooled to ꢀ788C. An ice-cooled solution of amide 19 (3.46 g,
15.5 mmol) in THF (15 mL) was added by cannula and the mixture was
stirred at ꢀ788C for 1 h, at 08C for 15 min, and at room temperature for
5 min before recooling to 08C.
A solution of iodide 18 (1.31 g,
3.87 mmol) in THF (11 mL) was added by cannula and the resulting solu-
tion was allowed to warm to room temperature and was stirred at this
temperature for 16 h. The reaction was quenched with saturated aqueous
NH4Cl (100 mL) and the phases were separated. The aqueous phase was
extracted with EtOAc (4ꢄ50 mL). The combined organics were dried
(Na2SO4), concentrated in vacuo, and purified by flash column chroma-
tography (1% Et3N in EtOAc) to yield amide 18a (1.55 g, 93%) as a col-
orless oil. To a solution of amide 18a (azeotroped from toluene twice
before use) (100 mg, 0.23 mmol) in THF (3 mL) at ꢀ788C was added
methyllithium (1.6m in hexanes, 0.43 mL, 0.70 mmol). The mixture was
allowed to warm to 08C and held at this temperature for 10 min. Excess
methyllithium was quenched at 08C by the addition of diisopropylamine
(32 mL, 0.23 mmol). After 15 min, a solution of acetic acid in Et2O (10%
v/v, 3 mL) was added. The mixture was partitioned between EtOAc
(4 mL) and saturated aqueous NaHCO3 (4 mL) and the organic phase
was separated and extracted with saturated aqueous NaHCO3 (4 mL)
and H2O (4 mL). The organic phase was dried (Na2SO4), concentrated in
vacuo, and purified by flash column chromatography (30% EtOAc/40-60
petroleum ether) to yield ketone 20 (56 mg, 86%) as a colorless oil. Rf
0.23 (20% EtOAc/40-60 petroleum ether); ½aꢁ2D0 =+80.0 (c=1.10,
1614, 1514, 1378, 1224, 1018 cmꢀ1 1H NMR (500 MHz, CDCl3): dH =7.25
;
(2H, d, J=8.6 ArH), 6.87 (2H, d, J=8.6 Hz, ArH), 4.93 (1H, s, H13a),
4.84 (1H, s, H13b), 4.41 (2H, s, OCH2Ar), 4.19–4.10 (1H, m, H20), 4.06–
3.99 (1H, m, H23), 3.80 (3H, s, ArOCH3), 3.69 (1H, d, J=7.3 Hz, H15),
3.66 (1H, dd, J=7.6, 1.6 Hz, H25), 3.60–3.56 (1H, m, H27), 3.54–3.49
(1H, m, H29a), 3.42–3.34 (2H, m, H17 and H29b), 3.29 (1H, brs, OH),
2.75 (2H, d, J=6.4 Hz, H22a and H22b), 2.11–2.02 (1H, m, H19a), 1.94–
1.79 (4H, m, H16, H18, H26, and H28), 1.76 (3H, s, Me14), 1.67–1.60
(1H, m, H24), 1.34 (6H, s, 2ꢄOC
(CH3)b), 1.25 (3H, s, OC(CH3)aA(CH3)b), 1.19–1.14 (1H, m, H19b), 0.99–
0.92 (15H, m, Me24, Me28, and Si(CH2CH3)3), 0.87 (3H, d, J=6.9 Hz,
Me16), 0.86 (3H, d, J=7.1 Hz, Me18), 0.85 (3H, d, J=6.5 Hz, Me26),
0.62 ppm (6H, q, J=7.9 Hz, Si
(CH2CH3)3); 13C NMR (125 MHz, CDCl3):
ACHTGNUERTN(GNUN CH3)aACHTUNRTGEG(NUNN CH3)b), 1.29 (3H, s, OCACHTUNGTRENNUNG(CH3)a-
A
R
CHTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
dC =214.7, 159.0, 144.4, 131.0, 129.2, 113.7, 111.8, 100.7, 100.7, 79.2, 78.3,
74.3, 73.2, 72.9, 70.3, 70.0, 55.3, 42.3, 41.7, 40.4, 39.5, 37.9, 36.1, 35.1, 34.8,
33.8, 33.7, 29.1, 23.8, 18.0, 15.5, 15.3, 13.5, 13.4, 11.8, 10.3, 6.8, 4.9 ppm;
HRMS (ES+) calculated for C43H74O9SiNa [M+Na+]: 785.4994, found:
785.4983. Minor diastereomer 21: Rf 0.16 (10% EtOAc/40-60 petroleum
ether); 1H NMR (500 MHz, CDCl3): dH =7.25 (2H, d, J=8.7 ArH), 6.87
(2H, d, J=8.7 Hz, ArH), 4.93 (1H, s, H13a), 4.84 (1H, s, H13b), 4.41
(2H, s, OCH2Ar), 4.22 (1H, td, J=6.4, 2.8 Hz, H23), 4.14 (1H, dd, J=
9.4, 3.7 Hz, H20), 3.80 (3H, s, ArOCH3), 3.69 (1H, d, J=7.3 Hz, H15),
3.58 (1H, dd, J=10.8, 4.3 Hz, H27), 3.54–3.49 (2H, m, H25 and H29a),
3.43–3.35 (2H, m, H17 and H29b), 3.28 (1H, brs, OH), 2.75 (2H, d, J=
6.5 Hz, H22a and H22b), 2.10–2.03 (1H, m, H19a), 1.92–1.79 (3H, m,
H16, H26, and H28), 1.76 (3H, s, Me14), 1.67–1.60 (1H, m, H18), 1.60–
CHCl3); IR (neat): n˜ =3470, 1714, 1458, 1378, 1223, 1082 cmꢀ1 1H NMR
;
(500 MHz, CDCl3): dH =4.94 (1H, s, H13a), 4.85 (1H, s, H13b), 4.22–4.17
(1H, m, H20), 3.80 (1H, d, J=4.5 Hz, OH20), 3.71 (1H, d, J=7.5 Hz,
H15), 3.44 (1H, dd, J=10.6, 4.4 Hz, H17), 2.22 (3H, s, Me22), 1.96–1.90
(1H, m, H16), 1.91–1.87 (1H, m, H19a), 1.85 (1H, dd, J=11.1, 3.2 Hz,
H18), 1.78 (3H, s, Me14), 1.51–1.45 (1H, m, H19b), 1.37 (3H, s, O
(CH3)b), 1.34 (3H, s, O(CH3)aA
ACHTUNGTRENNUNG
N
N
CHTUNGTRENNUNG
0.90 ppm (3H, d, J=6.9 Hz, Me16); 13C NMR (100 MHz, CDCl3): dC =
211.0, 144.2, 111.9, 100.9, 79.2, 75.9, 73.5, 37.4, 36.1, 30.4, 25.3, 24.9, 23.8,
18.0, 16.0, 11.8 ppm; HRMS (ES+) calculated for C16H29O4 [M+H+]:
285.2060, found: 285.2063.
1.52 (1H, m, H24), 1.35 (3H, s, OC
(CH3)aA(CH3)b), 1.29 (3H, s, OC(CH3)aA
(CH3)b), 1.18–1.12 (1H, m, H19b), 0.99–0.95 (12H, m, Me24 and Si-
(CH2CH3)3), 0.94 (3H, d, J=6.9 Hz, Me28), 0.87 (3H, d, J=6.8 Hz,
Me16), 0.87 (3H, d, J=7.1 Hz, Me18), 0.85 (3H, d, J=6.8 Hz, Me26),
0.62 ppm (6H, q, J=7.9 Hz, Si(CH2CH3)3).
A
(CH3)b), 1.34 (3H, s, OC-
A
E
E
N
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
Ketone 11: To a solution of alcohol 20 (389 mg, 1.37 mmol) in CH2Cl2
(25 mL) at ꢀ788C was added 2,6-lutidine (0.64 mL, 5.47 mmol). The re-
action mixture was stirred at ꢀ788C for 10 min before triethylsilyl tri-
fluoromethanesulfonate (0.93 mL, 4.10 mmol) was added. The reaction
mixture was stirred at ꢀ788C for 30 min and then quenched by the addi-
tion of saturated aqueous NH4Cl (30 mL). The phases were separated
and the aqueous phase was extracted with CH2Cl2 (3ꢄ25 mL). The com-
bined organic phases were dried (MgSO4), concentrated in vacuo, and
purified by flash column chromatography (10% EtOAc/40-60 petroleum
ether) to yield ketone 11 (546 mg, 99%) as a colorless oil. Rf 0.63 (20%
EtOAc/40-60 petroleum ether); ½aꢁ2D0 =+4.5 (c=1.75, CHCl3); IR (neat):
AHCTUNGTRENNUNG
Methyl ethers 22 and 23: To a solution of alcohols 9 and 21 (148 mg,
0.19 mmol) in CH2Cl2 (18 mL) at 08C was added Proton Sponge (250 mg,
1.16 mmol) followed by trimethyloxonium tetrafluoroborate (114 mg,
0.78 mmol). The resulting solution was strirred at room temperature for
1 h and quenched by the addition of saturated aqueous NaHCO3
(20 mL). The phases were separated and the aqueous phase was extract-
ed with CH2Cl2 (3ꢄ20 mL). The combined organic phases were washed
with citric acid (10% weight solution, 40 mL), dried (Na2SO4), concen-
trated in vacuo, and purified by flash column chromatography (15%
EtOAc/hexanes) to yield methyl ethers 22 and 23 (125 mg, 83%, ca. 2:1
n˜ =1717, 1458, 1377, 1223, 1083 cmꢀ1 1H NMR (500 MHz, CDCl3): dH =
;
604
www.chemasianj.org
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2009, 4, 594 – 611

Total Synthesis of (ꢀ)-Spirangien A
d.r. by 1H NMR analysis) as an inseparable mixture. Major diastereomer
stirred at ꢀ788C for 1 h and then quenched by the addition of saturated
aqueous NH4Cl (4 mL). The phases were separated and the aqueous
phase was extracted with CH2Cl2 (3ꢄ5 mL). The combined organic
phases were dried (Na2SO4), concentrated in vacuo, and purified by flash
22: Rf 0.30 (10% EtOAc/40-60 petroleum ether); IR (neat): n˜ =1718,
1513, 1458, 1378, 1223, 1091 cmꢀ1 1H NMR (500 MHz, CDCl3): dH =7.25
;
(2H, d, J=8.4 Hz, ArH), 6.87 (2H, d, J=8.7 Hz, ArH), 4.93 (1H, s,
H13a), 4.84 (1H, s, H13b), 4.41 (2H, s, OCH2Ar), 4.20–4.13 (1H, m,
H20), 3.80 (3H, s, ArOCH3), 3.77–3.71 (1H, m, H23), 3.69 (1H, d, J=
7.5 Hz, H15), 3.59–3.49 (2H, m, H25 and H29a), 3.43–3.33 (3H, m, H17,
H27, and H29b), 3.28 (3H, s, OMe), 2.84 (1H, dd, J=17.5, 9.3 Hz,
H22a), 2.67 (1H, dd, J=17.6, 4.0 Hz, H22b), 2.13–2.00 (1H, m, H19a),
1.93–1.86 (1H, m, H16), 1.85–1.78 (4H, m, H18, H24, H26, and H28),
column chromatography (5% EtOAc/hexanes) to yield TES-protected
20
spiroacetal 24a (18 mg, 94%). Rf 0.71 (10% EtOAc/hexanes); ½aꢁD
=
+22.6 (c=0.25, CHCl3); IR (neat): n˜ =1514, 1458, 1246, 1087, 1002 cmꢀ1
;
1H NMR (500 MHz, CD3OD): dH =7.27 (2H, d, J=8.8 Hz, ArH), 6.91
(2H, d, J=8.6 Hz, ArH), 4.98 (1H, s, H13a), 4.79 (1H, s, H13b), 4.45
(2H, AB quartet, J=3.6 Hz, OCH2Ar), 4.20 (1H, d, J=4.8 Hz, H15),
3.99 (1H, m, H27), 3.82 (3H, s, ArOCH3), 3.68 (1H, m, H23), 3.59 (2H,
m, H25 and H29a), 3.48 (1H, m, H20), 3.35 (3H, s, OMe), 3.32 (1H, obs,
H17), 3.20 (1H, dd, J=9.2, 7.7 Hz, H29b), 2.29 (1H, m, H28), 2.07 (3H,
m, H16, H18, and H24), 2.02 (1H, dd, J=12.5, 4.4 Hz, H22a), 1.91 (1H,
m, H26), 1.83 (3H, s, Me14), 1.80 (1H, obs, H19a), 1.41 (1H, ddd, J=
13.9, 3.7, 3.6 Hz, H19b), 1.40 (1H, dd, J=12.5, 12.2 Hz, H22b), 1.10 (3H,
1.77 (3H, s, Me14), 1.35 (3H, s, OC
(CH3)aA(CH3)b), 1.25 (3H, s, OC(CH3)aA
(CH3)b), 1.17–1.10 (1H, m, H19b), 0.96 (9H, t, J=7.8 Hz, Si
0.91 (3H, d, J=7.0 Hz, Me24), 0.89–0.83 (12H, m, Me16, Me18, Me26,
and Me28), 0.61 ppm (6H, q, J=7.9 Hz, Si
(CH2CH3)3); 13C NMR
A
(CH3)b), 1.29 (3H, s, OC-
A
E
E
N
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
(125 MHz, CDCl3): dC =212.4, 159.0, 144.4, 131.0, 129.2, 113.6, 111.8,
100.7, 100.7, 79.5, 79.2, 75.0, 73.2, 73.1, 72.2, 70.2, 57.7, 55.3, 40.1, 39.1,
38.7, 38.6, 37.6, 37.4, 36.1, 35.7, 33.8, 29.1, 24.7, 23.8, 23.5, 18.0, 15.2, 13.4,
11.7, 10.0, 8.4, 6.8, 4.9 ppm; HRMS (ES+) calculated for C44H76O9SiNa
[M+Na+]: 799.5151, found: 799.5114.
d, J=7.1 Hz, Me28), 1.02 (27H, t, J=8.2 Hz, 3ꢄSi
d, J=7.0 Hz, Me26), 0.80 (3H, d, J=6.6 Hz, Me18), 0.73 (6H, m, Me16
and Me24), 0.65 ppm (18H, q, J=7.6 Hz, 3ꢄSi
(CH2CH3)3); 13C NMR
ACHTNUGTRNEN(UGN CH2CH3)3), 0.85 (3H,
AHCTUNGTRENNUNG
(125 MHz, CD3OD): dC =160.7, 149.5, 131.9, 130.1, 114.7, 113.8, 99.7,
81.5, 77.7, 76.8, 76.8, 76.2, 73.5, 73.0, 71.7, 55.7, 55.4, 43.0, 41.9, 38.3, 36.5,
34.3, 33.5, 25.8, 20.1, 18.6, 15.9, 13.2, 9.3, 7.7, 7.4, 7.3, 7.0, 6.0, 5.9,
4.4 ppm; HRMS (ES+) calculated for C50H94O8Si3 [M+Na+]: 929.6149,
found: 929.6176.
Spiroacetals 24 and 25: To a solution of ketones 22 and 23 (126 mg,
162 mmol) in MeOH (5 mL) at room temperature was added CSA
(3.9 mg, 16.2 mmol). After stirring at room temperature for 16 h the reac-
tion was quenched by addition of saturated aqueous NaHCO3. The
phases were separated and the aqueous phase was extracted with CH2Cl2
(3ꢄ10 mL). The combined organic phases were dried (Na2SO4), concen-
trated in vacuo, and purified by flash column chromatography (10!40%
EtOAc/hexanes) to yield spiroacetals 24 (47 mg, 51%) and 25 (12 mg,
13%). Spiroacetal 24: Rf 0.11 (30% EtOAc/hexanes); ½aꢁ2D0 =+10.0 (c=
Alcohol 26: To a solution of PMB ether 24a (5 mg, 5.5 mmol) in CH2Cl2
(400 mL) and pH 7 buffer (40 mL) at 08C was added DDQ (1.5 mg,
6.6 mmol). The resulting solution was stirred at room temperature for 2 h
and then quenched by the addition of saturated aqueous NaHCO3
(1 mL). The phases were separated and the aqueous phase was extracted
with CH2Cl2 (3ꢄ2 mL). The combined organics were washed (H2O),
dried (Na2SO4), concentrated in vacuo, and purified by flash column
chromatography (5% EtOAc/hexanes) to yield alcohol 26 (3.5 mg, 80%)
as a colorless oil. Rf 0.53 (10% EtOAc/hexanes); ½aꢁ2D0 =+23.4 (c=0.35,
0.69, MeOH); IR (neat): n˜ =3407, 1614, 1514, 1456, 1247 cmꢀ1 1H NMR
;
(500 MHz, CD3OD): dH =7.30 (2H, d, J=8.7 Hz, ArH), 6.92 (2H, d, J=
8.7 Hz, ArH), 4.93 (1H, s, H13a), 4.91 (1H, s, H13b), 4.49 (2H, s,
OCH2Ar), 4.14 (1H, d, J=9.5 Hz, H15), 4.06 (1H, d, J=9.9 Hz, H27),
3.82 (3H, s, ArOCH3), 3.76 (1H, dd, J=10.4, 2.0 Hz, H25), 3.72 (1H,
app. dt, J=12.0, 4.5 Hz, H23), 3.66 (1H, dd, J=8.9, 4.0 Hz, H29a), 3.60
(1H, dd, J=10.4, 1.9 Hz, H17), 3.56 (1H, dd, J=9.2, 5.9 Hz, H29b), 3.44
(1H, t, J=2.9 Hz, H20), 3.38 (3H, s, OMe), 2.19 (1H, m, H24), 2.08 (1H,
dd, J=13.0, 4.8 Hz, H22a), 1.97 (1H, m, H18), 1.88 (1H, m, H28), 1.83
(1H, m, H26), 1.81 (1H, m, H16), 1.79 (1H, dd, J=6.4, 2.5 Hz, H19a),
1.74 (3H, s, Me14), 1.65 (1H, dt, J=13.3, 3.6, 3.6 Hz. H19b), 1.40 (1H,
dd, J=12.5, 12.5 Hz, H22b), 0.94 (3H, d, J=7.0 Hz, Me28), 0.83 (3H, d,
J=7.2 Hz, Me26), 0.81 (3H, d, J=7.0 Hz, Me24), 0.77 (3H, d, J=7.0 Hz,
Me16), 0.74 (3H, d, J=6.5 Hz, Me18); 13C NMR (125 MHz, CD3OD):
dC =160.7, 147.7, 132.0, 130.2, 114.7, 114.3, 99.5, 78.9, 78.4, 74.9, 74.0,
73.8, 72.8, 71.9, 70.9, 55.7, 55.5, 37.8, 37.8, 37.4, 37.2, 33.8, 32.9, 25.9, 17.6,
16.2, 14.7, 9.6, 7.7, 4.0 ppm; HRMS (ES+) calculated for C32H52O8Na
[M+Na+]: 587.3554, found: 587.3552. Spiroacetal 25: Rf 0.07 (30%
EtOAc/hexanes); ½aꢁ2D0 =+34.6 (c=0.46, MeOH); IR (neat): n˜ =3415,
CHCl3); IR (neat): n˜ =3482, 1459, 1381, 1232 cmꢀ1 1H NMR (500 MHz,
;
CD3OD): dH =4.90 (2H, obs, H13a and H13b), 4.23 (1H, d, J=5.0 Hz,
H27), 4.00 (1H, dd, J=4.9, 2.3 Hz, H15), 3.73 (1H, dd, J=10.8, 2.3 Hz,
H29a), 3.71–3.67 (1H, m, H23), 3.62 (1H, dd, J=10.3, 2.2 Hz, H17), 3.52
(1H, t, J=2.8 Hz, H20), 3.42–3.33 (2H, obs, H25 and H29b), 3.37 (3H, s,
OMe), 2.19–2.08 (4H, m, H18, H24, H26, and H28), 2.04 (1H, dd, J=
13.2, 4.9 Hz, H22a), 1.99–1.92 (1H, m, H16), 1.90 (1H, dd, J=13.2,
2.9 Hz, H19a), 1.85 (3H, s, Me14), 1.57 (1H, dt, J=13.5, 3.7, 3.7 Hz,
H19b), 1.23 (1H, dd, J=12.2, 12.2 Hz, H22b), 1.12 (3H, d, J=7.0 Hz,
Me1), 1.10 (3H, d, J=6.7 Hz, Me1), 1.08 (9H, t, J=8.0 Hz, Si
1.03 (9H, t, J=8.0 Hz, Si(CH2CH3)3), 1.02 (9H, t, J=7.8 Hz, Si-
(CH2CH3)3), 0.89 (3H, d, J=6.9 Hz, Me16), 0.88 (3H, d, J=6.7 Hz, Me1),
0.78 (3H, d, J=7.1 Hz, Me1), 0.70 (6H, q, J=8.1 Hz, Si
(CH2CH3)3), 0.68
(6H, q, J=7.5 Hz, Si(CH2CH3)3), 0.65 ppm (6H, q, J=7.8 Hz, Si-
(CH2CH3)3); 13C NMR (125 MHz, CD3OD): dC =149.6, 113.8, 99.8, 81.5,
ACHTNUGRTNE(NUGN CH2CH3)3),
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
1613, 1513, 1456, 1246 cmꢀ1 1H NMR (500 MHz, CD3OD): dH =7.30
;
77.7, 77.2, 76.9, 76.6, 71.6, 65.1, 55.4, 44.2, 43.1, 38.5, 36.6, 34.4, 33.5, 25.8,
20.1, 18.6, 15.6, 13.2, 9.4, 7.7, 7.4, 7.3, 6.9, 5.9, 5.9, 4.3 ppm; HRMS (ES+)
calculated for C42H86O7Si3Na [M+Na+]: 787.5754, found: 787.5726.
(2H, d, J=8.7 Hz, ArH), 6.92 (2H, d, J=8.7 Hz, ArH), 4.95 (1H, s,
H13a), 4.90 (1H, s, H13b), 4.49 (2H, s, OCH2Ar), 4.29 (1H, d, J=9.3 Hz,
H15), 4.09 (1H, dd, J=10.6, 2.1 Hz, H25), 4.05 (1H, d, J=9.8 Hz, H27),
3.82 (3H, s, ArOCH3), 3.67 (1H, dd, J=8.9, 4.0 Hz, H29a), 3.63 (1H, dd,
J=10.4, 1.7 Hz, H17), 3.55 (1H, dd, J=9.1, 6.1 Hz, H29b), 3.51–3.48
(1H, m, H23), 3.40 (3H, s, OMe), 3.40 (1H, app. t, J=3.1 Hz, H20), 2.25
(1H, dd, J=15.4, 1.5 Hz, H22a), 2.01–1.93 (1H, m, H18), 1.93–1.85 (2H,
m, H26 and H28), 1.85–1.77 (2H, m, H16 and H19a), 1.76–1.75 (1H, obs,
H24), 1.74 (3H, s, Me14), 1.64 (1H, dt, J=13.2, 3.7 Hz, H19b), 1.48 (1H,
dd, J=15.4, 3.8 Hz, H22b), 0.94 (3H, d, J=6.7 Hz, Me26), 0.93 (3H, d,
J=7.1 Hz, Me28), 0.81 (3H, d, J=7.0 Hz, Me16), 0.80 (3H, d, J=7.0 Hz,
Me24), 0.74 ppm (3H, d, J=6.7 Hz, Me18); 13C NMR (125 MHz,
CD3OD): dC =160.7, 148.0, 132.0, 130.2, 114.7, 113.9, 98.2, 80.4, 78.2, 75.1,
74.0, 74.0 72.7, 71.6, 67.3, 55.9, 55.7, 37.9, 37.8, 37.3, 37.0, 34.3, 28.9, 25.6,
17.7, 16.6, 14.7, 10.4, 10.0, 7.7 ppm; HRMS (ES+) calculated for
C32H52O8 [M+Na+]: 587.3554, found: 587.3553.
Iodide 27: To a solution of alcohol 26 (3.5 mg, 4.4 mmol) in toluene
(300 mL) at room temperature was added triphenylphosphine (1.4 mg,
5.2 mmol), followed by triethylamine (0.7 mL, 5.2 mmol). The resulting so-
lution was cooled to 08C and a solution of iodine (1.1 mg, 5.2 mmol) in
toluene (300 mL) was added slowly by cannula. After 5 min, imidazole
(ca. 0.5 mg, catalytic) was added and the solution was allowed to warm to
room temperature. After stirring at this temperature for 2 h the reaction
was quenched by partitioning between Et2O and H2O. The phases were
separated and the aqueous phase was extracted with Et2O (3ꢄ2 mL).
The combined organics were dried (Na2SO4), concentrated in vacuo, and
purified by flash column chromatography (5% EtOAc/hexanes) to yield
iodide 27 (3.9 mg, 98%) as a colorless oil. Rf 0.88 (10% EtOAc/hexanes);
½aꢁ2D0 =+15.2 (c=0.35, CHCl3); IR (neat): n˜ =1457, 1233, 1086, 1005 cmꢀ1
;
1H NMR (500 MHz, CD3OD): dH =5.01 (1H, s, H13a), 4.84 (1H, s,
TES ether 24a: To a solution of triol 24 (12 mg, 21 mmol) in CH2Cl2
(2 mL) at ꢀ788C was added 2,6-lutidine (49 mL, 0.42 mmol). The reaction
mixture was stirred at ꢀ788C for 10 min before triethylsilyl trifluorome-
thanesulfonate (48 mL, 0.21 mmol) was added. The reaction mixture was
1
1
H18, H24, H26, and H28 overlap in the H NMR spectrum; the signals
corresponding to Me18, Me24, Me26, and Me28 could not be unambig-
uously assigned.
Chem. Asian J. 2009, 4, 594 – 611
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
605

I. Paterson et al.
FULL PAPERS
H13b), 4.21 (1H, d, J=4.5 Hz, H17), 3.91 (1H, dd, J=5.5, 3.5 Hz, H27),
3.71 (1H, dt, J=12.2, 4.7, 4.7 Hz, H23), 3.63 (1H, dd, J=10.2, 2.1 Hz,
H25), 3.53 (1H, t, J=2.8 Hz, H20), 3.46 (1H, dd, J=9.9, 2.9 Hz, H29a),
3.37 (3H, s, OMe), 3.39–3.32 (1H, obs, H15), 2.95 (1H, dd, J=9.8, 9.8,
Hz, H29b), 2.39–2.31 (1H, m, H28), 2.18–2.07 (3H, m, H16, H18, and
H24), 2.04 (1H, dd, J=12.8, 4.0 Hz, H22a), 1.95–1.87 (2H, m, H19a and
H26), 1.83 (3H, s, Me14), 1.59 (1H, dt, J=13.5, 3.7, 3.7 Hz, H19b), 1.25
(1H, dd, J=12.1, 12.1 Hz, H22b), 1.18 (3H, d, J=6.9 Hz, Me28), 1.11
petroleum ether) to yield alcohol 32 (395 mg, 98%) as a colorless oil. Rf
0.61 (10% EtOAc/40-60 petroleum ether); ½aꢁ2D0 =ꢀ18.6 (c=2.25,
CHCl3); IR (neat): n˜ =1462, 1379, 1226, 1092 837 cmꢀ1
;
1H NMR
(500 MHz, CDCl3): dH =3.50 (1H, dd, J=9.6, 8.0 Hz, H29a), 3.46–3.40
(3H, m, H29b, H25, and H27), 3.40–3.35 (2H, m, H23a and H23b), 1.89–
1.82 (1H, m, H26), 1.70–1.62 (1H, m, H28), 1.46–1.38 (1H, m, H24), 1.35
(3H, s, OC
G
N
ACHTUNTGRNENGU(CH3)aAHCTUNGTREN(NUGN CH3)b), 0.93 (3H, d,
J=6.9 Hz, Me24), 0.89 (9H, s, SiCAHCTUNGTR(EUNNNG CH3)3), 0.88 (3H, d, J=6.8 Hz,
(3H, d, J=7.1 Hz, Me16), 1.07 (9H, t, J=8.0 Hz, Si
(9H, t, J=8.0 Hz, Si(CH2CH3)3), 1.02 (9H, t, J=9.0 Hz, Si
0.92 (3H, d, J=7.0 Hz, Me26), 0.87 (3H, d, J=7.0 Hz, Me24), 0.80 (3H,
d, J=6.6 Hz, Me18), 0.76 (6H, q, J=8.1 Hz, Si(CH2CH3)3), 0.69 (6H, q,
J=7.5 Hz, Si(CH2CH3)3), 0.65 ppm (6H, q, J=7.8 Hz, Si(CH2CH3)3);
G
Me28), 0.86 (3H, d, J=6.8 Hz, Me26), 0.04 (3H, s, SiCH3), 0.03 ppm
(3H, s, SiCH3); 13C NMR (100 MHz, CDCl3): dC =100.6, 73.6, 72.3, 64.8,
39.2, 34.9, 33.9, 26.1, 25.9, 23.6, 18.2, 17.0, 16.6, 12.3, 10.8, ꢀ5.4,
ꢀ5.4 ppm; HRMS (ES+) calculated for C19H40IO3Si [M+H+]: 471.1786,
found: 471.1786.
E
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
N
ACHTUNGTRENNUNG
13C NMR (125 MHz, CD3OD): dC =149.5, 113.7, 99.9, 81.4, 78.4, 77.7,
76.7, 76.3, 71.5, 55.4, 44.5, 42.5, 38.9, 36.9, 34.3, 33.7, 25.9, 20.0, 19.2, 18.7,
13.6, 9.9, 7.6, 7.4, 7.3, 6.8, 6.0, 4.4 ppm; HRMS (ES+) calculated for
C42H85IO6Si3Na [M+Na+]: 919.4591, found: 919.4622.
Alkene 33: To a solution of (2E)-2-bromobutene (1.72 g, 12.8 mmol) in
dry THF (50 mL) at ꢀ1008C was added tBuLi (1.58m in pentane,
16.2 mL, 25.5 mmol) dropwise and the resulting yellow solution was
stirred at ꢀ1008C for 15 min. The organolithium solution was then trans-
Silyl-migrated product 28: To a solution of (2E)-2-bromobutene (27 mL,
0.27 mmol) in THF (0.5 mL) at ꢀ788C was added tert-butyllithium (1.7m
in pentane, 0.31 mL, 0.53 mmol). The resulting stock solution was stirred
at this temperature for 10 min and then an aliquot (84 mL) added to a so-
lution of iodide 27 (8 mg, 8.9 mmol) in THF (0.5 mL) at ꢀ788C. After
stirring at ꢀ788C for 10 min the solution was allowed to warm to 08C,
stirred for a further 20 min, and then quenched by addition of saturated
aqueous NH4Cl (2 mL). The phases were separated and the aqueous
phase was extracted with CH2Cl2 (3ꢄ2 mL). The combined organics were
dried (Na2SO4), concentrated in vacuo, and purified by flash column
ferred into a suspension of CuCN (0.57 g, 6.38 mmol) in dry Et2O
(50 mL) at ꢀ788C and the resulting pale yellow, homogeneous solution
was stirred at ꢀ508C for 1 h. To this solution was added iodide 32
(1.50 g, 3.19 mmol) in dry Et2O (15 mL) and the resulting bright yellow
solution was stirred at ꢀ508C for 2 h. The reaction was warmed to 08C
and stirred for 2 h, allowed to warm to room temperature, and stirred for
a further 30 min. The reaction was quenched with saturated aqueous
NH4Cl and the phases were separated. The aqueous layer was extracted
with Et2O (3ꢄ60 mL) and the combined organic phases were washed
with brine (50 mL), dried (MgSO4), filtered, and concentrated in vacuo
to yield a pale yellow oil. Purification by flash chromatography (5%
EtOAc/40-60 petroleum ether) afforded 33 (1.25 g, 98%) as a colorless
oil. Rf 0.66 (10% EtOAc/40-60 petroleum ether); ½aꢁ2D0 =+ 0.6 (c=6.10,
chromatography (5% EtOAc/hexanes) to yield the undesired silyl-mi-
20
grated product 28 (6.1 mg, 89%). Rf 0.76 (10% EtOAc/hexanes); ½aꢁD
=
+30.8 (c=0.61, CHCl3); IR (neat): n˜ =3605, 1458, 1380, 1233 cmꢀ1
;
1H NMR (500 MHz, CD3OD): dH =5.10 (1H, s, H13a), 4.89 (1H, s,
H13b), 4.22 (1H, d, J=5.6 Hz, H27), 3.79–3.71 (2H, m, H23 and H25),
3.58 (1H, dd, J=5.4, 4.4 Hz, H17), 3.53 (1H, t, J=10.6 Hz, H20), 3.51
(1H, d, J=10.6, H15), 3.37 (3H, s, OMe), 2.21–2.12 (1H, m, H26), 2.04
(1H, dd, J=12.5, 4.4 Hz, H22a), 2.01–1.92 (3H, m, H16, H18, and H28),
1.90–1.80 (2H, m, H19a and H24), 1.77 (3H, s, Me14), 1.58 (1H, dt, J=
13.6, 3.6, 3.6 Hz, H19b), 1.24 (1H, dd, J=12.5, 12.5 Hz, H22b), 1.05 (3H,
CHCl3); IR (neat): n˜ =1461, 1378, 1253, 1226, 1069 cmꢀ1 1H NMR
;
(500 MHz, CDCl3): dH =5.18 (1H, q, J=5.8 Hz, H31), 3.51 (1H, dd, J=
9.7, 7.9 Hz, H23a), 3.46–3.40 (2H, m, H23b and H25), 3.26 (1H, dd, J=
10.5, 4.2 Hz, H27), 2.58 (1H, d, J=13.3 Hz, H29a), 1.89–1.82 (1H, m,
H26), 1.73–1.62 (2H, m, H28 and H24), 1.58 (3H, d, obs, H32), 1.57 (3H,
s, Me30), 1.42 (1H, dd, J=13.3, 11.0 Hz, H29b), 1.30 (3H, s, OC
ACHTUNGTRENNUNG(CH3)a-
A
E
N
ACHTUNGTRENNUNG
d, J=7.1 Hz, Me16), 1.04 (9H, t, J=7.8 Hz, Si
(CH2CH3)3), 1.02 (18H, t,
(3H, d, J=6.9 Hz, Me24), 0.85 (3H, d, J=6.9 Hz, Me26), 0.70 (3H, d,
J=6.6 Hz, Me28), 0.04 (3H, s, SiCH3), 0.03 ppm (3H, s, SiCH3);
13C NMR (100 MHz, CDCl3): dC =134.7, 119.8, 100.4, 74.3, 73.8, 65.0,
43.8, 39.3, 35.4, 30.7, 25.9, 24.9, 23.7, 18.2, 15.5, 14.5, 13.4, 11.8, 10.8, ꢀ5.3,
ꢀ5.4 ppm; HRMS (ES+) calculated for C23H47O3Si [M+H+]: 399.3289,
found: 399.3290.
J=6.5 Hz, 2ꢄSi(CH2CH3)3), 1.01 (1H, obs, H29a) ,0.98 (3H, d, J=
ACHTUNGTRENNUNG
6.7 Hz, Me18), 0.87 (3H, d, J=7.0 Hz, Me24), 0.84 (3H, d, J=6.6 Hz,
Me28), 0.78 (3H, d, J=7.1 Hz, Me26), 0.70 (6H, q, J=8.1 Hz, Si-
A
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
13C NMR (125 MHz, CD3OD): dC =148.6, 114.4, 99.2, 80.9, 78.6, 78.2,
75.3, 75.0, 71.8, 55.4, 41.0, 37.4, 36.9, 34.9, 34.5, 33.2, 25.9, 20.6, 19.0, 18.7,
14.4, 10.3, 7.9, 7.6, 7.3, 6.0, 6.0, 5.1, 4.3 ppm; HRMS (ES+) calculated for
C42H86O6Si3Na [M+Na+]: 793.5630, found: 793.5657.
Alcohol 33a: To a solution of TBS ether 33 (276 mg, 0.69 mmol) in THF
(7 mL) at 08C was added TBAF (1m in THF, 1.39 mL, 1.39 mmol). The
resulting solution was allowed to warm to room temperature, stirred for
2 h, and then quenched by the addition of saturated aqueous NH4Cl
(2 mL). The phases were separated and the aqueous phase was extracted
with CH2Cl2 (3ꢄ1.5 mL). The combined organics were dried (Na2SO4),
concentrated in vacuo, and purified by flash column chromatography
Alcohol 17b: To a solution of PMB ether 17 (771 mg, 1.61 mmol) in
CH2Cl2 (45 mL) and pH 7 buffer (6 mL) at 08C was added DDQ
(437 mg, 1.93 mmol). The resulting solution was stirred at room tempera-
ture for 1 h and then quenched by the addition of saturated aqueous
NaHCO3 (50 mL). The phases were separated and the aqueous phase
was extracted with CH2Cl2 (3ꢄ30 mL). The combined organics were
washed (H2O), dried (Na2SO4), concentrated in vacuo, and purified by
flash column chromatography (10% EtOAc/toluene) to yield alcohol
17b (542 mg, 93%) as a colorless oil. The data for this compound was in
agreement with that reported.[45]
(20% EtOAc/40-60 petroleum ether) to yield alcohol 33a (195 mg, 99%)
20
as a pale yellow oil. Rf 0.50 (30% EtOAc/40-60 petroleum ether); ½aꢁD
=
+5.6 (c=0.93, CHCl3); IR (neat): n˜ =3383, 1458, 1378, 1225, 1020 cmꢀ1
;
1H NMR (500 MHz, CDCl3): dH =5.18 (1H, q, J=6.3 Hz, H31), 3.75
(1H, dd, J=7.3, 3.3 Hz, H23a), 3.63 (1H, dd, J=10.7, 3.9 Hz, H23b), 3.50
(1H, dd, J=7.2, 3.0 Hz, H25), 3.28 (1H, dd, J=10.3, 4.2 Hz, H27), 2.57
(1H, d, J=13.2 Hz, H29a), 1.96–1.89 (1H, m, H26), 1.88–1.82 (1H, m,
H24), 1.71–1.65 (1H, m, H28), 1.58 (3H, d, obs, H32), 1.57 (3H, s,
Iodide 32: To a solution of alcohol 17b (310 mg, 0.86 mmol) in toluene
(10 mL) at room temperature was added triphenylphosphine (271 mg,
1.03 mmol), followed by triethylamine (0.14 mL, 1.03 mmol). The result-
Me30), 1.43 (1H, dd, J=13.2, 10.7 Hz, H29b), 1.34 (3H, s, OC
ACHTUNGTRENNUNG(CH3)a-
A
R
CHTUNGTRENNUNG
0.88 (3H, d, J=6.6 Hz, Me26), 0.71 ppm (3H, d, J=6.6 Hz, Me28);
13C NMR (100 MHz, CDCl3): dC =134.5, 120.0, 100.7, 78.1, 74.3, 67.2,
43.7, 37.7, 34.5, 30.7, 25.0, 23.7, 15.5, 14.4, 13.3, 12.4, 10.8 ppm; HRMS
(ES+) calculated for C17H33O3 [M+H+]: 285.2424, found: 285.2425.
ing solution was cooled to 08C and
a solution of iodine (262 mg,
1.03 mmol) in toluene (5 mL) was added slowly by cannula. After 5 min,
imidazole (ca. 10 mg, catalytic) was added and the solution was allowed
to warm to room temperature. After stirring at this temperature for 3 h
the reaction was quenched by partitioning between Et2O and H2O. The
phases were separated and the aqueous phase was extracted with Et2O
(3ꢄ10 mL). The combined organics were dried (Na2SO4), concentrated in
vacuo, and purified by flash column chromatography (10% EtOAc/40-60
Aldehyde 31: To a solution of alcohol 33a (157 mg, 0.55 mmol) in
CH2Cl2 (3 mL) at room temperature was added NaHCO3 (371 mg,
4.42 mmol) followed by Dess–Martin periodinane (937 mg, 2.21 mmol).
The resulting solution was stirred at room temperature for 1 h and then
606
www.chemasianj.org
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2009, 4, 594 – 611

Total Synthesis of (ꢀ)-Spirangien A
quenched by the addition of saturated aqueous Na2S2O3 (3 mL) and satu-
rated aqueous NaHCO3 (3 mL). The phases were separated and the
aqueous phase was extracted with CH2Cl2 (3ꢄ3 mL). The combined or-
ganics were dried (Na2SO4), concentrated in vacuo, and purified by flash
column chromatography (15% EtOAc/40-60 petroleum ether) to provide
aldehyde 31 (141 mg, 90%) as a colorless oil. Rf 0.41 (10% EtOAc/40-60
petroleum ether); ½aꢁ2D0 =+46.4 (c=1.40, CHCl3); IR (neat): n˜ =1727,
38.1, 36.2, 35.6, 30.8, 30.7, 29.1, 24.9, 24.8, 23.9, 23.8, 18.0, 15.5, 15.4, 14.5,
13.3, 12.0, 11.8, 7.1, 6.8, 4.9 ppm; HRMS (ES+) calculated for
C39H72O7SiNa [M+Na+]: 703.4945, found: 703.4936.
Methyl ethers 36 and 37: To a solution of alcohols 30 and 35 (238 mg,
0.35 mmol) in CH2Cl2 (22 mL) at 08C was added Proton Sponge (450 mg,
2.10 mmol), followed by trimethyloxonium tetrafluoroborate (207 mg,
1.40 mmol). The resulting solution was strirred at room temperature for
1.5 h and quenched by the addition of saturated aqueous NaHCO3
(30 mL). The phases were separated and the aqueous phase was extract-
ed with CH2Cl2 (3ꢄ25 mL). The combined organic phases were washed
with citric acid (10% weight solution, 50 mL), dried (Na2SO4), concen-
trated in vacuo, and purified by flash column chromatography (15%
EtOAc/40-60 petroleum ether) to yield methyl ethers 36 and 37 (213 mg,
87%, ca. 2:1 d.r. by 1H NMR analysis) as an inseparable mixture. Major
diastereomer 36: Rf 0.50 (5% EtOAc/40-60 petroleum ether); IR (neat):
1
1456, 1376, 1221, 1017 cmꢀ1; H NMR (400 MHz, CDCl3): dH =9.71, (1H,
d, J=1.2 Hz, CHO), 5.18 (1H, q, J=6.3 Hz, H31), 3.75 (1H, dd, J=7.3,
3.3 Hz, H25), 3.29 (1H, dd, J=10.5, 4.2 Hz, H27), 2.57 (1H, d, J=
13.4 Hz, H29a), 2.42 (1H, qdd, J=7.0, 3.7, 1.2 Hz, H24), 1.98–1.89 (1H,
m, H26), 1.75–1.67 (1H, m, H28), 1.58 (3H, d, J=5.9 Hz, H32), 1.57
(3H, s, Me30), 1.43 (1H, dd, J=13.2, 11.0 Hz, H29b), 1.32 (3H, s, OC-
ACHTUNGTRENNUNG(CH3)aACHTUNGTRENNUNG(CH3)b), 1.26 (3H, s, OCACHTUNGETRNN(GNU CH3)aACHTNGURTEN(NUGN CH3)b), 1.15 (3H, d, J=7.0 Hz,
Me24), 0.92 (3H, d, J=6.8 Hz, Me26), 0.70 ppm (3H, d, J=6.6 Hz,
Me28); 13C NMR (100 MHz, CDCl3): dC =204.3, 134.4, 120.0, 100.9, 74.2,
74.1, 49.2, 43.7, 35.0, 30.7, 24.6, 23.6, 15.5, 14.4, 13.3, 12.1, 7.9 ppm;
HRMS (ES+) calculated for C17H30O3Na [M+Na+]: 305.2072, found:
305.2087.
n˜ =1718, 1458, 1378, 1224, 1096 cmꢀ1 1H NMR (500 MHz, CDCl3): dH =
;
5.18 (1H, q, J=6.3 Hz, H31), 4.93 (1H, s, H13a), 4.83 (1H, s, H13b),
4.20–4.13 (1H, m, H20), 3.80–3.75 (1H, m, H23), 3.69 (1H, d, J=7.5 Hz,
H15), 3.43–3.33 (2H, m, H17 and H25), 3.28 (3H, s, OMe), 3.27–3.22
(1H, m, H27), 2.84 (1H, dd, J=17.4, 9.2 Hz, H22a), 2.57 (1H, brd, J=
13.8 Hz, H29a), 2.55 (1H, dd, J=17.2, 2.1 Hz, H22b), 2.03–2.17 (1H, m,
H19a), 1.93–1.86 (1H, m, H16), 1.85–1.75 (3H, m, H18, H24, and H26),
1.76 (3H, s, Me14), 1.71–1.64 (2H, m, H19b and H28), 1.57 (3H, d, obs,
H32), 1.56 (3H, s, Me30), 1.42 (1H, app. t, J=11.5 Hz, H29b), 1.34 (3H,
Aldol adducts 30 and 35: To
a
solution of (ꢀ)-Ipc2BCl (136 mg,
0.42 mmol) [dried by stirring under vacuum (1 mm Hg) at room tempera-
ture for 1.5 h] in Et2O (2 mL) at 08C was added triethylamine (63 mL,
0.45 mmol), followed by ketone 11 (106 mg, 0.27 mmol) in Et2O (2 mL)
by cannula. The reaction mixture was stirred for 1 h, cooled to ꢀ788C,
and a solution of aldehyde 31 (40 mg, 0.14 mmol) in Et2O (2 mL) was
then added by cannula. After 1 h at ꢀ788C and 16 h at ꢀ278C, the reac-
tion mixture was quenched by the addition of pH 7 buffer (4 mL),
MeOH (4 mL), and H2O2 (30% aqueous, 2 mL). After allowing to warm
to room temperature and stirring for 1 h, the phases were separated and
the aqueous phase was extracted with CH2Cl2 (3ꢄ5 mL). The combined
organics were washed with brine (10 mL), dried (Na2SO4), concentrated
in vacuo, and purified by flash column chromatography (10% EtOAc/40-
60 petroleum ether) to yield aldol adducts 30 and 35 (51 mg, 53%, ca.
s, OC
(CH3)aA
(CH2CH3)3), 0.92 (3H, d, J=7.0 Hz, Me24), 0.88 (3H, d, J=7.1 Hz,
A
R
ACHTUNTGRENNGU(CH3)aACHUTGNTREN(NUGN CH3)b), 1.27 (3H, s, OC-
A
N
G
CHTUNGTRENNUNG
AHCTUNGTRENNUNG
Me16), 0.87 (3H, d, J=7.0 Hz, Me18), 0.86 (3H, d, J=7.0 Hz, Me26),
0.70 (3H, d, J=6.8 Hz, Me28), 0.61 ppm (6H, q, J=8.0 Hz, Si-
AHCTUNGTRENNUNG
(CH2CH3)3); 13C NMR (125 MHz, CDCl3): dC =212.4, 144.5, 134.7, 119.9,
111.8, 100.7, 100.4, 79.6, 79.2, 75.0, 74.2, 73.3, 57.7, 43.8, 40.1, 38.8, 37.6,
37.4, 36.3, 36.2, 30.7, 29.1, 24.9, 24.7, 23.9, 23.6, 18.0, 15.5, 15.2, 14.5, 13.4,
12.0, 11.8, 8.4, 6.8, 4.9 ppm; HRMS (ES+) calculated for C40H74O7SiNa
[M+Na+]: 717.5102, found: 717.5117.
1
2:1 d.r. by H NMR analysis) as an inseparable mixture. Major diastereo-
mer 30: Rf 0.25 (5% EtOAc/40-60 petroleum ether); IR (neat): n˜ =3524,
Spiroacetals 38 and 39: To a solution of ketones 36 and 37 (213 mg,
0.31 mmol) in MeOH (8 mL) at room temperature was added CSA
(7.1 mg, 0.03 mmol). After stirring at room temperature for 16 h the reac-
tion was quenched by addition of saturated aqueous NaHCO3. The
phases were separated and the aqueous phase was extracted with CH2Cl2
(3ꢄ10 mL). The combined organic phases were dried (Na2SO4), concen-
trated in vacuo, and purified by flash column chromatography (30%
EtOAc/40-60 petroleum ether) to yield spiroacetals 38 (78 mg, 52%) and
39 (31 mg, 21%) as colorless oils. Spiroacetal 38: Rf 0.31 (30% EtOAc/
40-60 petroleum ether); ½aꢁ2D0 =+8.8 (c=0.71, MeOH); IR (neat): n˜ =
1716, 1458, 1379, 1224, 1018 cmꢀ1 1H NMR (500 MHz, CDCl3): dH =5.18
;
(1H, q, J=5.8 Hz, H31), 4.93 (1H, s, H13a), 4.83 (1H, s, H13b), 4.19–
4.12 (1H, m, H20), 4.08–4.00 (1H, m, H23), 3.69 (1H, d, J=7.4 Hz,
H15), 3.65 (1H, dd, J=7.7, 1.7 Hz, H25), 3.37 (1H, dd, J=10.5, 4.2 Hz,
H17), 3.32–3.29 (1H, m, OH), 3.28–3.23 (1H, m, H27), 2.76 (2H, d, J=
5.8 Hz, H22a and H22b), 2.56 (1H, brd, J=13.8 Hz, H29a), 2.13–2.05
(1H, m, H19a), 1.97–1.84 (3H, m, H16, H18, and H26), 1.77 (3H, s,
Me14), 1.72–1.62 (2H, m, H24 and H28), 1.58 (3H, obs, H32), 1.56 (3H,
s, Me30), 1.46–1.38 (1H, m, H29b), 1.34 (6H, s, 2ꢄOC
1.29 (3H, s, OC(CH3)aA(CH3)b), 1.22 (3H, s, OC(CH3)aA(CH3)b), 1.00–0.93
(3H, obs, Me24), 1.17–1.10 (1H, m, H19b), 0.96 (9H, t, J=8.0 Hz, Si-
(CH2CH3)3), 0.89–0.83 (9H, m, Me16, Me18, and Me26), 0.71 (3H, d, J=
6.9 Hz, Me28), 0.61 ppm (6H, q, J=8.0 Hz, Si
(CH2CH3)3); 13C NMR
ACHTUGTNRENNUG(CH3)aACHTUGNTERN(NUGN CH3)b),
3436, 1456, 1381, 1234, 1114 cmꢀ1 1H NMR (500 MHz, CD3OD): dH =
;
A
N
G
CHTUNGTRENNUNG
5.25 (1H, q, J=6.5 Hz, H31), 4.93 (1H, s, H13a), 4.90 (1H, s, H13b), 4.13
(1H, d, J=9.5 Hz, H15), 3.79 (1H, dd, J=10.6, 2.0 Hz, H25), 3.77 (1H,
d, J=9.7 Hz, H27), 3.73 (1H, app. t, J=11.9, 4.7 Hz, H23), 3.61 (1H, dd,
J=10.3, 1.8 Hz, H17), 3.44 (1H, t, J=2.8 Hz, H20), 3.38 (3H, s, OMe),
2.68 (1H, brd, J=13.1 Hz, H29a), 2.18 (1H, m, H24), 2.10 (1H, dd, J=
13.2, 4.7 Hz, H22a), 2.04–1.97 (1H, m, H18), 1.88 (1H, dd, J=10.3,
7.1 Hz, H26), 1.85–1.80 (2H, m, H16 and H19a), 1.80–1.76 (1H, m, H28),
1.76–1.69 (1H, obs, H19b), 1.74 (3H, s, Me14), 1.63 (3H, s, Me30), 1.63
(3H, d, J=5.9 Hz, H32), 1.63 (1H, obs, H29b), 1.41 (1H, dd, J=12.5,
12.5 Hz, H22b), 0.84 (3H, d, J=6.5 Hz, Me26), 0.83 (3H, d, J=7.1 Hz,
Me18), 0.81 (3H, d, J=6.9 Hz, Me24), 0.78 (3H, d, J=7.0 Hz, Me16),
0.75 ppm (3H, d, J=6.7 Hz, Me28); 13C NMR (125 MHz, CD3OD): dC =
147.7, 136.0, 121.1, 114.3, 99.5, 78.8, 78.3, 75.8, 73.8, 72.0, 70.9, 55.5, 46.0,
37.7, 37.6, 37.3, 35.0, 33.9, 32.8, 26.0, 17.7, 16.2, 15.8, 15.6, 13.5, 9.6, 8.0,
4.0 ppm; HRMS (ES+) calculated for C28H50O6Na [M+Na+]: 505.3505,
found: 505.3498. Spiroacetal 39: Rf 0.27 (30% EtOAc/40-60 petroleum
ether); ½aꢁ2D0 =+22.8 (c=1.07, MeOH); IR (neat): n˜ =3429, 1456, 1380,
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
(125 MHz, CDCl3): dC =214.5, 144.4, 134.6, 120.0, 111.8, 100.7, 100.4,
79.2, 77.4, 74.5, 74.3, 73.2, 43.8, 42.3, 40.9, 40.5, 37.9, 36.1, 35.2, 30.7, 29.1,
24.8, 24.7, 23.8, 23.7, 18.0, 15.5, 15.3, 14.5, 13.4, 12.0, 11.8, 10.4, 6.8,
4.9 ppm; HRMS (ES+) calculated for C39H72O7SiNa [M+Na+]: 703.4945,
found: 703.4937. Minor diastereomer 35: Rf 0.25 (5% EtOAc/40-60 pe-
troleum ether); IR (neat): n˜ =3498, 1710 1458, 1378, 1224, 1017 cmꢀ1
;
1H NMR (500 MHz, CDCl3): dH =5.18 (1H, q, J=6.7 Hz, H31), 4.93
(1H, s, H13a), 4.84 (1H, s, H13b), 4.26–4.20 (1H, m, H23), 4.14 (1H, dd,
J=9.4, 3.8 Hz, H20), 3.69 (1H, d, J=7.3 Hz, H15), 3.52 (1H, dd, J=7.5,
2.4 Hz, H25), 3.37 (1H, dd, J=10.5, 4.3 Hz, H17), 3.31 (1H, brs, OH),
3.29–3.23 (1H, m, H27), 2.76 (2H, d, J=6.3 Hz, H22a and H22b), 2.56
(1H, brd, J=13.2 Hz, H29a), 2.12–2.02 (1H, m, H19a), 1.93–1.84 (2H,
m, H16 and H26), 1.81–1.72 (1H, obs, H18), 1.76 (3H, s, Me14), 1.72–
1.60 (2H, m, H24 and H28), 1.58 (3H, obs, H32), 1.56 (3H, s, Me30),
1209, 1099 cmꢀ1 1H NMR (500 MHz, CD3OD): dH =5.25 (1H, q, J=
;
1.42 (1H, dd, J=13.5, 11.2 Hz, H29b), 1.36 (3H, s, OC
1.34 (3H, s, OC(CH3)aA(CH3)b), 1.29 (3H, s, OC(CH3)aA(CH3)b), 1.28 (3H,
s, OC(CH3)aA(CH3)b), 1.18–1.10 (1H, m, H19b), 0.99–0.94 (3H, obs,
Me24), 0.97 (9H, t, J=8.0 Hz, Si(CH2CH3)3), 0.89–0.84 (9H, m, Me16,
Me18, and Me26), 0.70 (3H, d, J=6.9 Hz, Me28), 0.62 ppm (6H, q, J=
7.9 Hz, Si
(CH2CH3)3); 13C NMR (125 MHz, CDCl3): dC =213.8, 144.5,
134.6, 119.9, 111.7, 100.7, 100.6, 79.2, 78.3, 74.2, 73.2, 71.2, 43.7, 41.8, 39.7,
ACHTUGTNRENNUG(CH3)aACHTUGNTERN(NUGN CH3)b),
A
N
G
CHTUNGTRENNUNG
6.5 Hz, H31), 4.95 (1H, s, H13a), 4.90 (1H, s, H13b), 4.28 (1H, d, J=
9.4 Hz, H15), 4.11 (1H, dd, J=10.5, 1.8 Hz, H25), 3.77 (1H, d, J=9.3 Hz,
H27), 3.63 (1H, dd, J=10.5, 1.6 Hz, H17), 3.52–3.48 (1H, m, H23), 3.42
(3H, s, OMe), 3.37 (1H, obs, H20), 2.69 (1H, brd, J=13.1 Hz, H29a),
2.26 (1H, dd, J=15.4, 1.5 Hz, H22a), 2.04–1.95 (1H, m, H18), 1.93–1.86
(1H, m, H24), 1.86–1.78 (3H, m, H16, H26, and H28), 1.76–1.70 (1H,
A
CHTUNGTRENNUNG
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
Chem. Asian J. 2009, 4, 594 – 611
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
607

I. Paterson et al.
FULL PAPERS
obs, H19a), 1.73 (3H, s, Me14), 1.66–1.60 (2H, obs, H19b and H29b),
1.63 (3H, s, Me30), 1.63 (3H, d, J=5.5 Hz, H32), 1.49 (1H, dd, J=15.4,
3.7 Hz, H22b), 0.94 (3H, d, J=6.5 Hz, Me24), 0.84 (3H, d, J=6.6 Hz,
Me18), 0.82 (3H, d, J=7.1 Hz, Me26), 0.81 (3H, d, J=7.2 Hz, Me16),
0.75 ppm (3H, d, J=6.6 Hz, Me28); 13C NMR (125 MHz, CD3OD): dC =
148.1, 136.1, 121.0, 113.8, 98.2, 80.4, 78.2, 75.6, 74.0, 71.6, 67.6, 55.9, 45.9,
37.8, 37.6, 37.1, 35.2, 34.3, 29.0, 25.6, 17.7, 16.6, 15.8, 15.7, 13.5, 10.4, 10.0,
8.0 ppm; HRMS (ES+) calculated for C28H50O6 [M+Na+]: 505.3505,
found: 505.3499.
7.7, 7.4, 7.3, 6.9, 6.1, 6.0, 4.4 ppm; HRMS (ES+) calculated for
C46H95O7Si3 [M+H+]: 843.6386, found: 843.6418.
Aldehyde 41: To a solution of alcohol 40 (25 mg, 29.6 mmol) in CH2Cl2
(1.5 mL) at room temperature was added NaHCO3 (20 mg, 0.24 mmol)
followed by Dess–Martin periodinane (50 mg, 0.12 mmol). The resulting
solution was stirred at room temperature for 1 h before saturated aque-
ous Na2S2O3 (1.5 mL) and saturated aqueous NaHCO3 (1.5 mL) were
added. The resulting biphasic mixture was stirred for ca. 20 min before
the phases were separated and the aqueous phase was extracted with
CH2Cl2 (3ꢄ3 mL). The combined organics were dried (Na2SO4), concen-
trated in vacuo, and purified by flash column chromatography (10%
EtOAc/40-60 petroleum ether) to yield aldehyde 41 (22 mg, 87%) as a
colorless oil. Rf 0.45 (10% EtOAc/40-60 petroleum ether); ½aꢁ2D0 =+15.4
TES ether 38a: To a solution of triol 38 (69 mg, 0.14 mmol) in CH2Cl2
(7 mL) at ꢀ788C was added 2,6-lutidine (67 mL, 0.57 mmol). The reaction
mixture was stirred at ꢀ788C for 10 min before triethylsilyl trifluorome-
thanesulfonate (97 mL, 0.43 mmol) was added. The reaction mixture was
allowed to warm to 08C over 20 min and then quenched by the addition
of saturated aqueous NH4Cl (10 mL). The phases were separated and the
aqueous phase was extracted with CH2Cl2 (3ꢄ10 mL). The combined or-
ganic phases were dried (Na2SO4), concentrated in vacuo, and purified by
flash column chromatography (5% EtOAc/40-60 petroleum ether) to
yield TES-protected spiroacetal 38a (184 mg, 93%). Rf 0.52 (10%
EtOAc/40-60 petroleum ether); ½aꢁ2D0 =+10.3 (c=1.20, MeOH); IR
(c=0.43, MeOH); IR (neat): n˜ =1720, 1458, 1381, 1231, 1110 cmꢀ1
;
1H NMR (500 MHz, CD3OD): dH =9.94 (1H, d, J=2.9 Hz, CHO), 5.24
(1H, q, J=6.6 Hz, H31), 3.92 (1H, dd, J=3.2, 1.0 Hz, H15), 3.89 (1H,
dd, J=4.8, 2.2 Hz, H27), 3.70 (1H, app dt, J=12.0, 4.5 Hz, H23), 3.53
(1H, t, J=2.6 Hz, H20), 3.38 (3H, s, OMe), 3.36–3.34 (2H, obs, H17 and
H25), 3.21–3.15 (1H, m, H14), 2.23–2.04 (6H, m, H16, H18, H22a, H24,
H28, and H29a), 2.02–1.94 (1H, m, H26), 1.89–1.82 (1H, m, H19a), 1.73
(1H, dd, J=13.3, 10.2 Hz, H29b), 1.64–1.60 (1H, obs, H19b), 1.62 (3H, d,
J=6.6 Hz, H32), 1.61 (3H, s, Me30), 1.29 (1H, app t, J=1.25 Hz, H22b),
1.22 (3H, d, J=7.3 Hz, Me14), 1.09 (3H, d, J=7.2 Hz, Me16), 1.07 (9H,
(neat): n˜ =1458, 1381, 1232, 1088, 1003 cmꢀ1
;
1H NMR (500 MHz,
CD3OD): dH =5.23 (1H, q, J=6.4 Hz, H31), 5.00 (1H, s, H13a), 4.81
(1H, s, H13b), 4.22 (1H, d, J=5.7 Hz, H15), 3.93 (1H, dd, J=4.8, 1.9 Hz,
H27), 3.70 (1H, app dt, J=11.8, 4.5 Hz, H23), 3.61 (1H, dd, J=9.9,
1.8 Hz, H25), 3.50 (1H, t, J=2.8 Hz, H20), 3.38 (1H, obs, H17), 3.37
(3H, s, OMe), 2.17 (1H, obs, H29a), 2.16–2.06 (4H, m, H16, H18, H24,
H28), 2.03 (1H, dd, J=12.4, 4.3 Hz, H22a), 1.96–1.89 (1H, m, H26), 1.85
(3H, s, Me14), 1.84 (1H, obs, H19a), 1.74–1.67 (1H, m, H29b), 1.62 (3H,
d, J=5.9 Hz, H32), 1.60 (3H, s, Me30), 1.57 (1H, dt, J=13.6, 3.9, 3.9 Hz,
H19b), 1.23 (1H, dd, J=12.9, 12.4 Hz, H22b), 1.12 (3H, d, J=7.3 Hz,
t, J=8.0 Hz, Si
(9H, t, J=8.0 Hz, Si
(3H, d, J=7.1 Hz, Me26), 0.90 (3H, d, J=6.7 Hz, Me18), 0.82 (3H, d,
J=6.7 Hz, Me24), 0.72 (6H, q, J=8.0 Hz, Si(CH2CH3)3), 0.71 (6H, q, J=
8.0 Hz, Si(CH2CH3)3), 0.67 ppm (6H, q, J=8.1 Hz, Si(CH2CH3)3);
A
ACHTNUGTNERN(UGN CH2CH3)3), 1.04
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
A
ACHTUNGTRENNUNG
13C NMR (125 MHz, CD3OD): dC =207.1, 135.6, 120.8, 100.0, 82.3, 78.8,
78.4, 78.0, 77.7, 71.7, 55.6, 50.0, 43.3, 42.7, 39.3, 38.1, 36.8, 34.1, 33.9, 25.9,
18.5, 17.6, 15.8, 15.8, 13.6, 13.1, 8.2, 7.7, 7.3, 7.3, 6.9, 6.0, 5.9, 4.6 ppm;
HRMS (ES+) calculated for C46H92O7Si3Na [M+Na+]: 863.6043, found:
863.6031.
Me16), 1.08 (9H, t, J=8.0 Hz, Si
(CH2CH3)3), 1.02 (9H, t, J=7.7 Hz, Si
Me24), 0.88 (3H, J=6.6 Hz, Me18), 0.86 (3H, J=6.5 Hz, Me26), 0.78
(3H, J=7.0 Hz, Me28), 0.75 (6H, q, J=7.4 Hz, Si(CH2CH3)3) 0.68 (6H,
q, J=8.0 Hz, Si(CH2CH3)3) 0.65 ppm (6H, q, J=7.9 Hz, Si(CH2CH3)3);
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
Spirangien diene 3: To a vial containing aldehyde 41 (6.2 mg, 7.3 mmol)
at 08C was added 4 ꢂ molecular sieves (pipette tip), followed by allyl
borane reagent 45 (3m in toluene, 50 mL). The resultant suspension was
allowed to warm to room temperature and left for 16 h, after which time
acetaldehyde (50 mL) was added. The solution was then dissolved with
toluene (1 mL) and filtered through a short plug of celite, eluting with
Et2O (5 mL). After concentration in vacuo the resultant crude material
was taken up in MeOH (0.25 mL) and THF (0.25 mL), cooled to 08C,
and aqueous KOH (6m, 0.5 mL) added. The resulting biphasic solution
was allowed to warm to room temperature and stirred for 16 h. The
phases were separated and the aqueous phase was extracted with CH2Cl2
(3ꢄ4 mL). The combined organics were washed with brine (10 mL),
dried (Na2SO4), concentrated in vacuo, and purified by flash column
chromatography (10% EtOAc/hexanes) to yield the desired diene 43
(3.0 mg, 50%). This material was taken up in THF (0.25 mL), cooled to
08C, and TBAF (1m in THF, 17 mL, 17 mmol) was added. The resulting
solution was allowed to warm to room temperature, stirred for 1 h, and
then recooled to 08C. Further TBAF (1m in THF, 17 mL, 17 mmol) was
added and the resulting solution was allowed to warm to room tempera-
ture. After stirring at this temperature for 2 h, the reaction was quenched
by the addition of saturated aqueous NH4Cl (2 mL). The phases were
separated and the aqueous phase was extracted with CH2Cl2 (4ꢄ2 mL).
The combined organics were dried (Na2SO4), concentrated in vacuo, and
purified by flash column chromatography (0!20% EtOAc/40-60 petrole-
um ether) to yield diene 3 (1.3 mg, 71%) as a pale yellow oil. This mate-
A
ACHTUNGTRENNUNG
13C NMR (125 MHz, CD3OD): dC =149.5, 135.7, 120.7, 113.9, 99.7, 81.6,
78.6, 77.8, 76.9, 76.6, 71.7, 55.4, 43.1, 42.7, 39.2, 37.8, 36.7, 34.3, 33.5, 25.8,
20.1, 18.6, 17.4, 15.8, 13.6, 13.1, 9.3, 7.7, 7.4, 7.3, 7.0, 6.0, 5.9, 4.4 ppm;
HRMS (ES+) calculated for C46H93O6Si3 [M+H+]: 825.6280, found:
825.6310.
Alcohol 40: To a solution of the alkene 38a (14 mg, 16.9 mmol) in THF
(0.5 mL) at 08C was added a freshly prepared solution of 9-BBN (0.5m
in THF, 101 mL, 50.7 mmol). The resulting solution was allowed to warm
to room temperature and stirred at this temperature for 1 h, before re-
cooling to 08C. The reaction was quenched by the addition of THF
(0.5 mL), MeOH (0.5 mL), NaOH (10% aqueous, 1 mL), and H2O2
(30% aqueous, 0.5 mL) and then stirred for 1 h. The phases were separat-
ed and the aqueous phase was extracted with CH2Cl2 (3ꢄ4 mL). The
combined organics were dried (Na2SO4), concentrated in vacuo, and puri-
fied by flash column chromatography (10% EtOAc/40-60 petroleum
ether) to yield alcohol 40 (10 mg, 70%) as a colorless oil. Rf 0.10 (10%
EtOAc/40-60 petroleum ether); ½aꢁ2D0 =+17.5 (c=1.50, MeOH); IR
(neat): n˜ =3499, 1459, 1381, 1233, 1001 cmꢀ1
;
1H NMR (500 MHz,
CD3OD): dH =5.24 (1H, q, J=6.5 Hz, H31), 3.93 (1H, dd, J=10.8,
3.2 Hz, H13a), 3.90 (1H, dd, J=5.0, 2.2 Hz, H27), 3.80 (1H, dd, J=3.4,
1.5 Hz, H15), 3.74 (1H, app dt, J=12.0, 4.7 Hz, H23), 3.55–3.50 (2H, m,
H13b, H20), 3.44 (1H, dd, J=10.0, 2.1 Hz, H25), 3.36 (3H, s, OMe),
3.38–3.33 (1H, obs, H17), 2.49–2.39 (1H, m, H14), 2.26–2.19 (1H, m,
H24), 2.19 (1H, brd, J=14.2 Hz, H29a), 2.16–2.06 (2H, m, H18 and
H28), 2.09 (1H, dd, J=12.8, 4.7 Hz, H22a), 2.05–2.00 (1H, m, H16),
2.00–1.96 (1H, m, H26), 1.89–1.82 (1H, m, H19a), 1.72 (1H, dd, J=13.5,
10.3 Hz, H29b), 1.64–1.60 (1H, obs, H19b), 1.62 (3H, d, obs, H32), 1.61
(3H, s, Me30), 1.29 (1H, app t, J=12.5 Hz, H22b), 1.18 (3H, d, J=
7.1 Hz, Me14), 1.13 (3H, d, J=7.2 Hz, Me16), 1.10–1.01 (27H, m, 3ꢄSi-
rial was further purified using reverse-phase HPLC, with
a Varian
column (250ꢄ4.6 mm), prepacked with Microsorb silica (5 m, 100 ꢂ),
equipped with a Gilson UV detector (Model 118) at a wavelength of
254 nm. 85% MeOH/H2O was used as the eluent and a flow rate of
1 mLminꢀ1. The observed retention time of spirangien diene 3 was 6 min
and 36 s. Rf 0.53 (5% MeOH/CH2Cl2); ½aꢁ2D0 =+34 (c=0.04, MeOH); IR
G
(neat): n˜ =3362, 1633, 1381, 1259, 1108 cmꢀ1 1H NMR (500 MHz,
;
CD3OD): dH =6.72 (1H, dt, J=16.8, 11.2, 10.1 Hz, H11), 6.08 (1H, dd,
J=11.1, 11.1 Hz, H12), 5.61 (1H, dd, J=10.6, 10.6 Hz, H13), 5.25 (1H,
m, H31), 5.23 (1H, dd, J=16.8, 2.2 Hz, H10a), 5.14 (1H, brd, J=
10.2 Hz, H10b), 3.73 (1H, dd, J=10.1, 2.0 Hz, H25), 3.69 (1H, m, H27),
ACHTUNGTRENNUNG
135.7, 120.8, 100.0, 82.7, 78.9, 78.5, 77.8, 77.4, 71.8, 65.8, 55.5, 43.5, 42.6,
39.3, 39.2, 38.1, 36.9, 34.4, 33.6, 25.9, 19.3, 18.6, 17.7, 15.8, 13.6, 13.2, 8.4,
608
www.chemasianj.org
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2009, 4, 594 – 611

Total Synthesis of (ꢀ)-Spirangien A
3.67 (1H, m, H23), 3.64 (1H, dd, J=10.5, 1.3 Hz, H17), 3.57 (1H, dd, J=
9.8, 2.5 Hz, H15), 3.43 (1H, m, H20), 3.38 (3H, s, OMe), 2.95 (1H, m,
H14), 2.70 (1H, brd, J=12.3 Hz, H29a), 2.16 (1H, m, H24), 2.07 (1H,
dd, J=12.9, 4.8 Hz, H22a), 1.96 (1H, m, H18), 1.87 (1H, m, H26), 1.78
(1H, m, H19a), 1.76 (1H, m, H28), 1.71 (1H, ddd, J=13.5, 3.4, 3.3 Hz,
H19b), 1.64 (3H, m, Me30), 1.63 (2H, m, H16 and H29b), 1.62 (3H, m,
H32), 1.41 (1H, dd, J=12.9, 12.8 Hz, H22b), 1.14 (3H, d, J=7.0 Hz,
Me14), 0.85 (3H, d, J=7.0 Hz, Me26), 0.83 (3H, d, J=7.0 Hz, Me16),
0.81 (3H, d, J=7.0 Hz, Me24), 0.79 (3H, d, J=6.6 Hz, Me18), 0.75 ppm
(3H, d, J=6.7 Hz, Me28); 13C NMR (125 MHz, CD3OD): dC =136.0,
133.7, 133.5, 130.5, 121.1, 117.7, 99.5, 78.8, 76.5, 76.1, 75.1, 72.4, 71.0, 55.4,
46.0, 40.0, 37.8, 37.3, 35.8, 35.4, 34.0, 32.9, 25.6, 19.6, 18.0, 15.8, 15.6, 13.5,
9.4, 7.9, 4.1 ppm; HRMS (ES+) calculated for C31H54O6Na [M+Na+]:
545.3818, found: 545.3832. This data is in accord with that reported by
Niggemann et al.[7] for material prepared by degradation of spirangien A;
see the Supporting Information.
(Z)-Vinyl iodide 7: To a solution of oxalyl chloride (0.33 mL, 3.88 mmol)
in CH2Cl2 (12 mL) at ꢀ788C was added dimethyl sulfoxide (0.4 mL,
5.67 mmol). After 15 min, a solution of alcohol 49 (280 mg, 1.89 mmol) in
CH2Cl2 (2 mL) was added dropwise. The resultant solution was stirred
for 30 min at ꢀ788C, then Et3N (1.6 mL, 11.3 mmol) was added. The re-
action mixture was maintained at ꢀ788C for 30 min, then allowed to
warm to room temperature and quenched by the addition of water
(7 mL). The phases were separated and the aqueous phase was extracted
with CH2Cl2 (3ꢄ20 mL). The combined organics were dried (Na2SO4),
concentrated in vacuo, and the corresponding aldehyde was used without
further purification. To a suspension of (iodomethyl)triphenylphosphoni-
um iodide (1.50 g, 2.84 mmol) in THF (4.5 mL) at room temperature was
added NaHMDS (1m in THF, 2.80 mL, 2.84 mmol). The resulting solu-
tion was stirred at room temperature for 10 min, cooled to ꢀ788C, and
HMPA (0.82 mL, 4.73 mmol) added. The resulting solution was then
cooled to ꢀ1008C before a solution of aldehyde (276 mg, 1.89 mmol) in
THF (0.5 mL) was added by cannula. The solution was stirred at ꢀ1008C
for 15 min, ꢀ788C for 30 min, and then allowed to warm to room temper-
ature. After stirring for 20 min, the reaction was quenched by the addi-
tion of saturated aqueous NH4Cl. The phases were separated and the
aqueous phase was extracted with Et2O (3ꢄ10 mL). The combined or-
ganic phases were washed with brine (20 mL), dried (MgSO4), and con-
centrated in vacuo. Purification by flash column chromatography (10%
CH2Cl2/hexanes!100% CH2Cl2) allowed separation of (Z)- and (E)-
vinyl iodides to yield (Z)-vinyl iodide 7 (268 mg, 53%) as a pale yellow
oil. Rf 0.31 (20% EtOAc/hexanes); ½aꢁ2D0 =+15.5 (c=1.68, CHCl3); IR
TBS ether 47a: To a solution of (S)-malic acid dimethyl ester 47 (1.50 g,
9.25 mmol) in THF (14 mL) at 08C was added borane dimethyl sulfide
(0.89 mL, 9.39 mmol) slowly. The reaction mixture was allowed to warm
to room temperature and was stirred for 45 min before being recooled to
08C. NaBH4 (17 mg, 0.46 mmol) was added slowly and the resulting reac-
tion mixture was stirred for 45 min at 08C, by which time gas evolution
had subsided. The ice bath was removed and the reaction was stirred for
1 h at room temperature. The organic volatiles were then removed in va-
cuo and the product was azeotroped with methanol (3ꢄ10 mL) and then
toluene (1ꢄ10 mL) to afford the 1,2-diol as an oil that was used directly
in the next step. To a solution of the crude diol (1.24 g, 9.25 mmol) in
CH2Cl2 (30 mL) at room temperature was added imidazole (0.79 g,
11.6 mmol) followed by TBSCl (1.53 g, 10.2 mmol). The resulting reac-
tion mixture was stirred for 12 h at room temperature and then quenched
by the addition of water (30 mL). The phases were separated and the
aqueous phase was extracted with CH2Cl2 (3ꢄ25 mL). The combined or-
ganic phases were dried (Na2SO4), concentrated in vacuo, and purified by
flash column chromatography (10% EtOAc/hexanes) to yield TBS ether
47a (2.21 g, 96%) as a colorless oil. The data for this compound was in
agreement with that reported.[46]
(neat): n˜ =2930, 1738, 1609, 1436, 1345, 1280, 1208, 1153, 1102 cmꢀ1
;
1H NMR (500 MHz, CDCl3): dH =6.54 (1H, d, J=7.9 Hz, H5), 6.19 (1H,
app t, J=7.9 Hz, H4), 4.43–4.38 (1H, m, H3), 3.70 (3H, s, OMe), 3.32
(3H, s, OMe), 2.60 (1H, dd, J=15.2, 8.1 Hz, H2a), 2.51 ppm (1H, dd, J=
15.3, 4.9 Hz, H2b); 13C NMR (125 MHz, CDCl3): dC =170.5, 140.1, 85.2,
79.5, 56.9, 51.8, 39.2 ppm; HRMS (ES+) calculated for C7H11IO3Na
[M+Na+]: 292.9645, found: 292.9635.
Bis-stannane 8: To
a solution of (E)-Bu3SnCH=CHCHO (440 mg,
1.27 mmol) and sulfone 50 (890 mg, 1.66 mmol) in THF (16 mL) at
ꢀ788C was added KHMDS (0.5m in toluene, 3.2 mL, 1.59 mmol). The re-
sulting solution was allowed to warm to room temperature and stirred
for 16 h before quenching by addition of H2O (20 mL). The phases were
separated and the aqueous phase was extracted with Et2O (3ꢄ15 mL).
The combined organic phases were dried (MgSO4) and concentrated in
vacuo. Purification by flash column chromatography (3% Et3N in 100%
hexanes) yielded bis-stannane 8 (571 mg, 68%) as a colorless oil. The
data for this compound was in agreement with that reported.[38a]
Methyl ether 48: To a solution of alcohol 47a (2.00 g, 8.06 mmol) in
CH2Cl2 (60 mL) at 08C was added Proton Sponge (10.4 g, 48.4 mmol) fol-
lowed by trimethyloxonium tetrafluoroborate (3.50 g, 24.2 mmol). The re-
sulting solution was stirred at room temperature for 1 h and then
quenched by the addition of saturated aqueous NaHCO3 (30 mL). The
phases were separated and the aqueous phase was extracted with CH2Cl2
(3ꢄ20 mL). The combined organic phases were washed with citric acid
(10% weight solution, 40 mL), dried (Na2SO4), concentrated in vacuo,
and purified by flash column chromatography (10% EtOAc/hexanes) to
yield methyl ether 48 (2.0 g, 95%) as a colorless oil. Rf 0.31 (10%
EtOAc/hexanes); ½aꢁ2D0 =ꢀ13.8 (c=1.00, CHCl3); IR (neat): n˜ =2931,
(Z)-Vinyl iodide 5: To a suspension of (iodomethyl)triphenylphosphoni-
um iodide (54 mg, 0.11 mmol) in THF (0.3 mL) at room temperature was
added NaHMDS (1m in THF, 0.11 mL, 0.11 mmol). The resulting solu-
tion was stirred at room temperature for 10 min, cooled to ꢀ788C, and
HMPA (25 mL) was added, followed by a solution of aldehyde 41 (17 mg,
19.9 mmol) in THF (0.7 mL) by cannula. After allowing to warm to room
temperature and stirring for 20 min, the reaction was quenched by the
addition of hexanes (2 mL) and filtered through a plug of celite, eluting
with hexanes (20 mL). The hexanes fractions were then concentrated in
vacuo and purified by flash column chromatography (5% EtOAc/hex-
anes) to yield vinyl iodide (14.2 mg, 74%, ca. 3:1 Z/E) as a colorless oil.
To a solution of this material (14.2 mg, 14.7 mmol) in MeOH (1.5 mL) at
room temperature was added CSA (catalytic). After stirring at room
temperature for 1 h the reaction was quenched by addition of saturated
aqueous NaHCO3. The phases were separated and the aqueous phase
was extracted with CH2Cl2 (3ꢄ5 mL). The combined organic phases were
dried (Na2SO4) and concentrated in vacuo. Purification by flash column
chromatography (30% EtOAc/hexanes) allowed separation of (Z)- and
(E)-vinyl iodides to yield (Z)-vinyl iodide 5 (7.1 mg, 78%) as a colorless
oil. Rf 0.37 (30% EtOAc/hexanes); ½aꢁ2D0 =+33.7 (c=0.43, MeOH); IR
2858, 1743, 1437, 1257, 1116, 1082 cmꢀ1 1H NMR (500 MHz, CDCl3):
;
dH =3.71–3.68 (2H, m, H4), 3.67 (3H, s, OMe), 3.57–3.52 (1H, m, H3),
3.39 (3H, s, OMe), 2.57 (1H, dd, J=15.7, 4.5 Hz, H2a), 2.45 (1H, dd, J=
15.7, 7.4 Hz, H2b), 0.87 (9H, s, SiCACTHNUTRGENNUG(CH3)3), 0.04 ppm (6H, s, SiACHTUNTGREN(NNGU CH3)2);
13C NMR (125 MHz, CDCl3): dC =172.3, 78.5, 64.2, 58.2, 51.7, 37.0, 26.0,
18.4, ꢀ5.3 ppm; HRMS (ES+) calculated for C12H26O4SiNa [M+Na+]:
262.1498, found: 262.1502.
Alcohol 49: To a solution of TBS ether 48 (700 mg, 2.67 mmol) in THF
(30 mL) at 08C was added TBAF (1m in THF, 5.3 mL, 5.3 mmol). The re-
sulting solution was allowed to warm to room temperature, stirred for
16 h, and then quenched by the addition of saturated aqueous NH4Cl
(10 mL). The phases were separated and the aqueous phase was extract-
ed with CH2Cl2 (3ꢄ20 mL). The combined organics were dried (Na2SO4),
concentrated in vacuo, and purified by flash column chromatography
(50% EtOAc/hexanes) to yield the alcohol 49 (380 mg, 96%) as a color-
less oil. Rf 0.34 (70% EtOAc/hexanes); ½aꢁ2D0 =ꢀ19.9 (c=1.00, CHCl3);
(neat): n˜ =3444, 1457, 1383, 1108, 996 cmꢀ1
;
1H NMR (500 MHz,
IR (neat): n˜ =3439, 2937, 1733, 1439, 1166, 1100, 1066 cmꢀ1 1H NMR
;
CD3OD): dH =6.36 (1H, app. t, J=2.5 Hz, H13), 6.36 (1H, d, J=2.6 Hz,
H12), 5.25 (1H, q, J=6.7 Hz, H31), 3.73 (1H, dd, J=10.3, 1.8 Hz, H25),
3.71–3.66 (2H, m, H23 and H27), 3.62 (1H, dd, J=10.3, 1.1 Hz, H17),
3.61 (1H, dd, J=9.8, 2.1 Hz, H15) 3.43 (1H, app t, J=2.9 Hz, H20) , 3.39
(3H, s, OMe), 2.78–2.72 (1H, m, H14), 2.70 (1H, brd, J=13.7 Hz, H29a),
(500 MHz, CDCl3): dH =3.77–3.72 (2H, m, H4), 3.70 (3H, s, OMe), 3.59–
3.52 (1H, m, H3), 3.42 (3H, s, OMe), 2.62 (1H, dd, J=15.7, 6.6 Hz,
H2a), 2.53 ppm (1H, dd, J=15.7, 6.0 Hz, H2b); 13C NMR (125 MHz,
CDCl3): dC =172.0, 78.1, 63.4, 57.6, 51.9, 36.1 ppm.
Chem. Asian J. 2009, 4, 594 – 611
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
609

I. Paterson et al.
FULL PAPERS
2.20–2.13 (1H, m, H24), 2.08 (1H, dd, J=13.0, 4.7 Hz, H22a), 2.04–1.92
(1H, m, H18), 1.91–1.82 (1H, m, H26), 1.81–1.68 (3H, m, H19a, H19b,
and H28), 1.68–1.54 (2H, obs, H16 and H29b), 1.64 (3H, s, Me30), 1.63
(3H, d, J=6.4 Hz, H32), 1.41 (1H, app. t, J=12.4 Hz, H22b), 1.12 (3H,
d, J=7.0 Hz, Me14), 0.87 (3H, d, J=7.0 Hz, Me16), 0.85 (3H, d, J=
7.1 Hz, Me26), 0.81 (3H, d, J=6.9 Hz, Me24), 0.80 (3H, d, J=6.7 Hz,
Me18), 0.75 ppm (3H, d, J=6.7 Hz, Me28); 13C NMR (125 MHz,
CD3OD): dC =142.7, 135.9, 121.2, 99.5, 82.9, 78.8, 76.2, 75.7, 75.0, 72.4,
71.0, 55.4, 46.0, 43.2, 40.2, 37.8, 37.3, 35.3, 33.9, 32.9, 25.6, 18.0, 17.6, 15.8,
15.6, 13.5, 9.6, 7.9, 4.1 ppm; HRMS (ES+) calculated for C29H51IO6Na
[M+Na+]: 645.2623, found: 645.2619.
DMF (200 mL) and THF (100 mL). The standard Stille reaction procedure
(see above) was followed, using either (Z)-vinyl iodide
5 (1.5 mg,
2.4 mmol) and tetraene 6 (12.3 mg, 24.1 mmol) or (Z)-vinyl iodide 7
(4.0 mg, 17.4 mmol) and tetraene 46 (1.5 mg, 1.7 mmol). In each case, pu-
rification by flash column chromatography (3% Et3N in 40% EtOAc/
hexanes) yielded spirangien methyl ester 4 (1.0 mg, 65% from 5) as a
yellow oil. Rf 0.41 (50% EtOAc/hexanes); ½aꢁ2D0 =ꢀ26.2 (c=0.08,
MeOH); IR (neat): n˜ =1740, 1491, 1472, 1381, 1103, 991 cmꢀ1 1H NMR
;
(500 MHz, CD3OD): dH =6.90 (1H, dd, J=14.6, 11.3 Hz, H7), 6.83 (1H,
dd, J=14.4, 11.0 Hz, H10), 6.69 (1H, m, H6), 6.64 (1H, m, H11), 6.40
(1H, app t, J=11.3 Hz, H5), 6.22 (1H, app t, J=11.2 Hz, H12), 6.20 (1H,
app t, J=11.1 Hz, H9), 6.15 (1H, app t, J=11.1 Hz, H8), 5.69 (1H, app t,
J=10.9 Hz, H13), 5.33 (1H, app t, J=10.3 Hz, H4), 5.26 (1H, q, J=
6.6 Hz, H31), 4.66 (1H, m, H3), 3.73 (1H, dd, J=10.2, 1.8 Hz, H25), 3.70
(3H, s, CO2Me), 3.70 (1H, obs, H27), 3.69 (1H, m, H23), 3.63 (1H, dd,
J=10.6, 1.0 Hz, H17), 3.60 (1H, dd, J=9.9, 2.1 Hz, H15), 3.43 (1H, t, J=
2.8 Hz, H20), 3.38 (3H, s, OMe23), 3.29 (3H, s, OMe3), 2.99 (1H, m,
H14), 2.70 (1H, brd, J=13.1 Hz, H29a), 2.65 (1H, dd, J=15.2, 8.2 Hz,
H2a), 2.49 (1H, dd, J=15.0, 5.4 Hz, H2b), 2.16 (1H, m, H24), 2.07 (1H,
dd, J=13.2, 4.9 Hz, H22a), 1.97 (1H, m, H18), 1.87 (1H, m, H26), 1.77
(1H, m, H19a), 1.76 (1H, m, H28), 1.72 (1H, m, H19b), 1.65 (3H, m,
Me30), 1.63 (5H, m, H16, H29b, and H32), 1.41 (1H, app t, J=12.5 Hz,
H22b), 1.14 (3H, J=7.0 Hz, Me14), 0.85 (3H, d, J=7.2 Hz, Me26), 0.84
(3H, d, J=7.2 Hz, Me16), 0.81 (3H, d, J=6.9 Hz, Me24), 0.79 (3H, d,
J=6.6 Hz, Me18), 0.75 ppm (3H, d, J=6.6 Hz, Me28); 13C NMR
(125 MHz, CD3OD): dC =172.9, 136.0, 134.8, 134.0, 132.3, 132.1 (2C),
131.0, 130.2, 130.0, 129.5, 129.0, 121.1, 99.5, 78.8, 76.6, 76.1, 75.2, 74.6,
72.5, 71.0, 56.6, 55.4, 52.2, 46.0, 41.7, 40.1, 37.8, 37.3, 36.1, 35.4, 34.0, 32.9,
25.6, 19.6, 18.1, 15.8, 15.6, 13.5, 9.4, 7.9, 4.1 ppm; HRMS (ES+) calculat-
ed for C42H68O9Na [M+Na+]: 739.4756, found: 739.4788. For comparison
with the NMR data reported by Niggemann et al.[7] for spirangien A, see
the Supporting Information.
Tetraene 6: This standard Stille coupling procedure, including the
workup and purification, was performed in the absence of light and using
base-washed amberized glassware. To a solution of (Z)-vinyl iodide 7
(12 mg, 44.4 mmol) and triene 8 (70 mg, 0.11 mmol) in DMF (1.2 mL) and
THF (0.3 mL) at room temperature was added [Pd2ACTHUNTRGNE(UGN dba)3] (2 mg,
2.22 mmol) and Ph3As (1.8 mg, 5.78 mmol). The resulting solution was
purged by evacuating for 1 min and then flushing with Ar (ꢄ3) and then
stirred at room temperature for 16 h. The reaction was then quenched by
addition of H2O (2 mL) and diluted with EtOAc (containing 2% Et3N).
The phases were separated and the aqueous phase was extracted with
EtOAc (containing 2% Et3N; 3ꢄ3 mL). The combined organics were
washed with brine (5 mL), dried (Na2SO4), and concentrated in vacuo.
Purification by flash column chromatography (2% Et3N in 5%!7%
EtOAc/hexanes) yielded tetraene 6 (13.5 mg, 59%) as a yellow oil. Rf
0.40 (20% EtOAc/hexanes); ½aꢁ2D0 =+12.9 (c=0.50, MeOH); IR (neat):
n˜ =1740, 1590, 1103 cmꢀ1 1H NMR (500 MHz, CD3OD): dH =7.12 (1H,
;
dd, J=18.5, 9.7 Hz, H10), 6.86 (1H, dd, J=14.6, 10.0 Hz, H7), 6.68 (1H,
dd, J=13.9, 11.4 Hz, H6), 6.42–6.36 (2H, m, H5 and H11), 6.10–6.05
(2H, m, H8 and H9), 5.34 (1H, app t, J=10.2 Hz, H4), 4.69–4.64 (1H, m,
H3), 3.70 (3H, s, OMe), 3.29 (3H, s, OMe), 2.65 (1H, dd, J=15.1,
8.0 Hz, H2a), 2.49 (1H, dd, J=15.1, 5.4 Hz, H2b), 1.61–1.57 (6H, m,
SnCH2CH2CH2CH3), 1.42–1.38 (6H, m, SnCH2CH2CH2CH3), 1.03–0.97
(6H, m, SnCH2CH2CH2CH3), 0.96 ppm (9H, t, J=7.5 Hz,
SnCH2CH2CH2CH3); 13C NMR (125 MHz, CD3OD): dC =172.8, 143.2,
137.7, 134.6, 133.8, 131.7, 131.4, 129.3, 129.0, 74.6, 56.6, 52.2, 41.7, 30.3,
28.3, 14.1, 10.4 ppm; HRMS (ES+) calculated for C25H44O3SnNa
[M+Na+]: 535.2204, found: 535.2215.
Spirangien A (1): To a solution of spirangien A methyl ester 4 (1 mg,
1.4 mmol) in MeOH (0.6 mL) and H2O (0.3 mL) at room temperature
was added aqueous KOH (10%, 25 mL) dropwise. After 16 h at room
temperature, 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 (5ꢄ2 mL). The combined organic phases
were then dried (Na2SO4) and concentrated in vacuo. Purification by ana-
lytical HPLC (Hypersil C18, 250ꢄ4.6 mm, H2O/MeCN 57%,
50 mmK2HPO4/NaH2PO4, pH 7; flow rate: 1 mLminꢀ1; Rt =12 min, UV:
320 nm) to remove any traces of minor isomers afforded spirangien A (1)
(0.83 mg, 85%). The compound deteriorated over time, even when
stored at ꢀ208C. Rf 0.37 (100% EtOAc); ½aꢁ2D0 =ꢀ17.5 (c=0.04, MeOH);
Spirangien tetraene 46: In this case, stock solutions of [Pd
2ACHTUNGTERN(NUNG dba)3] and
Ph3As were used: [Pd2A(dba)3] (2 mg) dissolved in a mixture of DMF
CHTUNGTRENNUNG
(200 mL) and THF (100 mL) and Ph3As (2 mg) dissolved in DMF
(200 mL) and THF (100 mL). The standard Stille reaction procedure (see
above) was followed, using (Z)-vinyl iodide 5 (2 mg, 3.2 mmol) and triene
8 (21 mg, 32.1 mmol). Purification by flash column chromatography (3%
Et3N in 20%!7% EtOAc/hexanes) yielded tetraene 46 (1.7 mg, 60%)
as a yellow oil. Rf 0.44 (30% EtOAc/hexanes); 1H NMR (500 MHz,
CD3OD): dH =7.11 (1H, dd, J=18.6, 10.2 Hz, H7), 6.77 (1H, dd, J=14.4,
11.0 Hz, H10), 6.62 (1H, dd, J=14.1, 11.3 Hz, H11), 6.33 (1H, d, J=
18.5 Hz, H6), 6.19 (1H, app t, J=11.3 Hz, H12), 6.06 (1H, app t, J=
10.8 Hz, H9), 6.00 (1H, app t, J=10.8 Hz, H8), 5.67 (1H, app t, J=
10.8 Hz, H13), 5.26 (1H, q, J=6.2 Hz, H31), 3.87 (1H, dd, J=10.3,
1.6 Hz, H25), 3.71–3.65 (2H, m, H23 and H27), 3.62 (1H, d, J=10.8 Hz,
H17), 3.60 (1H, dd, J=9.9, 2.0 Hz, H15) 3.43 (1H, app t, J=2.7 Hz,
H20), 3.39 (3H, s, OMe), 3.04–2.95 (1H, m, H14), 2.71 (1H, brd, J=
12.5 Hz, H29a), 2.19–2.13 (1H, m, H24), 2.07 (1H, dd, J=13.0, 4.5 Hz,
H22a), 1.99–1.93 (1H, m, H18), 1.90–1.84 (1H, m, H26), 1.78–1.76 (1H,
m, H19a), 1.76–1.74 (1H, m, H28), 1.73–1.70 (1H, m, H19b), 1.68–1.54
(2H, obs, H16 and H29b), 1.64 (3H, s, Me30), 1.63 (3H, d, obs, H32),
1.62–1.57 (6H, m, SnCH2CH2CH2CH3), 1.43–1.37 (7H, m, H22b and
SnCH2CH2CH2CH3), 1.16 (3H, d, J=7.0 Hz, Me14), 1.03–0.97 (6H, m,
SnCH2CH2CH2CH3), 0.96 (9H, t, J=7.5 Hz, SnCH2CH2CH2CH3), 0.85
(3H, d, J=6.9 Hz, Me26), 0.84 (3H, d, J=6.9 Hz, Me16), 0.81 (3H, d,
J=7.3 Hz, Me24), 0.80 (3H, d, J=7.0 Hz, Me18), 0.75 ppm (3H, d, J=
6.6 Hz, Me28); HRMS (ES+) calculated for C47H84O6SnNa [M+Na+]:
887.5182, found: 887.5197.
IR (neat): n˜ =3520, 1742, 1471, 1389, 1218, 1109 cmꢀ1
;
1H NMR
(500 MHz, CD3OD): dH =6.89 (1H, dd, J=14.6, 10.9 Hz, H7), 6.82 (1H,
dd, J=14.5, 11.0 Hz, H10), 6.69 (1H, m, H6), 6.64 (1H, m, H11), 6.40
(1H, app t, J=11.2 Hz, H5), 6.22 (1H, app t, J=11.1 Hz, H12), 6.20 (1H,
app t, J=11.1 Hz, H9), 6.14 (1H, app t, J=11.1 Hz, H8), 5.68 (1H, app t,
J=10.6 Hz, H13), 5.34 (1H, app t, J=10.4 Hz, H4), 5.25 (1H, q, J=
6.6 Hz, H31), 4.66 (1H, m, H3), 3.73 (1H, dd, J=10.2, 1.9 Hz, H25), 3.70
(1H, m, H27), 3.68 (1H, m, H23), 3.63 (1H, dd, J=10.5, 1.0 Hz, H17),
3.60 (1H, dd, J=9.7, 2.3 Hz, H15), 3.43 (1H, t, J=2.9 Hz, H20), 3.38
(3H, s, OMe23), 3.30 (3H, s, OMe3), 2.99 (1H, m, H14), 2.70 (1H, brd,
J=13.1 Hz, H29a), 2.59 (1H, dd, J=15.1, 8.2 Hz, H2a), 2.43 (1H, dd, J=
15.0, 5.2 Hz, H2b), 2.16 (1H, m, H24), 2.07 (1H, dd, J=13.1, 4.9 Hz,
H22a), 1.97 (1H, m, H18), 1.87 (1H, m, H26), 1.77 (1H, m, H19a), 1.75
(1H, m, H28), 1.72 (1H, m, H19b), 1.64 (3H, m, Me30), 1.63 (5H, m,
H16, H29b, and H32), 1.41 (1H, app t, J=12.5 Hz, H22b), 1.15 (3H, J=
7.0 Hz, Me14), 0.85 (3H, d, J=7.0 Hz, Me26), 0.84 (3H, d, J=7.2 Hz,
Me16), 0.81 (3H, d, J=6.9 Hz, Me24), 0.79 (3H, d, J=6.6 Hz, Me18),
0.75 ppm (3H, d, J=6.6 Hz, Me28); HRMS (ES+) calculated for
C41H66O9Na [M+Na+]: 725.4605, found: 725.4570. This data is in accord
with that reported by Niggemann et al.[7] for natural spirangien A; see
the Supporting Information.
Spirangien A methyl ester (4): In this case, stock solutions of [Pd
and Ph3As were used: [Pd2A(dba)3] (2 mg) dissolved in a mixture of DMF
(200 mL) and THF (100 mL) and Ph3As (2 mg) dissolved in a mixture of
2ACHTUNGTNER(NUNG dba)3]
CTHUNGTRENNUNG
610
www.chemasianj.org
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2009, 4, 594 – 611

Total Synthesis of (ꢀ)-Spirangien A
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Acknowledgements
We thank the EPSRC (EP/F025734/1), the Swiss National Science Foun-
dation (C.N.), and Merck Research Laboratories (A.D.F.) for support,
Dr. Edward Anderson (Cambridge) for advice, the Spencer Group at
Cambridge for valuable HPLC assistance, and Dr. J. Niggemann (Helm-
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Received: November 27, 2008
Published online: January 27, 2009
Chem. Asian J. 2009, 4, 594 – 611
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
611